Research Outreach Issue 105

The outreach quarterly connecting science with society
ISSN 2517-701X
ISSUE 105
FEATURING RESEARCH FROM:

Russian Academy of Sciences; University of Texas Southwestern Medical Center; Medical College of Wisconsin;
University of Kentucky College of Medicine; Kaunas University of Technology; Kanagawa Institute of Technology;
New York University; Syntrix Pharmaceuticals; University of São Paulo; Nilupul Foundation; Indian Institute of
Chemical Biology; Louisiana State University; Cylerus, Inc.; University College London; Aerospace Research Centre
of the National Research Council Canada; University of California; Columbia University; Tohoku University; Solynta;
Research Features 3
Royal Holloway, University of London; Children’s Hospital Oakland Research Institute; Polytechnic University of
Turin; Technical University of Crete; University of the Witwatersrand; University of Bristol; BetaStem Therapeutics.
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RESEARCH OUTREACH ISSUE 105

WELCOME
The outreach quarterly connecting science with society
ISSN 2517-701X
ISSUE 105
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ENGAGE This issue has a truly global feel with researchers featured FEATURING RESEARCH FROM:
Russian Academy of Sciences; University of Texas Southwestern Medical Center; Medical College of Wisconsin;
University of Kentucky College of Medicine; Kaunas University of Technology; Kanagawa Institute of Technology;
ISSN 2517-701X
from institutions around the world. Reflecting the international
New York University; Syntrix Pharmaceuticals; University of São Paulo; Nilupul Foundation; Indian Institute of
Chemical Biology; Louisiana State University; Cylerus, Inc.; University College London; Aerospace Research Centre
of the National Research Council Canada; University of California; Columbia University; Tohoku University; Solynta;
Research Features 3
Royal Holloway, University of London; Children’s Hospital Oakland Research Institute; Polytechnic University of
Turin; Technical University of Crete; University of the Witwatersrand; University of Bristol; BetaStem Therapeutics.
face of research is something we are particularly proud

of and hope to expand on in future issues.
THIS ISSUE
We’re also proud to publish under Creative Commons
Published by: Research Outreach
(CC) licensing. Building a genuinely open, transparent and
international publishing community has become easier Founder: Simon Jones
simon@researchoutreach.org
thanks to CC licences. Graham Steel (Publishing Consultant
Editorial Director: Emma Feloy
and Interim Representative for the United Kingdom to the CC emma@researchoutreach.org
Global Network Council) explains more. Operations Director: Alastair Cook
audience@researchoutreach.org
Editor: Hannah Fraser
The American Heart Association has been educating people hannah@researchoutreach.org
on CPR, heart health, stroke and heart disease worldwide Designers: Craig Turl, Carlton Hibbert
Global Project Director:
for nearly 100 years. Chief of Mission Aligned Businesses and Julian Barrett
Healthcare Solutions, John Meiners, tells us more about the julian@researchoutreach.org
Association’s key strategies including a focus on prevention. Project Manager:
Tobias Jones
tobias@researchoutreach.org
Research Publishing International offer a An important factor in assisting research We also have a review of the Society for Neuroscience’s
Contributors: Rachael Baker, Emma
completely barrier-free publishing portal. We have teams to maximise their exposure is the use of annual meeting, Neuroscience 2018. Members of
Green, Rebecca Ingle, Matt Jarvis,
a multi-media presence and readership, through modern social media techniques. Combined with the Research Outreach team attended and were full Gillian Livesey, Kate McAllister,
both digital and physical print copies of Research traditional digital and physical distribution of our of enthusiasm when they returned. Jessica Money, Rachel Perrin,
Emily Porter, Kate Porter, Niall
Outreach magazine, and provide online hosting of publications, we engage heavily with the wider Taylor, Polly Wells, Cheryl Whiting,
research articles through feature webpages and community through the use of various social media In this edition of Research Outreach, we cover Health Stuart Wilson.
downloadable PDF documents. channels. & Medicine, Physical Sciences, Biology, Engineering &
/ResearchOutreach
We abide by the Creative Commons (CC) RPI has over 30 years of collective expertise in Technology, Education & Training and Behavioural Sciences /ResOutreach
license terms to ensure widespread, open-access science communications. Our know-how ensures – as diverse in topic as it is in geography, I hope you enjoy
dissemination of all the work featured across our that we work efficiently and cost-effectively, reading about this broad mix
various platforms. boosting the impact of your research globally. of research.
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Research Outreach
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CONTENTS 68 44
6 LICENSE TO SHARE: 26 TIME FOR A NEW APPROACH 44 MOVING BEYOND DANGEROUS

How the Creative Commons TO SEVERE TRAUMATIC OPIOIDS FOR PAIN
licensing system encourages BRAIN INJURY AND STROKE Dr John A. Zebala
the remixing and reuse of
published materials.
Dr James Stone
Developments in automated,
real-time monitoring of brain
Syntrix Pharmaceuticals hope to
tackle the opioid crisis by producing
opiates with low lethality compared
104
10 NEW 3D TECHNOLOGY stem function. to schedule II opioids.
TO HELP IN THE BATTLE
AGAINST BRAIN TUMOURS 30 BICAMS: SHEDDING LIGHT 48 ALCOHOL OVERUSE:
Dr. Darin T. Okuda ON COGNITION IN MULTIPLE CUTTING TO THE BONE
Novel methodology to visualise SCLEROSIS Dr Martin Ronis
brain tumours in 3D. Professor Dawn Langdon Linking the damaging effects of
The Brief International Cognitive alcohol consumption on bone in
14 CARCINOGENESIS: WHEN Assessment for MS (BICAMS), women of reproductive age with students from underrepresented Equations or Fokker–Planck against invading pathogenic
TRANSMISSION OF is a short, much-needed tool increased risk of osteoporosis. backgrounds pursuing and Equations are better for microorganisms.
EPIGENETIC INFORMATION to assess cognitive function for graduating with a STEM major. understanding how atoms move
GOES AWRY people with Multiple Sclerosis. 52 LOCAL DRUG DELIVERY TO between lattice points within 108 BETTER AND STRONGER
Professor Patrick Riley PROSTHETIC VASCULAR GRAFTS 68 IMPROVING MATHS solid materials. POTATOES USING HYBRID
Investigating the effect 36 FACTORS ASSOCIATED Dr Ronald Shebuski PERFORMANCE IN SOUTH BREEDING
of epigenetic changes on WITH YOUNG CHILDREN Preventing failure of prosthetic AFRICA’S PRIMARY SCHOOLS 88 DYNAMIC VERSUS STATIC: Dr.ir. Sjaak van Heusden
carcinogenesis, the formation EXHIBITING PICKY EATING grafts in haemodialysis patients. Professor Hamsa Venkat EVOLVING MECHANICAL Solynta has developed an
of cancer. BEHAVIOUR Improving primary maths teaching CHARACTERISATION innovative method for targeted
Dr Pauline Emmett and Dr 56 CLINICAL RELEVANCE AIMS TO and learning. Dr Meysam Rahmat breeding which will change
18 REDUCED PSA PROSTATE Caroline Taylor UNCOVER NOVEL REGULATORS Dynamic mechanical the production and global
CANCER SCREENING: Using data from the Avon OF HUMAN CORONARY ARTERY 72 CAREERS IN SCIENCE characterisation of materials, distribution of potatoes.
LIFE-THREATENING Longitudinal Study of Parents FUNCTION Professor Hollie Swanson particularly nanocomposites.
CONSEQUENCES? and Children (ALSPAC) to The Human Vascular Research Summer Training in Environmental 112 GUINEA PIG AS A MODEL
Dr Thomas E. Ahlering investigate factors associated Group (HVRG) and Pharmacological Sciences 92 PEERING INSIDE: 3D TO STUDY THE CAROTID
Demonstrating that high-risk with picky eating to determine The HVRG studies the complex (STEPS) aims to enhance IMAGING IN MATERIALS BODY-MEDIATED CHRONIC
prostate cancer results from whether the behaviour should relationship and physiological student learning and help Prof Dr Elena Jasiūnienė INTERMITTENT HYPOXIA
USPSTF-enforced reduced be a source of concern effects of vascular stress response prepare students from a variety Investigating the properties of EFFECTS
prostate cancer screening. for parents. in health and disease. of backgrounds, for successful various materials, particularly Dr Ángela Gómez-Niño
science-related careers. self-compacting concrete, using Dr Asuncion Rocher
22 LYMPH NODES TARGETED 40 COULD STEM CELLS 60 MENDING BROKEN HEARTS: X-ray computed tomography. Using the guinea pig as a model
IN NOVEL CANCER THERAPY OFFER A VIABLE TREATMENT The American Heart Association 76 TECHNOLOGICAL to explore the mechanisms that
Professor Tetsuya Kodama FOR RETINOPATHY? and its life-saving treatment LEAPFROGGING THE GLOBAL 96 BLACK HOLE BINARIES mediate long-term effects of
Focusing on early diagnosis Dr Stephen Bartelmez guidelines ENERGY CRISIS AND GRAVITATIONAL WAVES exposure to low oxygen levels.
and treatment of lymph node BetaStem Therapeutics aims to Professor José Goldemberg Professor Zoltan Haiman
metastasis, observed in most treat diabetic retinopathy using 64 STEM SUMMER PROGRAM Relieving the world’s crushing Seeking evidence for the 116 MINDFULNESS-BASED
cancers, such as breast cancer a patient’s own stem cells. Children’s Hospital Oakland dependence on fossil fuels with existence of massive black INTERVENTION (MBI)
and head and neck cancer. Research Institute a move to cleaner ethyl-alcohol hole binaries. PROVIDES POSITIVE
Aiming to increase the number of based fuels. OUTCOMES FOR THOSE
100 CREATING A IN LOWER SOCIOECONOMIC
80 OPINION DYNAMICS AND BETTER OSCILLATOR ENVIRONMENTS
CONSENSUS IN SOCIAL Dr Koichi Narahara Ven Karma Jiga
NETWORKS The physical phenomenon Assessing the feasibility
Denis Fedyanin and Alexander generated by travelling-wave of teaching mindfulness
Chkhartishvili field-effect transistors, such techniques to those in poverty
I am very proud that the

Modelling opinion dynamics of as electric pulses, shockwaves to help improve their physical
social networks to analyse how and solitons. and mental well-being.
international Multiple
individuals’ internal parameters
affect their social power. 104 PATHOGENIC 120 NEW BRAIN RESEARCH
MICROORGANISMS SPARKS EXCITEMENT
Sclerosis community has come 84 WHEN KINETIC THEORIES
CLASH, MIND THE LATTICE STEP
TARGETED BY
COMPLEX CELLULAR
AT NEUROSCIENCE 2018
together to address and manage Professor Giorgio Kaniadakis

and Professor Dionissios
COMMUNICATIONS
Dr Malini Sen
122 COMMUNICATION: SCIENCE
IN BREWING
the cognitive aspects of MS. Hristopulos

Investigating whether the Master
Deciphering the role of a protein
called Wnt5a in defending
30 PROFESSOR DAWN LANGDON

Page 30
Health & Education & Physical Engineering & Biology Behavioural
Medicine Training Sciences Technology Sciences
4 www.researchoutreach.org www.researchoutreach.org 5
Thought Leader
The spectrum of rights
Copyright Creative Commons Public Domain

All Rights Reserved Some Rights Reserved No Rights Reserved
Re-use requires the Re-use is permitted without permission May be used without
permission from the under the specifications shared in the permission.
copyright owner. licence.
Making sense of The Spectrum Of Rights.
reuse of their works by offering them real-time communications to Slack which

for use under generous, standardised I joined and contribute to daily. Over the
terms; those who want to make creative last few years, CC has been rebooting its
uses of works; and those who want to global network structure, which resulted
benefit from this symbiosis. CC’s vision in the relaunch of the CC United Kingdom
is to help others realise the full potential chapter. I was elected to serve as Interim
of the internet. CC has affiliates all over Representative for the United Kingdom
the world who help ensure CC’s licences to the CC Global Network Council (GNC).
work internationally.
Why are licences important
Science Commons was an initiative for scientific content?
launched by CC in early 2005 which Copyright, as we know it today, came
ran until 2009. Its primary focus was on along in 1710, so by default, publishers
building infrastructure for open science. (not authors) owned the copyright
License to share:
More broadly, CC has undertaken projects to academic papers. This remained
to build commons-based infrastructure for the norm until around 1991 with the
science through identifying and lowering formation of arXiv, an e-print service
unnecessary barriers to research, crafting in the fields of physics, mathematics,
policy guidelines and legal agreements computer science etc. OA publishing/
Ryan Merkley, CEO of Creative Commons. and developing technology to make publishers started to emerge around the
How the Creative Commons licensing system encourages

research, data and materials easier to find, same as major players such as BioMed
share and use. Central and The Public Library of Science
What is Creative Commons (CC), in 1998 and 2000 respectively. Once
the remixing and reuse of published materials and what is Science Commons? What does your role at CC involve? CC had been established and launched
CC is a global non-profit organisation After discovering Open Access (OA) a suite of CC licences, OA publishers
that was set up in 2001 by Lawrence academic papers in 2006, I became started to publish research papers under
In a world where news, data and images are increasingly shared freely online, whether correctly or not, Creative Commons Lessig, Hal Abelson and Eric Eldred (with aware of CC-licensed works. I made direct CC. As of December 2017, the Directory
(CC) has stepped up to make allowing others to reuse and remix your research easy. By creating, maintaining and promoting the support of the Center for the Public contact with co-founder Lawrence Lessig of Open Access Journals listed 10,567
all of the available CC licences, the organisation hopes to help an international community of scientists, educators and activists Domain), that enables sharing and reuse and then released most of my musical OA journals. In total 94.8% of these
realise the benefits of the commons. In this interview with Graham Steel (Publishing Consultant and Interim Representative for of creativity and knowledge through works under CC licences, sent out at now have CC licences. The most used
the United Kingdom to the CC Global Network Council), we found out the real advantages of publishing under a CC licence.
the provision of free legal tools. The least 1500 t-shirts that related to CC licence is the CC-BY licence (43.8%).
code layer of each licence was designed works and spread the word about CC to This licence lets others distribute, remix,
by the late Aaron Schwartz. CC’s legal family, friends, work colleagues and the tweak and build upon your work, even
C
reative Commons (CC) licences make their licensing system discoverable the CC has its eyes set firmly on tools help those who want to encourage general public. In 2016, CC migrated their commercially, as long as they credit you
are free, international, easy-to- and usable across the globe and across how CC licensing can shape a better
use copyright licences that can disciplines. future. Interim Representative for the
The number and choice of licences as they stand work

be utilised by any authors or publishers. United Kingdom to the CC Global
They specifically allow research and data With goals such as opening up education Network Council, Graham Steel, told
to be reused and remixed collaboratively.
The CC organisation, which created
for all, accelerating innovation in science
and medicine through collaboration
Research Outreach more about how
the organisation came to be, how the extremely well and offer an option to suit everyone’s needs.
these licences in 2001, builds tools that and inspiring works of art and culture, licensing works and why it is so important.
Thought Leader
CREATIVE COMMONS Licence Conditions

LICENSES
to Elsevier’s role in the European Union
open science project. The details of these licences depend on its version and comprise a selection of four conditions.
COPY ATTRIBUTION COMMERCIAL MODIFY CHANGE
& PUBLISH REQUIRED USE & ADAPT LICENSE
CC has been established for more than ATTRIBUTION NON-COMMERCIAL
(BY) (NC)
16 years now. What does the next five You may copy, distribute, display You may copy, distribute,
PUBLIC DOMAIN years hold? What are the strategic and perform the work and display and perform the
goals of the organisation? make derivative works based work and make derivative
on it only if they give the author works based on it only for
CC BY CC has moved beyond simple licensing, or licenseor the credits in the noncommercial purposes.
towards making the commons more manner specified by these.
vibrant and usable, and enabling more
CC BY-SA collaboration and gratitude to help it NO DERIVATIVE WORKS SHARE ALIKE
flourish. They are focused on a variety (ND) (SA)
You may copy, distribute, You may distribute derivative
CC BY-ND of initiatives and products to make display and perform only works only under a licence
this happen. An example of this is CC verbatim copies of the work, not identical to the licence that
Search, currently in prototype, which derivative works based on it. governs the original work.
CC BY-NC is being built as a ‘front door’ to the
commons. CC Search not only surfaces NOTE: A licence cannot feature both the Share Alike and No Derivative Works options.
The Share Alike requirement applies only to derivative works.
CC BY-NC-SA CC-licensed content that is freely
available to anyone, it also provides
tools to make lists and attribute work
CC BY-NC-ND with one click, and serves up a massive in making the world more open, make Murdoch look like a socialist.
collection of images by utilising open and making culture more accessible The Guardian 29 August 2011. www.
media application program interfaces. and available to all. theguardian.com/commentisfree/2011/
aug/29/academic-publishers-murdoch-
You can redistribute You have to attribute You can use the work You can modify and You can choose license Another example is the Creative Can you provide some links to socialist (date last accessed 26 October
(copy, publish, display, the original work commercially adapt the original work type for your adaptations Commons Certificate, an in-depth resources where researchers can learn 2018).
communicate, etc.) of the work. educational course about the ethos more about CC licences? Moody G. Elsevier will monitor open
The Creative Commons licences explained. of openness, as well as CC licences If you are in the United Kingdom and science in EU using a measurement
and how they work. The course is interested in CC, please feel free to join system that favours its own titles.
for the original creation. This is the most without using a CC licence, but this process that the Science Commons Data
accommodating of licences. is in the minority. Protocol emerged as the best – and
possibly only – solution to the challenges
CC has moved beyond simple licensing, towards making
Are there too many licences? Should
CC BY be the default for text?
CC has been and remains a pivotal
element of OA. It has provided visionary
collectively identified at that time. the commons more vibrant and usable, and enabling more
The CC licences have become widely thinking and evangelising about the In the scientific and academic collaboration and gratitude.
adopted both within and beyond benefits and possibilities of OA via communities, the benefits that
academia with over 48 million media conferences, networking with the main digital technologies offer in terms
files in the Wikimedia Commons alone. stakeholders within the OA movement, of facilitating the greater and more available to everyone and is geared the United Kingdom CC Slack channel Techdirt 09 July 2018. www.techdirt.
They provide a range of options that and calling upon the CC board of efficient dissemination of research towards empowering individuals and (https://slack-signup.creativecommons. com/articles/20180706/09314440182/
give authors control over how their work directors to give talks about CC and OA. and knowledge have not yet been fully institutions to better advocate for org/ and jump to CC UK). elsevier-will-monitor-open-science-eu-
can be reproduced and remixed. CC hosted convenings, such as the 2006 harnessed – what are your thoughts openness and to help them be fully You can also find more information using-measurement-system-that-favors-
Information Commons for Science on this? up to speed on how to interact with CC via the following links: own-titles.shtml (date last accessed 26
The number and choice of licences Congress at the National Academies There has been substantial movement licences and CC-licensed works. •C reative Commons October 2018).
as they stand work extremely well and of Science in Washington, D.C., where over the years in this regard, but I •C reative Commons FAQ’s Pirwowar H, Priem J, Lariviere V, et al.
offer an option to suit everyone’s needs. renowned scientists and scholars from agree there is certainly still much more There’s also the Creative Commons • Choosing a CC licence The state of OA: a large-scale analysis
It is certainly refreshing to see alternatives the United States and other countries that can and should be achieved. On Summit, an annual event. The summit is •H ow should I decide which licence of the prevalence and impact of Open
to the norm in subscription-based gathered to discuss data-sharing the positive side, as of 2017, there are an opportunity for everyone interested in to choose? Access articles. Peer J 6:e4375.
publishing/publishers. strategies. In 2007, CC co-sponsored almost 1.5 billion CC-licensed works. this work to get together in person with an •F act Sheet On Creative Commons
with the Committee on Data for There also has been a substantial international community of technologists, an Open Science
Should CC BY be the default for text? Science and Technology (CODATA) the growth in the field of pre-prints and in culture creators, academics and activists • Creative Commons Licensing Explained
With reference to the text of academic Workshop on Common Use Licensing a 2018 paper, Piwowar et al found that to share ideas and decide on the best (video)
materials, yes I think it should be. of Scientific Data Products in Paris. This in 2015, 45% of the scholarly literature ways to move the movement forward. •B uilding on the Past’ – An explanation
conference included representatives is OA. On the not so positive front, of how Creative Commons works.
Creative Commons licensing
OA and CC – are they separable? from the Global Biodiversity Information in 2011, George Monbiot released a Finally, there’s the Creative Commons Winner of the Creative Commons
Can you expand on CC’s relationship Facility, and leading legal scholars, sobering piece for The Guardian titled Global Network. This is a membership Moving Image contest (video). E: info@creativecommons.org
W: https://creativecommons.org/
and thoughts on OA? Can a journal be scientists and CC International affiliates ‘Academic publishers make Murdoch programme for organising, expanding
: @CreativeCommons
OA without using a CC licence? actively working on data sharing look like a socialist’. Concerns have been and empowering the global community REFERENCES
Yes, a journal can be open access policies. It was through this collaborative also raised very recently with regards of people who are actively invested Monbiot G. Academic publishers
Health and Medicine ︱ Dr. Darin T. Okuda
New 3D technology to
help in the battle against
brain tumours
A
G
Dr. Darin T. Okuda is a lioblastoma multiforme (GBM) HOLDING US BACK
clinician-scientist and is a destructive and fast-growing Studying the brain is notoriously difficult
professor of Neurology and brain cancer. It is the most as access to the brain is very tricky –
Neurotherapeutics at the common cancerous brain tumour in adults especially when trying to study the brains
University of Texas Southwestern and with a five-year survival rate of just of living subjects. Different imaging B
Medical Center in Dallas. Dr. 5%, the outlook for patients with GBM is techniques have been designed to help
Okuda strives to transform poor. Current treatments for GBM include scientists peek inside the brain; one of
healthcare by developing new surgery for tumour removal followed these is 2D MRI. This technique is useful The contrast is clear between 2D MRI (left), the initial 3D image (centre) and data from the coverage analysis (far right). The patient in the top row exhibits 3D
diagnostic tools that challenge by chemotherapy and radiotherapy. for imaging tumours like GBM. These coverage data highly suggestive of tumour progression. Note how much more informative the 3D data are in comparison to that provided with 2D MRI.
current clinical practices. To monitor the effectiveness of these 2D MR images are currently used to help
His research group recently treatments, clinicians rely on imaging the healthcare providers monitor the effects growth and fail to reveal the complexity of the contrast enhanced region to reveal thickness of the contrast enhanced
designed a novel method tumour and observing changes over time. of treatments on tumours. of the tumour, specifically the shape details about the tumours in a way that outer shell was different between
to visualise brain tumours in and texture. Dr. Okuda’s laboratory had never been seen before. The clinical groups. In patients with stable
three-dimension (3D). This latest Currently, the gold standard imaging During MRI, a chemical called gadolinium has developed novel software to innovative software was not only able to tumours, the thickness of the shell
research aims to revolutionise technique is two-dimensional (2D) is injected into the body to enhance help uncover the true characteristics effectively isolate the contrast enhanced was found to be more evenly spread
the evaluation and management magnetic resonance imaging (MRI). and improve the visualisation and of GBM tumours. portion of the tumour, but it was able compared to worsening tumours. The
of patients with glioblastoma
However, this 2D imaging method has understanding of how leaky blood to edit the acquired images in 3D, an shells also tended to be thinner than
multiforme (GBM).
many problems when managing patient vessels are. Clinicians use these images SEEING THINGS DIFFERENTLY aspect not previously available with other in those patients with tumour growth.
treatment. With the available technology to monitor GBM development. Currently Dr. Okuda’s research group was able platforms. Three different approaches Scientists are still trying to understand
it is hard for healthcare professionals it is accepted amongst healthcare to reveal 3D spatial, structural and surface were used to study the acquired 3D files. whether the width of the shell changes
to know if the treatment needs changing, professionals that an increase in the features of GBM using a novel approach. during tumour growth – more research
if the tumour is worsening or if the MRI contrast signal, known as a contrast In a recent study, would be needed
Dr. Okuda’s laboratory have designed

treatment is effective. Dr. Okuda’s enhancement, suggests tumour growth. fifteen patients to clarify this. Dr.
laboratory designed a more advanced were recruited and Okuda’s research
three-dimensional (3D) imaging technique
enabling clinicians to observe tumours
This sounds simple – when the contrast
enhancement increases, the tumour
divided into two
groups: 1) clinically
a more advanced 3D imaging technique group suggests that
monitoring individual
more clearly. is getting bigger. Unfortunately, it is stable without enabling clinicians to observe tumours patients over time
not that easy to interpret what is going new or worsening may be more
Dr. Okuda’s imaging on in a 2D MRI; there are important neurological more clearly. meaningful when
techniques allow for greater limitations to take into account. Treatment symptoms and looking at outer shell
tumour information.
for GBM, such as radiotherapy, can cause 2) patients with new or worsening A technique known as ‘principle width during disease progression. This
an increase in the contrast enhancement neurological symptoms unattenuated component analysis’ was used to new technology could help healthcare
on the MRI. This phenomenon is known by steroid treatment whose combined understand more about the shape providers understand more about how
as pseudoprogression and it is often symptoms and MRI changes warranted of the tumour. The outer shell of the their patient’s tumour changes over time.
indistinguishable from tumour growth. a change in their established treatment tumour’s active region was analysed
This makes it very difficult for clinicians plan. Each patient had MRI scans and and the distance along three different ‘Coverage analysis’ was used to identify
to understand the true nature of the the resulting 3D images were studied axes was studied to reveal the tumour’s the number of holes in the tumour’s
tumour and provide the best treatment and the two groups compared. The sphericity. The researchers predicted contrast enhanced outer shell. The
for their patients. researchers started by investigating tumours which were getting worse would relationship between the inner and outer
the most active region of the tumour, the be more spherical in shape compared surfaces of the tumour were studied to
In order to treat GBM patients effectively, contrast enhanced region. to stable tumours. understand the integrity of this region.
it is vital that tumour growth be viewed The researchers found that in patients
accurately. These 2D forced perspective The software that Dr. Okuda’s group The researchers used ‘medial axis with worsening tumours there were fewer
MRIs limit the understanding of tumour developed allowed in-depth analysis transformation’ to determine if the holes in the outer shell compared to those
Behind the Research
Dr. Darin T. Okuda
E: Darin.Okuda@UTSouthwestern.edu T: + 1 214 645 8215 (office)
W: https://profiles.utsouthwestern.edu/profile/146752/darin-t-okuda.html
Research Objectives References

Dr. Darin T. Okuda and his team from UT Southwestern Hansen M, Pan E, Wilson A, McCreary M, Wang Y, Stanley
Medical Center in Dallas developed novel methodology T, Pinho M, Guo X, Okuda D. (2018). Post-gadolinium
to visualise brain tumours in 3D. 3-dimensional spatial, surface, and structural characteristics
of glioblastomas differentiate pseudoprogression from true
tumor progression. Journal of Neuro-Oncology, 139(3), 731-
Detail 738
Darin T. Okuda, M.D., M.S., F.A.A.N., F.A.N.A. Newton B, Wright K, Winkler M, Bovis F, Takahashi M,
Professor of Neurology & Neurotherapeutics Dimitrov I, Sormani M, Pinho M, Okuda D. (2017). Three-
Director, Neuroinnovation Program Dimensional Shape and Surface Features Distinguish Multiple
Sclerosis Lesions from Nonspecific White Matter Disease.
Director, Multiple Sclerosis & Neuroimmunology Imaging
Journal of Neuroimaging, 27(6), 613-619.
Program
Dr. Okuda examines a 3D printed model Director, Radiologically Isolated Syndrome Consortium
created from his team’s 3D data. Okuda D. (2018). 2018 American Academy of Neurology
Department of Neurology & Neurotherapeutics Brainstorm. YouTube. Available at www.youtube.com/
UT Southwestern Medical Center at Dallas watch?v=w_4aAVfyZq8&feature=youtu.be
This 3D morphological data provides

with stable tumours. The research group 5959 Harry Hines Blvd.
had expected to see this in a growing Dallas, Texas 75390
tumour because with nothing to prevent
tumour growth, the cells migrate
a vital tool in monitoring tumour USA
outwards resulting in a more spherical, progression in patients in order Bio

fuller shape with less holes. Dr. Okuda is a clinician-scientist and professor of neurology,
to provide better treatment. specialising in neuroimmunology. His work aims to create Personal Response
In combination, these three analysis next generation healthcare by developing innovative
techniques bring together a 3D picture advancement based on shape, texture simulations of the tumour could be connections between patients and providers that transform What difference will this make to brain tumour
of a tumour’s shape and texture. The and structural patterns. This will aid better printed to create a 3D model. The patient medical management. He is involved in the implementation treatment from a patient perspective?
3D data was able to provide much management of patients and any changes could then see the exact size and shape of extreme healthcare concepts focused on delivering care
Our work allows for patients to be better educated on
more thorough information than the in treatment to occur more efficiently. of the tumour: this is much more tangible more accurately, efficiently, and intelligently.
their condition as the acquired 3D images and models from
conventional 2D images. Furthermore, than viewing a series of 2D images. The tumours are immediately intuitive. This approach surpasses
the researchers were able to show that For clinicians and patients, being able to acquired 3D files may also be used with Collaborators education that is provided with current 2D MRI views on
the changes in 3D spatial, structural distinguish between pseudoprogression augmented and virtual reality platforms. • Madison R. Hansen a computer screen. These techniques, once confirmed
and surface features correlated with and true tumour progression is key. The • Edward Pan in larger groups, will allow for the earlier recognition of
the clinical status of the tumour. This 3D technology could also be used to monitor Dr. Okuda’s research group is currently • Andrew Wilson tumour advancement as compared to treatment effects,
morphological data provides a vital tool in the effectiveness of various treatments conducting studies using larger patient • Morgan McCreary the prevention of unnecessary neurosurgical procedures
from being performed, and for treatment changes to occur
monitoring tumour progression in patients such as immune-based therapeutic groups to confirm their findings • Yeqi Wang
more quickly. In addition, our 3D approach provides a more
in order to provide better treatment. strategies which harness the immune and ultimately aim to measure the • Thomas Stanley
eloquent platform that may quickly inform on the value
system to fight cancerous tumours. While impact of their findings on patient care. • Marco C. Pinho of new and novel GBM treatments for our patients.
WHAT NEXT? immunotherapy is well established for The group also hopes to use 3D data • Xiaohu Guo
This emerging 3D technology provides some cancers, it is still being evaluated to identify disease progression before
new hope for GBM patients. The for the treatment of GBM. It is possible symptoms manifest in patients by
3D view of the tumour extends way that this 3D technology could play a leveraging machine and deep learning
beyond the traditional, constrained 2D part in evaluating the therapeutic effect techniques. These efforts extend beyond
images and provides more dynamic of such treatments. the current routine disease surveillance
and comprehensive information about measures and their methodology
the tumour. This 3D technology will Not only is this 3D technology useful may one day be systematically applied
allow healthcare providers to gain new in monitoring tumours and treatment of to the management of all GBM patients
insights into tumour progression and the patient but it may also be a useful tool in the near future.
gain a greater understanding of tumour for patient education. These 3D computer
Health & Medicine ︱ Professor Patrick Riley
Duplication of the nucleosome
Carcinogenesis:
Newly
synthesised
Recycled histones
histones
p53
Methylated
cytosine
When transmission of epigenetic information goes awry Quality control

inspection of
reassembled
A
histones
Genes are blueprints that lthough we all started as a Pathology at University College London.
DNA DNMT3a/3b
code for proteins and in turn, single cell with a half-genome Professor Riley suggests that defects polymerase DNMT1
DNA p53
proteins drive most activities from each parent, that single in the somatic inheritance of epigenetic
Unmethylated
within our cells. But between cell quickly divided, new cells were information offer an explanation for cytosine
genes and their protein products created and became different from each the development and characteristics
is the layer of epigenetics other. This process of cell differentiation of cancer.
– genes may be expressed enables multicellular organisms to
differently depending on the contain hundreds of different cell types, TURNING GENES ON AND OFF
heritable, epigenetic features each capable of carrying out specialised The process of differentiation involves
that switch them on and off. functions. It was initially thought that gene silencing and relies on small,
Charting new territories in these differences were the result of the reversible changes to the DNA complex
carcinogenesis, Professor Patrick loss of parts of genetic material from the that makes up chromosomes; these
Riley at University College fertilised egg. However, transplantation include DNA methylation and histone
London explores the idea that studies revealed that each cell expresses modification. Within a cell, segments
cancers arise when inheritance only a proportion of the genes in its total of DNA are tightly packed around
of epigenetic information
repertoire, and that the answer lies in the proteins called histones to form
goes awry.
way that each cell deploys its genome. nucleosomes. In turn, nucleosomes Highly schematised view of the stages in the duplication of the nucleosome organisation. The double-stranded DNA on the left is shown with the pattern of
Epigenetics is the process by which are strung together to create chromatin, methylated cytosines (●) associated with a set of histones forming the initial nucleosome structure with associated proteins (in this case DNMT3a and 3b). The
histones are removed and the two strands of DNA separated. Each of the single strands of DNA is copied by DNA polymerase, with the newly-synthesised
cells designate some genes for use and the fibre from which chromosomes complementary strands containing unmethylated cytosines (○). DNMT1 attaches to the hemi-methylated DNA and methylates sufficient of the unmethylated
others for storage. In essence, epigenetic are made. This tightly packed coiling cytosines to enable the DNA to reassemble with the initial set of histones (some recycled and some newly synthesised as indicated by the arrows). With
changes allow cells to regulate their gene provides a way of strictly controlling gene the proper nucleosome structure reformed, the associated DNMT3 enzyme complex completes any residual cytosine methylation reconstituting the initial
nucleosomal pattern and ready for inspection by the p53 system. Possible sources of error are: (1) faulty methylation by DNMT1; (2) faulty reconstitution of
expression without permanently changing activity (or gene expression). nucleosome through faulty synthesis, modification or selection of histones; (3) failure to complete cytosine methylation due to absence of attachment or
the genes themselves. malfunction of DNMT3a/3b; (4) failure of the quality control system to detect nucleosomal abnormality.
To activate a gene, the portion of
Pushing the boundaries of our knowledge DNA containing the gene must be how readable the genetic information PRESERVING THE STATUS QUO during embryonic development) or failure
of the fascinating field of epigenetics accessible. Histones control how is. Loosely packed nucleosomes (as In order to perpetuate the correct of expression of previously active genes.
is Patrick Riley, Emeritus Professor of Cell tightly the DNA is packed, and thus in euchromatin) allow the DNA to be pattern of gene expression it is essential
transcribed and the genes expressed. that at each cell division (when DNA ERROR-PRONE EPIGENETIC
In contrast, tightly packed nucleosomes is replicated), specific methylation INHERITANCE
(as in heterochromatin) prevent access patterns are replicated too. That is, In a 2014 publication, Prof Riley
of transcriptional machinery so that genes DNA methylation has to be accurately proposed that carcinogenesis could be
on these stretches of DNA are silenced. copied to the newly made strands of a result of a process involving defective
The major way in which genes are duplicated DNA (i.e. correct transmission transmission of epigenetic information,
silenced involves the building on an idea
attachment of methyl first suggested
groups to specific Professor Riley suggests that defects in 1979 by Holliday1.
cytosine bases of
the DNA molecule. in epigenetic inheritance offer an This concept is
seen as a rational
This modification
to part of the DNA
explanation for carcinogenesis. explanation for the
main characteristics
determines the of cancer including
way that DNA associates with histones, of essential epigenetic information). the disturbances of chromosome structure
consequently regulating which genes Since the methylation pattern of DNA and function, and the variable and
are able to be expressed. Epigenetic ultimately determines the chromosomal abnormal patterns of gene expression
markers such as methyl groups keep cells structure, any defective copying of resembling hypermutability.
on the straight and narrow – ensuring they DNA methylation could lead to altered
divide in an orderly manner and remain chromosomal structure, resulting in
true to their nature (e.g. that kidney cells inappropriate re-expression of previously 1
Holliday R. (1979) A new theory of
remain kidney cells). silenced genes (such as those expressed carcinogenesis. Br J Cancer; 40:513–522.
The crucial characteristic of malignant
cells is abnormal migratory behaviour
and as Prof Riley explains: “plants, whose
Behind the Research
cell walls preclude migration, do not
get cancer. In animals, cell migration
Professor Patrick Riley
is an important feature of embryonic
development but is strictly limited in E: rebc900@ucl.ac.uk T: (+44) 20 8445 5687
the adult.” He noted that any defective
expression of migratory behaviour
normally associated with development
would be catastrophic, particularly if it Professor Riley, University College London, investigates Riley P A. (2014) Failure of fidelity of vertical transmission
were a result of unscheduled expression the effect of epigenetic changes on carcinogenesis, of epigenetic patterning as the basis for cancer. Melanoma
of normal genes, as this would go the formation of cancer. Research, 24: 424-427.
unrecognised by the immune system.
Riley P A. (1985) Pathological Migration: From Melanin to
Malignancy. University College London.
Prof Riley also observes that cancer does
not occur in non-dividing cells, suggesting
The key to carcinogenesis may lie, not in genetics, but in epigenetics.
Detail Riley PA. (2018) Epimutation and Cancer: Carcinogenesis
that the crucial genetic errors arise only POSSIBLE SOURCES OF ERROR- developing into tumours, and is the most Professor Patrick Riley Viewed as Error-Prone Inheritance of Epigenetic Information.
J. Oncol. 1-4.
during DNA replication, as would be the PRONE EPIGENETIC TRANSMISSION common mutation detected in over Totteridge Institute for Advanced Studies
case if they resulted from failure of fidelity Prof Riley’s current research has focused 50% of cancers. Prof Riley puts forward The Grange Riley P A. (1982) Is the establishment of a clone exhibiting
of epigenetic copying. on unpicking the processes that may the intriguing idea that the p53 system Grange Avenue defective DNA repair the initial stage of carcinogenesis? Med.
be responsible for defective epigenetic might be viewed as the ‘guardian of the London Hypotheses, 9: 163-168.
CONFIRMATORY OBSERVATIONS transmission, in particular the faulty epigenome,’ suggesting that one of its N20 8AB Riley P A. (2017) The Epigenetic Theory of Carcinogenesis:
Research by others is consistent with Prof methylation of DNA. The addition functions is to detect differences between UK p53 as the Guardian of the Epigenome. J. Oncol. Canc. Res.,
Riley’s conjecture. All cancers display of methyl groups to DNA is controlled the epigenomes of the division products 1: 1-4.
abnormal DNA methylation patterns, at several different levels, and is carried of differentiated cells. Those that are Bio Riley P A. (2018) Cancer Incidence in Relation to Species Size:
they show variable and abnormal gene out by a family of enzymes called DNA detected as abnormal are earmarked Patrick Riley qualified in 1960 from UCHMS. He joined The Peto Paradox in the Light of the Theory of Epigenetic
expression, as well as chromosomal methyltransferases (DNMTs). One for elimination by apoptosis (controlled Claude Rimington’s Department of Pathological Carcinogenesis. J. Med. Oncol., 1: 11-15.
anomalies. In addition, it has been shown particular enzyme, DNMT1, is of crucial cell death). In effect, p53 safeguards Chemistry in 1966 and worked on free radical mechanisms
that the likelihood of malignant change importance because it recognises hemi- the accurate transfer of the epigenetic in pathology, including lysosomal damage and
pattern, so that the differentiated photosensitisation with Trevor Slater. He was successful Personal Response
Professor Riley suggests that an aberrant pattern of gene expression and silencing in cultivating melanocytes in vitro and collaborated with
is retained. Peter Sutton on culturing cancer cells. He spent much of his Pharmaceuticals that reverse epigenetic changes have
quality control system is an important academic career studying melanocytes and melanoma, and exciting potential for a variety of cancers. How far are
THE FUTURE: we from making this a realisation?
factor in malignancy.
developed experimental approaches to melanoma therapy
EPIGENETIC THERAPY? involving metabolically targeted pro-drugs activated by Unfortunately, although epigenetic engineering
If the proposed model of carcinogenesis tyrosinase. has exciting potential in some areas, I do not see a
occurring in a tissue is related to the methylated strands of DNA. During DNA is correct, the initiating lesions consist significant future for it in cancer because (given that the
number of stem cells and proportional replication in differentiated stem cells, of mutations affecting one or more Collaborators proposed model is along the right lines) the fundamental
to the rate of stem cell growth the methylation pattern is maintained components of the epigenetic copying • Dr Mark Burkitt mechanistic error will be repeated each time a cell from an
and proliferation. by a DNMT1 complex which methylates mechanism, and it is probably unrealistic • Professor Roger Dean affected clone divides – that is why the phenomenon is so
devastating. Advances in genetic insertion might enable
the newly-synthesised strand of DNA. to be able to reverse the defective • Professor Charles Harding
cancer to be eradicated by increasing the number of copies
Interestingly, there are differences Another important step involves the process; but it may be possible • Professor Ferdy Lejeune
of p53 in the human genome, as suggested at the end
between the majority of adult cancers reassembly of nucleosomes and the to devise an agent able to sensitively • Mr Brian Morgan of the article.
and cancers of childhood (developmental incorporation of the correct histones. detect abnormal post-division • Professor John Vince
malignancies). However, they both These reconstituted structures determine methylation patterns and thus enable At present the most promising therapeutic advances
are explicable within the concept of the associated enzyme complexes that the development of uniquely targeted seem to be in the field of immunology, and an interesting
an epigenetic origin. Developmental are important in the replication of the cytotoxic therapy. development might be to couple a powerful antigenic
cancers appear to arise from the failure correct methylation pattern (as indicated molecule to an agent capable of detecting anomalously
methylated DNA, thus alerting the immune system to any
of differentiation. As Prof Riley explains: in Scheme 1). Clearly there are several However, in view of the apparent
epigenetically-defective cell.
“childhood cancers arise from a lack steps in this copying process that may importance of the gatekeeper function
of initial DNA methylation necessary be rendered defective by initiating of p53, there may be scope for preventive
to silence certain genes which impose mutations, such as, for example, by a treatment by the introduction of extra
restricted genetic patterns on the tissues mutation affecting the activity of DNMT1. copies of the gene, especially in high-
of the developing organism. In these risk individuals. There is evidence that
cases, the genesis of malignant behaviour QUALITY-CONTROL MECHANISM the comparatively low cancer incidence
appears to rest on the failure to initiate A common defect in cancer cells involves in elephants is due to multiple copies
the proper epigenetic pattern rather than inactivated p53. Acting as a ‘safety of the p53 gene.
in the failure to perpetuate it.” net,’ p53 prevents abnormal cells from
Health and Medicine ︱ Dr Thomas E. Ahlering
Average Volume of Radical Prostatectomies per Year Average age of patients at time of surgery per year
Reduced PSA Prostate

3000 63
Multi-institutional Trends in 62.5

2500
Number of Patients
Demographics and Adverse Pathologic
62
Features of Men Undergoing Radical 2000
Cancer Screening: Life-

Prostatectomy. 61.5
Age (Years)
1500
61
1000
60.5
threatening Consequences?
500 60
0 59.5
2009-2012 2013 2014 2015 2016 2009-2012 2013 2014 2015 2016
Average PSA of patients at time of surgery per year Number of patients with pGS≥4+5 per year Number of patients with LNI per year
6.20 250 250
6.00
Number of patients
Number of patients
P
200 200
Total PSA (ng/mL)

5.80
In 2012, the United States rostate cancer is the second most (a physical inspection of the prostate).
5.60 150 150
Preventive Services Task common cancer worldwide and Another method used to detect prostate 5.40
Force issued a grade D the sixth leading cause of cancer- cancer is the ‘prostate-specific antigen’ 5.20 100 100
recommendation against PSA- associated death among men. In 2012, (PSA) blood test introduced in 1988. 5.00
50 50
based prostate cancer screening. there were approximately 1.1 million PSA is a protein produced by the prostate 4.80
This is because early diagnosis cases and 307,000 deaths. Generally, and prostate cancer cells. As men age 4.60 0 0
2009-2012 2013 2014 2015 2016 2009 2010 2011 2012 2013 2014 2015 2016 2009 2010 2011 2012 2013 2014 2015 2016
of low-grade cancers can lead prostate cancer affects men over the and the prostate gland becomes larger
to unnecessary overtreatment age of 50 years old (around 42% of cases) the level of PSA naturally increases.
and patient suffering. However,
Limitations of the PSA blood test
and the majority of patients are over 60 However, abnormally high levels of the patient to unnecessary suffering
many epidemiologists are years of age. The prostate is a small gland PSA can be a potential sign of cancer. associated with overtreatment. Treatment
led to the United States Preventive

concerned that this could in the pelvis that is only found in men. A major benefit of the PSA blood test for prostate cancer can have severe
lead to severe unintended The main function of the prostate is to is that it can be used to detect early-stage side effects impacting the patient’s
consequences. Dr Thomas E.
Ahlering, from the University of
produce seminal fluid that is then mixed prostate cancer in asymptomatic men. quality of life including urinary, bowel Services Task Force issuing a grade
with sperm made by the testicles. Often This has reduced the number of deaths and erection problems.
California, has further explored
these concerns and has shown
patients suffering from prostate cancer from prostate cancer by at least 50%. D recommendation.
are asymptomatic until the prostate GRADE D RECOMMENDATION
in a ground-breaking study that
is large enough to affect the urethra However, there are several limitations These limitations of the PSA blood test by this observation, Dr Ahlering and his (PLCO) and European Randomised Study
reduced PSA-screening can
and urination. of the PSA blood test: i) in some cases led to the United States Preventive team decided to perform a more in-depth for Screening of Prostate cancer (ERSPC).
lead to increased incidence of
high-risk disease and increased men have a raised PSA level even if they Services Task Force (USPSTF) issuing study to investigate the effects of reduced The PLCO results revealed no significant
mortality rate. THE PROSTATE-SPECIFIC ANTIGEN do not have prostate cancer, ii) the PSA a grade D recommendation in May 2012. PSA screening. mortality differences with PSA screening
BLOOD TEST test can miss prostate cancer – around This means that PSA blood tests are and the ERSPC showed that around
Currently, there is no single test used 15% of patients with a normal PSA level no longer used as a diagnostic tool for SHORTCOMINGS OF 1400 patients needed to be screened
to diagnose prostate cancer. A variety may actually have cancer, ii) the PSA test prostate cancer screening. The task force THE USPSTF STUDY in order to prevent one death. However,
of different diagnostic tools can be can diagnose a slow-growing prostate argued that the benefits of the PSA blood The D grade recommendation was there are some significant flaws in these
used including MRI scans, blood tests, cancer which wouldn’t shorten the test did not outweigh the costs. mainly based on two randomised trials – studies. The PLCO assigned men
biopsies and digital rectal examinations patient’s life and could, in fact, expose Prostate, Lung, Colorectal and Ovarian randomly to a PSA screening or usual
However, Dr Ahlering and other
epidemiologists are concerned that
a reduction in PSA screening could
lead to several severe unintended
consequences. These include: I) more
men suffering from the effects of non-
curative interventions such as radiation
and hormonal therapy ii) physiological
complications of recurrent prostate cancer
iii) an increased incidence in high-risk
disease and iv) a potential increase
in prostate cancer-associated mortality.
Alarmingly, Dr Ahlering observed that
the Task Force policy had a significant
impact on his practice – there was a 20-
25% reduction in referrals 4 months post-
recommendation. Dr Ahlering and his
team also noticed that patients were older
and had higher PSA levels indicating
more advanced disease. Concerned
Behind the Research
Dr Thomas E. Ahlering
E: tahlerin@uci.edu T: +1 714 456 7354 W: http://urology.uci.edu/prostate/

Dr Thomas E. Ahlering from the University of California, Ahlering, T., Huynh, L.M., Kaler, K.S., Williams, S., Osann, K.,
shows that high-risk prostate cancer results from USPSTF- Joseph, J., Lee, D., Davis, J.W., Abaza, R., Kaouk, J. and Patel,
enforced reduced prostate cancer screening. V. (2018). ‘Unintended consequences of decreased PSA-based
prostate cancer screening’. World journal of urology, pp.1-8.
Detail Harrison, P. (2018). ‘Prostate Cancer More Aggressive in Post-

USPSTF Era’. Medscape. Available at: https://www.medscape.
School of Medicine com/viewarticle/900073. [Accessed 11/11/2018].
University of California, Irvine
333 City Blvd West, Suite 2100, RT 81 Sadeghi-Gandomani, H., Yousefi, M., Rahimi, S., Yousefi, S.,
Mail Code: 5395 Karimi-Rozveh, A., Hosseini, S., Mahabadi, A.A., Abarqui,
Orange, CA 92868 H.F., Borujeni, N.N. and Salehiniya, H. (2017). ‘The incidence,
USA risk factors, and knowledge about prostate cancer through
worldwide and Iran’. World Cancer Research Journal, 4(4),
care group. In-depth analysis revealed
that there was a high contamination rate
The one-year biochemical recurrence Bio
Dr Ahlering is a highly regarded surgeon in Urologic
pp.1-8.
(52%) via PSA testing in the usual care post-radical prostatectomy increased cancers. Since 2002, Dr Ahlering’s research efforts have 2018. Prostate Cancer. NHS. Available at: www.nhs.uk/
group. Additionally, the ERSPC trial was concentrated on maximizing functional recovery and conditions/prostate-cancer/ [Accessed 11/11/2018].
insufficient. Typically, prostate-cancer from 6.3% to 17.5%. patient-reported outcomes following robot-assisted radical
associated mortality, from initial diagnosis, prostatectomy. His work continues to be highly regarded 2016. The PSA Test. Prostate Cancer UK. Available at
is 10-12 years. However, the follow-up seminal vesicle invasion and lymph node for age and PSA across both the pre- among the scientific community, with over 400 published prostatecanceruk.org/prostate-information/prostate-tests/psa-
time in this trial was only 7 years and a metastases. policy and post-policy screening eras. abstracts and journal articles. test [Accessed 11/11/2018].
re-analysis revealed that the number The team show that there is a stepwise
of patients needed to be screened to The results confirmed that the proportion increase in high-risk disease each year Collaborators
prevent one death was 293. of low-grade prostate cancers dropped after the policy was put in place. • Linda My Huynh
from 30.2% in the pre-policy era to 17.1% • Kamaljot S. Kaler Personal Response
THE STUDY in the post-policy era. However, compared FUTURE STUDIES • Stephen Williams
In response to the grade D to the four-year average pre vs post policy Overall, Dr Ahlering and his team have • Kathryn Osann How can we reduce overtreatment but ensure that
recommendation, Dr Ahlering and there was a 22.6% reduction in surgeries highlighted the concerning effects • Jean Joseph prostate cancer is diagnosed early so it doesn’t develop
his colleagues performed a nationwide performed, an increase in median PSA of limited PSA screening. Although • David Lee into a high-risk disease?
study, collecting data from an additional (from 5.1 to 5.8 ng/ml) and increase the recommendation has reduced • John W. Davis To prevent (i.e. minimise) high-risk prostate cancers,
8 high-volume surgeons throughout in mean age (from 60.8 to 62 years) and surgical treatment for low-grade cancers, • Ronney Abaza the disease must be asymptomatic. Presently, organised
the United States. Overall, the team a doubling of high-grade Gleason cancers, the study has shown that reduced • Jihad Kaouk PSA screening is the best means of identifying these
collated data from over 19,000 patients meaning that the prostate cancers were screening can lead to an increased risk • Vipul Patel men. The key to preventing overtreatment has two
undergoing robot-assisted radical much more aggressive post-policy. in aggressive forms of prostate cancer. • Isaac Yi Kim complementary paths. First, active surveillance/
prostatectomy pre (October 2008 Furthermore, the team found a 3.5- This affects the patient’s quality of life • James Porter watchful waiting with intent to pursue no treatment
based on “expected” overall survival versus “estimated”
– September 2012) and post-policy fold increase in patients with advanced and significantly increases mortality rate. • Jim C. Hu
cancer aggressiveness. In contrast, another path is to
(October 2012 – September 2016). seminal vesicle involvement, a tripling Furthermore, the increase in biochemical simultaneously improve treatment outcomes in order
Population datasets take approximately of lymph node metastases and the one- recurrence after 12 months of surgery to reduce the treatment burden. In essence, liken a radical
10-20 years to mature. However, year biochemical recurrence post-radical will lead to additional consequences prostatectomy to an appendectomy: a low-risk procedure
instead of waiting for this long period prostatectomy increased from 6.3% associated with secondary treatment. with minimal risk for complication. It is our assertion
of time, Dr Ahlering and his team used to 17.5%. This is where PSA blood levels Clearly, it is of great importance that that overtreatment with minimal burden is superior
oncological metrics that are highly rise following treatment, which could we find a compromise so that screening to no burden at the cost of lives.
predictive of disease aggressiveness. indicate that the cancer has come back. is effective and minimises overtreatment
These methods include the pathologic but preserves early diagnosis.
Gleason grading system, whereby biopsy A major strength of this study was
samples are used to diagnose patients, the use of propensity score matching
Health and Medicine ︱ Professor Tetsuya Kodama
by targeting these lymph nodes with
Lymph nodes targeted

chemotherapy directly introduced into
Vein
the lymphatic system.
Staging of cancer is based on TNM
in novel cancer therapy

classification. T category describes the
primary tumour site. N category describes
Lymph
the regional lymph node involvement. Node
M category describes the presence or Lymphatic
otherwise of distant metastatic spread. Vessel
In TNM classification, T0 is defined as Vein
no detection of a primary tumour, N0 is
the absence of metastasis in the regional
lymph nodes, and M0 is defined as no Artery
distant metastases. The factors of TNM
classification other than T0, N0 or M0 are
defined by the type of tumour. Classifying
tumours according to the TNM system,
however, has its limitations. One such
limitation is the frequency at which lymph
nodes are incorrectly described as ‘N0’. Sentinel
If cancer has spread beyond the sentinel Primary Lymph
lymph node, but the downstream lymph Tumour Node
nodes do not exhibit noticeable swelling,
‘false-negative’ results are obtained.
This makes the conventional treatments LYMPHATICS DRUG DELIVERY SYSTEM
(surgical lymph node resection, A high dose of an anticancer drug into a metastatic lymph node (sentinel lymph node) and deliver the
radiotherapy and/or chemotherapy) for drug to downstream lymph nodes lymphatic network, thereby treating or preventing metastasis in the
lymph node metastasis unsuitable to treat injected lymph node and downstream lymph nodes. The amount of drug used in the LDDS is extremely
small compared to systemic chemotherapy, thus there are few side effects on the whole body.
N0 false-negative metastatic cancer.
drugs become diluted in the blood Research into improving the treatment
In addition, chemotherapy administered resulting in low concentrations of of lymph node metastasis had been
into the bloodstream through an I.V. the drug reaching the lymph nodes. previously limited largely due to a lack
injection or infusion (known as systemic Chemotherapy can also cause adverse of appropriate animal models of the
administration) has been found to have side effects because it circulates in the disease. Kodama and his collaborators
limited success in treating cancer in the body, rather than selectively treating the were able to establish a novel mouse
C
90% of global deaths caused ancer was estimated to have metastasise via the lymphatic system: lymphatic system as the chemotherapy malignant target. model that contains lymph nodes of a
by cancer are the result caused 9.6 million deaths these cancer cells travel to nearby lymph similar size to that of humans (up to 10
of its metastasis. Cancer can globally in 2018. In 90% of nodes (known as regional lymph nodes) mm), allowing lymph node metastasis
spread throughout the body cases, it is not the primary tumour that where they develop, causing the lymph to be studied in animals for the first time.
through the blood system or is lethal, but it’s metastasis. Metastasis nodes to swell, and then circulate
the lymphatic system. With is the spread of malignant (cancerous) around the body to other ‘downstream’ Lymphatic drug delivery systems were
funding from JSPS KAKENHI, cells around the body resulting in lymph nodes. When cancer has reached developed to allow direct administration
Professor Tetsuya Kodama the growth of secondary, metastatic the lymph nodes, it is also possible of drugs to the lymphatic system
at Tohoku University in Japan tumours. When a tumour metastasises, cancer will spread into the bloodstream through injections in lymph nodes (also
and his collaborators established it can spread through the bloodstream in what has been termed ‘lymph node- known as intranodal injections). Using
a novel mouse model to study (known as a hematogenous spread) mediated hematogenous metastasis’. fluorescent dyes, Kodama and his team
cancer metastasis through were able to visualise how fluid drains
the lymphatic system. With this
model, they identified lymph
In 90% of cases, it is not the primary from the ‘upstream’ sentinel lymph node
to ‘downstream’ lymph nodes in their
node metastasis as the starting
point of metastatic disease.
tumour that is lethal, but it’s metastasis. novel mouse model. From these findings,
lymphatic drug delivery systems were
Their research has focused
or through the lymphatic system (known This theory suggests that the first lymph able to be developed to specifically target
on developing a new cancer
as a lymphatic spread). The lymphatic node or group of nodes that cancer cancer in the lymphatic system.
therapy to target specifically
system is comprised of lymphatic vessels travels to (known as the sentinel lymph
lymph node metastasis and
that circulate lymph (fluid containing node/nodes) is the ‘start point’ of Using their mouse model, Kodama
holds huge revolutionary
white blood cells, amongst other metastasis. Professor Tetsuya Kodama and his collaborators observed how
potential for the treatment
of metastatic cancer. components), forming an important part of Tohoku University, together with his cancer metastasises through the
When you go to the hospital feeling abnormality such as a lump, the palpation is performed first. Next,
of the body’s immune system. Cancers colleagues have developed a new way image diagnosis such as mammography, ultrasonography (echo) MRI and CT are conducted, finally lymphatic system. Their research shows
such as breast, head and neck cancer to effectively treat metastatic cancer biopsy is conducted to confirm the diagnostic results. a decreased flow from the sentinel
Behind the Research
Professor Tetsuya Kodama
E: kodama@tohoku.ac.jp T: +81 22 717 7583 W: www.ecei.tohoku.ac.jp/kodama/english/index.html

Metastasis, a characteristic of many tumour types, is Cancer Research UK (2017) TNM staging. [Online] Available
estimated to be responsible for the death of 90% of all at: https://www.cancerresearchuk.org/about-cancer/
patients with cancer. However, effective treatment of breast-cancer/stages-types-grades/tnm-staging [Accessed
metastasis has not been established. In Professor Tetsuya 17/10/2018].
Kodama’s laboratory, they focus on early diagnosis and
treatment of lymph node metastasis, observed in most Fujii, H., Horie, S., Takeda, K., Mori, S. and Kodama, T. (2018).
cancers, such as breast cancer and head and neck cancer. ‘Optimal range of injection rates for a lymphatic drug delivery
system’. Journal of biophotonics, [online] p.e201700401.
Detail Available at: https://doi.org/10.1002/jbio.201700401

[Accessed 12/10/2018].
Director of Biomedical Engineering Cancer Research Center
Laboratory of Biomedical Engineering for Cancer Kodama, T., Hatakeyama, Y., Kato, S. and Mori, S. (2015).
Graduate School of Biomedical Engineering Tohoku ‘Visualization of fluid drainage pathways in lymphatic vessels
University and lymph nodes using a mouse model to test a lymphatic
4-1 Seiryo, Aoba, Sendai 980-8575, Japan drug delivery system’. Biomedical optics express, [online]
The lymphatic network consists of lymphatic vessels. Lymph nodes are organs, which are located in lymphatic vessels to remove foreign bodies. There are about
6(1), pp.124-134. Available at: https://doi.org/10.1364/
total 600-800 lymph nodes spread out in the body. Bio BOE.6.000124 [Accessed 13/10/2018].
Dr Tetsuya Kodama is a Professor at Tohoku University. He is
lymph node to downstream lymph This treatment has a huge potential the Director of the Biomedical Engineering Cancer Research Kodama, T., Matsuki, D., Tada, A., Takeda, K. and Mori, S.
to reduce cancer mortality by stopping

nodes when cancerous tumours develop Center, Graduate School of Biomedical Engineering Tohoku (2016). ‘New concept for the prevention and treatment of
in the vessels between them. Instead, the University. He gained a PhD in engineering and a PhD in metastatic lymph nodes using chemotherapy administered via
flow was orientated to the blood system.
This observation led the researchers
cancer before it can spread beyond medicine from Tohoku University (Japan) in 1992 and 2011,
respectively.
the lymphatic network’. Scientific reports, [online] 6, p.32506.
Available at: https://doi.org/10.1038/srep32506 [Accessed
to theorise that ‘lymph node-mediated the lymphatic system. 13/10/2018].
hematogenous metastasis’ is the Funding
final stage in lymph node metastasis, allowed to flow to downstream lymph chemotherapy to ensure the drug flowed JSPS KAKENHI Grant Number: 17K20077, 17H00865, Tada, A., Horie, S., Mori, S. and Kodama, T. (2017).
and the sentinel lymph node should, nodes prior to surgical resection of the to downstream lymph nodes. 26242051, 24650286, 23300183, 21650124 ‘Therapeutic effect of cisplatin given with a lymphatic drug
therefore, be targeted as the ‘start point’ primary tumour and sentinel lymph node, delivery system on false negative metastatic lymph nodes’.
of cancer metastasis. dramatically reducing the risk of cancer The group will design Phase I clinical Collaborators Cancer science, [online] 108(11), pp.2115-2121. Available at:
recurrence. This treatment has a huge trial to investigate the safety and • Dr Shiro Mori, Tohoku University Hospital, Japan. https://doi.org/10.1111/cas.13387 [Accessed 13/10/2018].
Cisplatin, a chemotherapy drug used potential to reduce cancer mortality effectiveness of lymphatic drug delivery • Dr Maya Sakamoto, Tohoku University Hospital, Japan.
to treat cancers such as breast cancer by stopping cancer before it can spread system using chemotherapy within a few • Dr Naoko Mori, Tohoku University Hospital, Japan.
and head and neck cancer, injected into beyond the lymphatic system. years, followed by Phase II clinical trials • Dr Koichi Ito, Tohoku University Graduate School Personal Response
the sentinel lymph node of mice was to confirm efficacy. of Information Sciences.
found to stop the growth of tumours Kodama and his colleagues are currently • Professor Kiyoto Shiga, Iwate Medical School, Japan.
Cancer death rates are so high due to late diagnosis –
in false-negative metastatic lymph researching factors that could limit Kodama and his colleagues’ work how do you think targeting lymph node metastasis with
nodes. In addition, Kodama and his team the success of lymphatic drug delivery has paved a new way in not only lymphatic drug delivery systems could help reduce the
observed fewer adverse side effects systems in treating false-negative lymph researching lymph node metastasis mortality rates of cancer?
to cisplatin, such as kidney disease, node metastasis. Their most recent paper using mice and thinking about how
Although our method targets N0, lymphatic drug
when given as an intranodal injection describes an investigation into the impact cancer metastasis, but also in how cancer delivery systems are applicable to lymph nodes ³ N0, i.e,
than when given systemically through of chemotherapy drug injection on therapy can be targeted. Lymphatic drug patients whose cancer has progressed into the lymphatic
an I.V. By administering chemotherapy the flow of the drug to downstream delivery systems using chemotherapy system to varying degrees. The method can also be applied
with lymphatic drug delivery systems, lymph nodes in mice. Their results show could dramatically improve the survival to patients who are unsuitable for surgical resection of their
the concentration of the drug is much that factors such as injection pressure rates across many types of cancer whilst lymph nodes, due to factors such as age or if the cancer has
higher when it reaches the target lymph and the volume of the sentinel lymph decreasing the side effects of treatment. spread beyond the sentinel lymph node and outside the
nodes, meaning dosage can be much node do not impact on the success of the The work briefly discussed here is likely region of lymph node dissection. For patients such as
these, our method can improve life prognosis greatly.
lower and fewer doses would be needed. treatment. They also identified an optimal to revolutionise cancer therapy.
Chemotherapy can be injected and range of injection rates to administer the
Health and Medicine ︱ Dr James Stone
pupils. A CT scan of the brain must Over the past 3–4 decades, critical not yet changed. At this desperate point,
Time for a new approach

be obtained as soon as possible to care emphasis for severe TBI has been a surgical decompression or debulking
determine the presence of skull fractures, on placement of an invasive ICP monitor of cerebral contusions or swelling
haemorrhage or contusion within within the ventricles (fluid-filled cavities (oedema) may be considered, but lacking
the cerebral tissue, and haematomas in the brain) or in the brain tissue itself. a brain function monitor to guide us,
to severe traumatic brain

(subdural or epidural) compressing Ventricular placement may provide timely opportunity often slips away.
the cerebral brain surface. Haematomas a more accurate pressure and fluid
or swollen brain tissue may cause drainage may help control ICP – but only It must be understood that the brain
concerning midline shift and crowding if the ventricles are adequately open and functions as an electrochemical organ
injury and stroke:

at the base of the brain, resulting in communicate. ICP monitors are routinely and ICP measurement does not
herniation of the medial temporal lobe. placed on the side opposite the major directly relate to any specific brain
This displaces the midbrain and adjacent damage, for fear of inciting further function: it remains a distinctly indirect
deep structures (vital to life) across the damage or deterioration in placement, measure of brain dysfunction. It should
midline (known as uncal or transtentorial and thus may underestimate the ICP level, be appreciated that development
Developments in automated, real-time monitoring herniation, TTH). or propensity for TTH. of non-invasive, robust, continuous,
neurophysiological recordings of basic
of brain stem function In this setting TTH is a frequent cause

of fatality or severe disability, as bruising
Because the brain is enclosed within
the hard, rigid skull one may assume
brainstem (midbrain) conductivity/
viability is within our reach. It has been
and damage develops in the midbrain a measurement anywhere within proved in controlled experiments in
portion of the brainstem or adjacent the skull or brain will reveal a global subhuman primates that a significantly
T
Traumatic brain injury and he human brain is an Brain malfunction due to head trauma regions. Onset of TTH is usually pressure – much like the air pressure earlier warning of TTH comes with such
stroke can lead to a potentially electrophysiological marvel. or stroke (insufficient blood flow to the associated with changes in pupil size in an automobile tire. Unfortunately, brainstem (midbrain) recordings from the
fatal condition known as By the virtue of ionic chemical brain) resulting in death or disability is not or reactivity and complicates severe TBI this is not so. In fact, the brain tissue scalp following auditory stimuli compared
transtentorial herniation (TTH). gradients creating minute electronic an infrequent occurrence. Indeed, stroke in about 30–40% of to ICP recordings.
Monitoring sedated patients
for indications that TTH is
pulses, about 80 billion nerve cells is the world’s second most frequent cause cases. Deterioration A non-invasive, real-time, automated
and alarmed warning system is
have set up an electrical grid with 20 of death (about 6.3 million deaths per leading to TTH may Dr Stone and
developing presents many Watts of power. Although just enough year, World Health Organization, 2016). also be seen in up to his team feel the
complications. Dr James Stone
from New York University has
to illuminate a small light bulb, the
complexity of the brain is far and away When both mortality and permanent
20% with moderate
TBI, large volume
necessary to capture the earliest signs goal should be
development
developed a modified version unequalled by any man-made system and disability are factored in, Traumatic stroke, or other of TTH – allowing adequate time for of continuous
physicians and surgeons to intervene.

of a test for brain activity in will likely remain so. Beginning with the Brain Injury (TBI) is estimated to affect brain conditions. neurophysiological
response to sound that shows first man-like creature, 4-5 million years 50 million people each year. Although Pupillary changes monitoring for the
promise in detecting early of evolutionary shaping and adaptation receiving more attention recently, TBI with TTH can occur earliest warning of
indications of TTH. This highly has led the human brain to a complexity has been a major but largely neglected within minutes or several hours or days itself (about 70% of the contents of the TTH, when the patient’s functions may still
sensitive monitoring tool, Coma
only partially mirrored on earth by our global problem. It is the leading cause after injury. Once present, TTH is not skull) is predominately a viscoelastic be salvaged.
AlertTM could enable earlier
primate ancestors. The durability of of mortality in young adults, a major cause always fully reversible following urgent (plastic) solid structure and not of liquid
intervention at the stage when
the human brain to maintain high level, of disability across all ages, and believed neurosurgical decompression. A non- composition like the ventricular fluid. Over the past 30 years, general advances
further severe damage could
sophisticated functioning for a lifetime, to increase the risk of late-life dementia. invasive, real-time, automated and Being highly non-compressible yet in Neuro-Intensive care including
be prevented and outcome
quality improved. under many manners of perturbation, Financial consequences of TBI are alarmed warning system is necessary deformable, the brain substance is prone the adoption of ICP monitoring have
speaks to a majestic beauty of design estimated to cost the global economy to capture the earliest signs of TTH to develop pressure gradients especially shown clear improvements in the
and architecture. $400 billion annually (Maas et al, Lancet and allow adequate time for physicians within semi-closed compartments like mortality of severe TBI, but significant
Neurol 2017;16:987-1048). and surgeons to intervene. the temporal and cerebellar cavities. improvement in the number of survivors
Invasive ICP monitors use a device placed inside the head of the patient.
Close to the brainstem, these are not with a favourable outcome has not
CURRENT APPROACHES In many other cases haematoma size, areas for ICP placement. The insidious been forthcoming. Recently, a study
AND LIMITATIONS brain swelling and midline shift are onset of TTH may thus occur. A non- protocol treating severe TBI patients
The key to improving outcome after not deemed significant to warrant invasive monitoring device that can in the absence of ICP monitoring showed
severe TBI, deteriorated cases of surgery, and the patient is observed in an capture the early development of TTH, that frequent CT scans, especially when
moderate TBI, large volume stroke, intensive care unit (ICU). Once or twice before pupillary changes occur, and elevated ICP was suspected and treated,
or any large space-occupying brain per day the sedation can be temporarily lead to prompt medical and/or surgical in addition to periodic sedation
condition with altered consciousness withdrawn in a cursory and often treatments would greatly decrease withdrawal clinical examinations, yielded
demands rapid diagnosis and timely unreliable effort to examine the patient’s the high mortality and very significant outcomes not significantly different
treatment. Prompt airway intubation and ability to respond to pain stimuli and permanent disability in those who survive. from those randomised to ICP monitor-
adequate ventilation is required to reduce move extremities. Unfortunately, many based protocols. The authors warn that
carbon dioxide levels – which lead to patients under observation deteriorate “Uncontrolled ICP” can be fatal. However, the above protocol warrants further
both engorgement of the blood vessels several days later, and without apparent that situation is more often encountered study, but “the evidence suggests the
in the brain and increased intracranial warning slip into various degrees of TTH. where surgery was not initially required, absence of ICP monitoring does not
pressure (ICP). Once intubated, the The culprit is often progressive brain but Neuro-ICU medical treatments begin preclude obtaining satisfactory recovery
patient must be sedated. Under sedation, swelling or consolidation of cerebral to fail. It likely indicates some gradual through aggressive management without
the usual clinical neurological indicators contusions, compounded by respiratory degree of TTH herniation has begun, such monitoring.” (Chestnut, et al J
are lost other than the reactivity of the or fluid issues. even if the pupil size and reactivity have Neurotrauma 35:54-63. 2018).
Dr Stone’s method of
monitoring is non-invasive.
different sound intensities, as well as
the mBAEP was also performed in over
100 patients. In more recent studies,
Stone used CT scans and MRI scans of
Behind the Research
the patients to document the size and
locations of the lesions and improvement
Dr James Stone
of mBAEP after surgical removal of the
mass lesion. This allowed the use of E: jlstone4@gmail.com T: +1 312 806-0145 W: www.societyns.org/society/bio.aspx?MemberID=181
multiple comparative measures to assess
validity and sensitivity. Compared to the
standard BAEP, Stone’s mBAEP produced
more prominent V and Vn waves for
Detail Research Objectives
latency and amplitude measurements. James L Stone, MD, FACS Dr James Stone’s work focuses on real-time, nurse-friendly
This allowed greater and more robust Professor of Neurosurgery, New York University, Langone monitoring of vital brainstem function in brain trauma patients.
statistical analyses. Importantly, this School of Medicine, NY, NY, and Chief of Neurosurgery
meant a faster and arguably more reliable Manhattan Veterans Hospital, NY, NY
measure of midbrain dysfunction than 440 E. 23rd St, Apt 3B References
the standard snapshot BAEP techniques New York, NY 10010
currently employed. USA Stone J,L. et al.(2012) Modified brain stem auditory evoked
A BETTER WAY? A strong correlation was found between responses in patients with intracranial mass lesions. Clinical
Dr James Stone has been studying TBI changes in BAEP, SSEP and increases in FUTURE DIRECTIONS Bio EEG and Neuroscience. 43:291-302.
function for over four decades. He has ICP as a balloon was inflated gradually As a collective, Stone’s work has sought Dr James L Stone, was born and raised in Chicago, IL USA, Stone J,L. et al.(2017) Brainstem monitoring in the
followed every milestone and progression over a four-hour period. BAEP gave to highlight the need for improved brain graduated from the University of Wisconsin in 1970 (BA), Neurocritical care unit. A rationale for real-time, automated
in technology the field has seen. Stone the most sensitive warning before TTH, monitoring of severe TBI, large volume and from St. Louis University School of Medicine with neurophysiological monitoring. Neurocrit Care 26:143-156.
recognised that as an electrical organ, signalled by changes in the pupils, stroke, and other space occupying brain honors in 1974 (MD). While a senior medical student in Vinciguerra L, Bosel J. (2017)Noninvasive neuromonitoring:
the brain would benefit from more direct followed by the ICP and SSEP. lesions and dysfunction at earlier stages 1973 he rotated to Chicago’s Cook County Hospital (CCH) Current utility in subarachnoid hemorrhage, traumatic brain
and sensitive measures of neural activity. than other popular approaches yielded. Trauma Unit – the USA’s first designated trauma centre. injury, and stroke. Neurocrit Care 27:122-140.
His early sub-human primate work A NEW STANDARD The introduction and progression of the There, Dr Stone was greatly influenced by the challenges
Remote Vital Monitoring Inc. (2018). Retrieved from https://
established animal models of ICP and From this point onwards, Stone aimed brainstem auditory evoked potentials of severe trauma care, and dynamic spirit of the Unit and remotevitalmonitoring.net/.
TTH progression and concurrent brain to establish a more sensitive and earlier (BAEP) continues to be a success in this its founding surgeons. His Surgical Internship was at CCH,
dysfunction monitored by sequential warning of TTH using the BAEP (Wave V direction. Across a number of studies, followed by Neurological Surgery Residency at CCH and
Evoked Potentials (EPs). and Vn amplitude and latency measures) Stone has demonstrated the efficacy the adjacent University of Illinois Hospital at Chicago (UIC)
Whilst at the Cook Country Head Injury

examination. At the time, BAEP waves
took approximately 7–8 minutes to
of mBAEP. completed in 1980. Neurology Residency and Clinical
Neurophysiology Fellowship were also obtained at UIC.
Personal Response
lab, Stone used an intracranial balloon record; Stone aimed to reduce this Whilst their improvements over other
within the temporal/parietal skull of delay to 3–4 minutes. To achieve this, measures are clear, limitations still exist. Dr Stone spent three decades treating and studying severe Is there any particular metric of success in this field
of post brain-trauma monitoring which you think would
monkeys to study increases in ICP and its he developed modified BAEP (mBAEP) These measurements at present are by no Traumatic Brain Injury (TBI) at CCH.
be easy to frame for the general public?
effect on brain function up to the point of in animals and human volunteers by means automated, requiring a technician
TTH. Vital signs, pupil size and reactivity altering the auditory stimulus used by to take repeated measurements, as well Dr Stone’s major research effort has been the development Recognition and early capture of transtentorial
and Evoked Potential (EP) responses were stimulating both ears simultaneously, as later interpretation of results. For Stone, of brainstem electrical recordings to be applied to the herniation (TTH), offers the best chance to improve
the outcome in severe TBI, large volume stroke and
also recorded. EP responses are a type increasing the rate of presentation (both there is a need to develop automated, serious clinical problem of Transtentorial Herniation (TTH).
other brain conditions. A fellow researcher put this as
of neural activity evoked by a particular build V and Vn amplitude) and utilising nurse/staff friendly neurophysiological follows: “Real-time assessment of global or regional
stimulus. Stone’s work primarily focused four diminishing loudness intensities. monitoring with alarms in the Neuro Funding brain dysfunction could help clinicians recognize early
on somatosensory evoked potentials Recording electrodes are placed on the Intensive Care Units to best utilise Natus Medical/Neurology University of Illinois / Chicago worsening, prompt specific management changes,
(SSEP) and brainstem auditory evoked forehead and neck. 75 normal hearing these vital BAEP measurements monitor response to therapy…(and) …used as surrogate
potentials (BAEP) also known as the human volunteers established appropriate (Stone et al 2017). He draws parallels Collaborators endpoints in clinical trials.” (Wijdicks EFM, Rabinstein
auditory brainstem response (ABR). In mBAEP testing modalities for study. with neurosurgical operating theatres • John Fino AA. Critical care neurology: Five new things. Neurol
simple terms, the test for BAEP involves Next, about 150 patients with cerebral where such monitoring already exists, • Kevin Kriegel Pract 2011;1:34-40). Additionally, such monitoring would
augment our present treatments and be utilised in patients
presenting patients with a sound, typically brain lesions were studied in order to implemented to alert staff when certain
not ordinarily considered for invasive ICP monitoring –
a ‘click’, at various loudness levels and test reliability of the mBAEP. A number critical thresholds are reached. Such a Disclosure such as somnolent patients with moderate head injuries,
monitoring the neural response from the of patients had concurrent measured system would achieve efficient, user- Dr Stone has Intellectual Property and a Corporation - stroke, and other brain lesions. (Stone JL, et al. Brainstem
midbrain portion of the vital brainstem. ICP values. The standard BAEP at two friendly monitoring of brain-trauma Remote Vital Monitoring, Inc. Both are in conjunction with Monitoring in the Neurocriticalcare Unit: A Rationale for
and other patients that is cost-efficient his earlier work at the University of Illinois at Chicago (UIC), Real-Time, Automated Neurophysiological Monitoring.
Neurocritical Care 2017:26;143-156.)
Recovery from brain trauma is a time
and staff-friendly with great potential IL, USA.
to enhance both patient survival and
game, where minutes really do matter. outcome quality. His goal is partnership
with industry to build a prototype of
Dr Stone is acting on behalf of UIC and the Corporation,
not NYU Langone or Veterans Hospital.
Diagnosis within the first three hours Coma AlertTM and begin implementation
and studies in New York City where
can drastically improve patient outcome. he presently resides.
Health & Medicine ︱ Professor Dawn Langdon
BICAMS:
Shedding light on cognition in Multiple Sclerosis
M
Multiple Sclerosis (MS) is a ultiple Sclerosis (MS)1 affects or worse symptoms 4, which generally affect daily tasks
disease that attacks the central more than 100, 000 people improve before another relapse occurs. such as keeping up
nervous system, leading to in the UK and millions This is called relapsing-remitting MS 5. with conversations or
a variety of symptoms, across more worldwide. It usually affects Most relapsing-remitting patients enter managing household bills
the physical and psychological people between the ages of 20 and the secondary progressive phase 5 sooner and can influence an individual’s
domains. For many people 50 years, and the average age of or later, when disability accumulates over ability to work 9.
with MS, symptoms can include onset is approximately 34 years. MS time. Patients with primary progressive
difficulties with memory and is a neurological autoimmune condition, MS 5 do not have remission or relapse An international team of experts
thinking, which impacts on the in which the body’s immune system cycles; instead their symptoms gradually led by Professor Dawn Langdon
quality of many aspects of their attacks its own nerve cells 2. worsen over time from the outset. of Royal Holloway University of BICAMS has been
life. Dawn Langdon, Professor London are paving the way to better developed to provide non-specialists
of Neuropsychology at Royal MS attacks the myelin sheaths 3 that Some medications are available that understanding of cognitive issues in with the ability to assess the cognitive
Holloway, University of London, surround brain and spinal cord cells. reduce relapses and slow disability MS. They have developed the Brief functioning of their MS patients, allowing
has led an international Myelin – a fatty substance that covers progression 6. Researchers are working International Cognitive Assessment for many more centres to address cognition.
project to develop BICAMS, neurons – speeds up the transmission of to identify treatments that will halt MS (BICAMS) 10, a short, much-needed The availability of a brief, easy-to-use and
an innovative battery of tests electrical signals between cells allowing the disease. tool aimed at helping clinicians and standardised internationally recognised
to revitalise our understanding
for efficient brain function. It is essential researchers quickly and effectively testing battery have also made it more
of cognition in MS, with the aim
for normal motor, or movement, control INVISIBLE SYMPTOMS understand the cognitive difficulties that likely that pharmaceutical trials are
that this aspect of the condition
and for other functions, including thinking MS is most known for its effects on affect more than half of patients. including assessments of cognition as and validity. Reliability refers to the test’s
will be better understood
and planning. In MS, the myelin sheath motor control, leading some people part of their outcome measurements, robustness over repeated testing and
and managed.
coating the nerves is damaged, leading to use wheelchairs eventually as the DEVELOPING BICAMS meaning that cognitive impairment could between raters, whereas validity refers
to ineffective signalling between brain disease progresses. However, due to Assessing cognitive to the ability of the
cells, and eventually cell death. its widespread impact on the central
nervous system, there are a constellation
impairment
traditionally
Cognitive problems – issues with test to assess what
it is intended to. A
Cognitive difficulties The majority of patients start of other symptoms linked to the requires a lengthy memory, thinking and attention thorough evaluation
skills – are common in MS, affecting

can have a major impact experiencing relapsing remitting condition and a high range of variability neuropsychological of BICAMS revealed
on employment for people
episodes, meaning that the between patients. Some of the lesser testing – tests that it fulfilled all
approximately half of patients living
with MS.
symptoms of the condition recognised effects of MS – sometimes that reveal how these markers of solid
with the condition.

come in waves of new referred to as the ‘invisible symptoms’ – brain function neuropsychological
can have a profound impact on quality and aspects testing, making
of life. The invisible symptoms include of cognition it a good measure.
fatigue, depression and pain. MS can also have been affected by disease or be better treated or managed in future12. Importantly, the battery has also been
impact cognition. trauma, such as a stroke or accident. Cognitive impairment can be taken into shown to be repeatable without marked
Neuropsychological testing is consideration when potential drugs in learning effects, where participants
Cognitive problems 7 – issues with conventionally carried out by trained the pharmaceutical pipeline are being do better on tests purely because they
memory, thinking and attention psychologists using in-depth and assessed. Importantly, taking only 15 have done them previously.
skills – are common in MS, affecting lengthy pen and paper assessments. minutes to complete and requiring only
approximately half of patients living with Whilst this approach is comprehensive, pen and paper, BICAMS allows cognition The BICAMS development process
the condition. Problems with thinking in it is also restrictive, limiting its use to to be tested inexpensively, maximising has had an international outlook13
MS are sometimes known as ‘cog fog’ 8 specialist neuropsychologists, who its potential use across centres from the outset, ensuring that the tests
as patients describe being unable to think are trained to use such assessments and across countries. would be available to as many people
as clearly as they had done previously. in scarce, well-resourced centres. As as possible. This validation process has
Cognitive impairment typically worsens such, many people with MS who have PRINCIPLES OF been carried out in eleven languages
as the disease progresses. As cognitive cognitive impairment receive few valid NEUROPSYCHOLOGICAL TESTING and in 16 different locations and cultures,
issues are not well known in MS, family tests of their cognitive function, meaning In order to be an effective again maximising its use across the world,
and friends can find them hard to that their difficulties go misunderstood neuropsychological test, assessments which is key for its usefulness in clinical
recognise and understand. Impairments or even neglected, resulting in must be shown to fulfil key criteria that trials, which are increasingly carried
in memory and concentration can mismanagement 11. measure robustness, including reliability out in multiple sites worldwide.
QA &
Professor Dawn Langdon is Co-Chair of the BICAMS initiative Myself and my Co-Chair, Professor
and has led on the development of the iPad version of the cognitive Ralph Benedict did our homework
assessment. She is passionate about raising awareness of the and worked to obtain a consensus.
cognitive impact of MS and using international collaboration to We published two consensus papers.
create meaningful progress. We spoke to her about her motivations, In fact, from there the international
the success of the BICAMS initiative and the reach she hopes it will MS community pretty much adopted
have globally. BICAMS and set out to validate it
in a proactive and committed way.
I did the usual academic things, writing
What inspired your it hard to follow fast speech or pick papers and speaking at scientific
work in this area? up information against a distracting conferences, but colleagues picked
I was working in a clinical job at background. Memory is also often up the BICAMS torch and ran with it.
the National Hospital for Neurology affected. However, everyday language I was always ready to accept invitations
and Neurosurgery in London, on functions are often pretty much OK. to speak about BICAMS and do
BICAMS is now available for many people with MS around
the world. Produced for triMS.online 2018 and reproduced a rehabilitation unit where half of This means in casual conversations, training sessions, but these were small
with permission from Oxford Health Policy Forum; for further the people had multiple sclerosis nothing seems wrong. Because MS contributions. I think that first, cognition
information contact: Info@trimsonlineconference.com.
(MS). It was very clear that many of cognitive difficulties are not on the was acknowledged to be an under
them were struggling with cognitive surface, they tend to get overlooked. recognised and poorly managed
aspect of MS, which made life difficult
BICAMS is a short, much-needed tool of the brain, assessed by functional MRI
studies. Whilst it is not known how this
I have tried to foster a sense of being in for people with MS and their families.
Secondly, committed health care
aimed at helping clinicians and researchers change impacts on the quality of life the BICAMS family. I think a shared purpose workers realised that a brief, feasible
quickly and effectively understand of patients, it is a positive indication

that some aspects of cognition can and understanding across nationalities
and psychometrically sound cognitive
measure would be very useful in their
the cognitive difficulties that affect be rescued with the right management.
creates bonds, trust and energy. practice. Unexpectedly, BICAMS has
more than half of patients. FUTURE STEPS

been utilised in many scientific papers
about MS cognition, which was not part
Already the BICAMS has made great difficulties, but this aspect of the Friends, families and workmates explain of our original planning and goals.
COMPONENTS OF BICAMS FINDINGS USING BICAMS inroads into understanding the cognitive disease was not recognised or well reduced participation and struggling
In deciding which items should be Since the BICAMS was introduced impairment that so affects the lives of managed by their families, friends, at work as the impact of physical
included in BICAMS, Professor Langdon it has been cited in a number of peer- those living with MS. It has recently or even health professionals outside restrictions, but cognitive glitches
and her team selected tests that would reviewed publications, going some way been adopted and recommended by of specialist centres. I wanted to try may also be to blame.
tap into the cognitive areas – or domains to filling the knowledge gap surrounding the American Academy of Neurology, to understand these difficulties better
– already known to be affected in some cognition in MS. A recent meta-analysis14 further cementing its place as the go-to and improve health care services. How do you get
people with MS. The tests included by Professor Langdon has shown testing battery for this condition. An an international
in BICAMS focus on how quickly people that BICAMS testing has highlighted iPad version of the BICAMS is currently Why do you think the community working
can process information, their ability significantly reduced cognitive undergoing validation studies and, cognitive impact of together in such
to remember a verbal word list and functioning compared to people living if successful, is only set to increase MS has been almost a successful
their memory of abstract shapes shortly without MS across all of the domains the amount it is used. Computerised overlooked in the past in manner?
after they have seen them. The battery tested, namely, information processing testing reduces raters’ variability, favour of physical symptoms? I convened an
utilises the most relevant components speed, immediate recall memory making the measurement even more Partly I think it is because physical international committee
of existing tests, including sections of and immediate visual recall memory, precise, and facilitates data collection to symptoms are immediately apparent of 12 neurologists and
the California Verbal Learning Test-II, the in 14 countries. databases on servers. Feasible, effective to other people, for example using neuropsychologists,
Brief Visuospatial Memory Test-Revised and inexpensive means of assessing a walking stick or wheelchair. Also, who were all experts
and the Symbol Digits Modalities Test. Excitingly, the BICAMS has also been cognition are absolutely crucial to patient cognitive difficulties can be hard to on MS cognition and
used in intervention studies, including management, disease monitoring and admit to and to talk about. The pattern represented all of the
one that demonstrated that six weeks of assessing the effects of interventions. of cognitive difficulties in multiple major language groups,
cognitive rehabilitation15 taking The development of BICAMS has sclerosis is not clear in conversation and countries on both
place on a computer at home started a small but powerful revolution in or even clinic consultations. This is sides of the Atlantic.
can lead to improvements on bringing cognition to the forefront of MS because information processing speed
some, but not all, aspects of management, shedding light on its effect is often the most affected ability, which
cognition. The improvements on quality of life. People living with MS can be thought of as band width. It BICAMS is a truly international initiative
with input from researchers across the
were mirrored by a change in are only set to benefit from its increasing is a bit like your own personal internet globe and from all major
the activation of some areas uptake by both clinicians and researchers. slowing and freezing. This can make language groups.
32 www.researchoutreach.org
What advice would you give
others about to embark
on a similar project i.e.
This range of funders means that
BICAMS doesn’t belong to a single Behind the Research
one that brings together
organisation or entity. It is truly owned
an international community?
I think a broadly based, expert by the international MS community,
Professor Dawn Langdon
consensus group to back and author
the project is essential. Encouraging which is an enormous benefit. E: d.langdon@rhul.ac.uk T: 01784 443956 W: www.BICAMS.net
engagement and offering support
to centres as and how they need it is studies across the world using BICAMS using BICAMS for routine clinical
essential, so everyone can be involved have been funded by national pharma, assessment. So far we know about Research Objectives
at the level, and as independently, as neurology associations, national MS 10,000 patients a year are being
they choose to be. Although everyone charities, or sometimes by colleagues routinely assessed on BICAMS. We The Brief International Cognitive Assessment for MS (BICAMS), is a short, much-needed tool
involved is a serious scientist and/or who had a master’s student who want to support and extend BICAMS’ to assess cognitive function for people with Multiple Sclerosis.
clinician, I have tried to foster a sense needed a project. Novartis have kindly use for routine clinical assessment. The
of being in the BICAMS family. I think
a shared purpose and understanding
funded a UK first implementer study.
Several international pharma are using
AAN endorsement helps and we are
involved in other groups producing
Detail
across nationalities creates bonds, BICAMS in major international drug guidelines for MS clinical assessment.
trust and energy. trials. This range of funders means that We are validating an iPAD BICAMS Professor Dawn Langdon Funding •P
rof Fred Foley, Yeshiva University,
BICAMS doesn’t belong to a single which we hope will make BICAMS Royal Holloway DL has participated in speaker bureau for Ferkauf Graduate School of Psychology,
BICAMS has received funding organisation or entity. It is truly owned even more feasible. Our vision is that University of London Bayer, Merck, Almirall, Execemed, TEVA, and Albert Einstein College of Medicine
from multiple sources. by the international MS community, every MS patient in the world will have Egham Surrey TW20 0EX Roche, Novartis, Biogen, Sanofi; has had in Bronx, New York.
Does this bring any unique which is an enormous benefit. access to routine cognitive assessment. UK consultancy from Novartis, Bayer, Merck, •P
rof Sten Fredrikson, Karolinska
challenges and/or benefits? There is a very widely used measure Biogen, TEVA, Sanofi; has had research Institute, Stockholm, Sweden
I am very proud of the “patchwork” What are the next stages of mainly physical disability in MS, the Bio grants from Bayer, Merck, Novartis, •D
r Paivi Hamalainen, Masku
model of funding that BICAMS has for rolling out BICAMS Expanded Disability Status Scale, or Having trained at St Hilda’s College, Biogen. All are paid into DL’s institution. Neurological Rehabilitation Centre,
created. We were very lucky to have worldwide? What are your EDSS. It would be wonderful if BICAMS Oxford and King’s College London, Dawn Finland
funding for our committee’s work hopes for this tool? could become the cognitive EDSS. Langdon worked at Queen Square for Collaborators •P
rof Hans-Peter Hartung, Heinrich-
and meetings from Bayer at the outset. We are currently working to identify Already there are studies that compare 16 years as a clinical neuropsychologist, •P
rof Ralph Benedict, Co-chair BICAMS, Heine-Universität Düsseldorf, Germany
Subsequently, validation and scientific clinics around the world who are and combine the two measures, so this obtaining a PhD from the Institute of University of Buffalo, New York, USA •P
rof Lauren Krupp, Stony Brook
may not be a far-fetched idea. Neurology, London. She is now Professor BICAMS committee: University Medical Center, New York,
of Neuropsychology at Royal Holloway, •P
rof Maria Pia Amato, University USA
This tool could make University of London, FBPS and BICAMS of Florence, Italy •P
rof Iris-Katharina Penner, University
a difference for people Co-Chair. She is a Trustee of the UK •D
r Jan Boringa, Meander Medisch of Dusseldorf, Germany
with MS around the MS Trust. Centrum, Amersfoort, Netherlands •D
r Anthony Reder, University of
world. How does it feel to •P
rof Bruno Brochet, Université Chicago Medical School, Illinois, USA.
be involved in work with Bordeaux-Segalen, France
such widespread impact?
I feel very humble as Co-Chair
of BICAMS as I work alongside References Personal Response
so many expert clinical researchers
putting their time and effort into Langdon DW, Amato MP, Boringa J, Brochet B, How could findings from BICAMS influence how
successfully developing the BICAMS Foley F, Fredrikson S, Hämäläinen P, Hartung HP, clinicians manage the care of people living with MS?
story, and also seeing the data Krupp L, Penner IK, Reder AT, Benedict RH (2012)
Cognitive assessment offers a range of benefits. It is
coming in from so many Recommendations for a Brief International Cognitive known that cognitive status at diagnosis predicts how fast
thousands of people with Assessment for Multiple Sclerosis. Multiple Sclerosis, the disease will progress and so clinics can monitor patients
MS who have consented 18(6), 891-8. more closely. Positive lifestyle choices and regular mentally
to participate in these studies. stretching activities can protect against cognitive decline
It is all about teamwork Benedict RH, Amato MP, Boringa J, Brochet B, Foley and cognitive assessment can form the basis of coaching
and each study has only F, Fredrikson S, Hamalainen P, Hartung H, Krupp L, people with MS to adopt these helpful behaviours. People
succeeded because of the Penner I, Reder AT, Langdon D (2012) Brief International with MS who have cognitive impairment are less likely
to manage their disease well, including medication, and
commitment and partnership Cognitive Assessment for MS (BICAMS): international
once alerted to cognitive impairment, clinics can present
of health professionals and standards for validation. BMC Neurology, 16, 12:55. information in a way that is easy to assimilate and monitor
people with MS. I am very disease management. Cognitive impairment makes
proud that the international Campbell J, Langdon D, Cercignani M, Rashid problems at work and unemployment more likely and
MS community has come together W. A Randomised Controlled Trial of Efficacy of clinics can refer for appropriate help. Cognitive impairment
in such an effective and influential Cognitive Rehabilitation in Multiple Sclerosis: A increases risks of falling and driving accidents,
way, to address and manage Cognitive, Behavioural, and MRI Study. Neural Plast. and clinics can act to reduce these risks.
the cognitive aspects of MS. 2016;2016:4292585.
Health and Medicine ︱ Dr Pauline Emmett and Dr Caroline Taylor HOW DOES EARLY CHOOSINESS RELATE TO LATER PICKY EATING?
Factors associated with

NOT
CHOOSY
CHOOSY
4040/56%
3130/44%
AT 15 MONTHS
young children exhibiting GREATLY

WORRIED
A BIT
WORRIED
NOT
WORRIED
picky eating behaviour

202/5% 1097/27% 2741/68%
NOT NOT NOT NOT

PICKY PICKY PICKY PICKY
34/17% 230/21% 979/36% 1912/61%
PICKY PICKY PICKY PICKY
100/50% 333/30% 463/17% 211/7%
P
Picky eating in preschool icky eating is usually classified as well as study-specific questions.
children is a well-documented as part of a spectrum of feeding In addition, a variety of prevalence rates
SOMEWHAT SOMEWHAT SOMEWHAT SOMEWHAT
phase when children are difficulties observed in children. were found of picky eating, spanning from PICKY PICKY PICKY PICKY
reluctant to try new foods and/ Strong food preferences and suspicion 6% to 50%. One of the few sources of 68/34% 534/49% 1299/47% 1007/32%
or show very strong preferences of new foods in childhood may have longitudinal data, where participants are
for particular foods. This had evolutionary benefits by reducing followed for an extended period of time,
AT 38 MONTHS
behaviour can create concern the risk of consuming toxins. However, is the Avon Longitudinal Study of Parents
for parents, and this has created in the modern world, these behaviours and Children (ALSPAC). The prevalence eating can be reduced by providing foods The figure shows the relationship between early choosiness, maternal worry about that choosiness
and later picky eating behaviour.
a whole market for advice and can provide a barrier to the acceptance of children being very picky eaters (based that help the child to learn to chew from
guidance, not all of which is
evidence-based. Dr Pauline
of certain food items. This often causes
concern amongst parents about nutrient
on a question about definite likes and
dislikes) in ALSPAC varied with age from
6 months or earlier, supporting mothers
through the second year of life when
A strong predictor of preschool-age picky
Emmett and Dr Caroline Taylor, intake and the risk of poor future health 10% to 15%, with the peak prevalence children have a natural tendency to be eating was the child being choosy with
food at 15 months, particularly if the
from the Centre for Academic outcomes. Determining whether this at 38 months. wary of new foods, providing fresh fruit
Child Health at the University behaviour is problematic is an important for the child, the mother often eating the
of Bristol, explore factors
associated with picky eating to
public health issue. PREDICTORS ASSOCIATED same meal as the child and feeding the mother was worried about this behaviour.
WITH PICKY EATING child home-prepared fresh foods. They
determine whether this should
DEFINING AND Researchers have also investigated also emphasise that parents should be (after 9 months). If mothers fed their child found consistent evidence that children
be a source of worry for parents.
MEASURING PICKY EATING factors which can predict picky eating reassured that picky eating is normal and vegetables regularly by age 6 months, who are picky eaters consumed fewer
There is no single widely accepted in children. ALSPAC data was used to continue to provide a variety of foods. this was associated with a lower risk fruits and vegetables than non-picky
definition of picky eating, and therefore to measure picky eating at age 3 years of being worried about choosy behaviour eaters, which contributed to a lower fibre
there is little consensus on how and then explore potential antecedents FACTORS ASSOCIATED in their children. Researchers suggest that intake. Picky eaters were also more likely
to measure it, resulting in a huge variety of of this behaviour. It was found that WITH MATERNAL WORRY providing support and advice to parents to have hard stools than non-picky eaters,
prevalence estimates. Dr Pauline Emmett feeding difficulties during complementary Factors associated with maternal worry when they begin complementary feeding which was explained by the difference
and Dr Caroline Taylor and their team feeding and the late introduction of were explored by Emmett and Taylor could help to alleviate worries about in fibre consumption. Researchers suggest
investigated the range of methods used to lumpy foods (after 9 months) were both because maternal worry was associated eating behaviour. that boosting fibre intake can be achieved
assess picky eating as well as the different associated with an increased likelihood with higher levels of picky eating through a number of different strategies.
sources of data used to determine of the child being a picky eater. A strong behaviour in children. Researchers used DIETARY FIBRE INTAKE These include encouraging parents
prevalence. Researchers reviewed the predictor was the child being choosy ALSPAC data again to measure levels Picky eating has been suggested to repeatedly offer their children small
literature on picky eating between 1990 at 15 months, particularly if the mother of worry amongst parents about choosy to be associated with an increased risk amounts of fruit and vegetables to
and 2015 and found that most studies on was worried about this behaviour. At 15 behaviour in their children at 15 months of constipation, as a result of a lower fibre overcome neophobia (fear of trying
picky eating were cross-sectional, which months, the majority (56%) of children of age. They also investigated feeding intake. Emmett and Taylor used ALSPAC new foods), to provide an example for
means that they only look at behaviours were considered to be choosy with food. behaviours and practices throughout data to determine dietary fibre intake at children by eating fruits and vegetables
and associated factors at one point in Of these children, 17% became very the first 15 months to determine 38 months and then to see whether this themselves and to adopt regular family
time. Such methods, therefore, do not picky at age 3 years if the mother was not predictors of this worry. was predictive of stool hardness at 42 mealtimes with the same meal being
allow for exploring the prevalence of worried, in contrast to 50% if the mother months. Picky eating at both these time offered but not forced onto children.
picky eating over time or the potential was greatly worried about the choosy It was found that half of the children points was also investigated. Researchers
health-related outcomes of the behaviour. behaviour. Feeding ready-prepared (56%) were described as choosy at 15
food was also a predictive factor for later months. Amongst these children, 27%
Emmett and Taylor found a wide picky eating. Protective factors against had mothers who were a bit worried % FIBRE FROM
range of tools used to assess picky eating were the mother providing and 5% greatly worried. Mothers were VEGETABLES (95% CI)
picky eating, including the fresh fruit and eating the same meal more likely to be worried if their child Picky eaters 8.9 (8.2, 9.7)
Children’s Eating Behaviour as her child. was first born and/or difficult to feed
Non-picky eaters 15.7 (15.5, 15.9) p<0.001
Questionnaire and or refused solids by 6 months of age.
the Child Feeding In light of these results, Emmett and Worried mothers were more likely Picky eaters obtain a smaller proportion of fibre from vegetables than non-picky eaters.
Questionnaire Taylor suggest that the likelihood of picky to have introduced lumpy foods late
Young children are often choosy
about food and this is a natural
part of their development.
‘Eat your greens’ – some vegetables
have flavours that are difficult for children
to learn to like. For tips on feeding
vegetables see www.habeat.eu.
Behind the Research
Dr Pauline Emmett Dr Caroline Taylor
E: p.m.emmett@bristol.ac.uk T: 44 (0)117 42 83096 W: www.bristol.ac.uk/social-community-medicine/people/pauline-m-emmett/
index.html W: https://research-information.bristol.ac.uk/en/persons/pauline-m-emmett(2e26d735-4184-4522-8163-7a986a7960eb).
html W: https://www.habeat.eu/page0e89.html?a=parents W: www.bristol.ac.uk/alspac
E: caroline.m.taylor@bristol.ac.uk T: 44 (0)117 42 83099 W: www.bristol.ac.uk/social-community-medicine/people/person/
caroline-m-taylor/overview.html @caroline1taylor
Research Objectives
Dr Pauline Emmett and Dr Caroline Taylor from the Centre for Academic Child Health, Bristol Medical School, University of Bristol
use data from the Avon Longitudinal Study of Parents and Children (ALSPAC), which is a long-term research project that enrolled
more than 14,000 pregnant women in 1991 and 1992. It has followed the resulting offspring and their parents since recruitment
using questionnaires and clinic visits. The research seeks to investigate factors associated with picky eating to determine whether
the behaviour should be a source of concern for parents. These factors include fibre intake, macro- and micronutrient intakes, as well
as child growth and body composition.
Detail References
MACRO- AND
MICRONUTRIENT INTAKES
Protective factors against picky eating Centre for Academic Child Health
Population Health Sciences
Taylor, C. M., Wernimont, S. M., Northstone, K., & Emmett, P.
M. (2015). ‘Picky/fussy eating in children: Review of definitions,
Macro- and micronutrient intakes are were the mother providing fresh fruit Bristol Medical School assessment, prevalence and dietary intakes’. Appetite, 95,
349-359.
another source of concern with picky University of Bristol
eating. Emmett and Taylor used ALSPAC and eating the same meal as her child. 1-5 Whiteladies Road Taylor, C. M., Northstone, K., Wernimont, S. M., & Emmett, P.
M. (2016). ‘Macro- and micronutrient intakes in picky eaters:
data to measure both picky eating and Clifton
a cause for concern?’. American Journal of Clinical Nutrition,
nutrient intakes when children were aged than non-picky eaters at age 7 years. Picky eaters were more likely to be slightly Bristol BS8 1NU, UK
104(6), 1647-1656.
3 and 7 years. It was found that picky Researchers suggest that alleviating smaller and lighter than non-picky eaters
Taylor, C. M., Northstone, K., Wernimont, S. M., & Emmett,
eaters at age 3 years had lower mean parental concerns about picky eaters but there were no significant differences Bios
P. M. (2016). ‘Picky eating in preschool children: Associations
carotene, iron, and zinc intakes than non- having inadequate nutrient intakes should between groups in terms of body fat. Dr Pauline Emmett: Senior Research Fellow (semi-retired), with dietary fibre intakes and stool hardness’. Appetite, 100,
picky eaters. This was also found at age be a key focus, along with encouraging The mean heights, weights and BMIs Centre for Academic Child Health, Bristol Medical School, 263-271.
7 years. Iron and zinc were the nutrients parents to include more nutrient-rich of picky eaters were consistently above University of Bristol. Experienced research Nutritionist
Emmett, P., Hays, N., & Taylor, C. (2018). ‘Factors associated
most likely to have intakes in picky eaters foods and fewer nutrient-poor foods the 50th centiles of reference growth charts and Dietician. Oversaw Nutrition Research for the Avon with maternal worry about her young child exhibiting choosy
below recommended amounts, with in their children’s diets. which indicates that the majority were Longitudinal Study of Parents and Children (ALSPAC) for 15 feeding behaviour’. International Journal of Environmental
free sugars intake much higher than growing normally. More than two-thirds years. Interested in nutrition in pregnancy and childhood Research and Public Health, 15(6), 1236.
recommended for optimal health. There GROWTH AND BODY COMPOSITION of picky eaters were not thin at any age particularly early growth and development of children. Emmett, P. M., Hays, N. P., & Taylor, C. M. (2018).
were no significant differences in energy IN PICKY EATERS point. However, almost one-fifth of the ‘Antecedents of picky eating behaviour in young children’.
intakes between the groups, and intakes A further worry with picky eaters is very picky eaters were thin at three or Dr Caroline Taylor: Research Fellow, Centre for Appetite, 130, 163-173.
were adequate for children’s estimated the potential risk of being underweight more age points compared with less than Academic Child Health, Bristol Medical School, University Taylor, C. M., Steer, C. D., Hays, N. P., & Emmett, P. M. (2018).
average requirements for energy. or overweight. Emmett and Taylor one-tenth of non-picky eaters. There was of Bristol. Caroline’s research interests are in nutrition ‘Growth and body composition in children who are picky
investigated whether picky eaters were no evidence of an increased likelihood of in pregnancy and childhood, particularly in how diet eaters: a longitudinal view’. European Journal of Clinical
The differences in nutrient intakes were different in terms of height, weight being overweight or obese in either the and the environment in pregnancy affect the growth Nutrition, doi: 10.1038/s41430-018-0250-71.
explained by lower intakes of meat, fish, and body composition from non-picky very picky or somewhat picky children. and development of the child.
vegetables and fruits in picky eaters than eaters using ALSPAC data. Children were Personal Response
non-picky eaters. Picky eaters also had measured on seven occasions between CONCLUSIONS Funding
higher intakes of sugary foods and drinks the ages of 7 and 17 years. Overall, findings from research by • The UK Medical Research Council and the Wellcome Are there other questions about picky eating that you
Emmett and Taylor suggest that picky Trust (Grant ref: 102215/2/13/2) and the University of both plan to investigate using the ALSPAC data?
eating in children is a normal part of Bristol provide core support for ALSPAC. The research We would be very interested to investigate long-term
Usually hard stool, without fibre Usually hard stool, with fibre
growing up and parents need not be on picky eating is funded by Nestlé Nutrition. picky eaters, that is children who are picky eaters over
adjustment (OR (95% CI)) adjustment (OR (95% CI))
overly concerned about this behaviour. • Dr Caroline Taylor is funded by a Wellcome Career many years, to assess if this has a greater effect on the diet
Not a picky 1.00 (ref) 1.00 (ref) However, there are a number of strategies Re-Entry Fellowship (Grant ref: 104077/Z/14/Z). and health than short-term picky eating. It would also be
that parents can employ to reduce valuable to find out whether the differences we found in
Picky eater 1.31 (1.07, 1.61) 0.65 (0.32, 1.35) dietary intakes between picky and non-picky children at
the risk of picky eating. These include
p=0.010 p=0.248 ages 3 and 7 years persist into the teenage years. Some
encouraging children to eat a varied
children who are picky at young ages are not picky at later
diet, including fresh fruit and vegetables, ages and it would be helpful to determine factors that
Multinomial models confirm that picky eaters are more likely to have hard stools than non-picky eaters as well as setting an example by eating predict this change, and which might provide an evidence-
and that this is mediated by fibre intake. a varied diet with their children. base for advice.
Health & Medicine ︱ Dr Stephen Bartelmez
Could stem cells

Diabetic Retinopathy
Superior Rectus Aneurysm
Muscle Abnormal Blood Hemorrhages
offer a viable treatment

Vessels
Sclera
Lens Retina
for retinopathy?
Fovea “Cotton Wool”
Spots
Optic Disc
Pupil
Cornea
Optic nerve
Ciliary body
T
Central Retinal
Diabetes is a growing global he macula is a part of the retina, In healthy people, blood vessels are Vein and Artery
Inferior Rectus
epidemic, with over 400 million located at the back of the eye. constantly regenerated by cells derived Muscle
affected and cases expected Although very small (about 5mm from circulating CD34+ stem cells.
in diameter), it is responsible for most These stem cells are generated in the Healthy Eye Diabetic Eye
to double in the next 10 years.
Retinopathy, or damage to aspects of our vision, including colour bone marrow and released into the The difference between a healthy eye and the eye of a diabetic patient suffering from retinopathy. The damage to the retina eventually causes loss of vision.
the blood vessels in the retina, vision and the fine detail of what we see. bloodstream and express the protein
occurs in most patients with Diabetic macular oedema is a swelling CD34+ on their surface. They divide
type 1 diabetes and 75 per cent
of patients with type 2 diabetes,
of the retina as a result of fluid leakage
from damaged blood vessels within
and mature into all nine types of blood
cells plus give rise to another cell type,
STEM CELLS AND TRANSFORMING
GROWTH FACTOR BETA 1
The team found that TGF-β1 regulates
leading to vision loss for many.
BetaStem Therapeutics is a stem
the macula caused by the diabetes. In
addition, macular ischemia (inadequate
endothelial cells, the building blocks
of all blood vessels. The stem cells and
All blood cells are derived from
haematopoietic stem cells in a process
mouse and human blood stem cells in the
cell therapy company led by Dr
Stephen Bartelmez. Their aim
blood supply) can eventually result in endothelial cells migrate to lesions known as haematopoiesis. This takes lab and in the body in a number of ways.
diabetic retinopathy (DR), or damage on blood vessels and facilitate repair. place in the bone marrow, and in a healthy
is to treat diabetic retinopathy to the blood vessels at the back of However, during the course of diabetes, adult, approximately 50 to 70 billion new the stem cells from making a targeted taken up by endosomes on the surface
by using the body’s own stem the eyes. DR is one of the leading causes the patient’s CD34+ stem cells become blood cells of nine different types are protein. The scientists studied different of the stem cells. The temperature of the
cells to repair the damage to of blindness in adults, and currently there dysfunctional: they can no longer give produced each day. To generate all these techniques to deliver PMO into cells incubation as well as the concentration
retinal blood vessels caused
is no effective treatment to repair cells rise to endothelial cells or regulate repair cells requires a complex series of events which included syringe loading, micro of the PMO was found to be important.
by diabetes.
and blood vessels damaged as a result of damaged blood vessels, both in involving many positive and negative injection, and by combining the PMO
of the disease. the retina, and in the rest of the body. signals from the surrounding tissue as well with fat molecules containing a positive This technique actually transiently inhibits
as within the stem cells themselves. charge, known as cationic lipids. the TGF-β1 in the CD34+ stem cells.
However, the best method for uptake of It acts as a switch to first inhibit the TGF-β1
Retinopathy can cause vision loss and even blindness. Transforming Growth Factor beta 1 TGF-β1-PMO into stem cells was found then the stem cell reacts to this inhibition
(TGF-β1) is a small protein secreted to be unassisted entry. Thus CD43+ by upregulating the TGF-β1 gene mRNA
by many cells in the body. Classified stem cells were incubated with the -TGF-β1. Next, the PMO is effluxed from
as a cytokine (a type of small protein PMOs overnight at 37 degrees Celsius the stem cell causing a burst of TGF-β1
important in cell signalling in blood during which time the TGF-β1-PMO was protein production.
and immune cells), Dr Bartelmez and
colleagues found that TGF-β1 is a major
regulator of haematopoiesis. TGF-β1 finely
inhibits cellular divisions at major cellular
checkpoints. Their work has helped
elucidate the key roles of TGF-β1 in stem
cells in human blood and bone marrow.
TGF-β1 CONTROLS ALL STAGES

OF HAEMATOPOIESIS
Using blood samples taken from mice
as well as humans, the scientists were
able to separate CD34+ stem cells
from other blood cells present and
grow them in the lab. Next, by treating
the cells ex vivo with an antisense
phosphorodiamidate morpholino
oligomer (PMO) the scientists could
inhibit TGF-β1 for a short period of time
in the stem cells. A PMO is a small DNA
analogue which temporarily blocks Stem cells in the process of dividing.
The protein was found to have many
functions. These include the ability
to: stimulate or prevent cells from
Image of a retina showing
signs of diabetic retinopathy.
Behind the Research
dividing; promote cells to self-destruct
or differentiate (change to another
Dr Stephen Bartelmez
cell type); or prevent these molecular
pathways from occurring. One key E: sbartelmez@betastemtherapy.com T: +1-206-427-0350
finding was that transient TGF-β1
inhibition induces a balance between
CD34+ cell growth, division, maturation,
and periods of cell inactivity.
In humans, Dr Bartelmez identified three Sitnicka E, Ruscetti FW, Priestley GV, Wolf NS, Bartelmez
BetaStem Therapeutics aims to treat diabetic retinopathy
markers of enhanced stem cell activity using a patient’s own stem cells. SH. (1996) Transforming growth factor beta 1 directly and
that increase after PMO treatment of reversibly inhibits the initial cell divisions of long-term
repopulating hematopoietic stem cells. Blood. Jul 1;88(1):82-
stem cells: 1) increased levels of CXCR4,
a protein necessary for stem cell homing
Detail 8. PubMed PMID: 8704205. b.
and adhesion; 2) increased Nitric oxide Dr Stephen Bartelmez Ruscetti FW, Bartelmez SH. (2001) Transforming growth
production, which is required for cell TGF-β1 helps to maintain the balance 2 Lower Crescent Ave Suite 2 factor beta, pleiotropic regulator of hematopoietic stem cells:
potential physiological and clinical relevance. Int J Hematol.
mobility; and 3) increased ability of CD34+
cells to migrate and repair vascular lesions.
between CD34+ cell growth, division, Sausalito
CA 94965
2001 Jul;74(1):18-25. PubMed PMID: 11530800 c.
maturation, and periods of cell inactivity. USA Ruscetti FW, Akel S, Bartelmez SH. (2005) Autocrine
transforming growth factor-beta regulation of hematopoiesis:
The group also studied how long-term
many outcomes that depend on the context. Oncogene. 2005
CD34+ haematopoietic stem cells were DIABETIC RETINOPATHY: vessels in the retina. The use of PMO Bio Aug 29;24(37):5751-63. PubMed PMID: 16123808. d.
able to regenerate and repopulate the MOVING TOWARDS A CURE is a feasible approach due to its ability Stephen Bartelmez, PhD, is the founder of BetaStem
Bhatwadekar AD, Guerin EP, Jarajapu YP, Caballero S,
bone marrow in mice after inhibition The goal of BetaStem Therapeutics is to to enter haematopoietic stem cells and Therapeutics. He completed his immunology training at UC Sheridan C, Kent D, Kennedy L, Lansang MC, Ruscetti FW,
of TGF-β1. They found that after lethal use the diabetic patient’s own CD34+ transiently inhibit TGF-β1 signalling. Berkeley & University of Glasgow and his stem cell training Pepine CJ, Higgins PJ, Bartelmez SH, Grant MB (2010)
irradiation, they were able to use as few to treat their retinopathy. They aim to PMOs do not “touch” the TGF-β1 gene at Einstein College of Medicine, NYC. Following this, he Transient inhibition of transforming growth factor-beta1
as sixty of these cells to rescue mice from do this by first isolating the CD34+ stem itself: they merely bind to the TGF-β1- sailed to Australia to work with Ray Bradley PhD, the father in human diabetic CD34+ cells enhances vascular reparative
death (>20,000 untreated stem cells were cells from the patient’s blood and then mRNA and block it from translation to the of modern blood stem cell research. Dr Bartelmez is a functions. Diabetes. Aug;59(8):2010-9. PubMed PMID:
required to achieve the same result). In correcting the dysfunctions in the CD34+ protein. The half-life of the PMO is short former member of faculty at Hutchinson Cancer Research 20460428 PMID: 24223881; PubMed Central PMCID:
addition, they found that when the retina stem cell ions by temporarily inhibiting and the stem cell rapidly effluxes the Center, U. of Washington, ViaCell Inc. He founded BetaStem PMC2911069
of mice was injured due to insufficient the patient’s TGF-β1 by incubating PMO-mRNA complexes. The molecules Therapeutics Inc. in 2006. Bartelmez, S., Storey, C., Iversen, P., Ruscetti, F. (2016)
blood flow, and the TGF-β1-PMO treated the CD34+ cells for 16 hours ex vivo also have an excellent safety profile. Transient inhibition of endogenous transforming growth
factor ß1 in hematopoietic stem cells accelerates engraftment
CD34+ stem cells were introduced into with PMO. This process rehabilitates Funding
and enhances multi-lineage repopulation efficiency. J Stem
the eye, the recruitment of diabetic the CD34+ stem cells which are then Transient, or brief, inhibition of TGF-β1 National Institute of Diabetes and Digestive and Kidney Cell Res Ther 1::00045 D01 f.
CD34+ cells to injured retinal capillaries introduced back into the patient’s eye. may lead to the treatment of other Diseases (NIDDK), National Heart, Lung, and Blood Institute
Patrick L. Iversen, Francis W. Ruscetti, Charles Garcia and
dramatically increased when compared to Here, the CD34+ stem cells specifically vascular complications and could (NHLBI), National Eye Institute (NEI) USA, and Stephen and Stephen H. Bartelmez (2018). Functional Activation of
non-treated stem cells. bind and repair the damaged blood potentially improve current bone marrow Elizabeth Bartelmez Autologous Human Diabetic Stem Cells for Cell Therapy,
transplantation processes used in the Gene Therapy, Dr Houria Bachtarzi (Ed.), Publisher: InTech,
treatment of blood cancers. The treatment Collaborators in press
poses a very low risk of adverse events. •F
rank Ruscetti PhD
However, challenges remain, particularly •P
at Iversen PhD
when it comes to the selection of animal •C
harlie Garcia MD Personal Response
models that can help predict the human •E
wa Sitnicka PhD
response to this treatment. •C
arl Storey What are your aspirations for BetaStem Therapeutics as
a company over the next five years?
BetaStem Therapeutics is now preparing We previously have had a “pre-IND” meeting with
to test TGF-β1 inhibition in diabetic the US-FDA in preparation to complete our IND to
patients for the first time in a clinical trial. proceed with our first patient studies. With sufficient
The next goal for the company will be the funding, our goal to test the safety and efficacy in diabetic
development of methods in the lab to patients with retinopathy looks realistic. Dr Charlie Garcia
further study TGF-β1 in haematopoietic (Ophthalmologist in Houston, Tx) has been working with us
stem cells. Moving forward they will for over four years and is helping design a clinical trial. He
has been working with patients with diabetic retinopathy
develop culture conditions in which cell
for more than 40 years. Currently, there are no effective
division of latent stem cells is stimulated treatments, making this an important unmet need. So far,
Diabetes is a risk factor for retinopathy but while their maturation and ageing is
it can be caused by other conditions such as
the stem cells look promising.
long-term elevated blood pressure. prevented, in the presence of either TGF-
β1-PMO or TGF-β1-inhibiting antibodies.
Health and Medicine ︱ Dr John A. Zebala
potential for abuse, through to schedule
Moving beyond dangerous

V with the lowest. Schedule I drugs are
further distinguished from schedule
II to V drugs as having no currently
accepted medical use (e.g., heroin,
opioids for pain:

LSD). There are currently 170 million
prescriptions for schedule II opioids per
year in the United States. Each of these
prescriptions has a high potential to be
abused, and it is believed millions of
Syntrix creates new drug for safer pain relief people are at risk of or already suffering
from opioid addiction and abuse.
The US government desperately wants
I
Opioids are currently the n the United States 25 million people the past sixteen years, the Centers for to reduce the costs associated with
mainstay treatment for the suffer from daily pain. Currently, Disease Control and Prevention (CDC) opioid-related fatalities. This year the
25 million people suffering opioids are the mainstay treatment for found in a recent report. In 2016, the United States Congress identified
from daily pain in the United these patients. But opioids are highly economic cost of the opioid epidemic research and development as an integral
States. Prescription opioids addictive, and can lead to misuse and in Washington State was calculated at part of the response to this crisis. They
have led to lethal overdoses lethal overdose. There are an estimated over $9.19 billion, with three-quarters recognised that the complexity of
and contributed in part to the 20,500 deaths involving prescription of the cost, or $7.18 billion attributed this evolving situation requires new
five-fold increase in opioid- opioids per year due to overdose in to fatalities. The economic and social discoveries and improvements to
related deaths from 1999 to the United States. If illicit opioids are impacts of the crisis demand immediate existing approaches, from the biology
2016. Investigators at Syntrix included, like heroin and fentanyl, action. Replacing the supply of available of addiction to overdose prevention
Pharmaceuticals (Auburn, deaths due to any opioid rise to about prescription opioids with a low-lethality and on a bipartisan basis quickly passed
Washington State) have 40,000 per year in the United States. alternative would be predicted to have the Substance Use-Disorder Prevention
developed desmetramadol, The American situation has reached a a significant impact on fatalities, which that Promotes Opioid Recovery and
a new and improved low- crisis point with the cost and scale of the is the major economic and social impact Treatment, or SUPPORT Act. The
lethality opioid to help tackle crisis growing across the country. With driver of the crisis. SUPPORT Act was signed into law by
the opioid crisis. their new low lethality pain drug, Syntrix President Trump on October 24, 2018.
Pharmaceuticals hopes to provide one THE PROBLEM WITH OPIOIDS
needed component in a broad effort Opioids are a group of drugs used The CDC has recommended reducing
to tackle the opioid crisis. to treat pain. Some are derived from the dose of schedule II opioids in has been working on a solution. They so small it appears no bigger than half
molecules obtained from the poppy patients to reduce opioid-related have a strategy to reduce fatalities a sesame seed. In other words, the lethal
CRISIS POINT plant, and others like fentanyl are overdosing and fatalities – but patients associated with prescription opioids dose of fentanyl is 2,500 times less that
The number of opioid-related overdoses obtained purely by chemical synthesis. still require effective pain relief. whilst providing effective pain relief for of tramadol. Overdoses on tramadol
continues to rise with deaths doubling in They bind to receptors in the body Other than the dangerous schedule II patients. The inspiration for their new alone are a rarity and therefore it has
the past ten years and quadrupling over called opioid receptors. These are found opioids, there are very few safer and drug came from tramadol. become popular with physicians as a
in the brain and spinal cord, and when less abuse-prone options for doctors safer pain medication. In the United
bound by opioids help to suppress pain. to prescribe. Syntrix Pharmaceuticals TRAMADOL: THE PROS AND CONS States, it is the second most commonly
When used for pain relief, many people OF A POPULAR PAIN DRUG prescribed pain relief with 41 million
will develop a tolerance to opioids: Tramadol is an opioid approved in prescriptions dispensed in 2017.
they gradually need to take more in the United States for the treatment of Tramadol sounds like a superhero amid
order to achieve the same pain-relieving moderate to moderately severe pain. the opioid crisis, but like any superhero
effect. The problem with opioids is that It is classified as a schedule IV drug, so it has its shortcomings.
the same receptor that controls pain it is less prone to abuse than schedule
transmission also controls the drive to II opioids and is safer. It is also more Tramadol is a complex drug. It must
breathe. In an overdose, the opioid difficult to overdose on tramadol than be broken down in the body into a
drug binds to a specific type of opioid schedule II opioids. A lethal overdose metabolite called M1 and it is this
receptor (the mu-opioid receptor) in the of tramadol is in excess of 5 grams, or metabolite that provides pain relief for
medulla of the brain that causes slow 100 tablets of tramadol in its typical the patient. Tramadol is broken down
and ineffective breathing or ‘respiratory 50 mg tablet strength. Compare this to into M1 by an enzyme in the body called
depression’. Untreated respiratory fentanyl, a schedule II opioid, for which CYP2D6. The amount of this enzyme
depression can in turn lead to death. a lethal dose is 0.002 grams, an amount activity can vary from patient to patient,
Opioids are so potentially dangerous

that the United States lists certain of
There are an estimated 20,500
Prescription opioids can provide
them under the Controlled Substances prescription opioid deaths per year due
Act. There are five categories, schedule
to overdose in the United States.
relief from daily pain. Desmetramadol technology replicates ideal
I – V, schedule I having the most severe CYP2D6 metabolism of tramadol without CYP2D6.
Behind the Research
Dr John A. Zebala
E: jzebala@syntrixbio.com W: www.syntrixbio.com

Syntrix Pharmaceuticals aims to tackle the opioid crisis by Senator Patty Murray. Senate Committee on Health,
producing opiates with low lethality compared to schedule Education, Labor, and Pensions. The Economic Cost of the
II opioids. Opioid Epidemic in Washington State. Available at: https://
www.murray.senate.gov/public/index.cfm/2018/4/opioid-
crisis-senator-murray-unveils-new-analysis-showing-opioid-
Detail crisis-costs-washington-state-billions. Accessed November 29,
2018.
Dr John A. Zebala
Executive Office of the President of the United States. Heath
Syntrix Pharmaceuticals
Research and Development to Stem the Opioid Crisis:
215 Clay Street NW
A Federal Roadmap. A report by the Fast-Track Action
Comparison of the relative amount of each substance required for a lethal overdose. Tramadol must be taken in much higher quantities before it is lethal. Suite B5 Committee (FTAC) on Health Science and Technology
Auburn, WA 98001 Response to the Opioid Crisis convened under the National
ranging from too much to too little.
And here lies the problem. If a patient
Syntrix Pharmaceuticals hopes USA Science & Technology Council of the Committee on Science.
October 2018.
has lots of the enzyme CYP2D6 they
are known as an ultra-metaboliser: they
to introduce a new low lethality drug Bio
Dr Zebala is the Syntrix President and CEO. During his
SBIR Phase 2b Research Proposal – Syntrix research proposal
to National Institute on Drug Abuse grant DA027304.
make lots of M1, potentially reaching to help tackle the opioid crisis. 10+ year tenure with the company, Dr Zebala established
dangerous levels in the body. company direction and brought company drug assets from
On the other hand, some patients are

have the safety features of tramadol
without its metabolic liabilities.
metabolic issues. Sixty participants were
recruited for the study and they were
discovery through Phase 1 and Phase 2 clinical trials. Dr
Zebala is the Principal Investigator on over $20 million in NIH
Personal Response
metabolically deficient because they all administered a CYP2D6 inhibitor. grants to the company. He is an inventor on over 20 issued
have too little CYP2D6 enzyme activity, MOVE OVER TRAMADOL: SYNTRIX Subjects were then randomly allocated US patents, and author to more than 25 peer-reviewed Do you think pain relief without opioids will ever
either because they are taking another DEVELOPS DESMETRAMADOL to receive desmetramadol, tramadol scientific articles. Dr Zebala received his MD and PhD be possible?
drug that inhibits the CYP2D6 enzyme, With generous grant support from and placebo, with each treatment from Cornell Medical School. Dr Zebala has served as an I certainly hope so. The most ideal pain medicine would
or because they were born lacking the National Institute on Drug Abuse, separated by two weeks. The researchers invited reviewer on NIH study sections and review groups presumably be one that was safe and free of any abuse
some or all of the CYP2D6 genes. Pain Syntrix developed desmetramadol. hypothesise that tramadol will lose its concerning drug development and therapeutics. potential. However, large pharmaceutical companies have
syndromes are often accompanied Desmetramadol delivers tramadol’s pain relief and act like a placebo, whereas been looking for non-opioid pain medicines for the last half-
by depression, and such patients active metabolite M1, but unlike desmetramadol will provide pain relief Funding century with many failures. They have yet to find anything
more effective for pain than the opioids. Opioids have a
are treated with antidepressants that tramadol, it doesn’t have to be broken superior to tramadol. The outcome National Institute on Drug Abuse
well-established mechanistic role in pain and so developing
are also powerful CYP2D6 inhibitors. down in the body. Syntrix hopes that cannot be predicted in advance since a low-lethality variant made sense to us as a strategy to
Tramadol has little benefit in patients desmetramadol will be the first opioid the behaviour of tramadol in the human Collaborators address the opioid crisis with a safer medicine that would
who are metabolically deficient due to with the low-lethality safety profile of body is complex. If successful, Syntrix • John A. Zebala* have a high likelihood of being highly effective in
either their genetics or a co-prescribed tramadol but without its metabolic believes that desmetramadol could • Shawn L. Searle† treating pain.
CYP2D6 inhibitor, because they fail to liabilities. Stuart Kahn, MD, Syntrix generally replace tramadol globally, and • Lynn R. Webster†
make sufficient M1 for pain relief. An Medical Director, stated, “Due to the that many of the 170 million schedule II • Matt S. Johnson‡ What first inspired you to work in this area?
estimated third of patients are either metabolic limitations of tramadol, prescriptions in the United States that • Aaron D. Schuler* When I was a young MD-PhD student in New York in
ultra-metabolisers or are metabolically large numbers of pain patients have contribute to the opioid crisis could be • Dean Y. Maeda* the early 1990s, I had just started a clinical rotation at the
deficient. These liabilities in tramadol’s not been receiving adequate relief on replaced by desmetramadol. • Stuart J. Kahn* Memorial Sloan-Kettering Cancer Center and was taking
metabolism make it difficult for clinicians tramadol. Often, they find relief only care of a patient with terminal breast cancer. She was in
to use it broadly as a substitute to from dangerous schedule II opiates. John Zebala, MD, PhD, President *Syntrix Pharmaceuticals, Auburn, Washington. severe pain due to metastases to her bones. Her opioid
prescription was so large it would have instantly killed a
the dangerous schedule II opioids. The side effects and risks those patients and CEO said, “With desmetramadol †PRA Health Sciences, Salt Lake City, Utah.
normal person. The pharmacy at Sloan-Kettering was the
face include dependency and death. broadly increasing the utility of ‡DF/Net Research, Seattle, Washington.
only pharmacy in the city that could fill it. It was at that time
It seems like tramadol isn’t a perfect Desmetramadol has the potential to tramadol and enhancing its safety, we that I decided I was going to pursue a career developing
low-lethality opioid solution to the provide effective pain relief to these expect to further accelerate the shift new therapeutics to broadly help many patients, rather than
opioid crisis, but it has provided an patients with greater safety.” away from schedule II opioids.” The become a practising physician seeing one patient at a time.
excellent starting point for Syntrix final stage of clinical trials is planned It probably also explains why Syntrix’s current drug pipeline
Pharmaceuticals. Learning lessons from In a recently completed clinical for desmetramadol in 2019 to 2020, is focused on drugs that treat pain and cancer. Pain is still
tramadol, Syntrix has developed a new trial, Syntrix hopes to show that and it is hoped that Food and Drug the #1 reason people see a doctor. Finding better ways
to treat it is critical.
medication to tackle the opioid crisis, desmetramadol provides the safety Administration approval will be obtained
desmetramadol, that is predicted to and pain relief of tramadol without its in 2020 to 2021.
Health and Medicine ︱ Dr Martin Ronis
Alcohol overuse: cytokines – play an important role ETHANOL EFFECTS ON BONE TURNOVER
in the process of ethanol-related skeletal
FORMATION RESORPTION
cutting to the bone

pathology. Excitingly, the team were able
Ethanol Ethanol
to protect fracture healing using inhibitory E2
antibodies against these cytokines STEM CELL STEM CELL
HORMONES
in the same rat models. ADIPOCYTE Ethanol
eg. Vit D3 IL-6
Wnt IGF-1, IGF-BPs
TNFα
This early work combined with the fact Cycling
that alcoholism is a known risk factor RANKL Female/Male
ROS
for osteoporosis led Prof Ronis to think
O
Building on several decades ur bones are living tissues that BETTER BONES about ways in which reduced bone mass Osteoblast RANK
Osteocyte ROS Osteoclast
of research, Dr Martin Ronis, continue to undergo change and This is where the research of Dr Martin (osteopenia) occurs after chronic alcohol Ethanol
replacement (bone remodelling), Ronis, Professor in the Department consumption, leading to increased E2/NAC
a Professor at the Louisiana Cycling
TRAP
State University Health Sciences even into adulthood. As we grow in of Pharmacology and Experimental risk of osteoporosis in ageing. Since Female/Male EtOH
Osteocalcin
childhood, our bone mass increases Therapeutics at the Louisiana State osteoporosis is predominantly a disease Pregnancy/
Center-New Orleans explores Post-Weaning
REDUCED NEW INCREASED BONE LOSS
the effects of alcohol on bone until it reaches ‘peak bone mass’ (PBM). University Health Sciences Center – that affects women, Prof Ronis decided BONE FORMATION AND RELEASE OF MINERALS
turnover. His current research Defined as the greatest amount of bone New Orleans comes in. His research to focus his research efforts on females Overview of pathways underlying ethanol effects on bone turnover. ROS – reactive oxygen species;
aims to better understand the an individual can attain, PBM is reached explores the effects of alcohol on bone and on unique physiological states TNFα – tumor necrosis factor α; Wnt – Wingless/Integrated signalling pathway; IGF-1 – insulin-
like growth factor 1; IGF-BPs – insulin-like growth factor binding proteins; E2 – estradiol; NAC –
molecular basis for the toxic in late teens and early 20s. Individuals turnover. He is particularly interested (including cycling, pregnancy and post- N-acetylcysteine; RANK – receptor activator of nuclear factor κβ; RANKL – receptor activator of nuclear
effects of alcohol, particularly with a higher PBM have a reduced risk of in the relationship between inhibition lactation), dovetailing with another area factor κβ ligand; IL-6 – interleukin 6; TRAP – tartarate resistant acid phosphatase.
in women, with a view to osteoporosis (a bone disease that occurs of bone formation and stimulated bone of his research into alcohol-nutritional
uncovering vital therapeutic
targets to prevent bone loss. As
when the body loses too much bone,
makes too little bone, or both), a leading
resorption associated with alcohol abuse
in young women and the increased risk
interactions in pregnancy, funded by
the National Institute on Alcohol Abuse
Prof Ronis’ current work aims
alcohol-induced bone loss shares cause of morbidity and mortality in older of osteoporosis – resulting from a failure and Alcoholism. to unpick in fine detail, the ROS
signalling mechanisms in bone after
many features in common with post-menopausal women. to attain PBM. His research involves
bone loss during menopause multidisciplinary basic sciences, including ETHANOL EFFECTS IN PREGNANCY
and ageing, his work provides
fundamental insights into
ALCOHOL AND BONE HEALTH whole animal physiology, nutrition and In a study published in 2006, Prof Ronis excess ethanol consumption.
Although the majority of people drink endocrinology, pathology and molecular directly tested the effect of ethanol
common pathways underlying
within safe limits, many consume alcohol biological techniques. Ultimately, Prof in pregnancy and cycling rats. The oxidative stress, which in turn promotes that they may be at increased risk
the regulation of bone growth
at levels proven to be harmful to their Ronis aims to better understand the team measured the effect of alcohol RANKL (receptor activator of nuclear of osteoporosis with age.
and turnover.
health. In the USA, approximately 20% molecular basis for the toxic actions on skeletal parameters including tibial factor κβ ligand, a substance needed
of women aged between 18-30 years of alcohol, which might uncover new bone mineral density (TBMD), bone for osteoclast formation) – inducing THE ROLE OF OXIDATIVE STRESS
(4.4 million) binge drink. Drinking more therapeutic targets to prevent bone loss. mineral content and bone mineral area osteoclastogenesis. This finding Intrigued by the differences in bone
alcohol than the safe limit can affect (BMA). A dose-dependent skeletal toxicity has significant implications for the remodelling during specific physiologic
bone health, and long-term alcohol Prof Ronis’ current work builds on following alcohol exposure was observed, use of contraceptive pills containing states (pregnancy, lactation and
consumption can interfere with bone a long history of alcohol research with demonstrated by decreases in TBMD oestrogens for protecting against menopause), Prof Ronis went on
and BMC. Their data suggested that alcoholic osteopenia (weak bones) in to explore the underlying molecular
Osteoporosis is a leading cause ethanol-induced bone loss in pregnant

rats is mainly due to inhibited bone
individuals who drink excessively. Notably,
the team also showed that anabolic
mechanisms further. In an elegant series
of experiments, the team showed
of morbidity and mortality in older post- formation. In striking contrast, bone loss bone rebuilding is completely blocked that ethanol inhibits bone formation
in non-pregnant rats was higher than by alcohol in post-lactation female rats. via a shift in the differentiation of bone
menopausal women. in that observed in pregnant rats and This has important implications for post- marrow mesenchymal stem cells. Rather
occurred through a different mechanism, lactating women who resume drinking than forming osteoblasts (bone cell
growth and remodelling. The resulting collaborators at the Department of concomitant with additional increases after stopping breast feeding, suggesting forming cells), these stem cells instead
reduction in PBM predisposes women to Pediatrics UAMS/Arkansas Children’s in bone resorption and a decrease
osteoporosis in later life. Clinical studies Hospital. The researchers explored in circulating estradiol levels.
show that alcohol abuse is correlated with the effect of chronic ethanol exposure
osteoporosis, a decreased bone mass in a rat model that mimics blood alcohol PROTECTIVE ESTRADIOL LEVELS
and the risk of fractures, and can delay patterns found in binge drinkers. Exploring the pregnancy-protective
fracture healing. Although it is well known They found that bone density, cortical effect of alcohol further, Prof Ronis
that women are more susceptible area, and mature bone strength and his team demonstrated the role
to the toxic effects of alcohol (i.e. were negatively affected by alcohol, of osteoclastogenesis – the process
ethanol) than men, much less and showed for the first time that whereby osteoclast cells are developed.
is known about the mechanisms chronic ethanol inhibits rapid bone Osteoclasts are the cells responsible
underlying the toxic effects formation during limb lengthening. for breaking down bone, resulting in Micro-computerized tomography images of mouse tibial trabecular bone demonstrating loss of bone
volume after ethanol (EtOH) consumption is greater in animals where the enzyme NOX4 (NADPH-
of alcohol overuse in women They also demonstrated that certain bone resorption. Prof Ronis showed that oxidase 4) is knocked out relative to bone loss in wild-type (WT) mice as a result of reduced stem cell
with respect to their bone health. pro-inflammatory molecules – called estradiol levels block alcohol-stimulated numbers in the knockout mice.
Behind the Research
differentiate into fat cells or adipocytes.
They demonstrated that oxidative stress
was an important mechanism for this.
Dr Martin Ronis
The team then went on to show that E: mronis@lsuhsc.edu T: +1 504 568 4514 W: www.researchgate.net/profile/Martin_Ronis
the production of excess reactive oxygen W: www.medschool.lsuhsc.edu/pharmacology/ronis_home.aspx
species (ROS) production by NADPH
oxidase (NOX) enzymes was responsible References Research Objectives
for the effects of ethanol on bone
turnover. Experiments of bone loss in Brown EC., Perrien DS., et al. (2002). ‘Skeletal Toxicity Associated The goal of Dr Ronis’ research is to better understand the
female rats and mice fed ethanol was
with Chronic Ethanol Exposure in a Rat Model Using Total Enteral molecular basis for the toxic actions of alcohol, particularly
Nutrition’. J Pharm and Exp Therapy, 301;3 1132-8. in women, with a view to uncovering therapeutic targets. In
blocked by dietary antioxidants including
Perrien, DS., Wahl, EC., et al. (2004). ‘IL-1 and TNF Antagonists particular, the results from research aim to link the deleterious
N-acetylcysteine (NAC), vitamin E and effects of alcohol consumption on bone in women of
Prevent Inhibition of Fracture Healing by Ethanol in Rats’.
also DPI an inhibitor of NADPH oxidase Toxicological Sciences, 82, 656-660. reproductive age with increased risk of osteoporosis, a major
(NOX) enzymes. cause of morbidity and mortality in post-menopausal women.
Shankar K, et al. (2006). ‘Physiologic and genomic analyses of
nutrition-ethanol interactions during gestation: implications for
Interestingly, Prof Ronis found that
the effects of ethanol to inhibit
fetal ethanol toxicity’. Exp Biol Med, 231:1379-1397. Detail
Shankar K, et al. (2006). ‘Different molecular mechanisms
osteoblastogenesis (the production underlie ethanol-induced bone loss in cycling and pregnant rats’. Dr Martin Ronis, LSU Health Sciences Center – New Orleans,
of osteoblast cells that form bone) Endocrinology, 147(1):166-178. 1901 Perdido Str. New Orleans LA 70112, USA.
and stimulate bone marrow adipose Shankar K, Ronis, MJJ, Badger TM. (2007). ‘Effects of Pregnancy Bio
cell formation were not blocked in and Nutritional Status on Alcohol Metabolism’. Alcohol Res, 30; Martin Ronis B.A., M.A. Nat. Sci. Cantab., PhD is a tenured
experimental genetic mice that lacked an H&E stained images of decalcified tibial bone from post-lactating female rats at the growth plate. 1:55-59. full Professor in the Department of Pharmacology &
Pink staining – mineralised bone, outside – cortical bone, inside – columns of trabecular bone. White Experimental Therapeutics at the Louisiana State University
active form of NOX1/2 enzymes. Since a circles – adipocytes (fat cells) in the bone marrow. Loss of bone after ethanol (EtOH) consumption is
Chen J-R, et al. (2008). ‘Protective Effects of Estradiol on Ethanol-
Health Sciences Center – New Orleans. He is a current
major component of ethanol pathology in accompanied by increased marrow adiposity (B) and this is reversed by co-treatment with the dietary Induced Bone Loss Involve Inhibition of Reactive Oxygen Species
Generation in Osteoblasts and Downstream Activation of the
National Institute on Alcohol Abuse and Alcoholism
bone is the generation of excess ROS, this antioxidant N-acetylcysteine (NAC).
Extracellular Signal-Regulated Kinase/Signal Transducer and (NIAAA) MERIT awardee.
led the team to hypothesise that another
Activator of Transcription 3/Receptor Activator of Nuclear Factor- Funding
source of ROS mediates this effect. The CURRENT RESEARCH suggests that a certain level of ROS kB Ligand Signaling Cascade.’ J Pharmacol. Exp Therap, 324, No. NIH (NIAAA): R01 AA012928, R01 AA012819, R01
researchers subsequently explored the Using a new mouse model of excess signalling is necessary for normal stem 1:50-9. AA018282, R37 AA018282
contribution of ROS-generating NADPH alcohol consumption, Prof Ronis’ current cell self-renewal and bone development Chen, J-R, et al. (2010). ‘A role for ethanol-induced oxidative stress Ronis Lab:
oxidase-4 (NOX4) and mitochondrial- work aims to unpick in fine detail the during ageing. To test whether NOX4 in controlling lineage commitment of mesenchymal stromal cells Drs Mats Hidestrand, Kartik Shankar, Jin-Ran Chen, Kelly
derived ROS in driving ethanol-induced ROS signalling in bone after excess is responsible for mediating the effects through inhibition of Wnt/beta catenin signaling’. J. Bone Min Res, Mercer, Alex Alund, the University of Arkansas for Medical
suppression of bone formation. ethanol. Excitingly, recent data also of ethanol on bone formation, ex-vivo 25: 1117-1127. Sciences and Drs James Watt, Kim Pedersen, Louisiana
(experiments on tissue removed from Mercer KE, et al. (2014). ‘Loss of functional NADPH oxidase State University Health Sciences Center – New Orleans.
Control EtOH the body) bone marrow cultures from 2 protects against alcohol-induced bone resorption in female Collaborators:
genetic mice that lack NOX 4 in selected p47phox-/- mice chronically fed ethanol’. Alc. Clin. Exp. Res., 38: Drs Thomas Badger, Charles K. Lumpkin, James Aronson,
bone cell types (osteoblast precursors, 672-682. the University of Arkansas for Medical Sciences and Dr Larry
osteocytes, osteoclasts) will drill down Chen J-R, et al. (2015). ‘Deficient Nox2-dependent ROS signaling Suva, Texas A&M University.
on the mechanisms involved. accelerates skeletal ageing in mice’. J. Biol. Chem, 290: 14692-
14704.
The teams’ recent findings suggest that Alund, A, et al. (2016). ‘Reactive oxygen species differentially Personal Response
regulate bone turnover in an age-specific manner in catalase
dietary antioxidants prevent alcohol-
transgenic female mice’. J. Pharmacol. Exp. Ther, 358: 50-60, Your contribution to the field of alcohol toxicology
induced osteopenia as a result of 2016. Journal Cover. is immense. What’s next for your research?
blocking excess hydrogen peroxide.
Alund, A.W., Mercer, K.E., Pulliam, C.F., Suva, L.J., Chen, J-R., In addition to my current work on alcohol and
NAC NAC/EtOH Hydrogen peroxide is a form of ROS Badger, T.M. and Ronis M.J.J. (2017). ‘Protection by dietary skeletal toxicity, I have spent many years working
produced as the result of the activation antioxidants against ethanol-induced osteopenia and changes in on alcoholic and non-alcoholic fatty liver disease.
of NADPH oxidase enzymes following bone morphology in female mice’. Alc. Clin. Exp. Res, 41: 46-56. Recently, we have focused on the role of nutrition
the metabolism (breakdown) of ethanol. Watt, J., Alund, A.W., Pulliam, C.F., Mercer, K.E., Suva, L.S., Chen, in the progression of liver pathology to liver cancer.
Importantly, since alcohol-induced bone J-R. and Ronis M.J.J. (2018). ‘NOX4 deletion in mice exacerbates Interestingly, we find that both alcohol and saturated
loss shares many features in common with the effect of ethanol on trabecular bone loss and osteoblast fats are liver tumour promoters. Changing dietary fat to
bone loss during menopause and ageing, colony formation’. J. Pharmacol. Exp. Ther., 366: 46-57. mono-unsaturated fats like olive oil and dietary protein
from dairy to soy protein can protect. Protection
molecular studies of alcohol actions on
appears linked to changes in gut microbiota. We
hydrogen peroxide downstream effects are currently studying these links between diet, gut
in bone may well provide fundamental bacteria and liver cancer. In addition, we are expanding
insights into common molecular pathways our studies on skeletal toxicity beyond alcohol to look
Immunohistochemical staining for nitrotyrosine protein adducts (brown) in female mouse tibial bone underlying the regulation of normal bone at the effects of environmental pollutants such as
following consumption of ethanol (EtOH) with or without co-treatment with the dietary antioxidant
N-acetylcysteine (NAC). Increased staining after EtOH indicates oxidative stress accompanies loss of growth and turnover. polychlorinated biphenyls.
bone (purple) and increased marrow adiposity (white circles) which is blocked by NAC.
Health and Medicine ︱ Dr Ronald Shebuski
Local drug delivery to

prosthetic vascular grafts:
Preventing failure of prosthetic grafts in haemodialysis patients
C
Dr Ronald J. Shebuski, President ylerus, Inc. was formed by result of the formation of excessive scar
and CEO of Cylerus, Inc., wants Dr Stephen Hanson in 2007 tissue which obstructs blood flow within
to revolutionise the way vascular to develop new drug delivery the graft, as well as in the blood vessels
grafts work. His company, approaches for preserving the lifespan connected to the graft.
Cylerus, has an innovative way of synthetic vascular grafts. Dr Ronald
to deliver an antiproliferative Shebuski was appointed as President There are two main types of blood
drug, sirolimus, in a consistent of Cylerus in 2010, bringing a wealth conduits; those created from the patient’s
and controlled manner. This of experience in biotechnology vein, or those made from expanded Analysis of the distribution of blood flow velocities in the ePTFE graft model utilised in humans for AV access. The prosthetic graft material is sewn end-to-side
method of drug delivery, via development. Also, part of the team polytetrafluoroethylene (ePTFE), between an artery and vein (called an anastomosis) to establish vascular access. Blood flow velocities in the conduit are lowest at the wall of the conduit and
fastest in the centre of the bloodstream which concentrates drug (sirolimus) near the inner wall where it is required to prevent obstruction of the graft conduit.
a porous graft material called is Drs Prabir Roy-Chaudhury, Diego also known as synthetic or prosthetic The major problem area of these conduits is downstream of the venous anastomosis (iliac vein in the figure) which becomes obstructed with proliferating
ePTFE, has the potential Celdran, and Heidi Mansour (U grafts. These prosthetic grafts are most cellular material.
to reduce failure of arterio- AZ-Tucson) and Dr Sandra Rugonyi commonly used to form arterio-venous
By 2020, it is estimated that over
venous access grafts crucial for (OHSU, Portland, OR). The vision of (AV) access grafts for haemodialysis Unresolved, this can lead to thrombosis
haemodialysis and to, therefore,
the company is to have a positive patients, which join an artery and vein (clotting) in the connection between
improve outcomes for patients
with chronic kidney disease.
impact in the haemodialysis graft to provide an access site for needle the ePTFE graft and the patient’s vein. 100,000 patients will be undergoing
dialysis 2-3 times a week in the US.
access market within a short time frame insertion to hemodialyze, or to bypass This provides strong support for the
once their novel drug delivery device an obstructed artery in peripheral vascular notion that there is both a medical and
is commercialised. disease. However, a high percentage an economic need to extend the length
of these grafts fail. For example, of time that prosthetic grafts are viable. that it prevents overgrowth of cells or refilled; this prolongs graft functionality,
VASCULAR GRAFTS prosthetic AV access grafts fail in around which may lead to stenosis of the whilst avoiding drug effects elsewhere.
Prosthetic vascular grafts will often 50% of cases, 3 months after placement. Currently, fistulas are the preferred graft. The Drug-Eluting Cuff (DEC) Drug delivery can also be stopped
become blocked due to obstruction method for vascular access during is placed around the ePTFE graft close at any time if any adverse effects arise.
(stenosis). Stenosis is frequently caused The primary aim of the Cylerus Drug- haemodialysis, 56% compared to a 32% to the graft anastomosis (the point where
by a proliferation of cells in the vessel, Eluting Cuff (DEC) graft is to prolong use of grafts in 2011. This is thought to the patient’s vein and the graft are joined As the drug is derived from a source
including smooth muscle cells and cells the functionality of ePTFE AV grafts be due to a campaign by the ‘Fistula First’ together). Due to the porous nature external to the graft, and then diffuses
called fibroblasts. Graft failure is the in end-stage renal disease patients program in 2003 and the fact that fistulas of the ePTFE graft, the drug is able through the walls of the graft, the flow
who require chronic haemodialysis. There have good durability and are low cost to move through the walls of the graft of blood through the graft itself is not
is also a pre-emptive focus, rather than with a low risk of complications. However, into the bloodstream. The drug is then modified. Altering the surface of the graft,
a reactionary one, meaning that possibility it is expected that as graft design and carried by the blood flow to the site e.g. coating it with a drug, runs the risk
of stenosis is accounted for in advance, graft construction materials continue of anastomosis, where it is able to of invoking adverse healing responses
rather than dealt with if it occurs. to advance, and therefore improve prevent the proliferation of cells, meaning or thrombosis.
the durability and longevity of prosthetic the graft does not become blocked
WHY IS A NEW PRODUCT NEEDED? grafts, the preference for grafts over and no secondary intervention is needed Indirectly competitive technologies,
In the US, there are approximately fistulas will increase. If managed correctly, to correct the graft. such as drug-eluting balloons, are also
125,000 haemodialysis patients with prosthetic grafts can be as effective, reported to be under development.
ePTFE grafts. These grafts require if not more so, than fistulas. As sirolimus is locally concentrated along However, the approach used by Cylerus
an average of 1.6 interventions per year the ePTFE graft and peripheral vessel has several advantages over these.
to maintain the functionality of the graft THE TECHNOLOGY wall, hyperplasia, or cell proliferation, For example, the balloons deliver
(around 200,000 interventions per year) The product designed by Drs Hanson is effectively prevented, whilst still the drug intermittently, so the effects may
Cylerus’ local drug delivery system comprising Electron micrograph of ePTFE graft material and to make sure it is possible to connect and Shebuski and the team at Cylerus maintaining safe circulating drug levels only be transient. In comparison, Cylerus’
an ePTFE graft (white), silicone rubber drug- demonstrating internodal pores (30 uM). The the patient to the dialysis machine. consist of a sirolimus filled pump, in the rest of the body. Furthermore, approach allows for constant, prolonged
eluting cuff (DEC) and reservoir around the graft, Cylerus technology takes advantage of these which is attached to a catheter leading using low doses of sirolimus means that drug delivery, directly through the
connecting tubing, and a drug-filled osmotic mini pores to deliver drug through the graft wall to
pump (an Alzet in this image). the inner lumen of the graft in a continuous and Stenosis is the most common cause of to a drug delivery cuff. Sirolimus is the drug infusion could last up to 90 days walls of the graft so that a concentrate,
circumferential manner.. graft failure which requires intervention. an antiproliferative drug, meaning before the pump needs to be replaced uniform amount of the drug is released
Behind the Research
Primary Patency
60%
in a continuous, circumferential
Primary patency is defined
and intraluminal manner. as the time from placement of
45%
Dr Ronald Shebuski
the access to the next procedure
Directly competitive drug-eluting grafts of any type on that access
are also under development. However, 30%
these may show limitations which Cylerus’
product does not, and have not reported E: rshebuski@gmail.com T: +1 321 421 7065 W: www.cylerus.com
the same decrease in thickening of vessel 15%
walls that Cylerus’ studies demonstrated.
These limitations include the amount 0%
3 Months 6 Months 12 Months 18 Months 24 Months
of drug that can be delivered, how it is
delivered and damage to the graft itself
Research Objectives
Incidence of prosthetic graft failure in human AV access. Primary patency is defined as the time from
during implantation. placement of the access to the next procedure of any type on that access. Note already at 3 months Dr Ronald Shebuski, President and CEO of Cylerus, Inc.,
that almost half of the implanted prosthetic grafts require intervention to maintain function and ability
to dialyze. Pflederer et. al. 2008. Semin Dial 21(4):357-363.
wants to revolutionise the way vascular grafts work.
PROOF OF PRINCIPAL Cylerus promotes the use of prosthetic vascular grafts
Cylerus received a Phase I grant from with the aim to improve AV access for patients undergoing
the National Institute of Health in 2012, haemodialysis.
and since then have been able to
demonstrate the effectiveness of their
product in preclinical trials.
Detail
Dr Ronald Shebuski
These studies included trials in baboons 733 Lake George Drive
and pigs. The trial carried out in baboons Melbourne, FL 32940
showed that sirolimus infusion in baboons USA
with implanted ePTFE grafts resulted
Concentration
in a 79% reduction in the amount that Bio
Boundary Layer
the vessel wall thickened. An important Dr Shebuski has 30 years’ experience in the pharmaceutical
note from this is that sirolimus showed industry (Merck, SKF, PNU) and currently is President &
an outstanding local antiproliferative CEO of Cylerus developing novel drug delivery technology
effect but did not suppress the immune Graft - Vessel to prolong the function of prosthetic vascular grafts,
system in the rest of the body. anastomosis particularly for patients requiring chronic haemodialysis. The
Infusate
Cylerus technology was licensed from OHSU in Portland,
Flow dynamic modelling of a baboon OR. References
ePTFE model showed a continuous Trans-graft Drug Delivery: The delivery of a therapeutic agent (drug, gene, cell or chemical) through the
flow of a predicted amount of drug porous ePTFE graft will result in extremely high concentrations of the drug at the graft-blood interface Funding Cylerus, Inc. Executive Summary and Commercialisation Plan,
where the flow velocity by definition is zero (Hagen–Poiseuille equation). The delivered agent will also
through the blood vessel. This study be preferentially pushed along the graft-blood interface in the direction of flow such that it will bathe National Institute of Aging (a Division of NIH) has funded a provided by Ronald J. Shebuski, 2018.
also demonstrated that Cylerus’ the graft-vein anastomosis and the distal (proximal) vein. Phase I/II Fast-Track SBIR awarded to Cylerus on 8/15/17 (PIs
product is able to provide sirolimus Drs Ronald J Shebuski and Prabir Roy-Chaudhury). Cylerus, Inc., Vascular Drug Delivery. Available at: https://www.
at a concentration which is high enough contain any drug or therapeutic, not just patients will be undergoing dialysis 2-3 cylerus.com [Accessed 21 October 2018].
to inhibit hyperplasia, not only at the body-temperature stable sirolimus times a week in the US. Collaborators
the graft anastomoses but within the formation used in this example, opening The University of Arizona-Tucson and Drs Prabir Roy- Shebuski, R.J. & Ray-Chaudhury, P. (2017). ‘Localized Delivery
surrounding blood vessels associated the door for many more applications With their latest preclinical studies due Chaudhury (co-PI), Diego Celdran, Heidi Mansour. Also Dr of Sirolimus to Hemodialysis Vascular Access Grafts’. Available
with the graft too. of this technology. Certainly, this may to finish in 2019, Cylerus, Inc. hope that Sandra Rugonyi (OHSU, Portland, OR). at: http://grantome.com/grant/NIH/R44-AG059279-01A1
form the basis for some of Cylerus’ they will soon be able to file the required [Accessed 21 October 2018].
The company has a current NIH-funded future products. regulatory paperwork to allow them to
SBIR project examining the safety and progress with the clinical investigational
efficacy of this novel drug delivery WHAT NEXT? use of their product. Filing these Personal Response
technology in pigs, a species which is The goal of the Cylerus’ drug delivery documents will also allow the Company
often used as a model for humans due technology is to extend the amount of time to make the jump from a start-up research How do you see Cylerus, Inc. developing over the next
to the similarity of size and anatomy of that prosthetic vascular access grafts can and development entity, to a fully-fledged 10 years?
the cardiovascular systems. In addition to be successfully used for haemodialysis. commercial entity.
Following the successful completion of Phase II of
the DEC graft, the drug-filled pump may By 2020, it is estimated that over 100,000 the current SBIR Fast Track Grant awarded Cylerus by the
Providing a drug-eluting device, such as is National Institute of Aging (NIA), the company will move
The goal of Cylerus is to extend the proposed here, may have a major impact into clinical development. The Phase II SBIR will fund
amount of time that prosthetic (ePTFE)

for patients with end-stage kidney disease, FDA-required preclinical safety work at the University of
as it will decrease the morbidity associated Arizona-Tucson, which is a key collaborator to Cylerus on
vascular access grafts can be used with synthetic graft maintenance, hence this project.
vastly improving quality of life, as well as
successfully for haemodialysis. significantly reducing healthcare costs.
Health and Medicine ︱ The Human Vascular Research Group (HVRG) CHANGE IN MEDIATORS OF FMD THROUGHOUT LIFE MECHANISMS OF ENDOTHELIUM-DEPENDENT DILATION
Clinical relevance aims to

100 A Age 0-18 B Age 18-55
80
*
60 NO * Physiological K+ AC
PGI2
Stimulus AA Ca
40 * * COX cAMP
uncover novel regulators of

* PGI2 *
20 * * * * *
* * PGI 2 PGI 2
% Max. Diameter
0 * * * K+ CYP450
* * BK
Ca++ dilation
*
-20 * * * * ADP (EET)
human coronary artery function

100 C Age >55 D CAD ACh O2 EDHF EDHF
MnSOD
80
H2O2 cGMP
60 Ca++ K+
Shear
Ca
40 NO
H2O2 I-Arg NOS NO NO GC
* * GTP
20 *
* * *
* *
0 * **
T
-20
Charting new territories in he microcirculation is made up coronary and adipose microvessels, Lumen Vascular Smooth Muscle
0 20 40 60 80 100 0 20 40 60 80 100
vascular disease research, The of a network of blood vessels, the factors that regulate these changes Endothelium
Flow gradient (cmH2O)
Human Vascular Research Group including small arterioles, are poorly understood. Although animal
capillaries, and venules. Its primary models provide some insight into blood Mediator of flow-mediated dilation is changed throughout life and with the onset of disease. Left Flow-mediated dilation (FMD) in isolated atrial
(HVRG) at the Medical College microvessels from: A children age 0–18, B younger adults age 18–55, C older adults age >55 and D subjects with clinically diagnosed coronary artery disease
of Wisconsin uses fresh human function is to supply oxygen and nutrients vessel regulation in health and disease, (CAD) independent of age. The mediator of FMD changed from mostly PGI2 (indomethacin inhibitable) with minor contributions of NO (L-NAME inhibitable)
tissues to address important to tissues and remove metabolic waste. they often do not translate directly in children to predominantly NO and a minor contribution of PGI2 in younger adults. In older adults, a small reduction in dilator capacity is observed due
to loss of PGI2 mediated dilation while with the onset of CAD NO-mediated dilation is lost with a compensatory increase in H2O2 (peg-Catalase inhibitable)
questions in vascular biology. The microcirculation is responsible for into humans.
production to flow stimulus.
Focusing on the microcirculation, orchestrating adjustments of blood
the smallest of blood vessels
inside our bodies, their aim is
vessels to match local blood supply with As microvascular function is extremely understanding and treatment of a variety The team has a wealth of expertise in
studying microcirculatory function in
oxygen demand of tissues – both in challenging to measure directly in of cardiovascular disorders.
to better understand coronary normal resting conditions and in response the human heart, alternative ways
artery disease (CAD) and other
clinical problems associated with
to external stimuli (e.g., increased heart
rate) that require increased amounts
to interrogate blood vessel function
are needed to further our understanding
A NOVEL APPROACH
The human microcirculation not only
intact human tissue samples, an approach
microvascular defects. Heart
disease is the leading cause
of oxygen and nutrients. of pathological changes observed plays a role in regulating tissue perfusion that provides obvious clinical relevance.
in human subjects. Taking a unique but has been recognised as a modulator
of death worldwide and new THE MICROCIRCULATION AND approach, the Human Vascular Research of the local tissue environment. The team provoked dysfunction leads to clinical A PIVOTAL ROLE OF ENDOTHELIAL
approaches to treatment
CORONARY ARTERY DISEASE Group (HVRG), consisting of Drs Julie believes that this provides an explanation implications (e.g. atherosclerosis). MITOCHONDRIAL FUNCTION
and prevention are vital.
Heart disease is the leading cause of Freed, David Gutterman, Matt Durand for the multitude of dilator and constrictor Two pathways involving the production
death worldwide and a significant portion and Andreas Beyer, is set to increase factors released from the endothelium THE STRESS-INDUCED SHIFT IN of ceramide and a reduction in telomerase
of heart-related deaths are directly linked our mechanistic understanding of changes (the cells lining the blood vessel walls) that MEDIATOR OF VASODILATION activity are critical in the shift from NO
to blood vessel dysfunction. Changes observed with onset of disease. The also influence vessels further downstream In human coronary arterioles from patients to H2O2. Both ceramide and reduced
in the microcirculation are a well-known group uses isolated microvessels from and the function of surrounding tissues. with CAD, loss of nitric oxide-mediated telomerase activity are known to suppress
early indicator for coronary artery surgically discarded tissue to explore why dilation to shear stress (flow-mediated mitochondrial function and promote
disease (CAD). While age and onset microvascular dysfunction is a powerful The HVRG team proposes a novel dilation, FMD) is compensated by the mitochondrial free radical production such
of CAD are associated with changes predictor of cardiovascular disease. idea: that communication between release of hydrogen peroxide (H2O2) as H2O2. The traditional role of telomerase
in the regulation of dilation of human Their aim is to identify clinically relevant microvessels and their surrounding from mitochondria in the endothelial is to protect the nuclear genome from
pathways and investigate these in more tissues is multimodal. That is, the release cells. Interestingly, both hydrogen shortening during cell division by adding
detail using animal models and cell culture of nitric oxide (NO, which causes vessel peroxide and nitric oxide are vasodilators, a repeat sequence to telomeres (regions
models in support of the findings obtained dilation) preserves normal tissue function yet they have opposing effects on of repetitive DNA sequences at the
from human microvessels. Their hope by blocking inflammation. Conversely, the health of the microvasculature end of chromosomes); thus telomerase
is to uncover novel targets for treatment in disease states or stress conditions, and surrounding tissue – nitric oxide protects the end of chromosomes from
and prevention of human heart conditions. the release of other substances from promotes latency, whereas H2O2 promotes damage. Under conditions of acute stress,
the endothelium leads to cellular inflammation and atherosclerosis. The TERT, the catalytic subunit of telomerase
ASSESSING MICROVASCULAR dysfunction, thrombosis, and fibrosis. HVRG is exploring the mechanisms that is translocated to the mitochondria where
FUNCTION Their theory neatly explains why switch the mediator released from the it has been shown to bind to mitochondrial
The team has a wealth of expertise in microvascular dysfunction is such a endothelium, believing it to be pivotal in DNA (mtDNA). The exact role of TERT
studying microcirculatory function in intact powerful predictor of cardiovascular injury. reducing tissue stress from inflammation. in the mitochondria is somewhat puzzling
human tissue samples, an approach that The researchers are investigating adaptive as mtDNA is circular and does not
provides obvious clinical relevance. Their Cardiovascular stress and disease expose autophagy (the regulated mechanism have telomeres to protect. Ceramide,
specialised method employs direct video- the dynamic nature of the mediators that disassembles unnecessary cellular a prototypical sphingolipid product
microscopy of cannulated, pressurized of microvasculature dilation, which components), which is shown to be of sphingomyelinase, is produced in
arterioles to assess microvascular function can be changed either acutely (e.g. necessary for the endothelial shear- endothelial cells, found in human plasma,
in vitro (outside the body). Through this, by changes in pressure within the vessel induced production of nitric oxide. Their and is a risk factor for atherosclerosis.
the HVRG team has unearthed several or pharmacological interventions) or by hypothesis is that by blocking autophagic Ceramide is a known inhibitor of
HVRG – Team Science: signalling pathways that play a key chronic diseases such as CAD. The HVRG flux, NO is reduced, and inflammation telomerase activity in the cancer literature,
Back row (left-right): Dr Karima Ait-Aissa, Matthew Rappelt, Dr David D. Gutterman. Middle back row role in the regulation of vascular tone team and collaborators explore changes increased, leading to a change from which makes ceramide and telomerase
(left-right): Dr Andreas M. Beyer, Dr Matt Durand. Middle front row (left-right): Todd Le, Dr Andrew
Kadlec, Dawid Chabowski. Front row (left-right): Dana Murphy, Kelsey Walters, Dr Julie K. Freed, during normal conditions, acute stress, in the dilator pathways, hoping to shed NO production to H2O2 as the mediator both active targets of investigation
Dr Natasha Zinkevich, Dr Laura Norwood Toro. and chronic disease that impact the light on ways that microcirculation- of FMD in CAD patients. for the treatment of various cancers,
however, to date unsuccessful. One of the
reasons why ceramide or anti-telomerase
activity has not paid off as a viable anti-
cancer treatment may be the general
Behind the Research
toxicity of such drugs that manifests
as cardiovascular toxicity. On the other
hand, however, targeting ceramide and
telomerase or their associated pathways
may be a novel therapeutic strategy for
the treatment of coronary artery disease
as well as cancer if risk versus benefit Andreas M. Beyer David D. Gutterman Matthew J. Durand Julie K. Freed
analysis is carefully evaluated.
Dr Julie K. Freed (right) and Mary Schultz (left) discussing E: abeyer@mcw.edu T: +1 414 955 7514 W: www.mcw.edu/Cardiovascular-Center/Research-Labs/Cardiovascular-Center-Faculty-
vascular responses during an experiment. Labs/Andreas-Beyer-Lab.htm W: www.mcw.edu/Cardiovascular-Center/Research-Labs/Julie-Freed-MD-PhD-Lab.htm
As mitochondrial function appears
W: www.mcw.edu/departments/pharmacology-and-toxicology/faculty/david-gutterman-md
Their theory neatly explains why

to be critical for physiological vasodilator W: https://fcd.mcw.edu/?module=faculty&func=view&name=Matt_Durand_Phd&id=6476
capacity in the human heart, the HVRG
is investigating underlying mitochondrial
damage as the causative link between
microvascular dysfunction is such a Research Objectives References
these pathways. Both activation of powerful predictor of cardiovascular injury.
telomerase or inhibition of ceramide The HVRG studies the complex relationship Gutterman D, Chabowski S, Kadlec A, Durand M, Freed J,
production contributes to the prevention inhibitory effect on the generation that the peripheral microcirculation (leg) and physiological effects of vascular stress response Ait-Aissa K, Beyer A. (2016). ‘The Human Microcirculation’.
in health and disease. The main focus of these labs is Regulation of Flow and Beyond. Circ Res. 118:157-172.
of mtDNA damage. The team has already of mitochondrial ROS and is known is significantly impaired after a stroke
to understand how the mechanisms of vasodilation change
demonstrated that TERT re-activation and to increase telomerase activity. and that improvements in microvascular
from nitric oxide (healthy individuals) to mitochondrial- Freed, J.K., et al. (2014). ‘Ceramide changes the mediator of
translocation to the mitochondria, as well function contribute to the improvement derived hydrogen peroxide (individuals with CAD). Several flow-induced vasodilation from nitric oxide to hydrogen peroxide
as decreasing levels of ceramide, can The relevance of these findings extends of motor function in this population. interconnected signalling pathways including ceramide, in the human microcirculation’. Circ Res, 115(5): p. 525-32.
restore the “normal” mechanism of flow- itself beyond the laboratory. Dr Durand, Further, the Durand lab is exploring extra-nuclear telomerase, PGC1α, LPA, and others
induced endothelium-dependent dilation in collaboration with Dr Allison Hyngstrom simple non-invasive means to improve have been identified to regulate mitochondrial function Beyer, A.M., et al. (2014). ‘An acute rise in intraluminal pressure
from H2O2 to NO (thus moving away at Marquette University, were the first microvascular function. Application of in the human microcirculation. shifts the mediator of flow-mediated dilation from nitric oxide
from a CAD phenotype). Their central investigators to quantify the hyperemic a technique called ischemic conditioning to hydrogen peroxide in human arterioles’. Am J Physiol Heart
Circ Physiol, 307(11): p. H1587-93.
tenet is that mtDNA damage is one of blood flow response to muscle (short, intermittent bouts of limb ischemia
the underlying causes that leads to an contractions in the legs of stroke survivors. using a blood pressure cuff) is sufficient Detail Beyer AM, Freed JK, Durand MJ, Riedel M, Ait-Aissa K, Green P,
increase in ROS production. Mitochondrial They discovered that reduced blood to improve paretic leg strength and Hockenberry JC, Morgan RG, Donato AJ, Peleg R, Gasparri M,
ROS has been shown to promote flow to the paretic leg (impaired function hyperemic blood flow by approximately Cardiovascular Research Center Rokkas CK, Santos JH, Priel E, Gutterman DD. (2016). ‘Critical
the development of arteriolosclerosis as a result of a stroke) during muscle 15%. This improvement in strength is also Medical College of Wisconsin role for telomerase in the mechanisms of flow-mediated dilation
and endothelial dysfunction, predisposing accompanied by an acute improvement Milwaukee, WI 53226 in the human microcirculation. Circ Res, 118(5):856-66.
contraction was strongly correlated with
MEB 4825, USA
individuals to vascular complications. reduced leg strength and poor motor in arterial flow-mediated dilation.
At the same time, NO has a well-known control. Their studies led to the finding Currently, Drs. Durand and Freed from Durand, M.J., et al. (2015). ‘Impaired hyperemic response
Bio to exercise post stroke’. PloS one, 10(12): p. e0144023.
the HVRG are jointly conducting a clinical The HVRG consists of several investigators with diverse
REGULATION OF THE MECHANISM OF FLOW INDUCED DILATION trial which will examine the effects of backgrounds. Dr David Gutterman is a cardiologist
IN THE HUMAN MICROCIRCULATION ischemic conditioning on peripheral with a prolonged interest in understanding the human
vascular function and frailty in pre-surgical, microcirculation; Dr Andreas Beyer is a trained geneticist
elderly colon cancer patients who and physiologist with a background in vascular function Personal Response
and hypertension research. Dr Julie Freed is a cardiac
traditionally have poor surgical outcomes.
In your research, you make elegant use of human vessels.
(Flow)
anesthesiologist with a focus on lipid signalling and vascular
function. Dr Matt Durand is a cardiovascular physiologist Can you explain some of the advantages of your methods
High Pressure Exercise Together these findings underline who studies the effect of a non-invasive intervention, called over animal models?
CAD Healthy Diet
Chemo/Radiation the growing recognition that dysfunction ischemic conditioning, on motor, neural, and vascular The human coronary microcirculation exhibits several
of the microcirculation contributes function in chronic stroke survivors. unique characteristics that have been identified through in
LPP3
to the development of cardiovascular vitro studies. Interestingly, dilator responses in commonly used
and other chronic diseases in humans. Funding model systems such as rodents, dogs, or pigs do not always
TERT Ceramide Ongoing research from the HVRG NIH/NHLBI, WE-Care Foundation, Advancing Healthier correlate with findings in human tissue, making studies in
LPA Wisconsin, American Heart Association human microvessels of critical need. Abnormal microvascular
(Autophagy) connects known functions of the
NO H2O2 function typically precedes and predicts the development
microvasculature that neatly explains Collaborators
its intimate link to disease development of conduit artery atherosclerosis and its risk factors. This
• Andreas M. Beyer indicates that it may be possible to reverse the negative effects
(Health) (Disease) in human subjects. Applying clinically • David D. Gutterman of microvascular defects before vascular disease progresses
relevant data from human tissues, the • Julie K. Freed to the development of large vessel atherosclerosis, plaque
HVRG team hopes to provide a detailed • Matthew J. Durand formation, and eventual cardiac events.
In healthy adult subjects (left), arteriolar endothelium produces NO which support a quiescent
nonproliferative/anti- atherosclerotic state. With onset of disease (CAD) or exposure to acute stress mechanistic understanding of disease with
(increased intraluminal pressure), flow through the microvasculature releases hydrogen peroxide, the goal to develop novel therapeutics
creating a proinflammatory environment throughout the organ, potentially leading to hypertrophy,
fibrosis, and atherosclerosis. LPP3, Autophagy, TERT, Ceramide and LPA among others have been that can translate into the clinic.
identified to play important parts in regulating this switch in dilator mechanism.
Thought Leader
Mending broken hearts:

guidelines into clinical processes that Can you tell us what your global
take patient population characteristics lifesaving programmes are and how
into account. We help healthcare the AHA works with many partners,
providers and patients achieve improved across many countries to address the
health with evidence-based information issue of non-communicable diseases
and tools for heart failure, stroke, blood and help save more lives?
The American Heart Association and its life-saving pressure and cholesterol management
through quality improvement initiatives
About 8 years ago, the organisation
began to increase its effort to address
treatment guidelines association, including Emergency

Cardiovascular Care (ECC), Workplace
and certification programmes. cardiovascular disease around the world,
offering technical support, scientific
Health, International Programs The Workplace Health department exchange and training to governments,
and Patient Quality Systems offers a suite of science-based, health care providers, hospital
When someone suffers a cardiac arrest, the first few minutes that follow the attack are crucial and can decide if someone
lives or dies. The effective administration of cardiopulmonary resuscitation (CPR) can greatly improve people’s chances.
The American Heart Association have been educating people on CPR, heart health, stroke and heart disease worldwide
for nearly 100 years and their latest mission is not just to save and treat patients, but to prevent heart conditions occurring
in the first place.
The American Heart Association’s mission is to be a relentless
force for a world of longer, healthier lives.
T
he American Heart Association’s In this interview with Research Outreach, world of longer, healthier lives. For
official guidelines on American Heart Association’s Chief nearly 100 years, we have been fighting Improvement. The Emergency evidence-informed tools and services and pre-hospital systems, workplaces
cardiopulmonary resuscitation and of Mission Aligned Businesses and heart disease and stroke, striving to Cardiovascular Care business is to help build and maximise an and communities.
emergency cardiovascular care are some Healthcare Solutions, John Meiners, save and improve lives. The Association comprised of more than 4,000 training effective workplace culture of health,
of the most respected around the world, tells us more about the Association’s was started in 1924 by six cardiologists centres and 450,000 instructors who last which can increase productivity, The American Heart Association system
not just in the United States. Their mission key strategies and how they aim to carry as a professional society for doctors year trained 22 million people in over reduce absenteeism and control of care approach – in coordination with
to save lives and prevent heart disease these out. and has evolved to unite more than 33 100 countries. healthcare costs. local cardiovascular societies, heart
and stroke begins with up-to-date and million volunteers and supporters as well and brain health advocates, business
reliable research and ends with hands-on Can you tell us more about as our 3,400 employees. Our Patient Quality Systems Our International team collaborates and government leaders – now drives
education on an international scale. Tools, the American Heart Association (AHA) Improvement team works to improve with governments and non- global heart and brain health at all levels
services and training are made available in terms of its background, history Can you tell us more about your role outcomes for patients by putting governmental organisations to adapt of society around the world.
by the Association to healthcare workers, and core mission? and responsibilities at AHA? knowledge into practice. We do this successful solutions from the United
patients and the public alike because The American Heart Association’s I oversee several revenue-generating by converting scientific research into States to extend the quality and lives In support of a country’s health priorities,
saving lives is everyone’s problem. mission is to be a relentless force for a mission delivery departments at the treatment guidelines, then translating of communities elsewhere. we provide our technical expertise and
Thought Leader
can double or triple a cardiac arrest

victim’s chance of survival. It is also
a fact that most cardiac arrests happen
at home so if you need to give CPR in an
emergency, you will most likely be trying
to save the life of someone you love:
a child, a spouse, a parent or a friend.
The American Heart Association is

the leader in resuscitation science,
education and training, and publisher
of the official AHA Guidelines for CPR
and ECC. How are the Association’s
guidelines helping save lives around
the world?
Healthcare professionals use CPR/basic
life support/advanced cardiac life support/
paediatric advanced life support to save
lives because that is the right thing to do.
At the time they are using one of these Association is a catalyst to achieving at saving lives of cardiac arrest patients
skills, they know they only have a very few maximum impact in equitable health in the hospital.
minutes to save a life. Many healthcare and well-being.
providers know that the American Developed through our strategic
Heart Association does a tremendous For more than 90 years, we have focused relationship with Laerdal, and launched in
job in evaluating research behind on treating cardiovascular disease. Over February 2015, the Resuscitation Quality
recommendations and that you can the last decade, we have turned our Improvement programme develops high-
experience in developing both patient health, such as Go Red For Women®, of the commitment to reduce premature
and public programmes to improve which educates women about their deaths from non-communicable diseases
This system of care approach drives global heart

the quality and length of people’s lives. greatest health risk, cardiovascular by 25% by 2025. World Heart Day
With our partners, we share the best disease, and is now promoted in more was started in 2000 and aims to increase
and brain health at all levels of society around the world.

in science with people around the world than 40 countries. We help improve awareness of heart disease and stroke.
through our annual Scientific Sessions, hospital systems of care with programmes The campaign for World Heart Day
International Stroke Conference and ten like Get with the Guidelines and Saving is about what you can do to get and keep
speciality conferences, and by supporting Children’s Lives in Botswana, Tanzania your heart healthy. This year’s campaign
joint science sessions with other and India, an initiative designed to – My Heart, Your Heart – was about trust what the Association says as being attention to preventing cardiovascular quality resuscitation skills through low-
countries’ cardiology societies at their empower community health workers creating a sense of commitment around cutting edge and reliable. We has been events. That effort requires improving dose, high-frequency CPR skills practice
local meetings. with skills to reduce under-fives mortality the common cause of heart health. World writing these guidelines for a long time health factors and risks that contribute and high-fidelity coaching. Validated
in low to middle-income areas. Heart Day resonates around the world so we are a trusted organisation. to not just cardiovascular disease by early evidence on actual patient care
We create educational programmes and plays a key role in spreading but many others including cancer and survival, more lives are being saved.
and tools that help people improve their We train 22 million people around awareness of cardiovascular disease When international training centres and diabetes, so we find ourselves
the world annually – from advanced and the simple steps we can all take open, they know that they will be focusing increasingly on total health. To find out more about the American
healthcare providers and corporate to reduce our risk. teaching reliable, proven techniques/ Over the next decade, we will address Heart Association, visit www.heart.org/en/.
employees to new parents – in first aid, skills/medications to their students. overall health and well-being, anchored
cardiopulmonary resuscitation (CPR) The American Heart Association When a health minister in China comes in cardiovascular and brain health, as well
and advanced life support. And, we encourages everyone to learn to us asking if we can teach resuscitation as health equity across all populations.
advocate for stronger public health how to perform CPR. Can you tell to 10% of their population, it is because
policies that support improved nutrition us why this is so important? they have done their homework and Additionally, we are seeking a paradigm
availability, obesity reduction initiatives It is estimated that more than six million recognise that the Association guidelines shift in hospital resuscitation practice.
and improved hospital treatment sudden cardiac deaths occur worldwide are developed in a rigorous way, and our Poor quality CPR is a preventable harm,
and systems of care. each year. Globally, the incidence business processes are uncompromising and timely delivery of high-quality CPR
of out-of-hospital cardiac arrest ranges with the patients survival and full recovery is the greatest determinant of survival Contact: Tracie G. Bertaut
The Association is a strategic partner from 20 to 140 per 100,000 people, as the critical outcome. from cardiac arrest. Unfortunately, even APR
with the World Heart Federation and and survival ranges from 2% to 11%. with trained professionals, poor quality 7272 Greenville Avenue
celebrates World Heart Day on 29th What are the plans for the American CPR is common. Advances in technology Dallas, TX 75231
September – can you tell us about this Statistics prove that if more people knew Heart Association next year? and evidence now show that low-dose, USA
collaboration, what this World Heart CPR, more lives could be saved. When As part of our mission to be a relentless high-frequency psycho-motor training E: Tracie.Bertaut@heart.org
day consists of and its global impact? a person has a cardiac arrest, survival force for a world of longer, healthier lives, is significantly more effective at increasing
T: +1 504 722 1695
The American Heart Association is a depends on immediately receiving we recently revised our Strategic Impact and maintaining CPR competency, and
John strives to identify unmet needs and W: www.heart.org
connect the dots to find inspiration and founding partner of the World Heart CPR from someone nearby. CPR, Statement, which guides how we go that resuscitation quality improvement
innovative solutions. Federation and an enthusiastic supporter especially if performed immediately, about our work: the American Heart initiatives are both necessary and effective
Education & Training ︱ Children’s Hospital Oakland Research Institute
STEM Summer Program:

sources, including the NIH (National
Institutes of Health), the CHORI summer
program offers in-depth research
opportunities in any of these fields. “I
have the privilege to work directly with
Inspiring the next generation of scientists these incredibly gifted young students.
They are the future face of science, and
they inspire me,” says Co-Director, Dr
T
More students in the United he number of students enrolling part of a community of students with Ellen Fung.
States are studying STEM to study STEM (Science, shared interests have all been shown
(Science, Technology, Technology, Engineering, to increase students’ persistence with CHORI SUMMER STUDENT
Engineering, and Mathematics) and Mathematics) subjects at university STEM subjects. Summer internships, RESEARCH PROGRAM
majors at university. However, in the United States has progressively such as the Children’s Hospital Oakland Over nine weeks, CHORI summer
there is a notable discrepancy increased over the last few decades. Research Institute (CHORI) Summer students: are paired with a mentor
in underrepresented students However, more than half of students Student Research Program (SSRP), offer who educates and empowers them in
choosing STEM, including that enrol in a STEM subject will effective interventions within a student’s a medical research field; attend weekly
racial minorities and those change their major during their time academic trajectory to develop their seminars and discussion forums to learn
first in their family to attend at university. The decrease in STEM confidence in STEM through one-on- about contemporary scientific research; Bonny Alvarenga, Chloe Ghent (fore), Nicolas
college. Research internships, enrolment and graduation is most one mentorship and broadening their design, carry out, and present their own Nido and Lara Ramirez (background)
such as the CHORI Summer discuss the challenges and occasional surprises
notable in ‘underrepresented’ students. scientific community. research project; join a community of like- in medical ethics during a weekly lecture.
Student Research Program, Underrepresented students include minded peers and CHORI alumni. Some
provide the much-needed ethnic and racial minorities and women. The CHORI SSRP was initiated in 1981, summer students have presented their
boost in scientific research They constitute 68% of all university the brain child of Dr Bertram Lubin, work at national scientific conferences, The program strives for diversity and individuals. It is about making new,
knowledge and confidence students in the States but remain now an internationally recognised and even co-authored published papers is committed to changing the statics valuable connections with my fellow
for underrepresented students
underrepresented in STEM careers. paediatric haematologist. He was first in with their CHORI SSRP mentors. behind underrepresented students CIRM [California Institute for Regenerative
to study and pursue careers
Providing encouragement for students to his family to attend college and therefore studying STEM. Medicine] friends, my mentors, and
in STEM. Co-directors of the
consider STEM careers before and during fully aware of the challenges present Studies have shown that summer research other students and scientists involved
program, Drs Bertram Lubin
university can change these statistics when negotiating the university system programs increase the likelihood of TESTIMONIALS FROM CHORI ALUMNI in the program. It is about getting
and Ellen Fung, firmly believe
programs such as these can and increase diversity in STEM fields. with minimal support. Almost 40 years underrepresented students pursuing Student testimonials speak volumes about inspired by the talks given by prominent
change the statistics behind later, Dr Lubin continues to Co-Direct the careers in STEM. Furthermore, programs the CHORI Summer Student Research scientific figures and the touching stories
underrepresented students A student’s self-confidence and program along with Associate Scientist, that include mentorship increase the
pursuing STEM futures and bring motivation are some of the greatest
factors that influence their pursuit
Dr Ellen Fung. In a highly competitive
selection process, CHORI SSRP selects
likelihood of these students pursuing
postgraduate education. Compared
CHORI summer program alumni are
greater diversity to science.
of a subject through university into underrepresented students from both to 2014 US census data, CHORI summer … more likely to pursue postgraduate
education than the US average.
a career. Research experience, “active high schools and universities. Real world program alumni are: 3.5 times more
learning” (problem-solving), and being research experiences are provided likely to pursue postgraduate studies
with practising medical and scientific than the US average for Asian or Pacific
professionals. CHORI SSRP interns Islander students; over 6 times more Program. Julia Nguyen, who took part in of bone marrow transplant pen pals.
develop their confidence in science, likely than average for Hispanic/Latino the program in the summer of 2017, says: And it is about learning the true ways
inspiring them to pursue futures in STEM students; and almost 9 times more “…this internship is about more than just of science and getting the opportunity
subjects, and encouraging greater likely than average for Black/African lab work. It is about joining a community to contribute to humanity’s growing pool
diversity in STEM fields. American students. of curious, intelligent, and like-minded of knowledge.”
CHORI is the renowned biomedical The CHORI Summer Student Research Percentage of CHORI SSRP Alumni who pursue graduate education*
research institute of the University of Program provides students not only
80.7%
California San Francisco (UCSF) Benioff with skills and knowledge to make them 76.0% 72.7%
Children’s Hospital Oakland. Students attractive candidates for future research
participating in the CHORI summer work as a professional, but with the US CENSUS
program have access to clinical research confidence needed to pursue a STEM CHORI Alumni
in close to 35 sub-specialty areas career. Furthermore, the CHORI Summer
including but not limited to, haematology, Program aims to provide students from
oncology, endocrinology and disadvantaged backgrounds, racial 28.5%
orthopaedics. Over 200 basic scientists, and ethnic minorities, and students with 21.4%
post-doctoral fellows, and laboratory staff disabilities, the opportunity to engage 13.5%
8.2%
guide students interested in basic science with and be inspired by STEM research. 4.7%
High school junior, Chima Ezeh, in his first basic in stem cell therapies, immunobiology, Greater diversity within STEM gives
laboratory experience, studied the colonisation Asian or Black/ African Hispanic/ Latino White/ Caucasian
infectious disease prevention, nutrition rise to greater creativity and innovation Pacific Islander American
of Neisseria Meningitidis in the laboratory
of Dr Gregory Moe at CHORI. and genomics. With funding from a – key characteristics needed to solve
variety of foundations and government today’s challenging scientific problems. *Of those respondents who have completed a minimum of undergraduate education.
Behind the Research
Dr Bertram Lubin Dr Ellen Fung
E: ssrp@chori.org T: +1 510-450-7604 W: www.chori.org/ssrp www.facebook.com/CHORISummerResearch/
The CHORI Summer Student Research Program

Catherine Campusano, a high school junior, spent her
summer in the laboratory of Dr Dario Boffelli gaining a deeper Research Objectives References
has been training underrepresented students understanding of the erythroid differentiation pathway.
in STEM for nearly 40 years. Carpi, A., Ronan, D.M., Falconer, H.M. and Lents, N.H.,
The Children’s Hospital Oakland Research Institute (CHORI)
Summer Student Research Program aims to increase the (2017). Cultivating minority scientists: Undergraduate
These feelings are echoed by other in the future?”, “Would I enjoy waking Program to Accelerate Regenerative number of students from underrepresented backgrounds research increases self efficacy and career ambitions for
students, including the 2018 CHORI up every day to know I will be working Medicine Knowledge] Award intern has pursuing and graduating with a STEM major. underrepresented students in STEM. Journal of Research
Summer Program participant, Chima in a lab?”, “Can I imagine myself given me the confidence that I could in Science Teaching, 54(2), pp.169-194.
Ezeh: “During this program, I have been eventually publishing a scientific paper?”, not only do research like this, but excel
Pender, M., Marcotte, D.E., Domingo, M.R.S. and Maton,
fortunate to integrate myself into such
Detail K.I., (2010). The STEM pipeline: The role of summer research
The program strives for diversity within
a diverse community of students who
experience in minority students’ Ph.D. aspirations. Education
share an ever-growing passion to further CHORI (Children’s Hospital Oakland Research Institute)
Policy Analysis Archives, 18(30), p.1
the field of science and medicine.”
STEM and is committed to changing the Summer Student Research Program
5700 Martin Luther King Jr Way Graham, M. J., Frederick, J., Byars-Winston, A., Hunter, A.
Students from the 2016 cohort are statics behind underrepresented students Oakland CA 94609, USA B., Handelsman, J. (2013) Increasing Persistence of College
excited about the future opportunities Students in STEM. Science, [online] 341 (6153), 1455-1456.
available to them after the CHORI studying science. Bio Available at: https://www.doi.org/10.1126/science.1240487
program: “…I am happy to say that this Bertram Lubin MD, Internationally recognised Haematologist [Accessed 25/10/2018]
summer full of discovery has been of large “How rewarding will it actually be to in research like this. From here, I see no and Associate Dean Children’s Health at UCSF, and Ellen
growth to me, and has brought to light pursue a PhD?”” says Raymundo Sanchez. other direction for me to go but up,” says Fung, PhD Associate Scientist at CHORI, Co-Direct the CHORI (2018) Summer Student Research Program. [online]
Available at: www.chori.org/Education/Summer_Internship_
unforgettable opportunities I thought Ava Daniel. Summer Student Research Program. With the same focus
Program/program_description.html [Accessed 23/10/2018]
were once far from my grasp. May this “Entering college with the experience for nearly four decades, the SSRP has trained well over 1000
be the beginning of many adventures and knowledge I have gained from this And whilst all the students developed underserved students interested in STEM, many of whom CHORI (2018) Blogs from CIRM High School Trainees. [online]
to come!” says Anna Victoria Serbin. internship will undoubtedly prepare confidence and knowledge in scientific are now practising physicians and basic scientists. Available at: www.chori.org/Education/Summer_Internship_
me for my coursework and allow research, some students also learned Program/CIRM_Blog.html [Accessed 24/10/2018]
“Working next to highly educated me to earn even more prestigious a sense of humour is often needed. Funding
scientists who are passionate about their opportunities. I feel extremely well Recounting his summer spent performing • NIH (National Institutes of Health)
research has allowed me to imagine equipped for the future in science qPCRs (quantitative Polymerase Chain • DDCF (Doris Duke Charitable Foundation)
myself in their shoes. It has led me
to ask myself questions like “Can I do this
and medicine that I want to pursue.
My experience as a CIRM SPARK [Summer
Reactions), 2018 CHORI Program
participant Jonathon Luo says: “It is often
• CIRM (California Institute for Regenerative Medicine)
• ACHPP (Alameda County Health Pathway Partnership)
Personal Response
said that baking is a science, but you
Collaborators What do you think student’s benefit from most by
Educational Background of Social & Economic Background rarely hear anyone saying science is
taking part in something like CHORI Summer Student
Parents of Students Served of Students Served like baking… Day after day, I laboured • Biology Scholars Program at UC Berkeley
Research Program?
to pipette drop after drop into their • CHAMPS (Community Health & Adolescent Mentoring
Did not graduate
from high school appropriate wells, bent over and Program for Success) at UCSF Benioff Children’s Dr Ellen Fung: As many of our students come from
10% Low
fatigued… the strain of pipetting started Hospital Oakland households with little to no science background and
Disabled Income* minimal experience with US secondary education, what
13% 12% to set in, reminding me that my right • Students Rising Above, Achieve Scholars, Biotech Partners
our students gain from just nine weeks in the SSRP is often
thumb was still getting a pretty hardcore immeasurable. In addition to practical laboratory and
Did not Did not
workout… I’ve learned countless nic • g
en de r • scient
clinical skill development, experience with hypothesis and
VERSI
eth ific
l• •a
c
new skills, gained a great amount of
ra
graduate attend college protocol generation, statistical analysis and presentation
ad
tu
cul
em i
c
Socially or
TY
DI
from college 32% knowledge in the field of molecular practice: CHORI SSRP students broaden their scientific
58% Economically
disadvantage biology, and of course, had lots of fun… CHORI
network. Their new scientific community is invaluable to
75% But perhaps most importantly, I will leave opening doors and improving opportunity for acceptance
this experience with extreme respect
CELEBRATING OUR
DIVERSITY into university, graduate school and future participation
in other highly competitive internships.
for laboratory scientists all over the
*In 2018, low income defined as world, who inarguably have the strongest
Includes data from recent CHORI student interns: 2012-2018. family of 4 with income <$44,000 thumbs on the planet.”
Education & Training ︱ Professor Hamsa Venkat
Improving Maths
performance in South
Africa’s primary schools
S
Professor Hamsa Venkat outh Africa faces a range of social Witwatersrand in Johannesburg. She
holds the SARCHi Research issues including high levels of leads the Wits Maths Connect project,
and Development Chair in unemployment, inequality and which is now in its second five-year
Primary Maths Education widespread poverty. The schooling phase. The project team works with
at the University of the system is dominated by low performing ten partner primary schools serving
Witwatersrand in Johannesburg. schools with large classes and few disadvantaged students, devising
She leads the Wits Maths resources serving the poor. The and trialling interventions aimed at
Connect project. The project schools, teachers and children face improving primary maths performance
team works with ten partner substantial poverty-related impediments. through a focus on supporting coherent
primary schools serving Internationally, there is limited research and connected classroom teaching.
disadvantaged student
populations, and develops and
on mathematics teaching and learning
among poor and hungry children.
Intervention models and materials with
evidence of success are being taken
These on-the-ground realities have intervention data on learner performance
and their approaches to solving the
researches interventions to help
teachers improve their students’
Professor Venkat seeks to redress this up in provincial and national pilots in to be taken into account to design problems. Weekly training workshops and
substantively useful and pragmatic

bias, providing a sense of these on-the- South Africa and beyond, and feed into supported teaching were also provided.
maths performance. Intervention ground realities that have to be taken into improvements in both the classroom
models and materials with
evidence of success are being
account to design substantively useful
and pragmatic intervention models.
and teacher education.
intervention models. Encouraging results from a series of
postgraduate students leading the
taken up in provincial and
PHASE ONE teaching with single classes led to a
national pilots in South Africa,
WITS MATHS CONNECT PROJECT During the first five years of the project teachers to focus their pupils’ attention quality of primary maths teaching when scaled-up project with the members
leading to improvements
Professor Hamsa Venkat holds a Research (2011–2015), the researchers worked on number relationships and properties, working from an evidence base of gaps of the project team acting as teachers
in both the classroom
and teacher education. and Development Chair in Primary with the partner schools supporting the encouraging them to employ strategic in teacher knowledge. It aims to address in nine classes of one of the partner
Maths Education at the University of the development of primary mathematics thinking with number, rather than relying this gap in mathematical knowledge schools. A test-teach-test sequence took
teaching and learning. One focus on counting to solve problems. Another and improve the teaching and learning place with weekly planning meetings
was building number sense through key element in phase two is expanding of multiplication and division across the with the teachers and research team
working with both teachers and learners work on multiplicative reasoning. primary grades. and also revealed promising results.
in the Lesson Starters Project. The second A further scaling, to involve classroom
was the I Hate Maths project aimed at THE MULTIPLICATIVE DEVELOPING THE MODEL teachers in all ten partner schools was
building communities of primary teachers REASONING PROJECT At this level of learning, there is evidence then designed.
and the public with an interest in talking Research into the educational quality that short sequences of well-structured
about mathematics. A 20-day Primary of South African primary teachers’ lessons can have a positive effect. A LESSON STRUCTURE
Mathematics for Teaching course was mathematical content knowledge short-term intervention, comprising four Based on these positive results, a four-
developed, with multiple trials showing revealed particular weaknesses relating lessons, carefully designed to take into lesson model was designed. Each lesson
robust improvements in primary teachers’ to multiplicative reasoning. Multiplicative account levels of learning and classroom was made up of the following four
mathematical knowledge. reasoning is the understanding and ability culture was developed. The pedagogic sections:
to solve mathematical problems involving approach, together with the structure 1. Revision of multiplication
PHASE TWO a multiplicative structure. This includes and content of the lessons, are based and division facts.
The 20-day course and the I Hate Math mutliplication and division problems, but on the ‘Big Books of Word Problems’ by 2. Students work in pairs followed
workshops are continuing through the extends to fractions, ratio and proportion Professor Mike Askew, a member of the by a whole class discussion of three
second phase of the project (2016–2020). situations, and is a fundamental part of project team. initial problems led by the teacher.
Building on the models of the Lesson mathematical learning. 3. Students work independently
Starters Project, an additional focus The pilot model was designed so that on six problems.
of the second phase is the Seeing The Multiplicative Reasoning project students would be tested before and 4. Multiplication and division
Number Structure project which includes builds on the project team’s experience of after the four-lesson sequence in order number sentence examples
workshops and in-class coaching to assist developing interventions to improve the to provide pre-intervention and post- for independent practice.
Behind the
The test was made up of 14 multiplicative
reasoning problems with five additive
reasoning problems, to see how students
Research
differentiated between the two.
APPLICATION
The project was then rolled out for all ten
partner schools across the Intermediate Professor Hamsa Venkat
Phase Grades 4–6. Two grade 7 maths
teachers, one from a government and team
fee-paying suburban school and one
from a government no-fee township E: hamsa.venkatakrishnan@wits.ac.za T: +27 (0)117173742
school, also offered to take part in the W: https://www.wits.ac.za/staff/academic-a-z-listing/v/
program. Although both schools serve hamsavenkatakrishnanwitsacza/ W: http://tiny.cc/WMCP
disadvantaged populations, the suburban
school benefited from smaller class
sizes and less crowded classrooms. The
teachers attended afternoon workshops, Professor Hamsa Venkat from the University of the Venkat, H. & Mathews, C. (2018). Improving multiplicative
led by members of the project team, Witwatersrand in Johannesburg focuses on improving reasoning in a context of low performance. ZDM
prior to leading the intervention lessons. primary maths teaching and learning. Mathematics Education. Available at: https://link.springer.
com/article/10.1007%2Fs11858-018-0969-6 [Accessed 12
The pre- and post- tests were Multiplicative reasoning is the understanding and November 2018].
ability to solve mathematical problems involving
administered by members of the project
team before the intervention commenced
a multiplicative structure.
Detail Venkat, H. & Askew, M. (2018). Mediating primary
and repeated six weeks later. Students Professor Hamsa Venkat mathematics: theory, concepts and a framework for studying
were told to answer the questions, appear to be more able to make sense of connect and deepen the subject advisers’ Wits Maths Connect Corridor practice. Educational Studies in Mathematics. https://link.
choosing the most efficient approach the problems through a ‘key models and mathematical knowledge together with Marang Block springer.com/content/pdf/10.1007%2Fs10649-017-9776-1.
and showing working out where they felt connections’ approach. their willingness and ability to have Wits School of Education pdf
it was required. constructive mathematically-focused St Andrews Road
These results indicate that well-structured conversations with primary teachers in Parktown Venkat, H. & Spaull, N. (2015). What do we know about
RESULTS short-term intervention models are order to support teaching development Johannesburg primary teachers’ mathematical content knowledge in South
The township school started with a lower useful, practical tools for teachers to of mathematics. South Africa Africa? An analysis of SACMEQ 2007. International Journal
performance profile than the suburban implement in order to improve their of Educational Development, 41, 121–130. https://doi.
school. The post-intervention results students’ performance in multiplicative National initiatives include the Bio org/10.1016/j.ijedudev.2015.02.002
showed an overall improvement in reasoning tasks. They work without Foundation Phase Grade 3 Diagnostic Professor Hamsa Venkat holds the NRF/FRF SARCHi
multiplicative reasoning performance disrupting broader curriculum coverage. Assessment. This is a three-week test- Research and Development Chair in Primary Maths Askew, M. (2005). Beam’s Big Book of Word Problems Year 3
across both schools, with larger The next step is to investigate if the teach-test diagnostic assessment model Education at the University of the Witwatersrand in and 4 (New edition). London: BEAM Education.
improvements in the township school, model can work with less input from with interim teaching activities focused Johannesburg. Her current work focuses on primary
and prompted a detailed analysis of the the project team. A roll-out involving on key mental mathematics skill areas. mathematics teaching and learning development. Askew, M. (2005). Beam’s Big Book of Word Problems Year 5
learning outcomes of the intervention provincial subject advisers working with It aims to use assessment to develop Previously, she was a mathematics teacher in London, and 6 (New edition). London: BEAM Education.
with these Grade 7 classes. This centred the intervention material and trialling the number fluencies and strategies. The before obtaining a BERA-award winning PhD from King’s
on matching students’ pre- and post- model with just one initial workshop for project team are working in partnership College London and moving into teacher education
tests and analysing the differences
in the students’ performance on the
teachers is planned. with the Rhodes Numeracy Chair and
the Department of Basic Education on
at the Institute of Education.
Personal Response
multiplicative reasoning problems and WITS MATHS CONNECT RESEARCH national trials of these assessment tools Funding
examining the observed changes in AND DEVELOPMENT ACTIVITIES and teaching activities. The multiplicative reasoning study and the broader work of What are your plans for future research in developing
primary maths performance?
the students’ approaches to solving The Wits Maths Connect project team the Wits Maths Connect – Primary project are generously
the problems. are involved in a number of other current The team members teach and supervise supported by the FirstRand Foundation (with the RMB), Promising results have led to provincial, national
research and development projects. across B Ed, Hons, Masters and doctoral Anglo American Chairman’s fund, the Department of and international interest in the intervention modes and
The test results reported in a recent paper Provincial initiatives include the Coaching programmes at Wits. They are also Science and Technology and the National Research materials that have been developed in the Wits Maths
Connect – Primary project. We are currently building a
by Hamsa Venkat and Corin Mathews 4 Development course for primary involved as partners in the Department Foundation.
longitudinal analysis of improvement in the sophistication
have shown substantial improvements in maths subject advisors. This is a 16-day of Higher Education and Training Primary of children’s approaches to solving number problems in
the students’ ability to use appropriate course split across University-based days Teacher Education (PrimTEd) project Research Team the context of our development work. The linked research
methods to calculate answers. Students and lesson observation days. It aims to which focuses on pre-service primary The research and development work of the Wits Maths and development activity has been powerful for producing
mathematics teacher knowledge and Connect – Primary project are supported by a team of evidence-based models and materials that policy-makers
Intervention models are useful, practical practice development as well as working

with the Department of Basic Education
staff and postgraduate students: co-Project Managers,
Dr Samantha Morrison & Corin Mathews, Wits Distinguished
and researchers can take up and trial. Over time, we feed
into better understandings of how to address and improve
tools for teachers to implement in order on the development and trialling Scholar, Prof Mike Askew, and team members: Dr Lawan primary mathematics learning outcomes for children in
contexts of disadvantage.
of national diagnostic assessments Abdulhamid, Herman Tshesane, Marie Weitz, Sameera
to improve their students’ performance. for the early grades Hansa, Thulelah Takane, Dr Lynn Bowie and Lincoln Lavans.
Education and Training ︱ Professor Hollie Swanson
Careers in Science:
Summer Training in Environmental and Pharmacological
Sciences (STEPS)
T
The future of scientific research he genesis of the STEPS project the STEPS project, whereby five
depends on a talented, diverse arose from Professor Hollie undergraduate students were enrolled
and inclusive workforce with Swanson’s reflections about her in a 10-week summer program.
high scientific proficiency. own career goals whereby she sought Subsequently, Swanson received a second
Undergraduate research to align her passion for research with source of funding from the National
experiences have been shown the needs of the scientific community. Institutes for Environmental Health
to play a key role in encouraging Swanson’s expertise in research pertains to Sciences, which provided support for
students, especially those from problems relating to environmental health an additional 12 undergraduate students
historically underrepresented sciences whereas her teaching activities as well as 12 peer mentors who offered Participants engaging in the improvisation workshop.
groups, to pursue careers focus on delivering pharmacology related career advice to students. The program
in science and healthcare concepts to undergraduate, graduate and is designed to introduce students to the
professions. In response to these professional students. Through her work, highly interdisciplinary and collaborative her local area of Kentucky because of discussing ethics, lab books as well as sustainable farming. Students discussed
needs, Professor Hollie Swanson, Swanson aims to use both her expertise nature of environmental health science the large numbers from socioeconomically the importance of communication in a way the use of outreach and the importance
from the University of Kentucky and teaching experience to encourage research, which is focused on solving key disadvantaged backgrounds whom that is enjoyable for students. This enables of using culturally appropriate ways to
has developed the Summer students from all backgrounds to pursue global health problems. An additional she wanted to encourage and support. them to get to know both the university reach an audience. In addition, on one
Undergraduate Research careers in science and research. focus is on preparing underprivileged and A particularly effective way to recruit campus and each other better. The strong week students worked with an agriculture
Fellowship (STEPS), which
under-represented students for successful onto the program was through obtaining group dynamics developed also help extension agent to check stream health
offers individualised research
Swanson was keen to develop a program careers in relevant fields. recommendations from other academic students to optimise their experience of by collecting insects and measuring water
experiences in different areas of
which could offer individualised research staff members. Swanson has developed the project. quality. They discussed runoff and the
pharmacology and environmental
experiences to undergraduate students. RECRUITING STUDENTS connections with a number of universities range of substances that can end up in
health sciences to undergraduate
students from a variety of Funding from the American Society Swanson carefully considered the including Eastern Kentucky University The students participating in the program the water supply.
backgrounds. of Pharmacology and Experimental target audience of the STEPS program. and Morehead State University. Both spend the majority of their time in their
Therapeutics provided initial support She sought to include students from institutions were actively looking for faculty mentor’s laboratories. Due to the Careers are a key concern of the students
research opportunities for students multidisciplinary nature of environmental participating so the program also involved
so were keen to become involved. health sciences and pharmacology, this lunches where researchers visited and
Professor Swanson and participants of the
includes a wide variety of departments discussed their research and career paths.
STEPS program pose at the end-of-program Swanson realised that beginning recruiting and colleges. Throughout the summer, Students are able to interact with these
reception celebration. early was essential in getting sufficient the students also work on developing professionals to become aware of the
students on board wide variety of career
and now begins the
recruitment before
Students are able to interact with these options available to
them. Shadowing
the students leave professionals to become aware of the opportunities were also
for their Christmas organised for students
break. The University wide variety of careers options available where they could
to them.
of Kentucky also establish networks to
produced a video to help them progress
help with recruiting towards their chosen
students onto the STEPS project. In soft skills, such as interview and oral career. These activities allow students
addition, as the program has become communication skills. to see how science is used in their local
more established, word of mouth has community whilst also having exposure
become a useful way of encouraging more Weekly activities are organised throughout to different potential career paths.
students to apply. the program, such as hiking. On one
week of the program, a hike at Red At the end of the program, the students
PROGRAM ACTIVITIES River Gorge was arranged through an prepare a poster that describes their
In order to prepare students for the outdoor centre. Another week, students research projects and presents them
program, they participate in several days received a visit from rapper Farmer to the faculty and staff of the involved
of orientation activities. This includes Brown, who raps about nutrition and departments. An event with around 50
Behind the Research
Professor Hollie Swanson
E: hollie.swanson@uky.edu T: +1 859 323 1463 W: https://med.uky.edu/users/hswan
W: https://surfsures.blogspot.com/ www.linkedin.com/in/hollie-swanson-522821a/
Research Objectives
Professor Swanson’s Summer Training in Environmental
and Pharmacological Sciences (STEPS) aims to enhance
student learning and help prepare students from a variety
of backgrounds, for successful science-related careers.
Detail
Dept. of Pharmacology and Nutritional Sciences,
MS 305,
University of Kentucky College of Medicine,
800 Rose Street,
Lexington,
Kentucky
Student participants presenting their research findings
at the end-of-program poster session. 40536, USA
Bio
attendees is organised where students
can receive feedback on their work
to discuss scientific concepts. Receiving
this feedback from students has been
involved in training a new student for
the project. Discussions have also started
The director of the Summer Undergraduate Program
in Environmental Health Sciences and Pharmacology,
Personal Response
from graduate students. This also hugely rewarding for Swanson, who has to take place about what phase two Professor Hollie Swanson received her PhD degree
provides the opportunity for graduate altered her view of professional success. of the program may look like. Swanson from Purdue University and completed postdoctoral Have you experienced any challenges whilst working
on the STEPS project?
students to gain experience in providing Through experiencing their talent, zest for is considering partnering with other training Michigan State and Northwestern Universities.
constructive advice. Participating learning and continued curiosity, she now institutions to provide students with She is currently Professor of Nutritional Sciences The biggest challenge has been overcoming my own
students are also provided with a token feels more confident about the future of different types of research experiences. and Pharmacology and directs the Women’s Executive personal characteristics. I love coming up with new ideas
as a reminder of their experience in the society. Particularly significant for Swanson For example, areas of particular interest Leadership Development program. and flying by the seat of my pants. In addition, and like many
introverts, I spend most of my life inside my own head.
program. They receive either a pestle is the feedback from students that she would be those focusing on the
These attributes can translate into poor execution and
and mortar or a relationship between Funding
Through experiencing their talent, zest
poor communication. This program involves 50-75 faculty,
globe, depending climate change • National Institutes of Environmental Health Sciences staff and students during the short 10-week program. This
for learning and continued curiosity,

on whether they and environmental (NIEHS) means I need to plan ahead, be specific, align everyone’s
have been engaged health. Another area • American Society of Pharmacology and Experimental expectations, get the most out of them and make sure
in pharmacology
or environmental
she now feels more confident about of interest would
be a partnership
Therapeutics (ASPET) it all runs smoothly. Fortunately, I have a very supportive
departmental chair and outstanding staff that I can rely on.
health science- the future of society. that would provide It has taken some trial and error, but we now function well as
a team developing timetables and effective administrative
related research. the students with
processes to ensure that the students have the best summer
These tokens are engraved with the word has changed their lives and subsequently insights pertaining to the global nature experience possible.
STEPS and the year of their fellowship. interacting with them in medical and of science and research. The possibilities
graduate school classes, taking steps for the future are working with non-profit What are your future plans for research in this area?
FEEDBACK FROM STUDENTS closer towards their future career organisations like the Alan Alda Centre Future plans for research in this area include:
Feedback is obtained from students in scientific research. for Communicating Science or COMPASS. 1) Understanding the needs of the students with
by administering pre and post program These are cross-disciplinary organisations respect to their career progression in STEM.
surveys about their expectations and THE FUTURE OF THE PROGRAM which aim to help scientists learn to 2) understanding how these needs differ amongst
experiences of participating. Preliminary Many of the students from the first year communicate more effectively with the different groups (i.e., gender, socio-economic,
results from these surveys indicate that of the program stayed in the lab and public. Swanson would also like students racial, first generation, etc.).
through participating students gain continued to work on their scientific to have the opportunity to participate 3) Identifying how undergraduate research
confidence, a greater understanding research. Swanson has been impressed in improvisation activities to allow them experiences (like the STEPS program)
of the nature of scientific research, with their continual motivation in their to become more confident in their can be modified to better meet the needs
how to formulate a research question, studies. One of the students from the communication skills. of all the participating students.
how to work independently and how first year of the program has also been
Physical Sciences ︱ Professor José Goldemberg
Technological leapfrogging
the global energy crisis:
How can changing the role of science in developing
countries help with an oncoming climate catastrophe?
T
In 1975, the Brazilian he impact that human beings commercial energy is consumed
government launched have had on the environment is by the 25% of the world population the government launched the National that was doomed to fail from the start on political pressures more than what is
the National Alcohol Program immeasurable – from the vast who live in industrialised countries, Alcohol Program (NAP) with the aim due to the fundamental requirement actually needed. In developing countries,
(NAP) with the sole aim areas of rainforest that disappear every with the remaining 30% being rationed of alleviating some of the country’s to shield pilots from the masses of funding is often directly related to the
of relieving the country’s single day, to the country-sized island out to the 75% of people living in dependence on fossil fuels. Back then, radiation produced using extremely research being undertaken in developed
crushing dependence on of plastic floating in the Pacific Ocean. developing nations. Professor Goldemberg was interested in heavy materials. Heavy materials and nations. As Professor Goldemberg
fossil fuels with a move Air pollution. Oil spills. Mass extinction. how crops, already in production in Brazil,
to cleaner ethyl-alcohol
based fuels – and, thanks to
Politicians who claim they don’t believe
in monsters, when a titanic monster
This situation is not a sustainable
one and it would be naive to expect
could be used to create ethanol and other
ethyl-alcohol fuels.
Scientific research is motivated not only
researchers like Professor José sits right outside our collective door, the balance to stay the same. If we look by curiosity of love for science, but also
Goldemberg, of the University
of São Paulo, the program
waiting. It seems that every day we draw
closer to blindly falling prey to its trap:
at the data, what we see is that the energy
use of industrialised nations has actually
In a 1978 paper, published in Science,
he looked specifically at the energy cost
by fashions and the perception that some
was an overwhelming success.
Combining the country’s
a climate catastrophe is just around the stabilised in recent years, while that of and expenditure of several different areas of research are more rewarding
own natural resources with
corner. In recent years, climate change
and the renewable energy sector have
developing countries continues to grow.
What happens when the scales begin
crops: sugarcane, cassava and sweet
sorghum. He focused on these specific than others.
technological leapfrogging received a lot of media attention – and to tip and developing countries consume crops because they are essentially a form
– and skipping over the less
you’d be forgiven for thinking that the more and more energy? particularly of non-polluting solar energy: the sun’s aircraft go together like chalk and cheese explains, ‘Scientific research is motivated
suitable technologies used
issues are controversial but, in fact, over energy from polluting fossil fuels? rays provide the crops with the energy and the aircraft program would eventually not only by curiosity of love for science
by industrialised nations – means
95% of practising climate scientists agree Professor José Goldemberg has spent they need to grow – and a little extra; be replaced with the submarines that but also by fashions and the perception
that, today, ethanol replaces
that human beings are the main driving his entire career looking at problems such that extra energy is stored by the plants we have today. History is littered with that some areas of research are more
50% of the gasoline that would
otherwise be in use in Brazil. force behind global warming. as these and, if man-made environmental – quite literally saved away for a rainy similar examples of ill thought out rewarding than others’. This often leads
Professor José Goldemberg degradation in general and climate day – and can be extracted in the form scientific endeavours. to politicians pouring money into projects
argues that it’s time to take It’s easy, perhaps even comforting, change is are going to be the bitterest of ethyl-alcohol at a later date. that are failed from the start because
the approach globally. to blame the generations that came pill our generation has to swallow, In science, funding is often provided the underlying infrastructure that makes
before us: to say that their carelessness perhaps we can take a leaf out of his work Professor Goldemberg’s work by organisations who lack experience something successful in one country
and greed is what led us to this point – to sweeten the taste with sugar. demonstrated that sugarcane in front-line science. Government bodies is missing in another. But is there
led the monster to our door – but that was the most efficient crop to use who look for buzz-words in funding a better way?
only tells part of the story. In fact, much SUGARCANE AS A when converting this solar energy into applications and dole out money based
like the uneven global distribution of SUSTAINABLE FUEL a chemical fuel and it paved the way
wealth, the majority of global energy It might seem like a starry-eyed idea from for the Brazilian energy-boom that
is consumed by a minority of people. one of Isaac Asimov’s novels but, in reality, followed. Today, an estimated 50% of the
Approximately 70% of the world’s Brazil has been using sugarcane to fuel gasoline that would be in use for fuelling
its cars for almost half a century. The cars in Brazil has been replaced with
idea started in 1975 when, in response ethanol from sugarcane, a renewable fuel.
to an international oil crisis, An achievement that was made possible,
in part, by what Professor Goldemberg
calls technological leapfrogging.
ENHANCING THE ROLE OF SCIENCE

IN DEVELOPING COUNTRIES
At the height of the Cold War, when
nuclear was everything, the US Air
Force was pouring millions of dollars
into developing the Convair NB-36H
nuclear-powered plane. A project
Behind the Research
Professor José Goldemberg
E: goldemb@iee.usp.br T: 5511 3091 5053 W: www.iee.usp.br/ W: http://www.iiasa.ac.at/web/home/about/achievements/awards/
Zayed-Lifetime-Achievement---Goldemberg.en.html W: www.af-info.or.jp/en/blueplanet/doc/list/2008essay-goldemberg.pdf

Goldemberg, J. et al (1978).’Energy Balance for Ethyl Alcohol
Professor José Goldemberg, of the University of São Paulo,
research aims to relieve the world’s crushing dependence on Production from Crops’. Science, Vol. 201 (4359), pp. 903-906.
fossil fuels with a move to cleaner ethyl-alcohol based fuels.
Goldemberg, J. (1998). ‘Leapfrog energy technologies’. Energy
policy, Vol. 26 (10), pp. 729-741.
Detail Goldemberg J. Johansson T. B., Reddy A. K. N. and Williams R.

Institute of Energy and Environment- University of São Paulo H. (1985). ‘Basic Needs and Much More With One Kilowatt Per
Professor Goldemberg believes that
developing nations can – and should
Expanding the Brazilian ethanol program Av. Professor Luciano Gualberto,
1289 São Paulo/SP Brazil
Capita’. AMBIO, Vol. 14 (4-5): pp. 190-200.
– leapfrog over the technologies that by a factor of 10 would supply enough 05508010 Goldemberg J. (1998). ‘What is the Role of Science in
are unsuitable for their specific situations.
Converting sugarcane to a fuel is one ethanol to replace more than 20% Bio
Developing Countries?’. Science, Vol 279 (5354), pp. 1140-
1141.
specific example of how this can work of the gasoline used [around] the world. Professor Goldemberg received his PhD in Physical Sciences
well, but the approach can be generalised
to many technologies around the globe. expensive electric generating station, technological breakthroughs have
from the University de São Paulo in 1954. Presently,
Professor Emeritus he was the Rector of the University
Personal Response
Take the issue of supplying lighting sending power over miles of transmission been reached. But, when focused from 1986 to 1990 and Minister of Science and Technology
to isolated villages around Africa, for and distribution lines, supplying a bulb so intensely on what has come before, and Minister of the Environment of Brazil. In 2000, he was Having worked within the energy field for such a long
time, you must have witnessed a lot of technologies
instance. The majority of the country lacks that ultimately converts less than 1% it’s easy to lose perspective on where awarded the VOLVO Environment Prize.In 2008, he was
come and go. Are there any technologies whose success
the electrical grid system that developed of the original fuel energy to light’. we’re going. At some point, during awarded the Blue Planet Prize and in 2013 the “Lifetime – or failure – you have found surprising?
nations use and, while this could be the years that have passed, some areas Achievement Award” from the Zayed Future Energy Prize.
implemented at great cost, professor If a similar technological leapfrogging in science and technology have resorted Successful examples:
•W ind-generated electricity, which was a curiosity 50 year
Goldemberg argues that it is unnecessary approach was adopted around the world to blindly following in the footsteps Collaborators
ago and today represents 4.4% of the world’s electricity
in most cases. in our fight against climate change, of predecessors, without considering • Dr José Roberto Moreira production mostly in developing countries
the energy crisis we are currently facing how useful their approach might be. • Amulya K.N. Reddy •C ooking with LPG (liquid petroleum gas) replacing
SUSTAINABLE DEVELOPMENT could be avoided. ‘A simple calculation Vision and perspective are important. • Robert H. Williams inefficient wood cooking stoves
OF ENERGY AROUND THE WORLD shows that expanding the Brazilian • Thomas B. Johansson • Cellular telephones eliminating fixed telephones grids
Typically, lighting in isolated villages ethanol program by a factor of 10 would The work of Professor José Goldemberg,
is currently supplied by kerosene lamps, supply enough ethanol to replace of the University of São Paulo, Brazil, Unsuccessful examples:
batteries or candles and replacing more than 20% of the gasoline used resonates over more than 200 years with • Supersonic commercial flights
•P roduction of gasoline and diesel oil from
these with standard incandescent [around] the world’ explains Professor those wise words from Isaac Newton.
shale sands in Canada
light bulbs would be a better solution. Goldemberg. The approach isn’t limited He reminds us that using what others • Large-scale storage of electricity in batteries.
However, imagine skipping over this to ethanol fuel or village lighting, have achieved previously can solve
old technology and going straight to though – it can be applied to a whole problems in often unexpected ways
Compact Fluorescent Lightbulbs (CFL), swathe of technologies around the world – but that it is important to consider
which are four times as efficient. This has and help fight the oncoming energy crisis the approach used in tackling a problem.
the knock-on effect that it is now feasible we are currently facing. Technological leapfrogging provides
to power the system using Photovoltaic a route for scientists to skip over the
(PV) solar cells, leapfrogging over less On describing his vision and potential stumbling blocks of using
efficient technologies, like the inefficient achievements in 1675, the world- unsuitable technologies and, in Brazil,
electricity grid and the expensive power renowned scientist, Sir Isaac Newton, it has been used to alleviate one of the
station that supplies electricity to it. ‘A PV- famously said ‘If I have seen further biggest problems we face today: the
CFL system is some 100 times as efficient [than others] it is by standing on the global energy crisis and global warming.
as kerosene and a half-million times more shoulders of Giants’. Serving as a source Expanding the approach globally could
efficient than candles’ says Professor of inspiration for scientists, this adage shape the energy-climate for future
Goldemberg. ‘The PV-CFL solution has been repeated around the world, generations around the globe.
leapfrogs over its alternative: a large, time and time again, when advanced
Physical Sciences ︱ Denis Fedyanin and Alexander Chkhartishvili
Opinion dynamics
each agent’s opinion is the weighted
sum of the opinions of the agents that
he or she trusts, where the weights are
the levels of confidence. A consensus
and consensus
arises if opinions converge to a single
value that is the overall opinion of the
network. This is always the case when
each person has non-zero confidence
in social networks
and there are no autonomous clusters
in the network.
The contribution of each agent

to the collective overall opinion can
be determined using linear algebra.
REAL LIFE OPINIONS
T
Denis Fedyanin and Alexander he development of online social the formation of opinion. It also provides Let us consider a group of friends
Chkhartishvili are researchers networks together with their a description of how individual members that form a social network. We have
at the V.A. Trapeznikov Institute inﬂuence on the social, economic of a group can reach a consensus. information on their initial opinions
of Control Sciences of the and political aspects of modern society, regarding a particular issue and we
Russian Academy of Sciences has triggered an escalation in interest The DeGroot model is based on a Markov construct a model where each person’s
The development of online social

in Moscow. They use statistical in social network structures. Social chain, a random process where the new opinion is a combination of their last
modelling of social network networks, however, have been around probability of any future event depends opinion and the opinions of their friends.
structures to simulate opinion
dynamics and decision making.
much longer than the internet. Where
people interact with each other, whether
only on its current state, not on its past
behaviour; so the future is independent
Given this model, we can measure the
influence of each person in the group.
networks has triggered an escalation
Their recent work focuses on they are acquaintances, friends or of the past. In this model, an agent is in interest in social network structures.
a consensus analysis of complex adversaries, information is exchanged, characterised by his or her opinion. Each It is unlikely that each person just
social network structures. opinions are influenced and social opinion is allocated by an arbitrary real constructs their new opinion based on comprising two agents, external and person in the initial network, they can
networks exist. number; not necessarily a probability their previous opinion and the opinions of internal, that interact with each other. calculate the new influences in a revised
as it would be with a Markov chain. other people in the social group. It is more model by including a simple formula
OPINION DYNAMICS The model pools the opinions of each likely there are some hidden advisors that CONSENSUS IN NETWORKS incorporating information of how much
How specific individuals influence the agent into a network model, which can also affect opinion. OF COMPOUND NODES a person respects his or her values
formation of another individual’s opinion gives a prediction on the final opinions Communication between a given node and how their values could be changed
is of particular interest to Denis Fedyanin of all persons. These opinions coincide COMPOUND NODES and other network nodes is carried by a person’s behaviour.
and Alexander Chkhartishvili and their if network consensus takes place. Fedyanin and Chkhartishvili have out by the external agent. The internal
research at the V.A. Trapeznikov Institute The model can also be used to determine modified the initial model to include agent can only interact directly with If there is a consensus in the original
of Control Sciences, Russian Academy how central an individual agent is within the influence of these advisors in the the external agent in the same node, model, then repetition of the iterative
of Sciences, Moscow. They are using a network’s decision making. formation of an individual’s opinion. and can be considered as taking the role process over a sufficient period of time
statistical modelling of the network Where previously each person, or of a personal advisor. leads to convergence in the modified
structures to simulate opinion dynamics MODELLING OPINION DYNAMICS node, in the network was represented model and results in the formation
and decision making. Their AND CONSENSUS by a single agent, each person is now The researchers have found that given of the collective overall opinion or
recent work focuses on Each agent can be depicted as a node represented by a compound node a measure of the influence of each consensus of all people in the group.
how a group of people, in a network. Initially, each agent has
a social network, can reach a specific opinion about an issue which is
a general agreement, or given a numerical value between 0 and
consensus of opinion. 1 that can be a probability or have other
interpretations. Opinions are updated over
THE DEGROOT MODEL time. All opinions evolve in accordance
The researchers have with an iterative and linear process
chosen to use the DeGroot whereby each agent’s opinion is updating
model to analytically describe opinion using a weighted average of the other
dynamics. This is a network interaction agents’ opinions. These weights are based
model known for its computational on influence and confidence. The level
efficiency. The DeGroot model simulates of confidence that agent A has in agent
the spread of information and the forming B is the same as the level of influence
of opinions within a social network. This that agent B has over agent A. The total
allows the researcher to understand confidence level of any agent is 1.
how the network’s structure influences Agents communicate by exchanging
the transmission of information and opinions. At each subsequent step,
MODELLING TWO
COMPOUND NODES
The researchers have also studied
Ann’s advisors Bob’s advisors
Behind the Research
No
?
the interaction of two compound
nodes and found that under certain
conditions a node’s level of influence Yes Denis Alexander
can have a stronger dependence
on the internal parameter. Ann Bob
Fedyanin Chkhartishvili
APPLICATION
The process can be applied to Social Network with Advisors
the following situation. Ann and Bob E: dfedyanin@inbox.ru T: +7 (926) 177 17 46 T: +7(465) 334 89 10
have to make a decision. Let us consider
two scenarios:
1: The decision is not very important,
so Ann and Bob do not involve Denis Fedyanin and Alexander Chkhartishvili from the Fedyanin D.N., Chkhartishvili A.G. (2018). ‘Consensus in Social
their advisors.
No Russian Academy of Sciences model opinion dynamics Networks of Compound Nodes’. Automation and Remote
2: The decision is very important, Ann Bob of social networks to analyse how individuals’ internal Control, Vol 79 (6), pp.1117-1124.
Yes
so Ann and Bob involve their advisors. parameters affect their social power.
Fedyanin D.N., Chkhartishvili A.G. (2013). ‘A model of
Someone’s opinion is determined
by how much he or she wants to agree
Social Network with NO Advisors Detail informational control in active network structures in case
of an incomplete awareness of the principal’. Automation
or answer ‘yes’ to a particular question. Denis Fedyanin / V. A. Trapeznikov and Remote Control, Vol 74 (12), pp.2155-2162.
A social network is an example of application.
These opinions are shown as colours Institute of Control Sciences of Russian Academy
They have established a model that

in the diagram: of Sciences, Fedyanin D.N., Chkhartishvili A.G. (2011). ‘On a model
• Green represents 100% agreement 65 Profsoyuznaya street, of informational control in social networks’. Automation
with ‘yes’.
• Red represents 0% agreement with ‘yes’
includes the overall influence of internal Moscow 117997,
Russia
and Remote Control, Vol 72 (10), pp.2181-2187.
factors like confidence in personal advisors. Fedyanin D.N., Zuev A.S. (2012). ‘Models of opinion control
Arrows depict influences. The larger Bio for agents in social networks.’ Automation and Remote
the arrow from A to B, the larger influence Can we derive the consensus opinion CONCLUSIONS Denis Fedyanin received his Master’s Degree in Applied Control, Vol 73 (10), pp.1753-1764.
of A on B. Bob’s influence on his advisors in a setting if we know the opinions in The DeGroot model is a powerful tool Mathematics and Physics from the Moscow Institute
is large but so is their influence on him. another one? Fedyanin and Chkhartishvili for studying matters relating to the spread of Physics and Technology. He is a researcher with both DeGroot, M.H. (1974). ‘Reaching a Consensus’. Journal
Ann’s influence on her advisors is small but have found a solution and stated it using of information and beliefs. It provides the Active Systems Laboratory at the V.A. Trapeznikov of the American Statistical Association, Vol 69 (345),
so is their influence on her. a simple formula. an explicit basis for measuring centrality Institute of Control Sciences, Russian Academy of Sciences, pp.18-121.
within a social network and identifying Moscow and the International Laboratory for Logic,
Opinion dynamics which individuals have the most influence Linguistics and Formal Philosophy at the Higher School
Basic Story Example 1 over the opinions of a group. of Economics. Personal Response
Ann Bob Ann Ann’s advisors Bob Bob’s advisors
1
0.9
1
0.9
Fedyanin and Chkhartishvili have Dr Alexander Chkhartishvili has graduated from the What motivated your interest in researching opinion
0.8 0.8 extended the DeGroot model to enable Faculty of Computational Mathematics and Cybernetics dynamics and consensus?
0.7 0.7
0.6 0.6 consensus analysis of complex network of Lomonosov Moscow State University. He is a Doctor Opinions play an important role in our life. People
0.5 0.5
0.4 0.4 structures where each node comprises of Science in Mathematics. Dr Chkhartishvili is the head easily change their opinions and these opinions lead to
0.3 0.3
0.2 0.2 two mutually interacting agents. They of the Complex Networks laboratory at V.A. Trapeznikov decisions and make important changes in the world – such
0.1 0.1
have established a model that includes the Institute of Control Sciences, Russian Academy of Sciences, as decisions on global warming, acceptable lines between
0 0
1 2 3 4 5 6 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 overall influence of internal factors on their Moscow. He previously worked at the Faculty of Public freedom and security, standards etc. These decisions could
initial opinions, without any restrictions Administration at Lomonosov Moscow State University. have an economic dimension too since they influence the
production and sales of goods and, this knowledge could
Example 2 Example 3 on the number of members in the social
be converted to economic benefits in a simple way. All this
Ann Ann’s advisors Bob Bob’s advisors Ann Ann’s advisors Bob Bob’s advisors network or the number of interactions Funding reasoning means that prediction of opinions deserves
1 1
0.9 0.9 between them. V.A. Trapeznikov Institute of Control Sciences one’s interest.
0.8 0.8
0.7 0.7
Social power, Compound nodes, DeGroot model.
0.6 0.6 The researchers have identified further
0.5 0.5
0.4 0.4 research involving the examination Collaborators
0.3 0.3
0.2 0.2 of the communication processes of nodes • Burkov V.N.
0.1 0.1
0 0
with more complicated internal structure, • Novikov D.A.
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 i.e. nodes where more than two agents • Giliazova A.A.
The horizontal axis represents time and the vertical axis represents a measure of attitude to “Yes” where interact, as well as further complex models • Gubanov D.A.
1 means 100% “Yes”, and 0 means 100% “No”. of opinion dynamics. • Kozitsin I.V.
Physical Sciences ︱ Professor Giorgio Kaniadakis and Professor Dionissios Hristopulos
The Kinetic Interaction Principle: π (t , x i −1 →x i ) π (t , x i +1 →x i )
π (t , x i →x j ) = w ij α (f i ) b (f j )
When kinetic theories

x i −1 xi x i +1
Atoms can move between lattice points (the green dots).
This diagram shows the transfer of probability to the
clash, mind the lattice step:

central point (in red) and from the centre point (in blue).
A statistical physics approach to the motion

π (t , x i →x i −1 ) π (t , x i →x i +1 )
of atoms within materials
A
What happens when the method t first glance, our entire universe a fort out of cardboard boxes. If you use
used to search out an answer appears to be continuous: an boxes which are cube shaped – with each
appears to have an effect on endless sea of space and time, one the same size – then when you build
the answer itself? In the field stretching out in every direction. It’s not – your fort up, the boxes will fit squarely
of Statistical Physics, two but it’s not obvious. It isn’t at all obvious, on top – and side by side – of one
different approaches have for example, that, when watching a another. You could even build another,
been used to describe the beautiful summer sun set on the horizon, much larger cube out of the boxes. Now
particle kinetics: the so-called you are actually looking at the sun imagine that an atom sits at every corner
Master Equations; and their through a sea of billions of tiny particles of a box. This is what happens in a simple
counterpart, the Fokker– of gas – and that the signature orange- cubic lattice structure.
Planck Equations. But which red haze in the sky is a by-product of
is better and why does the the fact that those gas particles are made Particles can – and do – move around
approach used have an effect up of discrete atoms and obey the rules in solid materials. Electricity, the In their recent paper, Nonlinear Kinetics
on the result? Professor Giorgio of Quantum Mechanics. We know this flow of electrons through conductive on Lattices Based on the Kinetic
Kaniadakis, of the Polytechnic now, but we didn’t always. Until recently, materials, is a notable example but Interaction Principle, Professor Giorgio
University of Turin, and Professor
everything in science was assumed entire atoms can also move around Kaniadakis (Polytechnic University of Turin)
Dionissios Hristopulos, from
Master equations are the mathematical
to be continuous – the discovery of between lattice points. And, just like and Professor Dionissios Hristopulos
the Technical University of Crete,
Quantum Mechanics changed that. energy and matter are quantised in (Technical University of Crete) investigate
tool used to describe the dynamic
are using a statistical approach
World leading scientists, such as Albert Quantum Mechanics, this motion of whether the Master Equations or
to try and find the solution.
evolution of physical processes
Einstein and Max Planck, set out to find atoms takes place in discrete jumps, Fokker–Planck Equations are better for
the rules that would allow us to make from lattice point to lattice point, and understanding how atoms move between
sense of this new universe. A universe
made up of discrete particles of matter
can be described in physics in a number
of ways. The Kinetic Interaction Principle
lattice points within solid materials. Their
paper presents some interesting points.
on lattices.
and energy. The theories they developed (KIP) expresses the transition probability WHEN THE APPROACH to tackle the problem. Starting with
at the turn of the century changed of a particle moving from one lattice The Master Equations are discrete in AFFECTS THE OUTCOME a simplified version of a well-known
the world forever. point to another. This motion of particles nature by construction, but the Fokker- Science is often described as the pursuit Master Equation, and applying it to
can be described by two different sets Planck Equations are not. ‘The motion of knowledge. While this idea isn’t a theoretical one-dimensional gas, they
Just as we can imagine a liquid (or of equations: the Master Equations of particles in lattices involves discrete entirely false, it isn’t entirely true either: show that it can be used to derive the
gas) as a sea of atoms, so too can and the Fokker–Planck Equations. jumps between the lattice sites,’ says it places too much emphasis on the Kinetic Interaction Principle (KIP) for that
we imagine a solid material. In the case Professor Kaniadakis. ‘Master equations ultimate goal, i.e., knowledge itself. In system. Studying the KIP, and generalising
of a solid, however, the atoms don’t THE DISCRETISATION PROBLEM are the mathematical tool used to science, the pursuit is also important. it into 3D space, allows the researchers
move around as freely: they are held When using mathematics to solve describe the dynamic evolution of When the road followed in the pursuit to make some physical predictions about
in place by stronger chemical bonds real physical problems, the first step physical processes on lattices [and] their has an effect on the outcome, something realistic lattice systems. The approach is
than their counterparts and end up is often to discretise the problem. solutions determine the probability of interesting is going on. In the case of then further refined by introducing a new
arranged in a well-structured manner. This means that we break the problem finding a particle at any time at a specific the Fokker–Planck Equations for specific quantity into the KIP: the Discrete Fokker–
Scientists call this array of atoms the up into smaller, more manageable lattice site’. On the other hand, the discrete systems different discretisation Planck Current. This allows Professors
crystal lattice – an imaginary construct chunks so that the rules of mathematics Fokker–Planck Equations assume that approaches produce different end results, Kaniadakis and Hristopulos to close the
that positions the atoms relative to one are easier to apply. To achieve this space is continuous. However, space obscuring the one, true solution. loop by arriving at a continuum Fokker-
another. As you can imagine, the crystal so-called discretisation, a number and time must be discretised in order to Planck equation starting from a discretised
lattice can take on different shapes, of different methods have been achieve a mathematical solution of these In order to overcome this ambiguity, Master equation.
depending on the chemical properties developed, each with their own sets equations on electronic computers. An Professors Kaniadakis and Hristopulos
of the atoms that occupy it, with the of assumptions and intricacies that need interesting result is that the method used used a Statistical Physics approach, The results show that the Master
simple cubic lattice being one of the to be considered when such methods to discretise the Fokker-Planck Equations which encompasses particles that Equations can be used to produce
easiest to understand. Imagine building are applied. has an effect on their final outcome. behave as fermions, bosons or anyons, a set of Fokker-Planck Equations which
can then be solved numerically for a real
physical problem. ‘This approach resolves
KIP and the Matthew Effect Behind the Research
the ambiguity that results from different
numerical discretisation schemes of DEMOCRATIC REGIME
the Fokker–Planck equation,’ they explain
in their recent paper. ‘The proposed Professor Giorgio Professor Dionissios
discretisation scheme based on the
master equation is physically motivated Kaniadakis Hristopulos
and follows from the KIP that describes
microscopic nonlinear dynamics’. This
means that the solutions are based on the E: giorgio.kaniadakis@polito.it E: dionisi@mred.tuc.gr T: +30-28210-37688 W: www.geostatistics.tuc.gr/index.php?id=4907
physical system itself and are therefore W: www.linkedin.com/in/dthchania/ W: www.researchgate.net/profile/Dionissios_Hristopulos
a better starting point for describing the
motion of atoms within a lattice than any
previous approach.
Professor Giorgio Kaniadakis (Polytechnic University of Turin) Kaniadakis, G & Hristopulos, D T. (2018). Nonlinear Kinetics
THE MATTHEW EFFECT and Professor Dionissios Hristopulos (Technical University on Lattices Based on the Kinetic Interaction Principle.
For whosoever hath, to him shall be given, of Crete) investigate whether the Master Equations or Entropy, [online] 20(6), 426. Available at: www.mdpi.
and he shall have more abundance: Fokker–Planck Equations are better for understanding how com/1099-4300/20/6/426 [Accessed 13 November 2018].
but whosoever hath not, from him shall EXTREME MATTHEW EFFECT atoms move between lattice points within solid materials.
be taken away even that he hath. Hristopulos, D T & Muradova, A. (2016). Kinetic model
Matthew 25:29
Detail of mass exchange with dynamic Arrhenius transition rates.
The Matthew effect describes how an unbalanced system
Physica A, 444(2016), 95-109.
You don’t have to be a religious person can have two equilbrium states - democratic, where mass is distributed Giorgio Kaniadakis
to recognise that the above statement equally or elitist, where the large get larger and small get smaller. Politecnico di Torino Kaniadakis, G. (2001). Non-linear kinetics underlying
holds true in certain economic situations: Department of Applied Science and Technology generalized statistics. Physica A, 296(2001), 405-425.
the idea that ‘the rich get richer while
the poor get poorer’ has been around
Using master equations as the starting Corso Duca degli Abruzzi 24,
10129 Torino,
for a very long time. Surprisingly, point, the researchers show how to Italy
Personal Response
Professors Kaniadakis and Hristopulos
have shown that it is an idea that applies
discretise the Fokker-Planck equations Dionissios Hristopulos
equally well to the exchange of mass in agreement with the physical reality. School of Mineral Resources Engineering On working on such a high-level mathematics based
problem, do you think there have been any particular
between interacting grains of matter. Technical University of Crete
Their new approach incorporates a system ‘Perhaps one could view the mass- fields, from psychology to traffic control Chania challenges or benefits to running a collaborative project
with a particular form of KIP that can have exchange grain system as a crude and even economics. 73100 from completely different countries? Collaborations
two equilibrium states: a democratic state, paradigm of social dynamics that Greece always appear to work best when each member
where the mass is distributed equally represents the exchange of wealth Professor Giorgio Kaniadakis, of of the team brings a specific skill, or approach, that
amongst the grains; and an elitist state, between individuals,’ jokes Professor the Polytechnic University of Turin, Bio complements with another team member’s skill,
where grains that were initially large Hristopulos. An idea that might not and Professor Dionissios Hristopulos, Giorgio Kaniadakis is a theoretical statistical physicist, or approach. How do you think your individual skills
increase in size over time, at the expense be as far-fetched as it sounds – statistical from the Technical University of Crete, author of more than 120 articles (h-index=29). He serves and experience have complemented each other?
of grains that were initially small. physics has found its way into many other took an advanced Statistical physics as Editor of several journals of physics and has edited 18 Geographical distance is not an obstacle for scientific
approach to describe how atoms move Special Issues of journals quoted in the Web of Science. collaboration these days. While it is nice to be able to meet
A model of a crystal lattice.
around on a crystal lattice. They show He has been involved in the organisation face to face and discuss ideas in front of a blackboard,
that, by using a set of well-known Master of more than 20 conferences and is the it is equally important to work with people who share
Equations as a starting point, they can founder of the SigmaPhi International research interests and have compatible methods of work,
solve the Fokker-Planck Equations that Conferences on Statistical Physics. from the planning of the research to the writing up of the
describe the system without any of results. Our skills are complementary in the sense that
the ambiguities associated with other Dionissios Hristopulos studied physics both of us have formal training in physics; one of us (GK)
approaches. Their solutions are based at Princeton University. After two years focuses on fundamental aspects of statistical mechanics,
on the physical state of the system itself in the Greek military, he worked as while the other (DH) emphasises applications of statistical
and are, therefore, a much better starting postdoc and then as research Assistant mechanics in other fields (e.g., data analysis). This research
point than any previously reported Professor in Environmental Sciences and is the result of an ongoing collaboration between the two
approach. Their results have interesting Engineering at the University of North groups, and provides a natural springboard
implications in a number of fields – from Carolina (Chapel Hill). In 2000 he moved for continuing the collaboration into the future.
Condensed Matter Physics to Solid State to the Pulp and Paper Research Institute
and Chemical Physics – and will help us of Canada and in 2002 to the Technical
to understand our world in a more robust University of Crete, where he currently
way than was previously possible. works as a Professor in Geostatistics.
Physical Sciences ︱ Dr Meysam Rahmat
Dynamic versus static:

Evolving mechanical characterisation
A
Materials used for aerospace erospace materials are some For such testing and modelling to
applications have to be of the most stringently tested be useful for aerospace materials, they
incredibly robust. For materials on earth. They have must effectively mimic the types of
commercial airlines, the materials to be capable of withstanding a wide forces the material would experience
used to build the aircraft need range of environmental conditions, such when in use. For example, the metals High speed compression of polymer
to be capable of withstanding as temperature and pressure, while used for aeroplane wings are tested
temperatures from -45 to 45 °C retaining their desired properties. While in the lab once they are made into
and windspeeds of over 400 durability of such materials is mandatory, wings by bending them and applying
kilometres per hour. All materials it is even more important that failures of stress and strain to the materials on a
must undergo stringent testing, the material are easily, and sufficiently variety of testing rigs. Through repeated
designed to replicate the real early, identified. The ultimate objective testing and modelling, a comprehensive
dynamic conditions encountered is to prevent accidents such as the China understanding of the metal behaviour can
during use. Dr Meysam Rahmat, Airlines Flight 611 crash, where metal be achieved to identify what early warning
in his research at the Aerospace fatigue led to the deaths of 225 people. signs can be used for in-situ testing once
Research Centre of the National the aeroplane is in use.
Research Council Canada, works Being able to detect impending failure
on designing new tests to more
of materials requires a comprehensive Many of the existing tests look at applying
accurately measure and test
knowledge of the material’s behaviour. static forces to the material. This is
the types of dynamic forces such Tensile tests on nanomaterials.
To do so, these materials are studied where the load applied to the material
materials experience during
using a variety of lab-based testing is essentially constant over a given time
use to better understand their
techniques, alongside numerical and would be a good way of modelling, Rahmat at the Aerospace Research Centre
behaviour and properties.
simulations, in an effort to predict how the for example, the constant force that the of the National Research Council Canada
material behaves close to the failure point. weight of the seats has on the plane’s has been pioneering new testing methods
structure. However, static stress tests that focus on the effects of dynamical DIC setup for tensile test.
cannot provide a good model for many stress on aerospace materials, which
of the rapidly changing forces that has revealed very different results to static,
Exclusively using static tests cannot

aeroplanes experience while in use. or quasi-static (where the force is applied
over a longer period of time than it would
To investigate how a material reacts when
a force is suddenly applied, dynamic
be for a dynamic test), with important
implications for aircraft safety.
provide a good model for many of the
testing is used instead. Dr Meysam rapidly changing forces that aeroplanes
STRESSFUL MEASUREMENTS
Foam compression with DIC To perform the dynamic strain tests, experience while in use.
Dr Rahmat uses a servo-hydraulic load
frame. Such frames can be customised One common issue with these types accuracy and whether these corrections
for different types and magnitudes of dynamic stress measurements is that to minimise the oscillations are applicable
of load. For Dr Rahmat’s dynamic tests, the values measured by the load cell to different materials.
he uses a load frame specifically designed oscillate during the measurement, making
to achieve high speeds. The frame can it difficult to extract the true stress-strain STRESS FRACTURES
reach speeds of up to eight metres per values experienced by the sample. One of the first materials Dr Rahmat
second as it suddenly applies load to the Some preventive actions, such as using has investigated using his approach is
stationary sample, resulting in the sudden lightweight clamps and optimising the an aluminium dogbone structure, named
transfer of force. A series of sensors mounting position of the gauges, can be for its resemblance to the shape of a dog
measure local deformation in different carried out to minimise these oscillations. bone. This is a typical shape for a tensile
locations on the sample to obtain ‘stress’ Part of Dr Rahmat’s work has been to test sample as the narrow section in the
(a measure of force acting on the sample carefully investigate how changing testing middle is subject to the majority of the
that can lead to deformation) and ‘strain’ parameters such as sample geometry deformation. This is important for ease of
Aluminum foam compression test. (a measure of deformation in the material affects the final values obtained for testing: if the stresses were concentrated
due to the force that can lead to cracking). the material properties to ensure their near the sides of the sample, where it
Behind the Research
FE model of puncture test.
Dr Meysam Rahmat
E: meysam.rahmat@nrc-cnrc.gc.ca T: +1 (613) 991 5360 W: www.nrc-cnrc.gc.ca/eng/

Meysam Rahmat, “Dynamic Mechanical Characterization
Dr Meysam Rahmat’s work focuses on dynamic mechanical
characterisation of materials, particularly nanocomposites. of Aluminum: Analysis of Strain-Rate Dependent Behavior”,
Mechanics of Time-Dependent Materials, 2018, In Press,
https://doi.org/10.1007/s11043-018-9393-0.
Detail Meysam Rahmat , Alex Naftel, Behnam Ashrafi, Michael B.

Aerospace Research Centre Jakubinek, Yadienka Martinez-Rubi, Benoit Simard, “Dynamic
National Research Council Canada Mechanical Characterization of Boron Nitride Nanotube—
1200 Montreal Road Epoxy Nanocomposites”, Polymer Composites, 2018,
Ottawa, ON In Press, https://doi.org/10.1002/pc.24995.
K1A 0R6
Canada
Personal Response
Bio
Dr Rahmat received his PhD in mechanical engineering What types of material do you want to explore next
Puncture test on composites. Punctured aluminum. Puncture test on polymer.
with this testing method?
from McGill University in 2011, and started working at the
National Research Council Canada (NRC) the following year. Any type of homogeneous (including metals, polymers
is clamped to the testing machine, this type of fractures the material experienced, nanoscale materials and have not been His main focus is on composite materials, nanocomposites, and ceramics) and non-homogeneous material (including
would lead to artificial readings as the depending on whether it had received well-studied using dynamic strain and dynamic mechanical characterisation of materials. composite materials) can be characterised using this
method. Also, different types of material architectures such
clamping of the sample would interfere the force very suddenly or gradually over methods. By testing a nanocomposite
as closed cell foams are currently being tested to evaluate
with the measurement. This is also a longer period. While small changes in formed of a common epoxy, with and Funding their energy absorption capabilities under impact.
beneficial for measuring elongation, as it the surface structure of the metal that can without boron nitride nanotubes, Dr National Research Council Canada through Security
means the measured change in length of only be observed by a microscope might Rahmat and his team were able to see Materials Technology Program, Project A1-006934 What is the most satisfying aspect of your work in
the material comes how the inclusion this field?
exclusively from
the material, not
The information obtained from such of the nanotubes
added greater
Collaborators
• Richard Desnoyers
Mechanical characterisation is an essential step in the
tests is highly valuable not just

iterative process of structural design; whether through proof
also from changes elasticity and tensile • Behnam Ashrafi of concept or screening tests in the earlier stages of the
for understanding material behaviour

in the clamps. strength to the • Alex Naftel process, or during full scale final evaluation of the structure
sample but had • David Backman for certification purposes. The main objective of these tests
but also from a design perspective.

During these little influence on • Gang Li is to ensure that during its service life, the structure will not
dynamic the shear properties • Michael B. Jakubinek experience any catastrophic failure after going through
measurements, what of the epoxy. • Yadienka Martinez-Rubi all those harsh experiments in the lab. When an aircraft
retires after many years of service with no major problem,
Dr Rahmat found was that for this well- seem trivial, this indicates differences • Benoit Simard: National Research Council Canada
it just shows that every critical element of its complex and
studied aluminium sample, there was a in the amount of energy absorption by The information obtained from such multi-disciplinary system worked to its best and served
large deviation for the ultimate strength the aluminium depending on the speed tests is highly valuable not just for its function. That’s when an engineer’s effort is paid off.
and the elongation at failure between of the force, showing the material would understanding material behaviour but also Also, there is no denying that crashing and breaking lab
the values measured dynamically have different resistances to different from a design perspective, as it becomes specimens at high velocity is fun!
versus quasi-static measurement. types of loading conditions. possible to determine which mixtures
This is important for not just making have the most desirable properties.
sure the testing of materials is realistic METALS TO NANOCOMPOSITES The methods Dr Rahmat has been
for what it will ultimately experience in All of this testing and model developing are also very generalisable
the field, but also refining the modelling refinement has ultimately enhanced to a wide range of substances, which he
of the responses of such materials our understanding of very well-studied will continue to explore in his future work.
to the anticipated stress and strain. materials, but Dr Rahmat has been
expanding this to nanocomposites
Optical microscope images of the tested as well. Nanocomposites are novel and
material also showed differences in the complex materials composed of different
Physical Sciences ︱ Prof Dr Elena Jasiūnienė
Peering inside:
different ways of strengthening concrete
and other lightweight, yet structurally
strong, materials. X-ray computed
tomography allows her to see how
different kinds of processing to create
these materials affect the structure
and location and size of defects. All
3D imaging in materials
of this can be used to refine production
methods and inspire approaches for
the design of customised materials
for specific applications.
T
New strong materials are in he idea of X-ray vision may its contents in full three-dimensional
demand in many sectors, leading have come from science fiction, detail. The ability is unique to X-ray LIGHTWEIGHT AND STRONG
to the development of different but the ability to see into solid computed tomography, an X-ray Part of the increasing demand for strong
hybrid structures. These can objects and take images of what is inside imaging technique that can be used materials that are still lightweight is
be made from dissimilar light them is now very much a reality. One on a wide variety of materials, including motivated by attempts to decrease
materials such as aluminium of the simplest forms of X-ray imaging metals, biological structures and many energy consumption. Lighter materials
alloys, which are joined by is used in hospitals, to allow medical complex materials, including hybrid have several benefits as less energy
incorporating reinforcing fillers professionals to image bones and other structures such as concrete combined is required to transport them and, if
into the weld, or self-compacting dense tissues inside the patient. This with steel or dissimilar metal joints with they are being used to make transport
fibre-reinforced concrete, produces a flat image where the densest nanoparticle fillers. vehicles, it reduces their fuel demands
which is reinforced using fibres. areas are highlighted in white as they too. A common way of achieving high
However, creating new materials absorb the greatest amount of the The versatility and non-destructive strength while reducing weight is to
is not without its problems. incoming X-ray radiation. nature of this approach is why Prof make alloys, mixtures of two or more
The process parameters can Dr Elena Jasiūnienė, Ultrasound different materials. Aluminium alloys
be imperfect or are affected by Now, using more modern X-ray imaging Research Institute, Kaunas University of are very popular for this purpose but
different variables or unforeseen methods, it is possible to image not Technology, Lithuania has been taking can be very hard to handle during
circumstances. The quality of the
just two-dimensional images of the advantage of the unique abilities of construction as they are difficult to
structure can be affected and
inside of an object, but reconstruct X-ray computed tomography to examine weld into structures using conventional
the performance of the loaded
welding techniques.
structure could be unexpected.
To see how these different The bulkhead and nosecone of the Orion
reinforcements influence the spacecraft are joined using friction stir welding. Some of this difficulty in the welding
properties of materials, Prof Dr process results in inconsistencies and
Elena Jasiūnienė, Ultrasound imperfections in the final weld on a
Research Institute, Kaunas microscopic scale. To identify such
University of Technology, uses deficiencies, Prof Dr Jasiūnienė and
X-ray computed tomography her team used a combination of X-ray
Defects formed in the inner structure of the samples friction stir welded by incorporating reinforcing
to allow her to peer inside computed tomography and acoustic fillers into the weld with different welding parameters: from top to bottom – after 1 pass, after 2 passes
the structures of materials microscopy to investigate the invisible in the same direction, after 3 passes in the same direction; after 2 passes in opposite directions.
and reconstruct them defects inside welds between different
in three dimensions. alloys. From the reconstructions of
the three dimensional images of the non-destructive imaging techniques. into moulds and manipulated until it
inside of the welds, they could pinpoint The non-destructive nature of the sets as a solid. While it is being poured,
exactly where the defects in the weld technique also means it is suitable the concrete needs to be compacted
zones formed. The 3D capabilities of for use on manufactured pieces that so that all the air bubbles and voids
3D tomography mean all of this can require checking and could potentially in the structure are removed to ensure
be done in real space and it is possible be done routinely to assess fatigue that there are no inhomogeneities in
to resolve defects that would overlap or accumulating damage. the structure of the concrete and it is
with each other in more standard as strong as required. This is achieved
2D imaging. SELF-COMPACTING CONCRETE by using a steel probe to act as a
Concrete is a mixture of cement and a continuous source of vibration while
The small size of the nanoparticles, binder that is usually liquified with water. the concrete is being poured.
and the defects they can cause, make After the mixture is made, it remains
them very difficult to identify with other in a gel-type form so it can be poured Self-compacting concrete eliminates
the need for continuous vibration
It is possible to image not just 2D images and typically has a higher strength for
a given water, cement and binder ratio
of the insides of objects, but reconstruct than the traditional form. One way
their contents in full 3D detail.

of making self-compacting concrete
is to include superplasticisers that help
Behind the Research
A B C
Prof Dr Elena Jasiūnienė

E: elena.jasiuniene@ktu.lt T: +370 698 00899 W: https://lt.linkedin.com/in/elena-jasiuniene-6a60082a
W: https://ultrasound.ktu.edu/ct/

Jasiūnienė, E., Žukauskas , E., Dragatogiannis, D.A.,
Prof Dr Jasiūnienė investigates the properties of various
materials, particularly self-compacting concrete, using X-ray Koumoulos, E.P., Charitidis, E.A. (2017) Investigation of
computed tomography both alone and in conjunction with dissimilar metal joints with nanoparticlefillers. NDT and
other methods. E International, 92, 122-129. Available at: https://doi.
Image A shows a photo of the concrete cylinder sample, which was investigated. Image B shows a slice of 3D CT data in the middle of the sample. Image C org/10.1016/j.ndteint.2017.08.005
reveals the 3D distribution of steel fibres within the self-compacting concrete.
Jasiūnienė, E., Cicėnas, V., Grigalinūas, P., Rudžionis, Navickas,
it to be more elastic and flexible than
normal concrete. By removing the
3D images of the inner structure allows Detail A.R., (2018) Influence of the rheological properties on the steel
fibre distribution and orientation in self-compacting concrete.
need for vibration or tamping after quality evaluation of the different Prof. Dr. Elena Jasiūnienė Materials and Structures, [online] 51(103), Available at: https://
structures non-destructively – making

pouring and as it also flows very well, Baršausko 59- A423 link.springer.com/article/10.1617%2Fs11527-018-1231-y
self-compacting concrete is much less LT-51423 Kaunas [accessed 16 Nov 2018]
labour intensive to lay and can be used
in areas where it is not possible to
the invisible visible. Lithuania
Bio
compact normal concrete or to create
more complex shapes that would not of reinforcement strength the steel tomography to see how the flow- Elena Jasiūnienė received an Applied Electronics Masters
Personal Response
otherwise be achievable. fibres will provide along different axes. properties of the concrete influence degree and a PhD in Technological sciences, Measurements
Visualising the orientation of such the eventual orientation of the fibres. engineering, from Kaunas University of Technology. She What other material and systems have you been
investigating with X-ray imaging tomography?
One type of self-compacting concrete fibres, given their small size, is the Her work has demonstrated that low later worked at the Federal Institute for Materials Research
uses steel fibres, much as traditional perfect problem for X-ray computed viscosity concretes show the greatest and Testing, Berlin, Germany. Currently she is Senior Investigations of very different types of materials/
concrete uses steel bars, to help tomography as it can capture the full amount of inhomogeneity in the steel researcher at Prof. K. Baršauskas Ultrasound Research structures have been performed: investigation of the
reinforce the structure. However, it is size, shape and relative orientation in 3D fibre distribution after being poured but Institute and Professor at Department of Electronics structure of 3D scaffolds for bone tissue regeneration;
investigation of titanium pin array structure produced
difficult to know exactly how all of the of the fibres in the concrete. also that steel fibres orientate parallel Engineering, Faculty of Electrical and Electronics
using additive manufacturing technology; human teeth
fibres are aligned after the pouring to casting direction after some distance. Engineering, Kaunas University of Technology. for investigation of root canal transportation and centring
process, even though the orientation Prof Dr Jasiūnienė has been applying Meanwhile in high viscosity concrete, ability of rotary endodontics instruments; visualisation of
of the fibres is critical in the amount her expertise in X-ray computed fibres are distributed all over the beam Funding inner structure of microchips; investigation of the integrity
more evenly, but they don’t orientate • FP7 Collaborative project “SAFEJOINT”. The abbreviation of concrete in order to assess the harmful consequences
parallel to casting direction as in low “SAFEJOINT” stands for “Enhancing structural efficiency of alkali-silica reaction on the composition of the material;
viscosity concrete. through novel dissimilar material joining techniques” investigation of glider longeron, made from CFRP to
(Grant agreement no.: 310498) determine porosity.
LOOK INTO THE FUTURE • Kaunas University of Technology under grant agreement
X-ray imaging tomography is a highly Nr.MTEPI-P-15010, project BeReTyr “Determination of
versatile, non-destructive technique that Dispersive Reinforcement and Structural Defects in New
is widely used in engineering for its ability Generation Concretes Using X-ray Micro Tomography“
to recreate 3D images of the insides of
many kinds of material. Prof Dr Jasiūnienė Collaborators
has been successfully able to use this • Dr Vaidotas Cicėnas, (Prof. K. Baršauskas Ultrasound
to better understand the microscopic Research Institute, Kaunas University of Technology)
structure of metal alloys and concretes to • D.A. Dragatogiannis, E.P. Koumoulos, C.A. Charitidis
help guide manufacturing decisions and (Research Unit of Advanced, Composite, Nano Materials
reproducibility of the desired mechanical & Nanotechnology, School of Chemical Engineering,
properties of such materials. In the future, National Technical University of Athens, Athens, Greece)
she will continue to develop and apply • Žymantas Rudžionis, Paulius Grigaliūnas (Faculty of
tomography and related methods for the civil engineering and architecture, Kaunas University
study of not just commonplace concrete, of Technology)
Understanding the inner structure of concrete but also for materials used in space
is essential to understanding its strength.
engineering and nuclear power plants.
Physical Sciences ︱ Professor Zoltan Haiman
Black hole binaries

and gravitational waves:
Unlocking the secrets of our universe in unexpected ways
A
When Albert Einstein predicted s far back as we’ve been able to sky – astronomy is, in fact, the oldest
the existence of gravitational crane our necks, our civilisation of the natural sciences, dating back to
waves over one hundred years has been looking to the stars prehistoric times. The sun went down and
ago, nobody could foresee what with a sense of wonder and awe. Our everyone was at it: the Babylonians, the
Photo Credit: CC BY 4.0

the implications could possibly earliest ancestors worshipped the skies ancient Chinese, the Greek philosophers, In the recently formed NGC 6240
be – but, as they make the move with a fierce superstition – and on the the Egyptian Pharaohs – every civilisation galaxy, there are two supermassive
from predicted theory to proven darkest of nights in the quiet of the that was advanced enough to record what black holes spiralling closer and
closer to one another.
fact, researchers like Professor countryside, away from the light pollution they were doing: all standing on the shore
Zoltan Haiman, of Columbia that plagues our towns and cities, it’s of an endless ocean of light, underneath
University, are devising ways
of using them to study binary
easy to see why: our heavens hold a
beauty that is unparalleled anywhere else
dark skies with bright and starry eyes,
meticulously studying the mechanics
of Newtonian physics. Einstein’s theory
of relativity changed that: time and space
Such massive black hole binaries are
systems of colliding black holes in the natural world. of celestial bodies far beyond their were no longer different entities but two expected to play a fundamental role in
sculpting their host galaxies, and their
and the very early universe comprehension; watching with a sense sides of the same coin, interlinked in a
in completely new ways. It wasn’t long before our ancestors started of wonder as points of light danced above system that is almost impossible for us
applying the rigour of mathematics to the them in the night. to comprehend (the fact that Einstein eventual mergers would be the most
Today, our knowledge of the Universe has
did is why he is so famous). It replaces
the force of gravity, proposed by Isaac energetic phenomena in the universe.
surpassed the wildest hopes and dreams Newton, with a seemingly abstract idea:
of those who came before us. We know space and time are a medium in which energetic phenomena in the known year, Professor Haiman predicted what
that some of those points of light are everything exists. Heavy objects, like universe – but much like gravitational happens when two black holes collide
actually giant nuclear fusion reactors planets, warp this medium and change waves, direct evidence of black hole as their host galaxies merge. As the black
called stars, just like our own sun; and its shape and that’s what we experience binary systems has so far been lacking. holes become close to one another,
some of them are galaxies so far away as a force pulling us towards the Earth This is because the black holes are too they begin to orbit around a common
that our eyes reduce them – a collection (gravity). Space-time is a difficult idea to close to each other to tell apart using centre of mass – a point somewhere in
of billions of stars – to one single point. grasp but the beauty of Einstein’s theory our current telescopes (see above image). space analogous to the pivot-point on
We know how stars are born – and how is that it explains so much of the universe That could be about to change. a seesaw, around which the masses at
they die – and that if a star is big enough so fully that it is impossible to ignore. That either end rotate. They move slowly at
when that time comes, it will collapse in and the mathematics stack up: scientists LISA first and, if the energy contained within
on itself to form a singularity: an object so have been trying – and failing – to prove In 2034, the European Space Agency their orbit was to remain the same, the
dense that not even light can escape its him wrong for over a hundred years. (ESA) plans to launch LISA, a Laser system could continue like this forever,
gravitational pull. We call these objects Interferometer Space Antenna, which will with the black holes caught in a never-
black holes. We know that at the centre An interesting prediction that comes be able to detect the gravitational waves ending dance. But energy is sucked
of almost every galaxy lies a supermassive out of Einstein’s theories is the existence resulting from the interaction between from the orbit in the form of gravitational
black hole and that galaxies often collide of gravitational waves – ripples in the two colliding black holes (see image waves. They cause the orbit to shrink in
with each other (see image to the left) fabric of space-time itself. Until recently, overleaf). This will provide astronomers size, and the black holes to spiral inward,
to form even larger galaxies. One thing a prediction was all that they were but with a shiny, new set of tools to probe colliding to form a single black hole.
we’re not entirely clear on, however, is since 2016, scientists have been able to the farthest reaches of our universe.
what happens when the black holes from measure them and, as our technology Until then, researchers like Professor The process takes an extremely long
two colliding galaxies meet and form advances, they will be able to further Zoltan Haiman continue to study time to complete and, in the last few
binary systems. exploit gravitational waves to investigate such binary black hole systems using years of the merger, the gravitational
what happens when two galaxies collide. theoretical calculations and advanced waves become extremely strong. It is at
THE GRAVITATIONAL WAVES computational simulations. this point that LISA will be able to detect
Photo Credit: CC BY 4.0
DISCOVERY SWEEPING THROUGH We know that black hole binary systems them. Unfortunately, though, LISA will not
ASTRONOMY play a fundamental role in shaping AN ASTRONOMICAL FINGERPRINT be able to detect the galaxy in which the
An image of two galaxies colliding For most of our history, astronomers the galaxies they belong to – and that FOR BINARY BLACK HOLE SYSTEMS tango took place. The gravitational waves
taken by the Hubble Space Telescope.
have viewed the stars through the lens their collision would likely be the most In a recent paper, released earlier this will be released as periodic undulations,
following the binary’s orbital motion --
what Professor Haiman calls gravitational
wave pulsars – and, in the last few months
of the merger, the system will be rotating
Behind the Research
at extremely high speeds (about 10% of
the speed of light, or around 30 thousand
Professor Zoltan Haiman
kilometres per second). Professor
Haiman’s research suggests that as a E: zoltan@astro.columbia.edu T: +1 212 854 6822 W: http://user.astro.columbia.edu/~zoltan/
result, the binary should release similar
periodic pulsations every few minutes or
so. Professor Haiman, with his graduate
student Daniel D’Orazio and colleague
Professor David Schiminovich at Columbia
University, has earlier suggested that the Professor Zoltan Haiman’s work at Columbia University 1: Haiman, Z (2017). The electromagnetic chirp of a compact
sinusoidal pulsations seen in optical and aims to find evidence for the existence of massive black binary black hole: a phase template for the gravitational
Photo Credit: Nasa, Public Domain
ultraviolet bands of a known bright distant hole binaries. wave inspiral. Physical Review, D96 (2), 023004.
quasar is due to the same phenomenon:
2: D’Orazio, D.J., Haiman, Z. and Schiminovich, D. (2015).
for a pair of more widely separated,
and less rapidly moving black holes,
Detail Relativistic boost as the cause of periodicity in a massive
these lower-energy pulsations would Professor Zoltan Haiman black-hole binary candidate. Nature, 525 (7569), 351-353.
be expected and appear consistent with Department of Astronomy, Columbia University
the observed data [Ref 2]. 500 West 120th Street, MC 5246 3: Tang, Y., MacFadyen, A., and Haiman, Z. (2018). The
When black holes move closer to each other, reaching distances not much larger than our solar system, New York, NY 10027, USA late inspiral of supermassive black hole binaries with
As both phenomena are caused by the they distort space time and emit gravitational waves. The LISA spacecraft (consisting of three separate circumbinary gas discs in the LISA band. Monthly Notices
satellites connected with laser interferometer links, indicated by the red triangle) will be able to see these
same orbital motion, they should occur gravitational waves. Bio of the Royal Astronomical Society, 476 (2), 2249–2257.
together and help astronomers pin down After completing high school in Budapest, Hungary, Zoltan
the location of the merger. As Professor
Comparing the distance to the galaxy Haiman completed his undergraduate studies in Physics
Haiman explains: ‘This tell-tale “X-ray
chirp”, accompanying the gravitational with its apparent recession speed will
at MIT and a post-graduate certificate in Chemistry at
Cambridge University, UK. A PhD in Astronomy from
Personal Response
wave chirp, should allow astronomers to
uniquely identify the host galaxy of the
map the expansion rate of the universe Harvard University was next, followed by a postdoctoral
fellowship at the Astrophysics theory group at Fermilab, What is it that motivates you to work in astronomy
merging black hole pair – since there over cosmic time, back to early Batavia IL and a Hubble Fellowship at Princeton University.
and cosmology?
epochs which are beyond the reach

will be only one galaxy with such X-ray He has been a member of the faculty in Columbia It is a privilege to be removed from the constraints
pulsation, matching the gravitational University’s Astronomy Department since 2003. of day-to-day business here on Earth, and to be thinking
waves’. In other words, black hole binary of [current methods]. instead about the unsolved mysteries of the universe.
And it is highly rewarding to contribute, even a tiny bit,
systems should have their own unique Funding
to our understanding of how things work in it.
astronomical fingerprint that can be universe back to the very beginning right – with the experimental verification NASA, NSF
traced to a well-localised point on the sky. of time. ‘Comparing the distance to of gravitational waves in 2016. A proof
The presence of strong X-ray pulsations, the galaxy with its apparent recession which is providing astronomers with a new Collaborators
in tandem with the gravitational waves speed will map the expansion rate of the lens through which to view our expanding Former graduate student and Professor Andrew
being detected by LISA, was also seen universe over cosmic time, back to early universe and unlock mysteries that our MacFadyen, co-authors of the related simulation work (both
in detailed hydrodynamical simulations, epochs which are beyond the reach of ancestors could only dream about. at New York University), and former graduate student Daniel
computing the response of the circum- the similar, Nobel-prize winning exercise Although astronomy is the oldest of the D’Orazio and Professor David Schiminovich, co-authors
binary plasma to the “propeller” motion done with supernovae,’ explains Professor natural sciences, it is also the one which of the study interpreting the optical/ultraviolet pulsation
of the black holes, by Professor Haiman Haiman. It will also allow astronomers holds the most potential for new of a known quasar (both at Columbia University).
and his collaborators Professor Andrew to test whether X-rays and gravitational discovery. This is even more true now –
MacFadyen and graduate student Yike waves propagate at the same speed – the research by Professor Haiman, and
Tang (at New York University) [Ref 3]. as Einstein’s theory predicts – and if they similar work done by others, have shown
don’t, then perhaps Professor Haiman’s that unexpected new breakthroughs can
ACCESSING INFORMATION FROM proposed method will be the one that be enabled by combining gravitational
THE BEGINNING OF TIME finally proves that Einstein’s theory waves with data obtained with traditional
Using this new approach, astronomers of relativity is not the full story. telescopes. It seems like hardly a day
will be able to unlock a whole host of goes by without there being a new
new information about black hole binary Over one hundred years ago, Albert discovery, or announcement, thanks to
systems and, by extension, our entire Einstein changed how we viewed the advancement of technologies and
universe. Determining the exact location the universe and, almost as a by-product theories by researchers such as Professor
of a handful of such black hole binary of his theory, predicted the existence Haiman. Throughout all of that, though,
systems will allow astronomers to connect of gravitational waves. It has only been one thing in astronomy has remained
black holes with their host galaxies. They in the past few years that astronomers the same: we still look to the skies with
will also be able to map the accelerating are beginning to prove that he was a sense of wonder and awe.
Schematic of TWFET.
Synchronization of dissipative solitons.
Engineering and Technology ︱ Dr Koichi Narahara
Schematic of TWFET.
Creating a
Gate line
SCHEMATIC OF TWFET SYNCHRONISATION OF DISSIPATIVE SOLITONS.
Drain line initial independent rotation
Gate line
ΔT
Drain line
better oscillator:
Source L1
Source
L1 L2 ΔT
time [0.5 µs/div]

Dissipative solitons and travelling-wave field‑effect transistors Drain line
Drain line rotating DSs eventually synchronized
L2
A
Gate line L1
The key to improving the travelling-wave field-effect Dr Narahara studies a method of
performance of high-speed transistor (TWFET) is a special amplifying short electrical pulses using
electronic circuits is the type of field-effect transistor (FET) TWFETs with electromagnetic couplings is essentially a pulse
Gate lineoscillator using
ΔT vanished.
generation of short electrical with electrodes employed as transmission (where an electromagnetic field in one TWFETs, which could someday render a L2
pulses with reduced phase lines in addition to its electrical contacts. set of electrical wiring or circuit leads valuable scheme for reducing phase noise.
noise. Dr Koichi Narahara An FET is a semiconductor device used to an electric charge in another) and
of the Department of Electrical to amplify or switch electrical signals has devised a way to use their nonlinearity In addition to the development time [0.5 µs/div]
The shock front operates as an

and Electronic Engineering and power, which has three terminals; for shaping electromagnetic waves of dissipative solitons, the nonlinearity
at Kanagawa Institute of the source terminal, where the electrons or pulses. These couplings induce in TWFETs induces several other wave
Technology studies electric
pulses generated by travelling-
enter, the drain, through which they two different propagation modes (ways phenomena usable for generation of high- approaching wall to the counter-moving
waves, the frequency of reflected wave
leave the channel, and the gate. By in which pulses travel) in TWFET. He frequency continuous or pulsed signals.
wave field-effect transistors. applying voltage to the gate, one can succeeded in confining all the pulse Without nonlinearity, waves are carried
becomes greater than the incident one
He found that the devices control the electrons that travel from the energy into one of the modes and by superposed sinusoidal propagation
possess unique properties source towards the drain. When a voltage amplified the pulses carried by that mode. modes, and exponential modes
that could provide increased
operating frequencies and
difference is generated between the body As long as a pulse travels in a unique cannot contribute to their propagation. through the Doppler effect.
and the gate, an electric field is created, mode, it is free from the distortions In contrast, a hybridisation of sinusoidal
decreased phase noise when
which increases the conductivity between caused by the difference between modes. and exponential modes becomes either multiphase, (de)multiplexed, each collision, and so the amplitude
compared to traditional
the drain and source terminals. A TWFET possible in the presence of nonlinearity. or phase-locked ultrashort pulse streams. of the colliding pulses decrease over
oscillators, rendering them
consists of two transmission lines: one Usually, short-wavelength waves travel Dr Narahara found that the hybrid-mode time. While an anticlockwise pulse has
invaluable to modern electronics.
or the other is periodically loaded with slower than long-wavelength waves supports quasi-stable propagation DISSIPATIVE SOLITONS a slightly smaller amplitude than the
current flowing from the gate and drain in TWFET, which causes dispersive of incident pulses and significantly A dissipative soliton generally possesses clockwise pulse before a collision, the
of a small grounded FET, respectively. distortions to the short and baseband compresses their widths. a uniquely defined amplitude and velocity amplitude discrepancy increases after
Since they were discovered in 1965, pulses. By introducing nonlinearity, and is able to interact with other solitons the collision; specifically, the amplitude
TWFETs have been studied for their this dispersion can be compensated In addition, he found that shockwaves as well as other types of waves. Repeated of the anticlockwise pulse decreases
use in broadband amplification. However, for. Moreover, a TWFET succeeds can be excited in TWFETs, which are head-on collisions of 2 dissipative solitons whereas that of the clockwise pulse either
owing to the electromagnetic couplings in balancing the dissipation and gain. special in that they can reflect any generate a series of small pulses. The increases or remains the same. After
between transmission lines, no efficient As a result, it supports dissipative solitons. incoming waves, resulting in an increase Experimentally
colliding pulses donate a fraction ofobserved
their several subsequent head-on collisions,
design method has been established A soliton is a type of wave that maintains of the frequency. In addition, the Doppler
energy to the generated effect
pulses within TWFET.the anticlockwise pulse disappears,
for short-channel TWFETs. its shape as it moves at a constant shockwave in a cavity exhibits interesting
velocity. In this way, Dr Narahara designed self-organisation. By the proper design EXPERIMENTALLY OBSERVED DOPPLER EFFECT IN TWFET
For limiting small signals, the output a TWFET that supports short electrical of the structure and applied voltage,
of any device is assumed to be linearly pulses without significant distortions. the shockwave reaches the far end Five-period sinusoidal
dependent on the input, meaning and is reflected backwards toward the wave (incident) Shock front
that the strength and shape of The interaction of dissipative solitons input. The edge is again reflected at
the electromagnetic wave has the potential to produce a the input to become a stable shock
which is produced will be technological break-through in the front. Through the repetition of this
unchanged. However, this phase-noise performance of oscillators. process, the shock front oscillates 0
assumption doesn’t hold Oscillators are devices that change in a TWFET cavity. When the input
for many devices, where the direct current obtained from a power amplitude is increased, two or more
1
properties such as resistance, supply to alternating current. They oscillating fronts develop autonomously
capacitance and inductance are are found in many common electrical and are mutually synchronised.
not constant. These devices are known devices but typically produce high levels
time [ μs]
space [cell]
as ‘nonlinear’ devices. Until now the of phase noise which can interfere with These phenomena can be combined
nonlinear properties of TWFETs have their functioning. By considering a closed with the dynamics of dissipative solitons, Reflected wave with 40 160
been generally neglected. topology, Dr Narahara has created what leading to sophisticated methods for increased frequency

Pulse shortening by TWFET.
and the clockwise pulse uniquely survives

and rotates on the closed TWFET.
When two TWFETs are connected to

PULSE SHORTENING BY TWFET
input
1st pulse
Behind the Research
Dr Koichi Narahara
2nd
another one via a resistor, a dissipative 3rd
soliton that rotates on one of them
attractively interacts with the dissipative 500 mV
soliton that rotates on the other TWFET. E: narahara@ele.kanagawa-it.ac.jp T: +81 46 291 3085 W: www.ele.kanagawa-it.ac.jp/~narahara/
Therefore, the two dissipative solitons
n=20
in these coupled TWFETs are phase-
n=40
synchronised in such a manner that they
simultaneously pass the connecting cells.
Using this property, a closed-TWFET
n=60
n=80
space
system can be used to generate phase- n=100 Narahara, K. (2018). ‘Synchronization of dissipative solitons
Dr Koichi Narahara studies the physical phenomenon
controlled pulse trains. Using the two- n=120 generated by travelling-wave field-effect transistors, in a system of closed traveling-wave field-effect transistors’.
point connections of the closed TWFETs, n=140 such≈as electric pulses, shockwaves and solitons. Nonlinear Dyn, 94:711-721 DOI 10.1007/s11071-018-4388-6.
the two dissipative solitons can be
designed to rotate in either the common
or mutually reversed directions. Similar
0 30 Detail Narahara, K. (2012). ‘Development of Shockwaves in traveling-
wave field effect transistors’. J. Appl. Phys. 112 , 084914 ; DOI:
time [µs]
synchronised dissipative solitons can Dr Koichi Narahara 10.1063/1.4762011.
develop even in three or more TWFETs. Dr Narahara derived the condition for of the applied pulses, when the shock 1030 Shimoogino
Such a scale extension can lead to various the shockwave formation on a TWFET front reaches the far end it is reflected Atsugi Narahara, K. (2018). ‘Dynamics of dissipative solitons
schemes of phase control, including and experimentally showed that the back towards the input. The edge is Kanagawa 243-0292 developed in a closed traveling-wave field-effect transistor’.
generation of multiphase pulse trains. TWFET successfully exhibited shockwave again reflected at the input to become Japan Int J Circ Theor Appl, DOI: 10.1002cta.2509.
formation. In addition, he showed a stable shock front. The process is
In particular, the connection of the two that the shockwave accompanied the repeated continuously to establish edge Bio Narahara, K. (2013). ‘Characterization of edge oscillation in
TWFETs where the size of one is set to drain current such that it reflected the oscillation. A similar oscillation develops Dr Koichi Narahara studied at the University a traveling-wave field-effect transistor’. Physical Review E 88,
an integer multiple of the other generates waves originating ahead. When a shock in a transmission line periodically of Tokyo and then worked at Nippon Telegraph 012907, DOI: 10.1103/PhysRevE.88.012907.
two or more dissipative solitons in the front is formed at the drain, it comes loaded with tunnel diodes and is shown and Telephone Corporation and Yamagata University.
larger one. Dr Narahara found that the in contact with counter-moving waves to be a kind of limit cycle that can be He moved to Kanagawa Institute of Technology in 2014 Narahara, K. (2011). ‘Characterization of Short-Pulse
two dissipative solitons interact repulsively and in doing so its frequency becomes synchronised with external oscillation and is now a Professor in the Department of Electrical Generation Using Traveling-Wave Field-Effect Transistors’.
in a closed TWFET. Hence, a stabilised greater than the counter-moving waves or possibly coexisting edge oscillations. and Electronic Engineering. Jpn.J.Appl.Phys, 50, 014104. DOI: 10.1143/JJAP.50.014104.
dissipative soliton in a closed TWFET due to a mechanism called the Doppler Moreover, the number of oscillating
can position the antipode of its paired effect. Essentially, says Dr Narahara: edges increases with the amplitude
dissipative soliton. This interaction “The shock front operates as an of the signal input to the gate line. Each
contributes to a reduction in inter-pulse approaching wall to the counter-moving edge can be synchronised with the other
spacing fluctuation, which results in waves, the frequency of reflected wave edges. Double and quadruple oscillating
the reduction in the phase noise present becomes greater than the incident edges were successfully detected by
in the pulse train output. one through the Doppler effect.” time-domain measurements performed Personal Response
by Dr Narahara.
SHOCKWAVES The Doppler effect is the change Can you tell us your future plans for research
One of the nonlinear effects in in wavelength of a wave in relation to THE FUTURE OF TWFETS in this field?
distributed systems is the development an observer who is moving relative to Dr Narahara is optimistic that TWFETs The synchronised dissipative solitons must be verified
of shockwaves. A shockwave is a type the wave source. As the observer moves could someday replace oscillators in experimentally in the near future. After the elaboration
of propagating wave that carries energy closer to the waves, each wave takes modern devices as electronics evolved of the device structure for pulse compression and shock/
like an ordinary wave but is characterised slightly less time to reach the observer to require ever-smaller and higher soliton generation, compound utilisation of TWFETs will
by an abrupt, nearly discontinuous, than the previous wave leading to a speed circuits. “Through the combined become highly valued. In general, wave phenomena are
dynamics between dissipative solitons realised through synergistic contributions by dispersion,
change in pressure, temperature and decrease in the time between the arrival
dissipation, gain, electromagnetic couplings, and
density of the medium. Shockwaves of waves at the location of the observer. and shocks, TWFET networks can lead to
nonlinearity. TWFETs contain sources of all these elements
have been observed in transmission lines This causes an increase in frequency. a new systematic scheme of designing so that they have significant potential to develop any
that are loaded along their length with oscillators,” said Dr Narahara. Much natural wave phenomena on a semiconductor wafer. I keep
either the voltage-dependent capacitors In addition, by properly designing the is still not known about the nature of studying what is possible in TWFETs without considering
known as varactors. transmission line size and voltage levels dissipative solitons and the knowledge technological values too much.
imparted by Dr Narahara’s research has
Through the combined dynamics between shown that the TWFET is a valuable
dissipative solitons and shocks, TWFET

tool for the study of these fascinating
waveforms, which have the potential to
networks can lead to a new systematic advance the field of waveform physics as
well as contribute enormously to future
scheme of designing oscillators. electronic technological breakthroughs.

Biology ︱ Dr Malini Sen
Pathogenic microorganisms
THE ROLE OF WNT5A
IN THE IMMUNE RESPONSE
The protein Wnt5a belongs to a family of
secreted glycoproteins that are involved in
targeted by complex
transmitting cellular signals. Wnt5a binds
to two proteins that transverse the cell
membrane: either the protein Frizzled (Fz),
or a type of cell-surface receptor protein
cellular communications
called ROR, or both. In the early stages
of mammalian development, Wnt5a is
involved in cell growth and differentiation.
During this time, Wnt5a plays a vital
part in cell migration and cytoskeletal
reorganisation (arranging and supporting
W
When the human body hen an infection enters own autophagy (literally, “self-eating”) the internal structure of the cell). Dr Sen
is challenged by infection, the human body, it triggers a machinery to break down the proteins and her colleagues decided to investigate
the defences of the immune sophisticated, complex and and organelles of the invading whether Wnt5a might contribute to the
system are called into action. targeted immune response. The invaders microorganism. process of phagocytosis in a similar way.
Dr Malini Sen of the Indian can take many forms – bacteria, viruses,
Institute of Chemical Biology parasites – but whatever the challenge, EVADING THE MACROPHAGE In 2012, Dr Sen and her team
is leading research into the the forces of the immune system have Sometimes, however, a microorganism published the results of a study with
role of a protein called Wnt5a a response. As part of the first line of gets the better of a macrophage, a non-pathogenic lab strain of bacteria
in defending against invading defence, macrophages (a name that leaving the body without one of its most that showed that signalling between
pathogenic microorganisms. comes from the Greek term for “big important defenders. When this happens, Wnt5a and Fz plays an important
Wnt5a is found in macrophages, eaters”) are a vital component of the people can develop chronic illnesses part in the phagocytosis of bacteria
large white blood cells that form immune response. In a process called that fail to respond to treatment. For where bacteria are “eaten” by the
one of the first lines of defence phagocytosis, these large white blood example, patients with diseases such as macrophage while being broken down Wnt5a-Fz5 Signalling in macrophages promotes clearance of bacterial pathogens through complex
against infection. Dr Sen cells locate, engulf and destroy threats Chronic Obstructive Pulmonary Disease and thus rendered harmless. The interactions among its signalling intermediates.
and her team have shown that
to the body. These threats can include (COPD) can develop sepsis as a result team demonstrated this by creating
Wnt5a plays a vital part in cell migration
Wnt5a signalling plays a key
pathogenic bacteria and other invading of infection by drug-resistant bacteria two models: one where Wnt5a
role in helping macrophages
microorganisms, foreign substances, like Streptococcus pneumoniae or production was inhibited and one where
to engulf and destroy
invading microorganisms.
cancer cells and cellular debris. Pseudomonas aeruginosa. Sepsis is a life- the Wnt5a receptor Fz5 was blocked. and cytoskeletal reorganisation.
threatening condition that can cause In both cases, uptake of bacteria into
Extensive research has shown that multiple organ failure, and is triggered the macrophage was inhibited. In a follow WNT5A AND LEISHMANIASIS of the disease leishmaniasis, known as
phagocytosis involves a complex by the body’s own overwhelming immune up study, published recently, Dr Sen While establishing the crucial role visceral leishmaniasis or “black fever.” This
yet highly coordinated cascade of response to an infection. Sepsis remains and her team demonstrated the effect of Wnt5a in tackling pathogenic bacteria condition is the second-largest parasitic
events. A variety of different proteins difficult to treat and is considered of Wnt5a-Fz5 signalling on phagocytosis the team decided to broaden the scope killer in the world (after malaria) and
and lipids on the macrophage to be a global health concern. and bacterial clearance (xenophagy) of their research. In 2017, Dr Sen and causes symptoms including fever, anaemia
cell surface work together to of pathogenic bacteria. her colleagues published their findings and swelling of the liver and spleen.
capture a bacterium and draw To better understand how some on the role of Wnt5a signalling in infection
it into the cell. Within the pathogens are able to evade the body’s THE IMPORTANCE OF SIGNALLING by the parasite Leishmania donovani. L. Leishmania donovani is a cunning
macrophage, numerous immune defences, Dr Sen and her It was important for Dr Sen and her team donovani causes the most severe form parasite, able to not only evade the host’s
organelles and protein- team investigate the ways in which to investigate the mechanisms by which
lipid interactions result the immune system is maintained. macrophages are primed to tackle Wnt5a gene encodes Wnt5a protein
in pathogenic bacterial Macrophages need to be infection. This immune homeostasis,
clearance in a process primed and maintained whereby immune cells are maintained
called xenophagy. in a constant state of in a steady state of surveillance for
Xenophagy, an readiness if they are to infection is essential if macrophages are
innate component be effective. Key to swiftly and effectively tackle infection.
of the immune to this process
system, makes is a protein Dr Sen and her colleagues established
use of the cell’s called Wnt5a. that basal (i.e. constant, low-level) Wnt5a
signalling both keeps macrophages
prepared to perform their innate immune
functions and supports their survival.
The team found that the recognition
and internalisation of bacteria and viruses
is partly dependent on a homeostatic Wnt5a gene location in chromosome 3 (human).
Wnt5a-based signalling system.

immune defences but to actually
use those defences to survive. When
a macrophage engulfs L. donovani,
the parasite creates a protective space,
Behind the Research
or niche, for itself. These safe spaces
are termed parasitophorous vacuoles
Dr Malini Sen
(PV). Sequestered in its parasite niche,
L. donovani is safe from the digestive E: msen@iicb.res.in E: msen648@gmail.com T: 91 332 499 5730 W: https://doi.org/10.4049/
mechanisms that would normally destroy jimmunol.1302817 W: https://doi.org/10.1073/pnas.1207789109 W: https://doi.org/10.4049/
microorganisms within the macrophage. jimmunol.1601927 W: https://doi:10.3389/fimmu.2018.00679
However, exactly how L. donovani
and other parasitic infections form
and sustain PV and avoid destruction
remains unclear. Chakraborty, A, Kurati, SP, Mahata, SK, Sundar, S, Roy,
Dr Sen’s research looks at deciphering the role
of mesenchymal stem cell factors such as Wnts in various S and Sen, M. (2017). ‘Wnt5a Signaling Promotes Host
The key to the puzzle may be found in the aspects of immune homeostasis, immune response Defense against Leishmania donovani Infection’. Journal
cytoskeleton, the structure that provides to infection and inflammation. of Immunology, 199, 992-1002.
mechanical support and maintains
internal organisation of the cell. There
is an established link between bacterial
Detail Maiti, G, Naskar, D and Sen, M. (2012). ‘The Wingless
homolog Wnt5a stimulates phagocytosis but not bacterial
pathogenesis (the way in which bacteria Division of Cancer Biology & Inflammatory Disorder killing’. PNAS, 109 (41), 16600-16605.
cause disease) and the cytoskeletal Indian Institute of Chemical Biology (IICB)
dynamics of the host cell. The protein 4 Raja SC Mullick Road Naskar, D, Maiti, G, Chakraborty, A, Roy, A, Chattopadhyay,
Wnt5a is also known to have an important Kolkata 700032 D and Sen, M. (2014). ‘Wnt5a-Rac1-NF-kB Homeostatic
relationship with the cytoskeleton. Dr India Circuitry Sustains Innate Immune Functions in Macrophages’.
Sen and her team, therefore, theorised Journal of Immunology, 192, 4386-4397.
Wnt5a mediated bacterial killing as depicted by confocal microscopy; (a) Red dots indicate Propidium
that Wnt5a signalling could influence Iodide stained bacteria (less in Wnt5a than PBS), (b) Green dots indicate LC3B punctae (more in Wnt5a Bio
the formation of PV by L. donovani. than PBS), which represent xenophagy (bacterial killing). PBS is vehicle control for Wnt5a. Dr Sen earned her Bachelor’s degree from Calcutta Jati S, Kundu S, Chakraborty A, Mahata SK, Nizet V and Sen M
University, India and her PhD from Albert Einstein College (2018). ‘Wnt5a Signaling Promotes Defense Against Bacterial
Dr Sen and her colleagues observed Basal Wnt5a signalling both keeps of Medicine, NY. She was an Arthritis Investigator at the Pathogens by Activating a Host Autophagy Circuit’. Frontiers
macrophages prepared to perform their

a decrease in Wnt5a in macrophages Dept. of Medicine, UCSD and became a faculty member in Immunology, 9: 679. doi: 10.3389/fimmu.2018.00679.
infected by L. donovani. The parasite in the Indian Institute of Chemical Biology, a unit of CSIR,
likely achieves this by suppressing
Wnt5a signalling in the host cell and/or
innate immune functions and supports India in 2007.
through the use of its proteases, enzymes their survival. Funding Personal Response
that can break down host proteins. Department of Biotechnology & Council of Scientific and
The consequent reduction in Wnt5a THE FUTURE destructive enzymes) with PV. This finding Industrial Research (CSIR), India. What are the next steps in investigating the role
protein could cause alterations to the During their research, Dr Sen and is potentially hugely significant in tackling of cytoskeletal dynamics in the immune response?
macrophage cytoskeleton and disrupt her team also discovered that bolstering infections by L. donovani and other Collaborators
We are trying to dig deep into the molecular details
immune homeostasis. L. donovani would Wnt5a signalling within a macrophage parasites that are able to evade the host • Suborno Jati, Research Scholar, IICB, India of how Wnt5a signalling intermediates in host macrophages
then be able to take advantage of the reduces parasite survival, probably immune response. While L. donovani • Arijit Chakraborty, Research Scholar, IICB, India are intertwined with the cytoskeletal dynamics during the
abnormal changes to build a protective because Wnt5a triggers fusion of thrives by inhibiting Wnt5a signalling • Sushil Mahata, Professor, VA Medical School, UCSD, USA immune response to different microbial pathogens. In this
niche within the macrophage. lysosomes (small organelles containing in the host cell, boosting Wnt5a function • Syamal Roy, Professor, NIPER, India regard, we are focusing on the influence of Wnt5a signalling
could potentially form the basis of • Victor Nizet, Professor, UCSD, USA on cytoskeletal actin binding and nucleating proteins,
a new treatment route for leishmaniasis. which come into play when a functional cytoskeleton reacts
to pathogen assaults. Through different experimental
procedures, we hope to figure out how Wnt5a signalling
Dr Sen and her colleagues hope that
utilises the cytoskeletal dynamics to distinguish pathogens
the knowledge gained from their research from non-pathogens during the arbitration of the host
will help to increase understanding autophagy circuit for pathogen clearance, thereby
of both the strategies invading resisting infection.
microorganisms use to evade their host’s
defences, and the ways in which immune What are your future plans for research in this area?
responses strive to resist and repel We would like to conduct experiments aimed at a
these attacks. One day, this knowledge detailed evaluation of the significance of Wnt signalling in
could be used to develop protocols the context of sepsis, which is associated with an impaired
to support and enhance the function immune system.
of macrophages and other immune
cells in patients with weakened immune
Macrophages interact with pathogens to initiate immune response. systems, thus preventing the spread
of deadly pathogens.

Biology ︱ Dr.ir. Sjaak van Heusden
Better and stronger

A flowering diploid potato plant.
potatoes using
hybrid breeding
P
Potato is a hugely important otato breeding techniques are relatively few calories, yet potatoes can be This diploid ‘germplasm’ contains
crop worldwide, being eaten lagging far behind those of other processed and cooked into many different a high level of heterozygosity but then
across the world and across popular crops such as rice, maize, forms – potentially providing varieties is repeatedly selfed (bred with itself).
cultures. Increased crop and wheat. This is because potato that grow where not much else can grow. Selfing gradually dilutes the level
productivity and strength will breeding suffers hinderances through With the help of the Solynta breeding of heterozygosity of the progeny until
help cater for the increasing its genetic complexity, resulting in slow technology, each of these traits can they are, after about 6 generations,
global population, and also progress. The cultivated potato Solanum be harnessed, genetically selected for, almost completely homozygous. These
serve to reduce famine in tuberosum is tetraploid, meaning it and reproduced. parental plants could be the first self-
challenging and impoverished has four sets of chromosomes – in this compatible, diploid potato plants ever
environments. The potato situation, it is easy for unfavourable A HYBRID BREEDING PROCESS made. Homozygous parents are needed
breeding company Solynta in alleles to make their way unseen into Historically, selection of better potato for the creation of hybrids.
The Netherlands has successfully the next generation, and introducing new, varieties took a very long time. Firstly,
produced a hybrid breeding favourable traits can be very tricky. it was simply trial and error to breed Due to inbreeding depression, the first
program for potatoes which will a suitably stronger crop, after this generations were in general weaker.
allow the rapid selection and At Solynta, a potato seed breeding the selected plant underwent a lengthy However, due to the selection of only
turnover of favourable traits,
company based in Wageningen, Holland, multiplication process. The best potato the most vigorous (strong) potato plants,
traits which could help feed
an innovative method for targeted would be selected and planted in the parent lines quickly became stronger
millions of people worldwide.
breeding has been developed which the ground to multiply the number and more homozygous. Strong parental Berry development after crossing. The yellow bag prevents the berries to fall off and to get mixed with
will change the production and global of tubers, this process takes a year. This plants can be hybridized to make F1 berries from other crosses.
distribution of potatoes. This method must be repeated year upon year, until hybrid seeds. The resulting hybrid potato
allows for the combination of beneficial after around seven years a commercially plants were generally better and stronger drastically reduce transportation cost potato plants is present, Solynta could
traits from different potato varieties viable number is produced. To make than the inbred parent lines (heterosis). and difficulty. then focus on isolating and selecting
to make ‘elite’ progenies which have matters worse, with time, these potatoes for beneficial potato traits. During this
a higher yield, disease resistance, and can become increasingly susceptible THE BENEFIT OF SEEDS The seeds are also pathogen free whole process, the traits needed for
of course, better taste. Furthermore, to diseases, such as potato blight The potato seeds can be harvested whereas tubers mostly have a low level strong potatoes were identified and then
this method allows for vastly Phytophthora infestans. when the hybrid plant forms berries. of disease-causing pathogens. True genetically targeted and selected for.
improved transportation These seeds (true potato seeds) potato seeds also withstand changes This was done using a process called QTL
which will be done at the This new targeted breeding process have an incredible benefit over the in temperature and humidity. Ultimately (Quantitative Trait Locus) mapping.
seed stage, rather than fully relies on a few important principles which previous method with tubers (tubers the reduction in transport will also reduce
grown potato tubers. counteract these historical problems. are also named seed potatoes). The carbon footprint. Each phenotypic trait (observed
The first is that the breeding process weight of 100 potatoes is equal to in the potato) is described by one or,
Potatoes are also a much is completed using diploid potatoes the weight of 16 million seeds, as it’s DISCOVERING TRAITS, normally more than one, gene. In order
more nutritious source rather than tetraploid. This is achieved possible to fit 2500 seeds in just one IMPROVING POTATOES to understand which genes control
of food than by diploidisation and using S. chacoense gram. This magnitude of difference will Now that a steady flow of strong, diploid the outcome of a potato, the team
other top crops diploid potatoes. The resulting organism looked at SNPs (Single Nucleotide
One huge application of Solynta’s potatoes

such as rice, is a diploid hybrid potato plant, Polymorphisms). Simply put, this
soy and with just two sets of chromosomes. is when one nucleotide differs on a
wheat. They
contain high
Normally, diploid potato plants are self-
incompatible but some S. chacoense
will be to help farmers and feed people, in particular individual’s genome. By using
sequencing and statistics, it’s possible
levels of plants contain a gene called Sli, which previously difficult or challenging locations. to determine when this is linked to a
vitamins and overcomes self-incompatibility. particular phenotypic trait. Plants with

Extracted and cleaned seeds (on white filter paper),
two halves of a berry and some potato tubers.
Behind the Research
Dr.ir. Sjaak van Heusden
E: sjaak.vanheusden@solynta.com T: +31 620 843 929 W: https://solynta.com/

Solynta has developed an innovative method for targeted De Vries M, ter Maat M, Lindhout P. (2016). ‘The potential of
breeding which will change the production and global hybrid potato for East-Africa’. Open Agriculture, Vol 1: pp.
distribution of potatoes 151-156.
Detail Lindhout P, de Vries M, ter Maat M, Ying S, Viquez-Zamora M,

van Heusden S. (2018). ’Hybrid potato breeding for improved
Dr.ir. Sjaak van Heusden varieties’. Achieving sustainable cultivation of potatoes, Vol 1,
Solynta pp. 99-122.
Dreijenlaan 2
6703HA WAGENINGEN Lindhout P, Meijer D, Schotte T, Hutten R, Visser R, van Eck
The Netherlands H. (2011). ‘Towards F1 Hybrid Seed Potato Breeding’. Potato
Research, Vol 54 (4), pp301-312.
Potato tubers of one of the
Potato seeds after cleaning. founder lines of Solynta. Bio
Sjaak van Heusden fields of expertise are tomato and D. Meijer; M. Viquez-Zamora; H. J. van Eck; R. C. B. Hutten;
diploid potato pre-breeding with emphasis on marker Y. Su; R. Rothengatter; R. G. F. Visser; W. H. Lindhout; A. W.
those detected genome alterations
are then selected for breeding.
These parental plants could be the first technology. Besides research, he is involved in international
teaching and cooperation. In the last five years, he has been
van Heusden (2018). ‘QTL mapping in diploid potato by using
selfed progenies of the cross S. tuberosum × S. chacoense’.
self-compatible, diploid potato plants mainly employed as a geneticist at the potato breeding Euphytica, 214:121
In order to further enhance this
process, the parental lines could then ever made. Homozygous parents are company Solynta.
be ‘backcrossed’ to add new ‘hybrid needed for the creation of hybrids. Funding
traits’ to one of the parent lines. This Solynta Personal Response
strengthened the parent lines, which were FEEDING GLOBAL POPULATIONS but even larger in low to middle-
then hybridized to make an even stronger One huge application of Solynta’s income countries. Collaborators If already successful in other crops, what has stopped
hybrid potato. Each time a stronger, potatoes will be to help farmers • Wageningen University and Research this process being achieved before in potatoes?
tastier, or larger potato was grown. This and feed people, in previously difficult The Solynta hybrid diploid potato seeds
Making diploid potatoes has already been tried
process is so rapid in Solynta because or challenging locations. The benefits were transported and tested in East for decades but was never successful. A better use of
of the speed of growth from seed, of these potatoes are going to be Africa, specifically the mountains of new technologies to overcome self-incompatibility and
and genetic selection of traits. large in the high-income countries, DR Congo. The results were extremely to follow the level of homozygosity in selected plants,
optimistic, with a much higher yield make it now possible to make the transition of tetraploid
of potato than under normal East potatoes to diploid potatoes. Over time, as we transition
African conditions. to diploid potato breeding, we will be able to undo
previous dogmas, such as a high yield is only possible
with tetraploid potatoes.
Furthermore, the seeds were extremely
easy to transport and were free of
pathogens which are so common in the What are your future plans for research in this area?
tropical African climate and can decimate Solynta wants to introduce successful varieties in Africa.
farmers’ stocks between seasons. It’s also To do this large numbers of clean seeds of plants with
very possible to adapt the diploidisation enhanced levels of resistance are needed. Later,
and genetic hybridization techniques from other markets will be targeted.
Solynta’s technology to African potato
varieties, increasing the breadth of choice
in these areas. It seems only a matter
of time before these farming methods
are being used worldwide in order to
catch up with the global demand for food
Collection of berries which developed after
self-pollinations of a diploid parent. production alongside our ever-expanding
human population.
Biology︱ Dr Ángela Gómez-Niño and Dr Asuncion Rocher
B N CIH A
Guinea pig as a model

125 *** *** *** ***
to study the carotid

100
fR (breath/min)
body-mediated chronic
75
Plethysmography recording of respiratory
parameters measured in normoxic (N) or
breathing air and intermittent hypoxia (CIH)
intermittent hypoxia effects

exposed guinea pigs. A. Image of awake and
50 freely moving guinea pigs during whole body
plethysmography recordings. B. Respiratory
frequency (or breaths per minute; fR) response
to air (21% oxygen), acute hypoxia (5 min)
25 (breathing 10 or 7% oxygen) and hypercapnia
(5% CO2) tests. Only intense hypoxia (7% O2) and
hypercapnia increased ventilation. No diferences
between control (N) and chronic intermittent
H
ypoxia is the reduction of CAROTID BODY CHEMORECEPTORS 0 hypoxia treated (CIH) guinea pigs were observed.
The ability to sense and respond (Data are expressed as mean ± SEM (n=8) Two-
oxygen supply to tissues to ARE STIMULATED BY HYPOXIA 21% O2 10% O2 7% O2 5% O2 way ANOVA; ***p<0.001 vs. 21%. O2)
to changes in oxygen is essential
for survival. Dr Ángela Gómez- below normal, physiological The CB is found in carotid arteries –
Niño and Dr Asuncion Rocher levels. Hypoxia can be produced, the main arteries that run along both
along with their research team for example, by exposure to high sides of the throat – and is sensitive to employs the use of the guinea pig. The (hypertension), and an increased risk to similarities between rodent and
at Valladolid University aim to altitudes. Mammals have developed the levels of blood gases. The CB has a guinea pig represents an exciting model of heart disease. human blood pressure control and
better understand the physiology different oxygen-sensing mechanisms high density of blood vessels and is made to help better understand the underlying cardiovascular responses. In contrast,
and pathophysiology of oxygen to maintain the oxygen supply within up of a cluster of specialised cells, called mechanisms mediating the long-term CHRONIC INTERMITTENT HYPOXIA experiments using guinea pigs, originally
sensitivity. In particular, the team cells in response to hypoxia. When type I cells, that are connected by nerve effects of hypoxia exposure. Specifically, Animal models exposed to recurrent from the Andes, showed a different
employ the use of the guinea the body senses a decrease in oxygen, endings from the carotid sinus nerve, their newly proposed model has hypoxia and re-oxygenation episodes response in early studies led by Dr
pig as a model to explore the its strategy is to increase breathing depth a branch of the ninth cranial pair nerve. important implications for understanding in CIH show increased CB sensitisation, Gómez-Niño. Her work demonstrated
mechanisms that mediate long- and rate (hyperventilation), in addition, Upon detecting a drop in blood oxygen the role of the CB in mediating the which in turn increases the secretory that guinea pigs show a poor or
term effects of exposure to low the heart beats faster. These strategies levels (or excessive carbon dioxide in pathological effects observed in sleep response and chemoreceptor input no ventilatory response to hypoxia
oxygen levels. With its unique are controlled through feedback the blood, known as hypercapnia), type apnoea disease. to the brainstem, exaggerating the compared to other mammals.
oxygen-sensing systems, the mechanisms triggered by sensory I cells release specialised signals (known resulting nervous reflex (sympathetic
guinea pig promises to be an receptors called chemoreceptors. One as neurotransmitters, for example, OBSTRUCTIVE SLEEP APNOEA reflex). Experiments have shown that Dr Gómez-Niño’s intriguing research
invaluable tool to study and
of the main chemoreceptors responsible catecholamines, ATP and acetylcholine) Sleep apnoea is a serious sleep if the CB is removed, these effects can demonstrates that unlike other rodents,
understand the pathological
for oxygen-sensing is the carotid body that stimulate the carotid sinus nerve, disorder that occurs when a person’s be reduced in response to intermittent the poor ventilatory response to hypoxia
effects occurring in sleep
(CB), which monitors and responds to carrying chemoreceptor information breathing is interrupted during sleep; hypoxia. The majority of hypertension in guinea pigs is due to low levels
apnoea disorder.
changes in the partial pressure of oxygen to the brainstem to initiate reﬂex loud snoring and episodes of breathing research is conducted on rodents, due of functional CB. The team measured
and carbon dioxide in arterial blood. responses. In this way, the CB reflex interruption during sleep are classic
The team are exploring the guinea pig

response, triggered by hypoxia, restores symptoms. In sleep apnoea disorders,
oxygen blood concentration to its breath can become very shallow or
normal level. Information from the CB
is thus transmitted to the brainstem,
may even stop briefly during the sleep.
In severe cases, the condition causes
as a model to better understand the
which increases breathing frequency breathing to repeatedly stop and start mechanisms that mediate long-term
(hyperventilation) as well as stimulating during sleep meaning that the brain,
the nervous system (sympathetic and the rest of the body, does not get effects of exposure to low oxygen levels.
activation), thereby counteracting enough oxygen. Chronic intermittent
the effects of hypoxia. hypoxia (CIH) is thought to be one of
the main causes of arterial high blood
A research team at the University pressure observed in obstructive
of Valladolid, led by Dr Ángela Gómez- sleep apnoea syndrome. It is believed
Niño, Professor at the Department of that repeated episodes of hypoxia/
Cell Biology, and Dr Asuncion Rocher, re-oxygenation produce oxidative
Professor of Physiology, explores stress, inflammation and sympathetic
the mechanisms involved in oxygen hyperactivity, generating dysfunction
Cardiovascular responses to hypoxia. Continuous recording of arterial blood pressure from a CIH
sensing and transduction in CB arterial of the blood vessel lining (endothelium) guinea pig breathing air (21% O2) or hypoxia (10% O2). To measure arterial pressure, guinea pigs were
chemoreceptors. Their research and high blood pressure. Indeed, anaesthetized (ketamine plus diazepam; 100 y 5mg/Kg, respectively; ip). After a incision in the neck,
has implications for hypoxia-related recent evidence suggests a positive they were tracheostomized and ventilated with room air (CL Palmer) or with the gas mixture (10% O2
and 90% N2). Once the right common carotid artery was located, it was cannulated with a catheter
Hartley guinea pig. pathologies, particularly sleep apnoea correlation between CIH, increased CB connected to a pressure transducer (Transpac IV; ICU Medical, San Clemente, CA) and signals were sent
disorder. One exciting focus of their work responsiveness and high blood pressure and stored (BIOPAC Systems, Inc. MP 150, Goleta, CA; Acknowledge 3.9.1) for later analysis.

Behind the Research
INTERMITTENT CENTRAL NERVOUS SYSTEM
HYPOXIA (Brainstem neurons)
CC Dr Ángela Dr Asuncion
CSN Gómez-Niño Rocher
CB CSN E: angela@biocel.uva.es E: rocher@ibgm.uva.es T: +34 983 423086 T: +34 983 423000 ext 4122

The picture shows the dissection of the bifurcation of the common carotid artery and Docio I. Olea, E, LLoret J-P, Gallego-Martin T, Obeso A,
the carotid body with the attached carotid sinus nerve. The decrease of oxygen in blood SYSTEMIC RESPONSE Dr Ángela Gómez-Niño and Dr Asuncion Rocher along
(hypoxia) is detected by chemoreceptor or type I cells (CC) of the carotid body that by with their research team at Valladolid University aim to Gomez-Niño A, Rocher A. (2018). ‘Guinea Pig as a Model
(cardiorespiratory response)
releasing neurotransmitters increase the frequency of action potentials or discharges in better understand the physiology and pathophysiology of to Study the Carotid Body Mediated Chronic Intermittent
the carotid sinus nerve (CSN). This information reaches the brainstem generating systemic Hypoxia Effects’. Front. Physiol. 9:694. doi: 10.3389/
responses (hyperventilation and increase of sympathetic activation that can produce oxygen sensitivity. In particular, the team employ the use of
hypertension). CC= chemoreceptor cell of the carotid body; CSN= carotid sinus nerve). the guinea pig as a model to explore the mechanisms that fphys.2018.00694.
This is what happens in humans and other animal models but not in guinea pigs. mediate long-term effects of exposure to low oxygen levels.
Gonzalez-Obeso, E., Docio, I., Olea, E., Cogolludo, A.,
SYMPATHETIC RESPIRATORY
The team showed an absence of the STIMULATION RESPONSE Detail Obeso, A., Rocher, A., and Gomez-Niño A. (2017). ‘Guinea pig
oxygen-sensing and carotid body functional properties’. Front.
hypoxia-driven CB reflex in the guinea pig. Dr Ángela Gómez-Niño

The University of Valladolid
Physiol, 8:285. doi: 10.3389/fphys.2017.00285.
UC/Plaza de Santa Cruz, 8, Olea, E., Gonzalez-Obeso, E., Agapito, T., Obeso, A., Rigual,
the guinea pig CB response to hypoxia chemoreceptors with cardiovascular 47002 Valladolid, R., Rocher, A., and Gomez-Niño A. (2018). ‘Adrenal medulla
and compared it to the well-known and respiratory responses to hypoxia. HYPERTENSION HYPERVENTILATION Spain chemo sensitivity does not compensate for the lack of
rat hypoxic response. Their research, hypoxia-driven carotid body chemoreflex in guinea pigs’. Adv.
published in Frontiers in Physiology, To mimic the situation of an obstructive be similar to that seen in neonatal Bio Exp. Med. Biol, 1071: 167-174.
demonstrated for the first time the sleep apnoea patient, the team exposed mammals (In Olea et al., 2018, the Dr Ángela Gómez-Niño is associated professor teaching
absence of the hypoxia-driven CB reflex male guinea pigs to acute hypoxia (30- team showed that it is not the case). cell biology and her research is focused on the mechanisms
in the guinea pig. This lack of guinea pig day exposure to CIH). They measured Neonatal mammals have an immature involved in oxygen detection and transduction in the carotid Personal Response
CB response to hypoxia would suppress CB secretory activity, ventilatory CB chemoreflex and respond to hypoxia body arterial chemoreceptors and the hypoxia-related
the chemo-reflex sensitisation, reducing parameters, systemic arterial pressure through another pathway – via the pathologies, mainly those associated to sleep apnoea What first drew you both to the guinea pig as a
or eliminating the respiratory and nervous and sympathetic activity. Their results direct effect of hypoxia on, the adrenal disorders. potential model organism to use in your research?
reflex (sympathetic reflex) effects of showed that guinea pigs exposed to CIH medulla. (It could be through the hypoxic Our previous experience working on mammal arterial
intermittent hypoxia exposure. The lack lack activity (as measured by release of stimulation of specific areas in the central Dr Asuncion Rocher is Professor of Physiology at the chemoreceptors was based mainly on rats. We have used
of response to hypoxia showed that catecholamine. Only severe hypoxia (7% nervous system). Medical School of the Valladolid University where she the rat as a model to mimic chronic intermittent hypoxia,
CIH does not modify the excitability of O2) resulted in an increased ventilatory teaches graduate and postgraduate courses in physiology the hallmark of sleep apnea disorder symptoms that appear
the CB. Their research did show, however, response and oxygen consumption Excitingly, the researchers at the and biomedicine. Her research is focused on arterial in patients. The literature showed that guinea pigs did
that intermittent hypoxia-induced to the CIH animals. In other words, University of Valladolid believe that chemoreception, oxygen sensing and hypoxia-related not hyperventilate in hypoxic environments what led us to
sympathetic hyperactivity and promoted CIH exposure blunted hyperventilation the guinea pig represents a useful pathologies. characterize the guinea pig carotid body. We demonstrated
that guinea pigs have a hypo-functional carotid body,
cardiovascular responses by increasing to hypoxia normalised to oxygen tool for examining the mechanisms
without adaptation to chronic hypoxia. Based in our
heart rate and arterial blood pressure and consumption. However, the team underlying the long-term effects of CIH Funding hypothesis of the carotid body as the origin of sleep apnea
that this is independent of CB stimulation. found that catecholamine levels were exposure – in particular, the brainstem MINECO/FEDER, UE BFU2015-70616R, ISCiii CIBER symptoms, we decided to use guinea pigs as a model to
increased in the blood, suggesting that sensitivity to hypoxia and cardiovascular CB06/06/0050 and FUNGE UVa PIP-063_166091. study the effects of intermittent hypoxia exposure.
INVESTIGATING THE LACK OF CIH induced nerve activity. The team responses generated by intermittent
RESPONSE TO HYPOXIA concluded that CIH does not sensitise hypoxia. The team’s hope is that this Collaborators
Dr Gómez-Niño went on to test the idea the CB chemoreceptor response to model will also provide evidence • Elvira Gonzalez-Obeso
that this lack of CB hypoxia response hypoxia but promotes cardiovascular for the role of the CB mediating • Inmaculada Docio
in guinea pig would suppress chemo- adjustments, albeit not via the pathological effects in sleep apnoea • Elena Olea
reflex sensitisation, thereby attenuating CB activation. diseases. Dr Gómez-Niño and Dr • Ana Obeso
or eliminating respiratory, sympathetic Rocher’s next steps are to examine the • Jesus Prieto-LLoret
and cardiovascular effects of CIH A MODEL TO INVESTIGATE CHRONIC missing mechanisms that underlie the • Teresa Gallego-Martin
treatment. The research team set out INTERMITTENT HYPOXIA lack of effects of intermittent hypoxia on • Ana Gordillo
to explore whether the guinea pig CB Dr Gómez-Niño and Dr Rocher postulate the guinea pig CB to provide evidence
can be overactivated by CIH; their aim that the absence of the hypoxia-driven for its role in mediating hypertension
was to correlate the CIH effects on CB CB reflex in the guinea pig is could observed in sleep apnoea disorder.

Behavioural Sciences ︱ Ven Karma Jiga
Mindfulness-Based Intervention (MBI)

provides positive outcomes for those
in lower socioeconomic environments
I
The western world today t is no surprise to find that those living is now arguably considered more normal
demands a great deal from its in lower socioeconomic environments for Westerners. Mindfulness, although
inhabitants, both physically are more prone to suffer from several it may mean different things to different
and mentally. The prevalence stress-induced physical and mental groups of people, has been defined as the
of mental health problems is disorders. Financial stress is often cited as awareness and acceptance of what arises
high, and none more so than one of their leading causes, particularly in and around you as it happens ; however,
those in low socioeconomic
status, with financial hardship
in westernised cultures. It is now well this requires developing an ability to let to the community are now becoming Mindfulness has been shown to reverse
neurophysiological changes caused
documented that extended periods of go of, and become less involved with our known, with participation increasing as
recognised as a root cause for stress, regardless of source, can increase thoughts, feelings and emotions as they the word spreads! Participants who have
life stress and anxiety. Although
trained in both eastern and
susceptibility to a myriad of illnesses and
disease, both physical and psychological.
come to mind. completed the course have said that they
feel more like their old selves and less
by prolonged stress.
western based mindfulness Most, if not all of us, can relate to Typical mindfulness-based interventions, stressed when dealing with circumstances and mental health issues encountered by of course completion by individuals.
techniques, Karma Jiga applies experiencing stress at some point in our such as Mindfulness-Based Stress without their control. those in low socioeconomic environments Knowing that high dropout rates were a
the western secular approach lives, but unfortunately for some, this can Reduction (MSBR) and Mindfulness- influences the interpretation of results common problem which could affect the
to reach this population. Using be a near lifelong affliction. Based Cognitive Therapy (MBCT) consist THE SCIENCE – DOES IT WORK? and makes for a complicated area of ability to produce a viable study, Karma
an adapted Mindfulness-Based of a 6-8-week programme delivered by An important measure for any type of study, let alone the fact that genetics may Jiga developed a recruitment protocol
Intervention (MBI), he delivers
BRIEF HISTORY OF trained practitioners. These combine basic treatment plan or psychoeducation course play a significant role in the occurrence that would determine the programmes
mindfulness techniques to those
TREATMENT APPROACHES Buddhist based meditation practices with is whether it works and can be verified of anxiety, stress and depression. Whilst initial feasibility. This protocol was
in poverty to help improve their
The treatment of stress is now at the a more science-based understanding of empirically. Early research investigating the validity and results of some studies effective in that it improved accessibility
physical and mental well-being,
forefront of medical and psychological stress and wellbeing. The idea is to allow the efficacy of MBIs was promising with in the mindfulness field have been called by providing for participants needs
without charge. The potential
benefits to the individual and sciences, both striving towards developing thoughts to come and go and let go of significant increases in several well-being in to question, the effects of mindfulness while taking into account participants
wider community could prove the most effective treatments for the desire to judge or focus on them. By measures found across twenty studies on those in poverty is a unique area of individual circumstances. Ongoing course
significant in a world where those who need them. Until relatively becoming less attached to these thoughts, (Grossman et al, 2004), and whilst some research which needs to be developed. evaluation provided information regarding
mental health issues seriously recently, the most prevalent approach the negative impact on a person’s current review studies have reported only programme feasibility.
affect 1 in 3 people. was pharmacological. However, mental state is lessened. Reports have moderate reductions in anxiety and stress A primary concern for any MBI
both pharmacological and non- yielded signs that these approaches levels (Goyal et al. 2014), the overall trend programme, especially with low SE Participants were 107 referred or self-
pharmacological approaches have their can positively influence physical and is positive. The variety of circumstances populations is attrition, i.e. the rate referred members of the public living on
merits and demerits. The pharmacological neurophysiological processes which are
approach can require dealing with both harmed by stress such as blood pressure ROBUST IMPROVEMENTS IN WELL-BEING
side effects and ongoing costs of drugs, and cortisol levels. The Training & Control
A 90 WHO-5 B GENERAL WELL-BEING
whereas the psychological approach can 80
5 groups – before & after –
have high initial costs and a reliance on Karma Jiga is trained in both eastern and all measures.
WELLBEING
WELLBEING
70
4
the will and confidence of the participant western mindfulness schools of thought 60
Scores
Scores
50 3
to approach their difficulties from a and techniques. He has developed a
40
different standpoint. However, for those mindfulness training course aimed at 30
2
participating in MBI’s from within low those in low socioeconomic areas called 20
1
socioeconomic environments, it is not Headroom, and is currently based in 10
0 0
uncommon for both approaches to be in Dundee, Scotland. Headroom is a nine-
Pre-training Post-training Pre-training Post-training
play at the same time. session mindfulness-based intervention
(MBI), based on the training in MBSR and C MENTAL WELL-BEING D MAAS
5 5
KARMA JIGA AND MINDFULNESS-
MINDFULNESS
MBCT he received at Bangor University.
WELLBEING
BASED INTERVENTION (MBI) He aims to develop mindfulness 4 4
Many practitioners and ordinary people techniques specific to the problems

Scores
Scores
3 3
are now switching their focus towards more commonly faced by those in low
2 2
treatments rooted in more Eastern ideals. socioeconomic environments, whilst
1 1
The words meditation and mindfulness are establishing their feasibility. Headroom is
becoming more common. What may have free and open to anyone earning less than 0 0
once seemed like a more ‘far out’ activity the real living wage. The potential benefits Pre-training Post-training Pre-training Post-training
Training group Control group
CHANGE IN OUTLOOK
A T1 THEMES B T1 THEMES
Behind the Research
Having needs met Healthy choices Karma Jiga
Taking action
Taking part, moving forward E: karmajiga@nilupul.org T: +044 1382 872020 W: www.nilupul.org W: www.mindfulnessdundee.co.uk
Making connections W: www.headroom.nilupul.org www.facebook.com/nilupulfoundation
Confidence, self esteem,
contentment
Feeling positive
Not feeling ill health

Developing resilience
Managing difficulty Managing difficulty Grossman, P., Niemann, L., Schmidt, S., & Walach, H. (2004).
Karma Jiga and his colleagues at Nilupul Foundation’s
research is aimed at establishing the feasibility of holding ‘Mindfulness-based stress reduction and health benefits’.
0 5 10 15 0 5 10 A metaanalysis. Journal of Psychosomatic Research, 57(1),
15 20 the courses in areas of socioeconomic depression, lowering
Coding references (frequency) Coding references (frequency) high levels of attrition by those suffering from the effects of 35–43. https://doi.org/10.1016/S0022-3999(03)00573-7.
poverty, and developing mindfulness techniques specific
NEGATIVE POSITIVE to problems more commonly faced by those in these

environments.
Goyal, M., Singh, S., Sibinga, E., Gould, N., Rowland-
Seymour, A., Sharma, R., et al. (2014). ‘Meditation programs
for psychological stress and well-being: a systematic review
Move from ‘day to day” reactive decision making, to longer term responsive planning.
and meta-analysis’. JAMA Internal Medicine, 29(6), 997–1003.
low incomes in the most deprived areas of comparing mean scores between side effects and the time of day –
Detail https://doi.org/10.1016/j.biotechadv.2011.08.021.
Dundee. However, with post-orientation the control and experimental groups the latter being an issue he is currently Nilupul Centre,
dropouts, mid-course dropouts and other were conducted. There were notable attempting to address and will monitor 51 Reform St,
considerations, the final research group significant differences in scores between as the research progresses. Dundee, Personal Response
total numbered 40 (20 experimental the experimental group completers DD1 1SL
conditions, 20 control). Participants were and control group completers, with FOOD FOR THOUGHT Scotland What is the main barrier to attendance and completion
guided through a series of exercises experimental/training course completers AND FUTURE DIRECTIONS of mindfulness courses and do you have any ideas of
and meditations to improve their sense having significantly higher scores on the Karma Jiga is still providing this incredibly Bio how to get around them?
of awareness and physical and mental WHO-5. The MAAS measures, however, valuable approach to the residents of Karma Jiga is trained in the Tibetan Buddhist Tradition At present, the main barrier is cost for the less well
wellbeing throughout the 8-week course. showed no significant change and requires Dundee and hopefully, this will continue and modern-day mindfulness. He is a former engineer, off. Mindfulness is more the domain of the middle and
These were assessed through the World further investigation. Further to this, the to gain momentum and support from award-winning musician, composer, author, artisan, project more educated class. Even among those who complete a
Health Organisation (WHO) Well-being experimental or training group showed other local authorities. Any ambiguity manager and current CEO of Nilupul Foundation. His mindfulness course, the number who apply themselves and
Index and Mindfulness Attention and significant positive differences between pre in the research surrounding mindfulness present-day research focus is to provide mental health engage meaningfully in the practices between sessions is
Awareness Scale (MAAS), both widely and post training in the qualitative analysis, highlights the need to give this and solutions for those suffering the effects of poverty. difficult to assess. Not everyone is willing to disclose how
much or even if they have applied themselves, despite the
used and verified in the field. In layman’s which also gave rise to free expression future research the due attention and
importance of personal responsibility for individual mental
terms, this part of the study was gauging through the addition of two open-ended opportunity to address any anomalies that Funding health and wellbeing being emphasised within the course
whether this adapted MBI course led questions. Thus, positive correlations arise, as the benefits of mindfulness can • Scottish Government & Big Lottery Fund sessions. So reduced cost and inspirational delivery seem
to an increase in awareness and well- between the changes in WHO-5 scores be profound. They compare favourably • Peoples Health Trust to me to be the way forward.
being, whilst assessing attrition rates to and General Wellbeing Scores collectively with the effects of pharmaceuticals but
establish the feasibility of the programmes imply the Headroom MBI typically led to with little or no negative side effects or Collaborators
further use. improvements across well-being measures. ongoing expense. Positive outcomes • Dundee City Council
from mindfulness may not be limited • Dundee Community Health Team
In addition, a thematic and more personal PERSISTING PROBLEMS solely to the individual, rather, they have • Community Support Workers
and unique pre and post-course qualitative OF ATTRITION the potential to positively impact the • Health & Social Care Integration specialists.
analysis were carried out to assess The persistent problem of attrition remains, wider community, and in turn the nation. • General Practitioners (GP’s)
how mindfulness practice had affected with the majority of dropouts in Karma Karma Jiga and his colleagues at Nilupul
participants and how they viewed their Jiga’s and others work in this area due to plan to develop a framework that would
states of wellbeing before and after the reasons beyond the control of the course allow this programme to be rolled out to
course. Both forms of analysis introduced provider, or the service user. According other cities, reaching anyone who would
self-report measures incorporating 5-point to Karma Jiga’s work, a frequent barrier benefit. Furthermore, he is looking into
Likert scales. Quantitative measures to course attendance were medication how Headroom can be developed into
a teaching programme within the further
There is a strong positive correlation education system to enable peer to

peer delivery of the programme within
between debt and poor physical socioeconomically deprived communities.
and mental health.

COMMUNICATION
New brain research
References
Neuroscience 2018 website:
sparks excitement
www.sfn.org/Meetings/
Neuroscience-2018
Abstracts from SfN website:
at Neuroscience 2018
www.sfn.org
•R . Jung, S. S. Kuntaegowdanahalli,
A. K. Thota, A. E. Pena, K. W. Horch,
J. Patrick, J. J. Abbas
Neural-enabled prosthetic hand
system to restore sensation in
upper-limb amputees. Program No.
Neuroscience 2018, the annual meeting of the Society for Neuroscience (SfN), is the world’s largest source of emerging
404.10. 2018 Neuroscience Meeting
news about brain science and health. SfN welcomed over 30,000 scientists from across the globe to deliberate,
Planner. San Diego, CA: Society for
debate and discuss new research. The Research Outreach team share their impressions of the conference. Neuroscience, 2018. Online
•B . V. Lananna, C. J. Nadarajah, C. A.
Mckee, M. R. Cedeno, P. Griffin, J.
I
nside the conference centre in San most diseases. It works by hijacking a was also on the agenda at Neuroscience Dimitry, E. S. Musiek
©Society for Neuroscience. All rights reserved. Photo by Joe Shymanski.

Diego the air was full of excitement virus to carry genes into cells where it 2018. Sleep disruptions are associated The astrocytic circadian clock gates
and curiosity. Rigorous questioning, gets to work altering genes to treat or with many different disorders including neuroinflammation and neuronal
new ideas, debating around every corner. prevent a disease. The unhealthy gene anxiety, dementia and traumatic brain health through regulation of
Over 30,000 scientists from across the might be replaced with a healthy copy injury. These disruptions are sometimes Alzheimer’s disease biomarker Chi3l1
(YKL-40). Program No. 267.11. 2018
world, all different ages and stages of their of the gene, it may be turned off or a seen as a side effect of brain disorders
Neuroscience Meeting Planner. San
careers, met with one common interest: new gene may be added to help fight but new research presented here
Diego, CA: Society for Neuroscience,
their dedication to understanding the a disease. New findings presented here suggests sleep disruption can make brain 2018. Online.
brain and the nervous system. The annual show the potential of gene therapy for disorders worse. • J . L. Lanciego, A. J. Rico, I. G.
meeting for the Society for Neuroscience, treating incurable neurological disorders Dopeso-Reyes, D. Marin-Ramos, E.
Neuroscience 2018, was underway. including Amyotrophic Lateral Sclerosis New research shows that sleep disruption Roda, A. I. Rodriguez-Perez, J. L.
(ALS) and Parkinson’s disease. could worsen Alzheimer’s disease. Labandeira-Garcia, D. Sucunza
The conference was vast, spanning five The biological clock is controlled by a set Glucocerebrosidase gene therapy
days in November in one of the largest Patients with ALS have a poor prognosis. of genes called clock genes. If the clock induces alpha-synuclein clearance and
stops disease progression. Program
conference centres in the world. Scientists It is a terminal disease leading to paralysis genes are not working correctly then
No. 292.01. 2018 Neuroscience
discussed all sorts of brain-related issues and eventually death. One of the most this disrupts sleep. But fascinatingly The bustling conference hall at Neuroscience 2018. Meeting Planner. San Diego, CA:
Society for Neuroscience, 2018.
used to physically control the body - intentions into actions, enhancing the Online.
Over 30,000 scientists from across the world, met with one incredibly useful research for people with
disabilities and prosthetics.
possibilities of brain–machine interactions. • J . Patel, E. Hildt, K. L. Laas
The ethical implications of media
common interest: their dedication to understanding the brain Current prosthetics are limiting for
Research into new technologies
such as new prosthetics often sparks
coverage on visual prostheses
in the words of visually impaired
and the nervous system. amputees as they have no sense of touch conversation around social implications. individuals. Program No. 028.02SU.
2018 Neuroscience Meeting
or control over the prosthesis. To address One research group was looking into
Planner. San Diego, CA: Society
this problem scientists developed a new how media coverage on visual prostheses for Neuroscience, 2018. Online.
from diseases and disorders to healthy well understood causes of ALS is a these genes also have a role to play prosthetic hand that communicates to affects visually impaired individuals’ feelings
•E . B. Simon, M. P. Walker
brain function and its impact on society mutation in the SOD1 gene. Scientists in Alzheimer’s. Researchers have shown the nervous system through implanted on prosthetics. A common theme from Under slept and Overanxious: The
to the ethics of neuroscience. have used gene therapy to carry a small that disruption of the clock genes can electrodes. It restores a sense of touch the research was the potential risks of the neural correlates of sleep-loss induced
molecule into cells to prevent SOD1 from cause increased damage to neurons by stimulating sensory neurons in the treatment and whether it fully restores anxiety in the human brain. Program
After immersing ourselves in five days being made. Using just a single injection and increased amyloid plaques, misfolded residual limb with fine wires implanted vision. These conversations are vital to help No. 192.11. 2018 Neuroscience
of neuroscience we were buzzing at some in the most severe ALS mouse model, proteins, adding to the progression inside the neurons. Sensors in the inform the next stages of their project. Meeting Planner. San Diego, CA:
of the new research. Check out what the researchers were able to show it was of Alzheimer’s disease. Another research prosthetic hand deliver stimulation pulses Society for Neuroscience, 2018.
Online
we discovered at Neuroscience 2018. safe and effective at reducing SOD1. group showed that anxiety is increased to the sensory neurons. This is just a snapshot of the incredible
•G . M. Thomsen, S. B. Likhite, S.
These animal studies are essential for in sleep deprived people and that deep range of research presented at
Corcoran, A. Kaspar, K. Foust, L.
GENE THERAPY insuring their safety and efficacy in ALS slow-wave sleep is needed to calm The Neural Enabled Prosthetic Hand Neuroscience 2018. The size and scale Braun, K. C. Meyer, B. K. Kaspar
Let’s start off in the exhibition hall. patients. This research is really exciting overactive brain regions. This new work (NEPH) provides amputees with of the conference demonstrates just Intrathecal AAV9-SOD1-shRNA
It was teeming with excitement as as it presents brand new steps towards highlights that sleep is a priority! sensations and better control of the how many people are dedicated to administration for amyotrophic lateral
thousands of researchers presented being able to prevent and treat disorders prosthesis. The research announced understanding the brain. It’s an exciting sclerosis. Program No. 208.16. 2018
posters and discussed their findings. that currently have no cure. PROSTHETICS at Neuroscience 2018 marks the first time for neuroscience with evolving Neuroscience Meeting Planner. San
Gene therapy is particularly intriguing – And then there’s the areas of research time a person has been fitted with technologies allowing innovative Diego, CA: Society for Neuroscience,
it essentially allows researchers to edit SLEEP where sci-fi becomes reality! Researchers a NEPH outside the laboratory. This and potentially game-changing advances 2018. Online.
genes. It is a relatively new concept Getting a good night’s sleep was essential at Neuroscience 2018 explained how provides researchers with a much greater to be made in the field.
that is still in the experimental phase for for five days of neuroscience. And sleep artificially connecting neurons can be understanding of how the brain translates

COMMUNICATION
Science in brewing
People have been brewing beer for thousands of years; taking advantage of the metabolism of a tiny fungus (yeast) to
Social Media
create that ever-popular social lubricant from grains and fruits. Today, it’s estimated that the world consumes a staggering
100 billion litres of beer each year. Here, we take a closer look at some intoxicating facts behind the amazing science
of those sweet amber suds.
G
rains, water, hops and yeast are
the four essential ingredients
needed to make beer. Grains
provide the all-important sugars for the
fermentation process. Hops – containing
alcohol as lager, giving its distinctive
sweet and fruity flavour.
BREWING SCIENCE
The four basic steps of brewing are
will kill any yeast), the mixture is now
ready to start fermenting. The chemical
process of fermentation is where the yeast
converts the unfermented beer (called
wort) into beer. It transforms the sugars
for Scientists
acids, tannins and oils – are added for
aroma and bitterness, and also help to
malting, mashing, boiling and fermenting.
Malt is a grain prepared for brewing by
into alcohol. From the yeast’s point of
view, alcohol is a waste product.
RSM was born out of multiple
preserve the beer. The largest ingredient
is water (making up 85–95% of even the
malting (unsurprisingly). Malted barley is
most commonly used, but wheat, corn,
Un-‘beer’ -lievable? As yeast continues
to grow and metabolise sugar, the
conversations with researchers who
strongest beers) and affects the flavour,
making a beer ‘local’.
fruit and even rice are good alternatives.
It’s the malt that provides the yeast with
accumulation of alcohol becomes toxic
and eventually kills the cells. Most yeasts
see a real benefit in connecting
A SOBERING THOUGHT
the sugar for the fermentation process and
thus determines how strong the beer is.
can tolerate an alcohol concentration
of 10–15%, hence the alcohol content
with a broad audience over an
Without yeast, there’s no beer. The yeast is
where the magic happens. French chemist MASHING AND BOILING
of beers (and wines) is typically in this
concentration range. To get the higher
ongoing basis. Social Media can
Louis Pasteur was the first to demonstrate
that fermented beverages result from
The brewing then kicks off, by soaking
then heating the grains. A process
alcohol concentrations associated with
spirits, distillation is required. Yeast also
now be considered one of the
the action of living yeast transforming called mashing. The grains absorb produces carbon dioxide, giving that
lovely fizz. Fermentation lasts from a few
most prominent and important
Yeast transforms sugars into alcohol ... days to a week. For stronger beers or
engagement tools of the modern
from the yeast’s point of view, alcohol
lagers, it’s longer, up to months. Finally,
is a waste product.

it’s ready to be bottled, kegged or served!
era. We help you get the ball rolling
glucose into ethanol. Realising that this water. Soluble sugars and starches are
Now that we’re not so new to brew,
let’s raise a glass and salute this fabulous
and can even provide long term
occurs in the absence of oxygen, he called
it ‘respiration without air.’
released. Important enzymes also get to
work during this stage - converting the
brewing science that leaves us feeling
tipsy. Cheers!
Social Media Management support.
starches into smaller, fermentable sugars.
ALE VERSUS LAGER Temperatures are carefully controlled to Rachel Perrin, PhD, is a science
Two types of yeast produce different optimise enzyme activity. After mashing, communication writer based in Bristol,
drinks: ales and lagers. The yeast comes rinsing (or sparging), to extract UK.
used to brew lager is Saccharomyces the sugars. Grains are separated from
carlsbergensis (isolated at Copenhagen’s the water by pouring through a sieve.
Carlsberg brewery). Ales use The grains are then discarded, and sugars
Saccharomyces cerevisiae (‘sugar fungus boiled. As the water evaporates,
ale’). But there are other differences. The the sugar concentration
Start your Social Media journey now:

name lager (from the German lagern: to increases. Next, hops are
store) hints as to its method of brewing. added. They’re a bit like the
www.researchsocialmedia.com
Lagers ferment slowly, from the bottom spice of beer, giving that
up and at low temperatures, giving them characteristic flavour.
their crisp flavour. Ales ferment quickly
from the top down and are brewed in FANTASTIC
a warm environment. This type of yeast FERMENTATION
doesn’t turn quite so many sugars into Once cooled (high temperatures
Partnership enquiries: simon@researchoutreach.org
Careers and guest contributions: emma@researchoutreach.org
www.researchoutreach.org

Research Outreach Issue 105

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FEATURING RESEARCH FROM:

RESEARCH OUTREACH ISSUE 105

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face of research is something we are particularly proud

Editor Copyright © and ™ 2018

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6 LICENSE TO SHARE: 26 TIME FOR A NEW APPROACH 44 MOVING BEYOND DANGEROUS

I am very proud that the

together to address and manage Professor Giorgio Kaniadakis

the cognitive aspects of MS. Hristopulos

30 PROFESSOR DAWN LANGDON

The spectrum of rights

Copyright Creative Commons Public Domain

Making sense of The Spectrum Of Rights.

reuse of their works by offering them real-time communications to Slack which

How the Creative Commons licensing system encourages

The number and choice of licences as they stand work

CREATIVE COMMONS Licence Conditions

Dr. Okuda’s laboratory have designed

Research Objectives References

This 3D morphological data provides

outwards resulting in a more spherical, progression in patients in order Bio

When transmission of epigenetic information goes awry Quality control

Reduced PSA Prostate

Multi-institutional Trends in 62.5

Cancer Screening: Life-

Total PSA (ng/mL)

led to the United States Preventive

Research Objectives References

Detail Harrison, P. (2018). ‘Prostate Cancer More Aggressive in Post-

Lymph nodes targeted

Staging of cancer is based on TNM

in novel cancer therapy

Research Objectives References

Detail Available at: https://doi.org/10.1002/jbio.201700401

to reduce cancer mortality by stopping

Time for a new approach

to severe traumatic brain

injury and stroke:

of brain stem function In this setting TTH is a frequent cause

physicians and surgeons to intervene.

Whilst at the Cook Country Head Injury

skills – are common in MS, affecting

with the condition.

quickly and effectively understand of patients, it is a positive indication

more than half of patients. FUTURE STEPS

Factors associated with

young children exhibiting GREATLY

picky eating behaviour

NOT NOT NOT NOT

Could stem cells

offer a viable treatment

TGF-β1 CONTROLS ALL STAGES

Moving beyond dangerous

opioids for pain:

The US government desperately wants

Opioids are so potentially dangerous

Research Objectives References

On the other hand, some patients are