News & views

death ligand 1 (PD-L1), which helps cancer cells complexes that involve PROTACs accelerate molecules that incorporate large groups, such
to evade the immune system. The next step target degradation, improving drug potency as antibodies and oligoglycopeptides, during
will be to establish whether LYTACs can also and selectivity 8. It will be crucial to understand drug discovery, but this problem can be over-
induce the degradation of multi-pass proteins how the complexes formed by LYTACs can be come by further engineering the structures
that span the membrane several times, such as optimized to improve degradation activity. of these groups11. Banik and colleagues’ new
the ubiquitous G-protein-coupled receptors PROTACs and LYTACs are larger molecules approach to degradation therefore warrants
and proteins that transport materials across than conventional drugs. As a result of their an all-hands-on deck approach.
membranes (ion channels and solute-carrier size, PROTACs often do not permeate well Scientists working in drug discovery will
proteins, for example). If so, it will be interest- through biological membranes, which can eagerly await the development of LYTACs
ing to compare the performance of LYTACs, make them less potent drugs than the biolog- and the emergence of other methods for the
which would bind to the extracellular domains ically active groups they contain. Size should drug-induced degradation of proteins12. Is no
of such proteins, with that of PROTACs, which be less of a problem for LYTACs because they protein beyond the reach of degraders?
can bind to the intracellular domains of these do not need to cross the cell membrane,
proteins (as was recently demonstrated6 for although they would still need to pass through Claire Whitworth and Alessio Ciulli are in
solute-carrier proteins). biological barriers to combat diseases of the the Division of Biological Chemistry and
As with any new drug modality, there is central nervous system. The development of Drug Discovery, School of Life Sciences,
scope for improvement. For example, Banik lysosomal degraders that are smaller and less James Black Centre, University of Dundee,
and colleagues’ first PD-L1-targeting LYTACs polar than LYTACs — and therefore more able Dundee DD1 5EH, UK.
produced only partial degradation of the to pass through membranes — will be eagerly e-mail: a.ciulli@dundee.ac.uk
protein, which the authors attributed to anticipated. Small ‘glue’ molecules that bind
1. Maniaci, C. & Ciulli, A. Curr. Opin. Chem. Biol. 52, 145–156
low expression of CI-M6PR in the cell lines to E3 ligases can already do the same job as (2019).
used. When the authors made a second type PROTACs9. 2. Deshaies, R. J. Nature 580, 329–338 (2020).
3. Gerry, C. J. & Schreiber, S. L. Nature Chem. Biol. 16,
of LYTAC that incorporated a more potent Targeted protein degradation is a promising
369–378 (2020).
PD-L1 antibody, degradation increased, therapeutic strategy, and the first PROTACs 4. Banik, S. M. et al. Nature 584, 291–297 (2020).
albeit in cells that expressed greater levels are currently in clinical trials10. LYTACs will 5. Burslem, G. M. & Crews, C. M. Cell 181, 102–114 (2020).
6. Bensimon, A. et al. Cell Chem. Biol. 27, 728–739 (2020).
of CI-M6PR than did the original cell lines. need to play catch-up, but they have earned
7. Zhang, L., Riley-Gillis, B., Vijay, P. & Shen, Y. Mol. Cancer
This shows that low abundance of the lys- their place as a tool poised to expand the Ther. 18, 1302–1311 (2019).
osome-shuttling receptor hijacked by the range of proteins that can be degraded. 8. Roy, M. J. et al. ACS Chem. Biol. 14, 361–368 (2019).
9. Hanan, E. J. et al. J. Med. Chem. https://doi.org/10.1021/
LYTAC (in this case, CI-M6PR) can reduce the Their development as therapies will require
acs.jmedchem.0c00093 (2020).
effectiveness of these degraders. Similarly, an understanding of their behaviour in the 10. Mullard, A. Nature Rev. Drug Discov. 19, 435 (2020).
the loss of core components of E3 ligases is a human body — their pharmacokinetics, toxic- 11. Chiu, M. L. & Gilliland, G. L. Curr. Opin. Struct. Biol. 38,
163–173 (2016).
common mechanism by which cells become ity, and how they are metabolized, distributed
12. Takahashi, D. et al. Mol. Cell 76, 797–810 (2019).
resistant to PROTACs7. Lysosome-shuttling and excreted, for example. It can be challeng-
receptors other than CI-M6PR could be used ing to optimize the biological behaviour of This article was published online on 29 July 2020.
by LYTACs as alternatives, should resistance
emerge. Degraders that target cell-type-spe-
cific receptors might also have improved Ecology

Rethinking extinctions
safety profiles compared with conventional
small-molecule therapeutics, which are not
always cell-type selective.
What sets PROTACs and LYTACs apart from
conventional drugs is their mode of action. that arise from habitat loss
For example, after a PROTAC has brought
about the destruction of a target protein, the
PROTAC is released and can induce further Joaquín Hortal & Ana M. C. Santos
cycles of ubiquitin tagging and degrada­ Does the loss of species through habitat decline follow the
tion, thereby acting as a catalyst at low con-
same pattern whether the area lost is part of a large or a small
centrations1,5. Mechanistic studies are now
warranted to determine whether LYTACs also habitat? An analysis sheds light on this long-running debate,
work catalytically. with its implications for conservation strategies. See p.238
Another aspect of the mode of action of
both PROTACs and LYTACs is that they bring
two proteins together, to form a trimeric com- Understanding how habitat size affects the implicated in more than one-third of animal
plex. A general feature of such processes is abundance of all the species living in a com- extinctions worldwide between 1600 and 1992
the hook effect, whereby trimer formation, munity provides ecological insights and is (ref. 3). A report from the Intergovernmental
and thereby the associated biological activity, valuable for developing strategies to boost Science-Policy Platform on Biodiversity and
decreases at high drug concentrations. This biodiversity. On page 238, Chase et al.1 report Ecosystem Services estimates that currently
is because dimeric complexes generally form results that might help to settle a long-running more than half a million species — about 9% of
preferentially at high drug concentrations — debate about the relationship between the all terrestrial species — might lack the amount
an undesirable effect that can be alleviated by area of a habitat and the diversity of species of habitat needed for their long-term sur-
ensuring that all three components interact it can host. vival4. Moreover, their disappearance would
in such a way that trimer formation is more Land transformation by human activity is a compromise many key ecosystem services,
favourable than is dimer formation1. major component of global change. The loss such as pollination or the control of pests or
Kinetics also matters for protein degraders. of natural habitats reduces the local diver- disease-causing agents.
For example, stable and long-lived trimeric sity and abundance of species2, and has been The effect of habitat loss on biodiversity has

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been conventionally estimated on the basis
of the relationship between area and species a Large ecosystem b Small ecosystem
richness, which was first described more than
150 years ago5. This seemingly universal rela-
tionship is simple: the larger a given habitat’s
area, the more species it holds, although the
number of species increases with area in a
nonlinear way6. There is a limit to the number
of individuals of ecologically similar species Sampled
that can persist in an area, owing to the limited area
resources that it harbours7. When a habitat
loses part of its area, therefore, for many Passive sampling Ecosystem decay Ecosystem decay
(individuals) (evenness)
species, it also loses its capacity to support
populations that are large enough to be viable.
These species become extinct as habitat area

Species
diminishes with land-use intensification8.
Chase and colleagues propose an elegant
and simple approach to account for the
dynamics of communities occupying habitat Abundance per sample Abundance per sample
patches of different size. Rather than consider-
ing only the overall number of species in each Figure 1 | Assessing how habitat size affects ecosystem dynamics. Understanding the relationship
habitat fragment, the authors focused on the between a decline in habitat area and the effect on species is crucial for designing conservation strategies.
number and relative abundance of different a, b, Chase et al.1 analysed studies that sampled species in particular habitats. The authors compared the
species in samples obtained from such frag- diversity of organisms, such as insects, in samples obtained from large ecosystems (a) with samples taken
ments. This allows the structure of ecological from the same sampling area in a smaller fragments of the same type of habitat (b). These graphs show
hypothetical results for species abundance per sample, and different species are shown in different colours.
communities to be compared directly2, while
This method enabled the authors to distinguish between three possible outcomes as habitats become
avoiding problems that can arise when tak-
smaller. In the passive-sampling model, species are equally distributed in habitat fragments of any size, so
ing into account the differences in the effort
the richness, abundance and relative species prevalence (evenness) per sample is constant, regardless of the
needed to sample large and small areas9. The total habitat size. In the ecosystem-decay (individuals) model, samples from smaller fragments have fewer
authors’ approach also allows a comparison individuals and species per sample than do samples from larger fragments, and all species abundances
of variations in the relative abundance of indi- decline in a similar way as habitat is lost. In the ecosystem-decay (evenness) model, species vary in their
viduals of all species, a measure of community response to habitat loss, and there is a change in their relative abundances. Chase et al. find that ecosystem
structure that is associated with ecosystem decay, usually following the evenness model, is the best match for the observed data.
dynamics10.
Thanks to this method, Chase et al. could
distinguish between three patterns of change owing to uneven changes in relative species species that are threatened or already gone,
that might occur as an outcome of habitat loss abundances coupled to species loss. In this but also the consequences of their loss for
(Fig. 1). In the pattern described by the ‘passive scenario, the species present have different ecological functioning and the provision of
sampling’ model, the structure of the com- responses to habitat loss, and therefore spe- ecosystem services.
munity remains the same in large and small cies become relatively more or less abundant Changes in biodiversity after habitat loss
fragments. Therefore, each sample provides in smaller fragments than in larger fragments. alter many ecological processes11, eventually
similar species richness (the number of spe- Their relative abundance becomes more causing catastrophic effects that accelerate
cies), abundance (the number of individuals) uneven in samples from smaller fragments the extinction process12. But local extinctions
and evenness (the allocation of individuals as some species increase their numerical are often not immediate. Some species persist
to the different species), regardless of the dominance, impoverishing the community with reduced abundances and declining pop-
total habitat size. In this case, species decline and causing it to become species poor. ulation dynamics — known as ‘extinction debt’
will mirror the loss of habitat area under the Using data from around 120 human- — that lasts until the final individuals perish13.
classical species—area theory5, and the total transformed landscapes worldwide, Chase This causes an uneven distribution of species
number of species in the entire fragment et al. show that, in general, samples from abundance that is vividly demonstrated by
would depend solely on its size. small fragments of natural habitat have fewer Chase and colleagues’ method. Their analysis
The other two patterns are described as individuals, fewer species and a more uneven reveals a few ‘winning’ species that dominate
types of ecosystem decay — a hypothesis pro- abundance of species than samples taken the community in small habitats, and a very
posing that a habitat that shrinks undergoes from larger fragments do. This outcome is large number of rare species, many of which
a disproportionately high loss of organisms consistent with a generalized pattern of eco- are probably heading towards extinction.
compared with the loss of habitat area. One system decay, mainly as a result of a decline Declining species can be replaced by others
type of ecosystem decay is proposed to occur in evenness (see Fig. 1), and this result holds, coming from the neighbouring human-altered
owing to excessive loss of individuals. Smaller regardless of the type of habitat or organ- landscape, particularly in habitat edges14, pro-
habitat fragments will contain fewer individ- ism studied. This implies that the alteration ducing what are described as ‘edge effects’
uals per sample than will larger ones, and all of natural habitats causes major functional that are comparatively more important
species are equally affected. This generates changes in ecosystem dynamics that go in smaller fragments. Indeed, in the early
communities with fewer species in smaller beyond simply losing populations and species. stages of land transformation, communities
fragments, but no changes in the relative Therefore, current estimates of extinctions in small fragments are more different from
abundance of species per sample between associated with habitat loss made on the pristine communities than are those in large
small and large fragments. basis of the passive-sampling model might fragments, with communities in small frag-
The other type of ecosystem decay occurs be underestimating not only the number of ments becoming more similar to those in large

Nature | Vol 584 | 13 August 2020 | 195

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News & views
fragments over time, as they recover from the Joaquín Hortal is in the Department of (Cambridge Univ. Press, 1995).
6. Arrhenius, O. J. Ecol. 9, 95–99 (1921).
effect of land transformation2. According to Biogeography and Global Change, Museo 7. Wright, D. H. Oikos 41, 496–506 (1983).
Chase and colleagues, the degree of decay Nacional de Ciencias Naturales, Spanish 8. Di Marco, M., Venter, O., Possingham, H. P. &
in diversity and species abundance found National Research Council, Madrid 28006, Watson, J. E. M. Nature Commun. 9, 4621 (2018).
9. Chase, J. M. et al. Front. Biogeogr. 11, e40844 (2019).
between large and small fragments is smaller Spain. Ana M. C. Santos is in the Department 10. Simons, N. K. et al. Agric. Ecosyst. Environ. 237, 143–153
in the older or ‘softly’ transformed European of Ecology, Autonomous University of Madrid, (2017).
landscapes than in the more recently and Madrid 28049, Spain, and at the Centro de 11. Dobson, A. et al. Ecology 87, 1915–1924 (2006).
12. Fischer, J. & Lindenmayer, D. B. Global Ecol. Biogeogr. 16,
dramatically transformed North American Investigación en Biodiversidad y Cambio 265–280 (2007).
ones. This indicates that, over time, species Global, Autonomous University of Madrid. 13. Tilman, D., May, R. M., Lehman, C. L. & Nowak, M. A.
moving in from the edges of the human-al- e-mails: jhortal@mncn.csic.es; Nature 371, 65–66 (1994).
14. Didham, R. K., Lawton, J. H., Hammond, P. M. &
tered habitats might compensate, at least in ana.margarida.c.santos@gmail.com Eggleton, P. Phil. Trans. R. Soc. B 353, 437–451 (1998).
part, for the ecological functions carried out 15. Holt, R. D. in The Theory of Island Biogeography Revisited
1. Chase, J. M., Blowes, S. A., Knight, T. M., Gerstner, K. & (eds Losos, J. B. & Ricklefs, R. E.) 143–185 (Princeton Univ.
by native species in larger habitats, causing May, F. Nature 584, 238–243 (2020). Press, 2010).
small fragments to reach a new — yet different 2. Newbold, T. et al. Nature 520, 45–50 (2015). 16. Harrison, M. L. K. & Banks-Leite, C. Conserv. Biol.
3. World Conservation Monitoring Centre. Global
— ecological balance. https://doi.org/10.1111/cobi.13438 (2019).
Biodiversity: Status of the Earth’s Living Resources 199 17. Simberloff, D. S. & Abele, L. G. Science 191, 285–286
Although this work underscores the key (Chapman & Hall, 1992). (1976).
role of habitat area in maintaining eco­system 4. Díaz, S. et al. (eds) The Global Assessment Report on 18. Fahrig, L. Glob. Ecol. Biogeogr. 29, 615–628 (2020).
Biodiversity and Ecosystem Services: Summary for
processes, there is little exploration of how
Policymakers (IPBES, 2019).
these processes are altered by habitat loss. 5. Rosenzweig, M. L. Species Diversity in Space and Time This article was published online on 29 July 2020.
Species from higher trophic levels (the upper
levels of the food chain), such as predators,
Mechanobiology
require larger areas to maintain their popu-

Stretch exercises for

lations compared with species from lower
trophic levels, so the number of individuals
supported by smaller habitat fragments might
not suffice to maintain populations of top
predators or consumers, and hence would stem cells expand the skin
produce shorter food chains and alter the
ecosystem structure15. Differences in extinc-
Matthias Rübsam & Carien M. Niessen
tion rates between trophic levels can cause
striking changes in ecosystem functioning at Stretching the skin of mice reveals that mechanical strain
habitat edges16, jeopardizing the functioning is communicated by a subpopulation of stem cells that
and ecosystem-service provision as natural
habitats diminish in size11.
proliferate and promote mechanical resistance, and so
Chase and colleagues’ results call for a generate extra skin. See p.268
reconsideration of the debate over whether
a single large area devoted to conservation
would preserve more species than would The cells of our bodies are exposed to a range from the surface, to be replaced by new cells.
several small ones that combine to make of mechanical forces — including compres- Aragona et al. set out to examine how the
up the same total size17. Some current evi- sion, shear and stretching — that they must epidermis responds to strain. The group
dence suggests that one continuous habitat resist to maintain tissue integrity and func- positioned a device used in human surger-
might host fewer species than do many small tion. For example, skin responds to stretch- ies — a self-inflating gel — under the skin of
patches that total the same area18. However, ing forces by expanding. Physicians have mice. They then examined indicators of force
the large ecological changes that these exploited this particular response for more perception, including changes in cell shape,
small fragments might undergo could end than 60 years1, implanting stretching devices the structure of a mechanosensitive protein
up resulting in massive reductions in eco- in the skin to cause tissue expansion for plastic called α-catenin, and a network of keratin
system function and, ultimately, increased surgery or to repair birth defects2. But exactly proteins that provides cells with mechanical
extinction rates of native species over the how mechanical strain creates extra tissue in resilience. This analysis revealed that epider-
long term compared with the case for a sin- a living organism has not been known. On mal stem cells do indeed sense and respond
gle, large protected area. page 268, Aragona et al.3 now provide com- to strain. The authors observed a temporary
Chase and colleagues’ approach is good for pelling insights (at the molecular, single-cell increase in stem-cell division, followed by
providing a general overview of the extent of and cell-population level) into how stem cells thickening of the epidermis. Thus, increased
these effects, but to understand exactly how in the skin of mice sense and communicate stem-cell renewal fuels stem-cell differentia-
ecological processes are changing locally, a stretch to make new tissue. tion. The two effects combine to maintain a
higher level of detail will be needed. This The surface of the skin — a multi-­layered functional barrier at the same time as extra
will require going beyond the studies of tissue called the epidermis — protects skin is generated.
trophic chains14,16 to assess more-complex organisms against dehydration and environ­ The researchers next genetically
food webs15, and to gather information on mental stresses, including mechanical engineered cells in the basal epidermal layer
changes in species’ functional responses and challenges. To ensure lifelong protection, the such that the stem cells and their descend-
trait diversity in increasingly smaller habitats. epidermis is constantly renewed through the ants were fluorescently marked. Tracking of
Ultimately, this information will reveal which generation of new stem cells in its basal layer. these cell lineages over time confirmed that
ecological processes are decaying, and what This renewal is balanced with differentiation stretching tips the renewal–differentiation
the consequences of such ecosystem decay and the movement of stem cells to generate the balance in favour of making more stem cells.
are for the maintenance of fully functional upper, barrier-forming layers of the epidermis. This explains why the epidermis expands in
biodiversity. Ultimately, the barrier-forming cells are shed response to stretching.

196 | Nature | Vol 584 | 13 August 2020

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