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Multiplying the efficiency and impact of
biofortification through metabolic engineering
Dominique Van Der Straeten 1 ✉, Navreet K. Bhullar 2, Hans De Steur
Wilhelm Gruissem2,4, Donald MacKenzie 5, Wolfgang Pfeiffer6,
Matin Qaim 7, Inez Slamet-Loedin8, Simon Strobbe 1, Joe Tohme9,
Kurniawan Rudi Trijatmiko 8, Hervé Vanderschuren 10,11,
Marc Van Montagu 12, Chunyi Zhang 13 & Howarth Bouis 14 ✉
3,
Ending all forms of hunger by 2030, as set forward in the UN-Sustainable Development Goal
2 (UN-SDG2), is a daunting but essential task, given the limited timeline ahead and the
negative global health and socio-economic impact of hunger. Malnutrition or hidden hunger
due to micronutrient deficiencies affects about one third of the world population and severely
jeopardizes economic development. Staple crop biofortification through gene stacking, using
a rational combination of conventional breeding and metabolic engineering strategies, should
enable a leap forward within the coming decade. A number of specific actions and policy
interventions are proposed to reach this goal.
M
icronutrient malnutrition or hidden hunger, the insufficient intake of vitamins and
minerals, has a detrimental impact on human health. Hidden hunger affects more than
two billion people worldwide, and has the highest prevalence in the African continent
and South Asia. Children and women of reproductive age are most vulnerable to malnutrition,
leading to stunted growth, health problems, and several birth related issues. Though seven
minerals (iron, zinc, copper, calcium, magnesium, selenium, and iodine1) and several vitamins2
are often lacking in human diets, iron, zinc, vitamin A, and vitamin B9 (folate) deficiencies are
amongst the most severe3–5. Biofortification, the elevation of the levels of micronutrients in food
crops through agricultural technologies, is advocated as a pivotal means to reduce micronutrient
malnutrition6.
Impressive progress has been made in biofortification of mainly single micronutrients across
an array of primary staple food crops6,7. Biofortified crops have been developed via conventional
breeding or genetic engineering, although the latter have yet to receive full approval for release to
farmers. Biofortification via genetic engineering can enable high level accumulation of
1 Laboratory of Functional Plant Biology, Department of Biology, Ghent University, K.L. Ledeganckstraat 35, B-9000 Ghent, Belgium. 2 Department of Biology,
Institute of Molecular Plant Biology, ETH Zurich, Universitaetstrasse 2, 8092 Zurich, Switzerland. 3 Department of Agricultural Economics, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium. 4 Advanced Plant Biotechnology Center, National Chung Hsing University, Taichung, Taiwan. 5 Donald Danforth
Plant Science Center, St. Louis, MO 63132, USA. 6 HarvestPlus c/o IFPRI, Washington, DC, USA. 7 Department of Agricultural Economics and Rural
Development, University of Goettingen, Platz der Goettinger Sieben 5, 37073 Goettingen, Germany. 8 International Rice Research Institute, Manila, The
Philippines. 9 International Center for Tropical Agriculture, CIAT, Cali, Colombia. 10 Tropical Crop Improvement Lab, Department of Biosystems, KU Leuven,
Heverlee, Belgium. 11 Plant Genetics, TERRA Teaching and Research Center, Gembloux Agro-Biotech, University of Liège, Gembloux, Belgium. 12 International
Plant Biotechnology Outreach, B-9052 Zwijnaarde, Belgium. 13 Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China.
14 International Food Policy Research Institute, Washington, DC, USA. ✉email: Dominique.VanDerStraeten@UGent.be; H.Bouis@CGIAR.org
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micronutrients and is not constrained by variation in available
germplasm. Biofortification strategies can combine conventional
breeding with genetic engineering. Genetic engineering enables
simultaneous augmentation of multiple micronutrients, along
with improving the post-harvest stability of vitamins, whilst also
including agronomically important traits, such as enhanced yield
and stress resilience.
In the last few years, the cost-effectiveness and feasibility of
implementing biofortification using conventional breeding techniques has been established as a key intervention to reduce
mineral and vitamin deficiencies in developing countries8. Consequently, a recent World Bank report takes the position that
biofortified cereal crops should be the norm rather than the
exception9.
HarvestPlus, which is a program under the Consultative Group
on International Agricultural Research (CGIAR) Research Program on Agriculture for Nutrition and Health, is an umbrella of
institutions working on biofortification in low- and middleincome countries. HarvestPlus collaborating institutions have
developed, tested, released, and promoted the uptake by farmers
and consumers of the following crops: zinc rice, zinc wheat, zinc
maize, provitamin A maize, provitamin A cassava, iron beans,
and iron pearl millet7. Approximately 8.5 million farm households across Africa, Asia, and Latin America are growing these
biofortified crops (https://www.harvestplus.org). In addition,
under the sponsorship of the International Potato Center (CIP),
CIP and its partners have led the development, testing, and
promotion of orange (high provitamin A) sweet potato10. CIP
estimates that nearly seven million farm households, primarily in
Africa, are now growing and consuming orange sweet potato
(https://www.cipotato.org).
Through their combined efforts, biofortified crops are now
released in 40 countries globally.
Additionally, a few other institutions have successfully worked
on particular aspects of the development and testing of specific
crops to achieve biofortification with minerals and vitamins
through conventional breeding. However, these individual efforts
are awaiting incorporation into breeding programs or to field
applications (for a review, see Garg et al.6).
Despite wide acceptance of the effectiveness of biofortification
and demonstrated high return on investment, the increase of only
one nutrient per crop (either iron or zinc or provitamin A)
remains a limiting factor– for example high zinc wheat, or high
provitamin A maize. The breeding and release process for the first
wave of biofortified varieties took 8–10 years. In a small number
of cases, there is sufficient germplasm variation within the target
crop species to add a second nutrient (e.g. high zinc into high
provitamin A maize) using conventional breeding techniques, but
this is expected to take an additional 8–10 years.
Metabolic engineering through transgenic technology enables
introducing multiple biofortification traits, including high iron,
high zinc, high provitamin A, or high folate, to most biofortified
crop varieties relatively quickly – that is, in significantly <8–10
years. It may also be possible to reduce or stop the decrease of
vitamin densities after harvest and during storage, which occurs
due to exposure to light, oxygen, and/or high temperature. Furthermore, multi-biofortification can not only create crop products
with stable enhanced micronutrients but also take advantage of
the most profitable, highest yielding, and locally best-adapted
varieties.
Hidden hunger is a huge problem for human health and
economies
Hidden hunger is the direct result of insufficient acquisition of
minerals and vitamins from the diet. An estimated 2 billion
2
people in the developing world suffer from health effects caused
by hidden hunger (mainly related to deficiencies of iron, zinc,
vitamin A, and folates (vitamin B9))11. This is primarily the result
of poor-quality diets consisting of adequate energy consumption
from inexpensive staple crops, but little consumption of expensive
vegetable, fruit, pulses, and animal products that are richer in
bioavailable minerals and vitamins. Inadequate intakes of essential vitamins and minerals affect disease resistance, cognitive
development, physical growth, work productivity, and survival
rate. Preschool children and women in their reproductive age are
most vulnerable to deficiencies because they require higher
micronutrient intakes12. Agricultural systems in developing
countries are not providing sufficient minerals and vitamins at
affordable prices for optimal nutrition and health. Supplements
often do not reach the populations in need13. As impaired
micronutrient status aggravates susceptibility to infectious diseases including COVID-1914,15, the current pandemic further
underscores the need to improve the nutritional status of poor
rural populations and increase their nutritional self-sufficiency
through staple crop biofortification.
To combat vitamin A deficiency, for example, 10 billion vitamin
A capsules (at an approximate cost of US dollar 10–15 billion) have
been distributed over the past twenty years to preschool children –
with the effect of reducing preschool mortality by an estimated
12–24%16. In addition, the Global Burden of Disease Study 2015
estimates that 1.5 billion people suffer from iron (Fe) deficiency
anemia, which impairs cognitive function in preschool children17.
Nearly 1.2 billion people are also at risk of zinc deficiency, which
is associated with weakened immune systems and higher
mortality18. Stunting, which likely results from zinc (Zn) deficiency
as well, affects one out of four children under the age of five.
Stunting is strongly associated with poor brain development and
cognitive function19. Moreover, folate deficiency, which causes
neural tube defects (NTDs) and megaloblastic anemia, and also
aggravates iron deficiency anemia, is a highly underestimated form
of hidden hunger. Worldwide, at least 300,000 births are affected by
NTDs annually, the majority of which are caused by inadequate
maternal folate status20. This number is largely underestimated
because of a paucity of data on stillbirths and elective terminations,
as well as lacking surveillance systems in low- and middle-income
countries.
Progress in achieving the global targets of reducing child
stunting by 40% and anemia by 50% by 2025 is still far too slow21.
Global losses in economic productivity due to macronutrient and
micronutrient deficiencies reach more than 3% of GDP22 at a
global cost of US dollar 1.4-2.1 trillion per year3,23. Micronutrient
malnutrition poses a great threat to global human health and
economic development. Therefore, eliminating or at least
restricting its occurrence is of utmost importance, which is in line
with the United Nations Sustainable Developmental Goal 2 (UNSDG2) i.e. achieving zero hunger.
Crop biofortification using conventional breeding techniques
Biofortification aims at increasing the content of one or multiple
micronutrients in staple food crops through agricultural technologies. In some cases, conventional breeding can be utilized to
achieve this goal, thereby ensuring higher vitamin or mineral
intake of the poor populations relying on the specific staple crop.
For example, HarvestPlus (https://www.harvestplus.org) seeks to
develop and distribute varieties of food crops (rice, wheat, maize,
cassava, pearl millet, beans, and sweet potato) that have higher
levels of iron, zinc, and provitamin A (one nutrient per crop)
through an interdisciplinary global alliance of more than
400 scientific institutions and implementing agencies in developing and developed countries.
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Table 1 Estimated proportion of the EAR supplied by conventionally bred biofortified crops.
Crop
Target increment
Beans
Cassava
Maize
44 ppm iron
15 ppm provitamin A
15 ppm provitamin A
12 ppm zinc
30 ppm iron
70 ppm provitamin A
12 ppm zinc
18 ppm zinc
Pearl millet
Sweet potato
Rice
Wheat
Estimated proportion of the estimated average requirement provided
Before biofortification (%)
After biofortification (%)
45
0
0
50
50
0
40
25
85
100
55
75
80
≥100
70
45
The values assume certain levels of per capita consumption, retention of nutrients in processing, storage and cooking, and bioavailability. Further information is provided in refs. 7,27,28. This table is
adapted from HarvestPlus website with permission (https://www.harvestplus.org/content/estimated-average-requirements-provided-biofortification). Source data are provided as a Source Data file.
To be successful, three requirements must be met for implementation of biofortification. First, high and stable micronutrient
density must be combined with high crop yield and productivity
at similar costs to be attractive for farmers and consumers. Second, efficacy for human health must be demonstrated – the
micronutrient status of human subjects must improve with regular consumption of biofortified varieties. Thus, adequate
micronutrient levels must be retained during storage, processing,
and cooking, and these nutrients must be sufficiently bioavailable.
Third, the biofortified crops must be adopted by farmers and
consumed by those suffering from micronutrient malnutrition,
which requires incentives, education, and an appropriate delivery
strategy.
Through the combined efforts of HarvestPlus and CIP and
their collaborating partners, more than 300 varieties of conventionally bred biofortified crops have been approved by varietal
release committees in 40 developing countries and are being
tested for release in an additional 20 countries (https://www.
harvestplus.org and https://www.cipotato.org). Efficacy trials have
demonstrated improved zinc, iron, and provitamin A status in
malnourished populations, improved cognitive function and
work performance, as well as lower morbidity24–26. The ultimate
vision is for all national agricultural research institutes to make
high mineral and vitamin density core, non-negotiable breeding
traits.
Biofortified crops offer a rural-based intervention that initially
reaches these more remote populations that comprise a majority
of the malnourished in many countries. This is then extended to
urban populations as production surpluses are marketed. Initial
investments in agricultural research at a central location can
generate high recurrent benefits as locally adapted biofortified
varieties become available in country after country across time at
low recurrent costs.
Conventionally bred biofortified crops can provide an extra
20 to ≥100% of the Estimated Average Requirement (EAR; median
daily intake value estimated to meet the requirement of half
the healthy individuals in a life-stage and gender group)
for specific nutrients7,27,28. The average addition to the EAR is
~25% for zinc crops, 35% for iron crops, and >85% for provitamin
A crops7,27,28 (https://www.harvestplus.org/content/estimatedaverage-requirements-provided-biofortification; Table 1).
Increasing multiple minerals using metabolic engineering
When the natural variation in sexually compatible germplasm is
insufficient to achieve satisfactory micronutrient levels in a specific crop by conventional breeding, biofortification via metabolic
engineering can offer a solution. In rice, this is the case for
multiple micronutrients, including iron, provitamin A, and
folates.
Increasing Fe and Zn content in rice, which is consumed by
~3.5 billion people, has a remarkable potential to alleviate
micronutrient deficiencies. To provide an additional 30% of the
EAR in women and children, the iron concentration in polished
grain needs to be increased by 11 ppm from the baseline of 2 ppm
to reach 13 ppm, assuming of 10% bioavailability; while for zinc,
an increase of 12 ppm from 16 ppm will provide an additional
30% of the EAR, assuming of 20% bioavailability7. Micronutrient
levels in polished grains are most relevant, as polished grains
represent the energy-rich white rice which is consumed by the
populations suffering from micronutrient deficiencies. Only a
limited variation for iron in polished rice is available in germplasm collections, which limits conventional breeding for this
trait. However, there is sufficient natural variation for zinc to
reach a concentration of 28 ppm. Several high zinc rice lines,
created through conventional breeding, have been released in
Bangladesh, and were recently released or are under development
for several additional countries (www.harvestplus.org).
In the abovementioned case where conventional breeding is
constrained by limited natural variation, genetic engineering can
be used to augment micronutrient content in crop plants. Identification of most of the key genes involved in Fe and Zn uptake,
translocation, and storage29,30 has facilitated the development of
enriched Fe and Zn rice by transgenic approaches31. For the same
event, a significant increase in both Fe (up to 15 ppm) and Zn (to
45 ppm) in polished grain was successfully achieved in a highyielding variety, without increased uptake of unwanted heavy
metals (cadmium, arsenic, and lead)32,33. The level of Zn in this
transgenic variety is significantly higher than in the released
conventionally bred Zn cultivars.
Combining Fe and Zn traits with other micronutrients and
agronomic traits in multiple high-yielding varieties is obviously
desirable. With respect to mineral micronutrient enhancement, it
should be emphasized that success of biofortification fully
depends on both the level and bioavailability of the different
minerals in the soil. Where the latter are insufficiently present in
the substrate, foliar, or soil fertilization can be applied34. These
agronomic strategies are complimentary to metabolic engineering
and breeding technologies in poor soils.
Filling in a biosynthetic gap towards provitamin A in rice
An example of how genetic engineering enables introduction of a
micronutrient that is essentially absent in a crop species is Golden
Rice, which is enriched in provitamin A (β-carotene)35. Rice
leaves, and indeed the photosynthetic tissues of all higher plants,
produce and accumulate β-carotene. However, non-engineered
polished white rice has no detectable provitamin A carotenoids,
as the outer layers of the kernel that do contain low amounts of
this vitamin are removed during the polishing process. No
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naturally occurring rice varieties have been reported that accumulate β-carotene in the grain and could be used for conventional
breeding, thus genetic engineering provides the only viable
approach.
The second-generation Golden Rice (GR2E)36 has been found
to accumulate up to 37 ppm dry weight total carotenoids in the
polished grains immediately after harvest, although the concentration is dependent on the genetic background and reduces
during storage after harvest. To make this trait suitable for cultivation in Asia, the transgenic GR2E rice required breeding into
farmer-preferred indica rice varieties, yielding lines containing
between 3.5 and 10.9 ppm dry weight total carotenoids in
polished grains37. Even with these lower concentrations of provitamin A, it is estimated that 100 g of uncooked GR2E can
supply 30−40% of the recommended daily allowance (RDA) of
vitamin A for children25, at least 75% of which remains after
cooking38.
Golden Rice has provided a number of lessons for future
programs to develop and introduce transgenic biofortified crops.
The process of moving from proof of concept to a product that
can be used by farmers and consumers is difficult, as illustrated by
the sequential evaluation of various transgenic GR2 events since
2006. Arguably, a more effective selection earlier in the process
would have accelerated the establishment of events qualified for
breeding. In addition, the challenges of working with a transgenic
regulated product in countries with new or changing regulatory
processes cannot be underestimated. These factors, combined
with the high public profile of Golden Rice as both a standard
bearer for plant biotechnology and a target of activists, have made
for an unnecessarily long and arduous journey. However, there is
reason for optimism. The December 2019 decision by the Government of the Philippines to authorize the direct use of GR2E in
food, feed, and for processing39 is greatly encouraging for its
eventual release. Submission of an application for commercial
propagation of Golden Rice in the Philippines is anticipated in
2020. In addition to the import approvals already obtained in
Australia, Canada, New Zealand, and the US40–42, an application
for cultivation and food use was submitted in Bangladesh in
November 201743, where it remains under review.
The slow progress of Golden Rice in Bangladesh illustrates a
fundamental problem for genetically engineered biofortified crops
that do not also provide an agronomic benefit. Especially in
countries with new and evolving regulatory frameworks, the
authorization of a genetically engineered crop requires committed
support among all key decision-makers, often at some political
risk. New products must not only meet environmental, animal,
and human health and safety standards, but must present a
compelling value proposition that can garner the support of not
only just nutritionists and ministries of health and family welfare,
but also ministries of agriculture who wield significant influence
in the decision-making process. Also critically important is how
the value proposition is framed, and by whom, recognizing that
local voices are the most authentic and persuasive.
Reaching the RDA in single food servings
Inadequate intake of B-vitamins is highly prevalent in regions
where rice is the main staple food. The natural variation of
folates in rice is far too low to reach the necessary increase of at
least 100-fold to meet the RDA value for pregnant women with
one or two servings of 100 g of white rice44. The first successful
example of a genetic engineering approach improving rice for
B-vitamins is the 100-fold increase of folates (vitamin B9) in
polished rice grains, reaching 1723 µg/100 g fresh weight, which
is close to the RDA and more than the EAR in a single
serving45.
4
Genetic engineering of the B-vitamin metabolic pathways has
been successful in different staple crops. Increased levels of
bioavailable vitamin B6 could be achieved in cassava storage
roots46, while folate levels could also be significantly increased in
potato tubers47 as well as wheat and maize grains48. Efforts to
engineer the vitamin B6 metabolic pathway in rice have revealed
limitations in increasing B6 vitamin levels in polished white rice;
however, the same strategy was capable of elevating B6 vitamin
levels in rice leaves49. Therefore, further research is needed to
understand the factors currently impeding the genetic engineering of the B6 and other B-vitamin metabolic pathways in rice
endosperm.
Reducing or stopping post-harvest vitamin degradation
A potentially more effective or complementary breeding strategy
for high vitamin levels in foods produced from biofortified crops
is the reduction or complete prevention of vitamin degradation
after harvest. Ensuring post-harvest storage stability of vitamins is
of paramount importance, especially considering the longer storage at elevated temperatures, which is a typical practice in
populations suffering from vitamin deficiencies50. Provided that
sufficient fundamental knowledge on vitamin stabilization is
available, engineering these traits in food crops can yield both
increased vitamin accumulation as well as elevated stability. The
long-term stabilization of vitamin B9 obtained by introduction of
genes encoding folate binding proteins or altering folate structure
to enable increased (post-harvest) stability are successful and
encouraging examples50. Moreover, the combination of this
B9 stabilizing strategy with the aforementioned folate biofortification approach has enabled the hyper-accumulation of folate (up
to 150-fold of wild-type rice levels) in transgenic polished rice
seeds50. Similar approaches might also help to increase vitamin
B1 and B6 stability in the polished rice grain.
Like folates, all other vitamins are prone to breakdown during
storage, with varying sensitivity depending on the specific vitamin
and food matrix. A study of β-carotene corn in Zambia showed
that provitamin A levels had dropped by 70% after 6 months51;
similar losses were reported for polished Golden Rice38. Nevertheless, amounts remaining after degradation can still provide an
additional amount of vitamin A in the diet, ~40% of the EAR, and
the rate of degradation asymptotically approaches zero after a
certain time point.
Different approaches have been shown to successfully stabilize
provitamin A in engineered staple crops. In potato, β-carotene
levels can be enhanced and stabilized by introduction of the
Orange(Or) gene52. Or induces the formation of chromoplasts,
which naturally function as a metabolic sink for carotenoid
accumulation. Overexpression of Or together with the two other
genes for β-carotene biosynthesis in GR2 enhanced β-carotene
levels in polished rice to 26 ppm dry weight, though stability of
the provitamin A still needs to be investigated53. Alternatively,
engineering towards decreased carotenoid oxidation, an important form of provitamin A degradation, increased provitamin A
stability in polished Golden Rice during storage54. Suppressing
provitamin A breakdown has also been implemented in wheat to
increase β-carotene levels 31-fold55. In another approach, combining engineering towards higher accumulation of tocochromanols, fat-soluble E-vitamins bearing antioxidant properties
with the approach used in GR2 has shown that vitamin E can
enhance the stability of provitamin A in sorghum grain, more
than doubling its metabolic half-life56.
Simultaneously increasing multiple nutrients
Combining, or stacking, multiple nutrient traits into high-yielding
varieties is important and preferable over single nutrient
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Single nutrient
Multi-biofortification combined with agronomic trait(s)
Vitamin 1
Vitamin 2
Mineral 1
Mineral 2
×
Agronomic trait 1
Genetic engineering of DNA sequence enabling
higher content of multiple micronutrients as
well as optimizing agronomic traits
Conventional breeding
ome
t gen
Plan
Introduction in local varieties
Multi-biofortified crop
Fig. 1 Multi-biofortification in combination with agronomic traits. Genetic engineering enables creation of a single DNA cassette, harboring information
to allow increase in multiple micronutrients (vitamins and/or minerals) as well as favorable agronomic traits, possibly in combination with (conventional)
breeding. The cassette can be targeted to a specific genomic location in multiple local cultivars of a crop plant of interest, e.g. rice.
enhancement57, similar to the routine stacking of transgenes for
insect resistance and herbicide tolerance in cotton and maize58,59.
Combining several nutrition-related genes from multiple parents,
including genetically engineered crops such as Golden Rice,
into a single genotype through conventional backcrossing is
possible, but very time-consuming and laborious. Also, care must
be taken to avoid undesired alteration of other favorable plant
characteristics in the backcrossing process and to prevent segregation of transgenic traits in subsequent generations. Therefore,
combining multiple traits through conventional breeding remains a
challenge, particularly given that simultaneous selection for multiple traits becomes increasingly difficult as the number of traits
increases.
Today’s transgenic technologies substantially reduce the time
frame in which a multi-nutrient product can be engineered and
identified. For example, a single locus multi-nutrient trait
improvement has been recently accomplished by simultaneously
increasing iron, zinc, and β-carotene content in polished rice60.
This illustrates the relative ease with which multiple micronutrients (iron, zinc, and provitamin A in this case) can be
tackled by insertion of a single DNA fragment into the rice
genome. This approach is encouraging and opens new perspectives for developing multi-nutrient staple crop varieties in one
step. It exemplifies an effective and sustainable way of addressing
multiple micronutrient deficiencies that often co-occur in affected
populations11,61. Metabolic engineering allows design of strategies
to jointly boost an array of different micronutrients (e.g. iron,
zinc, vitamin A, and vitamin B9), whilst also taking the aforementioned stability into account. Moreover, with the advent of
genome editing technologies, it is now possible to insert a gene
cassette at a pre-defined location (safe harbor) in the genome of a
crop plant, thereby avoiding adverse effects such as yield losses62.
On a cautionary note, researchers need vigilance to recognize
unintended metabolic consequences of biofortification. For
example, provitamin A biofortification of cassava and sweet
potato significantly reduces dry matter content of storage roots63.
Since dry matter is a major factor influencing food texture, it is an
essential component in product adoption. Enhancing other
micronutrients might have a similar negative impact, possibly
exacerbated in multi-biofortified crops.
As a health intervention, even single-nutrient biofortification is
inherently cost-effective due to very low recurrent costs once
varieties have been developed at a central location and widely
distributed. Other micronutrient interventions, such as supplementation and industrial fortification of processed foods, involve
much higher recurrent costs and are not directed at solving the
underlying cause of micronutrient deficiencies, which is that
agricultural systems are not producing affordable supplies of
required minerals and vitamins7. Multi-nutrient biofortification
can realize even more substantial economies of scale. While
genetically engineered biofortified crops are associated with
substantial development and regulatory costs, they are estimated
to be highly cost-effective, often more than conventional or
complementary approaches64. Ex-ante evaluation of multinutrient rice (provitamin A, folate, zinc, iron) in China, for
example, has confirmed the potential, long-term cost-effectiveness65. Aside from synergies through aggregated health impacts
and cost savings (from development to dissemination), multinutrient biofortification can lead to much higher market coverage, as competition between several single-nutrient biofortified
varieties is avoided.
Simultaneous improvement of nutritional and agronomic
traits
A multi-nutrient trait locus stacked with genes of interest can be
easily transferred to farmer-preferred crops, either by breeding or
direct transformation in shorter time period. Genetic cassettes
can now combine many more stacked genes and therefore it is
conceivable that simultaneous micronutrient improvement of
staple crops is no longer limited to three traits. Also, gene stacks
for nutritional traits can be combined with important agronomic
traits in the same genetic locus, such as pest and disease resistance
(e.g., resistance to bacterial blight, army worms, brown plant
hoppers, or stem borers in rice) or abiotic stress tolerance (e.g.,
drought, heat, salinity, cold, flooding tolerance; Fig. 1). This will
make it more attractive for farmers to adopt nutritionally
improved staple crop varieties and therefore accelerate the
percentage of the total supply of rice (or other staple food crops)
that is biofortified. Single insert gene cassettes using proven
genes can be customized for specific regional needs or consumer
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preferences, which might also be favorable from a regulatory
point of view. In an era of global climate change, the single locusmultiple trait approach combining nutritional traits with stress
resilience genes can provide region-specific solutions for sustainable agriculture with benefits both for farmers and consumers. In doing so, genetically engineered biofortified crops
might acquire a higher economic value that positively impacts
their regulatory review66.
Small-scale farmers and low-income rural communities in
Africa and Asia are the ones suffering most from micronutrient
deficiencies and are likely also the ones that will be hit hardest by
climate change and related weather extremes. Genetic engineering
technologies alone are not a magic bullet that will solve these
problems, but they can help considerably in making small-farm
systems more productive, resilient, and nutrition-sensitive. In the
past, with conventional breeding approaches, breeding for higher
yields was sometimes associated with lower crop robustness and
lower nutritional value. Such tradeoffs can now be avoided.
Another important advantage of genetic engineering is the much
greater speed of breeding, especially against the background of
climatic changes leading to new weather and pest infestation
conditions that are not always predictable. Studies suggest that
harnessing new breeding technologies for combining nutritional
and agronomic traits can lead to large economic and social
benefits in developing countries and represent an important step
towards sustainable food security67,68.
Proposed actions and policy interventions
UN-SDG2 of ending all forms of hunger and malnutrition by
2030 needs much swifter actions than those that are currently
deployed. Implementation of biofortified crops, either obtained
by conventional breeding, genetic engineering, or their combination can substantially contribute to reach this goal. Fortunately,
the speed at which novel crops can be developed is more rapid
than ever due to advances in gene cloning and genome editing
technologies69,70. Together, these technologies provide the means
of minimizing trait loss due to instable genomic context and
optimization of gene expression levels.
Reaching health-relevant nutritional targets is often not possible by conventional breeding. Presently, the combination of
genetic engineering and conventional breeding is the most powerful approach when aiming at multi-nutrient crops. There are
currently no examples of sufficient nutrient enhancement via
genome editing approaches. Genome editing technologies alone
are indeed not solving the problem until we have a better
understanding of the tissue-specific activity of relevant gene
promoters or unless mutations can be identified that boost the
reaction rate of required enzymes. Genetic engineering should go
hand in hand with conventional breeding and could be assisted
by novel breeding technologies for site-specific (safe harbor)
insertion.
Conventionally bred biofortified crops have been extensively
tested for efficacy, even showing improved functional outcomes
such as lower morbidity, improved cognitive performance, and
work capacity. These trials have taken into account nutrient losses
due to processing and cooking, and during storage. The presumption is that higher nutrient levels, as consumed, in transgenic foods will show even better nutrition and functional
outcomes, although trials are needed to confirm this. Modern
breeding technologies including genetic engineering should be
applied to elite germplasm for combining nutritional and agronomic traits to produce high quality-high yield crops.
In this context, therefore, the following specific actions and
policy interventions are recommended (Fig. 2):
6
1. There is a need to expand germplasm collections as well as
screen existing germplasm to better characterize natural
diversity of micronutrients as the benefit could be two-fold:
availability of genotypes for conventional breeding
approaches and genetic material to better understand
vitamin biosynthesis and micronutrient accumulation in
planta.
2. Key to making biofortified crops successful is their
accessibility in a way that vulnerable population groups
and smallholder/subsistence farmers can affordably receive
these biofortified crops. Release of the biofortified crop
products needs to be preceded by ethically approved and
well-designed dietary studies supporting their effect.
Humanitarian licenses will be needed from institutions
that own intellectual property rights on these crops as well
as genome editing technologies and genetic elements used
in biofortification approaches. This enforces independence
from seed companies, which will allow for a better public
perception of genetic engineering technology, especially if
clear health (consumer-related) and economic (farmerrelated) benefits are demonstrated.
3. Single locus, multi-nutrient trait strategies facilitate qualitative product improvement without altering plant health
and creating environmental issues. The safety of genetically
engineered crops for consumers and the environment was
endorsed by Science Academies worldwide (http://nas-sites.
org/ge-crops/category/report/) and by over 100 Nobel
laureates71. However, there is still a need to provide
independent and science-based information to the public
on safety of genetically modified crops.
4. Regulatory frameworks for genetically engineered foods and
crops need to be established, or updated and modernized in
different countries, to acknowledge three decades of
experience and evidence of their safety. Regulations should
be proportionate to the level of risk, considering both
familiarity and history of safe use. The May 2020
announcement by the U.S. Department of Agriculture’s
Animal and Plant Health Inspection Service (APHIS) to
exempt certain categories of gene edited plants from its
regulatory oversight signals an important shift from
process-based regulation to an approach that focuses on
the new traits themselves. Many countries (e.g. in Africa)
either do not have a regulatory framework or very
restrictive for the release of transgenic crops. The establishment of local non-profit organizations (e.g. Cornell Alliance
for Science) aiding the public, media and policymakers in
understanding the implications of introduction of multibiofortified crops, both from a health and a socio-economic
perspective, should ease the process towards cultivation of
biofortified crops by small-scale farmers and release of the
products to low-income rural communities. Publicly funded
bodies, preferably with additional financial backing of
charitable organizations, coordinated by governments in
concert with local academics could ensure a non-profit
route towards population groups in need.
5. Capacity needs to be built in developing countries to
increase impact by implementation of technologies in
farmer- and consumer-preferred crop varieties. Empowering research and product development capacities in regions
where metabolically engineered biofortified crops are
needed is the key to facilitate technology adoption72,73.
Regional research centers and universities, for instance, can
focus on the development of genetic transformation and
genome editing tools in local recalcitrant genotypes.
Likewise, local agricultural institutions, particularly in
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rformance
mic pe
o
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ag
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an
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Provid
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ati
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ZERO
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NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19020-4
an
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Update regulatory
frameworks
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Techn
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Fig. 2 Proposed actions and policy interventions. Achieving zero hunger (UN-Sustainable Development Goal 2, UN-SDG2) requires actions (greenyellow) using different tools and trait/technology combinations (blue). Yellow-labeled actions specifically aim to achieve better accessibility by the poor,
whilst green-labeled actions aim to acquiring more efficient product development (light green involves genetic engineering only, dark green includes both
genetic engineering and conventional breeding).
Metabolic engineering
Combined approach: genetic engineering
and breeding
Conventional breeding
Supplementation
Industrial food fortification
Nutritious food
Satisfactory
micronutrient
intake
SDG2: ending
micronutrient
malnutrition
Nutritional education
Dietary diversification
Fig. 3 Ending malnutrition requires concerted efforts from different angles. Biofortification (red), dietary interventions (blue), and fortification or
supplementation (black) can help affected populations to reach sufficient micronutrient intake, leading toward eradication of micronutrient malnutrition
and its related diseases. Metabolic engineering of crops for better micronutrient content is an efficient, cost-effective strategy complementary to
conventional breeding and offers several benefits. It allows faster trait introduction, including the stacking of multiple traits as a single genetic locus in a
crop genome, and achieves increases in essential minerals and vitamins while simultaneously improving vitamin stability. Conventional breeding is far less
constrained by regulatory issues however, which today unnecessarily slow the deployment of novel genetically engineered varieties with increased
micronutrient content to improve human health. Lessons learned from Golden Rice have already led to a better understanding of multilevel stakeholders
and the strong need for joint efforts of bringing an important nutritive trait from the lab to farmers and consumers66. If adopted multi-nutrient biofortified
crops currently under development can help millions and particularly women and children sustainably, complementing other nutrition interventions. We
emphasize that ending malnutrition needs increased efforts on a wide array of interventions, including making healthy diets more affordable through higher
incomes and lower food prices. Together with nutrition education, these efforts result in greater dietary diversification. Increasing incomes of the poor and
adding relatively expensive vegetables, fruits, pulses, and animal products to diets are important for improved micronutrient status and other better
nutrition-related outcomes, but will only be realized over several decades. Supplementation and industrial food fortification are important interventions in
the short and medium run, but biofortification can and should play a larger role as a cost-effective and agriculture-based improvement of human health.
Achieving sustainable change needs a substantial increase of investments, demanding global governmental action in all parts of the chain, from research
and development to education and dissemination. Public funding of such efforts is of paramount importance.
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regulatory-benign countries, can be involved in the
development phase of the work under the form of field
trials. This is particularly important for crops requiring
extensive breeding programs due to a long life-cycle,
asynchronous flowering, and high heterozygosity.
Conclusions
Metabolic engineering, combined with conventional breeding,
can catalyze a much more rapid approach to the realization of
zero hunger and to reducing malnutrition by crop biofortification
along the successful path paved by HarvestPlus and other public
institutions. Based on decades of experience with the widespread
and safe production of transgenic maize and soybean as food
crops, the consensus among Academies of Science globally is that
transgenic crops introduced thus far are not harmful to the
environment and are safe for human consumption. Considering
the fact that many crop species, including sweet potato, yams, and
banana, are naturally transformed by T-DNA from Agrobacterium74, common sense should prevail when governments decide
on legal frameworks for the release of transgenic crops. Such
decisions should be solely driven by the determination to improve
human welfare and sustainability. However, scientists have an
important role to play beyond the walls of their labs, notably in
transferring of knowledge and making sure that regulatory decisions are based on ratio. Academies of Science over the globe can,
together with the publicly funded bodies advocated above, function as a motor in the process of knowledge transfer towards
policymakers.
Biofortification, in combination with dietary diversification
and nutrition education, holds great potential to eradicate
micronutrient malnutrition and increase global human health
(Fig. 3). The next gene revolution should focus on sustainable
solutions for malnutrition, as part of a humanitarian intervention,
concerted with educational efforts as a cornerstone to halt
population growth, improve living standards, and bring about
global peace.
Data availability
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Source Data are provided with this paper.
Received: 25 June 2020; Accepted: 24 September 2020;
25.
26.
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Acknowledgements
D.V.D.S. is grateful to Ghent University for financial support (BOF Special Research
Fund, GOA project 01G00409). S.S. acknowledges the Ghent University Special Research
Fund for a Post-Doctoral fellowship (BOF.P-DO.2019.0008.01). H.B. was director of
HarvestPlus during 2003-2016 and interim CEO of HarvestPlus during 2018-2019.
HarvestPlus has been supported by multiple donors (https://www.harvestplus.org/).
Author contributions
Coordination and primary drafting of the manuscript was undertaken by D.V.D.S. and
H.B.; N.K.B., H.D.S., W.G., D.K., W.P., M.Q., S.S., I.S.L., J.T., K.R.T., H.V., M.V.M., and
C.Z. provided pieces of text, comments, and suggestions for improvement on several
drafts of the manuscript, and approved the final version.
Competing interests
The authors declare no competing interests.
Additional information
Supplementary information is available for this paper at https://doi.org/10.1038/s41467020-19020-4.
Correspondence and requests for materials should be addressed to D.V.D S. or H.B.
Peer review information Nature Communications thanks Leena Tripathi, Philip White
and the other, anonymous, reviewer(s) for their contribution to the peer review of
this work.
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