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OCR for page 5968
Proc. Natl. Acad. Sci. USA
Vol. 96, pp. 5968-5972, May 1999
Colloquium Paper
This paper was presented at the National Academy of Sciences colloquium "Plants and Population: Is There Time?"
held December 5-6, 1998, at the Arnold and Mabel Beckman Center in Irvine, CA.
Biotechnology: Enhancing human nutrition in developing and
developed worlds
GANESH M. KISHORE* AND CHRISTINE SHEWMAKER
Nutrition and Consumer Products, Monsanto Company, 800 North Lindbergh, St. Louis, MO 63167
ABSTRACT While the last 50 years of agriculture have
focused on meeting the food, feed, and fiber needs of humans,
the challenges for the next 50 years go far beyond simply
addressing the needs of an ever-growing global population. In
addition to producing more food, agriculture will have to deal
with declining resources like water and arable land, need to
enhance nutrient density of crops, and achieve these and other
goals in a way that does not degrade the environment.
Biotechnology and other emerging life sciences technologies
offer valuable tools to help meet these multidimensional
challenges. This paper explores the possibilities afforded
through biotechnology in providing improved agronomic "in-
put" traits, differentiated crops that impart more desirable
"output" traits, and using plants as green factories to fortify
foods with valuable nutrients naturally rather than externally
during food processing. The concept of leveraging agriculture
as green factories is expected to have tremendous positive
implications for harnessing solar energy to meet fiber and fuel
needs as well. Widespread adaptation of biotech-derived prod-
ucts of agriculture should lay the foundation for transforma-
tion of our society from a production-driven system to a
quality and utility-enhanced system.
Over the last 50 years, our society has faced the challenge of
feeding an ever-growing world population. Human population
has literally doubled in the last 40 years and increased 6-fold
in the last 200 years. Since the beginning of this century,
agriculture has intensified first, with the discovery of eco-
nomic, chemical processes to reduce nitrogen to ammonia and
the use of nitrogenous fertilizers in agriculture, superior
genetics with hybrid as well as varietal crops, resulting in a
global green revolution, and finally, with the discovery and use
of chemical pesticides to manage a range of pests, including
weeds, microbes, and insects. Intensive agriculture as practiced
today fully leverages all of the above advances and in addition
is benefited by superior irrigation techniques, better tillage
systems, etc. Global cereal yields practically doubled between
1960 and 1990. Yields of both rice and wheat, crops largely
consumed by the rapidly growing Asian population, have
dramatically increased.
These agricultural technologies, however, have not kept
pace with projected population increases. If population out-
strips food availability, more marginal land will necessarily be
placed into agricultural use, heavier inputs will be applied, and
food self-sufficiency, especially in emerging economies, will be
compromised. The challenge over the next 50 years will be to
not only feed more people, but to do so in such a way that takes
into account these facts:
· There will be less arable land. A combination of overplow-
ing, overgrazing, and deforestation has caused soil erosion
to exceed soil formation. Countries particularly hard hit are
PNAS is available online at www.pnas.org.
those in continents like Africa, where soil is shallow to begin
with. The next generation of farmers in Africa will need to
feed not the 719 million people of today, but 1.45 billion
people in the year 2025 and with far less topsoil (1~. Even
so-called low-tech agriculture, sometimes viewed as more
sustainable, still relies on chemical inputs and involves
techniques, such as plowing, that degrade the soil.
· There will be fewer resources, particularly nonrenewable
resources like phosphorus and potassium, which go into
fertilizers. The U.S. Bureau of Mines showed a 7-fold
increase in consumption of U.S. industrial minerals, includ-
ing fertilizers and feed stocks from 1900 to 1980, and this
trend is expected to continue (2~. While it could be argued
that we have sufficient natural deposits of these minerals to
last another 200 years, technologies that minimize ore
extraction and dispersion over vast areas of land will en-
hance the sustainability of our agricultural systems.
· There will be less water, and the quality of remaining water
also will be reduced as demand increases. Also, competition
for reduced water supplies between rural and urban societies
will increase. Water use has tripled since midcentury (3),
and water tables are falling all around the world. Seventy
percent of all the water pumped from underground or drawn
from rivers is used for irrigation, and if we face a future of
water scarcity, we also face a future of food scarcity.
· Fewer people will be engaged in primary agriculture in both
developed and developing countries. In the United States,
less than 1 To of the population is engaged in primary
agriculture, compared with 60% of the population in the
early 1900s (U.S. Bureau of the Census).
People engaging in primary agriculture will be older. The
breadbaskets of the world, particularly Western Europe and
North America, have the most graying population. The
generation born in the U.S. during the baby boom of the
1950s will be in their 60s by 2010, ushering in an age of
unparalleled increase in absolute numbers of elderly. Ac-
cording to the U.S. Bureau of the Census, by 2010, half of
the U.S. population will be 37 or older a very high median
age (44. This aging society will need technologies that will
allow it to produce food in a more cost-effective, less
labor-intensive, and more convenient way than they have
done in the past.
· Health-care costs will continue to increase as the population
ages, putting more demands on public aid. Governments'
ability to pay for Social Security and health care will decline
as the population increases and the number of people
contributing to Social Security, once the baby-boom gener-
ation retires, will decrease. This will be particularly critical
for the developed nations of this planet. For the developing
economies, health care oriented toward prevention and
*To whom reprint requests should be addressed. e-mail: ganesh.
m.kishore@monsanto.com.
5968
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Colloquium Paper: Kishore and Shewmaker
health delivered inexpensively is critical as their middle class
expands and human longevity dramatically increases.
· As a result, food that can provide more than just calories and
essential nutrients but has the ability to delay the onset of
degenerative diseases and aging will be a powerful contrib
utor to a healthy, global society.
We need an array of new and improved technologies, which
can form the foundation for infrastructure and cultural im-
provements, to help address these challenges.
Luckily, we are entering an epoch rich with opportunity for
breakthrough technologies. Termed the information revolu-
tion, this era is certain to have at least as big an impact on
society as the agricultural revolution and the industrial revo-
lution. Information-driven agriculture will have two compo-
nents. The first is information based on genomics, the study of
genes, the strands of life, which is an enabling link across life
sciences, including agriculture, food and nutrition, and phar-
maceuticals. This constitutes the next tier in scientific under-
standing and opportunity and is discussed in greater detail
later.
The second component is information that is based on the
silicon revolution of the present time. Computer and modern
electronic communication systems can be applied across the
life sciences to maximize value. Today, in agriculture, farmers
are taking advantage of the system for precision agriculture
that optimizes inputs, characterization of outputs so that they
can match the needs of their customers with specific products
as well as managing their business based on real-time infor-
mation.
Biotechnology is a discipline that has developed rapidly
during the last two decades. This technology is based on our
fundamental ability to precisely introduce genetic changes into
an organism. Plant biotechnology in particular has evolved
rapidly over the course of the last 15 years. Every major crop
can be subject to precise genetic modifications based on our
ability to introduce and express genes in crops. Plant biotech-
nology therefore should substantially augment plant breeding,
which in many respects was based on our ability to harness
genes into plants either by sexual crossing or laboratory
techniques such as cell fusion. We anticipate that plant bio-
technology will go through three phases of development,
creating significant value at each stage. The first is agronomic
trait development, the second is differentiated crop develop-
ment, and the third is use of plants as factories. These are
discussed in detail below.
Agronomic Traits
Since 1995, major products with improved agronomic traits
have been introduced in the U.S. and other parts of the world.
These are mostly single gene traits where a single gene has had
a dramatic positive impact on grower productivity. This is
reflected in the widespread acceptance and use of genetically
improved crops in the United States, which is estimated to be
46 million acres. A few examples of these products are
Monsanto's Roundup Ready soybeans and YieldGard corn
and are discussed below.
Roundup Ready soybeans contain a gene encoding the
enzyme 5-enolpyruvylshikimate 3-phosphate synthase (EP-
SPS) involved in the biosynthesis of aromatic amino acids in
plants. The EPSPS gene naturally present in soybeans pro-
duces a form of the enzyme sensitive to glyphosate, the active
ingredient of Roundup, whereas the gene in Roundup Ready
soybeans encodes a catalytically active and glyphosate-tolerant
form of the same enzyme (54. Expression of this gene in plants
renders adequate commercial tolerance to this herbicide.
Roundup Ready soybeans are one of the most widely
accepted products that have been introduced in the history of
agriculture. Within 3 years of commercialization, the crop has
grown to the point where it now accounts for almost 40% of
Proc. Natl. Acad. Sci. USA 96 (1999) 5969
total U.S. soybean acreage. Roundup Ready soybeans offer
several benefits to farmers, including a superior weed man-
agement system. Roundup, a post-emergent, broad spectrum
herbicide controls most weeds in the field and needs to be used
only when weed control is needed. Indeed in 1997, U.S.
growers used only Roundup on 83% of the Roundup Ready
soybean acres. Another benefit is yield optimization (5%
higher yield with lower operating costs). Roundup also has
demonstrated favorable environmental characteristics. It
breaks down over time in soil to innocuous products (ammo-
nia, phosphate, carbon dioxide and water), is highly unlikely to
move in groundwater, does not accumulate in the environment
or food chain, and is practically nontoxic to multiple life forms
such as aquatic, avian, animal, and human. The combination
of the Roundup Ready soybeans and Roundup also enhances
the ability of the farmer to use the seeds in conjunction with
less resource-intensive farming practices like conservation
tillage, which helps conserve topsoil.
Before the introduction of this product into the marketplace,
we conducted a number of safety assessments for not only the
herbicide but also the genetically improved soybeans. Those
studies demonstrated the nutritional equivalency of the soy-
beans containing the Roundup Ready gene to those without
the gene. The gene product also was investigated for its safety
and digestibility and demonstrated to be a rapidly digested
protein similar to many other proteins found in our food chain
(6~.
YieldGard corn uses a plant-modified version of the gene
encoding an insecticidal protein from a naturally occurring
bacterium, Bacillus thuringiensis (~7, 8') to help the plant resist
the European corn borer, which annually infests some 40
million acres of crops in the U.S. Average annual yield loss
caused by the corn borer is 6% and can be as high as 20% and
represents $1-2 billion in losses to farmers depending on the
extent of infestation of the corn borer. With YieldGard,
farmers achieve 11-15 additional bushels of corn per acre.
Even subclinical infestations, which otherwise would go un-
treated resulting in smaller yields, can be avoided, thereby
boosting yields. The YieldGard gene significantly reduces the
damage caused by the European corn borer to the corn
crop damage that has the potential to cause onset and spread
of fungi and other microbes in the corn plant and produce
undesirable toxins. Safeguarding the corn plant against the
corn borer therefore provides secondary benefits of yield
protection from other pests as well as quality protection.
While our discussion above has been restricted to two
examples of products of biotechnology, it should be pointed
out that several other products within the category of agro-
nomic traits have been introduced into the marketplace. These
include Bollgard cotton, Roundup Ready canola, cotton, and
corn, Liberty Link canola and corn, New Leaf potato, virus-
resistant squashes, and melons.
Near term, a number of other agronomic traits are expected
to be commercialized. In our own laboratories at Monsanto, we
are working on a trait that will protect corn from corn root
worm, a major insect pest of corn that causes losses approach-
ing $1 billion in the U.S. Healthy root systems, crucial for water
and fertilizer uptake, are destroyed by this pest. By controlling
root worm, it is our expectation that not only is the yield likely
to be better protected but the crop also will have greater
drought tolerance and fertilizer use efficiency, leading to
better grain quality.
Resistance against head scab disease in wheat, caused by the
fungus Fusarium graminareum, is another agronomic trait
under development. Longer-term agronomic traits such as
crop architecture redesign, better fertilizer utilization, heat,
frost, and drought resistance, as well as salinity and heavy
metal tolerances are expected to be developed. Understanding
the functions of many of the genes in plants will be critical for
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5970 Colloquium Paper: Kishore and Shewmaker
these advances to occur. Plant genomics will play a pivotal role
in this endeavor.
Differentiated Crops
While agronomic traits discussed in the previous section have
largely focused on input traits, differentiated crops are more
focused on grain quality or output traits. Classical breeding has
produced a diverse array of differentiated crops such as canola
vs. high erucic and glucosinolate containing rape; waxy and
high amylose maize vs. yellow dent corn; basmati vs. long grain
rice; durrum wheat vs. regular wheat, etc. With biotechnology,
our ability to create differentiated, value-added products that
create value downstream of production is greatly enhanced.
Such differentiated crop offerings are beginning to appear in
the marketplace and are discussed below.
A vast majority of the grains in the Western Hemisphere are
used for feeding animals, and it is not surprising that a
significant activity in the differentiated crop arena is focused
on improving the feed quality of crops. Two types of products
now are being created-one focused on increasing caloric
density of the grain by increasing its oil content and another
on nutrient density, particularly the levels of protein, essential
amino acids, and other micronutrients.
High-oil corn, introduced by DuPont, is the first example of
this type of product. High-oil corn typically has an oil content
of more than 6% as opposed to the 3-4% found in commodity
corn. This near doubling of the oil content is expected to
dramatically reduce the exogenous addition of fats in the diets
of animals and birds. One of the major problems with high-oil
corn germplasm has been the yield drag associated with the
product. This has been substantially addressed by a technique
known as TopCross. Although high-oil corn is not strictly a
biotechnology product of the type described earlier for agro-
nomic traits, molecular aspects of breeding have facilitated the
rapid creation and commercialization of the product. Our
understanding of the genome of corn and other cereals should
facilitate molecular breeding and harness the genomic poten-
tial of these crops much more powerfully in the future.
High-oil corn now is being improved by the addition of
high-protein genes as well as by increasing the essential amino
acid content of the grains. The high-protein trait itself is also
a product of molecular breeding, while high lysine is derived by
introduction of critical genes altering the flux of carbon and
nitrogen via the lysine pathway in the seed. In the future, we
should expect cereals fortified with all the critical essential
amino acids such as lysine, methionine, threonine, and tryp-
tophan, and thus be able to reduce the exogenous applications
of these amino acids in feed rations. In addition to corn, other
crops such as wheat, soybeans, and canola are being subjected
to similar improvements.
Direct utilization of the grain by improvements in nutrient
density and taste/texture appeal for human consumption will
go a long way toward meeting not only the food demands of our
ever-growing population but also indirectly will benefit our
society by increasing the levels of phytonutrients, which are
being increasingly shown to have health-oromotin~ attributes
in humans (9, 10~.
Or =~-,^~
Our research efforts have focused on oil modification of
canola and soybeans. Most of the oil derived from oil seeds is
used in human consumption. Vegetable oils generally are
preferred to oils and fats from other sources because of their
higher content of mono- and polyunsaturated fats. Fats and
oils are one of the most important flavor and texturizing
components of food. To create the appropriate texture and
mouth feel in foods, it is often necessary to hvdro~enate
vegetable oils, a process that results in the production of
trans-fatty acids. There is a growing body of evidence that
suggests that trans-fatty acids found in hydrogenated fatty
acids may potentially increase total and low density lipoprotein
Proc. Natl. Acad. Sci. USA 96 (1999'
(LDL) cholesterol in humans. Total and LDL cholesterol now
are widely accepted as some of the important biomarkers of
the risk of cardiovascular disease in humans, and a number of
countries are making significant efforts to educate people on
the benefits of keeping the levels of these two biomarkers in
the healthy range (National Cholesterol Education Program).
By inhibiting the conversion of stearate to oleate in plants,
it is possible to produce a trans-fatty acid-free solid or semi-
solid fat directly in oilseeds. One of the advantages of stearate
over other saturated fatty acids is that it is not hypercholes-
teremic (11~. High stearate soybean and canola now have been
produced and are being evaluated for their commercial utility.
Grain legumes are some of the most valuable sources of
vegetable protein in the human food and feed chain. Soybean,
a legume grown on a majority of the legume acreage of the
world, is a vital protein source for many people living in Asia.
Its use as a protein source can be further enhanced if several
attributes such as flatulence, beany flavor, texture, and emul-
sification properties can be addressed. A number of laborato-
ries are attempting to address these issues.
Plants as Factories
Plants, nature's best manufacturing system, provided the sole
source of food, feed, and fiber to society for many centuries
until fossil fuel use began. The concept of using plants in place
of chemical or nutrient factories to supply food, feed, and fiber
is gaining significant attention and constitutes the first step
toward biotech-based, nutritionally fortified foods.
An important example is high carotenoid canola, rich in beta
carotene a precursor to vitamin A. Many of the western
countries address the problem of vitamin A needs of humans
by fortifying milk with this vitamin. However, this system is
impractical in most parts of the world. According to WHO
(12), vitamin A deficiency is today a global epidemic 250
million children are at risk of vitamin A deficiency on an
annual basis, and somewhere around 10 million people suffer
from significant illness and death resulting from a vitamin A
deficiency in their diets. This deficiency results in impairment
of vision, protein malnutrition (vitamin A affects amino acid
absorption and utilization), and impairment of immune func-
tions.
Essentially all countries in Latin America, Asia, and Africa
are either clinically or subclinically deficient in vitamin A (13,
14~. The best sources of vitamin A are the carotenes, partic-
ularly beta carotene, found in many fruits and vegetables.
These carotenes are effectively converted into vitamin A and
generally are accepted to have much higher safety than vitamin
A itself. Fruits and vegetables with high carotene content are
not routinely available at affordable prices to poor people, and
for those who can afford them appropriate food sources that
are fortified with these precursors are not available. One of the
most important contributions that biotechnology can make to
world health is to produce crops naturally fortified with this
important nutrient that people can grow in varied global
regions and that would become part of their regular food
intake. This also would reduce the need to exogenously fortify
foods with nutrients produced outside of the plant.
Fortification within the seed enhances nutritional quality for
all types of farmers. With fortification, local crops grown by
subsistence farmers and best suited to their growing conditions
naturally would include these nutrients. Large, commercial
farmers would reap the same benefit. This represents a whole
new way of thinking about food fortification. Biotechnology
could be used as a delivery system that benefits all levels of
farming from the subsistence farmer to the large-scale, global
gra~n grower.
We have introduced the gene phytoene synthase into canola
and demonstrated that the expression of this gene results in
OCR for page 5971
Colloquium Paper: Kishore and Shewmaker
high levels of beta carotene accumulation within the rape seed
(Table 1).
Rape seed, popularly known as mustard seed, is grown in
many parts of the world, including Africa, Asia, and Latin
America, and its use is increasing. These are the same regions
with high levels of vitamin A deficiency. Interestingly, in
addition to containing high levels of beta carotene, rape seed
oil expressing the phytoene synthase gene has a higher level of
alpha carotene, lutein. In comparison with other sources of
provitamin A, such as red palm oil, this annual crop has the
ability to provide a varying range of carotenes, vitamin E, and
a healthier profile of fatty acids. Harnessing the full genetic
potential of the rape seed crop can go a long way toward
addressing the nutritional needs of our ever-growing popula-
tion the high beta-carotene canola is expected to be com-
mercialized within the next 3-4 years.
While the example provided above illustrates the power of
biotechnology for addressing the nutritional needs from the
perspective of a well-established nutrient, the same technology
can be harnessed to address the nutritional needs of even
advanced countries of the world by producing new nutrients in
grains. As our understanding of the human genome and the
biochemical reactions associated with the onset of degenera-
tive processes in the body increases, we are likely to understand
the role of many nutrients in our food that can both accelerate
as well as inhibit such processes. By using biotechnology, we
can eliminate antinutrients (which will accelerate the degen-
eration of health and progression of disease) and increase the
levels of nutrients that can help us live healthier lives. One
example of such a nutrient is provided below.
At the present time, cardiovascular diseases account for
most deaths in Europe and North America and are becoming
more prominent in urban societies in the rest of the world. The
cost to society in the United States is estimated to be $260
billion annually from cardiovascular-related disorders, includ-
ing heart disease, coronary artery disease, stroke, hypertensive
disease, and congestive heart failure. As described earlier, total
and low density lipoprotein cholesterol are important biomar-
kers of cardiovascular health and are routinely monitored to
assess the health status of individuals (15~. High total choles-
terol levels contribute to cardiovascular disease and levels
below 200 mg/dl are desirable. Approximately 115 million
people in the United States appear to have cholesterol levels
between 200 and 239 mg/dl and have a higher risk of death
caused by myocardial infarction (American Heart Association
data). While people with cholesterol levels above 240 mg/dl
are given prescribed drugs, drug therapy generally is not
recommended for people with lower cholesterol levels in view
of the considerations of cost, safety, etc. Very few people who
have these intermediate levels of cholesterol strictly follow the
recommended practice of reducing the saturated fat intake and
exercising, thereby increasing the risk of contacting the disease
and cost to society.
It has been known for quite some time that phytosterols have
the potential to reduce cholesterol in humans by 10-15% by
Table 1. Composition of high carotenoid canola
High carotenoid
canola oil,
~g/gm
2025-2466
690-920
470-530
8-33
85-196
760-820
400-500
400-500
Red palm oil,
~g/gm
480-672
280-392
175-245
7-9
Carotenoids (Total)
,13-carotene
c-carotene
Lycopene
Lutein
Phytoene
Tocopherols
Tocols
10-15
90-150
600-1000
Proc. Natl. Acad. Sci. USA 96 (1999J 5971
interfering with cholesterol absorption in the gastrointestinal
tract (16, 17~. Indeed products containing these phytosterols such
as Benecol and Take Control are beginning to appear in the
market to assist individuals in managing their cholesterol levels
more aggressively. Phytosterols are not currently available in
adequate quantities in the foods that we ordinarily consume. It
has been known for some time that expression of genes in the
phytosterol pathway in plants increases the sterol content of plant
tissues. Based on these and other novel genes, we now are working
on increasing the phytosterol content of several grains.
While the above example serves to illustrate the power of the
technology in the context of cholesterol, several other nutrients
and their relationship to human health now are being investi-
gated. A range of fatty acids that modulate inflammatory reac-
tions in the human body, and antioxidants that have sparing
effects on antioxidant vitamins such as vitamin C and E and that
also boost the levels of antioxidant defense enzymes in the human
body are just a few examples of a multitude of discoveries that are
likely to emerge in this area in the near future (18~.
Most of the progress to date has been made by using either
single genes or first-generation molecular breeding capabili-
ties. Rapid accumulation of sequence data from both chro-
mosomal DNA and expressed sequence tags of plants and
other species is giving us significant insights into the genetic
makeup and functions of several genes in plants (19~. Comple-
mentation of the sequence information with high throughput
gene expression analysis and mutation/gain of function bio-
logical analysis is beginning to open the doors to a vista of
knowledge on the role and functions of many of these genes.
Plant genomics, which is only a few years old, is expected to
provide whole new insights into designing crops that are
superior in every aspect of both input and output traits that are
described here.
In summary, biotechnology adds value across the system from
crop to farmer, customer and consumer. Biotechnology can, and
is, enhancing the quality of food in addition to improving the
quantity of food. Biotechnology can improve the sustainability of
production systems by requiring fewer inputs to control pests and
better protect the quality of water and land mass around us.
Biotechnology can add health and vitality to humans. As we look
at food production in a more holistic way, biotechnology will be
an important component of that holistic system.
We gratefully acknowledge the contributions of Diane Herndon and
Tracy Farmer in preparing the manuscript.
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Representative terms from entire chapter:
agronomic traits
