Biotechnology for Agriculture and Food in the Future - ACS Publications

Chapter 26

Biotechnology for Agriculture and Food in the Future

Downloaded by SUNY STONY BROOK on February 9, 2015 | http://pubs.acs.org Publication Date: January 7, 1988 | doi: 10.1021/bk-1988-0362.ch026

Ralph W.F. Hardy Boyce Thompson Institute for Plant Research at Cornell, Tower Road, Ithaca, NY 14853 and BioTechnica International, Inc., 85 Bolton Street, Cambridge, MA 02140

Biotechnology products and processes are expected to provide necessary inputs for agriculture and food including increased productivity, higher value-in-use food products and new products for non-food markets. Several examples of recent major science, technical, and policy developments are highlighted: N2 fixation, microbial pesticides, plant cell culture regeneration and somoclonal variation, genetic engineering of plants, monoclonal antibodies and DNA probes, microbial production of animal products, genetic engineering of animals, reproduction technology, genetically-engineered yeast, designed genes, regulation of gene expression, chemical agriregulators, proprietariness, and regulation and field testing. Types of products and processes for each of crops, animals, and foods are identified with indicated sequence of commercialization. World sales of $5 to $10 billion are projected by 2000. B i o l o g i c a l science and technology f o r a g r i c u l t u r e and food has been i n accelerated advance i n recent years. From these b i o l o g i c a l advances are expected s i g n i f i c a n t products and processes to meet major needs of a g r i c u l t u r e and food i n developed and developing countries. The needs are increased production e f f i c i e n c y , increased value-in-use of animal and plant food products, and new a g r i c u l t u r a l products f o r major non-food markets. These innovations are expected to come from the new biotechnology. Biotechnology has been used i n a g r i c u l t u r e f o r centuries. T r a d i t i o n a l biotechnology used genetic engineering a t the organismal l e v e l with s e l e c t i o n and breeding as the key techniques. The new biotechnology enables genetic engineering at the c e l l u l a r and molecular l e v e l . This new biotechnology w i l l be

0097-6156/88/0362-0312S06.00/0 © 1988 American Chemical Society

In The Impact of Chemistry on Biotechnology; Phillips, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.


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the focus of my comments. These new biotechnology products and processes are expected to have s i g n i f i c a n t impact on a g r i c u l t u r e i n the 1990's and beyond. Surveys of informed public- and privatesector researchers and farmers suggest that the new biotechnology i s expected to be the major source of innovation by the beginning of the t w e n t y - f i r s t century. Biotechnology products and processes w i l l include chemicals, diagnostics, microbes, seeds, and animals. Examples of major a n t i c i p a t e d products are s e l f n i t r o g e n - f e r t i l i z i n g crops that would eliminate the need f o r the $20 b i l l i o n annual worldwide expenditure for f e r t i l i z e r nitrogen and genetically-engineered meat-producing animals with major improvements i n e f f i c i e n c y of production and i n dietary q u a l i t y of the meat. These advances i n science and technology are being driven by the t r a d i t i o n a l a g r i c u l t u r a l research l a b o r a t o r i e s but to a much greater extent by a few p r i v a t e u n i v e r s i t i e s , research i n s t i t u t e s , and a major investment by established and development-stage companies focused on generating the science and technology and converting i t to u s e f u l products and processes. Bioscience. Biotechnology and Related Advances f o r A g r i c u l t u r e and Food Several key advances w i l l be h i g h l i g h t e d below. C o l l e c t i v e l y , they document the strength of the growing base of relevant knowledge and r e l a t e d p o l i c y f o r biotechnology products and processes. The knowledge base i n a g r i c u l t u r a l science t r a i l s , to a major extent, that i n human health science and explains why the i n i t i a l impact of the new biotechnology on a g r i c u l t u r e w i l l t r a i l that i n human health care. Nitrogen F i x a t i o n . The best-understood gene system of a g r i c u l t u r a l s i g n i f i c a n c e i s n i f , the n i t r o g e n - f i x a t i o n complex. These seventeen genes have been characterized, and t h e i r r e g u l a t i o n i s understood so as to enable t h e i r r e s t r u c t u r i n g f o r increased a c t i v i t y . Genes involved i n the symbiotic r e l a t i o n s h i p between legume plants and r h i z o b i a l b a c t e r i a are being i d e n t i f i e d . A recent advance i s the recognition that a plant flavone, l u t e o l i n , signals the expression of r h i z o b i a l genes f o r nodulation. Although the N 2 " f i x a t i o n system i s complex, several of the t e c h n i c a l hurdles have been crossed on the way to create n i t r o g e n - f i x i n g higher plants. The route i s defined f o r achieving t h i s major technical advance. Laboratory ^ - f i x i n g plants are expected now by the e a r l y 1990's, a much e a r l i e r date than projected a few years ago. M i c r o b i a l Pesticides. A v a r i e t y of formulations of Bacillus thuringiensis have been used f o r several years as p e s t i c i d e s . Molecular biotechnology i s enabling modification of Bacillus thuringiensis f o r improved e f f i c a c y . The t o x i n gene has been incorporated into Pseudomonas, a rhizosphere inhabitant, to enable protection against s o i l insects. I n addition, there are a large number of other known v i r a l and fungal pathogens of insects, diseases, and weeds. Molecular and c e l l u l a r biotechnology i s expected to generate u s e f u l products based on these other pathogens. One of the largest c o l l e c t i o n s of fungal pathogens f o r


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insects--about Institute.

IMPACT OF C H E M I S T R Y ON

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750 accessions-- i s located at the Boyce Thompson

C e l l Culture Regeneration and Somoclonal V a r i a t i o n . The number of d i f f e r e n t plants that can be regenerated from c e l l cultures i s increasing. Beyond the t r a d i t i o n a l tobacco, carrot, and other early examples, i t i s now possible to regenerate soybean and most recently r i c e as the f i r s t example of a major cereal crop. This l a t t e r success was f a c i l i t a t e d by Rockefeller-Foundation support focussed e x c l u s i v e l y on r i c e . I t i s expected w i t h i n the next few years that plant regeneration from c e l l cultures w i l l become standard p r a c t i c e f o r most crop plants. Plant c e l l s i n culture undergo a process c a l l e d somoclonal v a r i a t i o n which leads to greater expressed genetic d i v e r s i t y i n regenerated plants than i n the parental plant. Somoclonal v a r i a t i o n i s proving useful i n crops such as sugar cane and maybe wheat and potato. Genetic Engineering of Plants. P r i o r to 1983 i t was impossible to g e n e t i c a l l y engineer plants at the molecular l e v e l i n contrast to microbial and animal c a p a b i l i t i e s . Since that time various techniques have been used to engineer successfully a wide v a r i e t y of plants. These techniques include the use of Agrobacterium tumefaciens and i t s modified T^ plasmid i n dicotyledonous plants and electroporation and micro-injection of naked DNA i n various plants. Successful examples of plant genetic engineering include incorporation of single foreign genes to detoxify or r e s i s t selected a n t i b i o t i c s and herbicides. Herbicides to which plants have been g e n e t i c a l l y engineered with resistance include the o l d herbicide atrazine, the middle-aged herbicide glyphosate, and the new high potency herbicides, sulfonylureas and imidazolinones. In most cases a single-base change i n the DNA converts an enzyme from susceptible to r e s i s t a n t . The majority of g e n e t i c a l l y engineered plants to date are s i n g l e gene additions to provide resistance to t o x i c chemicals. More recently, disease and pest resistance are being molecularly engineered into plants. E a r l i e r t h i s year the gene f o r a coat p r o t e i n of tobacco mosaic v i r u s was incorporated into tomato and other plants with expression of protection against TMV by the engineered plant. In another case, a gene f o r the Bacillus thuringiensis t o x i n was incorporated into a tobacco plant enabling t h i s plant to r e s i s t c e r t a i n insect pests. A recent e x c i t i n g example i s the incorporation of the genes for b a c t e r i a l and f i r e f l y l u c i f e r a s e into higher plants. For b a c t e r i a l l u c i f e r a s e , t h i s i s the f i r s t example of the incorporation into a plant of two genes whose coordinate expression i s required f o r the formation of a functional enzyme, l u c i f e r a s e i n t h i s case. These plants with the l u c i f e r a s e gene emit l i g h t . This two-gene example suggests that more complex genes w i l l be engineered g e n e t i c a l l y into plants i n the near future. Monoclonal Antibodies and DNA Probes. DNA probes and monoclonal antibodies are proving useful f o r diagnosis of disease i n plants and animals. DNA probes are also useful f o r l a t e n t v i r a l disease and are being used commercially w i t h i n the l a s t year f o r


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i d e n t i f i c a t i o n of c e r t a i n human diseases, food contaminants, and i n f e c t i o u s b a c t e r i a associated with periodontal disease. I n addition, one of the early products i n animal biotechnology was a monoclonal product named Genecol 99 f o r reduction of scours i n newborn calves. M i c r o b i a l Production of Animal Products. Advances i n biotechnology f o r human health have provided the basis f o r m i c r o b i a l products f o r the animal industry. These products include vaccines, lymphokines, and hormones. Lymphokines such as i n t e r f e r o n have been produced i n microbes and may be u s e f u l i n animal health. Bovine growth hormone produced by microbes s i g n i f i c a n t l y increases milk production per animal and production e f f i c i e n c y ; porcine growth hormone increases the rate of gain by swine, decreases the amount of feed needed f o r a pound of gain, and increases s u b s t a n t i a l l y the leanness of pork. M i c r o b i a l vaccines have been produced f o r foot and mouth disease as w e l l as f o r pseudo rabies and other viruses. A synthetic subunit vaccine f o r foot and mouth disease has been constructed using two separate but small parts of the v i r u s gene, an example of how biotechnology knowledge w i l l d i r e c t chemical synthesis. Genetic Engineering of Animals. I n 1981 f u n c t i o n a l f o r e i g n genes were f i r s t incorporated into animal embryos. The most dramatic example of transgenic engineering i n animals was the 1983 introduction of m u l t i p l e copies of growth hormone into rodent embryos. The r e s u l t a n t rodents grew up to double the s i z e of t h e i r l i t t e r mates who d i d not have the a d d i t i o n a l growth hormone genes. S i m i l a r covers i n the early 1980's of Nature and Science. showing transgenic super rodents, are the most v i s u a l representations of the power of biotechnology. Much experimental work has sought to extend these rodent experiments to domestic animals with no successful report to date. However, one expects molecular genetic engineering of domestic animals to succeed and thereby improve health, e f f i c i e n c y of production, and value-in-use of animals. Reproduction Technology. S i g n i f i c a n t advances have occurred over the l a s t decade i n reproductive technology. Embryo transfer has become commercial enabling major increases i n progeny of g e n e t i c a l l y superior females through the use of superovulation and transfer of f e r t i l i z e d embryos to surrogate mothers. In vitro f e r t i l i z a t i o n i s another u s e f u l technique. Advances have also occurred i n sperm sexing to enable production of the economicallydesired animal sex. Genetically-Engineered Yeast. I n d u s t r i a l yeasts are involved i n the production of many beverages, foods, and some i n d u s t r i a l products. These products include cheese, bread, beer, wine, s p i r i t s , and i n d u s t r i a l alcohol. Molecular genetic engineering techniques have been developed i n recent years to enable the engineering of i n d u s t r i a l yeasts. One example i s the engineering of these m u l t i - p l o i d y yeasts f o r the production of l i g h t beer--beer with reduced c a l o r i e s by reduction i n r e s i d u a l starch. Normal yeasts are unable to completely convert starch to alcohol because of t h e i r i n a b i l i t y to degrade the starch beyond i t s branch points. A debranching-enzyme gene has been engineered into the i n d u s t r i a l


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yeast so that i t can completely convert starch to alcohol, r e s u l t i n g i n the production i n a single n a t u r a l step of l i g h t beer. In another case, an i n d u s t r i a l yeast has been g e n e t i c a l l y engineered with the incorporation of a gene to enable lactose u t i l i z a t i o n , a by-product of cheese manufacture, i n the production of high concentrations of ethanol, eliminating a p o t e n t i a l p o l l u t a n t and producing a u s e f u l source of energy. Other genes could be incorporated into i n d u s t r i a l yeasts to improve the e f f i c i e n c i e s of manufacture of cheese, bread, wine, and s p i r i t s and to make other u s e f u l products. Designed Genes. P r i o r to the early 1980's mutagenesis of genes was a random, unpredictable procedure using chemical mutagens or r a d i a t i o n . In the early 1980's genes were f i r s t mutagenized i n a directed manner by a process c a l l e d s i t e - s p e c i f i c mutagenesis (SSM), an a p p l i c a t i o n of chemistry to biotechnology. One of the e a r l i e s t demonstrations of SSM was the change of a gene f o r the p e n i c i l l i n - i n a c t i v a t i n g enzyme, β-lactamase--a serine at the active s i t e was replaced by a cysteine. The product of the designed gene was a thio-β-lactamase, a novel enzyme with a c t i v i t y a l t e r e d from the n a t u r a l β-lactamase. Since that time, s i t e - s p e c i f i c mutagenesis has become a major chemical-biotechnology a c t i v i t y . This SSM technique i s expected to design genes i n a d i r e c t e d way so that t h e i r products are more u s e f u l f o r production of crops, animals, foods, or other areas. One opportunity f o r major impact on a g r i c u l t u r e from s i t e - s p e c i f i c mutagenesis i s the redesign of the carbon d i o x i d e - f i x i n g enzyme, the most abundant enzyme i n nature, to eliminate i t s wasteful oxygenase a c t i v i t y and increase i t s u s e f u l carboxylase a c t i v i t y . The outcome could be a doubling i n the y i e l d of most crop plants with minimal a d d i t i o n a l input. Regulation of Gene Expression. Introduced genes must be expressed at the appropriate time to be e f f e c t i v e . Understanding of the regulation of gene expression i s c r i t i c a l . Recent work has i d e n t i f i e d genetic elements involved i n l i g h t r e g u l a t i o n of gene expression. In addition, studies of so-called s i g n a l sequences associated with chromosomal genes whose products are transported e i t h e r outside the c e l l or to organelles w i t h i n the c e l l have advanced. Chemical Agriregulators. Genes are expressed at defined times during the growth and development of an organism. As the knowledge of the r e g u l a t i o n of gene expression advances, i t i s expected that synthetic chemical molecules w i l l be designed f o r r e g u l a t i o n of gene expression. These agriregulators w i l l cause expression of plant protectants at the desired time, control of growth and development, and a l t e r a t i o n of the composition of the harvested product as a few examples. Herein l i e s a major opportunity f o r future agrichemical products. Proprietariness. In 1980 a Supreme Court a c t i o n extended the patent act to include a novel, l i v i n g organism--a microbe that digested o i l . L i f e forms were no longer denied patent protection. In 1986 a novel seed containing an elevated tryptophane l e v e l was awarded a patent. This extension of patent proprietariness to a


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seed w i l l encourage commercial investment i n the development of improved p l a n t s . Similar extensions may be a n t i c i p a t e d f o r engineered domesticated animals. Regulation and F i e l d Testing. In the 1970's there was a major concern that recombinant DNA, the basic process f o r molecular genetic engineering, might lead i n the laboratory to unsafe products. This fear has not been substantiated, and i n f a c t , the r i s k to the health of humans has been n e g l i g i b l e to zero from the products of recombinant DNA. In the 1980's a major concern has been expressed about deliberate release or i n t r o d u c t i o n of molecularly g e n e t i c a l l y engineered organisms into the environment. In a g r i c u l t u r e , f i e l d research i s a necessary and normal extension of laboratory research. On June 26, 1986 the Federal Register announced the f i r s t regulatory steps f o r a g r i c u l t u r a l products. Emphasis was placed on product r i s k / b e n e f i t rather than on process representing s i g n i f i c a n t progress over an e a r l i e r proposal. An excessively cautious approach and an unwillingness to recognize the centuries of successful and safe a g r i c u l t u r a l experience with t r a d i t i o n a l biotechnology has produced major delays i n f i e l d research on organisms and processes produced by molecular genetic engineering. To date a dead genetically-engineered Bacillus thuringiensis, three genetically-engineered tobaccos, and some animal vaccines have been f i e l d evaluated. A l l agree that product not process should be assessed f o r r i s k . Yet i n the current U.S. regulatory environment, a product made by the process of recombinant DNA i s subjected to much evaluation p r i o r to the i n i t i a l f i e l d t e s t while an equivalent product made by t r a d i t i o n a l or c e l l u l a r genetic engineering requires no such evaluation. Such i l l o g i c a l thinking i s constraining and, to some extent, constipating f i e l d research with biotechnology products and processes produced by molecular genetic engineering techniques. Already at l e a s t one t e s t of an a g r i c u l t u r a l product has been done with approval outside the country ( i n New Zealand) p o s s i b l y because of the u n r e a l i s t i c U.S. regulatory p o l i c y . Bioproducts and Bioprocesses f o r Food and A g r i c u l t u r e I t i s very early i n the development of products and processes from the new biotechnology f o r commercial use i n a g r i c u l t u r e and food. World sales of such products are probably not more than $100 m i l l i o n i n 1986. Conservative projections suggest that they might be $5 to $10 b i l l i o n by the turn of the century with considerable growth thereafter. These products and processes are expected to s i g n i f i c a n t l y lower u n i t costs of production of commodity crops and animals. In addition, they are expected to provide s i g n i f i c a n t a d d i t i o n a l value-in-use to e x i s t i n g commodity a g r i c u l t u r a l products. An early example was the conversion by Canadian s c i e n t i s t s of rapeseed, an i n d u s t r i a l o i l seed crop, to canola, an edible o i l seed crop. This biotechnology conversion has made canola the major source of edible o i l i n Canada. Canola has j u s t been recognized as GRAS, generally recognized as safe, i n the U.S. C e l l u l a r and molecular biotechnology should provide many a d d i t i o n a l changes that w i l l increase the value-in-use of crops and


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animals. I n a d d i t i o n , the need f o r processing of animal and plant food may, i n part, be replaced by genetic changes i n the animal or crop to eliminate the need f o r some of these expensive chemical and engineering processes. Some examples of suggested products and processes w i l l be l i s t e d below. Products and Processes f o r Crop Production. Diagnostics w i l l enable the e a r l y detection of disease pests and r e s i s t a n t pests so as to provide more e f f e c t i v e crop protection. Diagnostics may also provide tools to i d e n t i f y crops with improved value-in-use. In addition, diagnostics may be used f o r f a c i l e i d e n t i f i c a t i o n of proprietary genetic material. R e s t r i c t i o n maps of genetic material are being evaluated f o r f i n g e r p r i n t proprietary b a c t e r i a l and crop material. M i c r o b i a l products w i l l become i n c r e a s i n g l y important i n insect and disease protection. Viruses, b a c t e r i a , and fungi are already being used i n various parts of the world f o r insect c o n t r o l . Genetically-engineered r h i z o b i a with improved nitrogen f i x a t i o n and y i e l d c a p a b i l i t i e s i n c e r t a i n legumes are expected to be i n f i e l d t r i a l i n 1987. Such improved r h i z o b i a are a n t i c i p a t e d to increase n u t r i e n t input and y i e l d of crops such as a l f a l f a and soybeans. Genetically-engineered microbes may also be u s e f u l i n post-harvest processing of crops such as s i l a g e making f o r improved n u t r i t i o n a l value of the s i l a g e . Undoubtedly, microbes w i l l become more important i n crop production, decreasing the need f o r chemical p e s t i c i d e and f e r t i l i z e r use. Genetically-engineered seeds w i l l be the major impact of the new biotechnology on crop production. In the near term, these seeds w i l l enable plants to r e s i s t or detoxify herbicides, thereby increasing the breadth of crops on which e f f e c t i v e and/or low-cost herbicides can be used as w e l l as enabling the farmer to rotate crops. The residues from previous herbicide treatments have constrained many such rotations i n recent times. Such herbicidesafe crops probably w i l l be the f i r s t generation of g e n e t i c a l l y engineered plants. Shortly thereafter, plants with disease resistance, e s p e c i a l l y f o r viruses and f o r i n s e c t s , should become a v a i l a b l e . I n a d d i t i o n to b i o t i c stresses, plants possessing resistance to a b i o t i c stresses are expected to be developed. One of the most c o s t l y inputs f o r crop production i s f e r t i l i z e r nitrogen. In the e a r l y 1990's plants g e n e t i c a l l y engineered to f i x t h e i r own nitrogen are expected to be developed i n the laboratory. Possibly before the turn of the century, s e l f n i t r o g e n - f e r t i l i z i n g crops would become i n i t i a l l y a v a i l a b l e f o r commercial use. Beyond these cost reductions, genetically-engineered plants with c a p a b i l i t i e s beyond those of present plants are expected. Such plants w i l l have t h e i r harvested parts modified i n quantity and/or q u a l i t y so as to more c l o s e l y match consumer needs. Herein l i e s one of the major opportunities of the new biotechnology f o r crop a g r i c u l t u r e and food. I n a d d i t i o n , e x i s t i n g or new crops w i l l be produced by biotechnology to provide materials u s e f u l f o r the non-food market. These may include i n d u s t r i a l chemicals, s p e c i a l t y chemicals, polymers, and other materials of use to society. A renewable competitive energy source may be the l a r g e s t impact of biotechnology on a g r i c u l t u r e enabling the use of our excess crop


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production capacity beyond that needed for food to be used to meet some of our non-food needs. Chemicals w i l l be designed based on knowledge generated by the new biotechnology. These biodesigned chemicals w i l l prove useful as agriregulators for the crop production process and may represent the future role of the agrichemical industry. Animal Biotechnology Products and Processes. Diagnostics and vaccines f o r improved animal health care are already being developed and to a l i m i t e d extent u t i l i z e d . Therapeutics based on natural b i o l o g i c a l molecules, such as the lymphokine interferon, w i l l improve animal health. Diseases are estimated to reduce U.S. livestock and poultry productivity by at least 20% annually, an estimated economic loss of $14 b i l l i o n per year. Biotechnology products should greatly decrease these s i g n i f i c a n t losses due to disease. Food additives w i l l improve the e f f i c i e n c y of animal production. Molecules based on natural b i o l o g i c a l products w i l l decrease the need for synthetic chemical feed additives and the attendant consumer concern with such products. The p o t e n t i a l for growth hormones i n milk and pork production are the e a r l i e s t such examples. I t i s interesting to note that supplemental ovine growth hormone i s not expected to be of major significance i n poultry production. The intensive poultry-breeding programs i n recent decades u t i l i z i n g t r a d i t i o n a l or organismal genetic engineering may have achieved the same r e s u l t over a long period of time, as now possible with molecular genetic engineering over a short period of time. Some of these bioregulator molecules w i l l improve the quality of the food product such as the indicated reduced f a t content of pork produced by porcine growth hormone. In the longer term animals modified by genetic engineering w i l l have a complem*^* of genes to minimize disease loss and maximize e f f i c i e n c y of production and quality of the product.

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Food Biotechnology Products and Processes. Research and development work on food products and processes i s less advanced than that i n the plant and animal area. For the most part, research to decrease process costs i s j u s t beginning. Undoubtedly, biotechnology w i l l enable improvement i n important consumer and health associated aspects of food. These may include longer shelf l i f e , improved appearance, improved flavor, and increased perceived healthfulness of the food among others. The light-beer example noted e a r l i e r i s one of the few completed products or processes i n the food area. Summary The progress made i n b i o l o g i c a l science and technology during the l a s t f i v e years has been impressive, providing a strong base for new biotechnology products and processes for agriculture and food. This science and technology base i s much more advanced than most recognize. The next major impact of biotechnology, a f t e r that i n i t i a l l y already being f e l t i n human health diagnostics and therapeutics, w i l l be i n the a g r i c u l t u r a l and food area. RECEIVED

September 3, 1987


Biotechnology for Agriculture and Food in the Future - ACS Publications

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