Chapter 1
`
`Foods and Food Ingredients Produced
`via Recombinant DNA Techniques
`An Overview
`
`Karl-Heinz Engel1, Gary R. Takeoka2, and Roy Teranishi2
`
`1Federal Institute for Health Protection of Consumers and Veterinary
`Medicine, Postfach 330013, D-14191 Berlin, Germany
`2Western Regional Research Center, Agricultural Research Service,
`U.S. Department of Agriculture, 800 Buchanan Street, Albany, CA 94710
`
`Commercial products resulting from recombinant DNA techniques
`in agricultural biotechnology have just entered or are about to enter
`the market. Some of the progress in improving nutrition and
`acceptability of foods as well as improving herbicide, insect, and
`virus resistance of plants are discussed. Enzymes and micro(cid:173)
`organisms can now be more precisely altered to optimize their roles
`in food production. Genetic modification of animals is much more
`complex than that of microorganisms and plants, nevertheless, some
`interesting progress is being made. The applications of genetic
`engineering in food production are evoking positive and negative
`reactions. The concepts presently being developed to assess the
`safety of foods derived from modem biotechnology are outlined.
`The aspects involved in creating a framework for regulatory
`oversight on genetically modified foods are also discussed.
`
`The use of microorganisms in the production of foods and beverages, such as
`bread, cheese, wine, or beer has a Jong tradition dating back to ancient days.
`Industrial biotechnology has its roots in the classical production of fermented
`foods. Therefore, it is a logical consequence that the application of the so-called
`"modem biotechnology" does not remain limited to areas such as medicine and
`pharmaceuticals but is increasingly applied in the production of foods and food
`ingredients. Developments in genetic engineering have created new dimensions
`in classical biotechnology. By using recombinant DNA techniques, it has become
`possible to direct the movements of specific and useful segments of genetic
`material between unrelated organisms, thereby crossing the barriers between
`plants, animals, and microorganisms. The scope of "modem biotechnology" goes
`beyond the traditional area of food fermentation processes. It is now possible to
`make specific genetic modifications in plants and animals that introduce traits or
`substances that could not be introduced by traditional methods.
`
`0097--6156/95/0605-0001$12.00/0
`© 1995 American Chemical Society
`
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` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 1 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`2
`
`GENETICALLY MODIFIED FOODS
`
`After fascinating developments in recent years on the level of basic
`the applications of recombinant DNA techniques in agricultural
`research,
`biotechnology are now heading towards attractive businesses. Commercial
`products have just entered or are about to enter the market. The spectrum of
`applications is comprised of genetically modified crops, foods produced from
`genetically modified microorganisms, as well as food ingredients/additives
`obtained from genetically modified organisms.
`
`Plants
`
`The enormous advances in genetic engineering of plants are due to progress
`in both cellular and molecular biology. The first practical technique for
`introduction of genetic material into plants was based on the use of vectors from
`Agrobacterium tumefaciens. Due to the narrow host range of this soil bacterium,
`the scope of the method had been limited to dicotyledonous plants. The progress
`in cell biology enabling the recovery of intact and fertile plants from single cell
`and protoplast cultures stimulated research activities in the area of direct DNA
`transfer. Because it is possible to introduce foreign DNA into protoplasts after
`electroporation or polyethyleneglycol treatment, the range of plants accessible to
`genetic engineering was increased significantly. A further decisive breakthrough
`the development of the biolistics approach
`involving
`was achieved by
`bombardment of the plant tissue with DNA-coated metal particles.
`It is now
`possible to engineer almost all important legumes and cereals (1-5).
`Genetic engineering offers the possibility not only to add new traits to an
`organism but also to down-regulate the activities of specific endogenous genes.
`A versatile and useful method for such a blocking of decisive steps in metabolic
`pathways is the so-called "antisense technique" (6). The methodology is based on
`the introduction of an oligonucleotide which is transcribed into messenger-RNA
`(m-RNA) consisting of sequences complementary to them-DNA produced through
`the transcription of the endogenous target gene. Due to the interaction
`(hybridization) of "sense" and "antisense" RNA,
`the
`translation of the
`corresponding enzyme is strongly reduced. The first genetically modified crop
`approved for food use, the Flavr-Savr™ tomato, is a prominent example of the
`commercial exploitation of the "antisense" technology (7).
`Analogous to the goals of conventional breeding programs, recombinant
`DNA techniques are applied to improve (i) agronomic characteristics of crops,
`such as yield and resistance to diseases and pests, (ii) processing parameters, e.g.,
`optimum solids levels or increased shelf life, and (iii) food quality, including
`factors such as aroma, taste, and nutritional value. Currently, the majority of
`commercial applications of plant genetic engineering aim at increasing the yield
`of food crops by influencing their tolerances to specific herbicides and their
`resistance to insects and diseases.
`
`Herbicide tolerance. One of the agronomically and commercially
`important applications, and at the same time an application of genetic engineering
`strongly opposed by consumer advocates, is the attempt to increase crop yields by
`increasing the tolerance of plants to particular herbicides. Strategies applied to
`achieve this goal demonstrate the diversity of tools offered by recombinant DNA
`
` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 2 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`1. ENGEL ET AL.
`
`Foods Produced via Recombinant DNA Techniques
`
`3
`
`techniques: (i) increasing the level of the target enzyme for the herbicide by
`overexpression, (ii) decreasing the sensitivity of the target enzyme by introducing
`a gene coding for an enzyme resistant to the herbicide either naturally (from a
`microbial source) or through specific mutation, and (iii) introducing a gene
`encoding an enzyme metabolizing and thus detoxifying the herbicide (8, 9).
`Soybeans
`tolerant
`to
`the herbicide glyphosate, oilseed rape
`tolerant
`to
`phosphinotricin, and cotton exhibiting tolerance to bromoxynil are examples of
`genetically modified crops presently entering the market (3, 10).
`
`Insect resistance. The use of the bacterium Bacillus thuringiensis (B.t.)
`to control plant insect pests has long been known (11). The insecticidal properties
`are due to the biosynthesis of different toxic crystal proteins. These pro-toxins are
`proteolytically cleaved in the midgut of the insects, bind to specific membrane
`receptors and finally lead to the death of the insect. The different strains of B. t.
`produce specific toxins differing in their activity against various classes of insects,
`such as the larval stages of Lepidoptera (moths and butterflies), Diptera (flies),
`and Coleoptera (beetles). By means of recombinant DNA techniques it is possible
`to create plants expressing the B.t. 6-endotoxins, thus making them resistant to
`insect damage. This concept has been applied successfully in commercially
`important crops, such as cotton, potato, tomato, and com (3).
`
`Virus resistance. Agronomically important results have been achieved by
`creating plants resistant to viral infections. The most successful approach, the coat
`protein mediated protection, is based on the long known observation that infection
`of a plant with a mild strain of a virus protected it from subsequent infection of
`a more virulent strain. By means of recombinant DNA techniques it has been
`possible to express the viral coat protein in plants, thus protecting them against
`viral diseases. From the first demonstration that the expression of the coat protein
`gene of the tobacco mosaic virus in tobacco conferred resistance to infection by
`this virus (12), this approach has been successfully applied in a wide spectrum of
`plant species (13).
`Plants can also be genetically engineered to express proteins which increase
`their resistance to attacks by fungi or bacteria (14). The increasing understanding
`of the molecular basis for the phenomenon of "systemic acquired resistance" (15)
`offers promising applications of recombinant DNA techniques. The strategy
`involving the expression of bactericidal enzymes from heterologous sources in
`plants is exemplified by the bacteriophage T4 encoded lysozyme reported to give
`rise to increased resistance of potatoes to Erwinia carotovora (16). Transgenic
`tobacco expressing a stilbene synthase from peanut was more resistant to infections
`of Botrytis cinerea (17).
`
`Food Quality. Texture, taste, and aroma belong to the major criteria
`determining the acceptance of a food by consumers. For tomatoes recombinant
`DNA techniques have proven to be suitable to improve these important attributes.
`By introducing either the "antisense" (7) or a truncated "sense" (18) polygalac(cid:173)
`turonase gene, the biosynthesis of this cell wall enzyme, responsible for the
`In terms of processing
`breakdown of pectin during ripening, is slowed down.
`
` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 3 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`4
`
`GENETICALLY MODIFIED FOODS
`
`characteristics, this results in optimum solids levels and viscosity. The reduced
`softening process can also be used either to increase the shelf life of the tomato
`or to improve its flavor properties by allowing the fruit to remain longer on the
`vine.
`
`The other approach applied to improve the flavor characteristics of
`tomatoes is to interfere directly with the metabolism of ethylene, the compound
`which triggers fruit ripening and aroma formation. By applying the "antisense"
`technology it is possible to inhibit either the 1-amino-cyclopropane-1-carboxylate
`(ACC) synthase, the rate-limiting enzyme in the biosynthetic pathway of ethylene
`(19) or the ACC oxidase, the enzyme involved in the conversion of ACC to
`ethylene (20).
`Potential future strategies to influence flavor properties of a plant have been
`demonstrated by results of the genetic transformation of a scented Pelargonium
`species, referred to as "lemon geranium".
`Transformation by means of
`Agrobacterium rhizogenes increased the production of essential oil and significantly
`changed the distribution of monoterpene alcohols (21).
`
`Nutritional Quality. An area which will attract increasing attention in the
`near future is the improvement of the nutritional value of foods by means of
`recombinant DNA techniques. Pioneering examples for changing content and
`composition of the macronutrients (fats, protein and carbohydrates) have already
`been described. The direction of fatty acid biosyntheses in favor of medium-chain
`fatty acids can be achieved by expression of a 12:0-acyl-carrier protein
`Increasing the level of sulfur(cid:173)
`thioesterase in transgenic oilseed plants (22).
`containing amino acids in soybean by introducing a gene from Brazil nut
`exemplifies the strategy to improve the balance of essential amino acids in
`important crops (23). However, this project also demonstrates potential limits,
`such as the influence of the genetic modification on the allergenicity of the host
`plant (24). The modification of carbohydrate metabolism by recombinant DNA
`techniques has been demonstrated for starch in potatoes. The composition of this
`biopolymer, i.e. the ratio of amylose to amylopectin, as well as its amount in the
`tubers can be influenced (25,26).
`Plants are increasingly being considered as "bioreactors" for production of
`industrially or pharmacologically important substances, such as proteins (27).
`Compared to microorganisms the eukaryotic plant cells offer the advantage that
`the post-translational processing necessary for many valuable proteins can be
`accomplished. Correctly processed human st;rum albumin could be obtained from
`transgenic potatoes (28).
`
`Microorganisms
`Microorganisms have played an important role in food production for
`millennia. The transition from the empirical use of microorganisms to an
`understanding of the underlying scientific principles was initiated by the pioneering
`discoveries of Pasteur in the middle of the last century. With the increase of
`knowledge there have always been attempts to optimize and standardize the
`microorganisms used in order to meet the requirements of food production. The
`modem food industry can make use of a spectrum of well-defined "starter-
`
` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 4 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`1. ENGEL ET AL.
`
`Foods Produced via Recombinant DNA Techniqlll!s
`
`5
`
`cultures" for the production of fermented foods (29). They are the result of
`mutagenesis and selection techniques based on classical bacteriological and genetic
`methods. By means of genetic engineering, the properties of microorganisms can
`be changed more precisely (30). Major goals are optimization of the production
`process, improvement of product quality, and safety (hygienic status), and
`enlargement of product diversity.
`Strategies applied are based on (i) increasing the copy number of the gene
`of interest, (ii) coupling genes with strong promoters or other regulatory
`sequences, and (iii) expressing genes from other sources in microorganisms which
`are safe for use in food production (GRAS) and which are easily handled under
`commercial fermentation conditions. There is a broad array of recombinant
`microorganisms available for industrial and agricultural applications (31).
`Because of its importance both as a model organism in basic research and
`as a production microorganism in the baking and brewing industry, the yeast
`Saccharomyces cerevisiae has attracted considerable attention among molecular
`biologists (32, 33).
`In the United Kingdom genetically modified baker's yeast
`with increased activities of maltase and maltosepermease (34) and a genetically
`modified amylolytic brewer's yeast (35) have been reviewed for food use.
`Lactic acid bacteria play an outstanding role in food fermentation (36).
`Accordingly, many examples for their genetic engineering have been reported (37,
`38). The construction of safe, so-called "food-grade", vectors has been especially
`and extensively studied with these microorganisms (39).
`
`Enzymes
`For many important processes in food production, enzymes rather than
`intact microorganisms are employed. These biocatalysts possess outstanding
`properties, such as substrate specificity, regioselectivity, and enantioselectivity.
`In particular hydrolases which do not require coenzyme regeneration are
`increasingly being used commercially. Amylases, pectinases or cellulases are
`applied in the starch and baking industry as well as in fruit juice production.
`Lipases are employed to modify the properties of triglycerides by hydrolysis,
`esterification, and interesterification (40).
`Enzymes are isolated from animal, plant, and microbial sources. Pure
`culture fermentations of selected strains of microorganisms are used to obtain
`enzyme preparations at industrial scale. Genetic engineering offers the possibility
`to increase the yield of the desired enzyme by introducing multiple copies of the
`corresponding gene into the production organism or by influencing the regulatory
`sequences. A major strategy is to introduce the gene encoding the enzyme in safe
`and efficient microorganisms. Yeasts have been proven to be ideal expression
`systems for heterologous proteins (41).
`One of the most prominent and pioneering examples for an enzyme
`obtained from genetically modified microorganisms is the milk-clotting protease,
`chymosin, the first food ingredient produced via recombinant DNA techniques
`which has been cleared for food use (42).
`In the future, applications of recombinant DNA techniques will not be
`limited to the production of enzymes, which are structurally and functionally
`identical to their traditional counterparts. Increasing emphasis will be placed on
`
` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 5 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`6
`
`GENETICALLY MODIFIED FOODS
`
`"protein engineering". This allows for the change of the DNA sequence and
`subsequently the corresponding amino acid at specific positions, thus designing
`enzymes with new and optimized properties. Adaptation of enzymes to specific
`conditions, such as pH and temperature, becomes possible. The use of designed
`proteases and lipases in the detergent industry indicates the future potential of this
`strategy in food production.
`
`Food Ingredients
`Biotechnological fermentation and biotransformation processes have been
`used for the production of food ingredients, such as vitamins, amino acids, organic
`acids, or sweeteners (43, 44). By using the strategies described above for the
`production of enzymes, recombinant DNA techniques can be applied in order to
`increase the yield and to improve the recovery and the purification of single
`compounds from fermentation broths (45).
`Because of consumers' demand for "natural" flavor, there has been
`increasing application of biotechnological methods such as fermentations and
`biotransformations of corresponding precursors in the production of flavor
`compounds in recent years (46, 47). Therefore, flavor compounds are ideal
`examples for food ingredients being suitable for the application of recombinant
`DNA techniques in the course of the production process.
`
`Animals
`The commercial use of recombinant bovine somatotropin (rBST), a growth
`hormone produced from a genetically modified microorganism, is an example for
`the indirect application of recombinant DNA techniques
`in farm animal
`production.
`In contrast to the progress achieved in genetic engineering of
`microorganisms and plants, direct application resulting in transgenic animals will
`require more years before it reaches the stage of commercialization. Genetic
`modification of animals is a much more complex task than that of microorganisms
`or plants (48). Goals of genetic engineering of animals focus on improved growth
`and on increased resistance to specific diseases (49). Most of the progress has
`been made with transgenic fish because the efficiency of integration of DNA into
`fish is much higher than for mammals (50, 51). Goals such as increased
`production efficiency and improved growth rate have been achieved by introducing
`mammalian and fish growth hormone genes. The transfer of the antifreeze protein
`gene from winter flounder to salmon is an example of improving the tolerance of
`abiotic stresses.
`A promising field is the so-called "gene farming", the production of
`pharmaceutically or nutritionally important proteins in the mammary glands of
`transgenic animals (52).
`
`Safety ASRSSment
`The outstanding and fast development of genetic engineering and the
`accelerating transition from basic research to commercial applications provoke
`both enthusiastic and very strong negative reactions. Today, it is acceptable to
`life-saving pharmaceuticals by means of genetically modified
`produce
`microoganisms. However, the application of this technology in the production of
`foods is still the subject of controversial discussion.
`
` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 6 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`1. ENGEL ET AL.
`
`Foods Produced via Recombinant DNA Techniques
`
`7
`
`The issues being raised can be divided into three major categories: (i) the
`fact that this technique touches the fundamentals of life by changing the genetic
`infonnation of organisms provokes ethical concerns; (ii) the release of viable
`genetically modified organisms into the environment raises e~logical issues; (iii)
`concerns are expressed whether unexpected or unintentional effects will occur as
`a result of the genetic modification of crops or microorganisms and whether new
`substances introduced into food will be safe.
`National and international organizations are involved in establishing
`principles for safety evaluations of foods and food ingredients produced via
`recombinant DNA techniques. The concept of "substantial equivalence" as
`developed by the OECD (53) is widely agreed upon. It involves the comparison
`of a food or food ingredient developed by modern biotechnology to its traditional
`counterpart. If substantial equivalence can be established, the new food or food
`component can be treated in a similar manner with respect to safety (54).
`Current evaluation procedures of genetically modified foods and food
`ingredients pay particular attention to the safety implications of (i) intentional
`changes, (ii) any unintentional changes arising from the genetic modification, (iii)
`the stability of the genetically modified organism under the intended conditions of
`use; and (iv) the likelihood of genetic transfer.
`There is a general consensus that the applicability of classical toxicological
`assessment procedures developed for single chemical substances, such as pesticides
`or food additives, is limited. Safety and wholesomeness studies with whole foods
`have to be carefully designed in order to avoid nutritional imbalances causing
`artifacts and uninterpretable results.
`Particular attention has been paid to the safety evaluation of marker genes
`and their respective expression products. Marker genes are needed to identify and
`select cells which have been successfully transfonned at an early stage of the
`genetic modification process. The most important ones are those conferring
`resistance to antibiotics and tolerance to herbicides, respectively (10). The safety
`assessment of the antibiotic resistance marker genes has been the subject of
`international organizations (10), and national
`investigations (55);
`detailed
`regulatory authorities (56) have discussed this issue.
`Another concern being raised is whether there is an increased potential for
`allergenicity of transgenic foods due to the transfer of new proteins. The above
`mentioned transfer of a gene from Brazil nut to soybean demonstrates that there
`are methods available to assess the allergenic potential of proteins derived from
`sources to which consumers have reacted and for which serum is available (24).
`However, at present the potential allergenicity of proteins that are derived from
`sources that are not recognized as allergens cannot be predicted.
`
`Regulatory Aspects
`There is a relatively broad consensus about the general scientific principles
`underlying the safety evaluation of foods and food ingredients produced via
`recombinant DNA techniques. However, the philosophies about regulatory
`oversight and the need for legislative restrictions vary in different countries.
`There are two major approaches: one is based on the assumption that the
`
` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 7 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`8
`
`GENETICALLY MODIFIED FOODS
`
`application of a certain technology, such as genetic engineering, bears the potential
`for specific risks and therefore requires a corresponding oversight; the second
`approach primarily focusses on the final product and its safety rather than on the
`technology applied. These philosophies are reflected in different regulatory
`frameworks set up around the world, and some of the world leaders discuss their
`regulatory policies in this book.
`
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` Engel et al.; Genetically Modified Foods
`
`ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
`
`Motif Exhibit 1013, Page 8 of 10
`
`Case No.: IPR2023-00322
`U.S. Patent No. 10,273,492
`
`

`

`1. ENGEL ET AL.
`
`Foods Produced via Recombinant DNA Techniques
`
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`