Commercial Biotechnology: An International Analysis (Part

Chapter 6

Agriculture

—-

Contents

PageIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161Animal Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162

Diagnosis, Prevention, and Control of Animal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 162Animal Nutrition and Growth Promotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167Genetic Improvement of Animal Breeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168Commercial Aspects of Biotechnology in Animal Agriculture . . . . . . . . . . . . . . . . . . . . . 169Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Plant Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172Improvement of Specific Plant Characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174Uses of Microorganisms for Crop Improvement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Commercial Aspects of Biotechnology in Plant Agriculture . . . . . . . . . . . . . . . . . . . . . . . 185

Priorities for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Animal Agriculture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Plant Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

TablesTable No. Page27. Viral Animal Diseases and Potential Vaccine Production . . . . . . . . . . . . . . . . . . . . . . . . 16428. World and U.S. Sales of Growth Promotants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16729.Global Animal Health Product Markets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17030.U.S.Producers of Animal Health Productsts . . . . . . .. .$..... ..., . . . . . . . . . . . . . . . . 17031. Sales of Major U.S. Animal Vaccine Products, 1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17132. Major Producers of Animal Vaccines Sold in the United States . . . . . . . . . . . . . . . . . . 17133. Plant Resistances of Economic Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17734.U.S. Soils With Environmental Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17735. Distribution of Insurance Indemnities From Crop Losses

in the United States From 1939 to 1978 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17736. Examples of Secondary Plant Products of Economic Value .....,... . . . . . . . . . . . . . 17937.Importance of Basic Research (Model Systems) on Nitrogen Fixation. . . . . . . . . . . . . . 183

Figure

Figure No. Page16.Steps To Create a New Variety of Plant by Using Biotechnology. . . . . . . . . . . . . . . . . 174

Chapter 6

Agriculture— . — —. —

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161

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162 ● Commercial Biotechnology: An International Analysis

Animal agriculture

The commercial use of biotechnology in animalagriculture is affected by several often-contra-dictory forces. Favorable forces include the exten-sive use of animals as test models in basic researchand, as is discussed in Chapter 15: Health, Safe-ty, and Environmental Regulation, less stringentregulatory approval processes for animal healthproducts than for pharmaceutical products in-tended for human use. Because animals are usedduring the development of pharmaceutical andbiologic products for humans, veterinary medi-cine stands to benefit from biotechnology re-search and development (R&D) such as that de-scribed in Chapter 5: Pharmaceuticals. Biotech-nologically made products for use in animal ag-riculture, such as MAb diagnostic products,growth hormones (GHs), and vaccines, are becom-ing available on a limited basis.

●

Among the factors that inhibit commercial ap-plications of biotechnology in animal agricultureis the fact that the low value-added nature of indi-vidual farm animals limits veterinary costs peranimal, veterinary medicine sales, and funding forveterinary R&D. In addition, some biotechnolog-ically made products do not suit current animalhusbandry practices. Commercialization of atleast one rDNA-made vaccine, the vaccine for foot-and-mouth disease (FMD), for example, awaitssuccessful applied research results to achieve pro-tection against several strains of the disease, few-er dosage requirements, lower costs, and otherimprovements that make the vaccine amenableto animal husbandry practices in the developingnations where FMD exists (20).

Biotechnological developments in the areasof animal disease control, animal nutrition andhealth, and genetic improvement of animal breedsare discussed further below. Distinctions betweenthe use of biotechnology to expand fundamentalknowledge and to develop specific products forcommercial use are noted.

Diagnosis, prevention, and controlof animal diseases

Losses due to animal diseases exceed hundredsof millions of dollars yearly in the United States, *giving strong impetus to efforts to improve animalhealth. A combination of the techniques of bio-technology is being used to better understandviral, bacterial, protozoan, and parasitic infectionsthat affect animal productivity throughout theworld, MAbs, for example, are being used as re-search tools to gain a better understanding of themolecular biology of animal diseases. MAbs mayalso be used for diagnosis of diseases, for monitor-ing the efficacy of drugs, and for providing short-term passive immunity against animal diseases.In addition, recombinant DNA technology andpolypeptide synthesis maybe used to develop vac-cines for long-term immunization against certainanimal diseases.

MONOCLINAL ANTIBODY DIAGNOSTIC PRODUCTS

The diagnosis of animal diseases can be accom-plished by the identification in the laboratory ofspecific antigens displayed by the infectious agent.As discussed in Chapter 3: The Technologies,MAbs that recognize specific antigens can be pre-pared readily. MAbs for several animal diseasesare now being made, and in vitro MAb diagnosticproducts for a number of animal diseases maybe used in the near future. MAb-based diagnostictests are currently being developed for blue-tongue, equine infectious anemia, and bovine leu -kosis virus. Furthermore, diagnostic MAbs are be-

● “Animal losses” are described by a number of parameters, in-cluding dollar value of animals lost, losses in productivity due tomorbidity, and value of potential progeny lost due to sickness ordeath of breeders. In this report, the dollar value of animals actu-ally lost to disease (as a primary cause of death) is used for the sakeof comparison in describing animal diseases. These estimates arebased on data collected for U.S. Department of Agriculture’s Ani-mal and Plant Health Inspection Service, Veterinary Services, Hyatts-ville, Md., and by Deane Agricultural Services, Inc., St. Louis, Mo.

Ch. 6—Agriculture ● 163

ing sought for canine parvovirus, canine rotavirus(a potentially fatal viral diarrhea in puppies), felineleukemia virus, and canine heartworm disease.For MAb diagnostic products to be effective diag-nostic tools and hence commercially viable, theymust recognize the large variety of disease strainslikely to be encountered (20).

The acceptance of iMAbs for field use by veter-inarians and animal owners remains to be dem-onstrated. Whether MAb products will have alarge role in the diagnosis of specific animaldiseases is unclear. Since livestock producers andpoultry growers attempt to spend as little moneyas possible per animal raised, the markets forindividual MAb diagnostic tests initially may belimited. Applications of MAb diagnostic as wellas therapeutic products initially may be restrictedto high-profit animals, animal products for export,and companion animals such as dogs, cats, andhorses. Although individual diagnostic kits are notcostly, the farmer’s narrow margin of return onother animals may prevent the routine use ofdiagnostic products.

In the future, diagnostic MAbs could substan-tially assist large-scale disease control programsin both developed and less developed countries(16). Such reagents might be used to detect diseasein order to select an appropriate vaccine and mon-itor the level of disease during the course of acontrol program.

Apart from potentially being used as diagnosticreagents by animal producers, MAbs can be usedas purification tools to isolate compounds (anti-gens) that may prove to be effective animal vac-cines. They can also be used to provide “passiveimmunity” to certain animal diseases. The applica-tions of biotechnology to the development of ani -mal vaccines

Preventionbeing soughtforts similar

is described further below.

ANIMAL VACCINES

of a number of animal diseases iswith rDNA subunit vaccines in ef -to human vaccine programs de-

scribed in Chapter 5: Pharmaceuticals. Subunitvaccines may solve some of the problems associ-ated with conventional vaccines. One problem,for example, is that “attenuated” and killed wholevaccines contain the genetic material of the path-ogen and therefore have the potential to cause

the infection they are supposed to prevent. Sub-unit vaccines do not contain the pathogen’s ge-netic material and therefore cannot cause infec-tion. Subunit vaccines may also be more stable,more easily stored, and of greater purity than con-ventional vaccines, but these qualities remain tobe demonstrated. Despite their potential advan-tages, subunit vaccines raise new technical prob-lems, as mentioned above, and these must beovercome if the vaccines are to prove useful inthe field (20).

Viral Animal Diseases. —The developmentof improved vaccines may allow the preventionof several problematic animal diseases caused byviruses (34). Most subunit vaccine research foranimals to date has been focused on viral diseases,particularly FMD and rabies, but some of the find-ings can be generalized to other viral diseases,Table 27 shows some viral diseases in animalsagainst which subunit vaccines may prove effec-tive and economic.

The development of subunit vaccines for FMDis currently receiving much attention from re-searchers (2). Although the disease is nonexistentin the United States, FMD affects livestock pro-ductivity and exportability throughout SouthAmerica, Africa, and the Far East. The world mar-ket for FMD vaccine is larger than that of anyother vaccine, either animal or human. In 1981,800 million doses of inactivated FMD virus vac-cine worth $250 million were used (36). Vaccinesfor all types of FMD commonly encountered ex-ist at present, but these vaccines vary in effec-tiveness against different FMD field strains. Evolu-tion of new field strains is a continuing problem,because a vaccine may lose its effectivenessagainst such strains. The impetus for developinga subunit vaccine for FMD is the hope that sucha vaccine will offer enhanced protection withgreater safety than conventional vaccines. Thedegree of protection offered, however, will onlybecome clear over the next few years as researchand field evaluations progress (9).

Three research groups have cloned the genethat codes for the major FMD viral surface pro-tein (5,14,15). The new biotechnology firm (NBF)*

“NBF”s, as defined in Chapter 4: Firms Commercializing Biotech-nology, are firms that have been started up specifically to capitalizeon new’ biotechnolo~v.

164 Commercial Biotechnology: An International Analysis

Table 27.—Viral Animal Diseases and Potential Vaccine Production

Potential Currentfor new vaccine

Disease biotechnology Company status

Viral diseases:Foot-and-mouth disease . . . . .

Rabies. . . . . . . . . . . . . . . . . . . . .

Parvovirus:Swine . . . . . . . . . . . . . . . . . . .Canine . . . . . . . . . . . . . . . . . .

Bovine Ieukosis virus . . . . . . . .Bovine papilloma virus . . . . . .Rift Valley fever . . . . . . . . . . . .

Marek’s disease (fowl) . . . . . . .Infectious bov ine

rhinotracheitis . . . . . . . . . . . .Pseudorabies. . . . . . . . . . . . . . .African swine fever . . . . . . . . .Rota viruses. . . . . . . . . . . . . . . .

Bluetongue . . . . . .

Hog cholera. . . . . .Newcastle disease

Bacterial diseases:Tuberculosis . . . . .Neonatal diarrhea .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

Bacterial respiratory disease .Anaplasmosis

Parasitic diseases:Babesiosis . . . . . . . . . . . . . . . . .Trypanosomiasis . . . . . . . . . . . .

Coccidiosis ., . . . . . . . . . . . . . .Helminithic diseases . . . . . . . .

+

+

+++++

+

+++—

+

—+

N.A.+

N.A.N.A.

++

++

Genentech (U. S. MJSDA (U. S.) MediumPirbright (U.’K.)Biotech Gen (Israel)MGI (U.S.)a

Wistar Transgene (France)Genentech (U. S.)Inst. Pasteur (France)

MGITechAmerica (U. S.)MGIMGIMG1/U.S. Department ofDefenseBRL (U.S.)C

MGIMGISpanish GovernmentVido InstituteUniversity of SaskatchewanBio-Tech Gen. (Israel)USDAN.A.USDA

N.A.Cetus (U. S.)/Norden (U. S.)InterVet (Netherlands/

Akza (U. S.)MGIN.A,N.A.

IMC (U.S.)d

American Cyanamid (U. S.)Genex (U. S.)Hoffmann-La Roche (Switz.)Eli Lilly (U. S.)Merck W. S.)

Variable

PoorMediumN.A.b

N.A.Good

Medium

MediumMediumNoneNone

Poor to medium

GoodPoor in some areas

NonePoor

PoorNone

NoneNone

GoodFair

Potent ia l fornew vaccine

Replacement

Replacement

ReplacementReplacementReplacementExport animalsReplacement

Replacement

ReplacementReplacementNew productNew product

Export animals

ReplacementReplacement

New productReplacement

ReplacementNew Product

ReplacementNew product

ReplacementReplacement

a MGl = Molecular Genetics, Incb N.A = Information not ava!lablec ~RL = Bethesda Research Laboratoriesd IMC = International Minerals & Chemicals Corp

SOURCE Board of Science and Technology for International Development, et al , “Prlorltles In Biotechnology Research for International Development—Proceedingsof a Workshop” (Washington, D C National Academy Press), and the Off Ice of Technology Assessment

Genentech Corp. (U.S.), in collaboration with theU.S. Department of Agriculture (USDA), clonedthe DNA that encodes the protein of one strain ofFXID into bacteria, made the protein product inlarge enough quantities for field trials, and testedit at USDA’s Plum Island Animal Disease Facility(14). The FMD subunit vaccine protected animalsagainst infection by the particular strain againstwhich the vaccine was made (although the field

trial was not extensive), but it was less effectivethan the whole inactivated vaccine. The two otherresearch groups working on a subunit FMD virusvaccine are a Swiss-West German team (Univer-sity of Heidelberg, Federal Research Institute forAnimal Virus Diseases at Tubingen, Max PlanckInstitute for Biochemistry, and Biogen S. A.) anda British team (Animal Virus Research Instituteand Wellcome Research Laboratories) (9).

C h . 6 — A g r i c u l t u r e . 7 6 5

Cloning of the genes that code for the surfaceproteins of viruses of fowl plague, influenza, ve-sicular stomatitis, herpes simplex, and rabies alsohas been achieved, and the cloned genes may leadto the development of effective subunit vaccinesfor these animal diseases (2). Cloning projects forvirus proteins that cause gastroenteritis, infec-tious bovine rhinotracheitis, Rift Valley fever, andparamyxovirus currently are underway (2), Dif-ferent challenges are associated with each proj-ect. Rabies projects, for example, have encoun-tered problems with the consistent expression ofthe surface protein from rDNA plasmids (34). In-fluenza virus projects, among others, face prob-lems in that the natural viruses spontaneouslychange their surface proteins to evade the im-mune system, making the choice of optimal genesfor cloning difficult.

Another method being used to prepare newsubunit vaccines for animals, aside from the useof rDNA technology, is chemical synthesis of pep-tides. Synthetic peptides corresponding to partof one viral surface protein of FMD protect testanimals against live FMD virus (3), and efforts areunderway to prepare synthetic rabies vaccines(28). As noted in Chapter 5: Pharmaceuficals, mostsynthetic vaccines are prepared with the use ofMAbs as purification tools, Chemically synthe-sized peptides ma-y prove useful in rapid screen-ing programs to determine which peptides act asthe best vaccines; subsequently, the DNA corre-sponding to these fragments may be cloned forlarge-scale production in microbial systems.

Whether produced from rDNA or chemical syn-thesis, subunit vaccines for viral animal diseasesmust satisfy several requirements to be effective.In most instances, subunit vaccines must containantigens from a sufficient number of differentstrains of virus to offer comprehensive protec-tion against field challenge. The new vaccinesmust induce a protective immune response to thesame or greater degree than conventional vac-cines if they are to compete for market shares.Proper dosage and timing of vaccination must bedetermined. Ideally, the vaccines should be ad-ministered in a single injection to be amenableto most husbandry practices throughout theworld where animals are dispersed over widetracts of land. Also, long shelf storage life and

stability when stored at room temperature aredesirable features of the new vaccines for use inall the countries affected by the particular dis-eases. *

In addition to subunit vaccines that provide ac-tive immunity, MAbs may be used to provide pas-sive immunity against a variety of viral animal dis-eases. Several MAb-based products currently arebeing developed. For instance, antirabies MAbsthat protect mice from active rabies virus havebeen made (19). The use of these products, how-ever, is likely to be limited to herds (e.g., dairyanimals) where the passive vaccines can be readilyand repeatedly administered.

Bacterial Animal Diseases.—The potentialfor biotechnology in fighting bacterial diseases inanimals is less clear than its potential in fightingviral diseases, but severaI promising advances arecurrently being made. In developing new methodsto prevent these diseases, an understanding of thenatural and pathogenic roles bacteria pIay in do-mestic animals is important. Numerous types ofbacteria are normal inhabitants of both humanand animal gut. In general, disease may resultwhen animals, especially those predisposed to in-fection (e.g., young, weak, or stressed animals),either succumb to pathogenic bacteria or sufferfrom overgrowths of their own native bacteria.Bacterial infections often occur simultaneouslywith other infections, including viral invasions.Because of the complexity of most of the currentlyimportant animal diseases in which bacteria areinvolved, the effectiveness of bacterial vaccinesproduced by biotechnology is difficult to predict.

Bacterial vaccines against colibacillosis (scours),a widespread disease that causes diarrhea, dehy-dration, and death in calves and piglets, are be-— . —

* ~lt p r e s e n t , the ral)ies sut)unit \LitxIn[I IS mosI }]r[)ll~isil]g III

meeting the criteriii for t) fw)ming a (umpetitii f> Ia(xInc ‘1’}NIIT ,ip -

pear to he onl) slight f’ariations in Sll[’tii(’(> ~)rott~in S(Y]U(JII(YS l) f~-

ttveen rabies t’irus strains, anci these surta(r prott>il)s eli(’it liir~(~i m m u n e r e s p o n s e s ‘1’h(’ RNA mroding s(w (>[iil \ ir.il surta(r pro-teins has been cloned and expressed In 1,, (’{)/1 (3-I ) (~llestlons tt)atremain concerning the efficaq of this \ ii(’(’lll(i il)(.l~](lf~ 1 J I ht’ ntv’(]

for gl~’ros~’lation of the rllNA-produ(. t tor pr(]f)[>l. flJII(.1 it)nil)g ISP(J

{’lldptel’ 5: P/]dl’rlI;](’fl( ltl(’ii/,Jj, iin(j Z) prop(>r ddifwy sj’stmns, pl’lllliiI’i-

I V to \\,ilc{ animal respr~oirs such as skunks and fox(’s, \th(lI-(l riil)](>~

proliferates, and to (lisp(~rse(l iininlitl hrr(ls surh ;is thos(” In !+]~lth.lmeri(:i, where thr (l(~iittl o f (iittl(~ infwted b~ the t)it(~s ot riil)i(i

I’;impir(’ I)ilt!l I’f>SUlt S in ill) t] Sti IlliitWi }’f~arll 10SS of morr t}lii[l $29. .

m i l l i o n (34)


ing made with biotechnology. Recombinant DNAtechnology is used to change bacterial plasmidsfound in pathogenic strains of enteric bacteriafrom a virulent to a harmless state. This approachis used by both Intervet (Netherlands) and CetusCorp. (U. S.) to prepare vaccines against colibacil-losis. These vaccines have been successfully testedin pregnant cows, which transferred immunityagainst colibacillosis to their offspring, and theproducts are now available commercially. *

Using another approach to fight colibacillosis,the NBF Molecular Genetics, Inc. (U. S.) uses hy -bridomas to produce MAbs against the attach-ment antigens of the bacteria responsible for thedisease. Incorporating these MAbs in milk fed toyoung calves within 36 hours of birth protectsthe animals through the period for which theyare most susceptible (36]. This product is ap-proved for use in the United States and Canada.

The development of biotechnological solutionsto bacterial animal diseases, as well as viral infec-tions, will require much basic research. Pasteurel-losis (a lower respiratory tract infection in cows,sheep, and pigs) and swine dysentery (whichcauses annual losses of $75 million in the UnitedStates) are among the major animal bacterial in-fections about which more knowledge is neededbefore applications of biotechnology are possible.The potential for biotechnological production ofnew bacterial vaccines and the development ofsuccessful delivery systems is largely unexplored.

protozoan and Paras i t i c In fec t ions o fAnimals. -Coccidiostats (compounds that pre-vent coccidiosis in poultry) and anthelmintics (sub-stances that fight helminthic parasites such asroundworms, tapeworms, lung worms, and liverflukes) constitute large, rapidly expanding animalhealth product markets. In 1985, the global mar-ket for coccidiostats is expected to be $500 million(compared to $300 million in 1981), and the globalmarket for anthelmintics may exceed $900 million

“These bacterial vaccines were made by replacing a “virulemx’gene” (a gene which encodes a protein that regulates cellular waterloss and is responsible for the diarrhea) located on a plasmid witha harmless gene and “infecting” animals with bacteria containingthese harmless plasmids. The bacteria continue to produce surfaceantigens, but they do not produce the \rirulence protein. The sur-face antigens stimulate an immune response that prm’ents adherenceof natural \’irulent harteria (18)

(compared to $450 million in 1981) (35). At pres-ent, coccidiostats and anthelmintics are synthe-sized by either chemical synthesis or microbialbioprocess methods. These agents, many of whichhave been discovered serendipitously, are com-monly administered in animal feed (10).

The widespread use of coccidiostats, anthelmin -tics, and antibacterial in animal feed raises con-cerns about the nurturing of drug resistanceamong populations of micro-organisms. Theserisks are outlined in a 1979 OTA report entitledDrugs in Livestock Feed (30). As described in thatreport, the genes in bacteria that encode resist-ance to most drugs are located on plasmids. Re-sistance to drugs may be shuttled via these plas-mids into pathogenic microa-oganisms such as Sal-monella. Widespread use of antibacterial selectsfor bacteria, including Salmonella, that containresistance genes, perpetuating drug resistanceamong bacteria. Thus, wide use of antibacterialin animal feed eventually may compromise theeffectiveness of the same drugs in treatment ofhuman diseases. Drug resistance among the pro-tozoa and parasites is even less well understoodthan is resistance among bacteria. Such resistanceis difficult to quantify but may be increasing(13,30).

Fundamental knowledge may be gained byusing rDNA technology to explore the structureand function of genes that confer resistance todrugs. MAb technology and other conventionalmethods may be used to isolate, purify, and bet-ter understand antigens found on parasitic cells,perhaps resulting in vaccines effective againstthese parasites. The increased use of vaccineswould decrease the use of feed additives and pre-sumably lessen the problems of drug resistance.

Strong needs, large market potentials, and safe-ty considerations characterize the further devel-opment of compounds effective against protozoaand parasites that afflict animal populations. Be-cause of the complexity of most parasitic infec-tions, however, biotechnological solutions maynot be forthcoming immediately. [n addition, therecent introduction of potent new antiparasiticfeed additive compounds, such as the avermec-tins (which are microbially produced) (8), maylower incentives to explore new antiparasiticpossibilities with biotechnology in the near term.

C h . 6 — A g r i c u l t u r e ● 1 6 7— .

one serious worldwide rickettsial disease thatrequires urgent attention is anaplasmosis. Ana -plasmosis, which is caused by blood-borne micro-organisms transmitted to cattle by ticks, causessevere anemia and subsequent death in afflictedanimals. In the United States, annual losses dueto anaplasmosis are estimated to exceed tens ofmillions of dollars. At present, an unsatisfactoryattenuated vaccine exists, and attempts to culturethe micro-organism and prepare better vaccineshave been only marginally effective (36).

Animal nutrition and growthpromotion

Practices and products that promote animal nu-trition and growth have the potential to producedirect, substantial returns on investments. Animalscientists seek better animal nutrition and feed-use efficiency in several ways, including the studyof gut bacteria that participate in animal diges-tion, feed additives that enhance absorption ofnutrients, and substances such as GHs that maydirectly stimulate growth and animal productivity.

Synthetic steroids and natural hormones areused widely to promote animal growth, as indi-cated in table 28. Furthermore, as noted above,health- and growth-promoting compounds fromindustrially grown micro-organisms constitute a

large share of feed additives (30). Some of thesecompounds act by enhancing the growth of ben-eficial micro-organisms in the gut, others by re-ducing the prevalence of harmful micro-orga-nisms and parasites throughout the gastrointes-tinal tract; still other compounds directly provideanimal nutrition. In cases where microbial meta-bolic pathways and products are known, biotech-nology may augment the production of com -pounds used as feed additives by increasing theproduction of specific microbial metabolizes. ” Atpresent, however, applications of biotechnologyto the production of metabolizes largely remainunexploited (10).

GHs produced by rDNA technology, in contrast,currently are undergoing trials in humans andanimals in efforts to demonstrate safety and ef-fectiveness in stimulating growth. Several U.S.NBFs, including Genentech Corp. (in collaborationwith Monsanto Corp.), Molecular Genetics, Inc.(for American Cyanamid), Bio-Technology Gener-al, Amgen, and Genex Corp., are producing GHsfor various animal species. In addition to yieldingpotential commercial products, rDNA GH projectsare stimulating widespread research into the na-ture of growth, development, and animal produc-

“’1’}1[> I)ro(iurti(m 01 (’ompoun(is” usf’d as fwd :Iddltiles is discussed

in [:liapter’ 7. Special t.\ [.’hemicals anci fi’ood Adcliti~ffis

Table 28.—World and U.S. Sales of Growth Promotants (millions of dollars)

Sales

1979

Products W o r l d U . S .

38 — 43 — 75 — 15 ”/0

$175 $ 95 $210 $106 $515 $246 250/o

168 . Commercial Biotechnology: An International Analysis

tivity. The results of experiments pertaining toGHs’ mode of action to date have yielded resultsthat suggest caution. Previous observations thatinjections of bovine pituitary gland extracts en-hance lactation in cows led to the finding thatpurified GHs increase milk yield by 10 to 17 per-cent, without a concurrent change in feed intake(24). Other experiments with sheep and pigs haveshown rapid growth following GH treatment (36).However, other evidence indicates that GHs stim-ulate growth and feed-use efficiency at the ex-pense of body-fat deposition (24). Thus, criticsargue, GHs may impair long-term animal healthand productivity (24).

Substantial hurdles must be overcome beforerDNA-produced GHs become commercially avail-able. In addition to requiring regulatory approval,the commercial success of GHs requires an ade-quate drug delivery system that introduces GHslowly to animals. Oral administration of GHs,although most convenient and marketable, is aninadequate system of delivery because polypep-tides such as GHs are degraded by digestive en-zymes. The hormones must be made available tothe body’s circulation, where they can reach en-docrine organs. Slow-releasing ear implants maybe used as alternatives to frequent injections (in-jections are not amenable to most husbandrypractices except those for dairy cattle), but, atpresent, dose requirements are too high for suchimplants to be practical (21). Eli Lilly (U. S.) is de-veloping a long-lasting bolus to be used in therumen. Presumably, enough GH is released direct-ly through gastrointestinal tract walls to avoid theproblem of enzymatic degradation. With the de-velopment of convenient delivery systems, bet-ter field trials to investigate the efficacy of GH mayresult.

,,

Genetic improvement of animal breeds

Throughout the history of animal agriculture,breeders have sought to improve animal produc-tivity by selecting animals with desirable traits forbreeding. Recent increases in the understandingof animal reproductive biology and the geneticbasis of traits have fostered new animal breedingtechnologies (31). As a result of increased knowl-edge due to biotechnology, the identification of

genes and gene products that influence traits ofproductivity, vigor, and resistance to certain dis-eases may be possible.

In the future, animal breeding programs maybe augmented by biotechnology to achieve de-sired changes with unprecedented speed andselectivity. Biotechnology may be used in ongo-ing breeding programs first to identify animalswith desirable genes (e.g., genes that make theanimals resistant to certain infections), and sec-ond, to transfer these genes directly into the germline (cells that contain the genes that will bepassed onto future generations) of other animals.Possible applications of biotechnology include theuse of MAbs to identify and isolate gene productscorrelated with certain traits, the use of rDNAtechnology to produce large quantities of desiredgene products for further study, gene transfer(micro-injection of isolated DNA into embryocells), and implantation of the embryo cells towhich genes have been transferred into surrogatemothers.

The technology of gene transfer is in its infan-cy. To date, it has been used only in laboratoryanimals, In most instances, the gene(s) to be stud-ied is fused within a plasmid to a gene with aknown “housekeeper” function required forgrowth. The plasmid is injected into a host cellthat is deficient in the housekeeper function. Onlyhost cells whose chromosomes incorporate theforeign DNA have the restored housekeeping ac-tivity and survive. These cells then are screenedfor activity of the desired gene. The GH gene hasbeen the subject of many recent gene transferexperiments,

Thus far, gene transfer experiments in animalshave increased fundamental understanding inseveral areas. Scientists have made great gains inpreparing receptive host cells, transferring genesfrom one animal cell to another, and recogniz-ing the successful recombination of foreign DNAin host chromosomes (1,6,32)33). Fundamentalunderstanding of mechanisms of gene control inmammals has also burgeoned in recent years. Sev-eral investigations have revealed that the hosttissues surrounding the cells that contain im-planted genes affect expression of the foreigngenes (as surrounding tissue may regulate gene

Ch.. 6—Agriculture 169

expression in normal cells) and that this “tissue-specific gene regulation” continues through suc-cessive generations (7, 12,23,25)27). Finally, genetransfer experiments have allowed the study ofthe expression of single genes that, with othergenes, comprise traits that might be too complexfor study by other methods.

Gene transfer studies may reveal much aboutthe function of single gene products. For instance,the transfer of genes implicated in immune re-sponses and resistance/susceptibility to disease arebeing studied (some of these genes encode immu-nological cell-surface proteins called the HLA an-tigens) (11). The ability to transfer such genes intoforeign cells to distinguish the production andfunction of their products may lead to valuableknowledge about animal diseases.

In the future, gene transfer may prove to bethe sole means of overcoming certain animal dis-eases that defy preventive vaccine technologyand/or veterinary treatment. An example of sucha disease is trypanosomiasis (“nagana” in cattle and“sIeeping sickness” in humans). Trypanosomiasisis caused by parasites borne in the saliva of cer-tain insects and impedes livestock productivitythroughout Africa (where the disease is trans-mitted by tsetse flies). Strains of cattle and sheepwith resistance to trypanosomiasis (trypanotoler-ance) exist, and their resistance may be traceableto several distinct genes (26,29). Gene transfermay prove useful in better identifying these genesand selecting animals for breeding programs de-signed to encourage trypanotolerance in affectedareas. In the future, transfer of these genes intocattle germ lines may rapidly foster widespreadtrypanotolerance where most other programs tocontrol trypanosomiasis have failed. The applica-tion of knowledge gained from gene transfer ex-periments to animal agriculture will not be im-mediate, but such knowledge eventually may leadto considerable agricultural advances.

Commercial aspects of biotechnologyin animal agriculture

Although field trials of several biotechnologyproducts for animals are underway and a fewproducts (e.g., vaccines for colibacillosis) havebeen approved for use, it is not yet clear to what

● hlajor [1 .S, producers include S>ntrk, Pfiz[,l. I,li I,il]>, 1‘p;ohnSmithKline Beckman, ,American (: Janamid, Nlerrk, ,Ameriran }ionwProducts, Johnson & Johnson, ‘1’ech America, and Schering-Plough\Iajor foreign producers inc]u(k) BL]l-]’ol]gl~s-\ \’tll]c’onlt~ (L1 .K ), Rhon~I-hlvrimlx Ik’ranw), ~{ow’hst ,4(; (h’ R (; ) [la} rr ,1(; [k- R (;.), (’onn,iughti(’anada], Beecham (L] K ), Sol\ a~ (Belgium) Ekwhringer lngt~lht~lnl(F’ R .(; .1, Intertet [Netherlands) and E;lt ,Aquit;iinc [E’rance),

25-561 0 - 84 - 12

—


Table 29.-Global Animal Health Product Markets

Estimated Estimatedsales, 1981 annual growth,

(millions of dollars) 1981-85

Nutritional products . . . . . . . . . . . . . . . . . . . . . .Medicinal products:

BiologicslVaccines . . . . . . . . . . . . . . . . . . . . .Antibacterial . . . . . . . . . . . . . . . . . . . . . . . . . .Anthelmintics . . . . . . . . . . . . . . . . . . . . . . . . . .Ectoparasiticides . . . . . . . . . . . . . . . . . . . . . . .Coccidiostats . . . . . . . . . . . . . . . . . . . . . . . . . .Growth promotants . . . . . . . . . . . . . . . . . . . . .Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Subtotal. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

$2,500

1,0002,000

450400300200650

5,000

$7,500

10-15%0

20-250/o10-15%025-300/o10-150/015-200/o24-300/o15-200/o

15-200/o

15-200/oSOURCE: S. J. Zimmer and R. B. Emmitt, “Industry Report: Animal Health Products Market” (New York: F. Eberstadt & Co.,

Inc., 19S1).

Table 30.—U.S. Producers of Animal Health Products

EstimatedEstimated Percent of animal health sales

animal health sales, Percent of corporate annual growth,1981 (millions of dollars) corporate sales operating income 1981-85

Pfizer . . . . . . . . . . . . . . . . . . . . $ 4 4 0 13 ”/0 130!0 100/0Eli Lilly. . . . . . . . . . . . . . . . . . . 365 130/0 150!0 200/0American Cyanamid. . . . . . . . 265 7%0 7“/0 11%0Merck . . . . . . . . . . . . . . . . . . . . 200 70/0 7“/0 270/oSmithKline. . . . . . . . . . . . . . . . 155 70!0 50/0 1 70/0Upjohn . . . . . . . . . . . . . . . . . . . 134 70!0 7“/0 110/0Syntex . . . . . . . . . . . . . . . . . . . 83 120/0 N+A.a 110/0e N A. = Information not available.

SOURCE S. J Zimmer and R B. Emmitt, “Industry Report Animal Health Products

product sales by the U.S. companies that producesuch products constitute a fairly low percentage(an average of 11 percent) of the companies’ totalsales. Investments in animal-related biotechnologyR&D in those companies probably average aboutthe same or less than the investments by the lead-ing NBFs that are applying biotechnology to ani-mal agriculture (22).

As noted in Chapter 4: Firms CommercializingBiotechnology, most major pharmaceutical andveterinary medicine companies are investing inbiotechnology R&D, but there is some questionas to their motivation for producing new productsfor large, established animal health care markets.Such markets include those for antibiotics, anthel-mintics, and coccidiostats. Established companieswith existing lines of conventionally made, widelymarketed animal health products may havestrong interests in maintaining these products. Inmany cases, therefore, their primary interests do

Market” (New York: F, Eberstadt & Co., Inc , 1981)

not lie in R&D to produce new animal healthproducts. As described earlier, applications ofbiotechnology to the production of animal prod-ucts involve a substantial investment in basic re-search. In some cases, healthy sales of conven-tionally made products may dissuade a companyfrom pursuing basic research that could lead tothe development of a competing product. In othercases, corporate developers may choose to pur-sue human pharmaceutical innovations of newbiotechnology, rather than applications ofbiotechnology to animal health. Because of theseconsiderations, innovation and new product de-velopment in animal agriculture might be slowed.

Innovation in smaller product market areas,such as animal vaccines and diagnostic products,however, is widespread, New or replacement ani-mal vaccines are among the most promisingapplications of biotechnology, as are MAb-baseddiagnostic products, Much of the innovation in

Ch. 6—Agriculfture . 171

Table 32.—Major Producers of Animal VaccinesSold in the United States

production of food from animals. MAb-based diag-nostic products exemplify this promise. Otherproducts, such as new vaccines, may face tech-nical problems of dosage, formulation, and deliv-ery before they are suitable to animal husbandrypractices. Until these problems successfully areresolved, the impact of biotechnology on improv-ing animal productivity will not be realized. Ap-plications of biotechnology such as gene transferexperiments and investigations into the nature ofgrowth using rDNA-produced GHs currentlyserve to increase basic knowledge about animalbiology.


Plant agriculture --

There are hundreds of forms of crop improve-ment whose purpose generally falls into one ofthree categories. The first is to increase cropyields by increasing resistances to pests or envi-ronmental conditions such as drought or soil salin-ity or by developing more productive plants, Thesecond is to improve crop quality by enhancingsuch features as nutritional value, flavor, or proc-essability. The third is to reduce agricultural pro-duction costs by reducing a crop’s dependenceon chemicals or by making harvesting easier (55,56).

During the last century, plant breeders havebeen efficiently and successfully addressing all ofthese goals. The use of new biotechnology in cropimprovement, as in other areas, is not a new be-ginning, but an extension of previously evolvedskills. New biotechnology alone will not producebetter crop plants, but combined with knowledgefrom other plant science and microbiological dis.ciplines, biotechnology will develop techniquesthat could be very powerful in improving agri-culturally important crops. Thus, the greatest ad-vances in crop improvement are likely to be madeusing an interdisciplinary approach.

The genetic manipulation and modification ofplants presents some special challenges. Most mo-lecular genetics to date has been done with simp-le unicellular organisms and, to a lesser extent,with laboratory animals. The application of mo-lecular genetics to plants is relatively more recentand consequently at an earlier stage of technicaldevelopment. Furthermore, there are fewer stud-ies of the physiology and biochemistry of plantsthan there are studies of these aspects of animals.The recent application of the new techniques ofmolecular biology to plants has produced astound-ingly rapid results, however, and these techniquesare sure to have an impact on crop improvementin the next several years.

Of the several hundred domesticated plants inthe world today, only about 30 are of great eco-nomic significance. Of these, eight domesticatedgrains, including rice, corn, and wheat, producemost of the calories and protein consumed by hu-mans and agriculturally important animals. The

legumes, which include soybeans, represent thesecond most common source of food for humanand animal consumption. There are two philoso-phies, which are not incompatible, with regardto improving crop plants. One is that there shouldbe diversification of crop plants and attentiongiven to the domestication and breeding of newmajor crop plants. Another philosophy is thatplant breeding, tissue culture, and biotechnologyefforts should be devoted to the most successfulcrop plants. The genetic diversity of some of theworld’s current crop plants is not great. Conse-quently, even if the major crop plants are thefocus of research efforts, some genetic materialfrom exotic sources may be required to effect thedesired improvements. In any case, the tech-niques discussed here are equally applicable tothe improvement of both common and exoticspecies,

Research on plants has shown that the geneticorganization of plants exhibits striking similari-ty to that of animals. The universal genetic codeis used, and most genes contain interveningsequences and are surrounded by very similarregulatory sequences. Unlike animals, however,plants have a characteristic called totipotencythat, for many species, indicates the potential forregeneration of a single cell into a complete plant.Because plants have this totipotent characteristic,certain genetic manipulations can be done in cellculture, and, after selection of cells with the ap-propriate qualities, the cells can be regeneratedinto parental plants (for breeding programs). Ad-justing the laboratory variables to achieve regen-eration from single cells is evolving from an artto a science and has yet to be accomplished con-sistently for the principle cereal grains (mono-cots *), but regeneration research is proceedingat a rapid rate. It is likely that many importantcrop plants will be able to be regenerated fromsingle cells in the next few years.

There are several potential applications of newbiotechnology for plants that may help in the im-

‘E;arly in the evolutionary history of flowering plants, tt~o maint~’pes of plants, monocots and dicots, clitwrged. [:ereal grains (corn,wheat, r}’e, barley, rice, etr. ) art’ monocots, whereas legumes ko~’-h{ Ians, etr ) :irv dirols

Ch. 6—Agriculture 173—

Phofo Credit Dean Eflgler Agrfgenef~c5 Corp

Freshly isolated plant protoplasts

Photo Credit” Dean Eng/er, Agrigeneflcs Corp

Plant shoots arising from protoplast-derived calli


provement of crop species, as shown in figure 16.New technologies for testing for the presence orabsence of traits, for example, will save years ofplant breeding time. Many applications to plantagriculture will be in the regulation of endogen-ous genes, and other improvements will be madeusing techniques such as the following, whichtransfer DNA from one species to another:

● The fusion of cells from two different plantspecies can be used to overcome species hy-bridization barriers. In order to be useful, theresulting cell fusion product must be regen-erated to form a whole plant. To date, regen-erated plants have only resulted from fusionsbetween closely related genera (62). The re-generated plants are selected to express ben-eficial characteristics of both parents (94). Asyet, no economically important variety hasbeen produced using this method (62).

● Transferring subcellular organelles such asnuclei or chloroplasts from one plant speciesto another can be accomplished by a varietyof techniques. One of these, liposome trans-fer, involves surrounding the organelle witha lipid membrane. Because chloroplasts carrymany of the genes important in photosynthe-

Figure 16.–Steps To Create a New Variety of Plantby Using Biotechnology

SOURCE. Office of Technology Assessment

●

sis, liposome transfer may be instrumentalin improving photosynthetic efficiency.Vector-mediated DNA transfer (and micro-injection of DNA) is the most specific, and po-tentially the most versatile, of the geneticmanipulation techniques. Recently, foreignplant genes have been inserted and expressedin plants.

Recent advances in the methods of plant cellculture and the techniques for introducing DNAfrom one plant species to another are discussedin Box C.—Methodology Important in Plant Agri-culture. The applications of these methods tospecific problems in plant agriculture, such as dis-ease resistance, photosynthetic efficiency, and ni-trogen fixation and the commercial aspects of bio-technology in plant agriculture are discussed inthe sections that follow.

Improvement of specific plantcharacteristics

Greater crop yields or a reduction in the costof crop production would be possible if plantswere resistant to disease and certain environmen-tal factors and contained a larger amount of high-er quality product. In the United States, there isgreat research interest in crop resistance andcrop quality improvement in academic, Federal,and industrial laboratories. Unlike most otherplant traits, some resistances and specific im-provements may be accomplished with one or afew gene modifications. This area, therefore, isprobably the most active area of industrial re-search, and it is likely that considerable researchprogress in this area will be made in the next 5to 10 years.

PLANT RESISTANCE FACTORS

Disease and environmental resistances are im-portant to most crops in most areas of the world.Important plant resistances are shown in table33. Productivity losses often can be attributed tothe lack of resistance to one or more factors (seetables 34 and 35). Thus, the study of resistancescould lead to greatly improved productivity andan increased realization of genetic potential (42).

Numerous single gene resistance factors areknown in higher plants. The most common re-


-,

. .-, ,, ,.,


sistance genes are those that confer decreasedsusceptibility to disease (54,71,79). In maize, forexample, there are resistance genes to severaldiseases such as northern corn-leaf blight (s1).Because most of the single gene resistance fac-tors confer resistance to a single pathogenic or-ganism, it is thought that a single characteristicof the host and pathogen determine the outcomeof an infection.

Most of the existing disease-resistance geneshave been introduced into economically impor-tant lines of interbreeding plant species by tradi-tional plant breeding. Currently, however, thereis interest in cloning disease-resistance genes fromplants in order to study the nature of resistanceand to determine the possibility of transferringresistance factors among species that do not nor-mally interbreed. It is not known in most cases

Ch. 6—Agricu/ture 177

Table 33.—Plant Resistances of Economic Value

Resistance to: Relevance in United States

Disease . . . . . . . . . . . . . . . . . . All CfOPS

Saline . . . . . . . . . . . . . . . . . . . . Irrigated soils, particularly inCalifornia and Southwest

Alkaline earth metals . . . . . .Southeastern United Statesand West

Anaerobic soil conditions. . . Areas subject to floodingDrought . . . . . . . . . . . . . . . . . .All cropsHerbicides . . . . . . . . . . . . . . . . All cropsPesticides . . . . . . . . . . . . . . . . All cropsSoil pH . . . . . . . . . . . . . . . . . . . Low pH on acid mine tail-

ings and soil affected byacid rain; high pH on mostWestern soils

SOURCE Office of Technology Assessment

Table 34.—U. S. Soils With Environmental Limitations

Environmental limitation Percentage of U. S. soilaffected

Drought . . . . . . . . . . . . . . . 25.30/oShallowness . . . . . . . . . . . 19.6Cold . . . . . . . . . . . . . . . . . . 16.5Wet . . . . . . . . . . . . . . . . . . . 15.7Saline or no soil . . . . . . . . 4.5Alkaline salts. . . . . . . . . . . 2.9Other. . . . . . . . . . . . . . . . . . 3.4None . . . . . . . . . . . . . . . . . . 12.1SOURCE: J S Boyer, “Plant Productivity and Environment,” Sclefrce 218443-448,

1982

Table 35.-Distribution of Insurance Indemnities FromCrop Losses in the United States From 1939 to 1978

Cause of crop loss Proportion of payments (0/0)

Drought . . . . . . . . . . . . . . . . . . 40.80/oExcess water . . . . . . . . . . . . . 16.4Cold . . . . . . . . . . . . . . . . . . . . 13.8Hail . . . . . . . . . . . . . . . . . . . . . . 11.3Wind . . . . . . . . . . . . . . . . . . . . . 7.0Insect . . . . . . . . . . . . . . . . . . . . 4.5Disease . . . . . . . . . . . . . . . . . .Flood . . . . . . . . . . . . . . . . . . . .

; : ;

Other . . . . . . . . . . . . . . ... , . . 1.5SOURCE” J. S Boyer, “Plant Productivity and Environment,” Science 218443-448,

1982

what the disease-resistance genes in plants actual-ly do to plant metabolism or structure. By under-standing how the products of plant disease-resist-ance genes work, better screening programs forenhanced resistance can be designed. Environ-mentally, it is desirable to develop pest-resistantplants, because such plants would reduce the

need for spraying crops with pesticide * chemi-cals, and disease control would be more effective.It should be kept in mind, however, that muchof the agricultural research effort is being madeby the agricultural chemical industry, and thisindustry may see the early opportunity of devel-oping pesticide-resistant plants rather than under-taking the longer term effort of developing pest-resistant plants.

Resistance to environmental conditions prob-ably depends on both single and multigenic inheri-tance. These traits, as well as disease resistance,can be selected for in tissue culture. If analogsof the disease or detrimental environment condi-tions can be applied to plant cells in culture, theentire procedure can take place in a few test tubesor petri dishes in a laboratory setting. Millions ofindividual cells can be treated simultaneously andthen examined for survivors. Stepwise selectionsunder gradually more stringent conditions (e.g.,a gradual increase in the salinity of the medium)are accomplished readily.

Some of the traits that could be selected in tissueculture are listed in table 33. Many of the traitsare resistance factors that confer protectionagainst disease and salinity. In selection schemesfor these factors, the test organism is exposedeither to normally lethal doses of the toxins pro-duced by a disease organism or to high doses ofsalt (to mimic salinity), and the surviving cells areidentified by their growth under these normallytoxic conditions. This protocol holds great prom-ise for identifying rare cells that have spontane-ously acquired a novel resistance. Somaclonalvariation probablv supplies much of the variationseen in tissue culture (see box C) (47).

A rate-limiting step in applying selection tech-niques more widely is the present inability to re-generate major cereal and legume crops fromindividual cells or small cell clumps on a routinebasis. Furthermore, some of the traits selected intissue culture for resistance to a specific factormay not be manifested in the whole plant, be-cause it is possible for cells to develop nongenet -

‘,4 pesticide is an agent (hat prm’ents the growth or propq+itionof deleterious organisms, including weeds an(i insects Both iler -i)icides an(i insecticides are pesticicies.


ic adaptations. Consequently, numerous regener-ated plants will be required to determine if a par-ticular selection procedure yields whole plantswith important agronomic traits. on the otherhand, pollen or embryo manipulation may cir-cumvent some of these problems.

Genetic manipulations can make plants resist-ant to chemicals or can enhance their responseto chemicals. These traits are of particular impor-tance to the agricultural chemical industry. Forinstance, various plant growth regulators are pro-duced by this industry. These chemicals can af-fect many stages of the growth or reproductionactivities of plants to give a crop with increasedyield. Enhanced response to these chemicals al-lows the crop to be grown at a lower cost.

Producing herbicide-resistant plants can havedefinite benefits, especially in crop rotation. Forinstance, corn is naturally resistant to triazineherbicides, whereas soybeans are not. Occasional-ly, soybeans do not grow well in a field the yearafter triazine-sprayed corn was grown there. Inthis case, one solution would be to introduce tri-azine resistance into soybeans. This particularresistance is due to a modified protein in thechloroplast membrane. Therefore, resistance be-tween dissimilar species could be transferred byprotoplasm fusion or liposome-mediated chloro-plast transfer (38,66). It should be noted, though,that increased use of agricultural chemicals couldhave serious environmental consequences.

PRIMARY PLANT PRODUCTS

The largest research effort in the modificationof plant products using biotechnology is concen-trated on the improvement of seeds and seed pro-teins. Seeds serve a dual role in agriculture. Theyare the major source of food for people and ani-mals and represent an easily stored form of plantmaterial, and they are also the material for propa-gating the next plant generation. The storage ma-terials of seeds contain all of the materials neces-sary to nourish a plant, because each seed mustsupport the initial phases of germinlation andseedling establishment until the plant is self-suffi-cient. During domestication, various crops haveundergone an enormous exaggeration of the nor-mal storage reserves. Today, far more materialis stored in agricultural crop seeds than in the

seeds of wild relatives; sometimes the increase isas much as tenfold (68).

Although the agronomic (applied) research ef-fort is devoted primarily to increasing the amountof seeds and seed protein, current basic researchefforts are devoted both to increasing the quali-ty of the stored materials and to exploring plantgene structure. Because plants are capable of syn-thesizing all of the amino acids required for pro-tein synthesis from simple carbon- and nitrogen-containing precursor molecules, the exact aminoacid composition of the stored protein in seedsmay not matter to a plant, and seed proteins oftenhave an unbalanced amino acid composition. Be-cause humans and most animals are unable tosynthesize eight amino acids (the essential aminoacids), the composition of ingested protein mat-ters very much in their nutrition,

Much is known about the structure of the stor-age-protein products and the genes encodingthese proteins in the major crop plants. In all casesstudied so far, the storage-protein genes are foundin small gene families with 3 to 30 members. Typ-ically, a few genes of the multigene family con-tribute a significant fraction of the total protein,There is not much genetic variation among theseed storage-protein genes of a given species, al-though this low variation might be due to the lim-ited diversity of the varieties currently studied,These crops may have lost much of the originaldiversity present in the progenitor species dur-ing the intensive plant breeding activities thathave occurred throughout history.

DNA clones of storage proteins are availablefrom several crop species: soybean, garden bean,corn, wheat, and other less significant crop plants.Changes in these genes can be made readily invitro to improve the balance of amino acids in theprotein. The difficult part is reintroducing thealtered storage-protein gene back into the cropplant and ensuring that this novel gene is ex-pressed appropriately. Most storage proteins arepresent only in seeds. Retention of this tissuespecificity is important; storage proteins’ presencein other plant cells may be detrimental. Anotherimportant consideration is that the storage-pro-tein genes are found in families. Introduction ofa new gene may change only a fraction of the totalprotein produced. To modify the overall amino


acid composition, several genes may have to beintroduced or the natural genes deleted andreplaced by novel genes. In some crops such ascorn, there are mutations that reduce the pro-duction of zein, the storage protein. These mu-tant genes can be used to reduce the zein concen-tration, thus allowing an introduced gene to havea greater impact on overall amino acid composi-tion.’

An alternative to the modification of existingcrop species’ genes is the introduction of com-pletely novel genes isolated from other organisms.Genes whose products are very rich in the aminoacids that are deficient in a particular seed typecould be introduced to increase the concentra-tion of specific amino acids. One promising ex-ample of this type is the storage protein of theBrazil nut (97). This protein is composed of 25 per-cent sulfur-containing amino acids (methionineand cysteine). Legume seed protein usually is defi-cient in these amino acids. Introduction of a fewcopies of the Brazil nut storage-protein gene intolegume species might overcome the sulfur aminoacid deficiency. Proteins of unusual compositionmay offer the quickest method of preparing agene to complement deficiencies in major cropstorage proteins.

SECONDARY COMPOuNDS FROM PLANTS*

Table 36 lists some of the desirable secondaryproducts from plants. Very little research hasbeen done on the tissue culture production ofthese compounds, yet it should be possible to pro-duce important high-value plant products usingculture systems instead of gathering plants fromnature. Cell culture offers the advantages of re-producibility and control over production whereseasonal variations, weather changes, or diseaseare not problems (40,57,95). On the other hand,a difficulty in the production of some productsis maintaining the plant cell culture in a differen-tiated state such that compound productionoccurs.

Biotechnology offers many opportunities for theproduction of secondary plant compounds. Thetransfer of the plant metabolic pathway for a— .

““[-his topic was cotered by a recent OTA workshop entitled“Plants: The Potent ial for Extracting Protein, Nledicines, and other(Isefu] (;h~mlra]s” ($j~)

Table 36.—Examples of Secondary Plant Products ofEconomic Value

Agricuitural chemicais:PyrethrinsRotenoneNicotineAllelopathic compoundsAntibiotics against soil microbes

Pharmaceutical drugs:CodeineMorphineSteroidsCardiac glycosidesAlkaloidsReserpineRetinoic acidCaffeineCannabinoidsAntitumor compounds

Fiavorlngs and saits:LicoriceCoumarin

Coiorings and pigments:Anthocyanins and betacyaninsCarotenoids

industrial intermediates:LatexLigninDye basesSteroid and alkaloids products

SOURCE Off Ice of Technology Assessment, adapted from E A Bell and B VCharlwood (ads.) Secondary Plant Products (New York” Springer-Verlag,1980).

compound to a bacterial or fungal cell, for in-stance, could offer an opportunity for providinga steady supply of these compounds, althoughmuch more knowledge concerning the geneticsand biochemistry of the pathways that producethese compounds is necessary. Another possibilityis identifying and modifying the gene coding forthe enzyme responsible for the rate-limiting stepin product production. Overproduction of theproducts could result from the plants beinggrown in culture or in the field.

There is little current U.S. research effort toimprove the yield of secondary plant compoundsfrom cultured cells or whole plants. The FederalRepublic of Germany, Canada, India, and Japan,on the other hand, have large research programs,as measured by the number of papers presentedat the 1982 International Congress of Plant Tissueand Cell Culture (58). Japan, for instance, hasscaled up the growth of tobacco cells to 7,000liters, and researchers at the University of BritishColumbia are growing 100 liter batches of Mada-


gascar periwinkle cells in order to isolate antican-cer compounds (58). In fact, the Japanese Gov-ernment is spending $150 million over 10 yearsfor research on obtaining secondary compoundsfrom plants. It is argued by some, though, thatplant cell culture for producing secondary prod-ucts is necessary only when good farm land is notabundant (65).

PLANT GROWTH RATE

The rate at which plants grow can limit boththe amount of harvestable biomass (food, fiber,secondary products) and the length of time be-tween planting and harvesting. Traditional plantbreeding has been quite successful in modifyingand improving plants to respond to modern ag-ricultural practices of herbicide, pesticide, irriga-tion, cultivation, and high-fertilizer application.These breeding programs have established thatthere is no single gene for yield. On the otherhand, much is known about the genetics of har-vestable products such as seed size. Additional-ly, there are single gene mutants, such as that forgibberellic acid, that can affect plant growthdramatically. Increased understanding of theseareas of genetics may have an impact on this areaof plant biology. For instance, a plant can be im-agined that had a decreased amount of total bio-mass but an increased amount of harvestableproduct.

PHOTOSYNTHETIC EFFICIENCY

Photosynthesis is the basis for most life onEarth. Higher green plants, algae, and some bac-teria can utilize the energy in sunlight to splitwater molecules; in this process, energy is gen-erated and utilized to combine atmospheric car-bon dioxide (CO,) into an organic form as well asto drive other energy requiring processes ofplants. A byproduct of this reaction is molecularoxygen (Oz). Thus, photosynthesis is not only theultimate source of fixed carbon we use as foodand fiber, but also of the oxygen we breathe.

Because photosynthesis is so important to foodproduction, much research has focused on themechanism of photosynthetic action. The photo-synthetic system is very complex, combining en-zymatic activities, key roles played by cellularorganelles, and plant anatomy as well as environ-

mental factors such as light, water, and temper-ature. Many proposals have been made to im-prove the efficiency of this system by geneticmanipulation.

The critical step of the photosynthetic COZ fix-ation cycle is catalyzed by the enzyme ribulosebisphosphate carboxylase (RuBPCase), probablythe most abundant protein on Earth. This enqymeis sequestered in chloroplasts, the cellular organ-elles where photosynthesis occurs. It is a complexmolecule synthesized from both chloroplast genesand nuclear genes (50,51).

When photosynthesis originated, the Earth’s at-mosphere is postulated to have been nearlydevoid of oxygen. The oxygen we have today isa byproduct of photosynthesis, and oxygen com-prises about 20 percent of our atmosphere. RuBP-Case initially evolved in a low oxygen atmospherebut now must fix CO. with a large excess of 0.present. RuBPCase can utilize this 0, in what ap-pears to be a nonproductive enzymatic reaction.This process is called photorespiration and resultsin a net loss of fixed COZ (45). Photorespirationcan decrease crop yields by as much as 50 per-cent (82). It is ironic that RuBPCase activity overthe past millions of years has produced the Oz

that now decreases the efficiency of photosynthe-sis. On the other hand, it has been postulated thatthe ubiquitous and continued presence of photo-respiratory activity implies some natural selectionadvantage (61).

Suggestions have been made for modifyingRuBPCase or other enzymes involved in the pho-tosynthetic system. For instance, genetic manip-ulations that would increase the affinity ofRuBPCase for COZ or decrease its affinity for Oz

could substantially increase net COZ fixation. Ithas yet to be determined what effects thesechanges would have on the survivability of plants.

In addition to manipulating the enzymatic sys-tem, changing the plant’s anatomy, such as thetypes of cells in leaves, might be possible. Severalgroups of higher plants have increased rates ofCOZ fixation that correlate with modified anatomyand physiology. Very little is known about thegenetic control of leaf and cellular anatomicaldevelopment, so near-term success in modifyingthese aspects of plant anatomy is unlikely.


Genetic manipulations to increase photosyn-thetic efficiency, and consequently food produc-tion, are very difficult now because of the com-plexity of the system. It will be several yearsbefore rDNA technology will aid in producingagriculturally important plants with increased in-herent photosynthetic efficiency.

PLANT-PRODUCED PESTICIDES

Some species of plants are highly resistant topotentially damaging insects. Although not verymuch is understood about this phenomenon, itappears that certain plants can produce com-pounds that are toxic to specific species of insectsOr that interfere w’ith the insects ) normal repro-d u c t i v e o r g r o w t h f u n c t i o n s ( 8 6 ) . A n A f r i c a nplant, for example, produces a compound that in-

te r feres wi th a par t i cular ca terpi l la r ’ s mol t ing ,

and, as a result, the insect cannot eat (48). otherplants a re known that produce chemica ls tha t

cause potentially harmful insects to avoid thoseplants for feeding or egg laying (59). The specifici-

ty of these plant-produced insecticides and non-preference chemicals allows the control of pestswhile permitting potentially useful insects to sur-

v ive . Many appl ied chemical pes t i c ides do nothave this specificity. 1t may be feasible soon to

clone and transfer the genes that code for these

naturally occurring chemicals, allowing them to

be expressed in other plants. The result of thesegene t ransfers could be to reduce great ly the

amount of agr icul tura l chemica ls needed and ,

hence , the cos t of product ion .

Investigations into chemicals released by someplants that adversely affect neighboring plants is

receiving an increased amount of attention ($10).

These herbic ides , known as a l le lopathic chemi-

cals, may influence another plant directly or may

act by inhibiting the micro~organisms normally

associated with that plant. Allelopathic chemicals

consist of a wide variety of chemical types, and

their actions range from inhibiting cell division

t o p r o t e i n s y n t h e s i s t o p h o t o s y n t h e s i s . M u c hmore still is to be learned about these naturallyoccurring chemicals, including the factors influ-

encing their production and how best to use themagriculturally. A goal of biotechnology is to iden-

tify the genes responsible for the synthesis and

release of the plant pes t i c ides and to t ransfer

them to nonresistant plants. Biotechnology alsocould aid in the understanding of their produc-tion and possibly help develop their productionin controlled laboratory culture systems.

Uses of micro-organisms forcrop improvement

Applications of biotechnology in the area ofcrop improvement include genetic manipulationsof micro-organisms that interact with plants innitrogen fixation, for example, or that producesubstances such as insecticides of potential benefitto plants. These applications are discussed fur-ther below.

NITROGEN FIXATION

Plants have a universal need for metabolicallyusable nitrogen in the form of ammonia (NH),which can originate either from the air or fromapplied ammonia fertilizer. Biological nitrogen fix-ation, the process by which living systems con-vert nitrogen gas in air to NH, is catalyzed in liv-ing systems by the enzyme nitrogenase. Nitrogen-ase, and consequently the capacity to fix nitrogen,is found only in prokaryotes, either bacteria orblue-green algae. Some nitrogen-fixing prokary -otes are free-living and can be either anaerobicor aerobic; other prokaryotes fix nitrogen onlywhen they coexist symbiotically with a higherplant host. The application of biotechnology tonitrogen fixation may result in more efficient pro-karyotic nitrogen fixation or the transfer of ni-trogen-fixing ability to plants themselves.

Nitrogen-fixing prokaryotes share some com-mon physiologic features. First, nitrogen fixationtypically does not occur in cells already suppliedwith usable nitrogen. Second, nitrogenase is ox-ygen-sensitive, so all nitrogen-fixing organismshave mechanisms for limiting oxygen. Third, NH,,which is toxic at high concentration, must be con-verted readily into organic nitrogen,

Biological nitrogen fixation is energy intensive(84,88,93), and in plant-microbe associations, thisenergy is derived from the plant. Estimating theenergy expenditures for biological nitrogen fixa-tion is difficult, and few reliable numbers areavailable. The energy cost of nitrogen fixation is


an appropriate concern, but this cost should becompared with the true cost of nitrogen nutri-tion in field-grown plants (i.e., the cost of chemicalfertilizer synthesis and other biological costs tothe plant).

It may be possible to decrease the energy re-quired for nitrogen fixation by 30 to 50 percentby preventing the evolution of hydrogen duringnitrogen fixation. Some bacteria have a set ofgenes that allow for hydrogen recycling. Thesegenes have been cloned and inserted into lessefficient nitrogen-fixing bacteria. The recipientbacteria showed increased nitrogen-fixing effi-ciency (37).

Agriculturally important nitrogen-fixation sys-tems discussed below are nonlegume nitrogen fix-ation and symbiotic nitrogen fixation in legumes.

Nonlegume Nitrogen Fixation.—Nitrogenfixation is performed by several groups of bac-teria and blue-green algae that live free in soil orin aquatic habitats. The best studied nitrogen-fixing bacterium is the free-living Klebsiella pneu-monia, which can easily be grown in the labora-tory. * The gene complex coding for the nitrogen-fixing function in Klebsiel]a pneumonia is com-prised of 17 genes, and the regulation and activi-ties of these genes now are being studied exten-sively. Still, the nitrogen-fixing function is ex-tremely complex and not well understood.

Algae have been used to fix nitrogen in Asianrice paddies for many years. Recently, researchhas produced strains of algae that could be usedin soil to fix nitrogen for domestic crops. Algaeare inexpensive compared to nitrogen fertilizer,and because they release nitrogen slowly into thesoil, algae bypass the problem of nitrogen leaching(60). Furthermore, algae are being considered thebotanical equivalent of yeast for genetic manipula-tion, and vector systems for algae transformationare in development (41).

Symbiotic Nitrogen Fixation in Legumes.—The legume-llhizobium symbiosis is the mostagriculturally significant biological source of fix-ed nitrogen. Both grain and forage legumes havelarge amounts of nitrogen fixed by Rhizobium.

● Two other free-living nitrogen-fixing bacteria, Azosporillum andAzotobacter, also are important agriculturally.

Recent work on legume-Rhizobium symbiosis hasfocused on several areas, including the determina-tion of energy costs, pathways of nitrogen assim-ilation and transport, the biochemistry of sym-biotic nodule development, and the genetics ofthe bacterial partner.

Symbiotic nitrogen fixation can be a significantsource of nitrogen nutrition for legume crops, butits practical application can be limited by severalsets of factors, some environmental, others intrin-sic to the plant-bacterial partners. Soil conditionsand environmental levels of fixed nitrogen havesignificant effects on rhizobial survival, noduleformation, and levels of nitrogen fixation. Onecrucial area, poorly understood at present, is therole played in symbiotic nitrogen fixation of soilmicro-organisms other than Rhizobium. Under-standing nodule formation in detail will help ex-plain environmental effects on infection that mayrelate to competitiveness and effectiveness ofvarious Rhizobium inocula. In addition, anunderstanding of why legumes, and not otherplants, can nodulate would be essential for at-tempting to extend host range.

Another nitrogen-fixing micro-organism, theactinomycete Frankia, is of interest because itnodulates a number of unrelated plant genera.This ability suggests a simpler genetic symbiosisthan that of Rhizobium and legumes. If this istrue, it may be easier to extend genetically thehost range of the symbiotic relationship of Frankiathan to extend that of Rhizobium (41).

Specific host proteins are produced in nodules.One of these is leghemoglobin, which controls theoxygen content of the infected nodule cells. Thisprotein is produced in high quantities in nodules.Two research groups have cloned the genes forsoybean leghemoglobin (77,96), but their mech-anism of action is not understood. Other new pro-teins appear when nodules develop (76). Theseare called “nodulins” and are likely to be essen-tial for symbiotic nitrogen fixation; however, theirexact role is not known. Some of these might beenzymes, such as those for ammonium assimila-tion (67). When nodulins and their functions arebetter understood, a logical extension of currentresearch will be to move cloned modulation genesinto other plants. This may make it possible toextend nitrogen fixation to other plant species.


Summary. -Individual nitrogen-fixing systemscan be improved or extended by a knowledge ofhow they work and by techniques that permit thegenes for nitrogen fixation to be altered and mov-ed. One line of research will be the improvementof existing systems. Some new nitrogen-fixing sys-tems have been proposed, as well. Proposals havebeen made, for example, to insert directly thegenes for nitrogen fixation into the plant genome.Success of these as well as other systems in theend will be measured by the practicality of thenew association, The problems of specificity, ox-ygen regulation, and effect on yield must be con-sidered, and these will require broad-based know-ledge of biochemistry, genetics, and physiologyin a variety of nitrogen-fixing organisms (see table37). There is a considerable amount of researchbeing done in the area of nitrogen fixation, andgenetically manipulated Rhizobiwn maybe fieldtested soon (85).

MICROBIALLY PRODUCED INSECTICIDES

Problems or drawbacks associated with chem-ical insecticides, including their increasing costand environmental hazards, their lack of specifici-ty, and the ease with which insect resistances tosuch insecticides are developed, have sparkedrenewed interest in microbially induced insectcontrol to improve crop yield. Microbial insec-ticides, because of their narrow host ranges, cancontrol specific pests while allowing natural pred-ators and beneficial insects to survive. Further-more, the few characterized microbial pesticides

do not appear to harm humans or animals, andthey are biodegradable.

There are three natural sources of microbialinsecticides: bacterial, viral, and fungal. About 100bacteria have been reported to synthesize toxinsthat are insecticidal. Very few of these bacteriahave been studied extensively, but in one case (Ba-cillus thuringiemis kurstaki), the gene that con-trols the synthesis of a toxin has been cloned usingrDNA technology (69). The cellular mechanism ofthe toxin’s insecticidal activity is not yet wellunderstood. Genes for bacterial toxins could beput into other bacteria that normally exist on thesurface of plants (48).

Viruses also can be insecticidal by virtue of theirability to cause disease in various insects. Severalfamilies of viruses have been identified as poten-tially pathogenic to insects, but the family Bacu-Zoviridae has received the most attention. The U.S.Environmental Protection Agency (EPA) has regis-tered, or is considering registering, several bacu-loviruses for the treatment of such diseases as cot-ton bollworm, Douglas fir tussock moth, gypsymoth, and alfalfa looper (81). One particular bacu-lovirus [Autographa californica nuclear polyhe-drosis virus (AcNPV)) has been genetically and mo-lecularly well characterized, making the use ofrDNA techniques with this virus feasible,

In contrast to bacterial and viral insecticides,fungal pathogens need not be ingested; they candisable or kill the insect by colonizing its surface.More than 500 fungal species can infect insects,

Table 37.—importance of Basic Research (Model Systems) on Nitrogen Fixation

Research area Or9anisms used in research Importance

Cloning nitrogenase genes. . . .

Physiology of nitrogen fixation

Biochemistry of nitrogenase . .

. . . . . . Klebsiella pneumonia Direct study of genesIntroduction of nitrogen-fixing genes into

other organisms

. . . . . . Azotobacter Improving energy efficiency of nitrogenAnbaena fixation in the cellKlebsie/la Understanding role of ammonia in

nitrogen fixation

. . . . . . Clostridium Understanding oxygen sensitivity ofAzotobacter n itrogenaseKlebsiella Improving energy efficiency ofRhodospirillum nitrogenase enzyme

Cell and developmental biology ofmodulation . . . . . . . . . . . . . . . . . . . . . Rhizobium Bacteriallplant recognition process

Modulation process

SOURCE Office of Technology Assessment

184 . Commercial Biotechnology: An /international Analysis

and there are susceptible hosts in all the majororders of insects (72). The use of fungal insec-ticides will require a better understanding of theirpathogenesis and ecological requirements. Thelarge-scale production of these pathogens is dif-ficult, and, in many cases, the technology is notdeveloped. Also, their safety with regard to higheranimals and humans has not been adequatelystudied (43,44)81).

DISEASE-SUPPRESSIVE AND GROWTH-REGULATING MICRO-ORGANISMS

Increasing plant yields may be achieved throughbetter understanding of the many bacteria thatprotect plants from naturally occurring, deleteri-ous conditions (80,92). Some of these bacteria actby producing compounds that bind iron. Othersact by altering the pH or the salinity of the soil.Still others prevent frost damage to leaves. Fur-thermore, there are other bacteria that producecompounds that regulate plant growth. Themechanisms by which these processes occur isnot well known. With better understanding of thegenetics and biochemistry of some of thesebacteria and their environment, it may be possi-ble to program them genetically to produce com-pounds to change any number of soil and growthconditions.

For two reasons, it probably will not be eco-nomically feasible to incorporate the useful micro-organisms directly into soil on a regular basis,because large amounts of the micro~organismswould be required and because the useful micro-organisms might not be able to compete with thewell-established microorganisms already presentin the soil. Instead of being incorporated into soil,the useful microorganisms could be given a com-petitive advantage by applying them to the seedsor other plant parts prior to planting. Then theywould already have established a niche allowingthem an advantage over naturally occurringmicro-organisms (92).

The first authorized deliberate release of genet-ically manipulated bacteria, planned for the fallof 1983, was to prevent frost damage. The genescoding for the compounds that initiate ice crystalswere identified and deleted from a bacterial strainnormally found on many crop plants. The re -

searchers intended to spray these new bacteriaon field crops early in the growing season, so thatthey became the established strain and crowdedout the natural, harmful bacteria. * It is thoughtthat this approach could prevent up to $5 billionworth of damage to crops throughout the world(80).

Conclusion

The first successes in DNA transformation ofplants to give novel characteristics have beenachieved. Continued research on vectors andplant tissue culture is needed to extend these suc-cesses from model systems to major crop plants.The identification of genes that would substan-tially improve a crop plant requires cooperationbetween traditional breeders and geneticists.Plant molecular biologists need the knowledge ofthe more traditional plant disciplines to produceagronomically useful plants more rapidly. Inter-disciplinary basic research on plant biochemistry,development, and physiology will be required tohelp identify important genetic traits, to definebiosynthetic pathways in plants, and consequent-ly, to develop better plants. Many single genetraits in agronomic species have been used in pastbreeding programs; such genes also can be stud-ied using new biotechnology, The novel technol-ogies also can introduce genetic material fromplants that normally do not interbreed and pos-sibly provide simultaneous introduction of manyspecific traits into a single breeding line.

The next 5 years will produce major break-throughs in DNA transformation in model sys-tems and routine regeneration of plants from ourmajor crop species. Problems such as changingthe composition of the storage proteins of cerealsand legumes are difficult, because multigenefamilies limit the impact of single gene introduc-tions. Within the next decade, however, genesconferring resistance to stress and disease arelikely to be introduced and expressed in plants.

● This experiment was indefinitely postponed pending the outcomeof a lawsuit filed against the U.S. Government raising the questionof the necessitJ’ of filing an I+;nvironmental Impact Statement priorto the deliberate release into the environment of a geneticallymanipulated microorganism.

Ch. 6—Agriculture . 185

The production of better plants has obvious val-ue in food production, but biotechnological de-velopments in plants certainly will have otherapplications. Contributions to health care in theform of novel biological substances may result.Floriculture and the forestry industry will bene-fit from the development of new strains and accel-eration of breeding programs. Plants could beused potentially as a source of industrial enzymes.The fiber industry is likely to see an increase inthe production and quality of plant fibers, andan increased production of biomass (organic mat-ter that grows by photosynthetic conversion ofsolar energy) should contribute to the generationof energy in the form of ethanol (39). The pro-duction of energy from biomass is discussed fur-ther in Chapter 9: Commodity Chemicals andEnergy Production.

Commercial aspects of biotechnologyin plant agriculture

Although the generation of new plant varietiesmay be important to the farmer in increasedyields or decreased costs of production or to theend processor in better food products, the com-mercialization of plants developed using new bio-technology is in the hands of seed and live plantproducers. The ability of the U.S. seed and plantproducers to develop and market new plants willdetermine the competitive position of the UnitedStates in plant agriculture. In general, seed pro-duction is not a business where international com-petition plays a role. Because the climates aroundthe world vary so greatly, researchers would haveto do field trials and grow seed in other countries.Thus, each locality generally does its own re-search and seed production.

Excellent research programs in the applicationsof biotechnology to plant agriculture exist in theUnited States, the United Kingdom, and Australia.Because of the climatic differences among thesecountries, the research is concentrated on dif-ferent species.

The seed market is one of the largest marketsto which biotechnology is directed. In the UnitedStates, $4.5 billion of seed are sold to farmers eachyear. Cuttings of vegetatively propagated plantsaccount for $500 million of this market, and the

largest segment of the market, $1.2 billion, is forcorn seed. The world market for seeds is esti-mated at $30 billion. The United States exports$250 million of seeds per year, and U.S. subsidi-aries overseas contribute to world seed produc-tion (85).

Another potentially lucrative market is the mar-ket for cut flowers. This market may be one ofthe easiest horticultural markets to enter withnovel plants produced by biotechnology becauseit readily accepts and depends on novel pheno-types.

It is likely that genetically manipulated plantsmay increase the demand for commercial seeds.Drought-resistant plants could increase the acre-age planted, and other plants might be plantedat higher density, both resulting in an increasein the number of seeds sold.

A phenomenon not necessarily related to bio-technology is the long-established movement byU.S. farmers toward buying new seeds everyyear, rather than saving and planting seeds fromcrops produced the previous year. The evidenceis gathering that seeds from companies give bet-ter results than a farmer’s own seeds. Becausethe cost of seeds is only 3 to 7 percent of agricul-tural direct costs, it behooves the farmer to getthe best seeds possible (85,100). The U.S. soybeanindustry, for example, has moved recently frombuying approximately 20 percent of its seeds afew years ago to buying approximately 40 per-cent of its seeds today (85). This trend couldamplify the demand for seeds produced by bio-technology.

The industrial production of agricultural chem-icals now produced by micro-oraganisms or plantscould be a substantial market. These pesticides,along with pest-resistant and nitrogen-fixingplants, could begin to capture the $10 billiondomestic agricultural chemical market (78).

U.S. corporate investment in agricultural re-search has been high in the last few years. Manyof the firms that have invested in plant biotech-nology are chemical firms, especially firms thatproduce agricultural chemicals. The investmentmay be a response to a potential decrease in theagricultural chemical market due to the develop-ment of plants not needing chemicals (e.g., nitro-

25-561 0 - 84 - 13


gen-fixing plants, pest-resistant plants), the devel-opment of biological pesticides, or the develop-ment of plants with enhanced responses to chem-icals. Another major industrial sector investingin plant biotechnology in the United States is thepetroleum industry. The firms in this sector maysee plants as the next source of energy, either inthe form of biomass or photosynthesis itself. Phar-maceutical and food companies also are investingin plant agriculture. How the large chemical andpetroleum corporations, the existing seed com-panies, and the NBFs will compete for marketshares is yet to be seen.

The seed and vegetative cutting market is verylarge, and it appears that U.S. companies are ori-ented mainly toward domestic markets becauseof the transportation costs and the expense andinconvenience of field trials in other countries.Probably because of large domestic markets,many new entrepreneurial firms are directingtheir efforts toward plant agriculture. In fact, thenumber of NBFs in plant agriculture is third onlyto the number in pharmaceuticals and animal ag-riculture (see Chapter 4: Firms CommercializingBiotechnology).

Priorities for future research

Animal agriculture

The prospects for the application of biotech-nology in the areas of animal and plant agricultureare truly exciting. To encourage the introductionand progress of biotechnology in animal agricul-ture, however, several persistent problems mustbe overcome. These problems include the fol-lowing:

●

●

●

●

●

developing effective delivery systems foralmost all products of new biotechnology tobe used in animals;achieving consistent expression of polypep-tides such as those used for subunit vaccinesfrom rDNA systems;developing host/vector systems that yieldproducts more closely resembling mammali-an molecules (e.g., glycosylated proteins) andthat secrete products for easier purification.demonstrating product stability under the cli-mactic and handling conditions where theseproducts (e.g., subunit vaccines) will be im-plemented; andachieving higher immune responses withsubunit vaccines, for example, by develop-ing delivery systems that prolong exposureto the vaccine.

More basic knowledge about biological proc-esses in animals and about the cellular andmolecular biology of pathogenic bacteria andanimal parasites is required before many biotech-

nological applications are realistic. Advances inbasic knowledge about metabolic pathways inbeneficial bacteria may lead to useful growth-en-hancing compounds. Finally, more basic knowl-edge concerning the actions of nascent productssuch as rDNA-produced GH is needed to discerneffectiveness and safety.

Given the novelty of disciplines such as molec-ular genetics and cellular biology in animal sci-ence, there is some question as to whether suffi-cient communicative links are established yet be-tween basic and applied scientists. The efforts ofapplied scientists usually are communicated toanimal growers in the United States through theland grant universities’ State Agricultural Experi-ment Stations and extension services, supportedby USDA. A corollary to the productiveness offuture research rests in encouraging the establish-ment of communication between basic and ap-plied scientists to encourage biotechnological ap-plications in animal agriculture.

Plant agriculture *

Because interest in plant molecular biology isfairly recent, the most important research priorityis an increased understanding of DNA structure

— . . —“Research goals similar to those outlined in this section were pub-

lished recently by the National Research Council (83) and the Na-tional Academy of Sciences (82).

Ch. 6—Agriculture . 187

and gene expression in plants. * The knowledgegenerated from investigations of DNA sequencesand their functions will be essential to the use ofbiotechnology in crop improvement, although theinitial contributions of biotechnology will not bein crop improvement but in acquiring a betterunderstanding of the basic biology of plants.

It is unlikely that results from laboratory“model” species can be extrapolated to agricul-turally important crop plants. Therefore, researchis needed for improving and understanding thelaboratory culture conditions for cells from theseimportant plants. These plants must be able tobe regenerated from single cells on a routine basisbefore many experiments using novel biologicaltechniques can be performed. Much more workneeds to be done before any plant cell vector canbe used routinely. Additionally, a continuedsearch for vectors for monocots is necessary ifrDNA technology is to have an impact on someof the most important crop species.

It also is important to develop better selectionmethods. For instance, it is essential to be ableto determine rapidly which cells carry specificgenes and whether or not those genes are actingappropriately.

Both basic and applied research efforts in im-proved plant characteristics are quite active. Theeconomic impact of finding disease or environ-mental resistances in the near term are potentiallygreat enough that this research area is the pri-mary thrust of many of the new plant geneticscompanies in the United States. Considerable ef-fort continues in universities, as well, althoughoverall funding for the university effort probablyis much less than that represented by the cur-rent industrial effort. For many desirable traits,the actual protein product of the gene is notknown. Cloning and genetic analysis of such geneswould greatly increase the knowledge of whatkinds of proteins are involved in disease and otherresistances. Other improvements in specific plantcharacteristics may be made by modifying genesin major crop plants or by the introduction of

● ’1’11[’S(’ prioriti[’s onl} c(n er the trrhniques discussed in this re-

port It should I](; noted, though, that gerwtir ad~ancm and applica-tions are ciependent on concurrent research in plant hiorhemistr}and ph~’siologj’

novel traits from other plants. Both approacheswarrant investigation.

Plants are known to produce a variety of sec-ondary metabolizes that have either pharmaceu-tical or agricultural uses, yet little is known aboutthe genetic regulation of their production or thedevelopment of culture systems for optimal pro-duction. Better understanding of these areascould lead to the production of new, improved,or less expensive drugs and compounds that at-tract or repel insects for controlling weeds andpests.

Goals for improved biological nitrogen fixationinclude extending nitrogen-fixing bacterial sys-tems to a wider variety of plants, transferring thebacterial nitrogen-fixing genes to plants, and mak-ing existing nitrogen-fixing systems more efficient.Genetic studies will reveal how nitrogen-fixinggenes are regulated, including how they respondto environmental levels of nitrogen and oxygen.

The extension of any of the nitrogen-fixing sys-ems depends partly on understanding more aboutsurvival and competition of nitrogen-fixingbacteria in field conditions. Temperature ex-tremes, nutrient and pH status of soils, and pres-ence of other micro-organisms are factors thatinfluence colonization of host plants. Reliable,analytical descriptions of the field ecology andphysiology of nitrogen-fixing organisms areneeded.

Much basic biology of microbial insecticides isyet to be understood. In order to determine theappropriate strategy for their use, it is necessaryto study the influence of such factors as sunlight,temperature, rain, and relative humidity on themicroorganisms. Additionally, little is knownabout the mode and schedule of application anddose required for effective use of microa--ganisms in the field. Criteria established by EPArequire an analysis of the pathogen’s possible ef-fect on human and animal health and the environ-ment.

Even with the lack of biological knowledge cur-rently, it is possible to apply the techniques ofbiotechnology to the field of microbial insecti-cides. Approaches include the development ofmore potent strains, an increase in their tolerance


to environmental stresses, and an extension oftheir host ranges. The cloning of the Bacillus toxingene, for example, opens up possibilities for thegenetic manipulation of this gene to produce amore potent toxin and for the transfer of the geneto other microaganisms.

The virus AcNPV currently is well enough char-acterized that its use as a vector is now possible.Some ideas for genetic manipulation include theintroduction of insect-specific toxins and broaden-ing the host range of the virus. The use of fungalinsecticides requires a better understanding of thephysiology, genetics, and pathogenicity of thegenes that code for these insecticides. This under-standing should lead to the development of strainswith increased virulence and greater ease of pro-duction in culture (81).

Plants are capable of producing insecticides, yetlittle is known about their biosynthesis or mode

of action. Further research on this topic wouldallow for more specific, effective, and environ-mentally sound insecticides.

Because of the complexity of the photosyntheticsystem, more basic research is needed on the en-zymatic processes of photosynthesis and theirregulation and compartmentalization. Photosyn-thesis is used for the production of carbohydrates,and understanding how these compounds arepartitioned throughout the plant may allow theability to direct them into the harvestable partsof the plant.

Finally, knowledge concerning the ecologicalresults of growing plants more densely or ofgrowing plants on marginal land is scant. Moreresearch is needed on soil and water use and min-eral cycling plants.

Chapter 6 references*

Animal agriculture references1

2

6.

7.

8.

9.

10.

11.

12.

13.


15,

16,

17,

18,

19,

20

24

25.

26

27

28

*31

32.

for the Office of Technology Assessment, U.S.Congress, August 1982.

Plant agriculture references

38.

*39.

40.

41.

42.

43.

44.

45


63.

64.

65.

66.

67.

68

69.

70,

,71

72

73

74

75

Ch.. 6—Agriculture . 191

79

80

81

*82

*83.

92

93

94

95

9 6

97,

98.

99.

100.

101

Documents

Commercial Biotechnology: An International Analysis (Part