224 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241application of biotechnology in other areas such as in based (Weber et al., 1995). These concerns common-the development of new and improved feedstuffs, as ly arise with the introduction of biotechnology and,well as in microbiology as related to food and for that matter, any other rapid major technologicalbioremediation. Advances in human medical bio- change in agriculture that will affect society.technology form an important basis for research and Acceptance of biotechnology varies to a certaindevelopment in animal biotechnology. degree between consumers from different nations A broad range of topics on biotechnology in (Hoban, 1997). However, the critical characteristicanimal nutrition, physiology and health will be identiﬁed among all consumers is the need foraddressed. This review does not cover areas related education and information on biotechnology. Theto transgenesis, reproduction and molecular genetics, concern about biotechnology relative to other foodwhich are covered in a companion paper in this risks is intermediate. Concerns about bacterial con-series, and b-agonists, steroid hormones and anti- tamination, pesticides, antibiotics and hormones,biotics. It does include reference to some present mold, product alteration, food irradiation, and limittechnologies, such as pro-biotics, that currently in the date passed ranked substantially higher. The accept-strictest sense may not be considered biotechnology, ance and impact of agriculture biotechnology inbut which show great potential for biotechnological developing nations is unclear, but Steinfeld et al.application. Extensive reviews on the application of (1997) suggest that biotechnology could be impor-biotechnology in animal production (Robinson and tant in nations developing a sustainable agricultureMcEvoy, 1993) and in animal nutrition (Wallace and base to supply food for a rapidly growing population.Chesson, 1995) are available. 3. Application of biotechnology for the nutrition2. Public acceptance of biotechnology of farm animals Acceptance of biotechnology in livestock product- 3.1. Feed additivesion is difﬁcult (Mersmann, 1996), and generallymore so than in areas such as crop production, The use of biotechnological products is relativelyhorticulture, food processing and microbiology. The well established in the feed industry and showsdebate about the ethics of cloning humans as a result considerable potential for further growth. A wideof the recent remarkable advancements in sheep range of applications, both current and potential, arecloning (Wilmut et al., 1997) illustrates this. Some presented in Table 2.of the underlying basic concerns governing accept-ance of animal biotechnology, are presented in Table 3.1.1. Nutrients1. The ﬁrst concerns related to ethics, food and The use of crystalline amino acids producedenvironmental safety, and animal welfare are typical through industrial fermentation is extensive (Ber-for consumers in increasingly afﬂuent societies and covici and Fuller, 1995) and has resulted in im-do not apply to biotechnology alone (Steinfeld et al., proved diet formulation and lower feed cost. New1997). The concerns about who will be the areas of research involve the rumen protection ofbeneﬁciary of the new technology and its socio- amino acids, which may lead to signiﬁcant improve-economic impact are relatively new and politically ments in ruminant production efﬁciency, and the useTable 1Factors governing acceptance of animal biotechnology? Ethical concerns: animals are closer to humans than plants and thus gene manipulation is questioned more readily? Risk: food safety and the environment? Welfare of animals? Beneﬁt: trivial or real? Who beneﬁts: the consumer, the producer, agri-industry or all?? Socio-economic impact: concern about the effect of rapid technological change on farm and rural structure.
M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241 225Table 2Application of biotechnology for improving feed characteristics? Silage innoculants? Supplementation of amino acids? Diagnostics for food safety (i.e. mycotoxins)? Removal of anti-nutritional factors and toxins through enzymes? Enzymes for increased digestibility of nutrients (monogastric and ruminant)? Enzymes for increased digestibility of non-starch polysaccharides? Supplementation of endogenous enzymes for improved digestion? Supplementation of immune products such as disease-speciﬁc antibodies? Supplementation of hormones and prebiotics to promote gut growth and health? Supplementation of probiotics? Supplementation of enzymes to reduce nutrient content in wasteof amino acid chelates to improve mineral absorption (Jongbloed et al., 1997), with coincidental improve-efﬁciency. Non-traditional applications of amino ment of dry matter and crude protein digestibility.acids may involve the use of arginine (Hurson et al., New areas of application being studied are the1995) and aspartic acid (Kuhara et al., 1991) as enzymatic destruction of lectins and trypsin inhibitor,potent stimulants of pituitary somatotropin release enzyme supplementation to augment the host’s en-and enhance growth and carcass quality. The novel dogenous enzymes including protease, amylase anduse of substrates such as glutamine, arginine, or- lipase (Classen, 1993), and the inclusion of ﬁbrolyticnithine and nucleotides for gut and immune system enzymes in diets for monogastric animals to improvedevelopment and function in young animals is an the digestibility of ﬁber.active area of research (Gardiner et al., 1995). Our understanding of the factors controlling effec- tiveness of enzymes remains rather limited. This3.1.2. Enzymes slows progress in many areas. In particular the The use of microbial enzymes to improve feed interaction between feed source, feed processingquality is extensive and several extensive reviews are including temperature, moisture and mineral con-available (Bedford, 1996; Wallace and Chesson, tent., diet nutrient composition, gut microﬂora and1995; Classen, 1993; Campbell and Bedford, 1992). the host on enzyme supplementation effectiveness isEnzymes are used to: (1) Remove anti-nutritional poorly understood and is an active area of research.factors and toxins; (2) Increase digestibility of The use of ﬁbrolytic enzymes in improving di-existing nutrients; (3) Increase digestibility of non- gestibility of ﬁbrous feeds for ruminants is also ofstarch polysaccharides; (4) Supplement host endog- considerable interest (McAllister et al., 1995). Theenous enzymes. Enzymes cannot be applied broadly beneﬁt of enzyme supplementation of ruminant dietsand their use is speciﬁc to certain feeds and phases is variable, probably because of complex interactionsof growth in poultry and livestock. due to the presence of the rumen fermentation Glucanase is aimed at improving digestibility of system and the much greater variability in the qualitynon-starch carbohydrates in viscous cereals such as of the feedstuffs, particularly of forages and silage.barley and oats, thus reducing the viscosity in the gut Feed enzyme supplementation has good potentiallumen of broiler chicks and piglets. Xylanases are for broader application, which largely depends ondirected at viscous polymers in wheat, rye and development of new enzymes, better identiﬁcation oftriticale. Recent research suggests that mixtures of the optimal conditions for feed processing includingxylanase, protease and amylases improve digestion physicochemical interactions, and identiﬁcation ofin low-viscous cereals such as corn and sorghum the optimal conditions ﬁr use in animals. Feed(Pack et al., 1998). Phytase has been used on large enzymes also have considerable potential to improvescale to reduce the phosphorous content in manure the availability of nutrients from by-products, suchthrough improved digestibility of the anti-nutrient as rice bran, which serve as an important source ofphytate and reduced phosphate content in the diet livestock feed in developing nations.
226 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 2413.1.3. Pre- and pro-biotics antibodies to speciﬁc diseases is in an early phase of Manipulation of the microﬂora in the intestine development. In the short term, however, the pro-through the use of prebiotics and probiotics repre- duction of antibodies in an alternate host showssents an additional opportunity for the improvement considerable promise. Laying hens can be vaccinatedof nutrient digestion, disease resistance and health against speciﬁc viral and bacterial pathogens com-(Kelly et al., 1994, Salminen et al., 1998). The monly responsible for high morbidity and mortalitycomposition of the intestinal microbial population in weaning pigs (Yokoyama et al., 1992). The eggand competitive exclusion of pathogens has pro- yolk, rich in disease-speciﬁc antibodies, is spray-gressively been recognized as a signiﬁcant factor dried and fed to weaning pigs with the addedimpacting on health and growth performance. Pre- advantage that a highly nutritious product is pro-biotics may be deﬁned as compounds, other than a vided. Vaccination protocols can be kept up to datedietary nutrient, that modify and balance the micro- by including the most recent pathogens of concernbial ﬂora, promote the growth of beneﬁcial bacteria and reﬂecting regional disease pressure, and the feedand thus provide a healthier intestinal environment product antibody content can be titered for maximalfor a better absorption of nutrients. Probiotics can be effect. These products generally target prevention ofdeﬁned as those microorganisms which, when ad- infectious disease, however therapeutic antibodyministered to animals or humans, may provide products also can be formulated (Kellner et al.,beneﬁcial effects to the host by improving the 1994). Antibody products, similar to pre- and pro-environment of the indigenous microﬂora. The shift biotics, would be expected to alter the gut microbialin microbial populations as a result of pre- and ﬂora and prevent adhesion of pathogenic organismspro-biotic treatments then leads to a reduction in the to the gut mucosa (Imberechts et al., 1997). Inproliferation and attachment of pathogenic organisms addition to the observed improved feed intake andand reduces the incidence of disease. Generally, pre- growth in young animals, these products may reduceand pro-biotic products have provided inconsistent the dependence on antibiotics for disease control.results, and research to better deﬁne optimal feed Other immune products under development in-processing and application in animals is ongoing. clude dietary immunostimulants that enhance mucos-The effects appear greatest in young fast growing al immunity in the gut, hormone-modulating anti-animals during speciﬁc periods when microbial ﬂora bodies and hormones. Oral delivery of the immunois subject to large change, such as after weaning, and stimulant oat b-glucan was shown to enhance gutdiminish with age. This age effect is consistent with mucosal immunity, reduce the oocyst discharge inthe capacity of the normal gut ﬂora to resist change mice infected with Eimeria vermiformis, and reverseas the animal grows. the immunosuppressive effect of dexamethasone (Yun et al., 1997). Similarly, Yun et al. (1995)3.1.4. Immune product supplements demonstrated that immunoneutralization of somatos- Immune products may be included in feeds spe- tatin, a gut hormone with immunosuppressive prop-ciﬁcally to alter microbial ﬂora and to reduce the erties, through systemic delivery of a monoclonaleffect of pathogens. One of these products is spray antibody increased resistance of mice to coccidiosis.dried plasma protein containing antibodies that pro- Oral delivery should yield a similar response. Epi-vide protection, sometimes variable, against common dermal growth factor (EGF) is a potent gut hormonepathogens. Spray dried plasma protein consistently that enhances intestinal development and reducesimproves feed intake and growth in pigs weaned bacterial translocation. Buret et al. (1997) demon-early (for review see Stein, 1996). This product is strated in E. Coli-challenged rabbits that oral EGFderived from blood collected at slaughter plants, and reduced colonization of E. Coli in the jejunum, ileumtherefore the protection provided depends on the and proximal colcin, and prevented a decrease inexposure of pigs to pathogens prior to slaughter. jejunal maltase and sucrase activities. The results Several different approaches in providing animals from these studies indicate that there may be signiﬁ-with protective antibodies through the diet are being cant opportunity for dietary non-nutritional productsstudied. The transgenic expression in plants of edible to improve gut health and development.
M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241 2273.2. Transgenic approaches for improved nutrition Research to improve feeding value of crops mustand metabolism be interdisciplinary involving both plant breeders and animal nutritionists so that trait modiﬁcation will3.2.1. Plant biotechnology beneﬁt both crop and livestock industries. Further- Traditionally plant breeders have focused on im- more, traits must be selected on the basis of improv-proving the agronomic characteristics of crops, in- ing the sustainability and efﬁciency of the entirecluding yield, disease resistance, and quality charac- production system from crop agronomy to animalteristics required for human food. Improved feeding production to meat processing. Typical examples arevalue of crops for animals was not emphasized and, the improved digestion of phytate through dietarymostly, animal feed is considered to be food not supplementation with phytase (Jongbloed et al.,suitable for human consumption or a byproduct from 1997) or incorporation of phytase in crops, and thefood processing. Consequently animal feed is char- development of hulless grains with improved pro-acterized by high variability in quality and unpredict- cessing characteristics and feeding value (Bell andable feeding value. These conditions limit animal Keith, 1993), both of which reduce the nutrientproduction efﬁciency and increase the burden on the density of animal waste.environment. Biotechnology allows the plant breeder Plant biotechnology also allows for some novelto incorporate very speciﬁc characteristics in crops, approaches in the production of valuable compo-including those (Table 3) that improve the process- nents, which could have a large impact on theing characteristics and feeding value for animals livestock industry (Table 3). Of particular interest is(Kuhn, 1996). Therefore, under favorable economic the incorporation in plants of edible vaccines (Dal-conditions, we may well see the emergence of crops sgaard et al., 1997; Mason et al., 1996), antibodiesspeciﬁcally designed for animal feed, targeted for a (Ma et al., 1995), and potentially of enzymes andcertain class and type of animal and may even hormones that could inﬂuence gut function.include speciﬁc enzymes and health products. Aspeciﬁc example is the development of high oil corn 3.2.2. Animal and microbial biotechnologywith signiﬁcantly enhanced feeling value (Adeola Genetic manipulation of animals and microorga-and Bajjalieh, 1997), which provides increased ﬁnan- nisms (Table 4) holds considerable promise, but willcial return to both crop and animal producers. require considerable time and investment, includingTable 3Application of plant biotechnology for improving animal feeds? Plant products will change from generic feed to speciﬁc feed tailored for deﬁned feeding purpose s and animal types? Diagnostics for identiﬁcation of cultivar, feeding characteristics? Improved nutrient composition? Reduction in anti-nutritional factors such as phytate, molds? Improved processing characteristics of feed product? Control of rumen fermentation rates of protein and carbohydrates? Incorporation of edible vaccines produced in transgenic plants to protect against infectious disease? Incorporation of antibodies speciﬁc to enteric disease? Incorporation of hormones and pre-bioticsTable 4Transgenic approaches in animals and microbes for improved nutrition and metabolism? Microbial biotechnology: rumen and gut recombinant organisms, including gut commensal organisms? Recombinant expression of gut enzymes? Recombinant expression of enzyme pathways for de novo substrate synthesis and for improved efﬁciency in nutrient metabolism? Recombinant enhancement of gut growth and nutrient absorption potential
228 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241a lengthy process to obtain the necessary regulatory active area of research (Forsberg et al., 1993) and isapproval. Transgenic introduction of metabolic path- covered by several papers in this Conference.ways may remove inherent nutritional and metaboliclimitations, leading to substantial improvement infeed utilization efﬁciency. 4. Application of biotechnology to increase Limited absorption of glucose and a high rate of performance in farm animalsgluconeogenesis (Brockman and Laarveld, 1986)characterize ruminant metabolism. Acetate and prop- Some of the earlier applications of biotechnologyionate are both major products of rumen fermen- were the growth and lactation enhancing agents, suchtation, but only propionate is an important as recombinant somatotropin, and development ofglucogenic substrate. Metabolic efﬁciency would be transgenic animals with enhanced growth perform-improved through the transgenic introduction of a ance. The areas of study (Table 5) have broadenedmetabolic pathway for converting acetate into glu- considerably as a result of a better understanding ofcose. Saini et al. (1996) have achieved this in mice the underlying physiology governing growth andby expressing the bacterial glyoxylate cycle genes in carcass composition, and because of the discovery ofliver and intestine. Introduction of these genes in novel hormonal systems such as those of myostatinruminants would be expected to enhance feed ef- and leptin.ﬁciency, particularly when forage-based diets arefed. 4.1. Myostatin The supply of sulphur amino acids can limit woolgrowth in sheep. Ward and Nancarrow (1992) are Skeletal muscle hyperplasia, commonly referred totargeting sheep rumen epithelium for the transgenic as double-muscling, is an inherited condition ob-expression. of the enzymes serine acetyltransferase served in several breeds of cattle. The molecular andand o-acetylserine sulfhydrylase. This pathway en- physiological mechanisms responsible for the hy-ables de novo synthesis of cysteine from inorganic perplasia are not well understood. Grobet et al.sulphur and removes a nutritional limitation to wool (1997) reported that in the Belgian Blue breed an 11growth. Other transgenic research focusing on im- base pair deletion in exon 2 for the bioactive domainproved digestion includes the expression of cellulase for myostatin on bovine chromosome 2 is respon-in the pancreas of monogastric animals (Hall et al., sible for the muscular hypertrophy, and recently the1993). Other potentially rewarding areas of trans- mutation was shown in exon 3 in the Charolaisgenic research would be the incorporation of meta- breed. Myostatin is a member of the Transformingbolic pathways to synthesize essential amino acids de growth factor (TGF-b) superfamily. The identiﬁca-novo or to enhance nutrient absorptive capacity. tion of the myostatin gene will allow the develop- Transgenic commensal organisms (Chang, 1996) ment of diagnostic tests for genetic selection in cattlehave considerable potential for improving nutrition, and other species. The discovery of the importantgut development and health in animals. These mi- role of myostatin within the TGF-b family alsocrobes, capable of colonizing tie gut, could deliver opens up a whole new area of study of the physio-recombinant products, including enzymes (similar to logical regulation of muscle development throughthose described in the enzyme section above), pre- myostatin-mediated pathways, including the myos-biotic compounds, immunostimulants, mucosal vac- tatin receptor, and the interaction with other growthcines and hormones. The development of these factors. This advancement will lead to new ap-recombinant commensal microbes is particularly proaches in the manipulation of muscle development,intriguing as this technology, in contrast to trans- including immunomodulation and transgenesisgenic animals, could be widely available to livestock targeting myostatin or its receptor.producers. Containment of these recombinant organ-isms is a concern (Ramos et al., 1995) and may be 4.2. Leptindealt with through co-incorporation of multiplesuicide genes. The development of transgenic rumen Leptin is a newly discovered hormone produced inmicrobes with enhanced ability to digest ﬁber is an adipose tissue. Mutations in the adipose-speciﬁc OB
M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241 229Table 5Application of biotechnology in animal physiology for improved growth, feed efﬁciency and carcass quality? Nutrient Partitioning and Growth Promotion: ? Recombinant proteins: – Somatotropin (ST) and related products including growth hormone releasing hormone (GHRH) – Insulin-like growth factor (IGF-1) and its analogues and binding proteins ? Induced mRNA expression of GHRH in muscle ? Regulation of GLUT 1 and 4 expression in gut and adipose tissues for control of glucose transport ? Immune modulation: – Immunoneutralization of somatostatin – Immunoenhancement of injected and native ST, GHRH, IGF-1 ? Genetic marker assisted selection for growth and carcass quality re]Lated parameters ? Control of stress-disease-growth interactions? Leptin and Control of Feed Intake: ? Genetic marker assisted selection against the OB (obese) gene ? Immunization against leptin to enhance feed intake ? Immunoneutralization (inactivation) of the leptin receptor? Muscle Development and meat quality: ? Immunocastration of boars ? Discovery of the myostatin locus responsible for muscular hypertrophy in bovine will a low for diagnostic testing for this trait ? Myostatin immunomodulation may allow control of muscle developmentgene producing leptin and in the OB-R gene produc- potential usefulness in increasing appetite in live-ing the leptin receptor result in obesity (for a review stock.see Houseknecht et al. 1998, Trayhurn, 1998). Leptinlevels in blood are strongly correlated with the 4.3. Administration of exogenous agents obtainedamount of adipose tissue accumulation, and high by genetic engineering (somatotropin and relatedleptin levels were ﬁrst observed to inhibit feed intake compounds)through binding to a speciﬁc receptor in the hypo-thalamus. It is now known that leptin regulates feed 4.3.1. Effects on performanceintake, energy metabolism, body composition, and The administration of natural or recombinantrecent observations point to a role in reproduction somatotropin (ST) accelerates muscle growth andand in the immune system. The discovery of leptin reduces fat deposition in most farm animals. ST isopens up a whole new area of study on the regulation very effective in pigs (Etherton et al., 1986; Camp-of feed intake and other areas important in metabolic bell et al., 1989), less so in ruminants (Moseley etefﬁciency. Leptin and its receptor have been gene al., 1992; Verstegaard et al., 1993) and mostlymapped for number of species and a number of ineffective in chicken (Bonneau, 1991b). Growthmicrosatellites have been identiﬁed to assist with hormone-releasing hormone (GHRH) or its analogsgenetic selection. Fitzsimmons et al. (1998) con- have the same effects as ST, however they are lessﬁrmed the potential application of selection for the effective in growth stimulation, particularly in theleptin gene in beef cattle using a microsatellite pig species which is relatively resistant to GHRHmarker. Polymorphisms were associated with differ- due to a high somatostatinergic tone. Insulin-likeent carcass fat characteristics, and the gene fre- growth factor-1 (IGF-1) is a potent mitogenic hor-quencies differed between British breeds and mone and its concentration in blood is highlyCharolais and Simmental breeds. The discovery of correlated with growth. However, the regulation ofleptin may lead to a range of new technologies, such the secretion of IGF-1 and its biological activity isas immunoneutralization, anti-sense and hormone highly complex (Brameld, 1997), and this maytreatments, aimed at reducing leptin and thus increas- explain why IGF-1 administration has had littleing feed intake. In particular 133-agonists have been effect on the performance of the farm animalsshown to reduce expression of leptin in adipose investigated thus far. Current investigation focusestissue and reduce plasma leptin, indicating their on IGF-1 analogs that are more potent than IGF-1
230 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241itself, and on manipulation of the binding proteins manufacturing properties of milk or on the or-for IGF-1 in plasma which appear important in ganoleptic quality of cheese (Laurent et al., 1992).determining tissue-speciﬁc biological effects of IGF-1. 4.4. Immunomodulation The administration of recombinant bovine STincreases milk production in dairy cows (Bauman Immunoneutralization of somatostatin, the hypo-and Vernon, 1993), and in excess of 1000 studies thalamic factor that inhibits ST release from thehave been conducted, involving over 20 000 dairy pituitary, has provided either positive or no growthcows (Bauman, 1992). Bovine ST now is in wide- responses. Different vaccination and experimentalspread commercial use in a number of countries. protocols used, and variable immune responses in The long-term delivery of these exogenous agents both titer and antibody afﬁnity are likely responsible.is accomplished through injectable slow-release Somatostatin has a wide range of physiologicalformulations, which are still variable. Recently, inhibitory effects in the brain, intestine, liver, pan-Draghia-Akli et al. (1997) demonstrated an alternate creas and immune system, resulting in complexmethod of delivery for GHRH, by injecting GHRH responses to immunoneutralization. Yun et al. (1995)DNA in a myogenic vector, resulting in expression showed that immunoneutralization of somatostatinof GHRH in muscle of mice and increased ST levels enhanced gut immune function in mice challengedin plasma. This delivery method would be applicable with a parasitic disease. This suggests that growthto other agents, but requires considerable further responses to somatostatin immunoneutralization maydevelopment before it can be applied commercially. be mediated, at least in part, through enhanced immunity. This could explain, in part, the variability of the responses observed and the observation that4.3.2. Consequences for product quality growth responses may be more likely in animals with The reduction of adipose tissue development in sub-optimal growth (van Kessel, 1992). A majorST-treated pigs may have favorable or adverse limitation to immunomodulation using active im-consequences on pork meat quality, depending on munization is that the level and duration of thegenotype of the animals. In very lean genotypes, the immune response and the magnitude of physiologicalobtained further reduction in fat development results response are poorly controlled. A passive immuniza-in carcasses that are too lean, with too little, poor tion approach using monoclonal or polyclonal anti-quality fat (soft and prone to oxidation) and lack of bodies may provide better control, but also is morecohesion between fat and underlying muscle. costly. ST or GHRH have little effect on the quality of The classical role of antibodies is to neutralize thebeef, mutton or pork. The lower intramuscular lipid compounds against which there were raised. In somecontent may be responsible for the slight reduction in cases, however, monoclonal (or sometimes eventenderness that is often observed in pork (Bonneau, polyclonal) antibodies raised against a hormone can1991a). Administration of pST has been shown to paradoxically potentiate the activity of the nativereduce the incidence of boar taint in entire male pigs hormone. This has been demonstrated for ST in(Hagen et al., 1991; Bonneau et al., 1992). sheep and pigs, and also for a number of other Changes in milk composition due to bST depend hormones, including TSR, GHRH and IGF-I (Pellon the energy balance of the dairy cow. Bovine ST and Aston, 1995). Provided that the relevant an-during negative energy balance increases milk fat tigenic portion of the hormone can be identiﬁed,content. Short term variations in milk composition vaccination (active or passive) of animals to poten-are observed in relation to the time of administration tiate the effect of their anabolic endogenous hor-of sustained-release formulations of bST. Milk fat mones can be envisaged for a more efﬁcient meat orcontent tends to increase whereas protein content milk production (Flint, 1995; Holder and Carter,tends to decrease in the week following the adminis- 1995). ´ ´tration (Verite et al., 1989). However, the effect over Fat deposition can also be directly inhibitedlong periods of time is minimal and no clear-cut through the development of antibodies directedinﬂuence of bST treatment has been observed on the against adipose tissue plasma membranes (Moloney,
M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241 2311995). Targeting pre-adipocytes rather than fully some aspects of health, including increased incidencedeveloped adipocytes might however be a better of osteochondrosis, cartilage soundness and stomachstrategy for future developments (De Clercq et al., ulcers (Sejrsen et al., 1996). ST treatment of pigs1997). also results in a state of insulin resistance character- Immunomodulation of growth and lactation could ized by elevated plasma levels of both glucose andbe considered as more acceptable than the exogenous insulin (Etherton et al., 1986). Finally, the need foradministration of growth promoters, since it does not repeated injection may cause some stress for therequire repeated injections of hormonally active animals.compounds. However, less stressful modes of im- In dairy cows, fecundity and fertility are nega-munization have to be developed and the innocuous- tively affected when bST is administered beforeness of the vaccines for both the animals and the breeding (Burton et al., 1994), in relation with theconsumers of animal products have to be fully negative energy balance of the animal. Otherwise,demonstrated (Mepham and Forbes, 1995). reproduction performance is little affected. However, depending on feeding regime, cows may sometimes4.5. Transgenesis be unable to reach a satisfactory level of fat deposi- tion before they start a new lactation (Chilliard et al., An excellent review of the potentials offered by 1998). On the whole, bST administration has notransgenesis for enhancing performance of farm effect on the incidence of infectious disease in dairy ¨animals is available in Muller and Brem (1996). cows (Burton et al., 1994). However, the frequencyGene transfer in farm animals appears to be much of clinical mastitis may be signiﬁcantly increased, inmore difﬁcult than anticipated from the relative ease relation with the augmentation of milk productionwith which it can be performed in mice. (Willeberg, 1993; White et al., 1994). Administration Numerous experiments were successful in trans- of exogenous pST to lactating sows results in severeferring somatotropin (ST) genes in ﬁsh and in large energy deﬁcit and difﬁculties for adjusting internalmammals. In most studies with ﬁsh (Brem, 1993; temperature. High rates of mortality were observedMaclean and Rahman, 1994) and pigs (Pursel et al., in ST-treated lactating sows in a tropical environ-1989), the ST gene was expressed and the transgenic ment (Cromwell et al., 1989).animals grew faster, had a better efﬁciency and were In a number of species, ST treatment reduces theleaner, the effects being similar to those obtained detoxifying capacity of the liver (Witkamp et al.,with the administration of exogenous ST (see above). 1993), which may have some negative consequencesTransfer of ST constructs in cattle, sheep, goat and on the elimination of xenobiotics by the animals.poultry were so far less successful because no Following the demonstration that hGH in vitro cantransfer was achieved or the transferred gene was not stimulate the replication of some retroviruses (Laur-expressed or the expression did not result in im- ence et al., 1992), preliminary results suggest thatproved performance. Pursel et al. (1998) have re- bST treatment could stimulate the production ofcently obtained increased muscle growth in the pig some viruses in ewes and goats (unpublished results).after targeted expression of IGF-I in muscle. Because it does not imply repeated injections of A c-ski gene construct was successfully trans- hormonally active compounds, immunomodulationferred and expressed into swine (Pursel et al., 1992) of growth could be considered as more acceptableand into a calf (Bowen et al., 1994), resulting in than the exogenous administration of growth promot-some degree of muscle hypertrophy. ers. However, less stressful modes of immunization have to be developed (Mepham and Forbes, 1995).4.6. Concerns over the safety of the In the ﬁrst studies involving transgenic pigs, thebiotechnological manipulation of performance in transferred GH gene was expressed ubiquitously andfarm animals was not regulated. The animals had severe health problems and were unable to reproduce (Pursel et al.,4.6.1. Safety and welfare for the animals 1989; Pinkert et al., 1994). In subsequent studies, Administration of high doses of ST to growing transferred GH or IGF-I genes were coupled topigs or steers may have adverse consequences on promoters enabling lower production of GH through
232 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241time control or tissue speciﬁcity of gene expression 5. Applications of biotechnology to improve(Polge et al., 1989; Wiegart et al., 1990; Nottle et al., product quality and safety1997; Pursel et al., 1997). The resulting transgenicpigs had no, or at least less, apparent physiological 5.1. Detection of residues and pathogens in animaltrouble. Transfer of the salmon GH gene in salmons productsor trouts results in a few symptoms of acromegaly(Devlin et al., 1997). The latest developments of biotechnology, par- The transfer and expression of the c-ski gene ticularly monoclonal antibodies, RFLP, DNA probingresulted in severe muscle degeneration in both pig and PCR, have opened large possibilities for the(Pursel et al., 1992) and calf (Bowen et al., 1994). improvement of methods for the detection of patho- gens and trace residues of drugs or other undesirable4.6.2. Safety for the consumers of animal products compounds in animal products (Mattingly et al., In contrast to steroids and 13-agonists, ST is 1985; Marshall and Hodgson, 1998).heat-labile, species-speciﬁc and destroyed by diges-tive enzymes. The very low levels of residual ST that 5.2. Immunomodulationcould possibly be found in the meat or milk ofST-treated animals are therefore not a real concern Immunocastration of male pigs can be envisagedfor human safety (Butenandt, 1996). The content of for producing boar taint free entire male pigs if atIGF-l in milk, although very low, is increased up to 5 would have most of the advantages of entire malefold (Burton et al., 1994) in the milk of bST-treated pigs without adverse consequence; on meat qualitycows. Yet, these IGF-l levels remain within the (Bonneau and Enright, 1995).normal range observed in human milk. According toButenandt (1996), ‘‘the use of growth hormone in 5.3. Transgenesismeat or milk production will not bear any risk for thehuman consumer’’. ST is deemed safe for human The composition of milk can be altered usingconsumption by many ofﬁcial regulatory agencies transgenesis (Houdebine, 1998), in order to: (1)and ofﬁcial professional societies. modify the proportion of natural components for better nutritional characteristics; (2) add new com-4.6.3. Safety for the environment pounds that can be beneﬁcial for human or animal Performance enhancement in animals through nutrition; (3) produce proteins with pharmaceuticalapplication of biotechnology leads to substantial or veterinary use (this latter possibility being out ofimprovement in efﬁciency of feed utilization and the scope of the present paper).reduces the excretion of nitrogen and phosphorus in Lactose-free (Stinnakre et al., 1994) or lactose-the manure. Therefore, the environmental impact is light (L’huillier et al., 1997) milk has been producedgenerally positive. in mice by disrupting the b-lactalbumin gene. In Because large mammals and poultry are usually homozygous mutant mice the milk was highlyraised in controlled conditions, the possibility that viscous and devoid of b-lactalbumin and lactose, andthey breed with wild animals, although existent (e.g. pups were unable to remove it from the mammarydomestic swine with wild pigs), is quite unlikely. gland. Heterozygous mutant mice showed a 40%There is therefore very little risk of dissemination of decrease in b-lactalbumin, but only a 10–20%transgenes into the wild animal population. However, decrease in the lactose content of their milk. Thesethe risk with transgenic ﬁsh is greater, since they results conﬁrm the importance of b-lactalbumin andcould escape conﬁnement more easily and compete lactose, through its important osmotic effect, inand / or breed with wild type ﬁsh. This problem can determining milk volume and demonstrate the po-be addressed by taking drastic precautionary mea- tential to manipulate milk composition.sures in farms raising founder ﬁsh populations, while Elevated proportions of casein-b (Persuy et al.,using only sterile animals (through for instance 1992) or casein-k (Guttieriez et al., 1996), thattriploidy) in regular production farms. would result in improved manufacturing properties,
M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241 233have been obtained in mice. Much work has still controlling animal diseases. However, they have aneeded before the genetic engineering techniques number of limitations. With live attenuated vaccines,that were used to achieve the above-mentioned there are always some concerns about the stability ofresults can be applied to farm animals (Mercier and the attenuation and possible recombination with wildVilotte, 1997). strains. In some cases, the traditional approaches are The production of compounds that are not normal unsuccessful in that it is not possible to produce amilk constituents can be achieved through gene vaccine that is both efﬁcient and innocuous. Vacci-addition. Human lactoferrin (that could be beneﬁcial nated animals cannot be differentiated from theirin human and animal neonates) his been produced in infected counterparts, which may cause numerousthe cow (Krimpenfort et al., 1991) and the pro- problems in disease control programs.duction of numerous other proteins can be envisaged New generations of subunit and attenuated vac-(Houdebine, 1998). cines have been recently developed with aid of biotechnology. Subunit vaccines rely on recombinant techniques to produce a relatively pure protective6. Application of biotechnology for improved antigen(s) for formulation with adjuvant (Doel et al.,health and welfare of farm animals 1990). Subunit antigen vaccination allows for dif- ferentiation of naturally infected versus immunized6.1. Application of biotechnology for improved animals but this approach does not always providehealth of farm animals for adequate protection. Pathogen attenuation by gene deletion and live Biotechnology has already had a major impact and vectoring of antigen by insertion of foreign antigenwill have numerous applications in a number of in gene deleted mutants (Brochier et al., 1991) offersmajor ﬁelds related to animal health, including promise of delivering antigen via natural mucosaltransgenesis, vaccines, diagnosis tests, treatment and routes. Mucosal routes of antigen delivery may bedisease control (Table 6). more efﬁcacious for induction of protective immune responses which is an idea highlighted by the6.1.1. Vaccines tremendous interest in this area (McGhee et al., Traditional vaccines, be they attenuated or inacti- 1992). Vectoring antigen in attenuated pathogens canvated, have often proved to be very efﬁcient in provide protection against the vector itself and theTable 6Application of biotechnology for improved health and welfare in animals? Vaccines: – Deleted vaccines – Recombinant sub-unit vaccines – DNA vaccines – Vaccine speciﬁc to genotype of animal – Vaccine adjuvants – Mucosal vs. Systemic vaccines? Vaccines and antibodies produced in plants and administered in a puriﬁed form? Edible vaccines and antibodies generated in plants? Immunomodulators (non-speciﬁc)? Immune diet supplements (preventative and therapeutic)? Pre- and pro-biotics? Diagnostics: – Genetic-BLAD, MHC, disease-genotype interactions – Disease speciﬁc-viral, bacterial, parasitic – Acute phase proteins indicative of early stage infection? Immunocastration vaccines for the control of fertility and undesired breeding behaviour? Neutralization of prolactin or VIP to control broodiness in turkeys
234 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241inserted foreign gene. Although vaccine vectoring Vaccination can be achieved through consumption ofhas been largely focused on viruses, an attenuated the whole plant material. Provided that the resultingsuicide bacteria was recently constructed to deliver immunogens are orally active, this would be a veryforeign antigen to macrophages (Dietrich et al., cheap and convenient way of producing and adminis-1998). Similar to subunit vaccines, gene-deleted and tering vaccines for farm animals. Promising resultsvectored vaccines are also advantaged in that vacci- have been obtained in mice (Mason et al., 1996).nated animals can be differentiated from their natu-rally infected counterparts (van Oirshot et al., 1990). 6.1.2. DiagnosisConcerns over biosafety are, at least in part, ad- The use of monoclonal antibodies and DNA / RNAdressed by construction of deletion mutants in such a probes offers large possibilities for improved diag-way so that they cannot be transmitted (Peeters et al., nosis tests (McCullough, 1993; Jackwood, 1994;1994.) or are unable to replicate (Eloit and Adam, Zarlenga, 1994).1995). Monoclonal antibodies have numerous advantages The injection of naked DNA constructs coding for over their polyclonal counterparts. They are highlyforeign antigen driven by eucaryotic promotors may speciﬁc for their antigens and they can be producedelicit an immune response that is speciﬁc for that in unlimited quantities. Like polyclonal antibodies,antigen (Davis and Whalen, 1995). The technique monoclonal antibodies can be used in immunoassays,provides for cytosolic antigen delivery potentially particularly in ELISA and related tests. Applicationfavoring a protective cell mediated immune response for such tests is widespread for the detection andwithout release of a viable organism. There are identiﬁcation of a variety of viruses, bacteria andhowever a number of problems to be solved before parasites (Weil et al., 1985; Lunt et al., 1988).naked DNA vaccination can be used in farm con- Because they are highly speciﬁc, nucleic acidditions. Procedures have to be standardized in order probes are very useful for the detection and recogni-to obtain less variable immune responses. Biosafety tion of a large variety of pathogens. Non-radioactiveis a real concern as the presence of the injected DNA probes are much easier to handle than the radioactivemust be avoided in germinal cells or in tissues ones, however they may lack sensitivity. This prob-destined for human consumption. Using mRNA lem can be solved via ampliﬁcation of the signalinstead of DNA could address the safety concerns, with PCR (Polymerase Chain Reaction; for a reviewhowever efﬁcacy, cost and ease of utilization re- see Pfeffer et al., 1995). PCR can also be coupledmains to be investigated. with RFLP (Restriction Fragment Length Polymor- Adjuvants are necessary to enhance the immuno- phism; Kwon et al., 1993) or nucleic acid sequencinggenicity of many vaccines. The development of for a better identiﬁcation of pathogens. The rapidlyadjuvants is, to a large extent, a quite empirical emerging DNA chip technologies will allow large-process. New generation adjuvants are being de- scale diagnostic and genetic testing (Marshall andveloped through chemical synthesis or genetic en- Hodgson, 1998).gineering, in order to reduce the inappropriate im- Comparatively to the classical morphological andmune response or potential severe contra-indications serological methods, the use of nucleic acid probes,of the traditional a adjuvants (Alexander and Brewer, sometimes coupled with PCR, can eliminate much1995). Modiﬁed bacterial toxins can also be consid- ambiguity and subjectivity in the identiﬁcation ofered as antigen delivery systems capable of enhanc- numerous unicellular or pluricellular parasites anding immunogenicity (Aitken and Hirst, 1995) Many have facilitated the detection of previously undiag-of the deleterious effects of the traditional adjuvants, nosed parasitemia (see review by McManus andincluding injection site trauma, may be avoided by Bowles, 1996).delivery of vaccines via mucosal routes. Live vector- The potential of acute phase cytokine and / oring, microspheres and liposomes all offer protective protein assays are being examined for clinical appli-mucosal responses without use of traditional ad- cation (Francisco et al., 1996) and applications injuvants. meat inspection (Eckersall, 1992). Analysis of the Vaccines can be produced in transgenic plants. acute phase response may provide for differentiation
M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241 235between viral and 14 bacterial infection, indicate represents a novel transgenic approach to improvedherd health status or identify animals which are disease resistance (Ward et al., 1993).likely to progress to overt clinical signs of infection. Although the transfer of disease-resistance capaci- ty is potentially very interesting, there are still very few applications of these techniques for farm ani-6.1.3. Treatment and disease control mals, particularly because their development needs The use of antibiotics, extracted from various huge investments in time and money.bacteria and fungi, is one of the most important Animal health is a major ﬁeld that will beneﬁtapplication of biotechnology for animal health. greatly from the development of biotechnology,Numerous antibiotics are now semi-synthesized or particularly of genetic engineering. The most ad-totally synthesized. Other molecules, from the Iver- vanced applications are in the area of recombinantmectine family, have been extracted from micro- vaccines and diagnostic tests, where the potential fororganisms and have been proved to be efﬁcient in development is still immense. The transfer of diseaseparasite control. resistance is potentially very interesting but still little Monoclonal antibodies can also potentially be developed in farm animals. There are also still veryused for the treatment of diseased animals. However, few applications of the latest development of bio-the costs associated with passive immunization of technology in the ﬁeld of disease treatment. Bio-farm animals may be too high in most cases. technology provides the opportunity to tackle dis- The availability of recombinant cytokines allowed eases thus far untreatable. Biotechnology can some-investigation of their application in control of infecti- times replace chemical or antibiotic therapies thatous disease of livestock. Modulation of immune may be costly, harmful to the consumer of animalresponse by systemic cytokine administration often products or induce antibiotic resistance in germshas not yielded the expected protection from clinical threatening human health.disease (Baca-Estrada et al., 1995, van Kessel et al.,1996). Positive results were dependent upon precisetiming of cytokine delivery in advance of infectious 6.2. Application of biotechnology in behavior andchallenge (Babiuk et al., 1991). Commercial viability welfare of farm animalsof cytokine therapy in disease control awaits de-velopment of more appropriate delivery systems and Anti-GnRH vaccination (immunocastration) is ana better understanding of highly complex cytokine effective way of castrating farm animals withoutnetworks. Natural immune stimulants, which evoke a causing them the suffering associated with themore physiological cytokine cascade, may provide physical castration (Bonneau and Enright, 1995).an alternative method to improve disease resistance Immunocastration has been shown to prevent aggres-in domestic animals (Yun et al., 1997). sive and sexual behavior in bulls, estrus behavior in heifers and boar taint in pigs. Alternatively, immuno-6.1.4. Transgenic disease-resistant animals castration could also been obtained via immunization The transfer of disease-resistance genes is poten- against the LH and / or FSH receptor, however, thistially a very important application of biotechnology technique has so far been effective only in rodentsin animal production. The genes may be identiﬁed in (Remy et al., 1996).naturally resistant animals. One example is the gene Dehorning of ruminants reduces the potential forcoding for the Mx protein which promotes resistance injury to animal and producer, but is increasinglyto viral infection. They may also be genes coding for criticized on the basis of animal welfare. It may bemonoclonal antibodies (Jones and Marasco, 1997), desirable to select ruminants on the basis of thefor compounds interfering with virus replication dominant polled (hornless) condition. Schmutz et al.(Salter and Crittenden, 1989), for antisense mRNA (1995) have reported two microsatellite markers,or ribozymes inhibiting / destroying virus mRNA or which will identify within families the heterozygousinhibiting its transcription. Expression of chitinase in and homozygous carriers for the polled gene. Thewool follicles to control blowﬂy strike in sheep marker-assisted selection for homozygous polled
236 M. Bonneau, B. Laarveld / Livestock Production Science 59 (1999) 223 – 241cattle will allow the rapid introduction of the polled these techniques depends largely on the stage ofcondition in non-polled populations. development of the countries. Developing countries, Broodiness in breeder turkeys reduces egg pro- where the shortage of animal products is still veryduction, and requires repeated intervention to prevent important, are more likely to accept biotechnology inbirds from incubating their eggs. Broodiness is contrast to developed countries where consumptionphoto-induced through pro lactin (PRL), and vasoac- of animal products is viewed as too high. Culturaltive-intestinal peptide (VIP) is the principle PRL- considerations also inﬂuence acceptance. Biotechnol-releasing hormone. Immunoneutralization of VIP in ogy is accepted more readily in North America thanegg-laying turkeys reduced photo-induced PRL sec- in Europe, where the concept of ‘‘natural’’ hod isretion, eliminated broodiness, and dramatically in- more prevalent.creased egg production (El-Halawani et al., 1996). Applications resulting in improved health, feedActive and passive immunization techniques for VIP efﬁciency and behavior of the animals may beare now under development as well as the intro- perceived as beneﬁting both the industry (lowerduction of an anti-sense gene for PRL in turkeys production costs through reduced losses and drug(Wong et al., 1997). treatments) and the public (lower residues in animal products; reduced germ resistance to antibiotics; reduced environmental impact; improved animal7. Conclusions welfare). Similarly, applications resulting in the development of new tools for a better control of food The latest developments of biotechnology, par- safety can be easily perceived as beneﬁcial by theticularly molecular biology, genetic engineering and consumers of animal products.transgenesis have a very large number of potential Finally, the use of biotechnology in animal pro-applications in animal production. The development duction should be mostly beneﬁcial for humanity. Inof these applications is not as rapid as was expected many cases, biotechnology is not accepted because10 or 15 years ago. Transgenesis, for instance, is people do not understand how it works and what ismuch more difﬁcult to apply to farm animals than to really at stake. The public needs to be educated onplants or rodents. The use of biotechnology also the reality of biotechnology and be informed aboutmeets some resistance from the general public that the positive and negative aspects of any givenperceives some risks for the animals, for human application of biotechnology. On that basis, peoplesafety and for the environment, whereas the socio- can make an educated choice on whether or not theyeconomic beneﬁts are sometimes perceived as either can accept it.non existent or restricted to the industry. The generalacceptance of biotechnology may depend on a clearcommunication towards the general public, explain- Acknowledgementsing the balance between the advantages and dis-advantages of a given application, taking into ac- The authors express special thanks to their col-count not only technical and economic considera- leagues who were most helpful in the preparation oftions, but also the impact on other aspects (society, the manuscript, particularly Y. Chilliard, M. Eloit,environment, animal welfare) that are less easily L.M. Houdebine and B. Poutrel (INRA), and H.L.quantiﬁed. The applications of biotechnology in Classen, A. Estrada, A.G. Van Kessel and S.M.animal production may be roughly classiﬁed into two Schmutz (University of Saskatchewan).groups, according to whether potential beneﬁts mayor may not be easily perceived by the general public. Most of the applications resulting in improved Referencesperformance and carcass merit may be perceived asresulting in large beneﬁts for the industry and little Adeola, O., Bajjalieh, N.L., 1997. Energy concentration of highor no beneﬁt for the public. The acceptability of oil corn varieties for pigs. J.Anim. Sci. 75, 430–436.
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