Introduction

This paper discusses new technologies designed to produce better livestock in three ways:

(i) they allow animals to use their feed more efficiently;

(ii) to excrete less waste into the environment; and

(iii) to produce carcasses that are large and lean.

Improved feed efficiency means simply that more meat is produced from less feed. This is important both for grain-fed animals, because of the high price of this commodity, as well as for grass-fed species, because of the need to satisfy increasing consumer demand without over-stocking, and sacrificing our grazing land to degradation.

Reducing the excretion of waste products such as nitrogen into the environment is becoming increasingly important as we move towards more intensive production systems such as cattle feedlots. Fortunately, this objective goes hand-in-hand with the first aim, as the more efficient an animal becomes depositing its feed protein in muscle, the less nitrogen will be excreted in the urine or faeces.

Finally, better quality carcasses are those that contain more muscle and less fat. In terms of feed costs, fat is an expensive commodity to produce, and there is certainly a demand for leaner meat in western diets.

The technologies discussed in this paper are capable of achieving all three of these aims to a varying extent, by causing a shift in metabolism so that more feed nutrients are directed into muscle, and less are either deposited as fat or excreted. First, the actions of ß-agonists and somatotropin are discussed, as examples of two types of compound that are close to becoming commercially available. Next, some possible future technologies are described, with a focus on growth promoting vaccines.

This is not a comprehensive review, but one intended to illustrate the great potential that exists to create better livestock, and to highlight the challenges that face researchers in this area.

ß-Agonists

This family of drugs takes its name from the ability to stimulate ß-adrenoceptors: proteins that are found on the surface of muscle cells and which act in nature as triggers for the metabolic effects of adrenaline. ß-Agonists have been used world-wide in the treatment of asthma since the 1970s, because of their ability to relax smooth muscle found in the airways. They are usually given in small doses through an inhaler, directly into the lungs, so that very little drug escapes into the general circulation to affect other tissues. However, in the mid 1980s it was discovered that when higher doses of ß-agonists are given by mouth, the drugs cause a rapid and marked increase in the growth of skeletal muscle and, at the same time, a reduction in body fat (Emery et al., 1984). This effect is seen in all animals that have been tested, ranging from rats, mice and rabbits, through poultry, sheep and cattle, to humans and fish. Almost every major animal health company has developed its own patented ß-agonist drug, but the best known and most infamous compound is clenbuterol.

Like all ß-agonists, clenbuterol affects growth in a very specific way. The drug causes little or no change in food intake, but increases the size of muscles that contain glycolytic and mixed fibres. Oxidative muscles respond also, but to a lesser extent. The net increase in carcass weight is always rapid and marked in small animals, reaching 7% or more in rats for example, after only 4 days of treatment (Moore et al., 1994). In ruminants the anabolic effect can be equally profound, with gains of up to 25% being reported in beef cattle (Vestergaard et al., 1994). However, the effect is usually much less than this, sometimes with no significant increase in total carcass weight, but a useful increase in the proportion of muscle deposited in the more valuable cuts of the hind-quarters (Moloney et al., 1994).

The increase in muscle mass usually results in an increase in carcass weight, and so body weight may increase also, but this is not always the case. Increasing muscle synthesis requires additional energy and protein. As there is no increase in food intake, part of the extra energy must come from an increase in the efficiency with which dietary energy is used, but part of it is also derived from the mobilisation of body fat (Lindsay et al., 1993). Thus, clenbuterol-treated animals have leaner carcasses, and in older animals in particular, the decrease in fat can offset the increase in muscle, so that there is no net effect on carcass weight, or body weight. Furthermore, whereas some of the additional protein required for muscle growth is obtained through a more efficient use of the diet, so that less dietary protein is excreted by the animal, extra protein is also obtained by raiding other body tissues such as the liver, kidneys and gut, which are often smaller than usual after clenbuterol treatment. As a consequence, the dressing percentage (carcass:offal ratio) is increased in ß-agonist-treated livestock (Chickhou et al., 1993).

Thus, ß-agonists may be used to achieve the three aims of improving feed efficiency, reducing nitrogen excretion and increasing the carcass muscle:fat ratio. Added to this, the compounds are orally-active, which makes them able to be used as a feed additive, and very practical for intensive livestock producers. Unfortunately though, their oral activity can also be a disadvantage from the consumer’s standpoint, who may be concerned about the effects that of any residues of these drugs may have, if they are found in meat.

Such fears are well-grounded, but have been fuelled out of proportion by two unfortunate coincidences. First, the European Economic Community decided to ban the use of all growth promoting substances in livestock from January 1988. Having recognised the economic advantage of using steroid growth promoters without ill-effects over many years, a number of producers turned to the black market for their supplies. This coincided with the discovery of the powerful anabolic effects of clenbuterol, a compound which is inexpensive to synthesise and easier to administer than the steroid implants used previously. The second unfortunate coincidence is that clenbuterol is highly-unusual as a ß-agonist because it is not rapidly broken down in the body and is prone to form high concentrations in adipose tissue and liver (Meyer and Rinke, 1991). The drug does not accumulate to a significant extent in muscle, so that even if a clenbuterol-treated steer was slaughtered with no withdrawal period, an individual would need to consume 2kg of meat per day in order to ingest the type of dose used therapeutically to treat asthma. However, because of its ability to concentrate in certain tissues, the same amount of clenbuterol can be found in only 200g of liver from the same animal. When the drug was used illegally, there was no regard given to the proper anabolic dose, so that some cattle were given very large amounts. The drug residues increased accordingly, with the result that 135 people were reported to have been hospitalised in Spain following an outbreak of clenbuterol poisoning caused by contaminated calf liver. On a positive note, it was also discovered that clenbuterol reaches very high concentrations in the eyes of cattle (Meyer and Rinke, 1991). From this observation a non-destructive and highly-sensitive residue test has been developed, and routine screening for the drug in parts of Europe is thought to have virtually eliminated clenbuterol abuse (Elliot et al., 1994).

Although there are many other ß-agonists that do not accumulate in animal tissues, so far all the drugs in this family that have been tested have been found to have another unfortunate effect on meat: that of increasing toughness. This effect occurs in proportion to the size of the anabolic effect on muscle, and it is suspected that the two effects are linked to the extent that it may not be possible to produce one without the other (Pringle et al., 1993). Meat toughness is not always an issue in Australia, where a considerable amount of meat is exported for use as ground beef. Unfortunately though, most of this type of beef comes from pasture-fed animals, where the use of a feed additive is impractical. So far there are no ß-agonist implants available. Ironically, the feedlots where ß-agonists would otherwise be ideal usually supply the most quality-sensitive markets, where meat tenderness is a key issue.

In summary, ß-agonists could be used to increase the efficiency of meat production, but the technical problems of eliminating their effects on meat tenderness or developing an implant suitable for grazing cattle, added to the perceived threat that they leave harmful meat residues as a legacy of clenbuterol abuse, currently provide a formidable barrier to their adoption.

Somatotropin

Unlike the ß-agonists, somatotropin (ST) is a natural protein hormone which is easily destroyed by cooking and rapidly broken down by the gut. These properties give ST the advantage over ß-agonists of being less of a threat in terms of tissue residues, but the disadvantage of not being able to be used as a feed additive. Instead, ST is given in the form of injections, which give the best results when administered daily. The hormone is already being used commercially by the dairy industry to increase milk yield, and several companies have demonstrated the potential of slow-release implants which are effective in dairy cattle for between two and four weeks (McLaughlin et al., 1994), thus alleviating the practical problem and labour costs of daily administration.

In terms of meat production, ST is most effective in pigs. Marked increases occur in muscle growth (Etherton et al., 1987), apparently without the detrimental effects on meat tenderness that are seen with ß-agonists. Fat deposition also decreases dramatically, and feed efficiency is improved. Unfortunately though, because pigs are highly-sensitive to the effects of ST on glucose metabolism, they seem unable to tolerate the wide fluctuations in plasma ST concentrations that result when implants are used, and daily injections remain the only practical means of treatment. At this time, Australia is the only significant meat-producing country to have licensed the use of porcine ST, and a marketing campaign for this product has not yet begun in earnest.

The effects of ST in beef cattle are much less impressive than in pigs, and although ST treatment does increase weight gain by an average of 10% (Moseley et al., 1992), the growth effect is uniform throughout the body, with much of the additional weight reflecting increases in rumen and liver mass (opposite to the effect seen with ß-agonists), so that dressing percentage is often decreased (Moseley et al., 1992). Because the effect on skeletal muscle is marginal, carcass weight may change from between -3% to +2%. A decrease in carcass weight usually reflects the lipolytic actions of ST, which in cattle seem to be more noticeable than the anabolic effects in muscle. This lipolytic action undoubtedly contributes to improved feed efficiency, and while ST-treated cattle tend to eat less, they continue to grow at the same rate. The resultant saving in feed costs and improvement in carcass grades appear to represent the main economic advantage of using ST in beef cattle. Unfortunately, one feature that ST shares with the ß-agonists is that both technologies are beyond the reach of the grazier because of their means of delivery. This is particularly significant in Australia, where 90% of beef cattle are grown at pasture.

Vaccines

Over the past decade there has been a concerted effort to develop alternative technologies capable of producing the type of metabolic effects seen with ST and ß-agonists, but without the need to administer either natural or synthetic hormones. Some workers have pursued this goal in the hope of circumventing the European ban on hormonal growth promoters; others have been concerned with adapting ST or ß-agonist-based technologies for use in extensive grazing systems; while others still have undoubtedly been driven more by scientific curiosity. A very common approach has been to attempt to develop growth-promoting vaccines.

Whereas antibodies are produced in nature to attack foreign proteins that invade the body, it was discovered some years ago that the immune system can be tricked into making antibodies that recognise the body’s own natural proteins, hormones and tissue receptors. By interfering with the action of these substances, such antibodies can provoke profound metabolic changes. The targets for experimental vaccines of this type have been numerous and diverse, but most fit into one of three categories, according to the way in which the antibodies work.

The first generation of vaccines caused the production of antibodies that bind to a natural hormone and, in doing so, prevented that hormone from reaching its target tissue. This has been a useful experimental tool to inactivate several types of catabolic hormone: those that under normal circumstances act to limit growth. Somatostatin, a hormone which restricts endogenous ST secretion; ACTH, a hormone that stimulates cortisol production; and cortisol itself, are among the targets that have been researched (Wynn et al., 1994). Anti- ACTH and anti-somatostatin vaccines have been shown to increase growth in rats and sheep (Sillence et al., 1992; Spencer et al., 1983), but are still a long way from being technologies that work reliably in other livestock.

The second type of vaccine researched also causes the production of antibodies which recognise and bind to endogenous hormones, but instead of inactivating those hormones, these antibodies increase their activity, presumably by protecting the hormones from degradation, lengthening their biological life, and assisting in their transport and delivery to the target tissues. Such vaccines have been made to enhance the activity of ST (Holder et al., 1985), and the tissue growth factor IGF-1 (Stewart et al., 1993). Again, success has been achieved in some rat and sheep experiments, but the results have not been consistent.

The third type of vaccine uses antibodies which ignore the circulating hormones, but instead attach directly to the target tissue. Such antibodies may be engineered to block the receptors on the tissue surface that are normally switched on by catabolic hormones; they may activate the receptors that are normally

triggered by anabolic hormones; or, in some cases, they may even destroy the cell itself. Vaccines of this type have been made to mimic the actions of adrenalin and its synthetic counterpart the ß-agonist drugs (Hoskinson, 1995), with good results obtained only in laboratory animals. A vaccine which destroys fat cells has been shown to be very effective at preventing lipid accumulation in young pigs, with lasting benefits in the form of a compensatory increase in muscle growth and an improvement in feed efficiency (Flint et al., 1994). So far, the inventors have had difficulty in producing similar effects in ruminants, however.

In general, the vaccine approach has demonstrated the potential of enhancing growth efficiency through modulating the immune system, but scientists have not yet discovered a way to control the intensity of the immune response. This lack of control has seriously hampered the developments in this area, and today there are still no commercially available growth vaccines, nor are any likely to emerge in the very near future.

Summary

This review has discussed a few of the new technologies that were designed to produce better livestock by increasing feed efficiency, reducing nitrogen excretion and encouraging lean tissue growth. It should be evident that an ideal technology has not yet been found, even though it seems that researchers have come tantalisingly close on several occasions.

At the dawn of such research when steroid growth promoters were first tested in the 1940s, the motive for these endeavours was probably profit alone, and since the European ban and increasing activity by proponents of ‘clean and green’ food production, work in this area has become increasingly unfashionable. However, while the profit motive is as important as ever, other issues have emerged such as the need to satisfy an increasing world demand for meat at the same time as reducing animal feed use, limiting environmental waste and preventing land degradation. It is difficult to see how such aims can be achieved without further research to improve the efficiency of animal growth, and hence to develop new technologies for the production of better livestock.

References

Chikhou, F.H., Moloney, A.P., Allen, P., Quirke, J.F., Austin, F.H. and Roche, J.F. (1993). Long-term effects of cimaterol in Freisian steers: I. Growth, feed efficiency and selected carcass traits, J. Anim. Sci., 71, 906.

1. Elliott, C.T., Shortt, H.D. and McCaughey, W.J. (1994). Detection and control of clenbuterol abuse in northern ireland. IGAPA, Research meeting Abstracts, 81.

2. Emery, P.W., Rothwell, N.J., Stock, M.J. and Winter, P.D. (1984). Chronic effects of ß₂-adrenergic agonists on body composition and protein synthesis in the rat. Biosci. Rep., 4, 83.

3. Etherton, T.D., Wiggins, J.P., Evock, C.M., Chung, C.S., Rebhun, J.F., Walton, P.E. and Steele, N.C. (1987). Stimulation of pig growth performance by porcine growth hormone: determination of the dose-response relationship, J. Anim. Sci., 64, 433.

4. Flint, D.J., Cryer, A., Kestin, S., Griffin, H., Butterwith, S., Rhind, S., Futter, C., Tonner, E., Kennedy, R., Cryer, J. and Marsh, J. (1994). Manipulation of body fat using antibodies raised against plasma membrane antigens of adipocytes. In Vaccines in Agriculture, Wood, P.R., Willadsen, P., Vercoe, J.E., Hoskinson, R.M. and Demeyer, D., Eds., CSIRO Australia, 129.

5. Holder, A.T., Aston, R., Preece, M.A. and Ivanyi, J. (1985). Monoclonal antibody-mediated enhancement of growth hormone activity in vivo. J. Endocrinol., 107, R9.

6. Hoskinson, R., Personal communication, 1995.

7. Lindsay, D.B., Hunter, R.A., Gazzola, C., Spiers, W.G. and Sillence, M.N. (1993). Energy and growth. Aust .J. Agric. Res., 44, 875.

8. McLaughlin, C.L., Hendrick, H.B., Veenhuizen, J.J., Hintz, R.L, Munyakazi, L., Kasser, T.R. and Baile, C.A. (1994). Performance, clinical chemistry, and carcase responses of finishing lambs to formulated sometribove (Methionyl bovine somatotropin), J.Anim.Sci., 72, 2544.

9. Meyer, H.H.D. and Rinke, L.M. (1991). The pharmacokinetics and residues of clenbuterol in veal calves. J.Anim.Sci., 69, 4538.

10. Moloney, A.P., Allen, P., Joseph, R.L., Tarrant, P.V. and Convey, E.M. (1994). Carcass and meat quality of finishing Freisian steers fed the ß-adrenergic agonist L-644,969. Meat Sci., 38, 419.

11. Moore, N.G., Pegg, G.G. and Sillence, M.N. (1994). Anabolic effects of the ß₂-adrenoceptor agonist salmeterol are dependent on route of administration. Am.J.Physiol. (Endocrinol.Metab.) 30, 267, E475.

12. Moseley, W.M., Paulissen, J.B., Goodwin, M.C., Alaniz, G.R. and Caflin, W.H. (1992). Recombinant bovine somatotropin improves growth performance in finishing beef steers. J. Anim.Sci., 70, 412.

13. Pringle, T.D., Calkins, C.R., Koohmaraie, M. and Jones, S.J. (1993). Effects over time of feeding a ß-adrenergic agonist to wether lambs on animal performance, muscle growth, endogenous muscle proteinase activities, and meat tenderness. J. Anim. Sci., 71, 636.

14. Sillence, M.N., Jones, M.R., Lowry, P. and Bassett, J.R. (1992). Passive immunization with antiserum to adrenocorticotropin increases weight gain in normal female rats. J. Anim. Sci., 70, 1382.

15. Spencer, G.S.G., Garssen, G.J. and Bergstrom, P.L. (1983). A novel approach to growth promotion using auto-immunisation against somatostatin. II. Effects on appetite, carcase composition, and food utilisation in lambs. Lives. Prod. Sci., 10, 469.

16. Stewart, C.E.W., Bates, P.C., Calder, T.A., Woodall, S.M. and Pell, J.M. (1993). Potentiation of insulin-like growth factor-I (IGF-I) activity by an antibody: supportive evidence for enhancement of IGF-I bioavailability in vivo by IGF binding proteins. Endocrinology, 133, 1462.

17. Vestergaard, M., Sejersen, K. and Klastrup, S. (1994). Growth, composition and eating quality of longissimus dorsi from young bulls fed the ß-agonist cimaterol at consecutive developmental stages. Meat Sci., 38, 55.

18. Wynn, P.C., Behrendt, R., Jones, M.R., Rigby, R.D.G., Bassett, J.R. and Hoskinson, R.M. (1994). Immuno-modulation of hormones controlling growth. Aust. J. Agric. Res., 45, 1091