Animal Biotechnology: Science Based Concerns
National Research Council Aug02
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We feel that, in many cases, the cautionary notes contained within this report are far too few and mild. It is well worth understanding how the authors feel about the various aspects of genetically engineered (GE) animals—most notably; the lack of knowledge, regulatory capabilities, and the fact that there is no removing the GE animal once it establishes itself in a community. The most clear warnings are aimed at genetically engineered fish, but in general, extremely little is known by anyone on the subject of genetically engineered animals. This is quite startling, especially considering that the industry is pushing hard for the release of such animals.
This report is also highly informative on a number of other issues related to GE animals. Besides the science and technology of genetically engineered animals, one should take note of the lack of respect that animals are shown by the food industry. Additionally, focus on the whole of our food supply and compare it to your own assumptions of how your food is produced and where it comes from. If you have not been exposed to the reality of what we have become as a species—the common every-day thoughtlessness for all life and the continuity of it—this report will be quite startling. In conclusion, what is evidenced by this report is a nearly complete lack of knowledge with respect to the results or consequences of the genetic mutations that are presently being created. And just think, there are humans being "produced" in such a manner with the same consideration given to the animals. !
COMMITTEE ON DEFINING SCIENCE-BASED CONCERNS ASSOCIATED WITH PRODUCTS OF
ANIMAL BIOTECHNOLOGY, HEALTH, AND THE ENVIRONMENT
BOARD ON AGRICULTURE AND NATURAL RESOURCES|
BOARD ON LIFE SCIENCES
DIVISION ON EARTH AND LIFE STUDIES
NATIONAL RESEARCH COUNCIL
NATIONAL ACADEMY PRESS Washington, D.C.
National Academy Press 2101 Constitution Avenue, N.W., Washington, D.C. 20418
Context and background
Research on genetic engineering has led to the development of a substantial variety of food and agricultural products as well as pharmaceutical and human health related products derived from several types of animals, including cows, sheep, goats, swine, fish, and insects. The federal regulatory system for genetically engineered animals and their products has been subject to increasing attention and discussion among research scientists and policymakers, as well as the public. In 2001, the food and drug administration center for veterinary medicine (CVM) recognized that it was an opportune time for external scientific discussion to identify the science-based risks and concerns associative with animal biotechnology prior to any regulatory review of the food and environmental safety of these products. CVM approached the National Research Council (NRC) and requested that the NRC's committee on agricultural biotechnology, health and the environment convened an ad hoc committee of experts to identify these risks and to indicate their relative importance and potential impact.
Issues related to plant biotechnology have been extensively addressed in previous NAS reports (NRC 1989, 2000, 2002) but a focus on animals was deemed unnecessary because animals posed a number of unique attributes. The products of panel biotechnology, such as organs, tissues, or pharmaceuticals, can be used for direct human health needs and food. Animals present unique challenges in that they are mobile as adults and often need special care. Furthermore, there is greater concern for the welfare of animals and plants, in part because animals are considered sentient organisms.
Over arching concerns of the committee
For over arching concerns over animal biotechnology dominated discussions before the committee. The first was whether anything could theoretically go wrong with any of the technologies. For example, is a theoretically possible that vector used for gene transfer could escape and become integrated into the DNA of another organism and thereby create a hazard? The second was whether the food and other products of animal biotechnology, whether genetically engineered or not, or from clones are substantially different from those derived by more traditional, extant technologies. A third major concern was whether the technologies raise novel environmental and animal welfare issues. Finally, there was concern as to whether the statutory tools of various government departments and agencies involved are sufficiently well-defined and whether the technological expertise and capacity within agencies are sufficient to cope with the new technologies, should they be deemed to pose a hazard. Before these issues are considered in the individual chapters that follow, the committee felt that it was important to articulate how it defines "concern". The term "concern" is used throughout the report and is defined as "an uneasy state of blended interest, uncertainty, and apprehension. Close quotes the committee also attempts to put the new technologies, which formed a focus of this report, into perspective and discuss some of what and it has learned from past animal agricultural practices, and particularly from those technologies that have reached fruition in the past half century.
The current state of animal-based biotechnology
Agricultural output of poultry and livestock in the United States exceeds $90 billion annually, of which around $11 billion consists of exports open (USDA, 2001). There are currently about 9 million very cows, 5 million dairy heifers, and 85 million beef cattle and calves in the United States, and approximately 100 million hogs are slaughtered annually. Even so, trends in food consumption are changing. Americans consumed 82 pounds of chicken per capita in 2000 compared to 69.5 pounds of beef, a reversal of the situation a generation ago. Sales of farming finish have also increased markedly as many consumers change their preferences from red meat to alternative proteins sources and as fish farming has become more productive and efficient. The main fish products traded domestically and internationally are shrimp (and ponds), Atlantic and coho salmon, and mollusks, but the market shares of tilapia, sea bass and sea bream are increasing (Lem, 1999). Per capita demand for high-quality need to products is expected to increase both in response to rising world population and to improvements in standard of living over the next 25 years (Pinstrup-Anderson and Pandya-Lorch, 1999). As a consequence of increased demand for meat and deterioration and loss of agricultural land, there is pressure to utilize the potential for biotechnology to improve productivity and animal agriculture. It is little appreciated that around 70 percent of the transgenic corn and soybeans grown in United States is said to livestock, poultry, and fish (Wisner, 1999), insuring a close association between biotechnology for crops and animal agriculture. As the techniques for producing transgenic animals are becoming more efficient and as more is known about controlling how inserted genes are expressed, it is likely that the approaches soon can be integrated into agriculture. Indeed, the commercial production of transgenic finish, which is likely to a core worldwide, is already imminent.
Genetically engineered poultry, swine, goats, cattle and other livestock are also beginning to be used as generators of pharmaceutical and other products, potential sources for replacement organs for humans, and models for human disease. The technology to produce foreign proteins in milk by expressing foreign genes in the mammary glands of livestock has already advanced beyond the experimental stage, with some of the products currently in clinical trials (Colman, 1996; Murray and Maga, 1999). In theory, transgenic animals can provide milk that is more nutritious for the consumer, or that is enhanced for certain protein components that might be valuable for manufacturing cheese or other dairy products. However, the major investments in the technology to date have been from pharmaceutical companies interested in producing enzymes, clotting factors and other bio active proteins in milk.
Companies are also interested in farming animals as possible sources of replacement organs for humans. Transplantation is an accepted and successful treatment of organ failure, but there is an enormous shortage of available human organs. As there are ethical and practical concerns related to the use of donor organs from primates, the pig, in particular, is being considered as an alternative. Unfortunately humans express antibodies to a carbohydrate epitope (terminal <alpha>1,3-galactose residues), which is present on the surface of porcine cells open (Sandrin et al., 2002).
Although the mouse, because of its small size, short generation times, fecundity, and well studied genetics, has become the animal of choice for providing models for human disease, farming animals might provide alternatives where the mouse is inappropriate. One possible future scenario is the creation of specific gene knockouts in farming animals in order to mimic human disease and a large animal model. For example, McCreath et al. (2000), have generated genetically-engineered sheep carrying a mutated collagen gene, and suggested that such animals could serve as models for the human connective tissue disease osteogenesis imperfecta.
It can the development of such technologies and others yet to be conceived and there in corporation into agricultural and biomedical practice raises concerns about whether the and products can be consumed safely, whether they are likely to be unwanted effects on the environment, and whether animal welfare will be adversely affected. The goal of this report is to identify concerns that will aid the Federal regulatory agencies in evaluating the possibility of such adverse outcomes. However, he for proceeding further, it is perhaps helpful to understand what is meant by biotechnology and to appreciate how far such biotechnology already has been incorporated into current agricultural and biomedical practice. It also is clear that the concerns of the public are focused on some of the more recent technological advances relating to gene transfer between organisms that would not normally interbreed and to assisted reproductive procedures, such as somatic nuclear cells transfer to create so-called clones (Eyestone and Campbell, 1999; box 1-1". Many of these recent advances have not yet left the experimental stage, but it is clear that several, including transgenic finfish, which are soon likely to be commercialized, are likely to assume importance both in agriculture and medicine.
Box 1-1 A Definition of Cloning
The verb "to clone" and the noun "clone" have a range of meanings and interpretations. The noun is derived from the Greek word klon, meaning a twig. Its original use in English was to describe a sexually produced progeny, and it has been in for milieu use imported culture for centuries. "To clone" in this context, therefore, means to make a copy of an individual. "Clone" was later adopted into parlance of modern cellular and molecular biology to describe groups of identical cells, and replicas of DNA and other molecules. Monozygotic twins are clones, but the term has recently become popularized in the media to mean an individual, usually a fictitious human, grown from a single somatic cell of its parent. The first reports animal cloning relate in the 1980s and were the result of the transfer of anucleated oocytes of nuclei from blastomeres (cells from early, and presumably on differentiated, cleavage stage embryos), a technique, which, in this report, is referred to as a blastomere nuclear transfer or BNT. Cloning of sheep, cattle, goats, pigs, mice, and, more recently, rabbits and cats, by transplanting a nucleus from a somatic, and presumably differentiated cell into an oocyte, from which its own genetic material has first been removed, was achieved about a decade later (Wilmut et al., 1997; reviewed by Westhausen et al., 2001), leading to the speculation that humans also could be clone. It is important to note that somatic cell transfer (SNT) also can be used to produce embryonic stem cells, giving researchers the opportunity to obtain on differentiated stem cells that are genetically matched to the recipient for research and therapy, which is independent of the decision here regarding the use of SNT for reproductive cloning of animals. Neither BNT nor SNT result in an exact replica of an individual animal, although the progeny are very similar to each other and to their donor cell parent. Any genetic disk similarity is likely to to the cytoplasmic inheritance of mitochondria from the donor a, which possesses its own DNA, and to other cytoplasmic factors, which seem to have the potential to influence the subsequent "reprogramming" of the transferred somatic genome in such a way that spatial and temporal patterns of gene expression in the embryo are affected as it develops (Cummins 2001; Jaenisch and Wilmut, 2001). For these reasons, many scientists have objected to the use of the term clone in the context of somatic cell nuclear transfer. The committee acknowledges this shade of meaning and has attempted to make the appropriate distinction when the term "clone" is used. Nevertheless, "clone" is now so widely accepted as a synonym for somatic cell nuclear transfer -- not just by the public at large -- at also by embryologists and other biologists, that the committee has retained it rather than an attempt to replace it with a more precise, but cumbersome, phrase.
Biotechnology is literally technology-based on biology; it is the application of scientific and engineering principles to the processing or production of materials by biological agents to provide goods and services. The application of biotechnology to animals has a long history, beginning in Southwest Asia after the last ice age when humans first began to trap wild animal species interbreed them in captivity, initially for meat and fiber and later for transport and milk. Of the approximately 4800 mammalian species, fewer than 20 have been successfully domesticated, (Diamond, 1999). Other than cats and dogs, only five of the species (cattle of the Bos genus, whose ancient ancestor is the now extinct auroch; sheep derived from the Asiatic mouflon species; goats, which are descended from the benzoar goats of West Asia; pigs dried from captured wild boar's; and horses, which originated from now extinct wild horses that roamed the steppes of southern Russia) are found worldwide (Diamond, 1999; box 1-2). As pointed out by Hale (1969) and Diamond (1999), the animals that have been successfully domesticated and farmed share and exhibit a unique combination of characteristics. They are relatively DOS I'll, are flexible in their dietary habits and can grow and reach maturity quickly on a herbivorous diet, and breed readily in captivity. They also have hierarchical social structures that permit humans to establish dominance over them and are adapted to living in large groups. They do not include species that generally have a tendency to be fearful of humans or disturbed by sudden changes in the environment. Our ancestors no doubt based their selection methods for improving their herds and flocks on how easy the animals were to farm, as well as on potential agricultural value. In turn, the animals are adapted to thrive in the domesticated environment.
Box 1-2 progression of technologies Inc. into modern animal agriculture1
- Vaccinations and other health technologies2
- artificial insemination3
- freezing a seaman4
- sire testing and selection5
- use of antibiotics in feet to increase gain6
- embryo transfer7
- embryo splitting and cloning from blastomeres8
- in vitro maturation/in vitro fertilization of oocytes and in vitro culture of resulting
- use of hormones to control ovulation in farm animals and induce bombing and fresh fish zygotes9
- hormonal sex reversal and production of monosex fish stocks
- chromosomes set manipulation10
- steroid administration to improve weight gain
- bovine somatotropin (BST) to increase milk production and dairy cows
- marker assisted selection
1 Technologies are presented in approximate sequential order of adoption; several technologies (such as artificial insemination, which was first described in 1910 do not widely adopted and told the 1950s) were developed years or decades before they were commonly used.
2 Vaccinations is used widely in the livestock and poultry industries as a protection against viral and bacterial pathogens.
3 Artificial insemination, in conjunction with the use of frozen seaman from select bulls, is common in the dairy industry are relatively rare and the U.S. beef industry. The use of fresh semen for AI is becoming increasingly important in the swine and poultry industries.
4 Bovine semen can be successfully frozen to yield high-quality, motile sperm upon following. The freezing of semen is problematic for swine and other livestock.
5 Used widely in the dairy industry and swine industries.
6 Used widely to increase meat production from cattle and hogs (except in certified organic herds) and used for pathogens control for farmed fish.
7 Mainly cattle, some swine.
8 Cattle only in the U.S.
9 These combined techniques underpinned human IVF procedures, but are widely used experimentally and sometimes commercially in the livestock industry.
10 Mollusks and finfish.
The fact that modern breeds of the species differ so markedly from their progenitor species is a reflection of how quickly directed reading can act. The modern Holstein, edge dominates the contemporary United States dairy industry, Little resembles its ancestors of only a half-century ago. Milk production for cow increased almost threefold between 1945 in 1995 (Majeskie, 1996), largely as a result of breeding from select bulls. There has been an accompanying drop in the number of cows, land devoted to dairy production and in the newer produced. On the downside, the cows have a tendency towards lameness, are considerably less fertile van in the 1940s, and are frequently maintained and heard for no more than 2-3 years or 2-3 lactations (Pryce et al., 2000; Royal et al., 2000), and represent a very narrow genetic lineage (Weigel, 2001). The export of these animals and their lineages to Europe and elsewhere as assuring the globalization of both the benefits and drawbacks of the American Holstein. Analogous changes ongoing in the swine industry, where the pressure to produce lean, fast-growing animals of uniform size is leading to the abandonment of old breeds (Notter, 1999). Paradoxically, unless the old livestock breeds are eaten, sheared or milk, they will not survive.
The dog (Canis familiaris), on the other hand, provides interesting example of the range of phenotypes that can be derived by selection with a single species. Dogs are believed to have originated in several separate domesticated as for molds (Canis lupus and Canis rufus) and coyotes (Canis latrans) before the domestication of livestock. They have undergone remarkable modifications in size and behavior over short periods of intense selection and to provide the diversity observed in modern breeds. This reflects the enormous pool of genetic variation within the species (Wayne and Ostrander, 1999), but (possibly) also the fixation of new mutations into different genetic lineages. Inbreeding of Bob breeds, as in domestic livestock, has led Tome major narrowing of interbreed variability (Zajc et al., 1997).
The same kinds of selective pressures that molded the large farm animals species has led to the creation of the modern breeds of farmed fall, which include chickens, ducks, geese, and turkeys domesticated further meat, eggs, and feathers. As in the dairy industry, there has been a remarkable improvement in the productivity of commercially produced chickens and turkeys for the last 60 years. Between 1940 in 1994, yearly egg production for laying hand increased from 134 to 254, mainly as a result of genetic selection. The broiler industry has shown similar gains (Pisenti et al., 1999). In 1950, a commercial bird to 84 days reaching market weight of 1.8 kg. By 1988, this market weight was reached by only 43 days (Pisenti et al., 1999) on about half the amount of feed (Lacy, 2000). In scientific breeding, combined with better nutrition and veterinary care, clearly has produced breeds of animals that are remarkably productive, although sometimes strikingly different and habits and appearance from those farmed early in the 20th century. The practice has also led to a loss of many breeds of livestock involved, and the decline in genetic diversity within the breeds that survive. For example it has been estimated that there were several hundred specialty lines of chicken in North America at the beginning of the last century, whereas the number of commercial hybrid strains now available for suppliers is fewer than 10 (North and Bell, 1990).
Aquatic animals, including finfish and shellfish, are now farmed. Specific breeds that have been selected for growth and other traits are now established in the largest industrial sectors of aquaculture, such as channel catfish, rainbow trout and Atlantic salmon. The growth and quality of such animals are also amenable to genetic engineering through modern biotechnology. Genetically engineered or highly selected aquatic species present special problems in terms of confinement, as the features that might make them attractive commercially might pose risks to the genetic basis of their wild relatives which they can interbreed (Hallerman and Kapuscinski, 1992).
Insects to have been domesticated for farming. The two best-known examples are the honeybee and silkworm where considerable genetic gains in productivity have provided strains far removed from the ancestral species from which they are derived. Attempts to develop strains of honeybee with improved resistance to pathogens and silkworm is that produce proteins other than silk from the horizon. If insects, like fish, are especially difficult to confine so that "escapes" are almost inevitable. In addition, insects, including ones that can be chance gently engineered, are likely to continue to be used as part of biocontrol programs for pest insects and invasive plant species and, as such, might be intentionally released into the environment. There will almost certainly be attempts to replace or to infiltrate native populations with insects that have been engineered in such a manner that they are less of the past or unable to transmit pathogens (Hoy, 2000). Private-sector companies have already begun to farm recombinant proteins (antibodies, cytokines, and designers and bioactive peptides) from insect larvae. Whereas USDA-APHS regulates release of insects for pest management, it is unclear who is responsible for protecting against accidental release of insects from mass rearing factories. Horizontal gene transfer, disruption of ecosystems, and native species extinctions are among the potential hazards that arise from permanent releases of transgenic arthroplasty into the environment (Hoy, 2000).
The traditional kind of biotechnology emphasized at the beginning of this section relies upon natural breeding procedures to select valuable phenotypes from variation in the existing gene pool of the species and is beyond the purview of this report, even though it has contributed so successfully to modern-day production agriculture. If it is firmly entrenched in our agricultural communities, and many are generally conversant with its benefits and risks. Importantly, other forms of research-driven biotechnologies, based on improved insight into reproductive physiology and Andrew chronology, embryology, genetics, and animal health have also made their way into standard farming practices over the last 75 years (box 1 -- to). A few of the procedures listed extend the boundaries of biotechnology to the development of organisms that have a combination of traits generally not attainable in nature through conventional breeding and are not themselves without controversy. Some of those listed are perceived by both scientist and laypeople as endangering human health or as adversely affecting animal welfare or the environment. Certain of the technologies can even have unintended, long-term consequences on the economics of agriculture itself. Finally, some of the concerns raised about the technologies of box 1-2 are quite relevant to those listed in box 1-3. Although several of these technologies remain experimental and have not yet become a part of standard agricultural practice, others (e.g., commercialization of transgenic fish) are undergoing government review for commercial approval. It is these newer technologies on
which this report is focused. For these reasons, it is worth while discussing box 1-2 and some of the issues that these technologies have raised before moving on to the ones perceived as associated with box 1-3.
Box 1-3 Examples of Technologies That Are Experimentally Established but Not yet in Widespread Use in Animal Agriculture
- Production of sexted semen
- production of transgenic animals by direct gene transfer
- production of transgenic animals through genetic engineering of sperm
- cloning of adult animals vice somatic cell nuclear transfer to produce "copies"
- cloning of animals by somatic cell nuclear transfer to achieve genetic engineering
CONCERNS REGARDING EXTANT TECHNOLOGIES
There are well-established guidelines for the application of technologies that maintain animal health, such as standard vaccination against viral in bacterial diseases. Indeed considerable efforts are being made to expand the range of such technologies in order to prevent epidemic spread of disease in flocks and herds, which are particularly at risk when farmed under intense conditions (BBC, 2001). Even the therapeutic use of antibiotics to treat animals that have bacterial infections or in danger of becoming infected seems not an itself to be controversial, except when antibiotics of medical importance to humans are employed.
Subtherapeutic Use of Antibiotics
The Food and Drug Administration approved antibiotics as feed additives for farm animals in 1951. There use since has been extended to fish farming, particularly with the global spread and dramatic increase of aquaculture in tanks and pond-like structures were into be on its are used for prevention in control of disease rather than to enhance growth (NRC, 1999). The treated animals are found to grow more quickly and utilize feed more efficiently and animals on regular feed. At least 19 million pounds of antibiotics are used annually for subtherapeutic purposes in animal agriculture, and are generally additives heating and water (sees NRC, 1999). Some of these compounds including penicillin,
tetracycline and floroquinolone used on livestock, also are prescribed treat human illnesses, and the practice has been shown in a few instances to contribute to antibiotic resistance of human pathogens (Chiu et al., 2002; Molbak et al., 1999). It is now generally accepted in the scientific and medical communities that into guide resistance can be exasperated by the widespread improper use of antibiotics. What remains controversial is whether agriculture contributes sufficiently to the problems associated with resistant pathogens to justify a complete curtailment of there use as growth promoters (DANMAP, 2000; Stephenson, 2002). A recent report from the National Research Council (NRC, 1999) failed to find a definitive link between the agricultural use of antibiotics in animal feed drinking water and into be a resistance of human pathogens. The report states, "The use of drugs in the food production industry is not without some problems and concerns, but does not appear to constitute an immediate public health concern." Since that report was released, additional information, raising further concerns, has been released (Fey, 2000; Gorbach, 2001). Consequently, the practice remains under intense scrutiny and as opposed by some scientific and medical organizations.
Assisted Reproductive Procedures
Artificial insemination (AI), and the latter, associated use of frozen semen, sire testing and sire selection are all part of a combinatorial approach to improve the genetic quality of farmed species. AI, when first introduced into agriculture, elicited an enormous outcry from farmers, the press, and religious groups. It was claimed to be against the laws of God, a repugnant practice that would lead to abnormal outcomes, and economically unsound (Herman, 1981; Foote, 1996). It gradually has become an accepted practice in agriculture, as well as in human and veterinary medicine. The ability to freeze semen and maintain a high degree of fertilizing ability in the thawed preparation extended the power of AI, since a few select bowls could be utilized to insemination many females in different geographic areas. Such bowls could be tested, not only for fertility, but also for their abilities to sire progeny that produce copious amounts of milk. By maintaining accurate records, breeding value estimations of particular bowls could be calculated. The result was the remarkable increase noted earlier in milk production. On the other hand, the process is leading to potentially destructive inbreeding since many of the select bowls are related. Inbreeding coefficients among modern Holsteins and Jersey breeds are now about 5 percent and rising (Weigel, 2001). The outcome might be inbreeding depression and broad susceptibility to be epidemic spread of disease. There also has been a remarkable recent loss for fertility, widths successful pregnancies resulting from first insemination dropping from more than 40 percent to as low as 20 percent or
less in some herds as milk yields have risen (Pryce et al., 2000; Royal et al., 2000).
Embryo recovery and transfer provides the opportunity for a particularly valuable animal to parent many more offspring in her lifetime ban would be otherwise possible (Siedel, 1984). The embryos can also be frozen and then either stored or transported before they are used to initiate a pregnancy. It is a relatively common technology and has been used to produce an estimated 40 to 50,000 beef calves every year (NAAB, 1996). The approach is to induce, by using hormones, the maturation and release of more than a single egg from the ovaries (superovulation; Draincourt, 2001). the animal usually isn't disseminated with semen from an equally select bowl, and the embryos are collected and transferred individually or in pairs, to the reproductive tract of less valuable cows, which carry the cast term. Modern technologies also provide the possibility of freezing and even sexing the embryos prior to transfer. The main concern with this technique, as with the AI-associated technologies discussed above, is that it can lead to narrowing of the genetic base of the breed, in this case involving both parents. A related technique is to use a needle to aspirate immature oocytes from the ovaries (in the case of livestock the oocytes are often taken from slaughtered animals at an abattoir) and to mature the oocytes for about one day in culture medium containing hormones. At the stage when oocytes reached a point made-way through the second division of miosis, they are fertilized with live sperm. In rare instances, fertilization is achieved by a single sperm or sperm head, which is injected through the tough outer zona pellucida of the oocytes, either beneath the zona or directly into the cytoplasm (intracytoplasmic injection or ICSI). Whatever method is used for fertilization, the resulting zygotes are usually then culture until the embryo reaches a more advanced stage of development. In humans, of course, these combined techniques form the basis of in vitro fertilization procedures and have resulted in hundreds of thousands of normal infants, but they have also become an important means of producing embryos for experimental purposes in agricultural research (First, 1991). Importantly, in vitro him maturation of oocytes underpins cloning and transgenic technologies (see chapters 2 and 6), where large numbers of competent, matured oocytes are needed to provide the many eggs necessary for nuclear transfer and pronuclear injection, respectively (see chapters 2). In vitro fertilization is also used commercially to preserve the genome of particularly valuable animals that happen infertility problems such as blocked oviducts or that respond poorly to superovulation (Boland and Roche, 1993), a technique described a low. This commercial application of IVF is relatively uncommon, with about 4000 calves born from its use annually (NAAB, 1996). Few concerns have been raised about this technique, which is essentially identical to that employed for in vitro fertilization in humans, although some animal welfare issues have been raised (chapter six)
In order to manage breeding programs more intensively, control over the reproductive cycles of livestock by hormonal intervention has increased. In general, the technologies are relatively benign and involving checking the animal with hormones, usually to stop progression through the existing estrous cycle and sometimes to mimic the events that lead to selection of a mature follicle(s) that will ovulate. Superovulation is a technique designed to mature cohort of follicles simultaneously, with the result that several eggs are ovulate it simultaneously (Nebel and Jobst, 1998; Britt, 1985). Or hormone treatment analogous to that used to produce a timed ovulation in large farm animals is used to induce gonadal maturation and fish (Mittelmark and Kapuscinski, 2001). None of these techniques have raised public health concerns, since the hormones are similar or identical to those in normal reproduction and the amounts used within the physiological range.
Splitting or bisecting embryos became an esoteric but well-established practice in the 1980s in order to provide zygotic twins (or in modern parlance, clones; Boland and Roche, 1993; Heyland et al., 1998). The pieces of the embryo -- usually "halves", which are genetically identical in terms of both their nuclear and mitochondrial genes (see box 1-1) -- are placed in an empty zona (the protective coat around early embryos) before being transferred to different recipient mothers to carry them to term. It has been estimated that only a very small number of calves (1 to 2 percent of those resulting from embryo transfer and United States and Canada) are produced in this manner (NAAB, 1996). Nevertheless these animals have been introduced into commercial herds and produce progeny; their milk and meet are consumed by the public.
Cloning binuclear transplantation from embryonic blastomeres (blastomeres nuclear transfer or BNT; see box 1-1) is an expensive procedure that also has its origins in the 1970s (Willadsen and Polge, 1981; Willadsen, 1989). What distinguishes it from somatic cell nuclear transfer, the technologies that lead to the creation of Dolly and much of the controversy over human cloning, is the stage of development at which the nuclei are transferred (Wilmut et al., 1998). In the older procedure the cells or blast demurrers used were from the so-called morula stage of cell development (although some were from the cleavage stage and others from the blastocyst stage) when the embryo is still an undifferentiated mass and its sales presumed still capable of performing all tissues of the fetus.
The cloning technologies of embryos splitting (EMS) and embryonic nuclear transfer (NT) were introduced into dairy cattle breeding in the 1980s. The Animal Improvement Programs Laboratory, U.S. Department Of Agriculture-Agricultural Research Service (ARS) is responsible for tracking performance of dairy cattle throughout the United States. Recently, working with a Holstein Association regarding the major dairy breed in the United States, they evaluated the performance of cloned Holsteins produced by EMS and NT (H.D. Norman, USDA-ARS, personal communication). The numbers of
EMS and NT clones were documented by gender and birth year. All NTs were from embryos rather than adults cells. The through 2001, there a total of 2226 EMS (754 males and 1472 females) and 178 and NT (61 males and 126 female) Holstein clones registered. Of female EMS clones, 921 had yielded records, and 551 had non-cloned full siblings with yielded records. Of the 126 female and key clones, 74 had yielded records, but only 11 had non-cloned full siblings. These familial relationships were used to compare the performance of cloned and non-cloned full siblings for standardized traits and genetic evaluations as part of the national evaluation program. The standardized traits included total milk yield (kg), fat (kg), fat (%), proteins (kg), proteins (%), somatic cell score, and productive life (months). Also calculated were yield from contemporaries and predicted transmitting ability. Norman and his colleagues concluded that the numbers of clones have decreased for EMS males and for all NT clones over the past decade. Animals that were selected for cloning were slightly superior genetically to the contemporary population means for yield traits; the yields of NT clones were similar to, and those of EMS clones were slightly less than, those of their non-cloned full siblings.
"Modern" cloning involves taking an unfertilized egg, removing its chromosomes, and introducing the nucleus for mate differentiated cell of the animals to be cloned, which is frequently and adults (box 1-1; Wilmut et al., 1997; Polejaeva et al., 2000; Kuhholzer and Prather, 2000). The introduced nucleus is reprogrammed by the cytoplasm of the egg and directs the development of a new embryo, which is then transferred to a recipient cow to allow it to develop to term. The offspring formed will be identical to their siblings and to the original donor animal in terms of their nuclear DNA, but will differ in their mitochondrial genes and possibly also in the manner their nuclear genes are expressed or biochemically engineered (see box 1-1 and chapter 2). Cloning from blastomeres, the older of the two procedures, has been reported to result occasionally in large calves (and lambs), the so-called large offspring syndrome (LOS; Young et al., 1998; Sinclair et al., 2000). Analogous, though possibly more serious, abnormalities might be associated with cloning from somatic cells and are discussed further in chapters to and 6 of this report.
Among the most contentious technologies used in animal agriculture is the use of steroid hormones to increase the rate of gain and to reduce the accumulation of fat deposits of young heifers and steers as part of the "finishing" process prior to slaughter (Heitzman, 1976; Lammers et al., 1999). The steroids are administered by slow release from a plastic implant embedded beneath the ski and of the year, which provides "physiologic" circulating levels of the hormone in the bloodstream. The hormones used are mainly Zeranol (in Ralgro TM), a naturally
occurring fungal metabolite of(zaeralenone) with estrogenic action, estradiol, progesterone and testosterone, or mixtures of the steroids (in various SynovexTM formulations) and trenbolone (Doyle, 2000). Concern about these hormones is probably, in part, a legacy of diethylstilbestrol, which was eventually Bay and from use in the poultry and beef industry because of its adverse effects on humans. However, the amounts of present-use compounds consumed from meet dried from treated cattle are small, and numerous scientific studies have generally indicated that these residues exist at such low concentrations that they pose little risk for consumers (Doyle, 2000; Lange et al., 2001), provided good veterinary practices are employed (e.g., using the correct number of implants and placing implants correctly in the ear cartilage), although the U.S. Geological Survey has recently documented the presence of hormones in a number of streams and rivers (some of these hormones likely, from implants; Kolpin et al., 2002). I for scientific evidence for safety, the European Union implemented a ban on imports, valued at over $100 million per year in 1989, of U.S. beef (Andrews, 1997). Concern that has not been extensively examined so far is whether these hormones pose any sort of environmental threat through their leaching into soil and water. For example, to recent studies have shown that he commonly used androgenic growth promoter -- trenbolone -- has been founding groundwater near cattle feed lots, and that this growth promoter has androgenic effects (Gray et al., 2001; Schiffer et al., 2001).
Of bovine somatotropin (BST) to increase milk yield from dairy cows has had a similar checkered history and has been the subject of trade disputes. Currently banned in Europe even for experimental studies, BST was approved by the Food and Drug Administration (FDA) for use in U.S. dairy cattle in 1993 because testing had revealed no concerns regarding consumer safety (Juskevich Guyer, 1990; Bauman, 1999). The Monsanto product, Posilac ™, is now widely used throughout the U.S. dairy industry, were milk production can be increased as much as 30 percent in well-managed, appropriately fed herds, without adversely affecting the quality or composition of the milk. The BST, which is almost indistinguishable in sequence from the natural hormone, is present in low concentrations in milk but has no biological activity in humans the level of IGF-1, the hormones induced by BST, is somewhat elevated but within the "physiologic range" for cows and is probably digested along with other milk proteins and the adults stomach, which it might have biologic activity in the intestine of neonates (Burrin, 1997). The FDA and its assessment does not believe that BST or IGF-1 pose any risk in either humans or
Animals that consume cows milk. As with other technologies that increase productivity, a concern frequently raised is why more milk is needed when the developed world appears to have more than enough of the product. One answer is that increase productivity translates into fewer animals, producing less waste in utilizing less land -- and extremely important consideration for future land management use. The greatest concerns about BST are probably in the area of animal welfare. High yield milking cows show a greater incidence of mastitis than lower producing cows, but studies have shown that mastitis is not exacerbated by BST administration (Judge et al., 1997). Another concern -- a practical one for the dairy industry -- is a recent trend to breed heifers only once and then to sustain milk production for as long as 600 days I using BST. Lengthening lactation via BST in second cows and older cows is a larger contributor to having fewer calves per lifetime and heard banned first-Heifers. The result has been a shortage of replacement heifers for producers, since only one calf is born during the milking life of the animal (Harlow, 2002).
Marker assisted selection involves establishing the linkage between the inheritance of a particular trade, which might be desirable, as in the case of milk yield or undesirable as in susceptibility to a disease, with the segregation of particular genetic markers. DOS, even if the gene that controls the trade is unknown, is presence can be inferred from the presence of the marker that segregates with it. This technology, which is particularly important for studying complex traits governed by many jeans, has only recently become a factor in animal breathing and selection strategies (Georges, 2001). Its use likely will increase exponentially as the industry incorporates the data from the various genome sequencing projects and as the density of useful, segregating markers increases on the chromosomes of the species. Initially, animals will be screened for jeans that controls simple traits, such as horns, which are undesirable and cattle, and halothane sensitivity, it segregates with metabolic stress syndrome in pigs. With time, easily identifiable markers will be chosen that accompany the many genes controlling more complex traits such as meet tenderness and taste, growth, calf size, and disease resistance. The approach has enormous potential for improving the quality of agricultural products, disease resistance, and other traits but could be misused (Dekkers and Hospital, 2002). For example, stringent selection of prime animals could potentially narrow genetic diversity even more banned is evident at present. The technique could also maximize short-term gain in productivity but as the expense of longer-term improvement due to what has been termed polygenic drag (Dekkers and Hospital, 2002). In essence, the cumulative effect of genes with effects to small to be exploited any marker
assisted selection program could contribute more to increase in desire traits than genes with major effects. However, marker-assisted selection might be a powerful measure to counter inbreeding by providing genetic measures of heterozygosity, encouraging breeding strategies that maintain diversity at the majority of sites in the genome, and allowing the genetic potential of rare breeds and while the ancestors to be utilized and incorporated into mainstream agriculture.
Chromosome Set Manipulation in Mollusks and Finfish
Altering the chromosome complement of an animal can be a useful way of rendering that animal infertile, is exploited widely in the production of fish and mollusks. Well-timed application of high or low temperatures, certain chemicals, or high Hydra static pressure to newly-fertilized groups of eggs can interfere with extrusion of the second polar body (the last step in miosis), resulting in "triploid" individuals with three, instead of the usual 2,chromosome sets (e.g., for oysters; Alan et al, 1989). A later treatment can suppress the first cell division of the zygote, resulting in "tetraploid" individuals with four sets of chromosomes. Crossing tetraploids, which are fertile in some species, with normal diploids can then produce large numbers of triploids (Scarpa et al., 1994). Such chromosome set manipulations have been applied to cultured Marine mollusks to produce confine stocks of triploids that are unable to reproduce. This application is a particular importance, as some of the shellfishes most suited to aquaculture are not indigenous to a given area and can pose ecological risks to native species should they or their larvae escape confinement and enter natural ecosystems (USDA, 1995). Induction of triploidy reduces the likelihood that and introduce species would establish self-sustaining populations, because such animals are theoretically sterile. For example the triploid Suminoe oyster Crassostrea ariakensis is being assessed for oyster production in the Chesapeake Bay, where diseases complicate restoration of the native eastern oyster C. virginica. Should triploidy prove an effective means for reproductive confinement, culture of sterile Suminoe oysters could support the recovery of the declining Chesapeake oyster production industry.
Another benefit of producing sterile mollusks is in maintaining product quality rough year. The meet quality of oysters is high just before they spawn, but Lowell after spawning. The product quality of reproductively sterile, triploid oysters remains high year-round. Hence, triploid stocks of Pacific oyster Crassostera gigas provide a tangible benefit to aquaculturists, and now makeup almost half of commercial production in the Pacific Northwest.
Unfortunately, repeatable and of 100 percent triploidy on a commercial scale poses a considerable technical challenge. Non-triploid larvae within batches of larvae easily can go undetected if their frequency is low (USDA, 1995). Should triploidy be desired for purposes of maintaining product
quality and the species is indigenous to an area, no harm is posed. If, on the other hand, triploidy is to be utilized for reproductive confinement purposes, the presence of reproductively fertile individuals -- even in low numbers -- might establish progeny and a self-sustaining population. There also are indications that a small percentage of triploid oysters can progress to a "mosaic" state, with diploid cells arising within the background of triploid cells, leading to the possibility that they could produce viable gametes (Calvo et al, 2001; Zhou, 2002).
Triploidy often used to reduce the likelihood that introduced finfish species would establish self-sustaining populations. Use of all-female triploid stocks has been suggested as a means of achieving reproductive confinement of transgenic fishes, including Atlantic salmon (leading candidate for commercialization). As with mollusks, however, repeatable induction of 100 percent triploidy poses a considerable technical challenge, and commercial net pen operations produce hundreds of thousands of salmon, with many escaping (Hallerman and Kapuscinski, 1992; Carr et al, 1997; Fisk and Lund, 1998; Volpe et al, 2000).
And other technology used on finfish is to farm monosex fish stocks (Beardmore et al, 2001), which are preferred by producers either because one gender grows faster or larger than the other (e.g., males and catfish and tilapia, females in rainbow trout), or because certain species (e.g., tilapia) attain sexual maturity before reaching harvest size. Monosex populations have been established in several ways, but most reliably through hormone-induced gender reversal. All-male fry and can be produced a by direct administration of testosterone in the, or all-females by administration of the estrogens. Monosex stocks also can be produced indirectly by gender reversal and progeny testing to identify XX males for producing all-female stocks (as in trout; Bye and Lincoln, 1986; and salmon; Johnstone and Youngson, 1984) or YY males for producing all-male stocks (as in tilapia, Beardmore et al, 2001).
LIMITS OF THE REPORT
The above examples illustrate that a spectrum of earlier biotechnologies already has become integrated into agricultural practice. The introduction of the technologies does not mean that there are no concerns were even dangers posed by their use, or that there is universal acceptance among the public. The experience of the last 50 years, if nothing else, illustrates that there must be continued vigilance even after technologies have been approved. Conversely, it should be recognized plainly that increases in agricultural efficiency brought about by new technologies, such as those discussed above, undouble the have contributed to a more abundant, cheaper, more varied and lower-cost food supply, into enormous savings in agricultural land use.
Some technologies in box 1-2 bridge the gap between what is an already established commercial practice and what is new (aux 1-3). For example, cloning from blast mayors (toxic 1-1) listed in box 1-2 in reality is a little different than nuclear transfer from somatic cells stood in box 1-3, except that the transferred nuclei might not have to be so extensively reprogrammed in the cytoplasm of the recipient oocyte. Similarly, chromosomal set manipulation remains partly experimental and partly an active commercial technology.
Box 1-3 is a partial list of technologies that are either very close to being commercially available (pending approval from the regulatory agencies) or are predicted to emerge from experimental to commercial use quite soon. The first one listed, the production of single sex sperm, is achieved through a cell sorting procedure that depends upon the higher DNA content of females sperm (Johnson, 2000; Lu et al, 1999). The technology is not expected to raise any new concerns and, provided the procedure can be scaled up, is likely to be highly beneficial in the dairy industry where there is a surfeit of low value bull calves, and to the beef industry where males have a higher production value than females. The remaining technologies, however, might be more worrisome to the public and to the regulatory agencies, and it is these that are addressed in this report.
In terms of the types of technologies discussed, the scope of the report had, of necessity, to be limited. For criteria are emphasized in this report:
1. The first criterion is immediacy of technological commercialization, particularly if the products already are impinging on the regulatory system. Is clear that some of these technologies (e.g., commercial production of transgenic finfish) already are beyond the experimental stages of development. In addition, some biopharmed drugs are in Stage 3 clinical trials and decisions must be made soon about the disposition of the livestock involved.
2. A second criterion is the potential impact of the technology. Some new procedures seem unlikely to raise concern (e.g., the sperm sexing discussed in the previous section) or represent relatively minor changes in practice. Other technologies might be broadly adopted, yet the possible harm they could cause and the overall benefits to society are difficult to evaluate.
3. A third criterion is whether there is sufficient information available about the technology to evaluate concerns properly. Indeed, the committee explicitly acknowledges that there are uncertainties associated with the application of each of the technologies discussed in only with attempts to determine how best to apply emerging technologies to animals, but also how to predict the impact of their application. Some hazards (see box 1-4) remain theoretical, uninvestigated, poorly characterized, or even unknown. Such uncertainties present significant challenges to scientists and policymakers who wish to estimate the
likelihood and distribution of horrors and benefits resulting from application of those technologies. For example, some outcomes of applications of the technologies listed in box 1-3, such as production of transgenic animals by gene transfer, are difficult to predict. Uncertainties of a range from near inexactness and unreliability to those that are fundamentally unknown a priori (Funtowicz and Ravetz, 1992). Clearly, technologies that pose high-stakes and high uncertainties posed fundamentally different challenges than those posing low stakes and little uncertainty for that reason, for each concern discussed in this report, the committee has attempted, where possible, to specify (1) what is known, (2) the certainty with which it is known, (3) what is not known, (4) was suspected, and (5) the limits of the science.
BOX 1-4 Harms, Hazards, and Risks
The charge of the committee was to identify risk issues concerning products of animal biotechnology and provides criteria for selection of those risk issues considered most important that need to be addressed or managed for the various product categories. In order to provide criteria for selection of risk issues, it is important to understand how risk is determined. As outlined in chapter 5 and as set forth by NRC (1983; 1996), a hazard: is an and or phenomenon that has the potential to produce harm, and risk is the likelihood of harm resulting from exposure to the hazard. This committee used the NRC (1996) definition of risk to develop a set of working steps to prioritize concerns. Because risk is the product of two probabilities: the probability of exposure, and the conditional probability of harm given exposure has occurred, the steps in risk analysis are to: (1) identify the potential harms, (2) identify the potential hazards that my produce those harms, (3) defined what exposure means and the likelihood of exposure and (4) quantify the likelihood of harm given that exposure has occurred. (The committee notes that risk analysis and other feels he and and does include additional steps in risk assessment; see Kapuscinski, 2000). Multiplying the resulting probabilities than misused to prioritize risk. While absolute probabilities are difficult to determine at this time, relative rankings from high to low or possible based on available evidence for each category. The risks, harms, and hazards are different for each chapter because the issues are different (i.e., a hazard resulting in an animal well-being concern until or human health concern).
The committee also recognizes that there are likely either species or categories of species of animals not discussed specifically regarding concerns
associated with biotechnology. Two examples of categories include companion animals and wildlife. While there are likely to be unique concerns that emerge with both categories, the concerns identified in the report regarding applications of the technologies (chapter 2), environmental issues (chapter 5), and animal welfare issues (chapter 6) are all relevant and should be included in any considerations of wildlife and companion animals species.
Discussion of concerns regarding impacts of GE mice on the environment and human health are also limited in this report for several reasons. He mice are not part of the animal production system for human food, and laboratory mice are highly unlikely to escape the confines of animal facilities because of their economic value and the generally high quality care given to laboratory rodents. Well mice might be a high-risk for escape, might feralize easily, and might carry many different transgenes, the functionality of the transgenes used in mice has rarely been for a construct that will increase fitness in natural environments. Thus the overall risk for most constructs is expected to be low. If mice were developed to be resistant to pest control measures (pesticides) or to be more disease resistant, then risks would be much higher. However, the use of mice in this way seems quite unlikely.
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COMMITTEE ON DEFINING SCIENCE-BASED CONCERNS ASSOCIATED WITH PRODUCTS OF ANIMAL BIOTECHNOLOGY, HEALTH, AND THE ENVIRONMENT
BOARD ON AGRICULTURE AND NATURAL RESOURCES
BOARD ON LIFE SCIENCES
DIVISION ON EARTH AND LIFE STUDIES
NATIONAL RESEARCH COUNCIL
NATIONAL ACADEMY PRESS Washington, D.C.
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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen further special competences and with regard for appropriate balance.
This study was supported by Contract No. 223-93-1025 between the National Academy of Sciences and the U.S. Food and Drug Administration, and funds by the National Research Council. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the organizations or agencies that provided support for the project.
This report has been reviewed by a a group other than the authors according to the siege is approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.
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Committee on Defining Science-Based Concerns Associated with Products OF Animal Biotechnology
JOHN G. VANDENBERGH, Chair, North Carolina State University, Raleigh ALWYNELLE (NELL) SELF AHL, Tuskegee University, Tuskegee, AL JOHN M. COFFIN, Tufts University School of Medicine, Boston MA WILLARD H. EYESTONE, Virginia-Maryland Regional College of Veterinary Medicine, Blackstone, VA ERIC M. HALLERMAN, Virginia Polytechnic and State University, Blackstone TUNG-CHING LEE, Rutgers University, New Brunswick, NJ JOY A MENCH, University of California, Davis WILLIAM. M. MUIR, Purdue University, West Lafayette, IN R. MICHAEL ROBERTS, University of Missouri, Columbia THEODORE H. SCHETTLER, Science and Environmental Health Network, Boston MA LAWRENCE B. SHOOK, University of Illinois, Urbana MICHAEL R. TAYLOR, Resources for the Future, Washington D.C.
KIM WADDELL, Study Director DEBRA DAVIS, Editor MICHAEL R. KISIELEWSKI, Research Assistant CINDY LOCHHEAD, Project Assistant
Committee on Agricultural Biotechnology, Health, and the Environment
BARBARA A. SCHAAL, Chair, Washington University, St. Louis MO DAVID A. ANDOW, University of Minnesota, St. Paul NEAL L. FIRST, University of Wisconsin, Madison LYNN J. FREWER, Institute Of Food Research, Norwich UK HENRY L. GHOLZ, National Science Foundation, Arlington VA EDWARD GROTH III, Consumers Union, Yonkers NY ERIC M. HALLERMAN, Michigan State University, East Lansing CALESTOUS JUMA, Harvard University, Cambridge MA SAMUEL B. LEHRER, Tulane University School of Medicine, New Orleans LA SANDFORD A. MILLER, Georgetown University, Washington D.C. PHILIP G. PARDEY, University of Minnesota, St. Paul PER PINSTRUP-ANDERSEN, International Food Policy Research Institute, Washington D.C. ELLEN K. SILBERGELD, Johns Hopkins University, Baltimore, MD ROBERT E. SMITH, R. E. Smith Consulting, Inc., Newport VT ALLISON A. SNOW, Ohio State University, Columbus PAUL B. THOMPSON, Purdue University, West Lafayette, IN DIANA H. WALL, Colorado State University, Fort Collins
JENNIFER KUZMA, Program Director SETH STRONGIN, Program Assistant
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