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Regular Article |
a Departments of Animal Sciences and Biochemistry, University of Missouri, Columbia, Missouri 65211
ABSTRACT
Reproductive studies on farm animal species have been part of the underpinnings that have led to the ready availability of low cost, safe, and nutritious food in the developed world. They have also made a significant contribution to reproductive medicine. Yet at a time when world demand for food is increasing and the National Institutes of Health budget is on course to double between 1998 and 2003, funding for animal agriculture remains low, erratic, and politically vulnerable. There are also those who question whether the food animals have value any longer as comparative models for studying reproduction as it relates to human health and well being. In this paper I describe how such research is presently funded at the federal level and discuss why support for agricultural science is in decline, despite many unmet needs. I then suggest that the human genome project and the developing areas of comparative gene mapping and functional genomics are beginning to provide new impetus to studies on farm animal species. Finally I argue that although rodents and, above all, the mouse, with all its genetic advantages, occupy lofty positions as models for studying reproductive processes and their abnormalities in the human, there will continue to be a need to take a broader comparative approach that will inevitably involve farm animals.
agricultural research support, reproductive technology
INTRODUCTION
Livestock farming constitutes between 30% and 40% of world agriculture, and poultry and livestock sales in the United States alone exceed $70 billion annually (Table 1). Successful reproductive practices managed by the farmer underpin this entire effort. It is not surprising, therefore, that research centered on the reproduction of farmed animal species has held an important place in modern agriculture and led to the impressive gains in efficiency in production of meat and dairy products, eggs, and fiber seen over the last half century. Farm animal species also continue to provide basic information relevant to reproduction in other species, including the human, although the large sizes of the farmed mammals, their long gestation lengths, and their general lack of genetic tractability provide a disadvantage compared to small laboratory species, especially the mouse.
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This paper is a personal perspective in which I attempt to make predictions about the future of research in agriculturally important animals. In particular, I make a case for the continued use of the farm species in biomedical, as well as agricultural research. The new genomics world I consider is one where the most common expressed genes of several mammals have been described in the form of their cDNA, and the sequence of the human genome is completed. The general question I address herein is whether basic research performed on farm animals can hope to survive in this new era.
What Is the Main Legacy of Studies on Farmed Species to Present Day Reproductive Biology?
As I outline below, agriculture has until quite recently been well funded. Many of the discoveries in agriculture, from the purification of hormones and key metabolic and synthetic enzymes to development of reproductive technologies, have contributed in a major way to human reproductive medicine and to understanding reproductive processes. Artificial insemination was first developed for horses during the early part of the century and applied seriously to cattle in the 1930s [1]. Its use has underpinned much of the genetic improvement seen in dairy cattle since then [2, 3]. Cryopreservation of sperm was performed first in cattle [4] and only later applied to the human and other species [5]. Superovulation, pharmacological control of the ovarian cycle, in vitro fertilization, embryo transfer, and sperm capacitation are among the many techniques important to agriculture that saw much of their development in farm animals. Cloning, long considered impossible, gave us first a sheep, not a mouse or a human [6]. Not surprisingly, many of the major figures in reproductive biology have worked on farm species but have regularly crossed the boundary between medicine and agriculture. Comparative studies will always be the major means of discovering the guiding principles of biology, as well as its quirks and back roads.
How Is Research in Reproduction of Farmed Animals Presently Funded?
Before World War II, agriculture received the largest share of federal research funds, about 40% of the total. By the 1950s, other agencies, including the National Institutes of Health (NIH) and the Natinal Science Foundation (NSF), had emerged, and the situation altered radically. The federal budget for research began to grow and shift proportionately away from agriculture. Larger allotments of funds were funneled into health-related projects, defense, atomic energy, a fledgling national space program, and basic research, particularly in areas such as high-energy physics and chemistry. Now, at the beginning of the new century, the government appropriation for research is almost $80 billion out of a $1.7 trillion budget. The nonmilitary portion of this spending in fiscal year 1999 (for which I have accurate figures) amounted to about $35 billion, with about $16 billion of that appropriated to the NIH (Fig. 1A). The NIH is now well on its way to doubling its budget between 1998 and 2003. The NSF budget has also improved, although not comparably to that of NIH (Fig. 1B).
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The U.S. Department of Agriculture (USDA) budget for research, unlike that for NIH, has struggled even to keep pace with inflation. Its 
4% share of the nondefense budget amounted to about $1.7 billion in 1999 and is split among several agencies (Fig. 1C). It continued to fall significantly in real terms over the 5-yr period between 1994 and 1999. (Fig. 1B). A large share of the USDA budget is directed at the intramural Agricultural Research Service or ARS (Fig. 1C). About $490 million is appropriated to CSREES (Cooperative States Research, Education, and Extension Service), one of whose major functions is to administer the monies (approximately $245 million) returned to the Experiment Stations in the form of direct payments to state universities of the land grant system (Fig. 1D). These so-called formula funds, are authorized through the Hatch and related acts of Congress and are used to support agricultural infrastructure at universities, particularly as they relate to problems the states consider important. Other CSREES funds (15% in FY 1999) are diverted to Special Grants that are earmarked appropriations made by members of congress to areas that they regard as crucial, usually to their districts. The budget of the National Research Initiative (NRI), the major program of competitive, peer-reviewed grants within the USDA research portfolio, was about $119 million for FY1999 and FY2000 and was reduced to $106 millon for FY2001. To put these figures in perspective, the reader should be aware that the initial authorization for the NRI in the 1990 Farm Bill was for appropriations to rise to $500 million within 5 yr. A recent report from the National Research Council of the National Academy of Sciences recently recommended an $850 million annual budget for competitive grants for agricultural research [7], but few in our nation's capital are optimistic that the recommendation will have any impact.
The function of the NRI is to fund high-risk, long-term outcome studies aimed at the research missions of agriculture. The one program devoted to reproductive biology, Animal Reproductive Efficiency, was able to award only 23 research grants in 1999 for a total of a little more than $4 million. I would argue that research on reproduction of farmed animal species cannot thrive under these conditions unless there is a major influx of new funding into the NRI. There must also be a more enlightened attitude within the USDA and the congressional committees that oversee agriculture, and the emergence of a political champion for basic research in agriculture. The Deans of our land grant universities must support change and be less fearful that peer-reviewed research will steal from their budgets. I should emphasize that it is not just reproductive biology that is underserved by the present system. All areas of agriculture are almost equally affected.
Surprisingly, a considerable amount of large animal reproductive research within the United States is supported by NIH grants, mainly through the National Institute of Child Health and Human Development (NICHD). Such research can be funded at NIH as long as it addresses health priorities, generally those considered important by the Reproductive Sciences Branch of the NICHD [8]. Topics of interest include fertility regulation, alleviation of infertility in individuals with impaired fertility, diseases and disorders of the human reproductive system, and reproductive endocrinology and neuroendocrinology. One additional broad topic area is the developmental biology of reproduction, which covers gamete development, fertilization, embryogenesis, and implantation. None of these areas specifically preclude the use of farm animal species as long as the animal model is appropriate. For example, livestock species commonly develop ovarian cysts, a relevant topic, but would be unlikely candidates for studying uterine fibroids. They can be excellent sources of tissues and cells, such as oocytes, but have little potential for genetic manipulation, except in special cases, such as the production of pharmaceuticals or organs for transplantation. It should be emphasized that no species, other than higher primates, is a particularly good model for implantation in the human, because this process varies so much across species [9].
Currently, the Reproductive Sciences Branch of the NICHD expends about $8 million annually for research on farm species (data supplied by Dr. K. Yoshinaga, NICHD), approximately twice that available from the USDA competitive program of research grants. I have no insight into support mechanisms within other countries but suspect that agricultural research is generally not a thriving enterprise anywhere. Perhaps the most distressing consequence of this failure to invest in agriculture is that young scientists are not drawn to the area, thereby exacerbating the decline.
Why Is Research on Food and Fiber so Poorly Supported?
It is a fair statement that agriculture is being victimized by its own success. A walk through a modern supermarket in Western Europe or North America is to be witness to a quantity and variety of high quality goods that were unimaginable only 50 yr ago. The average American family now spends less than 10% of its income on food, and the average American adult was more than 8 pounds heavier in 1995 than in 1985. Butter mountains, even lakes of wine, have plagued Europe as payments to farmers encouraged overproduction of agricultural produce. Many commodity prices in the United States reached record lows in 1999. The number of farms declines as urban sprawl spreads. Consumption of meat has been related to cardiovascular and other health problems. Finally, starvation in sub-Sahara Africa and Asia is attributed to poor food distribution networks rather than a shortcoming of the food production enterprise. Is it any surprise that attempts to raise the consciousness of the Western world about research aimed at producing food even more efficiently have failed and that most innovations are viewed with suspicion, even anger? The great debate about genetically modified crops, whose future is by no means certain, could destroy a technology with enormous potential for producing healthy food more efficiently and in an environmentally friendly manner.
Yet, agriculture is constantly being required to do more on less land. The genes of pests and parasites adapt rapidly to confront defense genes. Land is eroding and water becoming more polluted, often as an outcome of agriculture. Whole ecosystems are at risk. There are at least 800 million people with insufficient food to meet their nutritional needs [10]. Millions of children suffer the physical and mental consequences of micronutrient deprivation. Our present 6 billion persons will likely stabilize between 8.7 and 12 billion by 2050, a sizeable increase by any reckoning [11]. Paradoxically, while many starve, the demand for meat products will increase (Fig. 2), particularly in the new emerging economies of countries such as China [12]. Investment in agriculture, including animal agriculture, is needed as much now as in the past.
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Agricultural Research Is a Successful Enterprise
The U.S. Congress appears dazzled by the successes of health-related research while ignoring those of agriculture. Surveys of consumers, particularly in Europe, suggest that while biotechnological innovations in medicine are acceptable, ones in agriculture generally are not. We can certainly expect to live longer as the result of antibiotics, new drugs, and intervention medicine, but long life is more than a function of medical advances and must take into account the many changes that have occurred in public health and altered social behaviors, such as smoking. But let us not forget that better food and nutritional awareness have had an impact too. Healthy people can expect to live longer, have higher quality lives, and agriculture should share some of the credit.
Let me provide one, not atypical, example of how science-based animal agriculture has been successful. The dairy industry in the United States (and elsewhere) has been spectacularly successful in raising productivity, largely through the genetic selection of elite animals. Although farmed cattle originated by a series of separate domestications from a now extinct species, the Auroch, over 10 000 yr ago in Eurasia [13], the development of true-breeding varieties through selection seems to have occurred only within the last 200 yr. The modern American Holstein is a different beast than it was even a half century ago (Fig. 3A). During that short period, there has been a remarkable threefold increase in average milk production per cow, which has been accompanied by a reduction in the number of dairy cows in production (Fig. 3B) [14]. Table 2 lists how the productivity gains have been achieved. In addition to better veterinary care and better nutrition, perhaps most improvement has come about through the practices of artificial insemination and the selection of high quality sires as a commercial source of frozen semen.
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The modern Holstein has its shortcomings, too. Their milk is relatively low in solids, and they suffer from a variety of foot ailments. Over time, the milking cows within the breed have become increasingly less fertile. New reproductive technologies in the form of better estrous detection and synchronization are likely therefore, to play important roles in the dairy industry. Bringing in new genetic stock, however, may be the path to the future.
A strangely contrasting situation has occurred in the thoroughbred industry. I obtained the winning times for the Kentucky Derby over the last 60 yr [15], disregarded those when the course conditions were wet or otherwise unfavorable, and plotted them by year (Fig. 4). To my surprise, I discovered that there had been no significant improvement in completing the 1-1/4-mile course over the same period that dairy cows had raised their milk production threefold. The one blip below 2 min was in 1973, the year that Secretariat won the Triple Crown. I can only suggest that either the arcane practices of the thoroughbred industry are to blame or an exceedingly narrow germplasm base has placed limits on what can be gained. Perhaps Secretariat was, indeed, the ultimate racehorse in terms of its genetic base. Agriculture, by contrast, has been particularly successful in exploiting the available genetic pool and using an expanding science base to advance its goals.
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Research Needs Perceived Within the Agricultural Sector
Despite the gains in productivity that have occurred by applying science-based approaches, the animal agriculture industry cannot stand still if it is to remain competitive. In Table 3, I have listed research issues related to reproduction that were raised at a recent meeting of producer stakeholders [16]. Although commodity prices, waste and odor management, the use of growth supplements and antibiotics, and animal health rank as top concerns, producer-farmers are fully aware that their livelihoods ultimately depend upon their ability to manage the breeding of their animals. I have divided the list of issues somewhat arbitrarily into needed research to improve existing technologies and broader issue topics, where there may be considerable accumulated knowledge, but specific technologies useful to the producer are not as obvious. I have listed germplasm preservation in the top grouping, even though it is a political as much as a scientific issue.
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There is insufficient space to discuss individually all the topics in Table 3. The importance of each and the need for further research are fairly obvious. The key question is whether there will be funding from the USDA, other federal agencies, and industry to do the work. One thing that is clear to producers and scientists alike is that knowledge gained from the various genome projects is going to determine the manner in which the research is done. As I shall emphasize later, the areas listed among the broad issue topics of Table 3 are not ones inherited in a simple Mendelian manner. They are quantitative traits, most likely controlled by multiple alleles at more than a single gene locus. Only by applying the technologies emerging from the postgenomic age will they be understood.
Genomics Projects on Livestock and Other Farm Animal Species
By July 2000, the initial stages of sequencing the human genome had been completed, with over 85% of the DNA nucleotide sequence already accessible through public databases. At least 80 000 short sequences derived from mRNA transcripts were also in the public domain, and the fully annotated sequences of the two shortest chromosomes, 21 and 22 had been published. The total cost of this international effort from its conception in 1985 to its final completion is difficult to estimate, except that it was several billion dollars. At present costs of $0.15 per annotated base, the price tag of a comparable project in a farm species, would be close to $500 million. Even so, unless there are major breakthroughs in sequencing technologies or an unanticipated investment of public funds, it is unlikely that any farm animal species, all of which have genomes of comparable size to that of the human (Table 4), will have its genome sequenced for some time to come.
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Animal genomics will, however, be cost efficient as a beneficiary of the Human Genome Project. The considerable similarity of the majority of the genes of livestock species, and even of poultry and fish, to those of the human will reduce the need for whole genome sequencing [17]. Linked genes in the human often retain a closer order on the chromosomes of domestic animal species than they do on the mouse, thereby simplifying mapping and allowing the location of candidate genes to be inferred. In addition, efforts are in progress to provide detailed genetic maps for many species. These maps are particularly well advanced for cattle and swine. The EST (expressed sequence tag) projects for cattle, pig, chicken, horse, and fish (Tilapia) are also being funded by the USDA, and it is reasonable to expect that as many as 40 000 annotated sequences will soon be available through GenBank for each of these projects as they move toward completion. In addition to GenBank, there are now a number of websites that provide information on food animal species genomics and related information (Table 5).
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Emerging Areas of Research in the Postgenomics World
Use of ESTs and functional genomics The availability of ESTs for each of the major agricultural species will soon circumvent the requirement for human chips and provide the necessary tools for investigators interested in more global patterns of gene expression than can be provided by the Northern blot or ribonuclease protection assays. As manufacturing costs decline, chip technologies will rapidly expand their reach within agriculture to each of the major species. The limitation will be cost and the accessibility of suitable bioinformatics systems. The outcome of this technology will be a daunting flood of information on gene expression in various cells, tissues, and organs during growth, development, and in response to endocrine signals and to pharmacological intervention.
An important feature of the use of DNA chips has, in my view, is that it provides an alternative (albeit a weaker one) to gene knockouts to pinning down the function of a gene in any cell or tissue. By following fluxes of gene expression over time and in response to specific signals, the position occupied by the protein product of that gene relative to others in metabolic and signaling pathways can likely be inferred. Functional genomics, combined with more futuristic applications, such as proteomics (protein expression patterns) and metanomics (measurements of metabolite concentrations and fluxes), will have the potential of describing the lifestyle and activities of any living cell at any chosen time. The applications of such technologies should help level the playing field relative to the comparative worth of small rodents and livestock in reproductive studies.
Marker-assisted selection for desirable reproductive traits The overriding justification for the Human Genome Project is the elucidation of the genetic mechanisms that cause human diseases. The optimal outcome will be the ability to predict, treat, or even reverse genetic conditions that lead to ill health. In contrast to the Human Genome Project, animal projects will be focused primarily on improving farm productivity. There will be no major effort to coax a genetically infertile sow to reproduce, for example. Flocks and herds will likely be screened for undesirable alleles and affected animals culled from the population.
Marker-assisted selection will not only be used to reduce the frequency of unfavorable genes in the population but will also be exploited in a positive manner to identify animals with desirable traits that can be used for breeding purposes. Once the loci for genes controlling the complex phenotypes discussed in the next section are identified, either as a specific gene or as a narrowly defined genetic locus, it will be a relatively simple matter to select animals carrying the desired genotype
Map-based cloning of alleles controlling quantitative reproductive traits Out-bred animal populations, and I include here the human, present a continuous range of phenotypic variability, because the majority of traits are controlled by multiple genes that themselves may be multiply allelic. This pool of genetic variation is sufficiently large to allow an animal population to respond relatively quickly to selective pressures. How well an allelic form is transcribed, where it is expressed, and over what duration the expression persists will help govern the resulting phenotype. Thus, mutations within regulatory DNA are likely to be the major source of genetic diversity that underlies quantitative trait variation. Domestication of animals by early farmers led to the selection of phenotypes that were perceived as valuable. These features would likely be toward the extremes of a continuum of variation. Initially, the animal would have a temperament that allowed it to be easily subdued and tamed. It might be smaller or larger than average, and happy to reproduce under confinement [13]. Over time there would be a dramatic change in the breed as it was selected for particular purposes, such as for milk rather than just for meat production. The wild Auroch, for example, would likely have produced sufficient milk for its single calf, but too much would place it at a disadvantage. The modern Holstein could probably support a dozen calves but it would fail to thrive in the wild. Like the reproductive traits listed in Table 3, milk production is quantitatively controlled and cannot be analyzed in a simple plus or minus manner.
Fortunately, experimental herds and flocks are available that permit quantitative measurements to be obtained across generations within closed populations and also after specific out-crosses to genetically dissimilar animals, thereby allowing trait segregation to be followed more easily [18]. Ultimately, the alleles associated with the increased value will be identified. Pedigree studies, such as these, can exploit recombination frequencies with known markers, including restriction-length polymorphisms (RFLPs), microsatellites, and ESTs, to place such quantitative (or economic trait) loci (QTLs) on a genetic map [17, 19, 20].
Although such mapping procedures remain crude in species such as cattle, in large part because herd sizes and the numbers of crosses that can be made are limited, an approximate chromosomal locus for a particular trait can frequently be deduced. If the mapped site falls within a region in which linearity of genes is well conserved relative to the human, it is likely that a candidate gene could be immediately recognized, and extensive sequencing might not be required. Comparisons of the nucleotide sequences of alleles resident at the locus would indicate whether the QTL effect was due to mutations, possibly in the open reading frame, or alternatively, in the regulatory region of the gene. Such studies are considerably easier to perform in farm animal species than in humans, but the candidate genes, once identified, could be immediately studied in the human population.
Combining genomics with phylogeny in comparative studies
The genomes of the majority of mammals are of comparable size and probably contain a roughly similar number of genes [17] (Table 4), although there are very different estimates as to what that number might be [21]. A significant proportion of these genes and their encoded proteins are well conserved. For many, easily recognizable orthologs are present in animal phyla that evolved several hundred million years before the emergence of mammals. It is reasonable to assume that such conserved genes have resisted major change because their function is so essential that even minor tinkering would be disadvantageous. Attempts to create a model animal cell will no doubt make use of these conserved genes because they are likely required for basic physiological processes. There is presumably a conserved hierarchy from gene 
protein metabolic and/or catabolic pathway functional cell.
In complex organisms, such as mammals, the hierarchy is extended further, from cells to tissues, from tissues to organs, onto the final animal. The fact that the basic body plan of all mammals is quite similar suggests that the majority of genes controlling mammalian development, for example the blocks of Hox genes, will remain conserved within the phylum. Such a generalization, if correct, will apply to the reproductive system, as well.
Reduced to its bare essentials, the process of mammalian reproduction, including the structures of the organ systems and the associated endocrine and neuroendocrine mechanisms, is superficially quite similar across the 4800 or so mammalian species. It is for this reason that much can be extrapolated from the mouse and the cow to the human. The mouse has the edge at present, not because it is closer to the human than the cow (its genes are in fact more distant) but because it is easier to conduct and interpret experiments on mice. As always in comparative biology, however, the devil lies in the details. No one mammal is a perfect match for another in the way it reproduces. It is these differences between species that are, to my mind, most intriguing because they can illuminate adaptive mechanisms that tell us something about ourselves and the species we have domesticated and how reproductive processes have evolved.
Some of the mutations that are responsible for causing adaptive changes are undoubtedly within cis-regulatory DNA, as discussed earlier. Others are likely to be new, i.e., paralogs rather than orthologs of more ancient genes. The latter should be recognizable because they will appear to be diverging rapidly from their ancestral genes or have had a burst of rapid change within the recent past [22]. Such genes arise either by duplication or through some other mutational event. A new gene is unlikely to survive for long in evolutionary time, even if it has neutral or near neutral effect, because it would either be eliminated without cost or inactivated as a pseudogene over time. If, on the other hand, such a gene provides some selective advantage, it will likely accumulate further mutations to polish its function, become fixed as an essential component of the genome, and then evolve more slowly.
Part of the postgenomics effort should, therefore, be to discover expressed genes in reproductive tissues that encode proteins that have diverged rapidly over relatively short periods of evolutionary time. This task will not be easy because it will, of necessity, require investigators to screen, either directly or through data banks, expressed genes in several species whose phylogeny is well established. The large farm animals are ideal in this regard. Robust statistical tools will then have to be applied to provide meaningful analyses of mutation rates and divergence times. The hypothesis is that many of the genes associated with major changes in phenotype will carry in their history a period when they rapidly accumulated nonsynonymous mutations, i.e., ones that altered amino acid sequence.
Let me illustrate the point that genes that deviate quickly in sequence from their progenitors are associated with change by citing work from my laboratory on the evolution of a family of proteins in the aspartic proteinase gene family, the pregnancy-associated glycoproteins (PAG) (Fig. 5). This family is represented by a single gene in carnivores, rodents, and equids (orders Carnivora, Rodentia, and Perissodactyla), but by multiple genes in Artiodactyla [23]. Within Artiodactyla, two main groupings emerge. One, more ancient, arose about 87 million yr ago, about the time that the Artiodactyla emerged from other ungulate mammals [24]. Its members are expressed throughout the trophectoderm. The second group, found in cattle, sheep, and goats, is much larger and is evolving rapidly. Many of its members are probably not active proteinases [25] and are expressed only in the binucleate trophoblast cells that are characteristic of the synepitheliochorial placentas of the Ruminantia, a suborder of the artiodactyls [26]. Importantly, they began to diverge from the older PAG group at a time (52 million yr ago) when the lineage that eventually led to ruminants separated from that which led to swine, camels, and whales. A further subset within the binucleate cell group appear to have diverged more recently, probably within the last 35 million yr, roughly about the time the true ruminants originated (see below). My prediction is that evolutionary changes in PAGs are functionally related to the placental changes that accompanied species diversification within the hoofed mammals.
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A second example, the evolution of interferon-tau (IFN-
), is also drawn from my laboratory and again is consistent with the above hypothesis. The IFN- are confined to true ruminants, the so-called pecoran mammals that include cattle, deer, antelope, giraffe, and related species [27, 28]. They are produced by trophectoderm for a few days prior to definitive attachment of the trophoblast to the uterine wall and play a primary role in preventing the regression of the corpus luteum. Phylogenetic analyses indicate that that the IFN- arose by the duplication of a related type of IFN gene, one encoding on IFN-
, about 36 million yr ago [29]. We have speculated that this event disrupted the promoter region and led to loss of viral inducibility and gain of constitutive expression in the trophoblast. The duplication occurred at about the same time that the pecoran ruminants emerged as a distinct suborder. Again, we see the emergence of a new placental gene coinciding with a time of major evolutionary change within a large order of mammals.
A point should perhaps be made here that the placenta and the associated events of implantation vary much more extensively across mammals than other features of the reproductive process. Indeed, the placenta, the very hallmark of the mammal, is arguably the most varied of mammalian organs, Placentas vary greatly in gross morphology, in the timing and extent to which they implant, and in how directly they are able to exchange metabolites and macromolecules with the maternal bloodstream [9]. Embryos that implant late appear to rely on nourishment provided in the form of uterine secretions, while early implanters, such as the human, rapidly gain access to maternal blood. Not unexpectedly the manner in which the embryo communicates with the mother also varies widely across species. The most likely reason for this is that the trophoblast-maternal interface is a site of intense genetic conflict that has driven high rates of evolutionary change [30]. It is perhaps not surprising that the examples I chose above were from the genetically foreign trophoblast, because that may be the easiest place to find gene families that are evolving quickly. The situation is reminiscent in many respects of the escalation of conflict occurring between pathogens and their hosts that results in rapid emergenic of new virulence on the one hand and disease-resistance genes on the other.
Loss of animal germplasm, a unique future challenge As might be appreciated, concerns about the abrupt narrowing of the germ line are real in many areas of animal agriculture where intense selection and breeding from a few select sires are practiced within a single breed. Animal breeds once common appear to be disappearing. These losses imperil our agricultural future by limiting the range of genetic resource available to future breeders.
I was struck by the particular case of the Oxford Sandy and Black, a hog variety that, according to the Oklahoma State Web Site [31], may already be extinct. I have no idea whether this sad creature carried genes that could confer particularly valuable characteristics for the modern breeder. Perhaps it was particularly resistant to disease or its meat had a good flavor. Alternatively, the Sandy and Black might have been a dud. What is certain, however, is that its virtues will never be known. Unless we continue either to eat such rare or unusual breeds or to maintain their genes in some form of repository from which they can be reincarnated at some future time, they will provide no genetic legacy.
Southern corn blight that devastated parts of the United States in the early 1970s was a wake-up call to plant breeders who had relied upon a narrow germ line. Germplasm in the form of seeds is, of course, more easily stored than animal germ cells or embryos. Also, given that freezing semen is still an imperfect technique and likely to be impractical in the field, other approaches are needed to save the animal resource base. The approach may well be to maintain each breed as a series of frozen diploid cell lines, obtained from skin or other tissue. Nuclear transfer to enucleated oocytes of a common breed and subsequent embryo transfer will then provide the path to breed immortality [32].
ACKNOWLEDGMENTS
This paper was prepared during the time the author was Chief Scientist with the National Research Initiative Competitive Grants Program (NRICGP)/CSREES/USDA, but represents his perspective and not necessarily the views of the Agency. He particularly thanks the following NRI scientific Staff members: Drs. Peter Brayton, Deborah Hamernik, Ed Kaleikau, Peter Johnson, and Sally Rockey. Additional information was provided by Drs. Michael Bedford (Cornell Medical College), Allen Garverick, Matthew Lucy, Barry Steevens, Michael Smith, and Jeff Firman (University of Missouri), and Koji Yoshinaga (NICHD). I am particularly grateful to members of my laboratory, who acted as sounding boards for my original lecture and to Carrie Neville, Kristen Koch, and Dr. Cheryl Rosenfeld who provided invaluable help with preparing the talk and the paper.
FOOTNOTES
1 The research discussed was supported by NRI/CSREES/USDA grants 96-35203-3257 and 96-35205-3706. 
2 Correspondence: R. Michael Roberts, 158 ASRC, 920 East Campus Drive, University of Missouri, Columbia, MO 65211. FAX: 573 882 6827;robertsrm{at}missouri.edu
REFERENCES
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