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U.S. Department of Health and Human Services

Animal & Veterinary

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BIOTECHNOLOGY: PUTTING CLONES IN CONTEXT

by John Matheson
FDA Veterinarian Newsletter March/April 1998 Volume XIII, No II

Cloning of mammals using somatic cells is big news in biotechnology. A nucleus from a diploid, mammalian cell culture derived from an organ other than the gonads has been substituted for the nucleus of a mammalian egg, the egg implanted into a surrogate mother and a viable offspring produced. This article will examine cloning in the context of how it might relate to products regulated by CVM.

News media attention to cloning reached new heights in February 1997 with the announcement from the Roslin Institute in Scotland that they had successfully created Dolly, a clone from a somatic cell derived from cultured mammary gland cells of an adult sheep. Instead of evaluating the impact of this advance upon animal biotechnology, the media and the public leaped ahead to consider the bioethical and social implications of cloned humans. The President's National Bioethics Advisory Commission last June proposed a 5-year moratorium on cloning directed at creating a human child, but not the cloning of human or other DNA in cell lines or the cloning of animals.

In an interview with The Washington Post published January 20, 1998, the Acting Commissioner of FDA, Dr. Michael Friedman, stated "Through the Food, Drug, and Cosmetic Act we do have the authority to regulate human cloning, and we are prepared to assert that authority." He added that human cloning is a form of cellular or genetic therapy that requires prior FDA approval. The same article goes on to further cite Dr. Friedman as saying that anyone wanting to attempt human cloning legally must file a formal application with FDA which would undertake a lengthy review. The FDA would initiate legal action against anyone failing to file that application.

Cloning of humans has long been recognized as an ethical and social challenge. Westerners have been conditioned by books like Brave New World and movies like Boys from Brazil to reject human cloning. Our society will probably still be debating the permissibility of cloning humans long after cloning becomes technically and economically feasible.

On the other hand, clones of plants have long been prominent members of agriculture and horticulture. Genetic uniformity is an important agricultural plant trait that, among other things, facilitates efficient machine harvesting of crops and helps standardize product quality. For example, each apple tree of a single variety is genetically identical to every other individual of the same variety apples and many other fruits are cloned through vegetative propagation, i.e., stem cuttings, because they do not "breed true". In other words, the reshuffling of genes that occurs during sexual reproduction of apples results in apple offspring that are too dissimilar from the parents to be reliable for propagation of apples for commercial production. However, there is no movement afoot to ban the cloning of apples or to consider the bioethical dilemmas posed by cloned apples on the fabric of human society. Cloned plants are accepted as a normal part of human society.

Aside from Dolly the sheep, clones of domesticated animals are rare compared to clones of plants in our everyday environment. One might well argue that this is only because clones of animals are more difficult to establish than plants. The goals of many selective breeding programs, many of which feature repetitive back-crossing and inbreeding, include establishing a population of animals, e.g., dogs, horses, cattle, fish, etc., that possesses desirable traits that "breed true." Selective breeding reduces genetic diversity in "breeds of domesticated animals. The extreme case of this selective breeding can be found in the many strains of laboratory rats and mice used for product testing. These strains are so genetically homogeneous that there is no tissue rejection when tissue from one mouse is transplanted to another of the same strain. They are practically genetically identical. This uniformity is important for animal testing because statistically powerful testing may be conducted with small numbers of test individuals. There is less statistical "noise" caused by individual variation. Since the results are similar, cloning of animals could be looked upon as an alternative to selective breeding, especially useful where selective breeding is not practical.

So, is Dolly the logical extension of sheep selective breeding, possessing all the desirable traits sought by sheep breeders of the past? Well, no. Dolly is proof that the process of cloning apparently can work in sheep. Why were sheep selected to clone? Economics. Sheep have shorter generation times than cattle and they still produce milk in reasonable quantities. Why the interest in milk? The mammary gland is a marvelous protein synthesis and secreting organ whose products cannot always be duplicated by bacterial fermentation or chemical synthesis. Domesticated strains of transgenic sheep or cattle might be used to secrete bioactive proteins in milk that can be used as drugs, biologics and animal drugs.

Transgenic animals are genetically modified to contain a grouping of inserted genes (transgenes) from practically any species or combination of species. One application of transgenic animals is for the expression of proteins or enzymes that are not normally present or for the expression of higher concentrations of proteins that are normally present. Expression may be throughout the animal or directed to a specific organ, for example, the mammary gland. Transgenic animals have already been created through various genetic modification techniques that secrete proteins of great value in their milk, e.g., drugs that can be extracted and purified. The only trouble has been that, like the apple, most transgenic animals do not breed true. A major application for the technique of cloning will be in reproducing, in one generation, copies of transgenic animals that yield a high value product.

January 20, 1998, also brought a report from the University of Massachusetts that transgenic Holstein calves had been cloned and born in Texas as part of a project sponsored by Advanced Cell Technology, Inc., and Genzyme Transgenics Corporation. The stated goal of the project is producing recombinant human albumin in cows milk. (This can be purified for use as a human blood product.) Like Dolly, these calves are clones and test models, rather than production animals. Unlike Dolly, the calves are genetically modified. They contain only a marker gene, however, instead of a human albumin gene. Then, too, they are a male clone. Dairy cattle are also capable of more efficient milk production than sheep, so the experiment is an advance toward commercial production in this respect, too.

Cloning of somatic cells in animals is more a tool to reproduce valuable animals, like transgenic animals that produce drugs or biologics, or endangered species, or the best results of selective breeding programs, like the dairy herd improvement plan. The societal benefit to cost ratio for cloning of animals is decidedly different from the ratio for cloning humans, and the use of cloning in animals deserves to be considered separately.

Will the successful somatic cell cloning of mammals open the product floodgates from animal biotechnology companies? Like almost everything in the field of biotechnology, this is hard to predict. For the time being, the answer is "probably not." Cloning will probably always be an expensive way to reproduce mammals compared to sexual reproduction and so will be limited to extremely valuable animals producing high value products.

Does CVM plan to regulate cloning of animals under the Food, Drug, and Cosmetic Act? The answer is probably yes and no. CVM regulates products. Cloning is a process. In the sense that cloning is a means to "manufacture" more transgenic animals and if those transgenic animals are producing an animal drug, then CVM could be involved in examining cloning carried out as part of the production process for the animal drug. CVM also regulates the drugs used on animals as part of the cloning process, for example, drugs for super-ovulation and estrus regulation. Other FDA Centers could similarly be indirectly regulating the cloning process as it is applied to transgenic animals producing a human drug or biologic.

Still under consideration is whether CVM should play a role in determining the safety of food derived from cloned animals that are not genetically modified, for example, clones of a high-producing dairy cow. Does the process of cloning have the potential to introduce changes in the quality of milk or meat derived from clones of normal dairy cows? While clones of food-producing animals are now starting to be developed, there are not yet enough of them to answer this question with hard data. Strictly on a theoretical basis, clones of normal animals should be indistinguishable from their parent in nearly all respects and, therefore, present no food safety concern.

John Matheson works in the Office of Surveillance and Compliance where, among other duties, he follows biotechnology developments for CVM.