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FDA Consumer magazine
May-June 2003
Table of Contents
By Linda Bren
Full Flush is a celebrity. No one asks for his autograph, but they do ask for his progeny. Named for a winning poker hand, the aging grand champion bull can't meet the demand of all the cattle ranchers who want more like him. But the bull's clones may keep his legacy alive. Full Flush's five clones "were as normal and healthy as any calves I've ever raised," says rancher and veterinarian Donald Coover of Galesburg, Kan., who bottle-fed the young calves and raised them for the first six months of their lives. The calves, born in 2001, will soon be ready to propagate herds of high-quality beef cattle.
To the uninitiated, animal cloning may conjure up visions of strange, robot-like creatures, but real clones are far from this science-fiction fallacy. "This is just an assisted reproductive technology," says Mark Westhusin, Ph.D., director of the Reproductive Sciences Laboratory at Texas A&M University's College of Veterinary Medicine. "We're not trying to resurrect animals or get animals back."
"Clones are biological copies of normal animals," says Larisa Rudenko, Ph.D., a molecular biologist and risk assessor in the Food and Drug Administration's Center for Veterinary Medicine (CVM). "In theory, they're pretty close to identical twins of an adult animal."
Although the technology to clone farm animals was developed more than 20 years ago, today's method of cloning, somatic cell nuclear transfer (SCNT), has been around only since 1996. Coover estimates that only a couple hundred of the 100 million cattle in the United States are SCNT clones. And you won't find meat or milk from SCNT cloned animals in your supermarket yet--the FDA has asked companies that clone animals not to introduce any of them, their offspring, or their food products into human or animal food until the agency has evaluated the safety of these products. The companies are cooperating, says Stephen Sundlof, D.V.M., Ph.D., director of the FDA's CVM. "And we're being very diligent to make sure if this new technology makes it to the marketplace, that it's safe for people to eat."
It's unlikely that you will eat a cloned animal anytime soon. At a cost of about $20,000 each to produce, clones are used for breeding--not for food. But some scientists and farmers are looking at the descendants of cloned cattle, pigs, goats and sheep as potential sources for food and clothing, if the FDA gives the OK.
Mandated with protecting the nation's food supply and animal health, the FDA is working to set a policy on cloned animals, based on the best available science. "We do not want these products on the market until there has been a thoughtful, thorough and deliberate evaluation of the issues," says Sundlof. "We want to make sure that the public is clearly informed and that they have had a chance to participate in the process."
Early methods of cloning in the 1970s involved a technology called embryo splitting, or blastomere separation. Embryos were split into several cells and then implanted into a surrogate mother for growth and development. But there were a limited number of splits that could be made, and only a few clones could be produced from one egg. The characteristics of the clone were also unpredictable because scientists were cloning from an embryo whose traits could not be predicted.
The practice of cloning took on new meaning in 1996 with the birth of Dolly the sheep, the world's first mammal cloned from an adult cell. Dolly was produced using SCNT technology. Since the cloning of Dolly, this technology has been used to clone cattle, mice, goats, pigs, rabbits, and even a cat. Unlike the embryo splitting method, in theory, SCNT can be used to make an unlimited number of copies of one animal.
The SCNT process starts with an unfertilized egg, or oocyte. Scientists remove the oocyte's nucleus, which contains the egg's genes, or hereditary "instructions." What remains after removal of the nucleus is a cell that contains nutrients essential for embryo development and other cellular machinery waiting for a new set of instructions.
A somatic cell from the animal to be cloned--or in some cases, just the cell's nucleus--is cultured in an incubator and then injected under the coating of the unfertilized oocyte. (Somatic cells are any cells of the body except sperm and eggs.) Stimulated by a mild electrical pulse, the oocyte cytoplasm (everything in the cell but the nucleus) and the genetic material from the donated somatic cell combine. If fusion is successful, the resulting fused cell divides just as if it were a fertilized egg and produces an embryo. The embryo is placed in the uterus of a surrogate mother and, if development proceeds normally, an animal clone is born.
But there's a tricky part to this process, says Rudenko. The nucleus of the adult cell is specialized, or differentiated, for a particular function. "The nucleus has matured to a point where its instructions are 'locked away' in a configuration specific to the job that the cell is intended to perform," says Rudenko. "For example, a muscle cell has a different job from a liver cell, and it has a different set of instructions available to it. The complicated part of cloning that we don't fully understand is how those instructions get reset."
The unlocking and resetting of instructions without making changes to the genetic code is called epigenetic reprogramming. This process allows the cell to develop into a new organism instead of continuing to do its old specified cellular functions. And it's the epigenetic reprogramming that scientists haven't yet mastered and that accounts for frequent cloning failures.
Steven Stice, Ph.D., explains epigenetics as the propensity for different outcomes from identical DNA sequences. An example of an epigenetic effect in normal human birth is the different fingerprint patterns of identical twins, says Stice, a professor in the Animal and Dairy Science Department at the University of Georgia and chief scientific officer for ProLinia Inc., a livestock cloning company in Athens, Ga. Epigenetic changes are not unique to cloning but are more noticeable in clones, Stice adds. "Everything from in vitro fertilization to artificial insemination can have epigenetic effects."
Proponents of livestock cloning see it benefiting consumers, producers, animals and the environment.
"The consumer is looking for a nutritious and wholesome product provided to them in a repeatable and reliable manner and produced in a humane and ethical way," says Coover, who also owns and manages SEK Genetics Inc., a beef cattle semen distribution company. "If a consumer spends $30 on a steak dinner at a restaurant, they expect a great steak, but don't always get it."
For farmers whose livelihoods depend on selling high-quality meat and dairy products, cloning can offer a tremendous advantage, says Coover. It gives them the ability to preserve and extend proven, superior genetics. They can select and propagate the best animals--beef cattle that are fast-growing, have lean but tender meat, and are disease-resistant; dairy cows and goats that give lots of milk; and sheep that produce high-quality wool. Through cloning, it would be possible to predict the characteristics of each animal, rather than taking the chance that sexual reproduction and its gene reshuffling provide.
Coover compares the process of identifying a superior animal to spinning a giant roulette wheel. "Sometimes you win, sometimes you lose, and sometimes you hit the jackpot." But a producer cannot tell if he's hit the jackpot with a young animal. "It's like trying to identify the school kid in the second grade who is going to grow up to solve the riddle of cancer," says Coover. "A rancher may think he has a good bull, but that bull has to sire calves, the calves have to mature and produce calves of their own, and this has to occur for several generations to know that it's not a fluke. By that time, the bull is dead and gone, and its genetics are lost to the industry." Through SCNT cloning, even deceased animals can be cloned if a tissue sample is preserved in life or within a short time after death.
Cloning has the potential to improve the welfare of farm animals by eliminating pain and suffering from disease. "From time to time, in nature, you find a naturally disease-resistant animal," says Rudenko. "You can expand that genome through cloning, and then breed that resistance into the overall population and help eliminate major diseases in livestock."
Cloning can reduce the number of unwanted animals, such as veal calves, says Ray Page, chief scientific officer and biomedical engineer at Cyagra, a livestock cloning company. Veal calves are commonly surplus male offspring from dairy cows. Since the males don't produce milk, they are not as useful to the dairy industry and are turned into veal calves. Cloning can ensure the creation of more female offspring for dairy production.
An environmental benefit could result from cloning grass-fed instead of grain-fed animals. Grain-fed animals are known to be better tasting and more tender, but once in a while, a high-quality grass-fed animal comes along. "If we can move our cattle-raising from a grain economy to a grass-fed economy, we can make food more efficiently and there are benefits to us as a society," says John Matheson, a toxicologist and environmentalist who serves as a senior regulatory review scientist for biotechnology in CVM. Grass is a soil-building crop. In addition to reducing erosion, grass does not need the quantities of fertilizers and pesticides required by grain. And because forage is cheaper than grain, production savings can be passed on to consumers.
"Cloning can help spread the best genetics over larger populations of animals," says Stice. When farm animals are cloned, genetic diversity may be reduced, but cloning can also be a tool to preserve rare genetics in livestock and, potentially, wild animals. Stice encourages zoos and wildlife refuges to preserve the tissue of endangered species in the hopes that technology in the theoretical stage today can be developed to regenerate these species in the future.
While cloning proponents see enormous capabilities for the technology, cloning critics have concerns on a number of levels. Social, ethical and religious convictions all weigh in to make people wary of cloning. Some find it hard to separate animal cloning from human cloning. But cloning scientists view animal cloning on a continuum of reproductive technology. Improving breeding practices in the hopes that offspring will be improved has been going on for thousands of years. Arab chieftains were using artificial insemination in horse breeding as early as the 14th century, according to historians.
"There's always been a fear of new technology," says Matheson, who notes that cloning animals is not a precursor to cloning humans. "We already know more about reproduction in humans than in any other species, so there's no learning curve to be gained in cloning cows."
Matheson explains that the FDA's role is to look at the safety aspects of cloning based on the best available science. The FDA needs to answer an important question to help it develop its regulatory approach to animal cloning, he says. "Is this risky new technology that endangers animals and our food supply, or is this just another small step in the evolution of food production technology?" To answer this question, the FDA is gathering more data.
The FDA commissioned the National Academy of Sciences (NAS) to identify and prioritize any safety concerns that bioengineered and cloned animals might present to food, animals and the environment.
After consulting with pioneers in the field of cloning and holding a public workshop, the NAS published its report, Animal Biotechnology: Science-Based Concerns, in August 2002. According to the report, "There is no current evidence that food products derived from adult somatic cell clones or their progeny present a food safety concern." The report recommends collecting additional information about food composition to confirm that these food products are, in fact, safe. Food should be analyzed for such essential ingredients as amino acids, vitamins and minerals and to make sure cloned animal products don't differ from those of normal animals in ways that might affect human health.
But this analysis is not as easy as you might think, says Matheson. "We don't know what the composition of 'normal milk' is. It may all taste the same from the market, but it can vary a lot in each individual animal depending on its age, what it eats, and the time of lactation. Qualitatively, most of the same ingredients are always present, but quantitatively, their actual concentration varies from animal to animal." This may be true for meat as well since each animal is different just like each human is different. "Even though we think of a pork chop as a pork chop and a steak as a steak, they're each a little bit different from one another in chemical composition," adds Matheson.
The NAS report cited environmental concerns regarding genetically engineered fish and other animals that could escape into the environment, reproduce, or compete successfully for food and mates with wild animals. But this concern does not extend to cloned domesticated animals, since cattle and other livestock generally do not run wild and have no wild counterparts in the United States with which to interbreed.
Cloning may someday reduce the number of animals needed for food and fiber production, according to the report, but could also have adverse effects on animal welfare. Calves and lambs produced through cloning tend to have higher birth weights and longer gestation periods, which may lead to difficult births. Repeated exposure of individual animals to invasive procedures to harvest oocytes for SCNT is likely to cause pain and distress. In addition, the survival rate of cloned fetuses is low, and some survivors have health problems such as heart and lung disease.
Speculation surrounds the death of Dolly the sheep. Dolly had been diagnosed with arthritis in her hind limbs when she was about 4 years old. In February 2003, she was euthanized at the age of 8 because of a degenerative lung condition most probably caused by a virus. Critics blame cloning for Dolly's lung disease and her arthritis. But others attribute her health problems to being overweight and to becoming infected with a virus present in the barn in which she was kept.
Low rates of success are inherent in any new technology, says Page. "But the people doing this are becoming better technicians. We're making improvements in the way we handle cells and embryos. Efficiency rates continue to improve year after year, and more of the embryos are surviving to term and more of the calves are healthy."
The Humane Society of the United States (HSUS) has asked the FDA to ban sales of products from cloned farm animals and their offspring because of "serious concerns about the health and welfare of cloned animals."
"We condemn cloning as yet another move away from regarding animals as animals, and yet another development that will favor large corporations over small ones," says Michael Appleby, Ph.D., HSUS vice president for farm animals and sustainable agriculture. The HSUS commends the FDA for commissioning the NAS report and requesting that food from cloned animals not enter the marketplace. "These measures show an appropriate, precautionary approach," says Appleby, "and we trust the FDA will further this by putting more weight on the animal safety issues outlined in the report."
The NAS's job was to identify the potential risks of cloning; now the FDA is studying those risks to determine how to manage them. The FDA is developing two risk assessments: one describing the potential risks, if any, of consuming food products from animal clones and their offspring, and the other describing health risks to animal clones and their offspring. The FDA will use these assessments to develop an appropriate science-based regulatory approach, in the form of policy or guidance for industry, to manage any food and animal health risks. The public will have the opportunity to comment on this guidance, planned for release by the end of 2003.
In its commitment to a transparent process, CVM gathered together food producers and food consumers to share their perspectives on bioengineered and cloned animals at a three-day public workshop. Held in Dallas in September 2002, the workshop was co-sponsored by the Pew Initiative on Food and Biotechnology, an independent source of information on agricultural biotechnology.
CVM will continue to inform the public as it moves toward a decision on the type of regulatory structure that will be needed for cloned animals. "The public will be well informed and nothing is going to happen that they won't know about," says Sundlof.
Cloned animals and transgenic animals are sometimes mistaken to be the same, but they are different, says Larisa Rudenko, Ph.D., a molecular biologist in the Food and Drug Administration's Center for Veterinary Medicine (CVM).
Transgenic animals or plants are produced by adding or removing genes, or by altering the expression of their existing genes. This process can involve genetic information taken from different species or created in DNA synthesizing machines. When a gene for insulin, for example, is inserted into a goat, the animal could produce insulin in its milk, which would then be purified into an injectable form to treat human diabetes. And genes for growth hormone from one fish species transferred into the genome of salmon can cause them to grow rapidly. (See "A New Kind of Fish Story: The Coming of Biotech Animals," January-February 2001 FDA Consumer.)
Cloned animals are produced using bioengineering techniques but are intended to be biological copies of existing animals.
CVM is developing guidance for cloning food production animals. Future guidance for developing transgenic food animals will build on the cloning guidance and further study.