ViaGen Preserving and Multiplying Superior Genetics

WASHINGTON, D.C. (July 24, 2008) – The European Food Safety Authority (EFSA) announced today its final scientific opinion that food from cloned cattle and pigs is safe, and there are no implications of animal cloning on the environment. Key findings of the EFSA Scientific Committee are:

There is no indication that differences exist in terms of food safety for meat and milk of clones and their progeny compared with those from conventionally bred animals.

Somatic cell nuclear transfer, or SCNT (the most common technique used to clone animals) results in the production of healthy cattle and pig clones, and healthy offspring that are similar to their conventional counterparts based on parameters such as physiological characteristics, demeanor and clinical status.

From the data collected, no environmental impact is foreseen.

Jim Greenwood, President and CEO of the Biotechnology Industry Organization (BIO) issued the following statement in response to the scientific opinion released today by EFSA:

“BIO supports the key safety findings of EFSA’s scientific opinion, which concludes that meat and milk from livestock clones and their offspring are safe, and are no different than foods from livestock produced through conventional breeding. EFSA’s findings are consistent with the U.S. Food and Drug Administration’s (FDA) January 2008 risk assessment on animal cloning, and the worldwide scientific consensus that livestock cloning is safe.

“Consumers benefit from cloning technology because the offspring of clones will produce better meat and milk products. This decision affirms the global scientific agreement that foods from livestock clones and their offspring are completely safe to eat.

“Cloning is a breeding technology that helps farmers and ranchers produce healthier animals. Animal clones are an exact genetic copy of an existing animal, a ‘twin’ born at a different time. The offspring of cloned animals are produced through conventional breeding, and their lineage gives them enhanced genetic traits.

“The primary goal of farmers and ranchers is production of healthy animals and this technology, like many others, advances that goal. As noted by EFSA and the FDA, there are no unique animal health risks associated with livestock cloning, as compared with other assisted reproductive technologies. In fact, cloning offers the potential to significantly improve health and well-being of the herd because cloned animals will be used to breed healthier offspring.

“Now is the time to invest in this and other science-based solutions to achieve an improved, sustainable and reliable food supply. Cloning is just one example of how agricultural biotechnology can provide those solutions to consumers, farmers and food processors and retailers around the world.”

In February 2007, the European Food Safety Authority (EFSA) was asked by the European Commission to provide a scientific opinion on the food safety, animal health, animal welfare and environmental implications of animal clones, obtained through the SCNT technique, of their progeny and of the products obtained from those animals. The final opinion also follows public consultation on a draft opinion issued earlier this year. The final opinion is posted online at: www.efsa.europa.eu.

For more information on cloning, visit www.clonesafety.org.

About BIO

BIO represents more than 1,200 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology products. BIO also produces the BIO International Convention, the world’s largest gathering of the biotechnology industry, along with industry-leading investor and partnering meetings held around the world.

Personally, I blame the Industrial Revolution. If the average British housewife had never been separated from her agrarian roots, we would not be in half the mess we are in. We’d grow our own organic vegetables, make low-fat casseroles out of pigs’ entrails and live healthily and hysteria-free beyond the subliminal control of the Tesco mother ship. We might also be a teensy bit bored, but that’s another column altogether.

Can there be anything more depressing than the oppressive superstition of today’s food shoppers – predominantly female – when faced with what they perceive as “bad food”? I doubt it. Logic doesn’t get a look in. Although faced with galloping bills, a grave world food shortage and unassailable evidence that the high-salt, high-fat and high-sugar processed diet that they favour is killing their loved ones with kindness, consumers are opposed to technological solutions.

For – surprise, surprise – the first credible survey into attitudes to food derived from cloned animals has revealed strong concerns. The public – for which read women – are worried about safety, ethics and animal welfare. The Foods Standards Agency found that they regarded cloned animal products as “interfering with mother nature”; “an unstoppable juggernaut”; and “a slippery slope” – and that they plainly preferred to die of stale clichés rather than drink fresh milk from cloned cows. They feared such products might be unsafe for human consumption and wanted extensive five to ten-year tests – presumably until the moon was in Aries and Gemini was in the ascendancy – in line with checks on new medicines.

It is a funny old world. As food riots break out in Haiti and Egypt and leaders at the UN food summit declare that a relaunch of agriculture is necessary to feed the planet, the great British shopper takes anti- science to new levels by objecting to increased food production.

We have been here before. This same emotional argument put a stop to the widespread use of genetically modified cereals in the UK. GM became a tainted brand that is now snuck into cheap food in small print. Yet if there is evidence that GM foods do any environmental or human damage, I’m still waiting to see it. (like I’m still waiting for the predicted millions to die of human form CJD from infected burgers.)

The ironies mount up: the same people who happily pay thousands of pounds for IVF babies, or seek gene therapy cures for their child’s asthma, condemn genetic modification as “dangerous”. The fastidious public, misshapen by obesity and sentenced to early death by doughnut, worry about “Frankenstein food”.

What this irrationality illustrates, vividly, is how ignorant people have become since they were divorced from the basics of agriculture. The land taught a wisdom we have lost. Genetic modification is simply selective breeding; it has been key to farming since the first hunter gatherer decided to stay put and find a bull for his cow. The slow-motion process of modifying animals by breeding has been going on for thousands of years and there is not a single strain of cow, sheep, pig, horse, dog, cat or hamster that is not the result of extensive generations of species manipulation by humans. An identical process went on with plants. And by doing so, productivity has improved immeasurably.

It is completely bonkers to think that today’s animals and plants bear any resemblance to what used to exist in the wild. Once upon a time all dogs looked the same; we simply modified them by breeding those with genetic abnormalities. And clever gardeners have done the same: creating, for example, broccoli, cabbage and cauliflower as mutations from the same species of plant.

Genome selection means nothing more radical than clever breeding – discovering what kind of genes work best and using them to improve existing strains or exclude disease. Cloning is a further acceleration of that process – jumping the time period that normal reproduction takes; speeding up of the selection of the most productive. Scientists tasked with solving the world’s food crisis – and we can’t leave it to politicians – know it’s safe. Similarly, the US Food and Drug Administration has decreed produce from clones and their offspring “as safe as food we eat every day”. The European Food Safety Authority, a little more cautiously – because it works on European snail time – says the same.

What happened with GM cereals cannot be allowed to happen again over meat and milk simply because the British shopper is overwhelmed by the “yuck” factor. There is a much more at stake than the sensibilities of the squeamish. It is as simple as this: the welfare, productivity, health and sustainability of farm animals have to improve if the world is going to keep eating meat. The oceans are being fished out, agricultural land is going to biofuels: something has to produce the protein to keep the world alive. The first cloned Holstein dairy cows, said to be capable of producing 30 per cent more milk, have been born in Britain. Instead of getting the vapours, we should rejoice.

April 29, 2008

The world’s first cloned horse, Prometea, has had a foal.

Pegaso, her son, is the first offspring of an equine clone confirms, once again, that cloned animals can grow and reproduce normally, giving rise to healthy offspring.

Prometea with her foal Pegaso: The development may help the breeding of champion racehorses

The name Prometea, a Haflinger mare, is a reference to Prometeo (Prometheus), who was punished for stealing fire from Olympus for the benefit of mankind.

She entered the history books in 2003 when she was unveiled as the world’s first horse clone, one that offered a way to preserve the genetic heritage of many exceptional horses whose genes are presently lost because champion geldings are castrated.

“During these five years Prometea has been in very good health and often at the centre of media attention,” says her creator, Prof Cesare Galli of the Laboratory of Reproductive Technologies in Cremona.

“The ultimate proof of her normality has just come with the birth of Pegaso, on March the 17th 2008, after a single insemination with the semen of the Haflinger stallion Abendfurst.”

Pegaso has special significance in racing because sporting horses are castrated at a young age. “When they become adult and demonstrate to be champion horses, they are unable to reproduce and it is therefore impossible to obtain the next generation: the champion’s offspring,” says Prof Galli.

“This is a bitter reality that clashes with the driving principle of animal breeding and selection that is based on the reproduction of superior individuals to pursue genetic improvement of the breed.

“Therefore, today, horse cloning is simply an assisted reproduction technique that allows us to obtain copies/clones of castrated champion horses and finally, from these clones, the champion’s offspring that otherwise would never be born.”

Prof Galli showed the technology could revolutionise blood stock breeding when he unveiled a cloned foal of Pieraz, an Arab endurance champion, in 2005.

He has cloned cattle and pigs too, and worked with human embryo cells, which led to him being excommunicated by the Catholic Church, even though he did not himself destroy embryos but used embryonic stem cells that had been derived in other countries.

Prof Galli first encountered problems with the authorities when he unveiled Galileo, Italy’s first cloned bull, which was confiscated by Italy’s Health Ministry.

It’s not often that American food companies join hands with environmental and consumer activists to call for greater government control over the nation’s food supply. But that’s just what happened last week after the U.S. Food and Drug Administration concluded that meat and milk from cloned cows, pigs, and goats are safe for consumers.

Despite the overwhelming science behind that finding, industry and activists have called for a ban on cloned food products. Naturally, you might think that lockstep agreement from such unlikely bedfellows is a little fishy. And you’d be right. The losers would be American consumers, farmers, and the environment.

Since 1996, when Dolly the sheep became the first mammal to be cloned from an adult cell, thousands of animal clones — including other sheep as well as cows, goats, pigs, horses, rabbits, and several other species — have been born and studied more intensely than the progeny of almost any other animal breeding technique. Critics claim the process will create monstrous new hybrids in some kind of barnyard “Boys from Brazil,” but the reality is that consumer safety is not seriously in doubt.

FDA took more than six years investigating the matter, and its comprehensive, 968-page report shows that thousands of nutritional and other compositional comparisons reveal no differences between the safety of clones and conventionally bred animals. Stephen Sundlof, head of the FDA’s Center for Food Safety and Applied Nutrition said at a news conference last Tuesday that agency scientists have “done a very extensive job of looking at anything that could possibly be a food hazard, and to be honest, we found nothing.”

Regulatory authorities in New Zealand, France, and the European Union agree. And government scientists in Australia, Canada, and Japan are expected to issue their own clean bills of health in the next year or two.

THIS OVERWHELMING agreement among scientists should pave the way for animal clones — or to be more exact, their offspring — to come to market. Cloning is expensive, costing as much as $17,000 for cows and $4,000 for pigs. So, the vast majority of clones will be used just for breeding. Only their naturally produced offspring should find their way into grocery stores during the next few decades.

Since there are no real questions about consumer safety, the critics have had to capitalize on zany scare stories and the public’s ambivalence about unfamiliar technologies. The Consumer Federation of America (CFA) says that a “flood of milk from highly productive cloned cows is not good for the taxpayers” who buy surplus milk from dairy farmers. The group also claims cloning will make our kids fat because “[s]urplus milk is turned into high fat products that then go to school children.”

At one FDA meeting, CFA’s Carol Tucker Foreman even exploited religious and ethical concerns, criticizing the agency for studying food safety without first considering any ethical and religious implications. Of course, FDA is not legally permitted to consider religious objections, as the activists point out when the agency evaluates controversial products they want approved.

More importantly, humans have been using sophisticated scientific methods to control animal reproduction for decades, so we have already settled the ethical arguments critics of animal cloning now raise in opposition. Cloning is really just a technological extension of methods such as in vitro fertilization (IVF) and embryo transfer that are now commonplace in animal breeding, though it uses one animal’s DNA to create an exact genetic copy, essentially an identical twin born a generation later.

While it has been just a decade since Dolly was born, most of the individual steps that make cloning possible are a close to a century old. The transfer of living embryos from one animal’s womb to another, for example, dates to the 1800s. Cloning itself has been conducted with invertebrates, amphibians, and other non-mammalian animals since the turn of the 19th century. And IVF was developed for animal breeding in the 1950s.

Even today’s proven method of cloning mammals — transferring an adult animal’s genetic material to an unfertilized egg — was first envisioned in the 1930s. Its use simply had to wait until these intermediate steps were perfected over the following decades. As a consequence, scientists know today far more about the health and well-being of cloned animals than the skeptics would have us believe.

None of the technical difficulties that cloning critics highlight is unique. Many clonal pregnancies result in miscarriage, and some clones have neonatal health problems, so critics insist that moving forward now is inhumane and unethical.

Each of these problems is also present in other assisted reproductive technologies, such as IVF and embryo transfer, as well as natural mating. Animal breeders have managed them for decades, so their presence in cloned animals presents no unique ethical or consumer safety issues.

THE ABUNDANT evidence of safety is why the critics have had to focus attention away from the science. Instead they ask, even if we can clone animals safely, why should we?

The answer is simple: Breeders can produce better and safer food by cloning rare animals that produce leaner meat, for example, or are especially resistant to common livestock diseases. Researchers in Asia have even cloned a cow that appears to be resistant to mad cow disease. The ability to drastically reduce illness among animals and to improve consumer safety arguably makes cloning more, not less humane than traditional breeding.

But that’s not all. Producing more meat or milk per animal helps reduce farming’s ecological footprint by, for example, allowing for a reduction in the size of herds and lowering the amount of waste the animals generate. And cloning is already being used to help increase populations of threatened and endangered animals, such as the gaur and banteng, which are related to our beef and dairy cattle. Many scientists hope that, one day, cloning can help recover endangered species such as tigers, rhinos, and pandas.

Still, the activists’ antics have scared one group of influential Americans: the dairy and packaged food industries. Rising demand in the U.S. for organic products makes many food companies believe consumers will reject meat and milk from clones. Others fear a trade backlash from technophobic consumers in places like France and Italy. That’s why several major food companies, including the largest U.S. meat producer Tyson Foods, have already announced that they had “no immediate plans” to buy cloned livestock.

THEY MAY NOT have the chance. Ever since 2001, animal cloners have complied with a “voluntary” moratorium on selling food products from clones while they awaited FDA’s safety study.

Yet, even as FDA unveiled its final assessment last week, the U.S. Agriculture Department bowed to food industry pressure and asked to extend the moratorium until consumer concerns could be resolved – possibly as long as two or three more years. And Democratic Senator Barbara Mikulski introduced legislation that would keep cloned animals off the market indefinitely.

Knowing that they are ultimately at the mercy of consumers and retailers, Texas-based Viagen and Iowa-based TransOva Genetics — two of three private sector U.S. cloning companies — developed a system to track cloned animals so that farmers, meat packers, and retailers who wish to do so can avoid them. John Kleiboeker, of the Missouri Beef Industry Council told the St. Louis Post-Dispatch that “the FDA may say it’s not required, but consumers may want labels, so discerning marketers will do it.”

Kleiboeker is right, of course. From organic milk and fair trade coffee to kosher and halal meats, many consumers have shown a preference for foods produced in certain ways.

But, that is exactly why extending the moratorium is unnecessary. American farmers and the food industry have proven perfectly capable of segregating foods from various new and old production systems whenever a genuine consumer demand for it exists. Whether it’s religious, ethical, or environmental concerns, all that is needed is for regulators to make a science-based judgment on safety and then get out of the way.

Gregory Conko is a Senior Fellow at the Competitive Enterprise Institute. His most recent book, The Frankenfood Myth: How Protest and Politics Threaten the Biotech Revolution, co-written with Henry I. Miller, was named by Barron’s as one of the best books of 2004.

FOR IMMEDIATE RELEASE

January 15, 2008

Statement from Mark Walton, ViaGen President on FDA Final Risk Assessment on Food from Cloned Animals

Austin, TX -“ViaGen applauds the release of the U.S. Food and Drug Administration’s (FDA) rigorous scientific analysis of the safety of food from cloned animals and their offspring.

FDA’s determination that meat and milk from animal clones is safe to eat concludes the most extensive food safety review in FDA’s history, and complements two earlier reports from the National Academy of Sciences that reached the same conclusion.

“Cloning companies will continue to work out an orderly marketing transition with the food industry and relevant government agencies – including FDA and USDA – as we move toward commercialization.

“The number of cloned animals in the barnyard today is miniscule compared to the size of the total livestock population. In addition, clones are to be used as breeding animals, not for consumption. Because of a supply chain management system that allows tracking of cloned livestock, consumers are unlikely to ever eat these animals.”

# # #

A long-awaited final report from the Food and Drug Administration concludes that foods from healthy cloned animals and their offspring are as safe as those from ordinary animals, effectively removing the last U.S. regulatory barrier to the marketing of meat and milk from cloned cattle, pigs and goats.

The 968-page “final risk assessment,” not yet released but obtained by The Washington Post, finds no evidence to support opponents’ concerns that food from clones may harbor hidden risks.

But, recognizing that a majority of consumers are wary of food from clones — and that cloning could undermine the wholesome image of American milk and meat — the agency report includes hundreds of pages of raw data so that others can see how it came to its conclusions.

Release of the analysis was slowed for years by several forces, including the dairy industry, concerned about the potential impact on exports of U.S. whey solids, foreign sales of which are growing for use as a protein supplement.

In the past month, as an announcement neared, members of Congress, led by Sen. Barbara A. Mikulski (D-Md.), sought to delay approval through legislation.

Trade-related agencies including the Foreign Agricultural Service and the Office of the U.S. Trade Representative, which for years have struggled to get countries to accept U.S. gene-altered crops, also raised red flags.

A final blitz of meetings with FDA officials last week brought grudging acquiescence, insiders said. And it is possible, sources said, that even after the risk analysis is released, there will be calls for farmers to voluntarily refrain from selling products from clones until the trade issues can be resolved.

To create its final risk assessment, the FDA gathered data on nearly all of the more than 600 U.S. farm-animal clones produced and hundreds of their offspring, as well as many from overseas. But it faced challenges in the process.

Those animals were made by scientists scattered among various universities and companies using different methods that in many cases were difficult to compare.

Moreover, many of those animals were not just clones but also had genes added to them for projects unrelated to food production.

In those cases, it was difficult for FDA reviewers to decide whether any problems were caused by those animals being clones or by their particular genetic alterations. (The FDA has said it will not approve gene-altered animals as food without additional tests for safety.)

Finally, there was the overarching problem of deciding which measures would best predict whether the food was safe. Most puzzling was whether to take into account the subtle alterations in gene activity, called epigenetic changes, that are common in clones as a result of having just one parent.

In the end, facing the reality that epigenetics have never been a factor in assessing the wholesomeness of food, agency scientists decided to use the same simple but effective standard used by farmers since the dawn of agriculture: If a farm animal appears in all respects to be healthy, then presume that food from that animal is safe to eat.

Scientists inside and outside the agency studied thousands of pages of veterinary reports describing weight, size, organ function, blood characteristics and other measures of clones and offspring. For cattle — the animals for which the most data exist — full health assessments were conducted for each of five different stages of the animals’ life: fetal, newborn, juvenile, sexually mature, and old.

They concluded that newborn cattle are often unhealthy, probably because of epigenetic changes. They are usually extremely overweight and have respiratory, gastrointestinal and immune system problems. (Cloned pigs and goats are mostly healthy from the start.)

The report also acknowledges that human health concerns are not the only issues raised by the emergence of cloned farm animals.

“Moral, religious and ethical concerns . . . have been raised,” the agency notes in a document accompanying the report. But the risk assessment is “strictly a science-based evaluation,” it reports, because the agency is not authorized by law to consider those issues.

In practice, it will be years before foods from clones make their way to store shelves in appreciable quantities, in part because the clones themselves are too valuable to slaughter or milk. Instead, the pricey animals — replicas of some of the finest farm animals ever born — will be used primarily as breeding stock to create what proponents say will be a new generation of superior farm animals.

When food from those animals hits the market, the public may yet have its say. FDA officials have said they do not expect to require food from clones to be labeled as such, but they may allow foods from ordinary animals to be labeled as not from clones.

Opponents of the approval, including some concerned about the welfare of the clones themselves, expressed dismay upon learning about the FDA’s intentions.

Joseph Mendelson, legal director of the Center for Food Safety, a Washington advocacy group that petitioned FDA to restrict the sale of food from clones, said his group is considering legal action.

“One of the amazing things about this,” Mendelson said, “is that at a time when we have a readily acknowledged crisis in our food safety system, the FDA is spending its resources and energy and political capital on releasing a safety assessment for something that no one but a handful of companies wants.”

Others countered that public opinion and politics should play no bigger role in the decision on clones than it should in the approval of a drug or a contraceptive.

“In fact, cloned animals have been studied much more than naturally produced animals,” said Cindy Tian, who has analyzed milk and meat from clones at the University of Connecticut. “We have more data on them than for any other animal that we eat.”

But those problems typically disappear within the first weeks or months of life as the animals somehow compensate. And since sick clones would not pass muster with food inspectors any more than sick conventional animals would, they pose no concern, the report says.

Studies of cloned farm animal behavior, including mating behavior, also showed them to be the same as ordinary animals. (One exception: On one farm, clones showed a peculiar preference not for the surrogate mother that gave birth to them but to the animal from which they were cloned.)

Scientists also looked at nutrient levels in meat and milk from a few dozen cattle and pig clones and hundreds of their progeny, and compared them with values from conventional animals. They measured vitamins A, C, B1, B2, B6 and B12 as well as niacin, pantothenic acid, calcium, iron, phosphorous, zinc, 12 kinds of fatty acids, cholesterol, fat, protein, amino acids and carbohydrates including lactose.

For almost every measure, the values were virtually the same. The few that differed were still within the range considered normal.

Separately, the agency looked at studies in which milk and meat from clones were fed to animals for up to 3 1/2 months. There was no evidence of health effects, allergic reactions or behavioral changes.

In the end, the agency concluded that it did not have enough information to rule on the safety of food from cloned sheep. It also decided that edible products from newborn cattle clones, which often are metabolically unstable, “may pose some very limited human food consumption risk.”

But it found no safety hazards for meat from healthy cattle clones more than a few weeks old, milk from cloned cows, or meat from cloned pigs or goats of any age.

“Food from cattle, swine, and goat clones is as safe to eat as that from their more conventionally-bred counterparts,” the FDA risk assessment concludes.

Looking ahead, the report says FDA is collaborating with veterinary and scientific organizations, notably the International Embryo Transfer Society, to create a database on the health of new clones, which will help the agency track the field as the industry grows.

Working with the FDA, the International Embryo Transfer Society is also creating the first manual of animal care standards for clones, to be made available to farmers and the public later this year.

Center for Veterinary Medicine

U.S. Food and Drug Administration

Monday, January 14, 2008; 9:46 PM

Conclusions Regarding Food Consumption Risks from Bovine Clones and their Progeny

As the first prong of our strategy to address the food consumption risks associated with clones, we have used the Critical Biological Systems Approach (CBSA) as a framework to search for subtle differences between clones and comparators that may pose food consumption risks. In general, these differences cannot be detected macroscopically but may be evident as differences in physiological parameters during the five developmental nodes. For bovine clones, our health-based assessment of food consumption risks is facilitated by a significant body of evidence from the peer-reviewed literature together with a large data set from Cyagra. Many bovine clones do not survive the neonatal period, and several abnormalities (e.g., those related to LOS [large offspring syndrome], prolonged recumbency, umbilical malformations) have been described during this developmental node. None of these abnormalities is unique to clones, and all have been observed in calves produced by other ARTS [assisted reproductive technologies] such as in vitro fertilization or following natural mating.

In clones that survive the neonatal period, some studies have identified differences in physiological measures between clones and comparators during the first few weeks of life. These findings support the notion that bovine clones are more physiologically unstable during the early juvenile period. There is evidence that the physiological transition from neonatal period to the juvenile period may take longer in calf clones (e.g., elevated body temperature during the first two months of life). Once their physiological status is stabilized, however, there is ample evidence to indicate that growth and development proceed normally in bovine clones. Similarly, several studies indicate that fertility in clones is normal, and there are no indications that the physiology or health of clones is compromised during the post-pubertal period.

In summary, we have searched for subtle differences between clones and their comparators to identify differences that may pose food consumption hazards. We have not found any such subtle differences, and based on this review of the health and physiology of bovine clones using the CBSA approach, we conclude that there is no reason to expect that food from bovine clones would pose additional food safety risks compared with the same products derived from conventionally-bred cattle.

Clone progeny are not expected to pose any increased food consumption risks compared with other sexually reproduced animals (NAS 2002b). Although the amount of data describing the health of progeny of clones is more limited than the amount describing the health of clones themselves, the results are consistent with the biological assumption. In the two studies that characterized the physiology of heifers produced by clones, growth, reproductive function, and telomere length were normal in clone progeny, and the incidence of general health problems was not increased in clone progeny compared with progeny of other sexually reproduced animals. Based on the CBSA approach, we therefore conclude that sexually reproduced progeny of clones are indistinguishable from other sexually reproduced animals, and pose no additional food consumption risks.

Conclusions Regarding Food Consumption Risks from Swine Clones and their Progeny

These studies and data evaluated indicate that there are no apparent anomalies present that would have a direct impact on the safety of food products derived from swine clones or their progeny. The measurements taken at 27 weeks of age are appropriate for the evaluation of food consumption risks because this is the approximate age at which pigs are sent to slaughter in the US. The identified abnormalities in the Archer et al. (2003a) (parakeratosis) and the ViaGen dataset (lung adhesion) are not unique to swine clones and do not pose a food consumption risk, as the affected tissues from the carcass would be condemned at the slaughterhouse and would not enter the food supply. The apparently normal status of the clinical measurements indicates that the clones in this study possess the same physiological functions and behaviors as their conventional counterparts, and thus do not contain subtle hazards that would pose food consumption risks compared with food from conventionally-bred swine.

Health information on the progeny of swine indicates that although occasional phenotypic abnormalities were observed in these progeny during the neonatal and perinatal periods (contracture of the flexor tendon, anal atresia, spraddle legs), none of these anomalies are unique to cloning and all occurred at frequencies similar to those observed in conventionally produced swine. Progeny of swine clones are healthy, grow at the normal rate, and do not appear any more susceptible to infection or disease that conventional pigs. Importantly, the studies reviewed indicate that physiological and phenotypic differences that might be observed in swine clones are not passed down to their progeny. These results provide further support for the hypothesis that epigenetic errors in clones are reset during gametogenesis, resulting in progeny that are healthy and physiologically normal. Therefore, based on the CBSA portion of this assessment, we conclude that progeny of swine clones, produced by normal sexual reproduction, do not contain any subtle hazards that would pose any increased food consumption risk compared with the offspring of any other sexually reproduced swine.

Conclusions Regarding Food Consumption Risks from Sheep Clones

Very few conclusions can be drawn about the health of sheep clones, due to the small database available for evaluation. Only one study provided detailed physiological data from sheep clones, and these data were limited to only a few metabolic and endocrine endpoints. Despite Dolly’s high public visibility, there are very few other reports of non-transgenic sheep clones. Until additional specific information regarding the health of sheep clones becomes available, the only inferences that can be made would be drawn from interspecies extrapolation from other ruminant clones, i.e., cattle and goats.

Conclusions Regarding Food Consumption Risks from Goat Clones

Based on the data reviewed, there do not appear to be any anomalies present in the goat clones that would have an effect on the safety of food products derived these animals, and no subtle hazards were identified in these clones that could pose food consumption risks. Goats appear to be relatively “cloning friendly” with a high degree of successful live births following confirmation of pregnancy. All reports of health of the goat clones seem to indicate that they are normal and healthy. The available data on the physiological parameters of goat clones indicate that these animals respond as their conventional counterparts to internal signals for growth. The apparently normal status of the clinical measurements indicates that the clones in this study possess the same physiological functions and behaviors as their conventional counterparts. Further, unlike the other livestock clones, data on the reproductive behavior of male goat clones indicate that reproductive function is normal. Finally, although cursory in mention, it appears that male progeny of clone bucks also reach puberty at the appropriate time. Thus, although the number of animals that has been evaluated is not as large as in the case of bovine clones, goat clones appear to be healthy, and do not appear to be materially different from conventional goats.

Summary Statement on Composition of Milk from Clones

Several peer-reviewed studies describe the composition of milk from bovine clones. In addition to gross composition (percent solids, fat, protein, and lactose), some reports include a detailed analysis of fatty acids, vitamins, minerals, and amino acids, and in some cases, comparisons are made with previously published reference values for milk composition. These studies indicate that milk from cow clones is not significantly different in composition from milk from non-clones. Some minor differences have been identified in the composition of milk from clones compared to non-clones or reference values, but in each of these reports, the authors attribute the minor differences to diet, environmental conditions, small numbers of animals, and limited numbers of genotypes, rather than to cloning per se. None of these differences, however, indicate the presence of hazards that could pose food consumption risks, as they all fall within published historical values for milk. We therefore that milk derived from bovine clones does is not materially different from milk from milk from conventionally bred cattle.

Conclusions from Studies Evaluating the Composition of Meat and Milk from Clones and Their Progeny

The second prong of our Risk Assessment is based on the hypothesis that food products from healthy animal clones and their progeny that are not materially different from corresponding products from conventional animals are as safe to eat as their conventional counterparts. CVM has reviewed several peer-reviewed publications that have evaluated gross (e.g., milk yield, carcass characteristics) and fine (e.g., individual amino acid and fatty acid components) characteristics of meat and/milk from clones, and in two studies, their sexually-reproduced progeny. All but one of these studies indicate that none of the characteristics that we examined differed in any biologically significant way between the clone and comparator. The only exception is a preliminary study in bovine clones which provides evidence that lipid metabolism may be altered in clones, resulting in slight alterations in the fatty acid composition of milk and meat. However, without a comparison of these data to historical reference values, it is unclear whether these differences are representative of all bovine clones or are specific to the limited number of genotypes used in the study.

For swine clone progeny, a comprehensive, peer-reviewed analysis of meat from a large number of animals provides strong evidence that there are no compositional differences between meat from swine clones and meat from conventional swine, and that meat from clone progeny and their comparators is not materially different.

Therefore, in this prong of the Risk Assessment, CVM concludes that the weight of evidence indicates that meat and milk from clones and their progeny do not differ materially from meat and milk derived from their conventional counterparts, and therefore, based on compositional analysis, do not pose any additional food consumption risks compared with meat and milk from conventionally bred animals.

Conclusions from Allergenicity and Feeding Studies in Rodents

The second prong of this risk assessment is based on the hypothesis that edible products from healthy cloned animals and their progeny are as safe to eat as edible products from conventionally produced livestock. CVM reviewed three studies in which the rat was used as a surrogate animal model to investigate possible biological effects of eating meat or milk from cattle clones. One of these feeding studies was conducted over an extended period (14 weeks) and included standard toxicological endpoints as well as a functional observational (behavior) battery. None of these studies demonstrated any change in the physiology or pathology of the rat following consumption of meat or milk from clones. Moreover, no evidence has been found to indicate that the allergenic potential of meat or milk from cloned cattle is greater than that of meat or milk from non-cloned cattle. No behavioral changes were observed. These findings are consistent with our conclusions using the Compositional Analysis approach, i.e., that meat and milk from clones and their progeny are not materially different from meat and milk derived from conventional counterparts and thus do not pose any additional food consumption risks relative to food from conventional animals.

The risk of allergenicity is one that is often cited for foods that do not have a long history of consumption. Although there is no reason to suspect that cloning will cause the synthesis of new proteins in animals that appear healthy and normal, there are two possible pathways that might pose an increased allergenic risk from the edible products of animal clones. One is an increase in the relative amount of an individual protein component of milk or meat that may only be present in very low or trace amounts. Cows’ milk has been associated with true allergies (Cows Milk Allergy or CMA) in approximately six percent of the US population (Bernstein 2003). Caseins, although the predominant proteins in milk, do not appear to be the key allergens associated with CMA. The other possible pathway is that processing of the proteins during their generation in the mammary gland or muscle cells somehow alters their antigenic presentation. The Center cautions that these are purely hypothetical pathways, and that there has been no demonstration that either of these actually occurs.

In theory, evaluating the relative concentrations of milk proteins in clone and comparator milk could provide information to determine if the first risk exists. The study by Tian et al. (2005) provides just such a comparison using SDS/page technology. In practice, however, even this study highlights the difficulty in establishing the appropriate comparator and minimizing variability. Milk from non-clone dairy animals may vary in relative composition due to the influences of breed, diet, number of lactations, where in the lactation cycle the milk is collected, etc. Further, the level of exposure (dose) required to elicit an allergenic response is not well understood, and has been the subject of much discussion in the scientific literature (Taylor 2002) and among international regulatory bodies (Codex Alimentarius 2003112). Nonetheless, the limited studies provided (Japan 2002) show that milk from both SCNT and BNT clone cattle showed similar digestibility characteristics both in vitro and in a rodent in vivo assay. In addition, a rodent bioassay for allergic response did not show any significant differences in response between clone and non-clone derived milk. Combined with the underlying biological assumptions, these data support the lack of a unique allergic response to milk derived from clone cattle.

Microbiological Effects

It has been suggested that epigenetic changes in animal clones could somehow alter the rumen and intestinal microflora of the ruminants (cattle, sheep, and goats), or the intestinal microflora of monogastric species (swine) (NAS 2002b). Such alterations in intestinal flora might be considered hazards because they could, in theory, result in increased levels of an existing zo?notic pathogen or the growth of a novel zo?notic pathogen. Shedding of these pathogens in fecal material could possibly result in a higher load of undesirable microbes on the carcass at slaughter, increasing the likelihood of contamination of the edible tissues.

The use of animal drugs has been postulated to alter the intestinal flora of treated food animals, resulting in an increased load of zo?notic pathogens in the food supply. The potential for animal drugs to induce this change was considered at length by the January 2002 CVM Veterinary Medical Advisory Committee on that topic113. Most of this independent scientific advisory committee found that animal drug use was unlikely to significantly impact pathogen load (or the prevalence of zo?notic pathogens), and that pathogen load has little or no impact on public health.

The Center is not aware of any studies that have characterized the intestinal flora of livestock clones, and the complexity of the intestinal microflora makes this an extremely difficult question to address directly. Although it is possible that epigenetic reprogramming in clones may have effects on the intestinal flora, this postulate can be challenged on the basis of animal health. The data reviewed in this risk assessment indicate that the vast majority of clones studied during the juvenile, reproductive and post-pubertal phases of life are as healthy as their sexually-produced counterparts. It therefore seems very unlikely that the milieu of intestinal microflora is abnormal in these animals, and that contamination of carcasses of clones due to bacterial shedding would pose a greater food consumption risk than that posed by conventional food animals.114 We further note that such alterations would not be unique to clones as all animals, regardless of their method of production, are subject to alterations in epigenetic programming.

Technology Changes

Significant changes in cloning technology, especially those accompanied by donor nucleus or o?cyte treatment regimens introducing new hazards into the overall process, would significantly increase the uncertainty associated with our judgments regarding the degree of risk that could accompany the resulting clones and clone food products. Without a careful evaluation of the animals arising from such methods, it would not be appropriate to speculate on the relative safety of the process from either an animal health or food safety perspective.

How Much (Information) Is Enough?

The question of determining when sufficient data have been collected in order to allow high confidence in risk-based decisions regarding edible products from animal clones is difficult to determine in the abstract. In practice, the answer is “it depends on what questions you ask, and how the data answer those questions.”

Because the nature of the technology has generally precluded generating large datasets on clones with good statistical power, CVM constructed a systematic approach to frame the appropriate questions (hazard identification), evaluated the available data (hazard characterization), and attempted to characterize resulting risk (probability of harm given that exposure occurs). This weight of evidence approach allows for the evaluation of the data from the CBSA and Compositional Analysis prongs of the Risk Assessment as part of an overarching whole. The conclusions from this risk assessment represent the judgment of CVM veterinarians, animal scientists, toxicologists, and risk assessors. The underlying assumptions for clones and their progeny were that the animals needed to meet all relevant federal, state, and local laws and regulations for conventional animals, and the food products derived from clones or their progeny also had to meet relevant federal, state, and local laws and regulations.

When considered across the Developmental Node spectrum, the data on the health of livestock clones were remarkably consistent across species, despite initial anomalies that appear to be species-specific. For example, although LOS may be more prevalent in cattle and sheep, most surviving animals normalize initial anomalies and become “healthy and normal.” This consistency has increased the value of even small datasets (e.g., goats), and has contributed significantly to the judgments regarding the health of these clones and their suitability as food sources. In addition, CVM evaluated a number of reports on the composition of meat and milk from clones and their progeny. No biologically important or safety-relevant differences were noted when compositions were compared to standard databases or contemporary comparator controls. If anything, these data confirm the rather wide variability in the composition of meat and milk eaten on a daily basis. In summary, no toxicological hazard of concern for the human consumer has been identified in any of the reported studies. Although additional data from other sets of animals, particularly in other species routinely used for food, could be useful in increasing the confidence that may be placed in overall judgments regarding food safety, the weight of the evidence at this time is sufficient for the agency to draw the conclusions it has made in this Risk Assessment with reasonable certainty.

Risk Management Plan for Clones and their Progeny

Surveillance for Changes in Cloning Technology and State of Knowledge that Could Affect Food Safety

1. Monitor and review additional animal health and food composition data on animal clones or their progeny as they become available.

- FDA will establish a close liaison with professional and scientific organizations such as the International Embryo Transfer Society (IETS), the Federation of Animal Science Societies, and the American Veterinary Medical Association to collect and access new animal health and production data as they become available, and will work with these organizations to collect and maintain an international, centrally-located database of animal clone and progeny health and production data, which would be made publicly available. In particular, the FDA is currently engaged in an ongoing project with the IETS to produce a publicly available international data base on the health of clones and the composition of food from them. This data base should become available in 2008.

2. Monitor and review changes in animal cloning techniques and technologies.

- FDA will routinely monitor the scientific literature and attend pertinent scientific conferences to stay abreast of animal cloning technologies. FDA will continue to maintain open and informal channels of communication with animal clone producers and researchers to remain up-to-date with these technologies.

3. Continue to consult with clone producers to review changes in the technology.

- FDA will continue to consult with clone producers to review changes in the technology. Clone producers with questions regarding whether their technology is different from that evaluated in the Risk Assessment are strongly encouraged to discuss their technology with FDA.

4. Monitor and maintain knowledge base on the biology of epigenetic mechanisms governing gene expression and their role in nuclear transfer.

- FDA will maintain an ongoing awareness of the scientific literature regarding the biology of animal clones and epigenetics, maintaining our scientific currency in accordance with our regulatory mission.

Risk to the health of animals involved in cloning

Increased risks of adverse health outcomes of the types previously observed in animals produced via other ARTs have been observed in surrogate dams and very young clones. Animal cloning, particularly in cattle and sheep, is associated with an increased risk of adverse health outcomes in the surrogate dams carrying late-term clone fetuses, as well as very young clones. Specific health issues of concern for the surrogate dams include the increased incidence of prenatal hydroallantois and/or hydrops in the surrogate dams carrying clone pregnancies to term. Health issues of concern for the clones themselves include perinatal symptoms related to LOS including, but not limited to, pulmonary and/or renal insufficiency, difficulty maintaining body temperature, and umbilical hernias.

In order to minimize the impact(s) of these animal health risks, we have been working with the International Embryo Transfer Society to prepare a publicly available manual on animal care standards for animals involved in the cloning process. This document is due to be released to the public on IETS’ website in early 2008.

FOR IMMEDIATE RELEASE

January 15, 2008

BIO Supports FDA’s Safety Conclusions on Animal Cloning

Washington, D.C-Biotechnology Industry Organization (BIO) President and Chief Executive Officer Jim Greenwood today issued the following statement in response to a risk assessment published today by the U.S. Food and Drug Administration (FDA) regarding the safety of milk and meat products from cloned animals and their offspring:

“BIO strongly supports the FDA’s risk assessment which concludes that meat and milk products from animal clones and their offspring are safe for human consumption, and are no different from foods from livestock produced through other breeding methods. The biotechnology industry applauds FDA for its comprehensive scientific review of this new assisted reproductive technology. FDA’s risk assessment is consistent with numerous studies world wide that have found the food from animal clones and their offspring to be safe. With this safety conclusion, ranchers and livestock producers may begin to choose cloning as a technology that will allow the rapid use of the best genetics to produce healthy animals.

“Livestock cloning is the latest step in a long history of reproductive tools for farmers and ranchers, and can effectively help livestock producers deliver what consumers want: high-quality, safe, abundant and nutritious foods in a consistent manner.

“FDA’s extensive review of over 700 scientific research studies, conducted over the past 30 years, has determined that foods from animal clones and their offspring are equivalent to foods from other livestock. These findings are consistent with two reports by the National Academy of Sciences.

“The biotechnology industry looks forward to working with the U.S. Department of Agriculture (USDA) and members of the food value chain to support an orderly transition and introduction of products from cloning technology into the marketplace. In December 2007, the major animal cloning companies introduced a Supply Chain Management Program, an animal clone registry database that allows food companies to identify animal clones. BIO believes that this tracking system will support a gradual transition of products derived from cloning into the marketplace by helping to promote a wider variety of choices in the world’s food supply and support smooth trade transactions.

BIO represents more than 1,150 biotechnology companies, academic institutions, state biotechnology centers and related organizations across the United States and in more than 30 other nations. BIO members are involved in the research and development of innovative healthcare, agricultural, industrial and environmental biotechnology technologies. BIO also produces the annual BIO International Convention, the world’s largest gathering of the biotechnology industry, along with industry-leading investor and partnering meetings held around the world.

Note to Editors: BIO will host a media teleconference on Tuesday, Jan. 15, 2008 at 2:30 p.m. EST that will feature a panel of experts on animal cloning. To access the teleconference, dial 800.895.1241, and provide the operator with the conference identification code “BIO.”

Note to Broadcast Editors: Video clips of BIO’s Managing Director of Animal Biotechnology, Dr. Barbara Glenn, as well as 4-H youth commenting on what cloning means to the next generation of livestock producers, can be accessed at http://www.clonesafety.org/imagelibrary/videos/.

Additional scientific resources on animal cloning and downloadable photos and video can be found at www.CloneSafety.org.

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