VETERINARY MEDICINE ADVISORY COMMITTEE on FDA’s Medicare Modernization Act Executive Summary of Animal Cloning: A Risk Assessment
MICHAEL K. HANSEN, PH.D.
Senior Research Associate, Consumer Policy Institute, Consumers Union*
November 4, 2003
Consumers Union, publisher of Consumer Reports, welcomes the opportunity to comment on the Food and Drug Administration’s (FDA’s) Medicare Modernization Act Executive Summary of its Assessment of Safety of Animal Cloning. We question the scientific validity of the FDA’s conclusion about the safety of consumption of milk and meat from cloned animals and also the framework and assumptions used to reach those conclusions. We believe that while milk and meat from cloned animals may be safe, there presently are not enough data to reach this conclusion. We strongly disagree with the notion that an animal that appears healthy must be safe to eat. We believe that FDA should require safety testing of the products of cloned animals before they are placed on the market. In addition, we believe that FDA should require labeling of the meat and milk from cloned animals.
Overview of Issues
We question the scientific validity of the FDA’s conclusions about the safety of milk and meat from cloned animals, and also the framework used to reach those conclusions. We must question FDA’s continued emphasis on qualitative similarities between cloned and conventional animals. To say that problems arise, but they are not qualitatively different from problems in conventional animals, is almost a meaningless statement in the context of food safety. The problems we are concerned about most in the food safety are problems of quantity, frequency and incidence—frequency and incidence of disease, of bacterial infection, of contamination with mercury, of presence of allergy-causing substances, of pesticide residues. To say that safety problems of clones are qualitatively no different from conventional animals is therefore not meaningful. It would be like saying a facility where 95% of the chicken is contaminated with salmonella is no different from one where 2% of the chicken is contaminated. The problems are qualitatively the same—but the quantity is of intense concern in terms of food safety. It is essentially to know the quantity, frequency and incidence of any problems.
As we will discuss further, FDA has almost no data on which to base a claim that meat and milk from cloned animals is safe. This is a risk assessment that appears to be based largely on speculation and assumptions and scientific theory, not on data. Unfortunately since the FDA has seen fit to share only a summary of its risk assessment, and not the full assessment itself, we cannot even thoroughly examine the theories it has used to come to conclusions. However we will attempt to discuss them as presented in this summary.
There are several questions that arise from existing studies of cloned animals where data are sorely needed. As we will discuss below, cloned animals may have weaker immune systems. If true, this could lead to higher incidence of disease and bacterial infection, which could affect human health directly (by ingestion of a pathogenic bacteria like salmonella) or indirectly (by requiring farmers to make greater use of antibiotics, and thus worsening the problem of antibiotic resistance).
FDA has also thus far completely ignored the issue of consumer choice, and whether consumers will be able to exercise it in relation to meat and milk from cloned animals. Ms. Carol Tucker-Foreman of Consumer Federation of America, here and elsewhere, has presented extensive data about consumer opinion, which is very negative about cloning and about eating products of cloning. We believe that a Presidential Commission must address the issue of whether animals should be cloned for food. At the least, FDA should require any products of cloning that go into the food supply to be labeled.
Scientific Issues Not Adequately Considered
We are seriously concerned by the lack of scientific rigor in the FDA’s Risk Assessment. The FDA Risk Assessment restricts itself to a particular type of cloning technology, somatic cell nuclear transfer (SCNT) and we will also restrict our comments to SCNT clones; we feel that this technology raises increased concerns about potential unexpected adverse effects that could negatively affect food safety or quality.
The National Academy of Sciences/National Research Council (NAS/NRC) noted that cloning frequently causes a range of negative effects on the health and wellbeing of young clones that could have direct and indirect effects on food safety: “The key scientific issue is whether and to what degree the genomic reprogramming that occurs when a differentiated nucleus is placed into an enucleated egg and forced to drive development of a clone might result in gene expression that raises food safety concerns. . . . A number of datasets suggest that the health and wellbeing of neonatal and young somatic cell clones often are impaired relative to those of normal individuals. Direct effects of any abnormality in patterns of gene expression on food safety are unknown. However, because stress from these developmental problems might result in shedding of pathogens in fecal material, resulting in a higher load of undesirable microbes on the carcass, the food safety of products, such as veal, from young somatic cell cloned animals, might indirectly present a food safety concern” italics added (NRC 2002: pp. 64-65). The NAS study then pointed out that no data were available comparing the composition milk and meat from clones and that such data are needed before the risks can be adequately characterized and assessed: “There are to date (August 21, 2002) no published comparative analytical data assessing the composition of meat and milk products of somatic cell clones, their offspring, and conventionally bred animals (although several studies are in progress; Bishop, personal communication, 2002). However, the committee found it difficult to characterize the level of concern without further supporting evidence regarding food product composition” italics added (NRC, 2002: pg. 65). Even with the case of meat and milk from an earlier cloning technology introduced in the 1980s—BNT (blastomere nuclear transfers—that the NRC thought posed “a low level of food safety concern,” the NRC still requested that FDA require data to back up this assumption: “it would seem appropriate that the FDA use available analytical tests to evaluate the compostion of food products from animals that themselves result directly from BNT cloning procedures to verify that they fulfill existing standards for animal-derived food products” (NRC, 2002: 64).
Although the NRC called for comparative analytical data assessing the composition of milk and meat products of clones and their offspring compared to conventionally bred animals, these data are still not forthcoming. There is a single study on milk from clones and non-clones and no studies comparing the composition of meat from clones and non-clones. The single study on milk from bovine clones, carried out by Infigen, involved only 16 cloned cows and 6 no-clones but found statistically significant differences in some of the fatty acids and in zinc and phosphate levels (Forsberg, 2002, available at http://pewagbiotech.org/events/0924/proceedings2.pdf). The authors try to dismiss these results by saying that these differences are due to differences in feed and housing conditions, but we have no further studies that would confirm or deny this view. There are no data on milk and dairy products from other species such as sheep or goats.
As for compositional studies comparing meat from clones and non-clones, none exist at this point. Although the NRC clearly called for more data comparing meat and milk from clones, their offspring and their uncloned siblings, FDA seems to have ignored this request for more data. Instead of data, the FDA comes up with a highly questionable and un-scientific framework/assumption—the Critical Biological Systems Approach—which assumes healthy animals must be safe to eat. As FDA states, “the Critical Biological Systems Approach, is based on the hypothesis that a healthy animal is likely to produce safe food products” (FDA, 2003: 6). The FDA goes on to assume that the deformed animals that result from cloning or that die relatively soon birth will not enter the food supply, so that the Risk Assessment only considers clones that “appear to be healthy” or that are exhibiting subtle health effects. Since the majority of health problems and/or birth defects have been seen in younger animals, the FDA just assumes these animals won’t make it into the human food supply because “local, state, and federal regulations . . . exclude frankly malformed, diseased, and otherwise unhealthy animals from the human food supply” (FDA, 2003: 5).
We find these statements to be amazing leaps of logic. If one agrees that an animal that looks healthy must be safe to eat, then we have no need of an entire HACCP system, because all health hazards would be visible and obvious. Healthy appearing animals can shed a number of pathogens—such as E. coli 0157:H7, Samonella enteridis, Campylobacter jejeuni, etc.—that could make their meat and milk less safe to consume. In addition, healthy-appearing animals can be contaminated with toxins from biological (e.g. mycotoxins such as aflatoxin and fumonisins) or chemical (e.g. PBB-contaminated feed scandal in Michigan during the 1970s) sources
As for adult bovine clones, the FDA states that the “underlying biological assumption for this developmental cohort is that there is no fundamental reason to suspect that animals derived via SCNT would produce toxins, there are no introduced genes from other sources, and any biological changes that are not immediately apparent (e.g. gross malformations) would, at most, tend to present subtle changes that do not pose food consumption concerns” (FDA, 2003: 8). The FDA goes on to argue that bovine clones that reach adulthood are healthy and reproduce normally: “The available information on reproductive function in cows or bulls of this age cohort [6 – 18 months] is quite limited, but appears to indicate that clones have normal reproductive function and give birth to healthy offspring. These observations provide a high degree of confidence to the Center’s judgement regarding the health of bovine clones” (FDA, 2003: 8).
We disagree both with the “underlying biological assumption” and with the notion that “clones have normal reproductive function and give birth to healthy offspring.” The problem with the underlying biological assumption is that changes associated with SCNT process itself could lead to food safety concerns. Even though the adults “appear healthy,” there could be effects that have an impact on food safety. As the NRC stated, the key issue is the degree of genetic reprogramming required when a differentiated nucleus is put into an enucleated egg and forced to drive development and the effect of that genetic reprogramming.
Since the NRC study was published, two new research has appeared which suggests that the degree of reprogramming is great and that, in the process, the regulation of many, many genes is seriously disrupted. A ground-breaking study by the top researchers in the field—including Dr. Rudolf Jaenisch’s team at M.I.T. and Dr. Yanagimachi team at the University of Hawai’i (Dr. Yanagimachi was the first to successfully clone mice)—published September, 2002 in the Proceedings of the National Academy of Sciences found that the process of cloning (e.g. SCNT) lead to abnormal gene expression in hundreds of genes (Humpherys et al., 2002). Using gene chips, the researchers looked at the expression profiles from more than 10,000 genes; they found that about “4% of the expressed genes in the NT placentas differed dramatically in expression levels from those in controls” (Humphreys et al., 2002: 12889). This study also suggested that a large percentage of the disrupted genes were imprinted genes (e.g. genes that are expressed differently when inherited from the mother than when inherited from the father). In press stories about the paper, Dr. Jaenisch thought these results would also happen in other animals and further suggested that seemingly normal animals may be affected as well: “ ‘There is no reason in the world to assume that any other mammal, including humans, would be different from mice,’ Jaenisch said. . . . Jaenisch believes genetic abnormalities will be found even in these seemingly normal animals. Some of the abnormalities are simply not fatal, he said” (Fox, 2002). The study even concluded that detailed molecular characterization of adult clones should be done before saying that they are “healthy” or “normal” with an explicit criticism of the paper “Cloned cattle can be healthy and normal,” published by industry-affiliated scientists in Science in 2001: “Our results are consistent with the hypothesis that most clones, independent of their cellular origin, may have gene expression abnormalities causing subtle phenotypes. . . Conclusions about the normalcy of surviving cloned animals therefore should not be based on superficial clinical examinations (Lanza et al., 2001) but rather on detailed molecular analyses of tissue from adult cloned animals” italics added (Humpherys et al., 2002: 12894). To date, such “detailed molecular analyses of tissue from adult cloned animals” have yet to be published.
A second study of gene expression profiling involving mice published earlier this year, involving even more genes—15,000 genes—found even more widespread disruption in gene regulation than Dr. Jaenisch’s team. Researchers from the U.S. National Institutes of Health and Japan found some 2,000 of the 15,000 genes investigated, or 13%, to have abnormal expression profiles (Suemizu et al., 2003). Among their major abnormalities found in the clones compared to the non-clones: 1) abnormal expression of imprinted genes, 2) altered expression of regulatory genes involved in global gene expression, 3) increased expression of oncogenes and growth promoting genes, and 4) discovery of many novel genes overexpressed in the clones. Particularly worrisome from a food safety/nutritional assessment perspective is the increased expression of oncogenes and growth promoting genes as well as the discovery of novel proteins appearing in the clones.
A study by Dr. Atsuo Ogura and colleagues from Tokyo’s National Institute of Infectious Diseases found that although they may appear normal, mouse clones die at a younger age than non-clones and had higher disease and cancer rates and appear to have an immune system defect (Ogonuki et al., 2002). These Japanese researchers compared 12 cloned mice with 7 mice from natural matings and six produced using in-vitro fertilization. The clones appeared active and healthy, gained weight normally and, in 14 of 16 physiological measurements, showed no differences with control animals. However, by day 800, 83% of the cloned animals (10 of 12) were dead compared to only 23% (3 of 13) for the controls (Ogonuki et al., 2002). The dead clones showed high rates of pneumonia, liver disease, cancer and lower levels of antibody production compared to the controls. Dr. Ogura told the press that “his team’s work suggests that some effects of cloning are not apparent in the days, weeks or even years after birth. ‘It is very probable that, at least for some populations of clones, some unpredictable effects will appear in the long run,’ he [Dr. Ogura] said” (Cohen, 2002, at http://www.newscientist.com/news/news.jsp?id=ns99991903).
Food Safety Implications
What are the food safety implications of all these adverse effects associated with cloning? At this point, there are too few critical studies to be able to answer this question. But there are some hypothetical food safety/nutritional problems that could arise. There definitely is the possibility of indirect safety effects that are the result of cloning. For example, if the immune system of the clone is impaired, as a number of studies suggest, then such animals may be more susceptible to disease and/or stress which could result in the need for more medications (such as antibiotics) to treat such diseases. In addition, as the NRC pointed out, the “stress from these developmental problems might result in shedding of pathogens in fecal material, resulting in a higher load of undesirable microbes on the carcass, [so that] the food safety of products, such as veal, from young somatic cell cloned animals, might indirectly present a food safety concern” (NRC, 2002: 65). What is most needed, though, are studies that directly look at this question.
In addition, if oncogenes and growth promoting genes are upregulated in clones, then more cancerous animals could be potentially entering the food system; such animals definately raise nutritional and food quality issues that clearly need to be assessed prior to permitting marketing.
As stated previously, the FDA bases the safety of meat and milk from clones on the notion that adult animals are probably healthy. Yet, the FDA says that they have virtually no data on health of adult animals: “No studies specifically addressing the health of post-pubertal clones were identified. Instead, cursory information from studies examining other portions of the clones’ life cycles was reviewed. No specific reports of risks to clone health were found.” (FDA, 2003: 4). However, the FDA appears to have ignored a study involving cloned pigs that was published over two months ago which found that all the adults died suddenly (Lee et al., 2003). In the study, 4 cloned piglets were born and one died within days. The other three pigs died unexpectedly of heart failure just before reaching 6 months of age. Dr. Jerry Yang, who led the research stated that “ ‘It was totally shocking,’ says Yang. He has dubbed the fatalities ‘adult clone sudden death syndrome’ “ (Pearson, 2003, available at http://www.nature.com/nsu/030825/030825-2.html). Since pigs are often sold to the markets at 5 months of age, this shows that adults can experience health problems.
The FDA also appears to place great faith in the study of Lanza et al. (“Cloned cattle can be healthy and normal): “Data from the [bovine] clone producer indicate that healthy clones of the oldest (6-18 months) cohort evaluated are virtually indistinguishable from their comparators . . . These observations provide a high degree of confidence to the Center’s judgement regarding the health of bovine clones” (FDA, 2003: 8). Since no references to the scientific literature are given in the FDA’s Risk Assessment Medicare Modernization Act executive summary, we can’t be sure that the FDA is referring to Lanza et al. (2001). However, if this is the study they are referring to, it is interesting to note that Dr. Jaenisch refers to the Lanza et al. study as merely “superficial clinical examinations” and calls for “detailed molecular analyses of tissue from adult cloned animals.” We agree with Dr. Jaenisch and feel that such studies should be required by the FDA before allowing milk and meat from cloned animals to enter the market.
Published research also disputes the notion that “clones have normal reproductive function and give birth to healthy offspring.” A study done by Infigen looked at cloning success rate and later reproductive success of cloned cows. Of 2,170 embryos transferred to cows, only 5.4% (117) were born and only 3.8% (82) survived past weaning age (Forsberg, 2002). Infigen then bred 35 cloned cows, 34 of which became pregnant and one of those aborted. Of the 33 births, almost one-quarter of them (8 of 33) resulted in stillborns. This is a very high rate of still births, suggesting that clone reproduction is not always normal.
In sum, we would answer the basic VMAC questions as follows:
a. Do the risks experienced by animals involved in the cloning process differ qualitatively from those experienced by animals undergoing other assisted reproductive technologies?
While there may be no qualitative differences in the risks experienced by animal clones compared to those produced using other assisted reproductive technologies, there are definitely quantitative differences that are important. The problem of hydroallantois rarely occurs in natural cattle pregnancies but occurs at a rate some twenty times higher for pregnancies established with cloned embryos compared to IVF embryos (40% and 2%, respectively) (Wilmut et al., 2002). The rate of stillbirths in a study of heifer cloned cattle by Infigen was 24%; this rate is 3.5 times the rate in Canadian Holstein heifers (2.9%) (Lohuis et al., 1993, available at http://cgil.uoguelph.ca/pub/articles/stillbirth.html). A study of the frequency and occurrence of late-gestation losses from cattle cloned embryos found that the overall rate of live births from IVF embryos was more than 7 times the rate for adult somatic clones (49% vs 6.8%, respectively) (see table 1 in Heyman et al., 2002). The incidence of loss for late-gestation losses (between Day 90 of gestation and calving) was 43.7% for adult somatic clones compared to 0% in the control IVF group. Also, a review article on SCNT, published last year, found that the number of clone embryos that developed to become live young was between 0 and 4%, a figure far lower than that for other assisted reproduction technologies (Wilmut et al., 2002). In sum, quantitative differences are important.
b. Are the edible products derived from animal clones and their progeny as safe to eat as the edible products derived from their conventional counterparts?
Based on our current knowledge, the answer is, we don’t know, as argued above. What are needed are studies assessing the composition of meat and milk products of somatic cell clones, their offspring, and conventionally bred animals. Since SCNT clones may have a weaker immune system than non-clones, data should be taken on the frequency of illnesses in clones vs. non-clones, the rate of medication for both groups and the incidence of various pathogens in the meat from such animals. Also, the recent gene expression profiling studies that found wide-scale dysregulation of normal gene expression patterns in mice clones should be repeated with bovine, ovine, caprine and swine clones to see if such affects are associated with SCNT process itself rather than being restricted to a given species.
1. Based on what we have presented, has the risk assessment adequately identified the hazards and characterized the risks relating to animal health?
2. Based on what we have presented, has the risk assessment adequately identified the hazards and characterized the risks relating to food consumption?
Absolutely not, as argued above.
Food and Drug Administration, Center for Veterinary Medicine. 2003.
Fox, M. 2002. Clones Flawed: Study determines all clones are genetically abnormal. Associate, Sept. 12. (available at: http://abcnews.go.com/sections/scitech/DailyNews/clones020911.html).
Heyman, Y., Chavatte-Palmer, P., LeBourhis, D., Camous, S., Vignon, X. and J.P. Renard. 2002. Frequency and occurrence of late-gestation losses from cattle cloned embryos. Biology of Reproduction, 66: 6-13.
Humpherys, D., Eggan, K., Akutsu, H., Friedman, A., Hochedlinger, K., Yanagimachi, R., Lander, E.S., Golub, T.R. and R. Jaenisch. 2002. Abnormal gene expression in cloned mice derived from embryonic stem cell and cumulus cell nuclei. PNAS, 99(20): 12889-12894.
Lee, J.-W., Wu, S.-C., Tian, X.C., Barber, M., Hoagland, T., Riesen, J., Lee, K.-H., Tu, C.-F., Cheng, W.T.K. and X. Yang. 2003. Production of Cloned Pigs by Whole-Cell Intracytoplasmic Microinjection. Biology of Reproduction, 69: 995-1001.
Narumi Ogonuki, N., Inoue, K., Yamamoto, Y., Noguchi, Y., Tanemura, K., Suzuki, O., Nakayama, H., Doi, K., Ohtomo, Y., Satoh, M., Nishida, A. & A. Ogura. 2002. Early death of mice cloned from somatic cells. Nature Genetics, 30(3): 253-254.
National Research Council (NRC). 2002. Animal Biotechnology: Science Based Concerns. National Academy Press.
Suemizu, H., Aiba, K., Yoshikawa, T., Sharov, A.A., Shimozawa, N., Tamaoki, N. and M.S.H. Ko. 2003. Expression profiling of placentomegaly associated with nuclear transplantation of mouse ES cells. Developmental Biology 253(1): 36-53.
Wilmut, I., Beaugean, N., De Sousa, P.A., Dinnyes, A., King, T.J., Paterson, L.A., Wells, D.N. and L.E. Young. 2002. Somatic cell nuclear transfer. Nature, 419: 583-587.
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