Invariably Bad:

Animal Cloning in Biomedical Research

By Crystal Schaeffer, MA Ed., AAVS Outreach Director

AV Magazine Spring 2007, Cloning for Biomedical Research

Over the past decade, there has been a great deal of debate regarding animal cloning, with much of it focusing on the technology itself. The controversy surrounding animal cloning is warranted due to its severe animal welfare implications. Nonetheless, researchers continue to tout the technology for use in biomedical research, and few have voiced concern over how the deficits of animal cloning will affect the reliability of data resulting from studies utilizing it.

The vast majority of animal cloning research, especially those studies that utilize mice, is aimed at refining the inefficiency of the technology. However, scientists also clone animals to create homogenous groups of research ‘subjects’ for use in experimentation in an attempt to reduce variability. At the Whitehead Institute in Massachusetts, for example, researchers are cloning mice to study cancer and its manifestation.^[1][2] Scientists are investigating the role of specific enzymes and their impact on gene expression in the development of cancer and further hope to distinguish whether cancer arises due to genetic or epigenetic changes. ^[3]

The fact is, however, that animal cloning has not generated the financial or scientific rewards hoped for by the biomedical industry. It has been widely reported within the scientific literature that animal cloning has a success rate of less than four percent. This statistic alone leaves one to question the judgment of researchers who choose to incorporate the technology, which is unreliable and expensive both in terms of dollars and animal life, in their investigative studies. For example, in its Draft Risk Assessment regarding the use of animal cloning for food, the U.S. Food and Drug Administration (FDA) stated that the vast majority of cloned fetuses develop abnormally and die in the womb, and also mentioned several specific studies demonstrating the inefficiency of animal cloning, including one that found that 24-26 percent of cloned animals who survive birth die within six months.^[4] The Assessment also reported that the majority of clone pregnancies require Caesarean section or another form of intervention for delivery, compared to fewer than one percent of conventional pregnancies,^[5] forcing animals to undergo invasive procedures at an added financial burden to the research study.

Cloned animals who do survive the first few months of life often suffer from a variety of health problems. For instance, respected cloning experts Ian Wilmut of the Roslin Institute where Dolly, the first cloned mammal, was ‘created,’ and Gerald Schatten of the Magee Women’s Hospital and the University of Pittsburgh School of Medicine stated in the journal Science that “Many cloned animals display birth defects, including respiratory failure, immune deficiency, and inadequate renal function—all leading to premature deaths….”^[6] Another study in Science concurred: “Even apparently healthy survivors may suffer from immune dysfunction or kidney or brain malformation, perhaps contributing to their death at later stages.”^[7]

The fact that cloned animals suffer many health consequences as a product of cloning technology can create unwanted variables that could impact the results of research. For example, it has been reported that animal clones who survive into adulthood have a higher risk of suffering from obesity,^[8] a condition that often relates directly to metabolism. Researchers at the University of Cincinnati are exploring the possible mechanisms involved in this phenomena and have found that “the obese phenotype is maintained over successive generations of cloned mice.”^[9] Because obesity can be tied to metabolic function or, specifically, how quickly a substance (whether food or drug) is absorbed by the body, it stands to reason that data derived from using cloned animals, who have a higher propensity to be obese, could be skewed.

Aging is another physiological activity that is impacted by the cloning process and in turn could affect research data collected using cloned animals. Scientists tracking cloned animals from birth to death have found that mice cloned from somatic cells have “a significantly shorter life span” than those conceived naturally.^[10] Furthermore, it was reported that cloned mice had lower antibody production, “suggesting that decreased immunologic function—a function that generally declines with advancing age—compromised the clones’ ability to fend off infection.”^[11] Utilizing cloned animals with weakened immune systems in research could also impact investigation results because their bodies would not be able to fight disease and/or infection normally.

Additionally, in another study discussed in the Journal of Reproduction and Development, researchers reported finding several phenotypic abnormalities^[12] in cloned mice that are not found in those produced through natural mating, including enlarged placentas, increased body weight, lack of eyelid fusion, and umbilical hernia.^[13] The researchers found that “almost all clones have shown various phenotypic abnormalities that are not present in animals produced by natural mating,” and further stated that “[t]hese abnormalities represent a barrier to the medical use of clones.” ^[14]

Also of question is whether cloning really reduces variability in scientific experiments. Beyond the health abnormalities that appear in cloned animals and confound studies, researchers at Texas A&M have found that clones are no more homogenous or identical for many traits than naturally produced animals.^[15] Therefore, animal clones are of limited used for reducing the size of groups and variability involved in animal experimentation. Given these findings, it is difficult to see how one could justify animal cloning for research purposes.

Another major application of cloning technology is for the reproduction of transgenic animals who have been engineered with genes from other species to study disease; produce pharmaceuticals in the milk, blood, urine or semen (pharming); or produce tissues and organs for transplantation into humans (xenotransplantation). For example, researchers at the University of Massachusetts Amherst are working to develop a method to produce human polyclonal antibodies (PAbs) in cloned calves, a process called pharming, to serve as a biodefense mechanism against a bioweapon attack.^[16]

Another study reported in Cloning and Stem Cells is investigating the possibility of pharming therapeutic human PAbs in bovines for use in patients suffering from autoimmune diseases or for the treatment and prevention of antibiotic resistant infections.^[17] This type of research is especially concerning due to the fact that it runs the risk of exposing immune compromised patients to possible animal retroviruses,^[18] viruses that are impotent in one species yet deadly in another. ^[19]

This same threat is extremely high in xenotransplantation, a process in which cells, tissue, or an organ is transplanted from one species into a different species. Despite this, cloning expert Jerry Yang is working to create “immune protected universal donor cloned transgenic pigs for xenotransplantation.”^[20] Yang justifies his research, citing a national shortage of organs for transplant, and he received over $160,000 taxpayer dollars last year to fund this project, money that could otherwise be spent supporting programs such as the United Network of Organ Sharing, which promotes human to human organ donation, a process that is much safer and less expensive than xenotransplantation.

The problems in assessing the health of cloned transgenic animals is highlighted by the FDA in its Risk Draft Assessment, which states, “Because these animals are transgenic clones, it is not possible to determine whether adverse outcomes result from the direct effect of the expression of the transgenic construct” [DNA sequence],…“the insertion of the construct,” the cloning process, or “some interaction of any or all of these processes.”^[12] Not being able to distinguish these differences is problematic since it would be difficult to determine what is responsible for the observations gathered during a study involving transgenic clones. These difficulties are worsened if scientist then attempt to apply the results to a different species such as humans.

As outlined here, there are many questionable issues surrounding animal cloning; not just concerning animal welfare but also for its implications in affecting data resulting from studies using animal clones. The biomedical community’s desire to use animal cloning is unsubstantiated, and “[a]t the moment, the long-term consequences of mammalian cloning remain poorly characterized. Data available thus far suggest that we should use this technology with great caution….”^[22] Indeed, the well-being of animals and the quality of science may well depend upon it.

Resources

[1] Jaenisch Lab Research Summary. Retrieved April 9, 2007, from http://www.wi.mit.edu/research/summaries/jaenisch.html.
[2] Jaenisch, Rudolf. (2006). Abstract. Epigenetics, Stem Cells, and Cancer. Retrieved on April 12, 2007, from http://crisp.cit.nih.gov
[3] Epigenetic changes occur due to environmental factors that affect gene expression. The gene itself does not change.
[4] Food and Drug Administration (2006). Animal Cloning: A Draft Risk Assessment.
[5] Ibid.
[6] Schatten, G., Prather, R., & Wilmut, I. (2003). Cloning Claim is Science Fiction, Not Science. Science. 299:344.
[7] Rideout, W.M., Eggan, K., & Jaenisch, R. (2001). Nuclear Cloning and Epigenetic Reprogramming of the Genome. Science. 293:1093-1098.
[8] Sakai, Randall R. (2006). Abstract. Food intake and obesity in cloned mice. Retrieved April 5, 2007, from http://crisp.cit.nih.gov.
[9] Ibid.
[10] Stephenson, Joan. (March 13, 2002). Shorter Life Span for Cloned Mice. Journal of the American Medical Association. Vol. 287, No. 13.
[11] Ibid.
[12] The outward appearance of how a gene is expressed.
[13] Nobuhir, Shimozawa, Shingo, Tajima, Noriyuki, Azuma, Kyoij, Hioki, Tomohiro, Kono, & Mamoru, Ito. ((2003). Histological Study of the Hypertrophic Placentas and Open Eyelids Observed in Cloned Fetuses. Journal of Reproduction and Development. Vol. 49, No. 3.
[14] Ibid.
[15] Archer, Greg S., Dindot, Scott, Friend, Ted H., Walker, Shawn, Zaunbrecher, Gretchen, Lawhorn, Bruce, Piedrahita, Jorge A. (2003). Hierarchical Phenotypic Epigenetic Variation in Cloned Swine. Biology of Reproduction 69, 430-436.
[16] Osborne, Barbara A. (2006). Abstract. Polyclonal human antibody in cloned HAC-transgenic cows. Retrieved April 5, 2007, from http://crisp.cit.nih.gov/crisp
[17] Roble, James M. (2007). Application of Cloning Technology for Production of Human Polyclonal Antibodies in Cattle. Cloning and Stem Cells. Vol. 9. No. 1.
[18] World Health Organization. Emerging Zoonoses. (n.d.). Retrieved August 25, 2006, from http://www.who.int/zoonoses/emerging_zoonoses/en.
[19] The common example of a retrovirus is HIV.
[20] Yang, Xiangzhong. (2006). Abstract. Cloned Pigs for Xenotransplantation. Retrieved on April 5, 2007, from http://crisp.cit.nih.gov
[21] Food and Drug Administration (2006). Animal Cloning: A Draft Risk Assessment.
[22] Tamashiro, K.L., Sakai, RR., Yamazaki, Y., Wakayama, T., & Yanagimachi, R., Developmental, behavioral, and physiological phenotype of cloned mice. Adv. Exp. Med. Biol. 2007;591:72-83.

Schaeffer, Crystal. (Spring 2007). AV Magazine. Pages 16-18.

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