Prof Schubert on cloning (1/4/2007)

NOTE: This incisive letter, published by the journal Nature Biotechnology, is from David Schubert, a Professor in the Cellular Neurobiology Laboratory at The Salk Institute.

A number of the points in the letter are applicable not just to cloning but also to genetic engineering, eg the difficulty in detecting diseases caused by foods developed through these technologies.

We received the text of Prof Schubert's letter without any paragraphing, so to assist the reader have introduced what we hope are logical breaks. We apologise for deviations from the original.
Nature Biotechnology, VOLUME 25, NUMBER 3, MARCH 2007, pp. 281-82

To the editor:

I believe that your editorial 'The emperor's new clones' (Nat. Biotechnol. 25, 1, 2007) and several articles in the January issue fail to highlight some major concerns as the US Food and Drug Administration (FDA) moves closer to clearing the way for the introduction of animals and animal products created by somatic cell nuclear transfer (SCNT) into the US food supply1. Although discussion has been intense regarding SCNT technology and related ethical issues, scant attention has been paid to other aspects of creating a food chain dependent upon clonally derived animals.

Significant problems arise as animals are inbred to create genetically similar populations. The use of cloned animals to facilitate the generation of these populations has advantages over traditional inbreeding because the latter tends to expose deleterious mutations. For example, the overall fitness and reproductive efficiency of highly inbred Holstein and Jersey dairy cattle has dropped as the milk yields have risen2. It is, however, necessary to consider the potential consequences of basing our food supply on large populations of nearly genetically identical animals.

The study that is a major basis of the FDA's decision to continue the approval process for cloned animals and products derived from them is the analysis of cloned dairy cattle1,3. There was no examination of their offspring or the milk from the
offspring, although there have been some data on swine offspring1,4,5. It is unlikely that clones per se will ever be a major food source. Their offspring are apparently intended to serve this function.

It is generally recognized that incomplete epigenetic reprogramming is responsible for the high mortality and ill health of cloned animals6. Although mistakes in reprogramming may not be obvious in the relatively few clones that survive to adulthood, reprogramming problems may become more apparent with breeding. For example, whereas cloned goats have normal telomere lengths, their offspring have greatly shortened telomere
lengths7. Reduced telomere lengths are easy to measure and have been associated with premature aging, but many other traits are not as easy to identify and may only become apparent with age. In addition, there will be epigenetic and mitochondrial differences between animals that we are calling clones, and their contribution to overall inheritance is not understood. Although there is also limited evidence that epigenetic problems
are corrected in later generations through normal reproduction8, we may not know the true phenotypic consequences of cloning until multiple generations are examined. The safety testing data that were used to claim similarity between cloned and parental cattle and swine were based upon very simple 'industry standards', such as total protein and fat content1,3,4.

Because cloned animals, and perhaps their progeny, tend to be more sickly than outbred animals, it is likely that they must suffer from some as yet unidentified abnormalities. The use of antibiotics and other medications, such as steroid hormones and growth factors, may therefore be required to get animals in clone-derived herds to market size. This will further increase the steady stream of potent bioactive molecules into our food and environment, where they are already of significant concern to the medical community.

Furthermore, if there is any increase in disease associated with the consumption of clonal animals, it will be impossible to detect against the normal background of disease unless the disease is unique or appears in a novel cohort. Although at present there are no data to indicate a food safety problem, if one assumes that to detect an epidemic of a relatively common disease an incidence of about twice the background is required9, then a very large of number of people will need to become ill before a problem is detected.

For example, if a biotech product were to enter our food chain that causes a disease like Parkinson, which has a incidence of about 20 per year per 100,000 (ref. 10), then an additional 60,000 new cases per year in the United States would have to be reported before any change in public health status could be detected. Assigning a cause to any epidemic of this type would be impossible. It follows that there should be extensive safety tests to detect potential health risks of any new type of food product, not simple compositional analysis.

Safety issues aside, the introduction of animal cloning and its use to create genetically homogeneous populations raises animal health issues that have also received insufficient discussion or analysis. In particular, there are concerns about the lack of immunological fitness of clonal populations. Each individual has a unique repertoire of possible immune responses, and although any given pathogen may kill an individual, if there is a wide variety of responses available within a population, then some will survive and reproduce. This is known as the herd effect, and genetic herd immunity is indeed the biological basis for the sustainability of large animal populations11. Unlike herds of genetically heterogenous animals, a clonal herd may thrive in one set of conditions, but a change in environment or pathogen exposure may eliminate the entire population.

An example of the downside of genetic monoculture is the demise of the clonal Cavendish banana due to its lack of resistance to a new race of Fusarium oxysporum and the absence of alternative commercial varieties12. Although herds of clones appear unlikely at the present time because of the inefficiencies of SCNT technology and economics, we would be foolhardy not to acknowledge that efficiencies are likely to increase and to allow our food supply to become dependent upon such vulnerable populations.

Another problem is the intrinsic link between SCNT technology and transgenic technology. Improvements in the efficiency of SCNT will potentiate the development of transgenic animals, moving producers away from current inefficient transgenesis methods such as pronuclear injection and hurtling these products toward the market in the context of a regulatory system that is woefully prepared to deal with them. Transgenic organisms potentially pose a much more complex and serious set of problems than cloned animals, yet the rate at which they are being created and bred is increasing, in part owing to the improved efficiency of SCNT technology.

Most everyone agrees that it would not be wise to create conditions where milk containing some potent pharmaceutical can make its way into our food markets. But the likelihood of this happening can only increase as production of transgenic cows producing protein drugs in their milk or of chickens laying eggs that contain interferon and monoclonal antibodies expands.

The National Research Council has warned that the US regulatory system will not be able to cope with this rapid rate of increase in transgenic technology13; indeed, the US government has already failed miserably at preventing the entry into the US food supply of unapproved genetically modified (GM) plant products14-16.

And the problems for regulators don't stop there: it should also be pointed out that the more we learn about cloning farm animals, the easier it will be to clone humans. In addition, there is the question of the impetus underlying farm animal cloning. Why is this technology being pushed so hard in a society that has an overabundance of cheap food? There is clearly no need for additional calories in the US and Europe, and the majority of the US population say they would not eat meat from cloned animals17.

Assuming that the undertaking becomes economically viable, the only benefactors of farm animal cloning, aside from a few individuals with prize animals, will be the companies that own the technology. Perhaps it is the goal of agribusiness to control our food supply through the introduction of patented genetically manipulated and cloned agricultural products. This goal is close to being achieved in the arena of seed production18, and the next logical step is the farm animal. If animal clones and their derivatives achieve the legal status of the GM crop plant, then patent law could dominate the animal side of our food chain just as it now does with corn and soybeans.

Finally, the FDA has stated that there will be no mandatory labeling of food derived from cloned animals or their progeny. Exactly as was done with GM crops19, the FDA has determined that the product is indistinguishable from the original on the basis of meager compositional data from research funded by those who own the technology1,3-5. As the FDA is determining if cloned animal products are safe, it has decreed that there is no need for consumers to know what they are eating. In concert, the producers claim that once the product is available to the public, the market will determine its viability. These statements are clearly contradictory, for unless consumers know what they are purchasing based upon required labeling, they have no basis on which to make a choice and thereby influence the market. Therefore, there is clearly not only a right to know what is on the dinner plate, but based upon the uncertainties and risks associated with farm biotech, a need to know as well.

The author declares that he has no competing financial interests.

David Schubert
Salk Institute, 10010 N. Torrey Pines Road,
La Jolla, California 92037, USA.
e-mail: [email protected]

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17. Pew Initiative on Food and Biotechnology/The Mellman Group. Public Sentiment About Genetically Engineered Foods, 2006 Survey (The Pew Charitable Trusts, Washington, DC, November 2006).
18. ETC Group. Communique, 1-12 (2005).
19. Freese, W. & Schubert, D. in Biotechnology and Genetic Engineering Reviews, vol. 21 (ed. Harding, S.E.) 299-325 (Intercept Ltd, Andover, 2004).

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