Drs. Jaenisch and Wilmut are neither convincing nor objective in their treatment of the controversial subject of Human Cloning.

The issue is of significant concern, as the potential use of Somatic Cell Nuclear Transfer (SCNT) technology as a reproductive option for infertile couples offers the only means by which a large proportion of these couples could ever hope to have their own genetically related children, a population segment constituting as much as 5% of the overall population.

I would like to address specific points made in their paper:

"There are many social and ethical reasons why we would never be in favor of copying a person"

1. Drs.Jaenisch and Wilmut boldly assert that SCNT will NEVER be an acceptable means of reproduction for anyone, under any circumstances, irrespective of the actual risks involved. They never specify the "many social and ethical reasons". They are openly biased.

2. Anyone who has given rational thought and study to the matter understands that a child born as the result of SCNT will be a unique individual, as unique as any other person, based on studies of identical twins. Dr.Wilmut himself has commented on the easily distinguishable behaviors seen in a group of cloned lambs in his lab. Dr. Wilmut is self-contradictory.

3. SCNT is not "copying"! That is obvious to any intelligent layperson that has given the matter serious consideration. Personally, I find the use of such derogatory misconceptualizations offensive and, to use the phraseology commonly employed by Dr.Jaenicsh "irresponsible".

"Animal cloning is inefficient and is likely to remain so for the foreseeable future"

1. A number studies have already demonstrated far higher rates of development, as measured in the proportion of live births to the number of blastocysts transferred, in some cases matching or exceeding developmental rates seen in human IVF [7,8,9].

2. While the number of cytoplasts utilized is relatively high, what reason is there to think that this will always remain so? If history is any indicator, one can reasonably expect that further refinements and insight to the process will improve efficiency rates even in this relatively unimportant respect as well.

"Circumstantial evidence begins to hint at defects in programming of gene expression in cloned animals."

"The most likely explanation may be failures in genomic reprogramming"

"Thus, even minimal disturbance of the embryo's environment can lead to epigenetic dysregulation of key developmental genes."

1. These statements illustrate the self-contradictory nature of their arguement(1,2 vs 3).The entire IETS preconference symposium at Maastricht in January 2000 was devoted to the concept that conditions encountered by the developing embryo go on to effect an individuals lifetime risk for a number of diseases. Culture conditions during embryo development have been proven to exert profound effects on the methylation status of various genes, including some but not all imprinted genes[10]. The IGF2r gene, the aberrant biallelic statement of which in ruminants which appears to play a prominent role in the development of large offspring syndrome (LOS), is interestingly enough expressed in a polymorphic pattern in humans [1,2,3,5].

Of particular interest are some quotes from this reference[4]: "These results indicate that inactivation of imprinted genes occurs postfertilization (most likely postimplantation) and that genomic imprinting and gene inactivation are separate processes." Also: "For these genes, this finding invalidates models of genomic imprinting that require them to be inactive from the time of fertilization."

2. The argument made is, in their own words "circumstantial". The conceptual details which they present of epigenetic programming errors remain poorly understood. To a large extent we are dealing here with the old "what came first, the chicken or the egg?" debate, veiled in new clothes. As they clearly point out in their own article, deficiencies of the culture environment are largely implicated in subsequent abnormalities of development, including aberrent patterns of epigenetic statement, which may then lead to subsequent abnormalities in development.

"There is every reason to think that the human cloning experiments announced by P.Zavos and S. Antinori will have the same high failure rates as laboratories have experienced when attempting animal cloning"

1. First, it should be noted that no form of screening methodology has been systematically employed in any animal cloning experiments published to date.

2. Several studies have been published demonstrating the birth of healthy live young and very high success rates[7,8,9]. One of the very references which they site demonstrated reasonable success rates with the birth of healthy live offspring[12]

3. Contrary to what Drs. Jaenicsh and Wilmut assert, there is every reason to believe that further refinement of techniques and culture environments will serve to further minimize developmental deficits seen in manipulated embryos[14], whether it be in human IVF or SCNT. Insights gained in minimizing or eliminating deficiencies of the culture environment will have wide ranging benefits in established forms of assisted human reproduction such as IVF and ICSI as well.

4. A distinct possibility exists that the overall risk could be even further reduced. The technique of SCNT completely eliminates the risk of a number of "normally" seen congenital abnormalities due to meiotic nondisjunction, the most common of which is Down's Syndrome (Trisomy 21), occurring at an incidence of about 1/700[11] live births in the normal reproductive population.

5. Additional screening methodologies, including but not limited to; the application of strict morphologic criteria, blastomere biopsy with whole genome chromosomal analysis[15], and assessment of early embryonic gene expression patterns can be fully expected to significantly improve success rates as determined by the final measure of the birth of healthy offspring.

6.Thus, I believe their conclusion to be premature and unwarranted.

Finally, I would like to include this quote from one of Dr.Jaenisch's own fairly recent publications[6]:

"However, our understanding of molecular details of the imprinting process, as well as evolutionary considerations, is rather consistent with imprinting having no intrinsic role in mammalian development."

There is every reason to believe that further elucidation of the molecular mechanisms involved during the processes of embryogenesis and the careful tailoring of subsequently developed culture conditions and manipulation strategies, when combined with appropriate screening methods, will eventually allow infertile couples to safely have healthy, genetically related children through Somatic Cell Nuclear Transfer technology.

It is my view that their paper is much more about politics and business, rather than about science and human welfare. There is little doubt in my mind, that had such a paper been submitted for publication by graduate students, it would have been summarily rejected on the basis of being self-contradictory, grossly misrepresentative of the facts, and openly biased.

REFERENCES

1: Novartis Found Symp 1998;214:251-9; discussion 260-3
Making sense of imprinting the mouse and human IGF2R loci.
Wutz A, Smrzka OW, Barlow DP.

2: Biochem Biophys Res Commun 1998 Apr 7;245(1):272-7
Absence of an obvious molecular imprinting mechanism in a human fetus with monoallelic IGF2R statement.
Riesewijk AM, Xu YQ, Schepens MT, Mariman EM, Polychronakos C, Ropers HH,Kalscheuer VM.

3: Genomics 1996 Jan 15;31(2):158-66
Maternal-specific methylation of the human IGF2R gene is not accompanied by allele-specific transcription.
Riesewijk AM, Schepens MT, Welch TR, van den Berg-Loonen EM, Mariman EM, Ropers HH, Kalscheuer VM.

4: Genes Dev 1994 Feb 1;8(3):290-9
Igf2r and Igf2 gene statement in androgenetic, gynogenetic, and parthenogenetic preimplantation mouse embryos:
absence of regulation by genomic imprinting.
Latham KE, Doherty AS, Scott CD, Schultz RM.

5: Biochem Biophys Res Commun 1993 Dec 15;197(2):747-54
Functional polymorphism in the parental imprinting of the human IGF2R gene.
Xu Y, Goodyer CG, Deal C, Polychronakos C.

6: Trends Genet 1997 Aug;13(8):323-9
DNA methylation and imprinting: why bother?
Jaenisch R.

7: J Reprod Fertil 2000 Nov;120(2):231-7
Cloning of calves from various somatic cell types of male and female adult, newborn and fetal cows.
Kato Y, Tani T, Tsunoda Y.

8: Science 1998 Dec 11;282(5396):2095-8
Eight calves cloned from somatic cells of a single adult.
Kato Y, Tani T, Sotomaru Y, Kurokawa K, Kato J, Doguchi H, Yasue H, Tsunoda Y.

9: Biol Reprod 1999 Apr;60(4):996-1005
Production of cloned calves following nuclear transfer with cultured adult mural granulosa cells.
Wells DN, Misica PM, Tervit HR.

10. Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM.
Differential effects of culture on imprinted H19 statement in the preimplantation mouse embryo.
Biol Reprod. 2000 Jun;62(6):1526-35.

11.Robbins Pathologic Basis of Disease, 4th Edition, p.123-135

12. I.Polaveava et al., Nature 407, 86(2000).

13. Patterson, D.: The causes of Down's Syndrome. Sci.Am.257:52,1987

14: Toxicol Lett 2001 Mar 31;120(1-3):143-50
Environmental effects on genomic imprinting in mammals.
Thompson SL, Konfortova G, Gregory RI, Reik W, Dean W, Feil R.