The Linacre Quarterly Volume 74 | Number 1 Article 6 February 2007 Partial Trajectory: The Story of the Altered Nuclear Transfer-Oocyte Assisted Reprogramming (ANTOAR) Proposal W. Malcolm Byrnes Follow this and additional works at: http://epublications.marquette.edu/lnq Recommended Citation Byrnes, W. Malcolm (2007) "Partial Trajectory: The Story of the Altered Nuclear Transfer-Oocyte Assisted Reprogramming (ANTOAR) Proposal," The Linacre Quarterly: Vol. 74: No. 1, Article 6. Available at: http://epublications.marquette.edu/lnq/vol74/iss1/6 Partial Trajectory: The Story of the Altered Nuclear Transfer-Oocyte Assisted Reprogramming (ANT-OAR) Proposal by W. Malcolm Bymes, Ph.D. The author is Assistant Professor, Department of Biochemistry & Molecular Biology, Howard University College of Medicine Washington, D.C. This past summer, President George W. Bush vetoed his first Congressional bill, the Embryonic Stem Cell Enhancement Act (H.R. 810) sponsored by Representatives Diana DeGette (D-Colorado) and Michael Castle (R-Delaware). The bill was one part of a three-part package of stem cell-related bills that was passed by the U.S. Senate and voted on by the U.S. House of Representatives; the other two bills were the Fetus Fanning Prohibition Act sponsored by Senator Sam Brownback (R-Kansas) and a bill promoting alternative, presumably ethically-acceptable methods of de!iving plulipotent stem cells. The centerpiece of this last bill, which was sponsored by Senators Rick Santorum and Arlen Specter (both RPennsylvania) and strongly backed by President Bush but which ultimately was not passed by the House of Representatives, was a controversial experimental proposal known as "altered nuclear transfer-oocyte assisted reprogramming," or ANT-OAR. This essay aims to tell the story of the ANT-OAR proposal, from its conception by Professor William Hurlbut of the President's Council on Bioethics to its adoption and promotion by a group of conservative, mostly Catholic philosophers, theologians and scientists to its eventual demise in Congress. It also will give some reflections on how ANT-OAR promotes a genetically deterministic view of the human organism and can lead down a slippery slope into a future in which human cloning and human genetic enginee!ing are more acceptable. For these reasons, it will be argued, ANT-OAR should be opposed by all who are against human genetic modification regardless of their political o!ientation. 50 Linacre Quarterly Conception and Early Development of ANT To understand ANT-OAR, one must first understand its parent, altered nuclear transfer, or ANT. The idea to use human "partial developmental trajectories" for medical therapy, which is what ANT proposes to do, is the brainchild of William Hurlbut, a member of the President's Council on Bioethics and a Consulting Professor at Stanford University. One of the first occasions on which the concept of ANT was discussed publicly was the July 24-25,2003, meeting of the council 1 In a fascinating dialogue with Professor Rudolph J aenisch of M.LT. and others, Hurlbut first deftly dispensed with Jaenisch's rival proposal that a human "clonote"a cloned human individualis not a true representative of the species and therefore can ethically be used to derive stem cells. Then, addressing the council, Hurlbut established his pro-life credentials, and masterfully introduced his own, not-so-different proposal -ANT for deriving stem cells. Hurlbut proposed to use genetic engineering and somatic cell nuclear transfer (cloning) to create an embryo-like entity that was designed from the beginning to self-destruct after the blastocyst stage. Thus, ANT replaced regular cloning, which would produce, according to Jaenish's argument, an embryo that is only statistically likely to be highly defective and therefore not a true member of the species; ANT would guarantee that the embryonic entity would be defective. Such a guarantee was necessary because Dolly, who clearly was a sheep, was proof that regular cloning could, at least in some cases, produce a true member of the species. Formally unveiled by Hurlbut at the December 3, 2004, meeting of the President's council,' ANT differs from regular cloning in that it involves the pre-transfer genetic alteration of the somatic cell nucleus that is to be transferred. Using what is known as RNA interference technology, the idea is to knock down the gene for a factor essential for development beyond a certain stage. Hurlbut chose the developmentally imp011ant transcription factor Cdx2 as the target for knockdown since Cdx2 is known to be essential for formation of the embryo's trophectoderm,' which eventually becomes the placenta, and without which an embryo cannot implant. More specifically, ANT involves introduction of a trans gene that encodes an agent (a short RNA molecule) that targets and destroys the Cdx2 RNA transcript. In this manner, Cdx2 is effectively eliminated from the embryo. The absence ofCdx2 eventually leads to the embryo's demise, but this does not happen until just after the blastocyst stage when the inner cell mass containing the sought-after stem cells forms. Until the blastocyst stage, the embryo develops essentially normally. After extraction of the stem cells from the inner cell mass, the transgene that was introduced earlier can be excised, restoring the normal genotype; this eliminates any unintended side effects in the stem cells due to an absence of Cdx2. The February, 2007

not a mechanistic-reductionistic description is sufficient to define the embryo, and the correct meaning of the Aristotelian-Thomistic axiom agere sequitur esse, "acting follows being," which both sides accepted as true, Walker, in particular, argued that ANT was "cloning with a twist," that it was simply the cloning of a severely disabled embryo, Much of this debate can be found on the Communio website6 and in the Spring and Summer 2005 issues of the National Catholic Bioethics Quarterly, In addition to these philosophical attacks on the morality of ANT, the scientific feasibility and ethical tractability of the proposal suffered a number of Cliticisms from scientists, including Douglas Melton, George Daley and Charles Jennings of Harvard University, and Davor Salter of the Max-Planck Institute ofimmunobiology in Frieberg 7 Developmental Changes Lead to ANT-OAR The original ANT proposal has weathered the scientific criticisms, mainly because of an elegant set of experiments performed by Jaenisch and Alexander Meissner, also ofMJT, which showed that ANT can work, at least in mice 8 Nevertheless, even after extensive debate, the problems with ANT as a morally-acceptable means of deriving stem cells for therapy proved intractable for some, In an attempt to resolve the impasse that had arisen over the ethical acceptability of ANT, a conference was convened in Washington, D ,C,, in April 2005 9 A number of Catholic and other Christian scientists, moral theologians and ethicists were present, After some deliberation, a document endorsing a new procedure, called "altered nuclear transfer-oocyte assisted reprogramming" or ANT-OAR, was formally adopted and signed by thirty-five persons in attendance, The thirty-five who signed this Joint Statement10 included members of the Christian Pro-Life elite, as well as a number of scientists, including Austriaco, Marcus Grompe of the Oregon Stem Cell Center, Kevin FitzGerald of Georgetown University, and Maureen Condie of the University of Utah, The essential difference between ANT-OAR and the original ANT proposal is that ANT-OAR aims to eliminate the "time gap" inherent in ANT, the time interval between the original nuclear transfer event and the point in the blastocyst stage at which the absence of Cdx2 (for example) becomes manifest, causing the embryo to lose its structural integrity, During this interval, the embryo would, for all intents and purposes, be normaL The Joint Statement proposed closing the time gap by introducing ab initio a "pluripotency factor" (the transcription factor Nanog was suggested) that would work together with the oocyte's cytoplasm to reprogram the somatic nucleus to be that of a plmipotent stem cellhence the name "oocyte-assisted-reprogramming," In this manner, the totipotent February, 2007 53 one-celled embryonic stage would be bypassed altogether. The newly-cloned entity would, from the moment of transfer, exist in a pluripotent state, Despite these efforts at resolving the impasse, Schindler and Walker, now joined by Jose Granados of the John Paul Institute and others, were not satisfied that the ethical issues were resolved11 They argued that even if the time gap were collapsed to zero, the ontological status of the embryo would not change, Furthennore, the time gap was not in fact zero because some time was needed for the reprogramming process to occur. Of course, all of this assumed that ANT-OAR could even work from a scientific perspective, a doubtful proposition since, although Nanog is known to maintain plrnipotency in stem cells / 2 there is no evidence that it could single-handedly establish it the different cellular context of a newlycloned embryo, Recently, it has become evident that a combination of factors may be needed for true reprogramming of a differentiated adult cell to the pluripotent state13 Finally, the prospect of reprogramming an adult cell directly by exposing it to a cocktail of factors in this manner essentially negates the need for ANT-OAR, whose goal is to generate the very same type of stem celL Thus, if reprogramming can work and there is mounting evidence that it can then ANT-OAR is entirely unnecessary, The rationale for having ANT-OAR disappears, Premature Death? From its very inception, ANT (and ANT-OAR) was designed, in part, to achieve a political objective, Opinion polls had shown that most Americans supported using leftover embryos from IVF clinics to obtain embryonic stem cells for medical research, Increasingly, President Bush and other Republican politicians who opposed such research were under attack by scientists and citizens' groups for standing in the way of urgentlyneeded medical therapies, Thus, they needed a way to show that they were not antiscience or antimedicine, ANT-OAR provided a perfect solution to this problem; by supporting it, these politicians could demonstrate that they were both pro-life and pro-science, Indeed, both Representative Roscoe Barlett's (R-Maryland) bill H,R, 3144 and the companion senate billS, 1557 were known as the "Respect for Life Pluripotent Stem Cell Act of 2005 ,'*There is evidence that the Bush administration was kept informed about developments in the ANT-OAR debate from the beginning, ANTOAR proponents readily admit to this political motivation; they see no reason why any possible means should not be employed in trying to advance the agenda of the Bush administration, which they see as pro-life, 15 This past summer, as the U, S, Congress voted on the companion bills S, 1557 and H,R, 3144, all of the hopes of the ANT-OAR "Pro-Life Dream Team" 16 would either come to fruition by these bills' passage, or 54 Linacre Quarterly I would be dashed by their failure. The team's hope was that the presidenl would veto H.R. 810 (which would allow surplus IVF embryos to be use~ to obtain stem cells) and sign H.R. 3144, which mandated the N.I.H. tq fund methods for deriving stem cell lines "without destroying humã embryos." At first, it appeared that things were going to work out as hoped! The senate passed its versions of both H.R. 810 and H.R. 3144, as well ã Brownback's anti-fetal farming bill; the thJee bills were part of an agreed* upon package that would be passed in toto or not at all 17 But in the House everything fell apart. H.R. 810 was passed but, surprisingly, H.R. 3144 fell short of the two-thirds majority vote needed for passage under the suspended House rules that were in effect. 18 In the end, only two bills arrived on Bush's desk, the anti-fetal farming bill, which he signed, and H.R. 810, which he vetoed. Although h~ had hoped to counterbalance his veto of embryonic stem cell research witb the signing of H.R. 3144, this was not to be the case. His hopes of being seen as pro-science as well as pro-life were not fulfilled. Bush expressed his disappointment in comments at the East Room veto-signing ceremony, and also praised the failed alternative bill, which he said would have "authorized additional federal funding for promising new research that could produce cells with the abilities of embryonic cells, but without the destruction of human embryos." 19 In an attempt to salvage what he could, he asked the Health and Human Services and the N.I.H. to "aid the search for stem cell techniques that advance promising medical science in an ethical and morally responsible way." Thus, in the end, the legislation authorizing ANT-OAR was not signed into law. Like the embryo it had sought to create, the ANT-OAR proposal apparently was only a "partial trajectory," having met its premature death in the halls of Congress.20 Looking Back In reflecting on the ANT-OAR story, a question arises. Why would religious and political leaders whose stated goal was to protect human life support a proposal to genetically engineer and clone human embryos? The reasons are probably various, but at least two come to mind. First, in theilj zeal to promote the conservative political agenda, they might have failed to' see that acceptance of ANT-OAR could lead down a slippery slope to a Brave New World in which human cloning and human genetic engineering are commonplace. Indeed, once human cloning technology is perfected through ANT-OAR, what would stop its application to embryos that are to be transferred to a mother's womb for gestation and birth? In other words, once the technology for human cloning is developed through ANT-OAR, i~ is a very short step to reproductive cloning. And, while ANT-OARi proponents might protest that ANT-OAR is not cloning, the truth or: February, 2007 falsehood of their argument is, in a certain sense, irrelevant because cloning technology will be used in ANT-OAR. The somatic cell nuclear transfer technology to be used for ANT-OAR and the technology that would be used for reproductive technology are one and the same 21 Moreover, although one could argue that society could simply pass a law banning the transfer of cloned embryos to the womb, we all know that the cu!Tent socio-economic and legal situation is really not this simple. In our pluralistic and free-market-d!iven society in which some parents will want to enhance the genetic makeup of their children, the very availability of human genetic engineering and cloning predictably will lead to the implementation of these technologies in the fertility clinic. One has to ask, then: Why were the ANT-OAR proponents so blind to these future possibilities? Could it be that their political ambitions clouded their vision? Second, at least some proponents of ANT-OAR may have embraced Hurlbut's (and others') philosophical view that the embryo, and indeed every organism, is defined by its genetic makeup. For, if a human embryo is denied membership in the species Homo sapiens because it has an engineered genetic defect, then this means that we all are defined by onr genetic composition. This statement is an articnlation of a belief in genetic determinism, which says that our identity is determined by our genes. Of course, although common, the belief in genetic determinism has been and still is a salient force in the eugenic practices of the past and those of the present. While a deterministic view is patently false from a biological perspective indeed, systems biology is revealing that organisms are holistic systems that cannot be defined as the sum of their parts22 the falsehood of this view has not stopped it from permeating society. Nevertheless, it is disturbing to hear genetic determinism being espoused by religious leaders, who should be aware of the social dangers associated with it. Conclusion It is imperative that all persons who are opposed to human genetic modification and human cloning whether Christian or not, liberal or conservative, in favor of embryonic stem research or opposed to itjoin together in defeating ANT-OAR and any future proposals that promote human cloning. Moreover, opposition is essential whether proposals of this sort originate from the political right or the political left.23 For, all such proposals that sanction human cloning, including ANT-OAR, will pave that way into a future in which the commodification of human life for medical ends is socially acceptable. Who among us would want this to happen? 56 Linacre Quarterly References 1. See the transcript of the 24-25 July 2003 meeting of the President's Council on Bioethics, session 3. Available at: http:/ /bi oe thics print. bioethics . 2ov /transcripts/ j ulyO 3/ ses s i on3 .h trnl Last accessed 9-17-06. 2. William Hurlbut, President's Council on Bioethics, "Session 6: Seeking Morally Unproblematic Sources of Human Stem Cells," transcript, December 3, 2004. Available at: ht1:p://www.bioethics.gov/transciiDts/dec04/session6.html Last accessed 9-17-06. 3. K. Chawengsaksophak, W. de Graaff, J. Rossant, J. Deschamps, and F. Beck, "Cdx2 is Essential for Axial Elongation in Mouse Development," Proceedings of the National Academy of Sciences USA 101 (18 May 2004): 7641-7645. 4. Hurlbut, President's Council, session 6 transcript, December 3, 2004. 5. Mentioned in Jocelyn Dong, "The Line Between Faith and Science: Stanford Professor Hopes to Further Stem Cell Research Without Destroying Human Embryos," The Palo Alto Weeklyonline edition (26 October 2005). Available at: http://www.paloaltoonline.com/weekly morgue/2005/2005 10 26.stemcell26.shtrnJ Last accessed 9-17-06. 6. Available at: http://www.communio-icr.com/ant.html Last accessed 9-17-06. 7. See D.A. Melton, G.Q. Daley, and C. G. Jennings, "Altered Nuclear TransferA Flawed Proposal," New England Journal of Medicine 351 (30 December 2004): 27912792; and D. Salter, "Politically Conect Human Embryonic Stem Cells?" New England Journal of Medicine 353 (1 December 2005): 2321-2323. 8 .A. Meissner, and R. Jaenisch, "Generation of Nuclear Transfer-Derived Pluripotent ES Cells From Cloned Cdx2-Deticient Blastocysts," Nature 439: 212-221. 9. For a description of this conference, see E. Christian Brugger, "Ethical Cornrnitment Stimulates Scientific 1nsight," National Catholic Bioethics Quarterly 5.3 (Autumn 2005): 445-446. 10. See "Production of Pluripotent Stem Cells by Oocyte-Assisted Reprogramming: Joint Statement with Signatories," National Catholic Bioethics Quarterly 5.3 (Autumn 2005): 579-583. Also available online at the Ethics and Public Policy website at: http://www.eppc .org/publications/pubiD .23 7 4/pub detail.asp Last accessed 9-17-06. 11. Articles in the contiiming debate can be read at the Communio website at http://www.communio-icr/ant.htm See also the Autumn and Winter 2005 and the February, 2007 57 Summer 2006 issues of the National Catholic Bioethics Quarterly, and the article Bymes, W, M, and L Granados, "ANT-OAR Fails on all Counts: Method of Harvesting Stem Cells Riddled with Scientific and Ethical Flaws," Science and Theology News (June 2006): 23-25. 12. L Chambers, D, Colby, M_ Robertson, L Nichols, S_ Lee, S. Tweedie, and A. Smith, "Functional Expression Cloning ofNanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells," Cell 113 (30 May 2003) 643-655; and K. Mitsui, Y. Toluzawa, H. ltoh, K. Segawa, M. Murakami, K. Takahashi, M. Maruyama, M. Maeda and S. Yamanaka, "The Homeoprotein Nanog is Required for Maintenance of Pluripotency in Mouse Epiblast andES Cells," Cellll3 (30 May 2003): 631-642. 13. K. Takahashi and S. Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors," Cel/126 (25 August 2006): 1-14. 14. The texts of these bills can be found online at: httn://www.govtrack .us/ congress/billtext.xpd ?bill-hI 09-3144 http://www I govtrack.us/congress/billtext.xpd ?bill-s l 09-1557 Last accessed 9-17-06. 15. See Fr. Thomas Berg's reply toW. Malcolm Byrnes, "Inconsistencies on the ProANT-OAR Position," National Catholic Bioethics Quarterly 6.2 (Suurmer 2006): 201-205. 16 This name was given by Joan Frawley Desmond in her article "Pro-Life Dream Team Confronts Embryonic Stem-Cell Juggernaut," Crisis Magazine (January 2006): 25-31. Available at http://www.crisisma!!azine.com/januarv2006/desmond.htm 17. Rick Weiss, "Senate to Consider Stem Cell Proposals," The Washington Post (30 June 2006): AS. 18. See Robert Novak, "Stem Cells: No One-Two Punch," The Washington Post (24 July 2006): Al9. Novak describes the high drama that unfolded as the "Republican high command" in the House snuggled to pass HR. 3144. He also gives the names of specific Republican congressmen who "defected," voting against the bill. 19. Whitehouse Press Release on July 19, 2006, "President Discusses Stem Cell Research Policy." Available online at: http:! /www. whitehouse .gov /news/releases/2006/07 20060719-3 .html. Last accessed 7-21-06. 20. Or has it? ANT was moved forward in large part by the sheer strength of the personality of William Hurlbut. There is evidence that Hurlbut has no intention of being deterred by the recem defeat of ANT-OAR in Congress. Indeed, he apparently 58 Linacre Quarterly