WASHINGTON INSIDER
Spring 2008

Congress and the Bush Administration focused chiefly on health care, military spending, and broader disagreements on spending levels and spending priorities in the latter months of 2007. Therefore, Washington did not present many new developments on bioethics issues—except for one development in stem cell research which may be the breakthrough of the decade.

Induced Pluripotent Stem Cells:
Reprogramming the Stem Cell Debate

On November 20, two peer-reviewed studies announced success in “reprogramming” ordinary adult skin cells into the functional equivalent of embryonic stem cells, by using viruses to transfer four gene transcription factors into the cells. Dr. Shinya Yamanaka of Kyoto University, who pioneered this technique using mouse cells in 2006, dubbed the new cells “induced pluripotent stem cells” (iPSCs).(1) The same day, Dr. James Thomson of the University of Wisconsin announced success using a slightly different protocol, which was able to forgo use of the potentially carcinogenic c-Myc gene in Dr. Yamanaka’s technique. Dr. Thomson, the first researcher ever to isolate and culture embryonic stem cells from human embryos, in 1998, and define their characteristics, says the new iPSCs “meet the defining criteria we originally proposed for human ES cells, with the notable exception that the iPS cells are not derived from embryos.” (2)

That is a very significant exception indeed, as embryonic stem cells have been the subject of intense ethical and political debate for nine years precisely because they are obtained by the destruction of live human embryos in their first week of development. Critics of human embryonic stem cell research were therefore enthusiastic in greeting the new breakthrough. Said Cardinal Justin Rigali, chairman of the U.S. Catholic bishops’ Committee on Pro-Life Activities:

This technology avoids the many ethical land mines associated with embryonic stem cell research: it does not clone or destroy human embryos, does not harm or exploit women for their eggs, and does not blur the line between human ­beings and other species through desperate efforts to make human embryos using animal eggs. … This advance reminds us once again that medical progress and respect for human life are not in conflict; they can and should support and enrich one another for the good of all. (3)
Similarly, ethically concerned scientists Maureen Condic and Markus Grompe wrote in the Wall Street Journal: “Reprogramming now allows us to exploit the advantages of embryonic stem cells without destroying human embryos. … This new finding offers the best possible outcome to a debate that for too long pitted science and ethics against each other.” (4)

More unexpectedly, scientists who have long promoted human embryonic stem cell research could not restrain their enthusiasm for the new technique, which offers distinct practical as well as ethical advantages over the old approach. Even before the public release of the new studies, for example, Scottish cloning expert Ian Wilmut cited Dr. Yamanaka’s work as a major reason why he is abandoning efforts at human “therapeutic cloning” to devote himself to adult cell reprogramming research. Saying that he found the new approach “extremely exciting and astonishing,” Dr. Wilmut told an interviewer that cell reprogramming, not the cloning of human embryos, represents the future for stem cell research. (5)

In this assessment he was joined by those who discovered the technique. Dr. Thomson is quoted as saying: “The world has changed. … It is the beginning of the end of the controversy that has surrounded this field. Over time, these [induced] cells will be used in more and more labs. And human embryo stem cell research will be abandoned by more and more labs.” (6)

The new technique not only avoids the ethical problem of destroying embryos but has a practical advantage as well. As Medical News Today notes: “The other advantage of the new method is the fact that using cells drawn from the patient’s own skin, the stem cells can be customized to the patient, bringing numerous benefits, such as the elimination of immune system rejection. Thomson put it like this: ‘They are probably more clinically relevant than embryonic stem cells.’” (7)
Thus, the goal long sought unsuccessfully through efforts to clone human human embryos for their stem cells may now be achieved with vastly improved ­efficiency through the iPSC technique.
Even more remarkably, the new advance has allowed some scientists to be more forthright regarding their own moral qualms about destroying human ­embryos—now that they see this practice as unnecessary for advancing pluripotent stem cell research. Dr. Thomson spoke candidly to the New York Times about his own internal struggle:

Similarly, Dr. Yamanaka has recounted the striking story of how he decided to find an alternative to embryo destruction when he was looking at a human embryo through a microscope at a friend’s fertility clinic: “‘When I saw the embryo, I suddenly realized there was such a small difference between it and my daughters,’ said Dr. Yamanaka, 45, a father of two. … ‘I thought, we can’t keep destroying embryos for our research. There must be another way.’” (9) It seems clear that the insight that destroying human embryos poses a moral problem provided a major inspiration for this scientific breakthrough.

To be sure, there are technical problems to be resolved before anyone can contemplate the use of iPSCs in a human therapy. Embryonic stem cells themselves are known to pose a risk of tumor formation when placed in animals, and the use of retroviruses as vehicles for injecting genes into adult cells may increase that risk. Therefore, the next challenge is to perfect another method for transferring such genes to create iPSCs—but most scientists in the field expect this to be achievable in the near future. Says Dr. Douglas Melton of the Harvard Stem Cell Institute, “Anyone who is going to suggest that this is just a sideshow and that it won’t work is wrong.” (10)

The new cells have already passed one important test, by successfully achieving a reversal of disease in an early animal trial. American researchers led by Dr. Rudolf Jaenisch derived iPSCs from mice with sickle-cell anemia, repaired the genetic defect in the cells, then returned them to the mice to reverse the disease.(11)This trial was more successful than an earlier effort to reverse a disease in mice using embryonic stem cells from cloning, which to researchers’ surprise were rejected by the mice despite having the same genetic profile.(12)

But politicians and biotechnology entrepreneurs who have invested money and reputations in research that destroys human embryos will not give up without a fight. “We need to continue to pursue all alternatives as we search for treatments for diabetes, Parkinson’s, and spinal cord injuries,” says Senator Tom Harkin (D-IA), a cosponsor of legislation to encourage destruction of human embryos for their stem cells.(13) A House cosponsor of the same bill, Rep. Diana DeGette (D-CO), is more forceful: “It’s terribly wrong for any politician to be trying to pick and choose one type of ethical research over another,” she says.(14)

Rep. DeGette apparently did not realize that scientists, not politicians, are showing the advantages of the new cells and heaving a sigh of relief over no longer having to be involved in such ethically compromised research. As Dr. Thomson said in one interview: “What a great bookend. Ten years of turmoil and now this nice ending. I can relax now.”(15)

These politicians also forget that, according to the ethical approach promoted by supporters of embryonic stem cell research, what made the destruction of ­embryos ethical in the first place was the argument that there was no alternative. As President Clinton’s National Bioethics Advisory Commission said in 1999: “In our judgment, the derivation of stem cells from embryos remaining following infertility treatments is justifiable only if no less morally problematic alternatives are available for advancing the research. … The claim that there are alternatives to using stem cells derived from embryos is not, at the present time, supported scientifically. We recognize, however, that this is a matter that must be revisited continually as science advances.” (16)

Now that it is clearly time to “revisit” that judgment, some may have become so politically committed to embryonic stem cell research as an end in itself that they have forgotten what the parameters of the debate were supposed to be. If there is another, equally or more promising method for pursuing the research without harming developing human life, the claim that destroying human embryos can still be ethical is false by any ethical theory proposed thus far.

Some supporters of embryonic stem cell research also now insist on emphasizing that the new breakthrough “could not have been possible without research on embryonic stem cells.” (17) The claim is a half-truth at best. Dr. Yamanaka conducted all his preliminary work in mouse cells, using other researchers’ findings regarding the gene expression patterns characteristic of mouse embryonic stem cells. He then tried the same factors in human skin cells, and found to his amazement that they worked without significant changes in the protocol. At no stage did his discovery require specialized knowledge of or research with human embryonic stem cells. “Neither eggs nor embryos are necessary,” he says. “I’ve never worked with either.” (18) If there is any remaining need now to use human embryonic stem cell lines to make additional comparisons between these cells and iPSCs, this can surely be done using the existing embryonic stem cell lines that are eligible for federally funded research under President Bush’s policy. His policy never set any limitations on federally funded research using animal embryonic stem cells.

A rather odd debate has even arisen over whether President Bush deserves some credit for the new breakthrough. Dr. Charles Krauthammer has argued eloquently that this advance vindicates the President’s insistence on finding ethical ways to pursue stem cell research.(19) This argument makes excellent sense. President Bush restrained the ambitions of those who wanted to rely on embryo destruction as the royal road to medical progress; he encouraged scientists to find morally acceptable alternatives (specifically including adult cell reprogramming); he promoted legislation to fund these approaches, ultimately signing an executive order to achieve the same goal last summer when the legislation was stalled; and Dr. Thomson’s new study in adult cell reprogramming was partially funded by the National Institutes of Health under the Bush policy. Yet columnist Michael Kinsley and the editors of the New York Times have indignantly contested this argument, with the Times calling it “far-fetched” without quite managing to explain why. (20) Rep. Michael Castle (R-DE) and Rep. DeGette, cosponsors of the bill to expand funding for embryo-destructive stem cell research, sent the Times editorial to all their House colleagues on December 3.

The argument of these critics is that the entire field of stem cell research would have advanced more rapidly, and be six years further along, if there had been no restraints or limitations at all on publicly funded human embryonic stem cell research from 2001 to the present. But one might as well say, with far more justification, that the diversion of attention and resources into embryo-destructive research could have been avoided altogether many years ago (thus ensuring sustained and potentially unlimited public support and funding for stem cell research) if researchers had used their knowledge of mouse embryonic stem cells the way Dr. Yamanaka has now—to find avenues that avoid destruction of human embryos.
The simple fact is that President Bush, the Catholic Church, and other critics of embryo destruction showed an active interest in Dr. Yamanaka’s adult cell reprogramming approach from the time he announced his results using mouse cells in 2006.(21) More broadly, the entire field of “alternative pluripotent stem cell research” has been championed for years by members of the President’s Council on Bioethics who oppose the destruction of human embryos for stem cell research, most especially by Dr. William Hurlbut of Stanford University.(22) Meanwhile, Reps. DeGette and Castle were calling such research a “highly speculative” and unnecessary diversion from the proven promise of embryonic stem cell research. They led a vigorous campaign last summer in the House of Representatives to defeat a bill, unanimously approved by the Senate, that would have ensured NIH funding for this kind of alternative.(23)
A note to Rep. DeGette et al.: It simply will not do to claim that those who promoted and funded a new breakthrough were actually slowing it down, or that by opposing it you were somehow bringing it about. The principle of noncontradiction applies even in politics.

Legislative Implications of
the Stem Cell Advance

However much some may deny it, the new breakthrough in morally acceptable “pluripotent stem cell” research shifts some possibilities regarding the fate of various bills on bioethics issues.
First, it helps ensure (in case there were any doubt) that President Bush’s veto of legislation funding embryo-destructive stem cell research will continue to be upheld. There were already sufficient votes to uphold the veto before this occurred, and the new advance takes political pressure off the backs of those who have stood firm against making taxpayers support destructive research.

Second, this advance may improve prospects for the Human Cloning Prohibition Act offering a genuine ban on all human cloning (S. 1036, H.R. 2564). The chief argument against a comprehensive ban has been that it may block progress in producing patient-specific pluripotent stem cells for research and therapy; that argument is now much more difficult to make.

Third, and for similar reasons, this advance may improve prospects for S. 2358, the Human–Animal Hybrid Prohibition Act recently introduced by Senator Sam Brownback (R-KS). Senator Brownback has introduced similar legislation before, but his bill’s urgency was underscored recently when the United Kingdom decided to allow researchers to use animal eggs in their efforts to create human embryos by cloning. If such embryos survived at all, they would have the full complement of human nuclear DNA but receive their cytoplasm and mitochondrial DNA from an animal species (leading some to coin the term “cytoplasmic hybrid,” or “cybrid”). No such efforts to blur the line between human and animal species could have “­therapeutic” justification if the entire project of human embryo cloning is rendered obsolete by iPSCs. The Brownback legislation is supported by an interesting combination of pro-life and religious groups (including the U.S. Conference of Catholic Bishops) and environmental groups such as Friends of the Earth. (24)

Fourth, this renewed emphasis on alternatives to embryonic stem cells might draw new attention to the Patients First Act (H.R. 2807) sponsored by Rep. Randy Forbes (R-VA), which now has twenty-four House cosponsors. This bill gives priority attention to non-embryonic stem cell research with “potential for near-term clinical benefit in human patients, as indicated by substantial evidence from basic research or by substantial clinical evidence,” such as documented evidence of improvement in human patients. Not to be forgotten in the excitement over iPSCs is the fact that adult and cord blood stem cells are still the gold standard for stem cell treatments in human patients, and are likely to remain so for years or decades to come.

Other Cloning Developments

Two new developments in cloning provide additional reasons why major proponents of “therapeutic cloning” like Ian Wilmut are abandoning the field.

First, Dr. Kevin Eggan recently revealed that, despite a year and a half of ­effort and a $100,000 advertising budget, he and his colleagues at the Harvard Stem Cell Institute have failed to persuade even one woman to undergo superovulation and donate her eggs for human cloning research. “We’ve had hundreds of calls from women who are interested in donating, but when they find out about the time, effort, and pain involved, they simply can’t take the time to go forward,” he said. He blamed this failure on Massachusetts regulations forbidding cash payments to these women—suggesting that the human embryo cloning project will not advance without broaching yet another ethical norm, risking the financial exploitation of poor women to obtain “material” for research. (25)

Second, a team led by Shoukhrat Mitalipov at Oregon Health and Science University reported the first success in obtaining embryonic stem cells from cloned monkey embryos. While hailed by scientists as a “proof of principle” that cloning from adult cells is possible in primates, the study also illustrated the enormous inefficiency and cost of any attempt to translate this approach into human therapies. The team used a total of 304 eggs to obtain just two cell lines, prompting cloning expert Alan Colman to comment, “It didn’t give me much encouragement that the technique would be worth pursuing in humans because the numbers are so poor.” (26) Colman’s former colleague Ian Wilmut clearly agrees.

Note that cloning’s potential for producing genetically tailored stem cells for individual patients has been seen by many as essential to solving the problem of tissue rejection using embryonic stem cells. If cloning human embryos for their stem cells is too wasteful, inefficient, and controversial to become a practical path to individualized therapies, the prospect of any therapies from current embryonic stem cell research is also thrown into serious doubt.

New VCU Poll on Stem Cell
Research and Biotechnology

On December 19, 2007, Virginia Commonwealth University released the latest version of its Life Sciences Survey, a telephone poll of one thousand adults nationwide that it has conducted every year since 2001.(27) The survey shows deep public ambivalence about unfettered research freedom in areas such as stem cell research, as well as the volatility of poll responses based on how questions are asked.
Three-quarters of respondents (75 percent) said they favor “medical research that uses stem cells from sources that do NOT involve human embryos,” although the poll did not really explain what that might mean; only 38 percent of respondents said they had heard of the new research showing that “human stem cells can also be made from adult skin cells.” Fifty-four percent said they also favor medical research using “stem cells from human embryos,” and only 39 percent said they oppose it. However, in a later question about policy priorities, 46 percent said that “making sure no embryos are destroyed in this research” is more important than “conducting research that might result in new advances,” with only 42 percent saying that new advances are more important; 52 percent of women said protecting the embryo is more important than research advances.

One explanation for this discrepancy is that the earlier question used a e­uphemism about cells “from” embryos, while the later question noted that embryos are “destroyed” in the process. Interestingly, while the poll’s 54 percent support for research using stem cells “from” embryos has been fairly consistent over several years, the new poll shows only 21 percent “strongly” favoring such research, the lowest figure since 2003.

On broader issues, 46 percent of respondents said that government regulation of scientific research is necessary to protect the public interest, while 39 percent said such regulation “usually does more harm than good.” The statement that “rules set by government will keep us safe from any risks linked to modern genetic science” garnered only 16 percent agreement, while 57 percent disagreed.

Respondents were also asked whether decisions about science and technology should primarily be made on the basis of “an analysis of the risks and benefits involved,” or on the basis of “the moral and ethical issues involved” (a false dichotomy if there ever was one); 51 percent chose the former while 32 percent chose the latter. Yet 63 percent said they agree with the statement, “Scientific research these days doesn’t pay enough attention to the moral values of society.” And 53 percent agreed with the statement that “Scientific research has created as many problems as it has solutions.”

These ambivalent answers should not bring great comfort to supporters or opponents of controversial research such as that using human embryonic stem cells. Rather, they suggest that the battle over ethically responsible restraints on biotechnology has yet to be won or lost. But the American people have not yet bought into the simplistic view defended by embryonic stem cell supporters like Senator Arlen Specter (R-PA), that all forms of stem cell research must be supported because “­science ought to be unfettered.” (28)

Richard M. Doerflinger

1 - K. Takahashi et al., “Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors,” Cell 131.5 (November 30, 2007): 861–872; published online November 20, 2007; abstract at http://www.cell.com/content/article/abstract?uid=PIIS0092867407014717. For an overview of Dr. Yamanaka’s previous work in this field and its implications, see Rev. Nicanor Pier Giorgio Austriaco, O.P., “Notes & Abstracts: Science,” in National Catholic Bioethics Quarterly 7.3 (Autumn 2007): 569–571.

2 - J. Yu et al., “Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells,” Science 318.5858 (December 21, 2007): 1917–1920; published online November 20, 2007; abstract available at http://www.sciencemag.org/cgi/content/abstract/1151526.

3 - U.S. Conference of Catholic Bishops, “Stem Cell Breakthrough Advances Science without ‘Ethical Landmines,’ Says Cardinal,” press release, November 20, 2007, http://www.usccb.org/comm/archives/2007/07-194.shtml.

4 - Maureen Condic and Markus Grompe, “Stem-Cell Breakthrough,” Wall Street Journal, November 23, 2007, A13.

5 - Roger Highfield, “Dolly Creator Prof. Ian Wilmut Shuns Cloning,” Telegraph (London), November 16, 2007, http://www.telegraph.co.uk/earth/main.jhtml?xml=/earth/2007/11/16/scidolly116.xml&page=1.

6 - Colin Nickerson, “Breakthrough on Stem Cells,” Boston Globe, November 21, 2007, http://www.boston.com/news/science/articles/2007/11/21/breakthrough_on_stem_cells/.

7 - Catharine Paddock, “Reprogrammed Skin Cells Could Replace Embryonic Stem Cells,” Medical News Today, November 26, 2007, http://www.medicalnewstoday.com/articles/89799.php.

8 - Gina Kolata, “Man Who Helped Start Stem Cell War May End It,” New York Times, November 22, 2007, http://www.nytimes.com/2007/11/22/science/22stem.html.

9 - Martin Fackler, “Risk Taking Is in His Genes,” New York Times, December 11, 2007, http://www.nytimes.com/2007/12/11/science/11prof.html.

10 - Gina Kolata, “Scientists Bypass Need for Embryo to Get Stem Cells,” New York Times, November 21, 2007, A21; http://www.nytimes.com/2007/11/21/science/21stem.html.

11 - J. Hanna et al., “Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin,” Science Express, published online December 6, 2007; abstract available at http://www.sciencemag.org/cgi/content/abstract/sci;1152092v1.

12 - See Gretchen Vogel, “Reprogrammed Skin Cells Strut Their Stuff,” ScienceNOW Daily News, December 6, 2007, http://sciencenow.sciencemag.org/cgi/content/full/2007/1206/2. Dr. Jaenisch’s earlier failed effort to achieve similar results using embryo cloning prompted this comment from other stem cell experts: “Jaenisch addressed the possibility that ES clones derived by nuclear transfer technique could be used to correct genetic defects in the hematopoietic system. … However, the donor cells, although derived from the animals with the same genetic background, are rejected by the hosts.” R. Tsai, R. Kittappa, and R. McKay, “Plasticity, Niches, and the Use of Stem Cells,” Developmental Cell 2.6 (June 2002): 710.

13 - Senator Tom Harkin, “Harkin Statement on Stem Cell Science Breakthrough,” press release, November 20, 2007, http://harkin.senate.gov/pr/p.cfm?i=287838.

14 - Laurie Kellman, “Stem Cell Breakthrough Could Benefit GOP,” Associated Press, November 20, 2007; available at http://www.boston.com/news/nation/articles/2007/11/20/stem_cell_breakthrough_could_benefit_gop/.

15 - Rick Weiss, “Advance May End Stem Cell Debate,” Washington Post, November 21, 2007, A4.

16 - National Bioethics Advisory Commission, Ethical Issues in Human Stem Cell Research, vol. 1, Report and Recommendations (Rockville, MD: NBAC, 1999), 53; http://bioethics.georgetown.edu/nbac/stemcell.pdf.

17 - “Stem Cell Breakthrough,” editorial, Washington Post, November 24, 2007, A16.

18 - Catharine Paddock, “Scientists Make Stem Cells from Skin of Mice Instead of Embryos,” Medical News Today, June 7, 2007, http://www.medicalnewstoday.com/articles/73381.php.

19 - Charles Krauthammer, “Stem Cell Vindication,” Washington Post, November 30, 2007, A23, http://www.washingtonpost.com/wp-dyn/content/article/2007/11/29/AR20071129 01878.html.

20 - “Behind the Stem Cell Breakthrough,” editorial, New York Times, December 1, 2007, http://www.nytimes.com/2007/12/01/opinion/01sat1.html; Michael Kinsley, “Why Stem Cells Are Still a Sticky Issue,” Time, November 29, 2007, http://www.time.com/time/magazine/article/0,9171,1689196,00.html. Kinsley also repeats the charge that “the new research would not have been possible without the kind involving embryonic stem cells, which Bush believes is immoral.” The new research relied on research in mouse embryonic stem cells, to which the President has never raised a moral objection.

21 - At the invitation of the Pontifical Academy for Life, Dr. Yamanaka presented his preliminary findings at a September 2006 stem cell conference that the Academy cosponsored in Rome, where Pope Benedict XVI expressed his strong support for stem cell research that does not harm human life. See Final Programme for the International Congress, “Stem Cells: What Future for Therapy?” September 14–16, 2006, http://frblin.club.fr/fiamc/stemcells/programme.pdf. Pope Benedict’s address can be found at http://www.stemcellsrome2006.org/registrazione_ENG.htm.

22 - See, for example, the President’s Council on Bioethics, Alternative Sources of Human Pluripotent Stem Cells: A White Paper (Washington, D.C., May 2005), http://www.bioethics.gov/reports/white_paper/alternative_sources_white_paper.pdf.

23 - See Richard M. Doerflinger, “Anti-Life, Anti-Science,” National Review Online, July 19, 2006, http://article.nationalreview.com/?q=ZGE1Zjc4YjljYTc2YjI2ZTQzOGQ4YmI1Z GYzZGE3ZWM=.

24 - For more on this legislation, see Richard M. Doerflinger, “Human–Animal Hybrids in the U.S.? The Need for Anti-Cloning Legislation,” Ethics & Medics 33.2 (January 2007): 3–4.

25 - Emily Singer, “Human Therapeutic Cloning at a Standstill,” Technology Review, October 9, 2007, http://www.technologyreview.com/Biotech/194880/.

26 - Monya Baker, “Monkey Embryonic Stem Cells Cloned,” Nature Reports Stem Cells, published online November 21, 2007, http://www.nature.com/stemcells/2007/0711/071121/full/stemcells.2007.119.html.

27 - Virginia Commonwealth University, “Widespread Support for Non-Embryonic Stem Cell Research, VCU Life Sciences Survey Shows,” press release, December 19, 2007, http://www.news.vcu.edu/news.aspx?v=detail&nid=2322. For survey questions and responses and an executive summary, see http://www.vcu.edu/lifesci/images2/survey2007.pdf.

28 - Sheryl Gay Stolberg, “Method Equalizes Stem Cell Debate,” New York Times, November 21, 2007, A21.