Scientists believe that chemical factors in embryonic stem cells have the power to turn the right genes on and off in the nucleus of an adult cell so that it can be turned back into a pluripotent stem cell. By taking an adult cell, such a skin cell, and fusing it with a stem cell, scientists should be able to create pluripotent stem cells that are the exact genetic match of the original adult cell. This would enable scientists to learn more about various diseases by producing and studying stem cells that have the genetic makeup for those diseases and to produce genetically matched cells for possible immune-free transplantation into patients. It thus gives us all the hypothetical benefits of research or "therapeutic" cloning without creating and destroying cloned embryos. Another approach to turning adult cells into pluripotent stem cells would be to use factors extracted from human eggs as the reprogramming agent.

Kevin Eggan of the Harvard Stem Cell Institute has announced that his lab has successfully fused a human embryonic stem cell to an adult skin cell, an announcement he made at the third annual meeting of the International Society for Stem Cell Research in San Francisco on June 24, 2005. "Eggan showed that the embryonic stem cell 'reprogrammed' the skin cell's nucleus, causing the skin cell to start behaving like a youthful, embryonic stem cell," according to an article on news@nature.com (Erika Check, "Rebooted Cells Tackle Ethical Concerns," June 27, 2005).

The cells produced by Eggan's team are still of limited use, because they contain the genes of the both the adult cell and the stem cell, twice the amount found in normal cells. But Alan Trounson of Monash University in Australia says he has developed a simple way to remove the stem cell's DNA after the skin cell's genes have been reprogrammed, according to the Washington Post. In addition, Yuri Verlinsky of the Reproductive Genetics Institute in Chicago reported at a meeting last month that he has succeeded in making new human embryonic stem cells by first removing a stem cell's DNA before fusing it with it with a human skin cell. He has not finished the tests that would show whether or not these new cells can function the same way that embryonic stem cells do, but according to Verlinksy, the tests that have been done so far indicate that they do (Rick Weiss, "Stem Cell Advances May Make Moral Issue Moot," Washington Post, June 6, 2005).

The President's Council on Bioethics found this approach to be ethically unproblematic and acceptable for use in humans, provided scientists are able to turn the adult stem cells back to a pluripotent state but not a "totipotent" or embryonic state, and if existing embryonic stem cell lines are used for cell fusion rather than creating new lines that require the destruction of human embryos. (See Proposal IV in the Council's report.)

2) Engineering nonembryonic biological artifacts

The second approach that has been widely discussed is bioengineering a "nonembryonic" entity that nonetheless can produce pluripotent stem cells. (See Proposal III in the Council's report.) Such entities exist in nature. For instance, a teratoma is a kind of tumor that produces even more advanced tissue and body parts, but no physician would consider a teratoma a living being.

One proposal that adopts this approach is called "altered nuclear transfer" or ANT, and has been put forward by William Hurlbut, a physician, bioethicist, and member of the President's Council on Bioethics. As with somatic cell nuclear transfer, or cloning, in altered nuclear transfer scientists would take the nucleus of an adult cell and place it in an egg cell whose own nucleus has been removed. But first, unlike in cloning, they would alter either the adult cell nucleus or the egg before transfer to prevent the creation of an embryo.

Hurlbut's proposal is a broad concept with a range of possible approaches, and the President's Council on Bioethics has recommended that this proposal be tested in animal cells first to demonstrate that the developing entity that is produced is truly not a human embryo and that the cells derived from it are normal human pluripotent cells.

One recently proposed variation of ANT is called "oocyte assisted reprogramming" (OAR) and was described in a Wall Street Journal op-ed by Markus Grompe, one of the country's leading stem cell researchers, and Robert George, a member of the President's Council on Bioethics. In this method, as with cloning, the nucleus of an adult cell is put into an egg cell whose own nucleus has been removed. But first, the relevant genes inside the adult cell's nucleus are switched on and off so that the egg cell would turn the adult cell directly into a pluripotent stem cell rather than an embryo. Grompe estimates that this method can be tested in animals in a year, and in humans in another year ("Creative Science Will Resolve Stem-Cell Issues," Wall Street Journal, June 20, 2005).

One moral objection that could be raised to both ANT and OAR is that it requires the use of human eggs. Some object to the use of human eggs for research because they are currently obtained by superovulating women, a procedure that is often painful and sometimes dangerous. The proponents of ANT and OAR, including Hurlbut, oppose superovulating women to obtain eggs for experimentation because it is medically risky and the long term effects on women are not well known. However, there may eventually be abundant sources of eggs from alternative sources. Recent studies suggest the procedure could be done with immature eggs that are left over from IVF procedures. Eggs might also be obtained from laboratory stimulation of ovarian tissues obtained during surgical removal of the ovaries for therapeutic reasons. Slices of ovarian tissue from mice have been cultured in vitro and yield a large number of eggs. This is proving more difficult with human ovarian tissue, but there are signs of progress. In the meantime, eggs might also be donated by women whose ovaries are surgically removed or taken from cadavers.

Like the first method, ANT and OAR would allow scientists to create stem cells with a full range of genetic types and with full control over the genetic makeup of the resulting stem cell lines.

3. Extracting stem cells from IVF embryos that are already dead

Many embryos frozen in IVF clinics are, in fact, already dead, and yet it might still be possible to derive useful stem cells from them. Before this approach can be carried out, scientists will have to develop non-invasive, non-harmful tests for determining embryo death. According to the President's Council on Bioethics, this method would require significant safeguards to ensure that only those embryos that die on their own are used, rather than using those spares that "are going to die anyway" but are not really dead. Another drawback of this proposal is that it would not allow scientists to control the genetic makeup of the stem cell lines produced, as they could with the previous two proposals. (See Proposal I in the Council's report.)

4. Extracting a single stem cell from early-stage embryos using a non-lethal biopsy technique

According to this proposal, a single stem cell (or "blastomere") could be removed from an early embryo that consists of at most eight cells (or "blastomeres") and then grown to produce useful pluripotent stem cells. Single blastomeres are already being removed from in-vitro embryos for genetic testing before implantation. However, it is too early to know whether there might be negative health effects on the born children as a result of this procedure. The Council found this proposal to be ethically unacceptable in humans because of the risks imposed by "embryo biopsy and blastomere removal on the born child the embryo might become, solely for research of no benefit to him or her." The Council saw no ethical reason why the approach could not be tried in animals, but did not see "how results from animal experimentation could alter this assessment of ethical propriety in humans." (See Proposal II in the Council's report.)

CONTACT:
MARY SCHWARZ
MEDIA CONSULTANT
ETHICS AND PUBLIC POLICY CENTER
(917) 526-3115