Two years ago, William Saletan¯Slate.com’s science reporter¯compared the typical approaches of Jewish and Catholic thinkers to bioethical questions . "The Catholics were clear about what was moral and what wasn’t. The Jews were fuzzy." He quoted Eric Cohen, a Jewish bioethicist, saying Jews ask lots of questions; and while Catholics may pose questions too, Catholics give answers . These answers weren’t coming from sources of revelation, but from science and reason. Catholics had a profound faith in reason, and in reason’s ability to answer profound questions of the day. Throughout the three-day conference I just attended, I witnessed a similar phenomenon.
Under the leadership of Fr. Thomas Berg, L.C., the Westchester Institute recently convened a Scholars Forum focusing on the meaning of totipotency : What does it mean to be totipotent, and how do we know when a cell (or clump of cells) is totipotent? What does it mean to be a human embryo, and how do we know when a cell (or clump of cells) is one? The conference gathered academics on the cutting-edge of scholarship relating to these questions: Molecular biologists, stem-cell scientists, medical doctors, philosophers, theologians, and legal scholars all brought their distinctive perspectives and expertise to bear on a question that requires real interdisciplinary collaboration. And while the conference was sponsored by a Catholic institution, the participants included non-Catholics, and non-Christians too.
Princeton professor Robert P. George moderated the sessions, while Markus Grompe, M.D. (a leading stem-cell scientist, a member of the board of the International Society for Stem Cell Science, and director of the Oregon Stem Cell Center), and Bill Hurlbut, M.D. (a professor at Stanford, a member of the President’s Council on Bioethics, and the creator of the ANT stem-cell proposal ), took leading roles in responding to presentations. Presentations were made by Professors Stuart Newman; Maureen Condic; Nicanor Austriaco, O.P.; Kevin Fitzgerald, S.J.; Shoukhrat Mitalipov; and Patrick Lee (five scientists and one philosopher). A dozen other scholars contributed to the discussions, and Fr. Kevin Flannery, S.J., professor of philosophy at the Pontifical Gregorian University in Rome, participated via teleconference. Like I said, it brought together some of the best and the brightest.
The impetus behind the conference was to clarify the biological criteria for evaluating proposed ethical alternatives to embryo-destructive research. To do so, one has to get clear about certain scientific concepts. A totipotent cell (a one-celled embryo, a zygote) is a complete organism possessing the genetic and epigenetic program to develop in a species-specific way to the mature stage of the organism. A totipotent human cell, it follows, possesses the active disposition to develop himself or herself (since sex is determined at conception) into a human adult. This is why no one is surprised when an IVF embryo that is transferred into a womb matures and nine months later is a bouncing newborn and nine years later is a rambunctious child. The embryonic human develops into an adult simply by growing and maturing, not by transforming into some other kind of entity. A totipotent human cell is already a human being, but a human being at the very earliest, most developmentally immature stage of existence.
The problem is that a four-day-old human being has some very valuable parts. Scientists can extract cells (called blastomeres) from the inner cell mass of the embryo, isolate them, and transform them into stem cells. But as things are currently done, to get these stem cells you have to kill the embryonic human being. It appears, though, that scientists may be able to get these cells without creating or destroying embryonic humans. Science could move forward and human life could be protected.
The phrase "human life" is imprecise. Every human cell is "human life" in some sense: a skin cell, for example, is genetically human and is living material. But very few cells (or groups of cells) are human beings . To be a human being it is not enough simply to have a human genome. In addition to the genome, the epigenetic state of the cell must be such that it is oriented to develop toward maturity as a member of the species. Human skin cells are genetically human but (due to their epigenetic state) are merely parts of a human being¯not the human being itself.
Stem-cell scientists have been hankering for embryonic stem cells because these cells are pluripotent ¯that is, capable of being manipulated into most any type of bodily tissue, but not capable (or actively striving) to develop into a mature organism (as totipotent cells are). The question is whether we can get pluripotent cells without creating and destroying human embryos.
This is where the conference’s conversation focused: What are the biological indicators of totipotency? What are the biological indicators of pluripotency? And how can we detect these? Two years ago, Bill Hurlbut proposed one such measure¯ Altered Nuclear Transfer (ANT). This proposal was to create an "embryonic-like" artifact whose epigenetic state was such that the entity was not oriented to develop toward maturity, and thus would not be a human being. As "embryonic-like," it could mature a little bit, far enough along that blastomeres could form, which could then be harvested. Some feared, though, that this wouldn’t create non-embryonic entities but disabled embryos.
That’s when Altered Nuclear Transfer-Oocyte Assisted Reprogramming (ANT-OAR) came on the scene. The idea here wasn’t to create a biological artifact that could serve as source material to harvest embryonic stem cells, but rather to produce "embryonic" (pluripotent) stem cells ab initio ¯right from the start, and from scratch. Because of increasing knowledge of epigenetics, scientists now know that cells are much more plastic than previously thought. While every human cell contains all the same genetic information, how this information is expressed¯which genes are "turned on" and which "turned off," how "strongly" they are manifested, etc.¯is a function of their epigenetic state. Scientists also know that certain proteins¯called transcription factors¯are responsible for causing a cascade of genetic expression, as they regulate which genes are turned on or off and to what degree. This knowledge allows scientists to "reprogram" cells back to "earlier," more plastic, states. Thus, a skin cell (a highly specialized cell) could be reprogrammed to a pluripotent state, from which it could be specialized into other cell types.
Concretely, the proposal is to alter a regular somatic (body) cell’s nucleus to eliminate certain transcription factors (like cdx2) and over-express others (like nanog or oct 3/4). Having first altered the nucleus’s genome, scientists would then transfer it into an enucleated oocyte. A new cell would be formed, and the cytoplasm inside it would work to reprogram the cell to a pluripotent state. How can we know? Because the transcription factor cdx2 is necessary for the epigenetic state of a cell to be totipotent, and transcription factors like nanog and oct3/4 are responsible for instructing a cell to be pluripotent. Since the cell never had any cdx2 but had nanog, it could never have been totipotent, only pluripotent. In fact, nanog is never found in oocytes or zygotes, but it is always found in pluripotent stem cells. When its expression is forced from the very beginning of a cell’s existence, we can be sure that the new cell is not totipotent but pluripotent. It’s not an embryo; it’s a non-embryonic, highly plastic cell.
This proposal has been around for a couple of years now, and not everyone in the pro-life community is convinced of its ethical validity. Some fear it still creates a disabled embryo, and that the resulting cell passes through a totipotent stage before reaching pluripotency. These objections have been raised largely by the editors and contributors to the theological journal Communio . But in a number of exchanges in Communio , the National Catholic Bioethics Quarterly , and our own pages , these objections have been put to rest (at least to my satisfaction, and that of the scholars at the Westchester gathering, including Fr. Tad Pacholczyk, a Yale-trained scientist and influential bioethicist who rejected the original Hurlbut proposal but believes that ANT-OAR eliminates the risk of creating a defective embryo, rather than a truly non-embryonic artifact).
It’s important to keep in mind that the real potential for embryonic stem cells does not lie in therapeutic cures. This was one thing all the scholars at the conference could agree on¯including those who were not morally opposed to all embryo-destructive research. Last fall, in the pages of First Things Dr. Maureen Condic rigorously detailed the scientific hurdles embryonic stem cells face and gave reasons why these hurdles were unlikely to be cleared. In an unsigned editorial in Nature Neuroscience the editors faulted Dr. Condic for writing the article, though they didn’t dispute a single argument or claim her evidence was wrong. Nonetheless, they attacked Dr. Condic in a clear attempt to damage her reputation. ( Nature Neuroscience is not devoted to stem cell research but is a journal in Professor Condic’s main field of research¯read by her colleagues and those who review her proposals for research grants and academic promotion.) Condic’s crime? Reporting scientific facts the scientific establishment would prefer the American public not know.
Nevertheless, pluripotent stem cells created by ANT-OAR would suffer the same hurdles that Dr. Condic outlined (though preliminary results indicate they would face fewer of them). Scientists are aware that embryonic stem cells may never be used therapeutically, but they want them all the same. Even if they never provide cures, they will be valuable as tools to increase our knowledge of embryogenesis and cellular life. The Westchester group is seeking a way to produce these stem cells ethically.
The conference was a chance for various experts to report on the latest scientific developments on stem-cell research and the ANT-OAR proposal. It was also an opportunity to clarify the science behind totipotency and pluripotency, and discuss how best to determine the genetic and epigenetic state of a cell. Various proposals were put forth, objections were raised, and progress was made. Many questions still remain, and the scholars are hard at work.
William Saletan should be happy to know that the Westchester group remains firm in their faith that science and reason will help lead us out of our current stem-cell dilemmas.