On June 20, President Bushed issued an executive order directing the secretary of the Department of Health and Human Services to expedite the funding of research into ethically acceptable alternatives to embryo-destructive stem cell research. I dedicated a column to this issue last August which you can read here. Executive order 13435 also directs the secretary to rename the "Human Embryonic Stem Cell Registry" as the "Human Pluripotent Stem Cell Registry."

For stem cell researchers, pluripotent cells are the gold hidden in the hills—and this biotech gold rush has been on in earnest since the late 1990’s. Harnessing the properties of these cells will conceivably lead to controlled growth of all the tissues in the human body and, therefore, to virtually unlimited therapeutic applications for diseases and conditions treatable by tissue replacement.

So, the change of nomenclature—from “embryonic” to “pluripotent”—is far more than mere wordsmithing. All indications are that it will have far-reaching implications for the future of the science and for our on-going national debate over ethical stem cell research. As Monya Baker has pointed out in a recent Nature Reports Stem Cell article, “Politics has, essentially, mandated that an answer be found to a fundamental scientific question.”

But, let’s back up a few steps to better understand what this all means.

First of all, the “registry.”

On August 9, 2001, President Bushed announced to the nation his decision to allow a limited amount of federal money for embryonic stem cell research—a policy he hoped would ultimately discourage the destruction of human embryos for research. Since then, the administration has made more than $130 million available for research on stem cell lines derived from human embryos—but embryos that had been destroyed prior to the President’s policy statement on August 9. Additionally, the administration has provided more than $3 billion for research on all forms of stem cells—including those from non-embryonic sources.

At the time, estimates suggested that upwards of 60 such lines of human embryonic stem cells were already in existence and available for research. Then, on November 7, 2001, the National Institutes of Health (NIH) launched the Human Embryonic Stem Cell Registry. The registry would, from then on, list all the stem cell lines eligible for federally funded research, along with information regarding the origins of the lines, the labs where they can be found and other information useful for researchers. Inclusion of a line of stem cells on the registry means automatic prestige for the lab that created them—a scientific imprimatur of sorts that the cells of genuine, and that research on them is eligible for coveted NIH funding.

Until June of 2007, the registry was limited to bona fide human embryonic stem cells already in existence prior to the August 9, 2001 Bush policy statement. The administration, genuinely desirous of increasing the number of available cells lines, wants to open the registry to candidate cell lines purported to hold the same key property of human embryonic stem cells—“pluripotency”—but which are derived from non-embryonic sources. In doing so, the administration is countenancing the genuine possibility that stem cell science has indeed discovered non-embryonic sources of such cells in the human body.

Consequently, inclusion of any such cells on the registry will constitute nothing short of a scientific endorsement that any new cells lines added meet a scientifically acceptable definition of “pluripotency.” And this is huge news for science, and for our nation which has been wrapped up in a bitter debate over the use of human embryos for stem cell research. Indeed, the pro life movement has correctly asserted for years that if science could discover adult (non-embryonic) sources of genuinely pluripotent stem cells in the human body, then the supposed urgency of creating new lines of embryonic stem cells would be largely quelled.

The crucial upshot, however, is the following: the change of nomenclature forces the NIH—specifically the NIH Stem Cell Task Force—to come up with a new workable definition of “pluripotency”. If this surprises you, it should. Here’s why.

The key question, of course, for most stem cell researchers is whether your newly derived cells (whether obtained from human embryos, or from certain non-embryonic sources such as the bone marrow or amniotic fluid) are truly pluripotent. It turns out, however, that the concept of pluripotency has always been somewhat fluid in the stem cell world. Consensus had generally settled on now standard definitions such as that proffered by the International Society for Stem Cell Research (ISSCR) in its December 2006 Guidelines for embryonic stem cell research: “The state of a single cell that is capable of differentiating into all tissues of an organism, but not alone capable of sustaining full organismal development.” The NIH currently defines a pluripotent cell this way: “Ability of a single stem cell to give rise to all of the various cell types that make up the body.” Such definitions were backed by a laboratory test for pluripotency. For many years, that standard test had been a procedure in which the candidate cells are placed subcutaneously in laboratory mice. Allowed to grow, if truly pluripotent, the cells would form a benign tumor known as a teratoma. If the excised tumor, upon examination, showed the presence of tissues whose sources were the three fundamental embryonic germ layers, then the cells were deemed to be pluripotent.

Very recently, however, researchers have settled on a new gold standard test called “tetraploid complementation.” Although it’s a mouthful, it is not that difficult to understand. It works like this. A tetraploid embryo is formed from the forced fusion of the two cells (blastomeres) of a normal (diploid) embryo when it is at the two-cell stage. The fusion of the two cells constitutes a single-cell embryo that contains twice the normal amount of DNA (literally, 92 chromosomes instead of the normal complement of 46; hence the term “tetraploid” embryo). The tetraploid cell, at this point, if allowed to continue development by itself, is not in a position to contribute to the formation of a fetal body, but only to the extra-embryonic membranes and tissues (such as the placenta). Researchers then take the cells they believe to be pluripotent and inject them into this tetraploid embryo as it reaches 5 or 6 days of development. The injected cells, if added in sufficient numbers, form an inner mass within the tetraploid host, and—if truly pluripotent—will go on to develop into a fetal body and eventually be born as a mouse pup.

This is proof in the pudding that the candidate cells were truly pluripotent, as they contributed to the entire new organism except for its placenta and related parts. The defectiveness of the older test was determined when it was found that at times, in mice, the same cells that would form teratomas were unable to generate full grown mouse pups.

The problem now facing the NIH is that the current best test hands down—tetraploid complementation—cannot be used with human cells. Everyone on all sides agrees (we should be grateful) that recourse to such a test would be unethical: we would literally have to grow a batch of the candidate cells into a human being within a host tetraploid embryo and see if the tiny human individual would survive to gestation and live birth—just as is typically done in mice.

Hence the current challenge: to settle on a definition and test for pluripotency that will apply to human candidate cells with the same rigor as tetraploid complementation. What new set of criteria for pluripotency the NIH will settle on remains to be seen. A better part of the stem cell world sees this new move by the Administration as a needless distraction, and a ploy to cover for its refusal to fund embryo-destructive research. Other scientists see it as an opportunity. We have no doubt that there are, indeed, scientists chomping at the bit to step forward and show the world their embryo-friendly, pluripotent stem cells. Over the past two years, I have seen a fairly steady flow of articles in scientific journals asserting the existence of just such cells. We now anxiously await to see if any of these cells rise to a new and scientifically rigorous standard of pluripotency. If that happens, a new day will have dawned in our efforts to curb embryo-destructive research.

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