The Beginning of the End of the Stem Cell Wars?

Syndicated columnist and one-time member of the President’s Council on Bioethics, Charles Krauthammer drew fire for a Washington Post op-ed published last Friday in which he asserted that a recent embryo-friendly breakthrough in stem cell research—somatic cell reprogramming—vindicates the Bush stem cell policy, and claimed that “the embryonic stem cell debate is over.” Since the breakthrough was announced two weeks ago, we have now come to understand that, while the former claim may be true, the latter one is clearly not. That notwithstanding, and if euphoria evidently led many of us to believe for a fleeting day or two that we had definitively reached “the end of the stem cell wars,” it is not unreasonable to believe that we find ourselves at least at the beginning of the end.

We need to consider very carefully the two principal reasons why the “wars” are not yet over and why we will need to work even harder to rein in the cultural scourge of embryo-destructive research.

First of all, the specter of human cloning looms near.

The recent breakthroughs in human reprogramming reported just before Thanksgiving in papers published by Shinya Yamanaka of Kyoto University, and by James Thomson of the University of Wisconsin, Madison have offered proof of principle that we now have a scientifically viable alternative to human “therapeutic” cloning (SCNT), and an alternative of such potential magnitude in terms of cost-effectiveness and simplicity—not to mention ethical integrity—that it could render moot the putative “need” for cloning. That theoretical success, however, will do little to stop the impetus of science to move ahead with human SCNT, especially now that recent research has apparently cleared any remaining obstacles to the cloning of primates and deriving viable lines of stem cells from the cloned embryos. Researchers now suspect that it will not be long—perhaps within the coming year—before these technological advances lead to successful human “therapeutic” cloning. Unless researchers now actively pursuing human cloning run into as yet unforeseen technical barriers, the successful cloning of human embryos appears inevitable.

Second of all, consider that the ‘holy grail’ of stem cell science has been a technique that would allow scientists to create stem cells genetically matched to a sick patient, and then grow and develop these cells into tissues for use in tissue replacement therapies (everything from regeneration of damaged heart tissue to Parkinson's to spinal-cord injury). A perfect genetic match, these tissues would not be rejected by the donor's immune system. The advent of somatic cell reprogramming would now appear to allow scientists to do just that, and to have stolen the prize from the human cloning enterprise—a technique that would conceivably afford the same benefit. We have to recognize, however, that while the ‘holy grail’ is certainly within reach of the reprogramming scientists, it is not yet in hand.

To be sure, the science of reprogramming still requires substantial refinement. Reprogrammed skin cells, the kind recently produced by Yamanaka and Thomson, are referred to as induced pluripotent stem cells (iPSCs). They are “pluripotent,” capable of producing all the tissue-types in the human body. However, multiple scientific studies show that all pluripotent cells, including human embryonic stem cells (hESCs), form tumors (teratomas) and can convert to cancer cells. Westchester Institute Senior Fellows Maureen Condic and Markus Grompe have pointed out to us that the risk of tumor formation may, at this time, be higher in iPSCs than in hESCs because the genes used for reprogramming remain inserted in the reprogrammed cells. However, leading stem cell biologists are optimistic that they can modify the iPSC technique to eliminate any added risk of tumor formation. Dr. Douglas Melton, co-director of the Harvard Stem Cell Institute, predicts this problem will be “solved quickly, maybe within a year or so” (AP, 22 November 2007), also noting: “Anyone who is going to suggest…that it won’t work is wrong” (New York Times, 21 November, 2007). Rudolf Jaenisch, a leading stem cell researcher at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts concurs, stating: “I don't think it is a big hurdle” (Washington Post, 21 November 2007). The ideal way to reprogram will ultimately be one which does not involve the insertion of genes (or the viruses that transport them) into the somatic cells at all. You have to believe that stem cell scientists are hard at it right now trying to make this work. The day we can reprogram stem cells this way, will be the day we have the holy grail in hand. While we don’t know how long it will take, the optimists say this too could happen within the coming year.

That said, however, let’s consider a number of key reasons why the advent somatic cell reprogramming could be the beginning of the end of the stem cell wars:

1- Advances in reprogramming undermine continued scientific claims regarding the putative superiority of hESC research.

In a response to the Krauthammer op-ed, Susan Solomon and Zach Hall purport to know that human ESC research is that which “remains the most promising and important.” Now, neither they nor any of us can look into a crystal ball and say which form of stem cell research known today holds most “promise.” And of course, their assertion begs the further question: what counts for “important” stem cell research these days, anyway? In the field, what counts today is not that stem cells be “embryonic” but that they be “pluripotent.” As I noted in my column last October, the Bush administration, in requiring the HHS to rename the "Human Embryonic Stem Cell Registry" as the "Human Pluripotent Stem Cell Registry" has simply adjusted itself to the fluctuating state of the science. The question today is which pluripotent stem cells—from embryos, from bone marrow, or from reprogrammed somatic cells—will be “most promising”. It is no longer a foregone conclusion that hESCs are the answer to that question.

Add to this that we now know three significant ways in which human iPSCs are better for research right now:

• First, patient-specific iPSCs are available “here and now,” compared to the merely theoretical prospects of getting such cells through human embryo cloning. Reprogramming is currently the only way to derive patient-specific stem cells for research on genetic diseases at this time. Reprogramming allows researchers to study the diseases in human cells in a Petri-dish, a real first in the field and holding out potential for research breakthroughs on any number of genetic diseases.

• Second, reprogramming makes multiple iPSC lines from an individual patient’s skin cells with relatively little cost or effort, especially when compared to the prospect of human cloning. This is an enormous scientific advantage. Obtaining iPSCs does not require the use of human eggs, nor access to fertility clinics, thus simplifying the requirements for research. And because these cells are easier to produce than hESCs, more scientists will work with them and research will advance much more quickly.

• Third, because iPSCs do not involve human embryos or human eggs, they will be subject to significantly simpler regulatory requirements. iPSCs are fully eligible now for funding by the NIH, and in fact the Wisconsin iPSC study was partly funded by the NIH.

2. Advances in reprogramming undermine continued scientific insistence on the “need” for new lines of hESCs.

It can be granted that reprogrammers will want to compare human iPSCs with lines of existing hESCs. From all that we can tell, and from what stem cell scientists have been telling me, however, such comparisons need not require cloning or destroying human embryos to make more hESC lines. At least 21 viable lines of human embryonic stem cells are available for federally funded research to make these comparisons.

Furthermore, Dr. Grompe notes that the non-human primate system now represents the best in-depth platform for comparative studies between types of stem cells. From rhesus macaque monkeys, primate pluripotent stem cells are available from all conceivable sources: IVF embryos, naturally conceived embryos (removed from the Fallopian tube after fertilization), SCNT-cloned embryos, parthenoids and soon rhesus-iPSCs.

3. Human embryonic stem cells are not the gold-standard any more; what “works” will now be the standard.

Solomon and Hall also asserted, as a chorus of scientists did over the past week, that “no one yet knows the extent to which these new cells will behave like true human embryonic stem cells”.

To this we could respond that Dr. James Thomson, the first scientist ever to isolate, culture and characterize human embryonic stem cells in 1998, and author of one of the two iPSC studies, found that iPS cells “meet the defining criteria” for embryonic stem cells “with the significant exception that the iPS cells are not derived from embryos.”

Mouse iPSCs have passed the strictest possible scientific tests for being functional equivalents of mouse ESCs. Tests for human cells are more limited, but human iPSCs have met all the available criteria for being the functional equivalent of hESCs. And as mentioned just above, this can be established with somewhat greater certainty by comparing human iPSCs with the existing hESC lines eligible for federal funding.

But I would like to go a step further here. The contention that human iPSCs “must measure up” to hESCs suffers a severe internal incoherence. To be sure, this view presupposes that hESCs represent some kind of absolute gold-standard. It presupposes the misconstrued notion that hESCs are some kind of natural, pure–the real deal—point of reference.

But we must remember that hESCs are as much a product of a Petri dish as iPSCs are. Human embryonic stem cells are a laboratory product; they are not literally “harvested” from the embryo. In embryo-destructive stem cell research, scientists remove special cells from a 6-day-old embryo (at the blastocyst stage). These are the “inner cell mass” (ICM) cells. These cells are, indeed, pluripotent. But extracted, and left on their own, they will not proliferate indefinitely—a key characteristic of stem cells. It is only in the Petri dish that the ICM cells acquire the characteristic of indefinite proliferation, and likewise come to remain in an unnaturally undifferentiated state (ICM normally rapidly differentiates into more specific kinds of human tissue in a developing embryo). The acquisition of these particular characteristics—in the artificial environment of the Petri dish and culture matrix—reconstitutes these cells as essentially something new, a laboratory artifact confected in vitro.

While at present the existing lines of hESCs may be the only point of reference we have for understanding the pluripotency of iPSCs and drawing comparisons, in the end, the question is not going to be whether the latter “measures up” to the former, but rather, which ones get the job done best, which ones will be most useful for giving us patient-matched tissues for therapy. And in that sense, iPSCs do not have to “behave like” hESCs. In fact, they may prove even more useful and versatile.

All of which makes the age of developmental biology and stem cell research all the more fascinating, complex and morally precarious. And we must vigorously continue our efforts to protect the dignity of embryonic human life in this arena.

And returning to Charles Krauthammer’s other point, yes, I believe recent events have at least partially vindicated the Bush stem cell policy. As Yuval Levin pointed out earlier this week, “the message Bush has tried to deliver with his policies and speeches on stem cell research is that he does not think curtailing the destruction of embryos for research needs to mean preventing the development of stem cell science.” This is a view that millions of reasonable people ascribe to. In our interest to see stem cell science proceed, we have also pondered the significance of allowing science to use human embryos as raw material for that research, and we find this utterly unreasonable. And we cannot help but believe, to borrow the words of Dr. James Thomson himself, that “if human embryonic stem cell research does not make you at least a little bit uncomfortable, you have not thought about it enough.” Seems to me like a lot of researchers in the field are owning up now to the fact that they find the prospect of embryo-destructive research not only discomforting, but deeply disturbing—which may itself turn out to be the best single indicator that we are indeed nearing the end of the stem cell wars.