Saturday, December 01, 2007


iPSo Facto

It must be wonderful to live in the world of right-wing punditry, where any "facts" that happen to coincide with your worldview, no matter how preliminary or contingent or complex, allow you to declare "victory" for your viewpoint. It's happening right now with the surge in Iraq, but it's also happening with the recent discovery that human skin cells (fibroblasts) can be very simply reprogrammed to be pluripotent, like embryonic stem cells. This means that they can, in principle, give rise to any other tissue in the body and might be therapeutically useful in treating a variety of diseases and catastrophic injuries. Here's an excerpt from one such victory announcement, by the uniquely bizarre columnist Charles Krauthammer writing in the Washington Post:
Even a scientist who cares not a whit about the morality of embryo destruction will adopt this technique because it is so simple and powerful. The embryonic stem cell debate is over.

Which allows a bit of reflection on the storm that has raged ever since the August 2001 announcement of President Bush's stem cell policy. The verdict is clear: Rarely has a president -- so vilified for a moral stance -- been so thoroughly vindicated.
But if you go and actually read the two scientific papers announcing these findings (here and here), and examine the technique that Krauthammer asserts has "ended the debate" over embryonic stem cells, you find that it involves adding copies of four different human genes to individual fibroblast cells using retroviruses to deliver the genes. The cell already has copies of these genes, but they're normally turned off in non-stem cells. The copies of the genes being delivered by the virus are eventually turned off by the cell as well, but they stay on long enough to reprogram the cell for pluripotency, which gives these cells the name "induced pluripotent stem" cells, or iPS cells. The viruses carrying the modified genes integrate randomly into the DNA of the skin cell, and the cell's own gene expression machinery directs expression of the added genes. What are the implications of the fact that the genes are being delivered into the cell using a virus? Here's an excerpt from the Yamanaka paper in the journal Cell (emphasis added):
We found that each iPS clone contained three to six retroviral integrations for each factor. Thus, each clone had more than 20 retroviral integration sites in total, which may increase the risk of tumorigenesis. In the case of mouse iPS cells, 20% of mice derived from iPS cells developed tumors, which were attributable, at least in part, to reactivation of the c-Myc retrovirus (Okita et al., 2007). This issue must be overcome to use iPS cells in human therapies. We have recently found that iPS cells can be generated without Myc retroviruses, albeit with lower efficiency (M. Nakagawa, M. Koyanagi, and S.Y., unpublished data). Nonretroviral methods to introduce the remaining three factors, such as adenoviruses or cell permeable recombinant proteins, should be examined in future studies. Alternatively, one might be able to identify small molecules that can induce iPS cells, without gene transfer.
Tumorigenesis? That means that the technique runs the risk of causing cancer if the iPS cells are introduced into a human being therapeutically. The risk of such an outcome is probably small and c-Myc, a known cancer-related gene, was not needed for reprogramming by the competing research group. But the risks associated with retroviral alteration of iPS cells are unclear, which is why it's so important to investigate other means for reprogramming the cells that don't have these risks. But clearly the technique is not at a point where "the debate is over" and we can move on to the glorious future announced by Krauthammer where there's no longer a need for research on embryonic stem cells.

But there's an even bigger issue that remains to be explored, and this is the fact that iPS cells are not identical to embryonic stem (ES) cells. The differences between the two cells types and whether they're meaningful still need a great deal of investigation, but until the basis for reprogramming of iPS cells by the four genes is better understood, no fair-minded person is in a position to say whether these cells will be able to substitute for ES cells in any or all cases. And even if they do, the therapeutic benefits of stem cells (either ES or iPS), while enormously promising, are still largely hypothetical.

Finally, Krauthammer's demagoguery reaches a crescendo when he makes the claim that the development of iPS technologies was driven by Bush's policies:
Because the moral disquiet that James Thomson always felt -- and that George Bush forced the country to confront -- helped lead him and others to find some ethically neutral way to produce stem cells. Providence then saw to it that the technique be so elegant and beautiful that scientific reasons alone will now incline even the most willful researchers to leave the human embryo alone.
It's not that Bush's viewpoint is wrong - it's reasonable to have qualms about destroying embryos to derive ES cells; but what's laughable is Krauthammer's idea that moral considerations were a driving force for the development of iPS. The fact is that, unless the stem cells used for therapies are derived from the patient's own body, they risk being rejected like other transplanted organs or tissues, which are attacked by the patient's immune system. Thus, avoiding rejection provided a strong scientific incentive for research to see if a patient's own cells could be reprogrammed into stem cells, thereby avoiding the risk of rejection. Moral considerations provide an added benefit, but it is still far from clear whether research on embryo-derived ES cells is obviated by the ability to reprogram iPS cells. No one can say, not even an apparently omniscient right-wing pundit.

The development of iPS cells has tremendous scientific and medical potential well beyond stem cell therapies, and I will discuss these issues when I have more time. But for now, it is safe, prudent, and correct to say that the debate about embryonic stem cells is far from over, notwithstanding the claims of ideologues who are more interested in pushing a point of view than in understanding the relevant scientific facts.

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