Thursday, November 22, 2007

Getting with the (re)program

An important breakthrough in stem cell research:

Two teams of scientists reported this week (here and here) that they have successfully reprogrammed mature human skin cells to become pluripotent stem cells that appear to be equivalent to Embryonic Stem (ES) cells. The NY Times report and the LA Times report on this work cover the attendant implications pretty well, so I won’t rehash it in great detail. The popular press reaction to this has naturally been to speculate that this work could eliminate the need for ES cell research. And, of course, the ignorant and the malicious policymakers alike in Washington have jumped on it to further their fundamentalist agendas (and, dare I say, antediluvian ideas) using pseudo-scientific claims.

Anyhooo, I think that this is a tremendous breakthrough, especially for the research in understanding the development and progression of many, many diseases. One can now take actual patient cells, reprogram them (to make induced pluripotent stem cells (iPS) as one of the groups of scientists termed them) and perform a multitude of crucially important studies that were previously impossible. So I have nothing but unreserved enthusiasm regarding this breakthrough, on that front.

Now, as to the therapeutic potential of iPS cells, I would urge a lot more restraint in optimism. And here are my reasons for the caution;

1) While the early results are promising, there is a lot more research to be done to determine whether iPS cells and ES cells are indeed equivalent in a variety of circumstances over time.

2) From the genes that are used to reprogram the skin cells, to their vehicle of introduction (retroviral vector), the reprogramming involves engineering whose long-term consequences are just not known. iPS cells will not come close to FDA approval in anything remotely resembling their current technological iteration.

3) Most importantly, we are dealing with reprogrammed adult differentiated cells. I refer you back to my previous post on cancer---adult differentiated cells can acquire damage over the course of their lifespan. There is no evidence to suggest that the aforementioned reprogramming can also magically rid the cells of this accumulated damage or that it can restore their genomes to their formerly pristine or clean states. If a cell with damage acquires the capacities for pluripotency and self-renewal, it could very well end up being a cancer stem cell. I think this issue could end up being the largest hurdle that stands in the path of using iPS cells in a therapeutic context.

It should be noted that such reprogramming was done with mouse cells last year (by one of groups of scientists mentioned above) and the reprogrammed mouse cells were used to generate whole mice. So the power of the reprogramming has been well demonstrated in an animal model system. It is also noteworthy that 20% of the mice generated from reprogrammed cells developed cancer. This was attributed to the fact that one of the genes used for reprogramming was c-myc, a known oncogene. But I don’t think it was proven that c-myc was the only reason.

The best approach in science is to let the system guide you and tell you what’s important. If a certain mature cell-type is not normally self-renewed in the body, then it is also likely that there has not been sufficient evolutionary selective pressure to keep that cell-type from accumulating damage over the course of its lifespan. It is very important to bear that in mind when thinking of ‘reprogramming’ such cells and re-introducing them into the human body. Of course, to appreciate that point one would have to appreciate (or at least acknowledge) evolution-----So I expect Washington to welcome this new breakthrough as an ultimate solution and escalate the war on all other types of ES cell research in 5, 4, 3, 2……

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