So last night we went out to watch the American Repertory Theatre's version of Eugene Ionesco's The Killing Game. Afterwards we ended up at Grafton Street for food, drinks and discussion.
Of course with Marius Wernig in attendance, the talk turned to this week's big news.
[In attendance as well was Mike Kharas, a postdoc in the Gilliland lab. In a weird coincidence, Mike worked on klf4 (krumpel-like factor4), the most mysterious of the four genes which are part of the cellular fountain of youth elixir.]
First it looks like everyone in the Jaenisch lab is jumping onto this project - turning somatic cells into stem cells. This finding is like discovering a new continent, there are so many directions to follow.
We also discussed why the conversion rate from somatic cells to stem cells (1 in 1,000-10,000) is so low. One reason might be the Goldilocks issue where cells need the the correct amount of each factor. Another reason is that certain cells may be more susceptible to the conversion process - so that perhaps the conversions are only occurring with adult skin stem cells. Also the sporadic cancer issue is a very serious issue (Marrius' mice now have tumours). The problem? Well expressing c-Myc, a classic oncogene is a problem. Another is the retroviral problem where the exogenous genes are haphazardly integrated into the genome. Another fascinating issue is DNA imprinting. I'm not sure what is happening with that (perhaps I had a bit to much Gin Tonic by then). Then the last problem is the difference between mice and humans. Human cells seem to be more resistant to this dedifferentiation procedure. Why? I think (and Marius agrees) that it has to do with cancer. You see, cancer and stem cells are intimately connected - in many ways cancer cells have dedifferentiated and have acquired many stem cell characteristics. Unlike mice, which in the wild does not experience much cancer, humans have been selected to be quite cancer resistant. Over our long lives, we accumulate many more mutations in our cells and thus have increased chance of getting cancer when compared to mice. Thus humans have undergone much more selection against cancer and we are equipped with many more checks and balances that protect us from the effects of oncogenes and dedifferentiation. This has been a big problem for those using mouse models of cancer, as mice are simply more susceptible to cancer. It takes much less effort to immortalize mice cells and form tissue culture cell lines derived from mice than from humans. Humans cells just have more tools to prevent the activation of stem cell-like genetic programs.
PS Yeah I stole my title from Dan's post, but last night we agreed that it was a great way of thinking about creating stem cells.
- Log in to post comments
Nice insight on the human/mouse differences and the possible role of selection against cancer. I'm not sure that the difference would be limited to just immortalization- and mutation-related issues, however. It seems to me that the pathways that modulate self-renewal itself could also be tweaked differently in humans vs mice. This would of course be for the same reason though - the lifespan problem (control over stem cell proliferation would need a tighter regulation during long lifespans, right?).