First, two cool papers came out recently.
In the first from the Jaenisch lab, mouse IPS Cells were differentiated into erythrocytes and used to cure sickle celled anemia in a mouse model. This would be a first application of these IPS cells in a therapeutic setting.
In the second paper from the Yamanaka group, mouse and human IPS Cells were created by overexpressing 3 of the 4 genes used in the original protocol. In fact the gene that was omitted in this new protocol is myc, one of the most potent proto-oncogenes. When these new IPS cells are incorporated into adult mice, the cells do not form teratomas (so far). It would seem that the biggest hurdle left is the retroviral issue. How to introduce these 3 genes, which have to be turned on for quite a while, without using retroviruses or any DNA technology that results in recombination?
Speaking of Yamanaka, here is a link to an interview in today's NY Times' Science Section. There are quite a few interesting items in there including a passage on how he figured out the IPS reprogramming protocol:
One challenge was figuring out which genes would reprogram adult cells. With hundreds of candidate genes, the number of possible combinations was almost infinite.
Dr. Yamanaka said he narrowed the field with a very unscientific method: he made an educated guess.
He said he used his instincts, as well as published research of other scientists, to pick the 24 most promising genes. In the lab, he found that the 24 did indeed contain four genes that could reprogram adult cells into stem cells.
"Choosing those initial 24 genes was almost like buying a ticket at the lottery," he recalled. "I was just lucky. I bought the right lottery ticket."
Yes it is still quite incredible that he picked the right genes. Especially that klf4 gene. It was off the radar screen. (Although Thomson's protocol to generate human IPS cells does not involve the expression of klf4 or myc, so maybe there are quite a few combinations of genes that can be used to reprogram cells.)
There is also this bit on the jump from mouse to human cells:
Another challenge was adapting the reprogramming method, which he first developed with mouse cells, to human cells.
He failed for months, and at one point even went back to the pool of 24 genes to see if human cells required a different combination of master regulator genes than those of mice. He also began experimenting with seemingly minor changes, like switching the gel-like culture solution in which the cells are grown. It was the small changes that worked, finally allowing him to reprogram human skin cells with the same four genes.
"If you had asked me back in June," he said, "I would have told you the same four genes wouldn't work in humans."
Finally here is a link to a bloggingheads.tv discussion between Carl Zimmer and Lee Silver on IPS cells. Some interesting issues are discussed, but I must say that I don't buy the idea that the term "IPS Cell" was created for political reasons. The term "IPS Cells" came from the first Yamanaka paper at a time when it wasn't yet clear whether IPS cells where equivalent to embryonic stem cells. Another topic discussed is the opposition to stem cell research. If IPS cells turn out to be equivalent to embryonic stem cells, then it would logically seem that there is nothing special about embryonic stem cells. The idea that one cell type has a soul and the other doesn't, is not tenable.
Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R.
Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin.
Science (2007) Advanced online publication doi: 10.1126/science.1152092
Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S.
Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts.
Nature Biotechnology (2007) Advanced online publication | doi:10.1038/nbt1374
Lucky...a little too lucky to believe...
There's a lot of epigenetic mucking around going on during the iPS protocol - disruption of chromatin structure through retroviral insertion, simultaneous activation of a bunch of powerful transcription factors and their binding to a huge number of target promoters. Maybe the cell just says enough is enough and hits the epigenetic reset button. That would be cool - and wouldn't matter so much which genes you used...