100% Success in Gene Reprogramming

First, there was the great hope of induced pluripotent stem cells (iPSCs), and then there was the inevitable letdown. When the announcement came, in 2006, that simple adult skin cells could be reprogrammed – reverted back to an embryonic stem cell state by the addition of just four genes – it seemed like an almost magical solution to the problems of using stem cells from embryos. But then some studies started to find that the reprogramming process was not perfect – iPSCs were similar, but not identical, to the cells from early embryos. More critically, only about 1% of the cells treated with the four-gene combination actually turn into iPSCs, and the process is painstakingly slow – around four weeks. That is just fine for a research lab, not so great for developing medical applications.

Of course, labs everywhere have been working to improve the process. So today’s report of a Weizmann Institute finding that can raise that conversion rate to 100% is, for lack of a better word, a breakthrough. (Breakthrough is a word we never, ever use, for fear of appearing to over-hype scientific findings.) In addition, it brings down the waiting time to a mere eight days and it gives researchers, for the first time, the possibility of synchronizing the process in the cells, so that it can be studied.

Dr. Yaqub Hanna says that his team’s spectacular success is due to the fact that, rather than trying to tinker with the existing formula, they turned to investigating the stage of natural human embryonic development in which stem cells start to differentiate. He was sure there was an active “brake” on the reprogramming process. That would explain the low success rate, on the one hand, and the fact that, even though only four genes are needed to reprogram our cells, it doesn’t happen on a day-to-day basis, on the other. He had even shown, mathematically, that there should be only one main brake that keeps cells that have already differentiated from reverting back to stem cells.

Left: Combined image of skin cells (red) and reprogrammed cells in the previous method (green) shows very few iPSCs. In contrast, most of the cells on the right have been reprogrammed with the new method

The team found their brake in an unassuming protein called MBD3. Their hint: MBD3 is expressed in all our cells all the time, and throughout embryonic development – except for the first three days after the egg is fertilized. In other words, the instant that embryonic stem cells start differentiating to the next level – taking their first step away from the pure ability to become any type of cell toward the ultimate goal of fully specialized adult cell – MBD3 apparently comes into play to ensure that the process can only move forward.

Then it was a matter of removing MBD3 from adult cells before inserting the reprogramming genes. The astounding fact that 100 percent of the cells were now reprogrammed shows, among other things, that there really is only one brake, and that brake can be released.

Is this the last word in stem cell reprogramming? We can’t tell you that. Nor can we tell you when, exactly, you will be treated with stem cells derived from your own adult cells. What we can say is that there are now more good reasons to hope.

http://www.youtube.com/watch?v=dvJoH6CQOZA