June 06, 2007
Mouse Cells Converted Into Pluripotent Stem Cells

For several years here I've argued the ethical conflict over human embryonic stem cell research would get resolved by discovery of techniques to dedifferentiate adult cells (make cells less specialized and more flexible). Well, at least with mice a method has been discovered to do exactly that. The use of gene therapy to turn on 4 genes in adult mouse cells transforms those cells to make them as flexible as embryonic stem cells.

Now, in three papers published simultaneously this week, Yamanaka and two other groups report that by turning on expression of the same four chemicals in adult mouse cells, the cells run their differentiation process backwards, reverting to an ESC-like state (Nature, DOI:10.1038/nature05934 and DOI:10.1038/nature05944; Cell Stem Cell, DOI:10.1016/j.stem.2007.05.014). "We have shown that cells can be generated by these four factors, that are indistinguishable from embryonic stem cells," says Konrad Hochedlinger of the Harvard Stem Cell Institute, who wrote one of the papers (watch a video of Marius Wernig - first author on the same paper - describing the cells - 3.8 MB, .wmv).

These cells are pluripotent which means they are capable of turning into all the cell types in a body. Need new parts to replace old worn out organs, blood vessels, muscles, tendons, and joint tissue? Pluripotent cells will some day serve as starter cells for the growth of replacement parts. Replacement cells and organs will usher in the age of regenerative medicide and eventually full body rejuvenation.

What was the enabler that made these experiments possible? The discovery by Yamanaka's team that 4 genes could cause a cell to become pluripotent. As scientists discover more about which genes control cellular differentiation (how cells change to take on specialized jobs) more ways to manipulate cell type will come from use of this knowledge.

Engineered viruses were used to deliver genes into the mouse cells.

Using artificial viruses called vectors, the team activated the same four genes in a batch of mouse skin cells. These genes, Oct4, Sox2, c-Myc and Klf4, are called transcription factors, meaning that they regulate large networks of other genes. While Oct4 and Sox2 are normally active in the early stages of embryogenesis, they typically shut down once an embryo has developed beyond the blastocyst stage.

It says something about the immaturity of gene therapy techniques in the year 2007 that only 1 in 1000 cells exposed to viruses with the 4 genes got reprogrammed by the attempt to add genes to the cells.

“We were working with tens of thousands of cells, and we needed to devise a precise method for picking out those rare cells in which the reprogramming actually worked,” says Wernig. “On average, it only works in about one out of 1,000 cells.”

To test for reprogramming, the team decided to zero in on Oct4 and another transcription factor called Nanog. These two hallmarks for embryonic stem cell identity are only active in fully pluripotent cells. The trick would be to figure out a way to harvest Oct4- and Nanog-active cells from the rest of the population.

Nicholas Wade of the New York Times claims the technique, once replicated with human cells, will clost less and take less effort than cloning to create embryonic stem cells.

The technique, if adaptable to human cells, is much easier to apply than nuclear transfer, would not involve the expensive and controversial use of human eggs, and should avoid all or almost all of the ethical criticism directed at the use of embryonic stem cells.

“From the point of view of moving biomedicine and regenerative medicine faster, this is about as big a deal as you could imagine,” said Irving Weissman, a leading stem cell biologist at Stanford University, who was not involved in the new research.

Replicating this study with human cells poses some problems which scientists must solve. But some of the scientists are optimistic about solutions:

A third issue is that two of the genes in the recipe can cause cancer. Indeed 20 percent of Dr. Yamanaka’s mice died of the disease. Nonetheless, several biologists expressed confidence that all these difficulties would be sidestepped somehow.

“The technical problems seem approachable — I don’t see anyone running into a brick wall,” said Owen Witte, a stem cell biologist at U.C.L.A. Dr. Jaenisch, in a Webcast about the research, predicted that the problems of adapting the technique to human cells would be solvable but he did not know when.

The threat of cancer is a big problem with stem cells. We need better methods of doing gene therapy so that stem cells can get genetically altered to repair all genes that prevent cells from growing uncontrollably.

Thanks to Brock Cusick for the tip.

Share |      Randall Parker, 2007 June 06 11:53 PM  Biotech Stem Cells

John said at June 7, 2007 12:49 AM:

We really need to come up with the equivalent for Moore's law with regards to genetics. Discoveries akin to these are becoming more and more frequent, and at the same time things have just begun.

Jonathan said at June 7, 2007 2:52 PM:

Kurzweil's book gives excellent examples on the exponential rate of progress on genetics.

Kurt9 said at June 7, 2007 2:55 PM:

The biotech version of "Moore's Law" is called "Carlson's Curves" and will be equally profound in the coming years.

Randall Parker said at June 7, 2007 7:17 PM:


Moore's Law is not even the only such law operating in computing. While processor speed has its doubling rate (which has varied between 18 and 24 months) the capacity of hard drives has a separate (and I think faster) doubling rate. Also, the doubling rate of optical fibers (9 months? near there) was much faster than for microprocessors for many years running. Not sure if that is still the case or not.

As for bio: Not sure what we should watch. We can watch the rate of increase in capacity of DNA gate arrays. But we can also watch microfluidic device complexity or DNA sequencing costs or DNA sequencing speed.

Bob Badour said at June 9, 2007 3:15 PM:

I suggest we watch diseases cured by simple inexpensive treatments.

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