The Niche

Human reprogramming changes everything, and nothing

That’s a paraphrase of what James Thomson at the University of Wisconsin-Madison told reporters at a press conference this morning when he announced that he’d induced human skin cells to take on the trappings of embryonic stem cells. His work is published online today in Science. Tying (or narrowly beating) Thomson is Kyoto University’s Shinya Yamanaka who reports his accomplishment in Cell. A news article from Nature is available here.

Thomson said that other researchers would be hard-pressed to distinguish his cells from human embryonic stem cells (ESCs) but repeated several times that whether these cells differ from ESCs in important ways remains to be seen. It does seem, however, that highly flexible cells could be made without collecting eggs from women and without destroying an early stage embryo.

Moreover, these pluripotent cells could be made from patients with known diseases. If the root causes of disease were genetic that could be a better way to study disease. It could also mean that replacement tissues for, say, diabetes patients using genetically identical cells. Thomson predicted that this research could lead to researchers testing drugs in ‘panels” of cell lines to figure out if toxicity and efficacy varied across genotypes.

Both Yamanaka and Thomson used a suite of four genes to transform cultures of skin cells. Both quartets included OCT3 and SOX2, well known markers of pluripotency. For the other two, Yamanaka used the KLF4 and c-Myc, which he’d shown earlier in mice. Thomson used NANOG (identified a few years ago as a master switch of pluripotency) and LIN28, implicated in processing mRNA. (According to a news article by Science.)

Besides these groups, there are many, many whispers of others about to publish similar accomplishments. Some report overcoming a remaining drawback: the transformed cells contain multiple copies of genes inserted into the genome by engineered viruses. “Nobody thinks we’re going to have those vectors even a year from now,” Thomson told reporters who had called in.

But he said, the major barriers still exist. The manipulations move cells back to what he called “a ground state” but for therapies and drug screening, researchers need a differentiated state. That was something he said was coming.

Synergies with other research

Thomson said that the time, cost, and expertise needed to make embryonic stem cells would likely push researchers to prefer genetically reprogrammed cells. Induced pluirpotent cells made by Yamanaka and Thomson come directly from cultured skin cells. Embryonic stem cells are made by scooping out cells from within an embryo and culturing them. Both types of cells can form teratomas and be differentiated into other cell types. Embryonic stem cells can also be made from cloned embryos, in which the nucleus of a differentiated cell is placed in an oocyte that is then activated to divide to form an embryo.

That feat was never been accomplished in humans (earlier reports were fraudlent). Nature did report it this week.

Thomson said that it would be useful to reprogram cells from the same monkey whose nucleus was used to make the embryonic stem cell lines. Then, cells generated from oocyte-assisted reprogramming and genetically engineered reprogramming could be compared directly.

Much of the speculation about what would need to happen to make the technique useful was reported when Yamanaka and other groups reported the accomplishment in mice. Here is a link to that article .


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