We are in the early and rapidly changing stage in Induced Pluripotent Stem (iPS) cell development. Until now, most research effort has been directed toward finding a way to introduce genes into an adult cell in order to return it to an embryonic stem cell state.
The step that isn't talked about much is the next one: after the cell is returned to an embryonic state it must then be coaxed or directed to become the type of cell needed in the therapeutic process or application. The holy grail of Induced pluripotent stem cell development would be to change an abundant adult cell into the type of cell needed in the patient's body. And the holiest of all grails would be to do it without removing the cell from the patient.
Using a technique they are calling "direct reprogramming," Harvard Stem Cell Institute co-director Doug Melton and post doctoral fellow Qiao "Joe" Zhou at the Harvard Stem Cell Institute have turned mouse exocrine cells, which make up about 95 percent of the pancreas, into precious and rare insulin-producing beta cells, and they have done so without returning the cells to an embryonic state, using only three genes (four have been used to create iPS cells in earlier research).
As is the case with all iPS work thus far, Melton's experiments involved using viruses to integrate the transcription factors into the target cells. Because of the risks that approach would pose to humans (virus use can also introduce cancer), the team is looking for chemicals that might effectively and, most important, safely replace the viruses.
"These findings are of a caliber that will revolutionize what is already a revolutionary field," said George Q. Daley, immediate past president of the International Society for Stem Cell Research and a member of Harvard Stem Cell Institute's Executive Committee.
The first induced pluripotent stem cells (iPS) were produced by Shinya Yamanaka in 2006. The first human induced pluripotent stem cells were produced in 2007, so we're not talking about old technology here. Since the beginning of 2008, iPS technology has been on high speed rails without small town stops. The research is world wide and both privately and publicly funded.
In addition to its value for the field of regenerative medicine, the Harvard Stem Cell Institute work also is a major step forward toward eventually developing a treatment for Type II – and eventually Type I – diabetes, a treatment that might someday eliminate the need for patients to constantly monitor their blood sugar and take insulin-adjusting medications, or even insulin. It is important to note, however, that there are numerous scientific hurdles that lay ahead before a treatment could be tested in humans.
Melton likened the the multi-step process a stem cell goes through during differentiation into a specific adult cell type to passing through a series of doors. "There are locks on all the doors," he said, "and the locks are transcription factors. We asked which ones are present in the beta cell, and that gave us 1,100 transcription factors to choose from. Eventually we learned that of the 1,100, only about 200 are actually expressed in cells that are involved in forming the pancreas.
"Next," Melton continued, "we decided that of the 200, we only cared about the ones that are expressed in the key part of the pancreas where the beta cells are – and that got us down to about 28. Then we did some lineage studies," he explained, "and we got it down to nine. Joe said, 'my best guess is it's these nine.' And he were right. It was a messy experiment, mixing all nine and injecting them into the pancreas. Then we found out that it got better and better as we removed one gene at a time from the nine, and eventually we found that it actually works best with three transcription factors – that six of them aren't that important. And that's the fun of science!" Melton said, a grin spreading across his face.
Adapted from the Harvard Science Announcement.
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