Thursday, May 2, 2013

CIRM President Alan Trounson — April’s stem cell research highlights

Each month CIRM President Alan Trounson gives his perspective on recently published papers he thinks will be valuable in moving the field of stem cell research forward. This month’s report, along with an archive of past reports, is available on the CIRM website.

My report this month starts with major advances from two teams at Harvard. One found a hormone that looks like it might cause insulin-producing Beta cells in Type 2 diabetics to proliferate enough to overcome the disease (my colleagues wrote about those projects here.). The other team used stem cells to create a kidney in the lab that was able to produce urine when it was transplanted into a Rat.

With this post, I want to focus on the work of four teams that made advances in direct reprogramming. This effort to turn one type of adult cell directly into another adult cell is a path many in the field think holds great promise for therapies. The ability to turn a type of cell that is abundant, often skin, into another cell type that is destroyed or damaged by disease has potential advantages over other approaches. It avoids passing through a pluripotent state, either as an embryonic stem cell or an iPS reprogrammed cell, which both leave the possibility of lingering pluripotent cells creating tumors or other unwanted tissue. (Pluripotent cells are ones like embryonic stem cells or reprogrammed iPS cells that hold the potential to form all types of cells in the body.) Direct reprogramming retains an advantage of iPS cells (that is, reprogramming adult cells into an embryonic-like state); it has the potential to create therapeutic cells that match the genetics of the patient and therefore might be accepted by their immune system.

One Italian team directly reprogrammed human skin to become pancreatic cells that were capable of producing insulin. What is more dramatic, they did not use any genetic factors traditionally used in reprogramming, which have some safety concerns. Instead, they manipulated the cell’s own switches that turn genes on and off. Much of this switching occurs through what is known as epigenetics and the placement of the chemical signal known as a methyl group near the gene. Altering those signals with a chemical resulted in the direct reprogramming.

Two teams, one at Stanford and one at Case Western in Cleveland, used genetic factors to directly reprogram rodent skin cells into the early brain cells that can produce the myelin protective sheath that is lost on the nerves of patients with multiple sclerosis (we wrote about the Stanford work here). Both teams showed that the resulting myelin cells were able to function. They insulated and protected nerves when transplanted into mice.

A team in Sweden went the ultimate step and directly reprogramed cells in the body—that is they did the reprogramming in the living animal rather than first in a lab dish prior to transplant. In their first experiments, they reprogrammed human cells that had been injected into the animals. The donor cells had been genetically modified to express three genes known to push cells to become neurons. But the inserted genes were rigged so that they would only be turned on when they came in contact with a certain drug. Once the donor cells were in place, the team put that drug in the mice’s water. The mice drank, the genes switched on and the cells became neurons. The team then tried inserting those same genes directly into the mice’s own brain tissue. They injected the virus carrying the genes into a type of brain cell that typically is in abundance even when neighboring neurons are being destroyed by disease. They found that they could convert those mouse cells that normally have a support role into active neurons.

Direct reprogramming has great promise and may indeed be where many treatment paths lead. These are still very early steps and are a long way from clinical use, but they do provide reason to believe we might be able to make this work for patients.

My full report is available online, along with links to my reports from previous months.

A.T.

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