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To reprogram adult cells into induced pluripotent stem cells (iPSC), scientists use four proteins to activate pluripotency. The big challenge lies in smuggling them through the cells’ protective membranes.
Originally, scientists delivered the proteins via potentially harmful viruses—a technology that has raised enormous concerns. Cells derived this way, when subsequently transplanted, have been shown to cause tumors in mice.
Now, scientists are working on eliminating the step that they fear is causing cancer-inducing mutations, says Elias Zambidis, M.D., Ph.D., an assistant professor of pediatric oncology. He cites recent research that shows it is feasible, if not yet routinely efficient, to derive iPSC from adult cells by dispatching the proteins with safer smuggling methods.
No. 1 concern: Cancer
Elias Zambidis, M.D., Ph.D.,
assistant professor of
pediatric oncology and
member of the Johns Hopkins
Institute for Cell Engineering.
The new wave of iPSC involves using non-viral mechanisms so there’s no risk of them integrating into the genome and causing harmful mutations, Zambidis says. “Before we talk about transplanting these in patients, in a clinical setting, we’ve got to figure out how to make them without these viral shuttles that have high potential for causing malignancy.
“We don’t want to tell people: Well we can cure you, but you might get cancer from our treatment,” he continues. “That is what burned gene therapy. It was going to cure everything— until it killed some people. Stem cell science has to learn a lesson from gene therapy; we need to be cautiously optimistic, and do the right research carefully before iPSC are ready for the clinic.
One forward-thinking method for generating iPSC is using so-called protein transduction that uses specially designed proteins that can shuttle directly into cells without viral vehicles, or even DNA. For example, chemist Sheng Ding of the Scripps Research Institute in April 2009 reported in Cell Stem Cell that he and colleagues made mouse iPSC without the use of harmful viruses. “Protein transduction may still be very inefficient, but they got it to work,” says Zambidis
There’s no kill switch
“If you give a drug to patients, and have a bad outcome, you can put them on dialysis and let it run its course,” says Valina Dawson, Ph.D., professor of neurology. “Not so with stem cells. Once you put them in, that’s it. You can’t withdraw them. There’s no kill switch.
Valina Dawson, Ph.D.,
professor of neurology and
co-director of the
Neurogeneration Program, a
division of the Institute for Cell
Engineering at Johns Hopkins
“When you’re debating their therapeutic potential, you need to consider your patient population,” Dawson continues. “Individuals with spinal cord injury may have sudden and severe loss of quality of life, but they generally can live many years. So if you’re giving them cells that are eventually going to turn into tumors and shorten their life span, I think that’s really troublesome.
“Stem cell transplants done in other countries have resulted in a number of patients developing tumors. We simply don’t know the long-term effect of these cells. We don’t monitor them for very long in animals. We don’t yet know how to make them safe for use long term.
“Even if we start doing human studies in patient populations with no other viable treatment options, we still run a risk, because if we forge ahead and get no effect, it can erode public will. If patients come to harm, it will erode public confidence. A number of researchers who think stem cells can be developed as useful therapeutic tools are very concerned that what happened with gene therapy will happen here, as well.”
--Interviewed by Maryalice Yakutchik