Since the stunning news nearly two years ago that scientists could take specialized cells from human skin and reprogram them to yield unspecialized pluripotent stem cells, research using these “induced pluripotent stem cells” (iPS cells) has moved swiftly, and in some stem cell labs has taken center stage.
“The generation of iPS cells is nothing less than a revolution in biomedical research,” says George Daley, whose lab at Harvard Medical School has already made iPS lines from the connective tissue cells called fibroblasts of people with Parkinson’s, Huntington’s, muscular dystrophy, Down’s syndrome and other disorders.
At the Society for Biomolecular Sciences meeting in Boston in early September, Daley and other researchers shared recent advances with iPS cells. It’s only natural, they said, that scientists are quickly gravitating toward these cells, given their many advantages over ethically problematic embryo-derived stem cells.
When properly reprogrammed, iPS cells appear to be every bit as pluripotent as embryonic stem (ES) cells: They, too, can be steered to become functional neural, heart, muscle, eye or other type cells and tissue, although, scientists warn, iPS’s require a great deal more testing to understand exactly how safe and functional they are. Their special appeal, meanwhile, is that U.S. scientists working with these cells avoid federal funding restrictions that still limit the making of ES cell lines, despite President Obama’s executive order last March.
Worldwide, iPS lines now exist for some twenty or more diseases and are rapidly increasing; they are easier and cheaper to create compared with embryonic stem cell lines. Once in hand, iPS cells in some cases can yield far higher numbers of specialized cells than ES cells can. For example, researcher Kevin Eggan says that in his Harvard lab, which investigates ALS, a lab tech could only make around 10,000 motor neurons in a day from ES cells, whereas now iPS lines from ALS patients yield vast quantities of motor neurons and glia, the cells implicated in ALS pathology.
Because of these newly available stem cells, speakers at the Boston meeting said, the vision of personalized medicine becomes more real. A person might have his own stem cell line, thus cells, available for therapy. Since the cells originate from the patient, there is no risk of an immune-system rejection. Moreover, iPS cells appear to carry fewer chromosomal defects than embryonic stem cells. This may be because cells from the embryo haven’t been through the rigorous selection process that takes place during development, whereas a reprogrammed skin cell appears to undergo that process, with fewer chromosomal abnormalities to show for it, says neuroscientist Clive Svendsen, co-director of the University of Wisconsin Stem Cell and Regenerative Medicine Center.
Reprogramming also restores the length of telomeres – the ends of chromosomes – in iPS cells. A shortening of telomeres in cells has been associated with aging and associated deficits. So this also bodes well for using iPS cell lines for cell therapy.
Watching disease develop
While iPS cells have the potential to hasten cell therapies, researchers are applying them to more immediate uses, namely the study of disease and the screening of drug molecules. “We are now able to move a patient’s cells into a Petri dish and watch how, in real time, they malfunction,” Daley says.
Spinal muscular atrophy (SMA), a rare disease that occurs when an infant is born without a certain gene, is an especially good disease to interrogate this way, says Svendsen. “The gene is missing from every cell in a child’s body, but only motor neurons die, and we have no idea why.” His work has shown that when you take a cell from a patient who has died from SMA, reprogram it back to pluripotency, and then drive it forward to become a motor neuron, “those motor neurons that are born in a dish survive for a while, but then undergo cell death right before your eyes.” If you can play that accident over and over again, and compare it with normal motor neurons, says Svendsen, “you can ask, right before anything went wrong, what was the molecular signature? Then when the cells start to die, what genes did they express?”
Looking at genomic changes in cells in a dish before and after they get sick – that is something researchers have never been able to do. “That,” said Svendsen, “is the power of using iPS for all diseases.”
Because SMA’s fatal mechanism comes to light in early childhood, researchers can easily watch its cellular and genomic features unfold in a dish in real time. One of the big unknowns, Svendsen believes, is whether the cellular abnormalities of disorders like ALS and Parkinson’s, most cases of which usually arise later in life, also will show up in a timely way in a dish.
“I’m excited by the concept” of using iPS cells to study disease, he says. “But the question is, will we see a disease like ALS in the time frame we have?”
The many unknowns about iPS cells are hardly holding researchers back. Present at the SBS meeting was Cellular Dynamics International, a company started by ES cell pioneer James Thomson. Though it originally used ES cells to make specialized cells for drug screening, the firm has since switched to using only iPS cells.
As Svendson noted in his lecture, titled “Back to the Future,” “by pushing cells back, this is the way our field is moving into the future.”