Stem Cells 2.0
Scientists have been searching for ways to directly reprogram adult cells for decades. That hunt has been pushed forward by the desire to develop an alternative to human embryonic stem cells, which are fraught with both technical and ethical issues. The cells are usually derived from four- or five-day-old embryos that would otherwise be discarded from in vitro fertilization clinics (although sometimes embryos have been created expressly for research purposes). Using this technique to create a robust cell line is tricky and highly inefficient. Not only are the embryos themselves hard to obtain, but the cells are delicate and difficult to grow.
Another technique, human therapeutic cloning, is even more controversial, and both technically and practically challenging. Scientists transfer the nucleus of an adult cell into the hollowed-out shell of an unfertilized egg cell–which can then develop into an embryo, yielding stem cells that are genetic clones of the adult cells. But the lack of human eggs for research has proved a huge hurdle, and scientists have yet to generate cloned human cell lines.
But three years ago Shinya Yamanaka, of Kyoto University in Japan, figured out how to return adult mouse cells to an embryonic-like state in a process that never involved an actual embryo. He found that using a virus to deliver genes for just four specific proteins to the nucleus of an adult cell could give it the ability to differentiate into a wide variety of cell types, just like the stem cells derived from embryos. Those proteins, typically found in developing embryos, appear to turn other genes on and off in a pattern characteristic of embryonic rather than adult cells. A year after Yamanaka’s discovery, his group and two others reported that they could induce human cells to do the same thing.
As a physician and venture capitalist closely following stem-cell research, Beth Seidenberg saw the potential almost immediately. Seidenberg, a partner at Kleiner Perkins Caufield and Byers, teamed up with another venture capital firm, Highland Capital Partners, to found iZumi in 2007, funding the company with $20 million. After 20 years in pharmaceutical research, Seidenberg has had a lot of time to think about what the industry is doing right and where it’s going wrong. She says, “I became really intrigued by the idea of starting with a patient who had a disease and working backwards, which is exactly the opposite of how we pursue new therapies for treatment of disease today.”
To illustrate the role iPS cells could play in drug discovery, John Dimos points to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease he has studied for years. About 2 percent of all cases have a known genetic cause–a mutation in a gene called SOD1. Nearly all the work in animal models has focused on this rare form of the disease, because researchers know how to use the gene to trigger it in mice. With the new technology, however, scientists can use a skin biopsy to generate pluripotent stem cells from any patient with ALS. The genetics and other possible factors underlying the disease are captured in the cells, even if no one knows explicitly what those factors are. The same holds true for Alzheimer’s, diabetes, autism, heart disease, and myriad other conditions whose complex origins have proved difficult to identify.
As a postdoc at Harvard, Dimos built a cellular model of ALS, making it possible to study a neurodegenerative disease outside an animal for the first time. He and his colleagues collected skin cells from an 82-year-old woman with ALS, reprogrammed them into iPS cells, and directed the cells to differentiate into motor neurons that were genetically identical to the donor’s defective cells. “It was the first paper to show that you can use a stem cell to see disease pathology in a petri dish,” says Douglas Melton, codirector of the Harvard Stem Cell Institute. “That means you can now study diseases in petri dishes and not in people. That’s huge.”