Thomas Okarma, director of Geron’s cell therapy programs, says replacement tissues for transplant will likely be the “big hit” for human ES cells. The first type of transplantable cell Geron hopes to make are heart cells. Okarma imagines inserting a “cassette” of genetic instructions into an ES cell that would direct it to turn down the differentiation path to heart tissue. “The cells could be injected directly into the failing part of the heart,” Okarma says. The result could shore up failing heart tissue, nursing heart-attack victims back to health or providing a stop-gap for patients waiting for the right heart for a transplant.
Although Okarma envisions “a fermenter full of cells” derived from ES cells that someday will pump out new heart tissue, he stresses that the research is at an extremely early stage. To give some sense of how early, he tells TR that he hopes that within three years Geron will be testing the heart-tissue approach, using ES cells from Rhesus monkeys transplanted into other monkeys.
But the benefits of identifying and cultivating the ES cells are not only practical; there will be substantial rewards for science as well. “In theory,” says Okarma, “we should be able to generate an infinite and stable supply of [normal] human cells.” In addition to their clear medical uses, these cells, which could be turned into particular types of tissues at will in the laboratory, would be hugely useful in research. Liver cells might be used to study drug metabolism and toxicity, while other cell types might be used to test the efficacy of drug candidates. A combination of ES cell and genetic engineering techniques could also generate many interesting cell lines. Just one example: brain neurons that quickly develop the type of amyloid plaque associated with Alzheimer’s disease, providing an invaluable system for testing potential drugs to treat the ailment.
The ES cell could also open an invaluable window on human development, partly because developmental biologists would like to know which genes tell an ES cell to differentiate into more specialized cells. The proteins coded for by such genes could turn out to be new targets for drugs, or in fact be used as drugs themselves to spur, say, the regeneration of worn-out cartilage, or even to grow back receding hair.
Although the scientists at Geron are optimistic that they will be able to deliver on these promises, not everyone shares that upbeat state of mind. In spite of the apparent recent progress, some researchers who have worked with embryonic human cells doubt biologists will learn to control their growth anytime soon. H. Ralph Snodgrass, former chief scientific officer at Geron’s Menlo Park neighbor Progenitor, says, “It’s one thing to say the cells have the capacity to differentiate into all these cell types; it’s quite another to exploit that. There are some significant hurdles.”
Snodgrass is in a position to understand the practical difficulties. In the early 1990s, Progenitor, a biotech firm that also specializes in developmental biology, worked with human blastocysts, hot on the trail of the ES cell’s close cousin-an undifferentiated version of the hematopoietic stem cell (which gives rise to the full complement of cells in human blood). But Snodgrass recalls that Progenitor’s scientists couldn’t control the embryonic cell on anything other than an experimental scale-developing an actual therapy that could withstand the scrutiny of the Food and Drug Administration seemed out of the question. Progenitor has largely dropped that effort, and now focuses on better understanding the genes that control the development process in mouse embryos.
Even those who aren’t quite as skeptical as Snodgrass point out that there may be an easier route to finding a cell that could be useful as a source of replacement tissue. The shortcut involves stem cells that have already changed into a cell family, say bone or nerve, but have not yet given rise to a specific type of cell. These stem cells are a step further down the differentiation tree from the embryonic stem cell. And many scientists believe they could be far easier to isolate (partly because they are still present in adults) and nearly as useful as a source of tissue for therapies involving replacement tissues.
With so many uncertainties and questions remaining, no one is ready to declare the race for the human ES cell over or predict the winner. And it could take years to sort out the competition. Proving one has the ES cell, or even an “ES-like” cell, is no easy task since no one is exactly sure what it should look like.