Nobel Prizes recall promise of and obstacles to stem cell medicine

Sir John Gurdon of the University of Cambridge and Shinya Yamanaka of Kyoto University were recently awarded Nobel Prizes for their work with induced pluripotent stem cells.

We used the occasion to ask Tim Townes, Ph.D., chair of UAB’s Department of Biochemistry and Molecular Genetics, for his comment on the state of the iPSC field, its wondrous potential and the remaining obstacles to human treatment.

Gurdon discovered in 1962 that an entire living tadpole could be created from an already mature frog intestine cell using a technique called nuclear transfer. But his technique required the use of an embryo, and led to the controversy over the potential use of human embryonic stem cells. Yamanaka’s work ended the controversy by showing you could turn skin cells into stem cells just using proteins called transcription factors (no embryos needed).

“Proving that a fully differentiated bodily cell could be turned back into a stem cell, and determining all the steps necessary to do so, were absolutely phenomenal accomplishments worthy of a Nobel Prize,” says Townes.

Just after Yamanaka did his Nobel-winning work in 2006, Townes’ team, in collaboration with scientists at the Massachusetts Institute of Technology (MIT), "cured” sickle-cell disease in mice using genetically altered induced pluripotent stem cells. This was the very first demonstration that researchers could not only take a differentiated cell back to a stem cell, but could also fix a genetic problem in iPS cells and transplant them to cure a disease.

In a perfect world, says Townes, you could take a few skin cells from a patient and coax them back along the differentiation pathway to become stem cells, which are capable of becoming many kinds of cells. Then you would program the stem cells to become, say, red blood cells to treat sickle cell anemia, or white blood cells to replace those causing leukemia. You might be able to make stem cells that attack tumors, or even keep them on ice for years to fight a disease you don’t have yet.

The problem is that the field must prove such cells are safe and potentially effective in humans before they are ever given to humans, even in clinical trials. Stem cells in our body rarely move backward from being fully mature differentiated cells to immature stem cells. Some kinds of tumor cells are among the exceptions, so it pays to tread carefully.

The traditional solution is to create a model of the disease in mice — for instance, ones genetically engineered to have a human gene responsible for a disease. But mice and humans have evolved to have considerable differences, and many treatments that work in one do not work in the other. Researchers are currently debating whether or not studies in a larger animal like a pig are needed to better ensure safety. Furthermore, how long do you wait after giving stem cells to an animal before you declare the treatment to be safe? It may be a few years, says Townes.

In the meantime, he and others are studying whether they can make the treatments safer by using more mature stem cells. After a certain point in the process of maturing, stem cells can no longer move backwards along the pathway to become immature (potentially cancerous) again. Treatments based on mature stem cells would not provide a permanent cure for a disease like sickle cell. Patients might need a monthly infusion, but it could potentially still bring considerable relief.

For those interested in learning more about induced pluripotent stem cells, Townes recommends the National Institutes of Health's stem cell website and its research site. Also see Yamanaka’s recent GEN article, which warns against putting stem cell treatments into human patients too soon, or without proper proof in place. Then there is the iPSC content offered by Genetic Engineering & Biotechnology News.