Douglas Melton, co-director of the Harvard Stem Cell Institute, has figured out how to transform one type of cell in a living animal into another, using a new process his research team has dubbed “direct reprogramming.” Melton, a Harvard College Professor who is devoted to treating or curing diabetes, created insulin-secreting pancreatic beta cells specifically. But reprogramming holds promise, as well, for treating other diseases that involve missing cells, including cardiovascular and neurodegnerative conditions such as Parkinson's and ALS.
Melton and his colleagues achieved their stunning result by delivering a combination of three transcription factors—a class of genes known to regulate cell fate during early development—to target cells in the pancreas of a mouse. During a years-long process of elimination, they chose the three genes—which were delivered using a virus—from among more than 1,100 potential candidates they had identified as being expressed in the embryonic pancreas. In adult mammals, about 95 percent of the pancreas consists of exocrine cells, while just 1 percent are beta cells that produce the insulin that is critical for the regulation of blood glucose levels. Using their three introduced genes, Melton's team was able to “flip” exocrine cells to become beta cells. The resulting individual cells are indistinguishable in shape and function from pre-existing beta cells.
Unlike conventional stem-cell science, which involves using undifferentiated cells and then figuring out how to coax them to become a particular cell type, Melton's work shows the way to a shortcut for treating any disease in which a cell type is missing. The trick to Melton's feat was learning which genes to use. “The idea of reprogramming one differentiated cell type into another of an adult tissue is very exciting, and it is applicable to achieve the regeneration of different types of cells in the body," says Paola Arlotta, an Assistant Professor of Stem Cell and Regenerative Biology at Harvard, who is performing related work to reprogram neurons of the central nervous system. Different genes will likely be needed to obtain reprogramming in individual tissues, but substantial progress is now being made in this regard.
“It's a wonderful piece of work,” says Sir John Gurdon, an emeritus professor of developmental biology at the University of Cambridge in England who oversaw Melton's graduate work at Oxford. “Particularly impressive is the idea of trying to derive the required cells from a related cell type, rather than going from adult cells back to the beginning and out again. It's much more logical, really.”
In some ways, Melton's path away from strict stem-cell research —de-differentiating adult cells to make them totipotent again, and then re-differentiating them to create new cell types—was inevitable, at least in his search for a cure for diabetes, in the wake of an earlier Nature paper he wrote in 2004. In it, he described his finding that in adults, new beta cells don't derive from stem cells, as so many other tissues in the body do; instead, they are produced by existing beta cells. This suggested that there might not be an easy way in adults to coax stem cells to become beta cells.
Melton's feat echoes that of Shinya Yamanaka of Kyoto University, who in 2006 employed viruses to reset adult cells to a primordial state. These induced pluripotent stem cells (iPS cells), as they are known, can be prodded to differentiate into more specialized kinds of cells. But no one has figured out all the steps to do this yet. Melton's simpler approach, directly changing one adult cell type into another, is the first to achieve such success. The Yamanaka technique also uses a type of virus that can induce cancer, whereas the virus employed in Melton's technique does not. Melton nevertheless hopes to identify a drug that will mimic the action of the gene transcription factors he has identified as critical for the transformation of exocrine cells into beta cells. This would facilitate FDA approval of treatments in humans, which could be as little as 2-5 years away, he said.
In announcing his discovery, Melton emphasized the importance of continuing to work with iPS and embryonic stem cells derived from fertilized human eggs because of the critical insights they continue to provide in the field of developmental biology.
For background on stem-cell research at Harvard, see this magazine’s previous cover article “Stem-Cell Science.” Click here to read a copy of the Harvard press release about the discovery.
