Douglas A. Melton, an HHMI investigator at Harvard University, is exploring what gives stem cells their special abilities—what accounts for their "stemness." And he has found hundreds of genes likely to play a role.

Together with his colleague Richard C. Mulligan and other Harvard associates, Melton compared the activity of the three best-known types of stem cells—embryonic, neural and hematopoietic (blood-forming)—with the activity of other types of mouse cells. The researchers discovered that 216 genes were turned on at least three times more frequently in the stem cells than in other cells. "These 216 genes are likely to reveal core stem cell properties, or 'stemness,' that underlie self-renewal and the ability to generate differentiated progeny," they reported in the September 12, 2002, issue of Science Express.

When the scientists tried to find out where these 216 genes were located, they were surprised to learn that only 60 of them had been mapped to any chromosome. An astounding fraction of these latter genes—12 out of 60—sat on mouse chromosome 17, which also contains genes known to be involved in embryo development and in sperm development. The 12, of course, will now be studied with special interest.

Another surprise was that the stem cells expressed unusually large numbers of "expressed sequence tags," which mark genes of unknown function. "For young scientists, this finding is especially exciting because it shows that ... no one has a clue to what the gene products do," says Melton. "It's easily a decade's worth of work just to define the functions of the genes that we have defined as characteristically active in these stem cells."

Although all stem cells expressed the 216 genes, they did so in varying proportions. "The three types of stem cells were not identical" in their activity, Melton points out. The activity of hematopoietic stem cells was more similar to that of other cells in the bone marrow than to the activity of any other samples, he says. By contrast, "embryonic stem cells and neural stem cells are much more similar to each other than they are to their differentiated counterparts .... This fits with a 'default' model we proposed, which is that the default fate of embryonic stem cells is to become neurons."

The team's studies are likely to aid the search for new types of stem cells, Melton believes. "For example, nobody has yet been able to identify adult pancreatic stem cells—a central effort in our laboratory," he says. "But now we know that if we're going to isolate such cells, we should look for those that express many of these 'stemness' genes."

Melton is motivated by more than scientific curiosity. Hoping to find a cure for his 10-year-old son, Sam, and millions of others with type 1 (juvenile) diabetes, he launched a major drive about a decade ago to turn human embryonic stem cells into the special kind of pancreatic cells, called beta cells, that supply the insulin diabetics lack. This effort has been slow going, he reports, but it did lead him to his stemness discoveries.

—Maya Pines

Photo: Kathleen Dooher

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Reprinted from the HHMI Bulletin,
December 2002, pages 22-27.
©2002 Howard Hughes Medical Institute