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Stemming Disease with Basic Research Douglas Melton’s desire to cure diabetes is professional and personal By Steve Mirsky What is the best way to get from the Midwest to Harvard University? For Douglas Melton, the optimal route to Cambridge, Massachusetts, passed through Cambridge University in England. Stops that he made there prepared him in a unique way for the subject matter that became his research focus: stem cells. Learning molecular biology gave Melton the scientific expertise to carry on such research. The study of the history and philosophy of science provided a useful context for an investigator who would later find himself engaged in biomedical research with social and political overtones. The son of a grocery store manager, Melton was born in Chicago and studied biology at the University of Illinois at Urbana-Champaign. A Marshall scholarship in 1975 took him across the Atlantic to Cambridge University, where he received a degree in the history and philosophy of science. “But I realized that even if I were a very good practitioner of that discipline,” Melton says, “I would spend my life commenting on what other, very smart people thought about.” Melton thus decided to become an experimental scientist, where he thought his chances of making original contributions were much higher. “I was fortunate,” he says, “to work in the laboratory of Sir John Gurdon, the first person to create an adult animal by nuclear transfer—by cloning.” In the 1960s, Gurdon had shown in frogs that you could remove the DNA from an egg, replace it with the DNA from an adult cell, and have an egg that could develop into a genetic duplicate of the DNA-donor adult. In Gurdon’s lab, Melton studied the early stages of development—how those cells with the potential to become all the different types of tissue in the body have their fates chosen. His inquiries in that basic-science question continued when he moved to Harvard University in 1981. In 1993, Melton was still studying frog cell fates when his own fate took a turn: his six-month old son was diagnosed with type I diabetes. “When something happens to your child,” Melton explains, “it gets your full attention. And I did what any parent does. I said, ‘I’m not going to stand by and do nothing. What can I do?’ Some parents raise money to help support research. Other parents lobby for public policy. In my case, I was fortunate to have the scientific training that allowed me to move my research focus to an area that would be immediately relevant to diabetes. But the point is that I did what any parent does.” In type I diabetes, the beta cells of the pancreas, which produce insulin in response to the presence of the sugar glucose, come under attack by the immune system and are destroyed, leading to a vast array of deleterious health consequences. “So I moved from looking at very early frog development to fully focusing on how mammals—humans and mice—make pancreatic tissue,” Melton says. “It’s still a problem in developmental biology, but it’s much more applied. And it has a very explicit medical goal.” Melton’s desire to address this medical issue was compounded later when his daughter also was diagnosed with the disease. Embryonic stem cells are totipotent—they have the potential to be any cell in the body. So-called adult stem cells, stem cells that are still present in fully developed organisms, are pluripotent or unipotent—they have the potential to be only a few kinds of cells or just one kind. For example, adult stem cells for blood exist—if you donate a pint of blood, your body quickly replenishes its own supply. A key question, therefore, was whether there might exist an adult stem cell that could make new pancreatic tissue to replace the beta cells lost in type I diabetes. “We’ve shown through a series of experiments that for some tissues, including the pancreas, there is not an adult stem cell,” Melton notes. “And that then says there are only two ways you can make more beta cells. One is from an embryonic stem cell. The other is beginning with a donor adult beta cell—say, from a cadaver—and then trying to make that donated cell make more of itself by dividing. We’re working on both of those possibilities. But I think embryonic stem cells hold the greater promise.” Melton’s research suggests that adult beta cells can’t divide and redivide forever, which could make it problematic simply to make enough of them to restore function in diabetes. The challenge with embryonic stem cells is, in a sense, the opposite—they’ll continue to divide numerous times but remain stem cells. The issue there is to coax them into becoming the beta cells that diabetics need. Melton’s lab is teasing out the details of the process whereby the stem cells “decide” to become beta cells. Another challenge would be how to keep those new beta cells from suffering the same destiny as the diabetic patient’s original beta cells. Because the immune system is primed to attack and destroy the beta cells in diabetes, implanted beta cells could also be targets. One promising possibility is called encapsulation. “It’s just putting the cell in a fishnet membrane,” Melton explains. “Glucose can come in and insulin can go out, but the immune system cells can’t get in and so can’t attack and kill the beta cells. The results from work done so far make many people think that that you could have a packet of cells about the size of a dollar bill, thin and long, and implant that packet into a patient. And those protected cells would control the patient’s glucose levels.” Melton is also interested in striking at the heart of the problem—the autoimmune response. To that end, he works on what is called somatic cell nuclear transfer, the same basic procedure that Gurdon performed. A somatic cell is a cell taken from any tissue in an adult body. Somatic cell nuclear transfer involves taking the DNA from that somatic cell and putting it into an egg from which the egg DNA has been removed. Melton thinks that by implanting DNA from diabetic patients into unfertilized human eggs, he can eventually make a diabetic embryonic stem cell. And by watching that cell develop, he may be able to see exactly where the development veers off on the direction that signals the immune system to attack it. “That’s a longer term project,” Melton says, “a decade or longer. But I believe that is one of the best ideas going to answer this difficult question about the causes of degenerative diseases, including Parkinson’s, Alzheimer’s, and other diseases that involve more than one gene and an interaction with the environment. What we’re really trying to do is move the study of these degenerative diseases from people into a petri dish.” For most researchers, the challenge is merely scientific. However, stem cell research is viewed by some as controversial—views differ regarding the status of a human embryo. As a result of tight federal regulation of embryonic stem cell research and restrictions on funding, Melton faces administrative and logistical issues that go well beyond those that confront a typical scientist. To address those issues, Melton initiated a collaboration in 2001 among Harvard University, Boston IVF, and the Howard Hughes Medical Institute to develop new human embryonic stem cell lines. The IVF clinic, one of the nation’s largest fertility clinics, supplies frozen embryos, with the donors’ consent, left over from fertility treatments. The project is funded by HHMI. To further the effort, Melton and Dr. David Scadden started the Harvard Stem Cell Institute in 2004, a collaborative effort involving Harvard University and its eight affiliated hospitals. The Harvard facility has created new stem cell lines that are now available for research. And the facility distributes the cells to other stem cell researchers free of charge. “We are committed to this research,” Melton says, “and we’re going to find a way to do it.” More information 11/06
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