Research: Chicago Researchers Search For Genetic Key To Diabetes

The quest to identify the genetic causes of diabetes makes other hereditary disease research sound almost easy by comparison. Whereas cystic fibrosis, Huntington's disease, and many other disorders are each the result of a single defective gene, the origins of diabetes are far more baffling. In diabetes, several genes seem to be responsible for the malady; environmental influences, such as obesity, play a role as well. None of this daunts molecular biologist Graeme I. Bell. In fact, when he came to the University of Chicago 3« years ago as a Howard Hughes Medical Institute associate investigator, he began examining non-insulin-dependent diabetes mellitus partly because it was such a complex challenge. "The advantage to working on a difficult problem is that no one publication is going to have the complete answer," he says. "That was an important consideration when I was trying to get set up. I didn't want to start working on something and then a month later have some other laboratory who'd been working on it for a bit longer publish the answer." Although Bell is convinced that no single paper can contain the key to the onset of diabetes, recent papers from his team have provided the field with some important clues. In the Journal of Biological Chemistry ("Evidence for a family of human glucose transporter-like proteins," 263:15245-8, Oct. 25, 1988; and "Cloning and characterization of the major insulin-responsive glucose transporter expressed in the human skeletal muscle and other insulin-responsive tissues," 264:7776-9, May 15, 1989), Bell's group has described a family of human proteins involved in glucose transport. The existence of the proteins was not news. But it wasn't until the Chicago team, building upon others' work, was able to sequence and clone the DNA encoding those proteins that the full extent of the proteins' natures, and their role in glucose metabolism, was realized. Since diabetes is characterized by faulty carbohydrate metabolism, the discovery of the genes that encode these new proteins may aid in understanding the disease. Equally as important as the finding itself is the way in which Bell and his team conducted the investigation. "He took an approach, which is classical molecular biology, into a field not dominated by molecular biology," says Morris Birnbaum, a molecular biologist whose team works on glucose transport at Harvard Medical School. "He followed a rationale based not so much on glucose transport, but on genetics and molecular biology," Birnbaum adds. The molecular biology strategy, which is being used by a handful of teams working in diabetes and glucose transport, has breathed new life into the field, Bell says. Most significantly, it has enabled other scientists, especially those who are investigating diabetes from a physiological viewpoint, to gain new perspectives on their own research. "There were many, many groups working on glucose transport, but they didn't really have any idea about the kinds of proteins they were working with," Bell explains. "What we were able to do was put a face on each of them." He adds: "The information we generated now allows people to make antibodies, to use cDNA probes, to look at changes in messenger RNA. So really it opened up the field. Molecular biology provided a rebirth." The tools of molecular biology have served Bell well in the past. In 1979, as a research biochemist at the University of California, San Francisco, Bell was a member of the team that cloned the human insulin gene. Next he spent five years as a founder and senior scientist at a biotechnology startup, Chiron Corp., in Emeryville, Calif. Upon his arrival at the University of Chicago, Bell set out to staff his lab with colleagues who shared his conviction that molecular biology had much to offer diabetes research. As it turned out, most of Bell's dozen team members learned their molecular biology from him. "They came primarily because they had been working in laboratories in which there had been an interest in diabetes, often more from a physiological rather than a molecular biology approach," Bell says. "Now they're learning molecular biology in order to utilize that tool in addition to the physiology." The result has been the creation of a team with an enormously deep and broad understanding of human physiology, from the molecular level on up. Ironically enough, Bell downplays the clinical knowledge of his associates. In a brief, humorous aside, he even refers to the molecular biology training he provides medical researchers outside his team as "technology transfer to the Third World." Yet his team members, many of whom are M.D./Ph.D.'s, point to their medical expertise as one of their strengths--and forgive Bell for not trumpeting this. "He denigrates us M.D.'s a lot," declares team member Charles Burant, showing not the least bit of concern. "But I think he does it more tongue-in-cheek, maybe out of a little jealousy." A fellow in endocrinology who also has a Ph.D. in biochemistry, Burant says that he has found his diverse background quite useful. "We're getting a lot of clinical material. You get clues about what's going on in diabetes with the clinical material. A lot of ideas get kicked around, articles from the New England Journal of Medicine [get read]." Susumu Seino, an M.D./Ph.D. who has been in Bell's lab since its inception, concurs. He declares that his research at Chicago finds its roots in his experiences as a physician, recalling that he and team member Hirofumi Fukumoto "started from clinical medicine and saw many patients. When we faced a problem we became interested in the disease and in what's going on in this patient." That curiosity prompted Seino to enter basic research, in which he says he still "always links the molecular biology to the clinical." Hard work, too, plays a role in the success of this team. These scientists work long days, often spending 70 or more hours at the lab each week, including Saturdays and Sundays, "beavering away," as Bell describes it. Burant says that Bell puts in more hours than anybody, occasionally even working at the bench himself, and urges his associates on with comments like: "Somebody is going to scoop us. We need to get this done." "Beavering away" and "scooped" are revealing words, implying as they do that success comes to those who persevere, that talent and brains alone can't do the job. A team that gets scooped, after all, is often on exactly the right track but just a length behind the leader. And the best way Bell's team has found to stay at the forefront is to beaver away steadily and not concern itself too much with the competition at Harvard Medical School--or Washington University or the Whitehead Institute. Indeed, hard work is the only weapon Bell uses to avoid getting scooped. Unlike those scientists who jealously guard their work-in-progress, Bell regularly swaps information, reagents, and cDNA clones with other labs. "We're very frank about what our interests are and what we're doing," he says. "We provide these clones even to people who potentially could compete against us." That spirit of cooperation, and shared purpose, may also be the driving force behind the lab's many collaborations. These joint projects go "up and down and sideways," says Burant, by way of describing the partnerships that occur between team members and other scientists both inside and outside the University of Chicago. Among the team's collaborations are projects with Jeffrey Pessin at the University of Iowa, Samuel Cushman at the National Institute of Diabetes and Digestive and Kidney Diseases, and Paul Pilch at Boston University Medical School. Pilch, one of the authors of the "Cloning and characterization" paper, observes that Bell's generosity with data and reagents "has had the effect of speeding the [glucose transport] field along very dramatically." This is as unusual as it is commendable, Pilch quickly points out. "Graeme is a bit of an old-fashioned scientist. It is my perception that most 1990 cell and molecular biologists have enormous egos and the ego is visible in all their dealings. Graeme is old-fashioned in the sense that he places getting the scientific answer ahead of his ego." Predictably, swelled egos have no place in Bell's lab, where cooperative efforts prevail. When team members run into trouble, they know their colleagues will willingly offer advice and technical assistance. Seino says, "I think that working as a team is very important for success, rather than this person doing this project independently. Basically, when this project is behind, then somebody helps." He slowly raises both hands, palms up, emphasizing how the fortunes in the lab are bound together and must either rise or fall together. For Seino, such a mode of operation helps make the lab a comfortable, even "homey," place. "That's very important, I think, to feel at home," he says. And the homey feeling extends beyond the collage of lab members' photos mounted on white posterboard or the vacation postcards adorning the refrigerator. For Seino it really is like home; his wife, Mitsuko Seino, is a technician here. So is Burant's wife, Mary Kay Treutelaar. In fact, family connections abound. Burant studied with team member John Buse's mother, Maria Buse, at the Medical University of South Carolina. And Seino's brother, Yutaka Seino at Kyoto University School of Medicine, is an occasional collaborator. Do all these family ties help promote congeniality and communication? It's hard to say, but certainly it doesn't hurt. "It's just an ordinary lab," Bell declares. But his wry smile invites challenge, and his research results belie the comment. Certainly many scientists would count themselves lucky if their labs were as "ordinary." Liz Marshall is a freelance science writer based in Pittsburgh.

Research: Chicago Researchers Search For Genetic Key To Diabetes

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