Boston Lab Small Scale, Grand Achievement

Geneticist Kunkel shows how breakthroughs can be made without big budgets, big staffs, or big bullies When it comes to tackling scientific problems of enormous difficulty, Louis M. Kunkel’s seven-member team at Boston’s Children’s Hospital proves that it isn’t always necessary to have a big staff or to have a big budget. And it’s not necessary to play rough, either. For five years, Kunkel and his crew have been doggedly pursuing the genetic basis of muscular dystrophy. The disease has perhaps a half dozen forms and afflicts tens of thousands of people in the United States. So the urgency is obvious— and so is the possibility of major prizes, perhaps even the Nobel, for the scientists who succeed in decoding the mystery of its genesis. Consequently, there are at least six major teams worldwide, all struggling for the honor and rewards— psychic as well as financial—that would attend any critical breakthrough in learning how to mitigate the effects of the disease. But even with the high-tech tools of genetic engineering, the work of finding the crucial genes and understanding how they go awry is daunting. And no one has been lucky enough to put the whole picture together. Kunkel’s team has been extraordinarily successful, though, staying ahead of its competitors by making one big discovery after another. In 1986, for example, it identified the gene that appears to cause the most common type of the disease— Duchenne’s muscular dystrophy, a sex-linked disorder that occurs in one of every 3,500 live male births and usually kills its victims before they reach the age of 30. By July of last year, Kunkel’s group had completed cloning the coding sequence for the gene. Then, using genetic-engineering techniques and animal antibodies, the team discovered that Duchenne’s dystrophy resulted from the absence in muscle tissue of a previously unknown protein, which they named “dystrophin.” In victims of the disease, the gene coding for dystrophin is apparently defective—hence the absence of the crucial protein. In their latest published work— the May 26, 1988, New England Journal of Medicine, (Vol. 318, No. 21, pp. 1363-1368)—the Boston researchers said Duchenne’s dystrophy victims of any age could now be identified by the fact that dystrophin is missing from their muscles. They found that dystrophin was not similarly lacking in those suffering from the milder and less common Becker’s muscular dystrophy or one of the other versions of the disease. Recognizing the importance of each of these advances in the study of muscular dystrophy, an editorial in the same issue of The New England Journal of Medicine (pp. 1392-1394) lauded the team’s most recent study as “one of a series of landmark papers” to come out of the Boston laboratory. So the question for eager scientists everywhere is: What is the Kunkel team doing right? One clue to the answer may be a surprise in this era of megaprojects and big budgets. Kunkel’s pioneering lab is tiny; his staff consists of two postdoctoral fellows, two technicians, one graduate student, and his secretary. And its annual budget is “on the order of $300,000,” Kunkel estimates, a mere drop in the funding bucket. More Participation The lilliputian team frees Kunkel from being a full-time administrator who directs an army of busy researchers. Drop in his lab anytime, and chances are that Kunkel will be there pretending to be his own technician. “I do part of the experiments because I like to,” he explains. “It gives me more active participation in the lab.” In addition, the small team is close-knit. “We’re small enough that we know what everyone is doing.” says postdoc Eric Hoffman. They should, because sometimes it seems that no one ever leaves the lab. Told that Kunkel estimated a team member’s average weekly hours at about 60, Hoffman just laughs. “It’s more like 70 or 80,” he says. Sometimes the researchers even spend the night. Yet dedication and teamwork don’t necessarily translate into major discoveries. Somehow Kunkel’s team was able to maintain a consistent lead of about six months over its equally driven competitors, avoiding the false trails and side al leys that delay more mortal scientists. “To be successful in such a competitive field, you have to be a little bit better or faster, or a little more clever, plus you have to be lucky,” says Hoffman. Kunkel attributes his success to “hard work and luck.” He also gives some credit to the way his staff is organized. “They each have projects they are working on— sometimes with help from me and sometimes on their own—so they feel it’s theirs,” he says. But others point to the obvious talent on Kunkel’s team. “They are really very bright people,” says Kevin Campbell, a University of Iowa researcher who has collaborated with Kunkel on aspects of the muscular dystrophy probe. Campbell also credits two other factors to Kunkel’s success: the team’s concentrated effort just on muscular dystrophy and advances in genetic engineering techniques, which, he says, “made the time right for it.” Kunkel’s success has also enabled him to take his team down a route not often traveled in today’s hotly competitive world of science. The rewards of breakthrough research seem to be driving many scientists to operate as if thay were market managers for the latest line of computer or protecting the secret formula of a soft drink. In the concurrent race for the gene causing cystic fibrosis, for example, rivalries between teams have become so heated, and notorious, they’ve been written up in the New York Times. Competitors have accused each other of hiding crucial knowledge and issuing tantalizing but misleading reports to trap the unwary into following false trails. Kunkel and his team, however, have taken precisely the opposite approach, sharing key genetic sequences with competitors to study. In 1985, Uta Francke at Yale Medical School gave Kunkel a piece of DNA from a patient suffering from three X-linked disorders, including Duchenne’s dystrophy. Kunkel and graduate student Anthony Monaco were able to isolate and clone missing strands of the sequence, which they then compared to samples from 57 boys with only Duchenne’s. To zero-in on the location of the gene, Kunkel arrived at an unusual collaborative agreement with 24 rival teams in the U.S., Canada, and Europe. Kunkel would supply the piece of DNA so that the other researchers could test-compare it to dozens of Duchenne’s dystrophy victims. Of course, Kunkel wasn’t exactly giving away all his secrets; this study would simply confirm what he was already pretty sure was true. What did Kunkel get for his generosity? His little platoon of seven in Boston was reinforced by a big international army of scientists. Together they confirmed that the sequence was in the immediate region of the Duchenne’s gene, and Kunkel moved on to find the actual gene. But dealing with all the information wasn’t easy. “It took us two years to publish the work,” Kunkel says. The result was a paper with 75 coauthors. The collaborative effort, “was tough,” Kunkel says, “and if you want my opinion, it probably won’t happen again (in muscular dystrophy research." The reason, he explains, is that scientists are working on more specialized bits and pieces of the muscular dystrophy problem, now that the gene has been isolated. Meanwhile, secure in their lead over the rest of the pack and anxious to speed the pace of scientific progress, Kunkel and his team have continued to freely share their data. “When we cloned the entire coding sequence for dystrophin, we sent it—before publication—to other laboratories because we knew they could use it,” he says. “And one of the other laboratories called us back and someone said, ‘You know, it was really a sad moment in the lab when that package arrived here, because we’d been working on this for years and now you’re giving us what were working on,’ “ says Kunkel. “So there was strong feeling, but the spirit was friendly.” Such cooperative effort, Kunkel believes, is the best way to reach the grail everyone is seeking, nothing less than finding a way to “alter the course of the muscular dystrophy in patients.” That’s a far cry from merely identifying the gene that marks one form of the disease. And the 37-year-old Kunkel sometimes wonders if even his team can keep up its frantic pace long enough to make the crucial breakthroughs. All the hard work could “easily “ lead to burnout, he says. “I’ve threatened numerous times that when I reach 45, I will retire and do something else.” But, one suspects, it won’t happen until Kunkel has finally found a successful treatment for muscular dystrophy. Karen Klinger is freelance writer based in Cambridge Mass.

Boston Lab Small Scale, Grand Achievement

Interested in reading more?

Become a Member of