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Summer 2003
photo by Arnold Adler
Roderick MacKinnon
A “detective at heart” wins Nobel Prize in chemistry

When Tufts Medical School graduate Roderick MacKinnon, M82, H02, set up his new laboratory at Rockefeller University in 1996, only one postdoctoral student from his Harvard Medical School lab volunteered to join him. His wife, a chemist, felt so sorry for him that she agreed to help out with the research. Other colleagues thought he was crazy to leave a full Harvard professorship and attempt something so difficult and far from his area of expertise.

But in just two years, MacKinnon and his small X-ray crystallography lab would make a dramatic breakthrough that provided the first detailed portraits of a class of proteins that underpin all movement, sensation, and thought.

In October 2003, MacKinnon, 47, was jointly awarded the Nobel Prize in Chemistry for visualizing the opening and closing of potassium ion channels on cell membranes, an achievement that promises to advance medical research on diseases involving malfunctioning electrical impulses in nerves and muscles.

“I can't believe that the Swedish Academy has given me this award,” said MacKinnon, the John D. Rockefeller Jr. Professor, head of the Laboratory of Molecular Neurobiology and Structural Biology, and a Howard Hughes Medical Institute investigator at Rockefeller University. “I'm just a regular person and I was just a regular kid like those in school today. I hope they realize that they can expect a lot of themselves.”

MacKinnon grew up examining bugs, blades of grass, and pond water under a small microscope in Burlington, Massachusetts. “I was a day dreamer,” says MacKinnon. “Teachers kept telling me to pay attention.”

He credits his high school gymnastics coach for teaching him that he could accomplish “beautiful” things through hard work and discipline. He later applied that attitude to tackling the medical books at Tufts—and scientific puzzles beyond.

MacKinnon majored in biochemistry at Brandeis University, graduating magna cum laude in 1978. He met Alice Lee there in an honors physics class, and they married in 1979. He also undertook a research project with a new professor, Christopher Miller, who became his lifelong mentor and is now a Howard Hughes Medical Institute investigator at Brandeis.

“Dr. Miller seemed to have so much fun. Being a research scientist seemed like a wonderful life,” MacKinnon says. Still, he decided to go to Tufts Medical School, against Miller's advice.

“I knew he was made to be a research scientist, so I tried to dissuade him,” Miller admits. But MacKinnon worried that he couldn't support himself as a researcher and felt that medicine offered a more secure career path.

"I also thought doctors were practicing scientists,” MacKinnon explains, “but I learned that's not true. Eight years later, I came back to Miller. I'm a slow learner.”

On the contrary. MacKinnon impressed everyone with his intense love of learning and his resolve to teach himself new fields. Dr. Paul Tung, M82, a Tufts classmate who now specializes in endocrinology and diabetes in New Hampshire, recalls MacKinnon encouraging him to read papers by a Nobel laureate physicist.

Classmate Dr. Barbara Kane, M82, who practices at Massachusetts General Hospital, told the spring 2000 Tufts Medicine magazine, "He was always curious, always asking questions" at the end of a lecture, such as, "Why does this happen? How do you explain it?"

Another classmate, Dr. Marc Montminy, M84, who is now a diabetes researcher at the Salk Institute, remembers talking to MacKinnon about their mutual interest in research and how supportive Tufts was of that interest, although the school's major focus was clinical medicine. “When Rod grabbed onto something,” Montminy says, “he became totally devoted to it.”

After graduating from Tufts in 1982, MacKinnon completed an internship and residency at Beth Israel Hospital in Boston. “He was exceptional and was allowed to short-track into research in my cardiology laboratory,” Beth Israel's Dr. James P. Morgan says. Although MacKinnon was an excellent clinician, Morgan knew he had doubts about continuing. “I urged him to hedge his bets and get cardiology training,” Morgan says.

MacKinnon received a training grant from the National Institutes of Health to study how the heart relaxes and contracts, which got him interested in potassium channels--and on the path toward the Nobel.

That research confirmed what Miller had suspected: MacKinnon wanted to be a research scientist, not a physician. “I realized that doctors don't get to the nuts and bolts of how little things actually work, which is what excites me,” he explains. That excitement led him back to Miller for postdoctoral studies in biophysics at Brandeis in 1986, and then on to his own laboratory at Harvard Medical School in 1989, where he focused on molecular biology, particularly exploring potassium channels. Potassium channels act as both gateways and gatekeepers on cell membranes, controlling the flow of ions and enabling brains to think, muscles to move, and hearts to beat. Malfunctioning ion channels contribute to epilepsy, arrhythmia, and other conditions.

But why did the channels admit potassium and nothing else? He and other researchers explored the genes for the section of the channel that opens and closes like a pore in the cell membrane. Amazingly, every species on earth has exactly the same instructions for that pore; nature thought it was the perfect solution.

“How exactly did it work?” MacKinnon recalls wondering. “I couldn't solve that puzzle without seeing it.” So he decided to learn X-ray crystallography, which produces three-dimensional images at the molecular level. A few problems, though: No one had crystallized an ion channel protein before, and he didn't know anything about this difficult technology. Besides, he didn't have an X-ray crystallography lab.

Rockefeller heard of his plight and lured him away from Harvard with just such a lab. Miller again advised him against this potentially career-ending move, and so did many others. "Nobody else tried this type of research because it was so immensely overwhelming and would never work," Miller explains. "Rod bet the farm and won."

Within just two years, MacKinnon stunned his doubters with a breakthrough paper published in the April 1998 issue of Science. He had not only taught himself this new technology, he had also captured the image of the pore and could explain how it simulates the chemistry and electrical forces of the ion's normal watery environment.

“The ion thinks it's in water when it's in the pore,” MacKinnon says. Other types of ions don't fit as snuggly in the pore, so they aren't enticed to enter. Since then, he has discovered more intricacies of the ion channel's gate-keeping activities. “For the first time, we can see the most basic element of hardware in our brains,” Miller says. “He changed the study of ion channels from the old way of doing it by indirect measurements by imagining how to look at them directly.”

MacKinnon, who shares the Nobel with Peter Agre of Johns Hopkins for separate research on other membrane channels, hopes his work will advance the effort to develop new therapies for diseases involving the body's electrical miscues. He feels humbled by the award, but admits to an extraordinary ability to focus on topics he cares about passionately.

But MacKinnon wasn't exactly flying under the scientific radar before the award. In 1997, he was named a Howard Hughes Medical Institute investigator, and Science magazine included his work as one of ten “Breakthroughs of the Year” in 1998. He received the 1999 Lasker Award, which is considered the “American Nobel” for medical and biological research and often foreshadows a future Swedish Nobel. The next two years brought an induction into the U.S. National Academy of Sciences, and the Rosenstiel and Gairdner awards.

In 2002, MacKinnon was the keynote speaker at Tufts University School of Medicine commencement, and the recipient of an honorary doctor of science degree. At that event, Tufts President Lawrence S. Bacow cited his accomplishments, “A physician by training and a detective at heart, you have drawn upon your Tufts medical education to uncover fields that previously eluded definition...Your discoveries...will influence human health and health care for generations to come.”

MacKinnon, in turn, urged the graduating students, “Don't be afraid to take a chance. What is most important is that you find your passion and pursue it.”

As Dr. Morgan, his proud former colleague at Beth Israel, puts it, “If he had listened to us, he wouldn't have won the Nobel Prize.”