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
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
“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
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,”
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
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
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
“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.”