WEB EXCLUSIVE

The Nobels: Behind the Music

By Laura Wright|Wednesday, October 15, 2003

For one week in October each year, the announcement of the Nobel Prizes lands arcane scientific concepts on the front pages of the papers and briefly imbues staid research labs with the carnival atmosphere of a Hollywood gala. On October 8, scientists at Rockefeller University in New York City got their turn in the spotlight, celebrating the crowning of Roderick MacKinnon, a professor of molecular neurobiology and biophysics, as a Nobel Prize winner in Chemistry for 2003. McKinnon responded by providing a personal perspective on what it means to win a Nobel. DISCOVER reporter Laura Wright was on the scene.

It is the wee morning hours of October 8, 2003, and Roderick MacKinnon lies asleep in his bed in his quiet summer house on Cape Cod. At around six o’clock, he wakes to his telephone ringing. It’s Wendell Chin, an assistant in his laboratory at Rockefeller University. “You’ve won the Nobel Prize,” Chin says. He’s just seen the news on the Web. In disbelief, MacKinnon tells Chin to get off the phone: He wants to go online to see the news himself, but he has only a dial-up Internet connection. MacKinnon logs on and does a quick Google search on Nobel Prize. There’s no mention of his name or anyone else’s under Chemistry. Wendell must be wrong, he thinks. He logs off. If it were true, surely someone else will call soon.

MacKinnon never gets back to sleep. The phone rings again. Another caller congratulates him. “Did you hear it from anybody from Sweden?” MacKinnon asks. No, just from folks at Rockefeller. Another call. Same news. But this time the person on the line is Paul Nurse, the president of Rockefeller University and a Nobel laureate himself. A credible source, MacKinnon decides. Finally, he believes that he has indeed won a Nobel Prize.

The potassium ion channel's selectivity filter allows

one kind of ion to pass into a cell—such as these four potassium ions (blue and green spheres, above), which fit perfectly into the notches between oxygen atoms (red)—while blocking out other ions.

Image Courtesy Roderick MacKinnon, The Rockefeller University.

Now, a few hours later, MacKinnon stands in front of cameras, reporters, and his Rockefeller colleagues in a university auditorium and humbly thanks those who have helped him over the years — the National Institutes of Health, the Howard Hughes Medical Institute, Rockefeller University, his students and colleagues, and most of all, his wife, Alice. “All of this work could never have been done by me alone,”  MacKinnon says. “It’s all the young scientists, the students and postdocs who come to work with me from all over the world, who make all the difference.”

The Nobel committee singles out one other scientist in particular. MacKinnon, a 47-year-old biophysicist, shares the 2003 Nobel Prize in Chemistry—and the $1.3 million purse—with Peter Agre, a 54-year-old biochemist at Johns Hopkins University. The pair is awarded the prize for their discoveries concerning molecular channels in cell membranes. Agre identified the protein that allows water, but not other small molecules or atoms, to pass through cell membranes. MacKinnon is honored for discovering the fundamental processes that mediate communication in the nervous system through his work on the structure and mechanics of ion channels, the microscopic pores in cell membranes that control the movement of charged atoms. The two researchers’ combined work promises to lend insights into myriad biological processes: the control of heart rhythm, the generation of nerve impulses, the secretion of hormones, and the loss of fluid control that occurs in cystic fibrosis.

MacKinnon’s work on ion channels elucidates a decades-old biological conundrum. In animals, ions carry electrical impulses from cell to cell. This flow of electrically charged atoms is, in essence, what turns thought into action. For years scientists had believed that there were channels that usher ions through the cell membrane, but nobody had seen their structure nor understood the mechanics of the process. Ions are naturally drawn to water and repelled by fats, so how they were drawn through an oily cell membrane was a mystery. MacKinnon, with dogged persistence and enough knowledge of enough disparate scientific fields to warrant several Ph.D.s, discovered not only the gatekeeping proteins’ physical structure but also the chemical and electric mechanisms used to control ion flow—all within the seven-year period from 1996 to 2003.

In the beginning, it was not at all clear that McKinnon had chosen a winning direction for his research. In fact, when he left his tenured position at Harvard University in 1996 to set up his laboratory at Rockefeller University, many questioned his sanity. Trained as a medical doctor at Tufts University, MacKinnon was then studying electrophysiology — a field that has nothing to do with investigating atomic structures. Desperate to learn exactly how electrical impulses are transmitted at the most basic level, he hatched a plan that would let him watch it happen. First, though, he’d have to teach himself X-ray crystallography, a process for visualizing molecular structures by shining a focused X-ray beam off a crystal and watching how the rays bounce off individual atoms. To gain that kind of expertise, MacKinnon would have to master computer science, math, physics, chemistry, and biology to make it all work.

One brave postdoc jumped Harvard’s ship to go to Rockefeller with MacKinnon, bringing his new lab’s staff to two. Soon his wife, a chemist, joined the team. “Alice starting working in the lab because she felt bad for me,” MacKinnon chuckles. Many of his colleagues predicted it would take MacKinnon a decade to see the ion channel at work. He was undeterred by this forecast. “My feeling was, So what if it takes 20, if I got to see it before I died,” he says.

MacKinnon didn’t have to wait nearly that long. Two years later he saw the pore structure, or at least a detailed computer representation of it. Another three years and he figured out how the pore chemically identifies which ions should be granted passage through the channel. And finally, earlier this year, MacKinnon discovered the voltage gating structure that transmits electrical impulses across cells, linking neurons and muscles—mind and body.

At the news conference, reporters pepper MacKinnon with questions, and he replies quickly and lightheartedly. His tousled auburn curls complete the picture of a man whose energy never fails to match that of his voice—at least on this day. What will he do with all that money? He’ll use the money to finally buy a cell phone and a sea kayak, he replies, and his eyes all but shut tight as he flashes his easy smile. But really, he’ll just keep hacking away at the kind of scientific puzzles that have brought him to this point. “When I go to sleep at night and wake up in the morning, they’re [ion channels] still on my mind. So that’s what I’ll keep doing,” he quips. MacKinnon scans a crowd dotted with white lab coats and budding scientists. When he speaks directly to the young scientists, his tone turns serious: “Let the question drive what you do. Don’t let anybody say you can’t do it, because you can.” Perhaps his love for his question gave MacKinnon the focused intensity that allowed him to discover the ion channel structure and to watch it at work. He certainly seems to think so. He wanted to see it so badly, he says, that he invested as much effort in the laboratory as necessary to succeed.

Later, sitting in front of a computer screen in a closet-sized room in his laboratory—a place where hallway corkboards are papered with the covers of journals such as Science and Nature that have highlighted his lab’s work—he scrutinizes tiny images of ion channels and molecular structures, looking for his favorite. “There’s a very beautiful picture that I like the most,” he says, hunching toward the screen. An image appears, a scaffold of colorful sticks and arcs that resembles a carefully constructed Tinkertoy tower. It’s the potassium ion channel’s selectivity filter, the feature that ensures that only potassium ions pass through the pore. MacKinnon spins around in his chair, grinning ear to ear, folds his arms, and crosses one socked-and-sandaled foot over the other. “It’s my favorite picture. It’s what I want on my tombstone,” he bubbles. “For people who know me, this is the picture.”

Leaning toward the computer monitor, he points at the red “oxygens” and blue “potassiums” on the screen, explaining how the oxygen atoms hug the potassium ion as it passes through the structure, mimicking the watery environment that a potassium ion prefers. This is how the body’s crafty biochemistry tricks an ion across the oily barrier of a cell membrane. A photographer points her camera at MacKinnon’s wide-eyed and bespectacled face. Like a proud parent, he deflects the lens. “Take the picture, not me!” he laughs, flapping his arm toward the intricate molecular model floating on his computer screen.

The winners of the 2003 Nobel Prizes

The week of October 6 marks the announcement of this year’s crop of Nobel laureates. Among those whose accomplishments will be extolled at the December 2003 ceremonies in Stockholm are:

Physics

Alexei A. Abrikosov, Vitaly L. Ginzburg, and Anthony J. Leggett

Alexei A. Abrikosov, Vitaly L. Ginzburg, and Anthony J. Leggett share this year’s Nobel Prize in Physics for their pioneering work in two fields of quantum physics, superconductivity and superfluidity. Abrikosov explained the theory of superconductivity in strong magnetic fields. He based his work on Ginzburg’s theories, which refined scientists’ understanding of superconductors that repel magnetic fields. Leggett is honored for explaining how atoms interact and are ordered in superfluids—liquids that have no internal friction.

Chemistry

Peter Agre and Roderick MacKinnon

Peter Agre and Roderick MacKinnon share this year’s Nobel Prize in Chemistry for the discovery of structures and mechanisms that transport water and ions through cell membranes. A decade ago Agre identified the first of 11 water channel proteins, or aquaporins, that are now known. Aquaporins are a critical part of the blood-brain barrier and are essential for water transport in muscle, lung, and kidney tissues. Over the past seven years, MacKinnon determined the physical, chemical, and electrical structures of the ion channel, the porelike protein that controls the most basic functions of the nervous system.

Physiology or Medicine

Paul C. Lauterbur and Sir Peter Mansfield

Paul C. Lauterbur and Sir Peter Mansfield jointly receive this year’s Nobel Prize in Physiology or Medicine for their work developing magnetic resonance imaging — familiar to many patients as MRI — for medical diagnosis, treatment, and follow-up. In a strong magnetic field, atomic nuclei rotate at a frequency proportional to the strength of the field. If they absorb radio waves of the same frequency, their energy state increases, and they are said to resonate. When they return to a lower energy state, they emit radio waves. By tuning into the effects of magnetic resonance, Lauterbur developed a method for creating two-dimensional pictures of a subject in a magnetic field where a gradient has been introduced; Mansfield devised a mathematical technique to analyze such information to create a useful medical imaging technique.

Peace Prize

Shirin Ebadi

Shirin Ebadi is honored as this year’s Nobel Peace Prize winner for her unfailing support of basic human rights as a lawyer, judge, writer, and activist. A promoter of women’s and children’s rights and democracy in Islamic culture, she was the first female judge in Iran before she was forced out in the 1979 revolution. The Norwegian Nobel Committee recognizes Ebadi’s work with the hope that "the Prize will be an inspiration for all those who struggle for human rights and democracy in her country, in the Moslem world, and in all countries where the fight for human rights needs inspiration and support."

Literature

John Maxwell Coetzee

J. M. Coetzee takes this year’s Nobel Prize in Literature for his oeuvre of exquisitely composed, analytically acute literary works that examine the diaphanous facade of morality in Western civilization. His novels and autobiographical works draw on the culture of apartheid and its aftermath but vary tremendously in setting and in tone. Coetzee was the first writer to win the coveted Booker Prize twice, first in 1983 for Life and Times of Michael K and again in 1999 for Disgrace.

Economics

Robert F. Engle and Clive W. J. Granger

Robert F. Engle and Clive W. J. Granger share this year’s Bank of Sweden Prize in Economic Sciences (the only one of the prizes not established by Alfred Nobel) for developing new methods to analyze market volatility, or random fluctuations in financial markets over time. Engle discovered a method for modeling time-varying volatility that is used by researchers and financial analysts to evaluate investment risks. Branger invented cointegration, a method for studying the relationship between two variables that vary independently over time, such as income and consumption.

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