gateways into cells usher in nobels

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nique and founded a company, Fonar, which makes MRI machines today. The machines use a version of Lauterbur’s gradient methods, however. Damadian believes that he should have been included in the Nobel award; last week his company took out fullpage ads in The Washington Post and The New York Times objecting to the “shameful wrong that must be righted” and urging readers to support his cause. “Damadian published some early papers outlining the concept,” says George Radda, an MRI expert at the University of Oxford and former chief of the U.K.’s Medical Research Council. But, he adds, Damadian’s idea for detecting specific signals from cancerous tissue “did not lead to today’s MRI.” Damadian did not respond to Science’s requests for comment. The bitterness of the early rivalries may have delayed the awarding of the prize, says Radda. Except for the controversy, “it could have been given 10 years ago,” he says. The contributions of Lauterbur and Mansfield rise to the top: “There is no question that these are the right two people” to receive the prize, he says. Lauterbur “deserves a lot of credit, not only for the invention of the idea, but also for proselytizing,” says Waldo Hinshaw, who was a postdoctoral fellow in the lab of Raymond Andrew in the early 1970s and helped develop some of the imaging techniques used in today’s MRI machines. Early on, Hinshaw notes, people doubted that magnets




big enough and powerful enough to produce highly detailed images of the human body could be built. But, he adds, Lauterbur “went around to everyone he thought might be interested and said, ‘Take it seriously.’ He even showed up at my apartment [in Nottingham] one evening to convince me that it was worthwhile.” Even before the prize, Lauterbur says, the work has paid off in a deeply personal way. “The most satisfying thing personally is when a physician looks at an MRI and says, ‘No problem there!’ which I have experienced and relatives of mine have experienced,” he says. And that can be almost as thrilling as winning a Nobel Prize.

solution (Science, 17 April 1992, p. 385). The cells ballooned up and exploded before their eyes as water gushed in. Researchers have since identified 11 human aquaporins—some of which play a role in diseases—and many more in bacteria and The 2003 Nobel Prize in chemistry honors designation. But his screens repeatedly net- plants. “I think [Agre’s discovery] is really Peter Agre and Roderick MacKinnon for ted a 28-kilodalton protein that seemed to one of the big breakthroughs in physiology,” their pioneering work on proteins that con- have nothing to do with Rh. It was prevalent says Robert Schrier, a nephrologist at the Unitrol which molecules pass into and out of not just in red blood cells but also in the versity of Colorado Health Sciences Center in cells. These gatekeepers are the basis of tubules of the kidney. Denver. It was followed by a “second big many vital functions, including the generaAgre credits his former mentor at the peak” in the mountain chain of work that led tion of nerve impulses and the ability to reg- University of North Carolina, Chapel Hill, to Agre’s Nobel, says Mark Knepper of the ulate the concentration of urine. John Parker, for suggesting that the protein National Heart, Lung, and Blood Institute in Agre, 54, of Johns Hopkins Bethesda, Maryland: structural School of Medicine in Baltimore, studies that revealed how the CHEMISTRY Maryland, claims half of the prize channel works. “This is probably for his discovery of water chanthe reason it’s the chemistry nels. These protein pores shuttle prize,” says Knepper, rather than a water into and out of cells much physiology Nobel. faster than it could diffuse through Each aquaporin channel can their fatty outer membranes. pass about a billion water moleSpeed is particularly critical in the cules per second. Yet the channels kidney, which reclaims water from exclude other molecules—most the urine to prevent dehydration. notably, protons, in the form of “You’d pee out 50 gallons of water H30+ ions. In recent years, Agre’s a day if these channels didn’t filter group has revealed the secret the water back into the body,” says to this remarkable selectivity. Robert Stroud, a biophysicist at Atomic-resolution images of an the University of California, San aquaporin showed that each chanFrancisco. nel accommodates about 10 water Agre’s bright future in chemmolecules at a time, lined up sinistry wasn’t always apparent. He gle file. The protein’s electric field got a D in the subject in high Crystallized honors. Peter Agre (left) and Roderick MacKinnon exposed forces the positively charged hyschool despite having both a fa- discriminating channels that allow molecules to pass in and out of cells. drogens on each water molecule ther who was a chemistry profesto point away from the center of sor and, he readily admits, a perfectly good could be a water channel. As early as the the channel, so that hydrogens on half of the chemistry teacher. “I was kind of a negligent mid-1800s, scientists had proposed that waters point toward the outside of the cell, high school student, more interested in mak- cells might need such channels to maintain whereas those on the other half point into the ing mischief,” he says. osmotic balance, but they’d never been cell. This orientation both repels protons Agre’s big breakthrough had an element found, and some biophysicists argued that from the ends of the channel and prevents of serendipity. A rheumatologist by training, diffusion alone could do the trick. The mat- them from crossing through by hopping from he was interested in identifying Rh antigens: ter was settled when Agre’s team put the one water molecule to the next. surface proteins on red blood cells that give protein, subsequently termed aquaporin, Choosy channels are also the focus of blood types their “positive” or “negative” into frog eggs and put the eggs in a watery MacKinnon’s work. In the early 1990s, while SCIENCE VOL 302 17 OCTOBER 2003

Gateways Into Cells Usher in Nobels







Prizewinning proteins. This year’s chemistry Nobel recognizes work on potassium channels (near left) and aquaporins.

at Harvard Medical School, MacKinnon decided that to really understand the channels he was studying, he needed to see them. That meant learning to do x-ray crystallography— a monumental undertaking tantamount to changing careers. “A lot of us questioned it,” says a postdoc in MacKinnon’s lab during that era, Kenton Swartz, now at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. Getting membrane proteins to crystallize is notoriously difficult, and ion channels are even more unwieldy than most. “It seemed like a pie-inthe-sky idea even to me,” MacKinnon concedes. But it paid off. In 1998 MacKinnon sent a jolt through the field with the first high-resolution picture of an ion channel derived from x-ray crystallography (Science, 3 April 1998, pp. 69 and 106). Based on the crystal structure, his team later presented an elegant model of how ions—in this case potassium ions— pass through the core of the channel and explained the channel’s ability to let potassium ions through while excluding smaller sodium ions. Just as a rock star moves through a crowd with a ring of bodyguards clinging to his person, a sodium or potassium ion moves through a solution with an entourage of water molecules. Passing through the potassium channel’s “selectivity filter,” however, requires leaving the escorts behind. The filter makes this easy for potassium ions by providing four conveniently located carbonyl groups. Potassium forms bonds with these just as easily as it does with water, and so it slips through the filter, leaving its waters behind. Sodium, however, is smaller. As a result, it can only bind two of the carbonyl groups at a time. This doesn’t provide the energetic incentive needed to lure sodium ions away from their waters; thus the ions retain their escorts and stay outside the filter. Although many in the field had predicted MacKinnon would one day take home a Nobel for this work, most envisioned him getting a slice of the physiology prize. “I think the choice of chemistry is actually very

clever,” says Gary Yellen, a biophysicist at Harvard Medical School in Boston. Although the question of how ion channels achieve their selectivity is critically important for biology, Yellen says, the answer was ultimately a matter of chemistry.

More recently, MacKinnon, now at Rockefeller University in New York City, stirred up the field with the first portrait of a voltagegated ion channel. These channels reload neurons after they’ve fired an impulse. Based on the channel’s structure, MacKinnon’s team presented a model of its mechanism that flew in the face of the view widely held by researchers in the field, many of whom refused to accept it (Science, 27 June, p. 2020). But even the critics acknowledge the research as a tremendous accomplishment and say it has energized the field. “He certainly deserves this,” says Clay Armstrong of the University of Pennsylvania in Philadelphia. “He’s packed two or three careers into 10 years.”

Three theorists have gotten a warm reception for their work on the very cold. Vitaly Ginzburg, Alexei Abrikosov, and Anthony Leggett have been awarded this year’s Nobel Prize in physics and will split the 10 million kronor ($1.3 million) award. Ginzburg, of the P. N. Lebedev Physical Institute in Moscow, and Abrikosov, currently at Argonne National Laboratory in Argonne, Illinois, were honored for their work on superconductors, materials that lose all electrical resistance at very low temperatures. In 1950, Ginzburg and a colleague, Lev Landau, formulated a theory that describes how superconductors behave in a magnetic field.

The Ginzburg-Landau theory implied that superconductors can respond in two different ways when exposed to ever-stronger magnetic fields. Type I superconductors are completely impermeable to magnetism; the “f ield lines” can’t pass through the superconducting material at all. If the magnetic field gets too strong for the material to resist, the superconductivity disappears. Type II superconductors, which include all of the famous high-temperature ones, allow field lines to penetrate under some conditions. Abrikosov built upon the GinzburgLandau theory to characterize the behavior of type II superconductors; he predicted, for example, that penetrating field lines would create a regular lattice pattern in the superconductor, a phenomenon observed directly in 1967.

Superheroes. Laureate Anthony Leggett (left) plunged into liquid helium; Vitaly Ginzburg (center) and Alexei Abrikosov braved the resistancefree currents of type II superconductors.


17 OCTOBER 2003

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Cool Theories Garner Super Kudos

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