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2 American Doctors Win Nobel Prize in Chemistry

October 09, 2003|Thomas H. Maugh II | Times Staff Writer

Two American physicians have won the 2003 Nobel Prize in Chemistry for their elegant studies of how water molecules and potassium ions pass in and out of cells -- research that could eventually affect treatment of diseases as diverse as cystic fibrosis and a syndrome that causes abnormal heart rhythms.

Dr. Peter Agre, 54, of the Johns Hopkins University School of Medicine, and Dr. Roderick MacKinnon, 47, of the Howard Hughes Medical Institute at the Rockefeller University in New York City will share the $1.3-million prize for their discovery of water channels and ion channels, respectively.

These minute pores allow water in and out of cells and produce the electrical communication between cells that controls nerve impulses.

"The role of these channels is so critical that we would not be alive were it not for the vigilance of these gateways in maintaining healthy cells," said Dr. Elias A. Zerhouni, director of the National Institutes of Health, which funded the work of both researchers.

Both of the chemistry awardees are physicians who decided they were more interested in research than patient care and who made major discoveries at an early age, solving problems that had eluded other researchers for decades.

Interestingly, the 2003 Nobel Prize in Physiology or Medicine was given to a physicist and a chemist, while this year's chemistry award was given to two doctors. "Increasingly, the margins between one field and another are blurred," Agre said. "Basic science has implications for clinical medicine, and the reverse as well."

Agre's discovery was a classic case of serendipity. In the late 1980s, he and his colleagues were attempting to find the protein that gives red blood cells their Rh factor, one of the complex characteristics of blood that control compatibility for transfusions. In the process, they isolated another protein that they initially thought was simply a contaminant. There was so much of it, however, that they decided to take a closer look.

When they purified the material and got its DNA sequence, they found that the protein was abundant in the kidney, which is responsible for filtering 40-plus gallons of water every day. That was a "clue that it might be a water channel," Agre said.

The gene was also common in plants, although its function was unknown. When they tested its function, the protein was clearly a water channel. "After the very first experiments, we knew we had hit the jackpot," Agre said, alluding to the fact that nobody had seen water channels before.

Agre subsequently determined the protein's three-dimensional structure and demonstrated how it permitted water molecules to enter the cell while keeping everything else out. Since Agre's 1992 paper in the journal Science describing the first water channel, researchers have identified 10 more in mammals and hundreds of others in bacteria, plants and other forms of life.

MacKinnon, in contrast, was seeking his prize, the potassium channel, but many experts didn't think he -- or anyone else -- would ever find it. The channel is embedded in the membrane of cells and is exceptionally difficult to isolate, purify and visualize.

He found the protein and got its DNA sequence, but no matter how many experiments his team tried, its members could not explain how it worked. "It was clear we would have to see it," he said.

MacKinnon then taught himself the intricacies of X-ray crystallography so he could determine the structure of the protein on his own. When he published the structure in Science in 1998, Dr. Clay Armstrong of the University of Pennsylvania School of Medicine, in an editorial, termed it "a dream come true for biophysicists."

That structure showed precisely how the potassium channel worked and how it could allow potassium ions into the cell while keeping slightly smaller sodium ions out.

MacKinnon showed that the channel had a cavity precisely the same size as the potassium ion. Oxygen atoms in the cavity would strip water off the ion and pass it through the channel. Because sodium is too small to bind with all the oxygen atoms, water would not be stripped away and that ion would be too large to enter.

MacKinnon isolated his potassium channel from a bacterium called Streptomyces lividans, but subsequent work suggests it is virtually identical in all species. "It's as if nature settled on one way to make a potassium channel," he said.

Defects in human potassium channels have already been found in diabetes and the heart disorder known as long QT syndrome, which can produce deadly arrhythmias. Researchers are now looking for drugs that can regulate the altered channels' activity.

"We have many more questions about the channels," MacKinnon said. "Every day I wake up as excited about the work as I was five years ago. We'll be studying them for a long, long time."

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