Hopkins scientist wins Nobel Prize


Dr. Peter C. Agre, a self-effacing Johns Hopkins School of Medicine biochemist who delights in telling colleagues that he earned a D in chemistry before dropping out of high school, was awarded the Nobel Prize in chemistry yesterday for his breakthrough discovery of the proteins that govern the movement of water in and out of cells.

Agre's identification of aquaporins, which he stumbled upon while doing unrelated blood experiments more than 10 years ago, opened avenues for promising research in areas as diverse as anti-malaria drugs, kidney ailments, brain swelling after strokes, lung problems in premature babies and even the mechanisms of root systems in plants.

A 54-year-old professor of biological chemistry, Agre will share the $1.3 million prize with Dr. Roderick MacKinnon, 47, a biophysicist at Rockefeller University in New York. MacKinnon helped unravel the operation of ion channels, electricity-generating molecules that stud the outer surface of cells and play an essential role in everything from the creation of thoughts to the tick of the heart.

Yesterday morning at his home in the Baltimore County neighborhood of Stoneleigh, where someone had tied balloons to the dogwood out front, Agre fended off congratulations with jokes and patiently spelled aquaporin for reporters calling from Denmark, Brazil, Germany, Argentina and Colombia.

"Life is interesting," Agre said, between pouring coffee for visitors and hugging a neighbor who dropped off a handmade card. "Most of your hypotheses in science turn out to be wrong. This one was right, and I guess that's why Stockholm called."

There had been some hints over the past few years - invitations to speak at the Nobel-awarding Karolinska Institute in Sweden, mysterious visitors to his cluttered lab in East Baltimore. But the 5:30 a.m. telephone call still came as a surprise, Agre and his wife, Mary, recalled a couple hours later.

"They said it was the Nobel Committee," he said. "I wondered if it might be some kind of a joke, but they sounded very convincing."

His memory of the next few moments is a little fuzzy. "What did I say?" he wondered. "I think I said, 'Yes!'"

His wife, meanwhile, was hoping the call was from Sweden. "We knew chemistry was today. So I heard the phone and I was like, 'God, could this be it?'" said his wife of 28 years, a preschool teacher.

Carly, 14, the youngest of the Agres' four children and the only one still at home, said she figured something good had happened when her father began behaving strangely.

"I heard him jumping up and down and giggling," she said. "I thought either he won the lottery or the Nobel Prize."

When Mary Agre reached her husband's mother in Minnesota, Ellen Agre expressed pleasure but quickly added an admonition: "Tell him not to let it go to his head."

There was little danger of that. A swimmer, bicyclist, Scouting leader and walker of the family's black lab, Jinx, Agre seemed determined to remain a regular guy. When Hopkins President William R. Brody called to congratulate him on the Nobel - the first for a sitting Hopkins faculty member in 25 years - Agre was taking out the trash.

As he and others tell it, Agre's great discovery was a classic piece of scientific serendipity, a dead-on illustration of Louis Pasteur's adage that chance favors the prepared mind.

"The humbling truth is we bumbled along and bumped into this," Agre said.

A physician specializing in blood disorders, Agre was working at Hopkins in the late 1980s on Rh incompatibility in pregnancy, a dangerous condition in which a mother with Rh-negative blood has a fetus with Rh-positive blood.

As Agre and his colleagues purified the Rh protein they needed for the blood studies, they noticed a "contaminant" - a different protein found in red blood cells.

"The smart thing to do would have been to discard it and go back to the important work," Agre said. But he was intrigued that the mysterious substance resembled proteins found in the human kidney and in plants. He couldn't resist following the byway.

When he realized that the protein might be the long-sought "water channel," Agre helped design a series of elegant experiments to test the idea.

"My approach to science might be described as the Huck Finn approach," he said at a news conference at the Hopkins medical school. "If it looks fun and it's doable, we're going to do it. ... The greatest element of all in this discovery is luck."

Dr. Landon S. King, a pulmonologist who collaborates with Agre on aquaporins, said his colleague's self-deprecation disguises an uncanny sense of which research paths will prove fruitful and a formidable capacity for grueling scientific labor.

"There's a certain element of chance in the discovery of the protein," said King, who arrived at Agre's house before 7 a.m. with another colleague, Dr. Masato Yasui, bearing bagels and champagne. "But the elucidation of its function and the rest of the biology were not at all chance. They were the result of hard work and rigorous study.

"As a scientist," King said, "Peter has a great ability to look at problems and identify the ones that are very important."

Students say Agre lacks the ego and pomposity that often accompany Nobel-quality brains.

"He's incredibly down-to-earth, very easily approachable," said Dan Gorelick, a 27-year-old graduate student in Agre's lab. Through his dedication to exercise and his involvement with his children, Agre "helped me personally to understand that it's possible to do science and have a life outside, too," Gorelick said.

When Agre arrived at his lab on the fourth floor of the Woods Basic Science Building yesterday, a dozen colleagues applauded and exchanged hugs. For once, they pointed out, he was wearing a tie.

Agre turned to a laboratory technician, Barbara Smith, who had worked on the aquaporin breakthrough, and reminded her that the tie, decorated with the periodic table of elements, was a gift from her. "I've been waiting for a special occasion to wear it," Agre said.

"That just typifies him," Gorelick said. "Here he's just won the highest honor in science, and he takes time to remember the technician he worked with back then."

Agre's humility may have its roots in his rocky experience in high school. "I didn't start with a high-level trajectory," he said.

Agre's father, Courtland Agre, was professor of chemistry at St. Olaf College and then at Augsburg College in Minnesota. Agre wasn't oblivious to his father's excitement about chemistry - he enjoyed meeting his father's friend Linus Pauling, a two-time Nobel winner - but he was more intrigued by politics.

"It was 1967, and we were bored by the school newspaper, the Roosevelt High School Standard. So we had the idea of putting out the Substandard. It was mirthful - making fun of the hockey coach, that kind of thing," Agre said.

But school administrators were not amused. The Substandard editors were given the choice of quitting their paper or quitting the school. Agre, who had been voted "most likely to succeed" by his fellow seniors but had withdrawn from chemistry with a D average, chose to drop out.

He recovered quickly, prodded to pursue his education after a stint as a truck driver transporting "war materiel for Vietnam, land mines and so on." He finished high school at night, became a pre-med student at Augsburg and got into medical school at Hopkins - "on the Norwegian-from-Minnesota quota, I think." After a fellowship in hematology at Case Western Reserve University in Cleveland, he returned to Hopkins in 1981.

In recent months, Agre has come to the defense of a man who taught him at both Hopkins and Case Western, Dr. Thomas C. Butler, an expert on plague at Texas Tech University who faces felony charges for allegedly mishandling plague bacteria. Agre considers the case an example of overkill by the Justice Department as it strengthens defenses against bioterrorism, and he said he may donate some of the Nobel Prize money to Butler's defense fund.

On the other hand, he said, "maybe I should give the money to my wife."

Agre's fellow honoree, MacKinnon, is described by colleagues as a worthy Nobel winner at an unusually early age.

"He's universally acknowledged to be an off-scale brilliant scientist," said Christopher Miller, a Brandeis University biochemist and MacKinnon's former mentor. "And he completely changed the field."

Scientists had been fascinated by electricity in the body since the 18th century, when Italian biologist Luigi Galvani found that he could make a dead frog's leg twitch by feeding a current into its spinal cord.

"That set people to thinking the rapid transmission of messages from head to toe had to be electrical," said Dr. Clay M. Armstrong, a University of Pennsylvania biochemist.

By the mid-20th century, scientists suspected that the passage of certain molecules through tiny pores in the walls of the cell were responsible for the electrical activity. In 1963 two British biologists won a Nobel Prize for showing that the passage of ions through the membrane causes nerve cells to fire. But scientists had never been able to see one of these channels in action.

In 1998, MacKinnon startled the scientific community by publishing the first picture of an ion channel using X-ray crystallography. "It went from the primary literature to the cover of textbooks in the span of a year," said biochemist Richard N. Armstrong at Vanderbilt University.

It was all the more surprising because MacKinnon came to research relatively late. Growing up outside Boston, he received a medical degree from Tufts in 1982. Four years later, he began to study ion channels as a postdoctoral researcher at Brandeis University.

Today the study of ion channels has become "steadily more important," said Penn's Armstrong, because they play a role in vision, the timing of the heartbeat, pain sensation and the formation of thoughts.

Despite Hopkins' status as a scientific and medical powerhouse, Agre's prize is the first awarded to a sitting member of the regular Hopkins faculty since Hamilton O. Smith and Daniel Nathans of the medical school shared the 1978 prize for medicine for discoveries in genetic research. Riccardo Giaconni had a research affiliation with Hopkins when he won the physics prize last year, and another 26 Hopkins graduates or faculty members have won Nobel Prizes when they were elsewhere.

Dr. Chi V. Dang, the Hopkins medical school's vice dean for research, who long worked in a lab next to Agre's and considers him a mentor, said the prize should inspire a new generation.

"This should be an encouragement for young scientists that persistence and dedication will yield the joys of discovery - and occasionally, fringe benefits," Dang said.

Sun staff writer Michael Stroh contributed to this article.

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