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  Good Chemistry

Peter Agre credits his mentors with inspiring the science that won him a Nobel Prize. A favorite among students and colleagues, he's spreading a little inspiration himself.

By Maria Blackburn
Photos by Sam Kittner

 
That "D" Peter Agre '74 (MD) got in chemistry his senior year at Roosevelt High School in Minneapolis — you know, the "D" he loves to bring up when he's expected to say something self-congratulatory about his 2003 Nobel Prize in chemistry for the discovery of aquaporins — he didn't get it for being dumb.

There he is in his high school yearbook — the lanky towheaded kid with the mischievous smile — member of the yearbook staff and the cross country ski team, Mr. Most Likely to Succeed. Agre, the Johns Hopkins professor of biological chemistry who won the Nobel for his discovery of the proteins that form the channels that transport water through cell membranes, credits his father, a college chemistry professor, with sparking his interest in science. He mentions two-time Nobel winner Linus Pauling, who stayed at his family's house once, as an inspiration, too. But high school chemistry just wasn't as exciting to Agre as The Substandard, the underground newspaper he and some friends started their senior year.

"He was probably really brilliant, but he really didn't apply himself," says James L. Thornton Jr., Agre's high school chemistry teacher, now 74. "He did the labs, but he never wrote them up. Peter was just a typical young guy who goofed off."

"I was impossible," says Agre, who dropped out of high school the later part of his senior year but has since then become a champion of the teachers who inspire children to learn about science. He laughs, slightly embarrassed at the thought of his young, rebellious self. "It was just boring high school chemistry, but I used it as an opportunity to act out."

Other people might hide the "D," bury it among past transgressions. Agre seems to revel in it. Owning up to the dismal chemistry grade establishes the 55-year-old scientist and internist as an ironic guy who doesn't mind poking fun at himself. It also serves as a reminder that when it comes to science, hard work, curiosity, and luck are as important as class rank, credentials from fancy schools, and honor rolls.

Maybe even more important.

"There are a lot of prima donnas in science," says Don Coffey, a professor in the Department of Urology who met Agre when Agre was a student at Hopkins School of Medicine in the early 1970s and has become one of his trusted advisers. "Then you see Peter, who is an honest, humble, enthusiastic man. In telling you about the "D", he's trying to tell you, you don't have to be Phi Beta Kappa or go to Harvard. You just have to be motivated, dedicated, and work hard, and you can do it."

Somewhere in between earning that infamous "D" and winning the Nobel Prize, Peter Agre came to see science not as a competition or a politically tinged academic endeavor but as a series of turns in the river that deserve to be followed. And he came to see himself as Huckleberry Finn.

"Science should be an adventure," Agre says. "It should be so exciting that you wake up at night and you want to go back to the lab not because, 'God, if I get eight more papers then I'll be promoted and we'll beat our competitor,' but because it's fun. Huck was unafraid to go his own direction, and there's a level of him that probably applies to me. That's why I couldn't concentrate in high school."

Peter Agre was voted "Most Likely to Succeed" in high school, even though he got a "D" in chemistry. Aquaporins are no run-of-the-mill discovery. These "water pores" are the key to the movement of water in and out of all human cells.

"A lot of the basic physiological processes that we all know about involve fluid transport," Agre says — processes like sweating, urinating, swelling, crying. Says Agre, "Aquaporins aren't important because they're the cure to cancer, but they are the answer to some of life's persistent questions."

"How can our kidneys concentrate urine so when we go out on a hot day we don't die of dehydration?" he asks. The answer: aquaporins. "How does an individual respond to starvation? Fat is stored in fat cells as triglycerides. How does it get out? It gets out through aquaporin secretion."

At the Nobel Prize ceremony in Stockholm in December 2003, Bengt Norden, chairman of the Nobel committee for chemistry, said Agre's discovery was intimately connected with the question, What is life? He added that the water channels were "a decisive discovery that opened the door to a whole series of biological, physiological, and genetic studies of water channels in bacteria, mammals, and plants."

Scientists had spent years looking for the water channels. Agre stumbled upon them while working on an unrelated project, and then threw himself into figuring out what they were and how they worked.

In the late 1980s, Agre, then a Hopkins specialist in blood disorders, was researching Rh incompatibility in pregnancy. One day, as he and his colleagues in the lab purified the Rh protein they needed, they noticed a "contaminant," a different protein found in blood cells. The protein was abundant and looked like proteins found in the human kidney and in plants. Intrigued, Agre decided to try to find out what it was.

"Most people would have discarded it as unrelated to what they were after," says Paul S. Lietman, professor of medicine at the John Hopkins School of Medicine. "He had the foresight to realize that what he stumbled onto was bigger than what he had set out to do."

"Imagine you are driving through Western Maryland and you come upon a town of 200,000 people that's not on any map," Agre explains. "That's what it was like."

Agre's office wall pays homage to some of the important people in his life: his children, his father, Nobel laureate Linus Pauling, and John Parker, who suggested that Agre had discovered the elusive water channel. Finding the channels wasn't enough, however. Agre wanted to see how they worked. "Most scientists did not believe water channels existed, since no one could isolate them," he says. A few scientists predicted that water channels existed, but no one knew for sure. "Having a great idea is wonderful," Agre says. "You have to actually prove that it's correct."

When John Parker, Agre's friend and former attending physician at University of North Carolina at Chapel Hill, suggested that this new protein could be a channel for water, Agre and William Guggino, Hopkins professor of physiology and pediatrics, worked out an elegant experiment to test his theory. In October 1991, Agre's lab cloned the DNA encoding the protein they had discovered and injected the corresponding RNA into six frog eggs. Test eggs injected with complementary RNA produced the new protein and became water permeable. In fresh water, they swelled and burst. Control eggs not injected with RNA failed to swell. The investigators performed many other experiments and checked many control conditions; every determination indicated that the new protein is a channel permeated only by water. They had found the elusive water channel. News of their discovery spread throughout the scientific community.

"Hokey smoke!" Agre says of the experiment. "People called us up within days. Scientists had been committed to solving the water transport problem."

Hanging on the wall of Agre's messy shoebox of an office is a photo of these exploding frog eggs — a series of fuzzy orange circles that look more like pieces of abstract expressionism than a career-making discovery. Since that experiment, 10 aquaporins have been identified in human cells. Present in such places as the blood, the kidneys, and the brain, aquaporins help regulate the balance of water inside cells.

While the egg pictures serve as a reminder of what he's done, other photographs hanging nearby tell more about who he is. Parker, the UNC doctor whose suggestion led Agre to his discovery and who died in 1993, is memorialized on his wall.

Above that photograph are portraits of his four children, Sara, 25, Claire, 23, Clarke, 18, and Anne, 14. Agre and his wife, Mary, a preschool teacher, have been married for 29 years. Even though his research has resulted in six-day workweeks and lots of travel, he's found time to be involved with his children's activities both as a recreation league soccer coach and as an assistant scoutmaster for Boy Scout Troop 35.

"One of Peter's major assets as a scientist is a willingness to do things other scientists wouldn't do," says Vann Bennett, Agre's former Hopkins roommate. "You do whatever you have to do," Agre says of balancing work and home life. He used to block out his schedule eight months in advance to ensure he'd be able to take his Scout troop on two-week trips backpacking in the Rocky Mountains or canoeing in the Canadian wilderness. As is typical with him, he makes sure to share the credit. "My wife does all of the hunting and gathering," he says. "She covers for me."

He loves to tell the story about how on the day he learned he won the Nobel, his daughter Anne returned home from high school and pronounced her father's Nobel "cool." His mother, two brothers, children, and wife all accompanied him to Stockholm for the award ceremony.

"Tell him not to let it go to his head," Agre's mother, Ellen, said to Mary when she learned her son had won the Nobel. There's little worry of that. "The children are not going to let that happen," Mary says.

Next on the wall hangs a black-and-white portrait of his father, Courtland Agre, taken when he was about 35 years old and working as a chemistry professor at St. Olaf College in Minnesota. Agre remembers his father, who died in 1995, as optimistic and filled with ideas. "He was never down," Agre says, surveying the image of the smallish man with the wavy red hair. "He was always looking forward, but in some ways with a lack of quality control with regard to some of his inventions." For instance, says Agre, his father invented a substance that could be used to strengthen shoe soles. Not feeling the need to refine the product further, he put it on the shoes of his five children. The soles left black scuff marks on all the floors. "Ninety percent was good enough," Agre recalls.

Courtland Agre served on the American Chemical Society's education committee with Linus Pauling. When Agre was 14, Pauling, who had just won the 1962 Nobel Peace Prize for initiating the Nuclear Test Ban Treaty, came to speak in Minnesota and stayed with the Agre family. Meeting Pauling made a big impression on Peter, who has hung his father's signed photograph of Pauling in his office, just under the picture of his dad.

Pauling "had a humorous way of connecting with people," Agre says. "It was an inspiration."

Agre tells the story of how Pauling, who was invited to a reception for American Nobel winners by President John F. Kennedy in 1962, used the invitation as an opportunity to take part in a demonstration outside the White House to protest U.S. atmospheric nuclear tests. "That evening at the White House, [Pauling] went through the receiving line and he came up to President and Mrs. Kennedy, and Kennedy turned to him and said, 'Dr. Pauling, I understand you've been around here earlier today.'"

Agre giggles at the thought. "Could you imagine Bush doing that?" he says. "[Pauling] would have been dragged away."

Agre's father encouraged his oldest son to become a doctor. And, after dropping out of high school, getting his diploma through night school, and delivering war materiel by truck for a few months, Agre went to Augsburg College in Minnesota and graduated in three years with a degree in chemistry.

Since Agre's discovery, studies have linked aquaporins to the maintenance of the blood-brain barrier; to the functioning of salivary and tear glands; and to the transportation of water in skeletal muscles, lung cells, and kidney cells.

With characteristic humility, Agre downplays his acceptance to Hopkins' School of Medicine. He told The Baltimore Sun he was admitted "on the Norwegian-from-Minnesota quota" and goes so far as to say that he and Hopkins cancer researcher Bert Vogelstein, both of whom graduated from Hopkins in 1974, claim to be the worst student in their class.

Former classmates and professors remember Agre as an intelligent, enthusiastic student. After graduation, Agre planned on practicing medicine, but when he encountered the lab where his roommate Vann Bennett was working, he became interested in research, too. The third floor lab in the Basic Science Building, run by Pedro Cuatrecasas, was a vibrant, dynamic place inhabited by a Spanish revolutionary, a Palestinian refugee, a Conservative Jew, and an Italian actor. They all became close friends.

"It was the people there who engaged me as much as the science," remembers Agre. "It was just scintillating."

Agre, who had an interest in international health, decided that he wanted to purify the E.coli bacteria that caused "traveler's diarrhea" and that the Cuatrecasas lab was the place to do it. He never asked permission — he just moved in and started working.

"The lab was big enough. Pedro didn't seem to mind," says Bennett '74 (MD), '76 (PhD), now the James B. Duke Professor of cell biology at Duke University Medical Center and an investigator with the Howard Hughes Medical Institute. "I just moved over and gave him some bench space."

Driven but "disorganized," as Agre describes himself, he never published the results of his research from his postdoctoral fellowship in the Cuatrecasas lab. After graduation from Hopkins he completed an internship and residency at Case Western Reserve University in Cleveland and a postdoctoral fellowship in hematology at the University of North Carolina at Chapel Hill.

Agre received his award in Stockholm, Sweden, from King Gustav. Agre returned to Hopkins in 1981 — not for some tenure-track professorship but as a research associate in the department of cell biology. He was working with Bennett, who had just moved his small lab from Burroughs Wellcome to Hopkins. To some, Agre's move looked like a step back.

"Peter came to Hopkins with no faculty guarantees... no guarantees this would lead to anything at all," says Bennett, adding that Agre wrote a clinical investigator grant to return to Baltimore. "While he was in the lab he learned a lot of red cell membrane biochemistry, which was helpful to him later, but it was a risky move. Here Peter sells his house in Chapel Hill and takes his family on a salary of $25,000 and moves back to Baltimore where the rest of his classmates were in private practice. Very few people would have done that, and if they had, most of them would have been terrified."

Agre, who has biked from Minneapolis to Baltimore and traveled the world alone, was too adventurous to stay put in North Carolina, Bennett says. "One of Peter's major assets as a scientist is a willingness to do things other scientists wouldn't do," Bennett says. "He combined this with real focus and dedication and super science, and the combination is lethal, in a good way."

For Agre the move seemed like a practical way to get more training. "Drug companies are a lot less exciting than universities," says Agre, who, during his first few years in Baltimore, moonlighted as the fight doctor at the Steelworkers Hall boxing matches in Dundalk. "It was no sure thing at Hopkins. It just seemed like we'd come up for three years, get some training, and move back to Chapel Hill."

Within three years Agre was a Hopkins assistant professor in the departments of medicine and cell biology. He worked in hematology and saw patients while doing research.

In 1993 when Hopkins started a new graduate program in cellular and molecular medicine, Agre moved between medicine and science, doing more research on aquaporins and the role they played in various diseases. "I felt like a kid in a candy store," Agre says. "You know, most people don't have the opportunity to go to work and have a lot of fun. But I always like to go to work. It's not like I have a sad home life. I have a lovely wife. The house is kind of beat up because we have four kids and the dog chews the shutters off, but it's a wonderful life."

After Agre's lab figured out how aquaporins worked, he didn't expand into a mega-lab filled with dozens of scientists or apply for huge grants so that he could systematically knock out every aquaporin in a mouse model. He didn't become hyper-competitive and secretive about his work. Instead, he reminded the dozen or so people in his lab to focus on experiments no one else is doing and not to worry about experiments that anybody could do. Agre told his lab to steer clear of the mundane.

"It looked like this was going to be very interesting," Agre says. "Everyone worked on aquaporins answering questions like, How are they regulated? How many related aquaporins are there? How are they expressed? and Which diseases are they involved in?"

Agre says he knew the field of study was going to "mushroom." It did. Over the next several years there were some 1,000 papers published on aquaporins. Since the frog egg experiment in 1991, studies have linked water channels to the maintenance of the blood-brain barrier; to the functioning of salivary and tear glands; and to the transportation of water in skeletal muscles, lung cells, and kidney cells. Scientists in Agre's lab are continuing to look at aquaporins' role in human diseases like malaria, brain edema, and osteoporosis.

Agre took his two minutes in the spotlight to recognize the "heroes behind past, present, and future Nobel Prizes — the men and women who teach science to children in our schools." Agre avoids direct scientific competition and encourages collaboration. His lab has worked on aquaporins with half a dozen Hopkins labs, as well as a dozen labs in Denmark, Norway, Switzerland, and Japan. "Science is a social endeavor," Agre says. "Scientists who don't interact with other scientists are less likely to succeed in their work."

And scientists who rush their work to try to be first invariably make mistakes. "'A researcher is just like a pilot,' Peter says," recounts Masato Yasui, assistant professor of pediatrics and a researcher in the Agre lab. "Even a single mistake shouldn't be allowed."

But not all of Agre's lessons are so easy for the less senior members of the lab to accept. Graduate student Dan Gorelick-Feldman used to complain to Agre when a competitor would do something Gorelick-Feldman thought their lab should have done. Agre's response was always the same. "Don't worry about it — they're doing our work for us," he'd say. Or maybe, "Science is a marathon, not a sprint."

"He's always telling me not to worry about what anyone else is doing," Gorelick-Feldman says. "Even if someone else beats you, sooner or later they're going to make a mistake."

And then there's his usual response to a paper about a ho-hum result for a middle-of-the-road scientific journal. Agre doesn't criticize it or the writer. Instead, with tact and civility, he pronounces it "a scholarly work."

"I'm going to use that one when I'm a professor," Gorelick-Feldman says smiling. "A scholarly work."

Agre's greatest strength as a mentor is that he is interested in the lives of his junior colleagues both inside and outside the lab, now and later, says Landon King. A Hopkins associate professor of medicine and biological chemistry, King has been working with Agre in the lab since 1993. "Peter addresses not just the issues you're facing in the lab day to day but how one puts the pieces together to form a career," he says. "He helps you see what you should be thinking about in a year from now."

In the months since the Nobel Prizes were first announced, Agre — who shared the prize with Roderick MacKinnon of Rockefeller University — has been launched into the world of scientific celebrity. At the awards ceremony in Stockholm, he found himself swarmed by scientists who wanted to know more about aquaporins and their role in everything from cataracts to kidney disorders. His calendar of speaking engagements is booked through this year and quickly filling up for 2005. And he's still trying to figure out how to begin responding to the 1,872 e-mails and thousands of invitations, congratulations, and requests for autographs he's received.

"They don't want me, they want some Nobel Prize guy," Agre deadpans while sitting at his desk a few feet away from the piles and cardboard boxes of letters that threaten to overtake his office.

Over the last six months Agre hasn't just been fielding inquiries, he's been figuring out ways to use his fame for a larger cause. Always willing to speak his mind, he used his stature as a Nobel Prize winner to protest the prosecution of scientist Thomas Butler of Texas Tech University. Butler, a respected plague researcher and former Hopkins clinical fellow in infectious diseases, faced felony charges for allegedly mishandling plague bacteria. He was convicted on 47 of 69 counts by a federal jury in December 2003.

William Guggino worked with Agre to develop the elegant frog-egg experiment.

"This is a gross miscarriage of justice," says Agre, who told The Baltimore Sun he wanted to use part of his $700,000 in Nobel winnings to help pay for Butler's defense. "I'm relieved that Dr. Butler was acquitted of all the serious charges, but he still faces three felony charges that include wire fraud and theft. Butler is the world's leading expert on plague. There are hundreds, thousands of poor people in the world dying of this. It's going to be a grave mistake if they put Tom Butler in prison." (Indeed, at press time, Butler was sentenced to two years in prison and fined $15,000.)

And then there's his mission of getting the world to appreciate science teachers. At the banquet speeches in Stockholm, other Nobel laureates talked about their families, their coworkers, and themselves. Agre took his two minutes in the international spotlight to ask the 1,300 dignitaries and their guests to recognize not the laureates but the "heroes behind past, present, and future Nobel Prizes — the men and women who teach science to children in our schools."

The speech received cheers from the crowd and a thumbs-up from the prime minister of Sweden, not to mention letters from science teachers asking him to come speak to their schools. Agre says he wasn't trying to be politically correct. "I just thought that was a point I could make where somebody might listen," he says. "What is it that is different about us now than our progenitors in the 14th century? They had Icelandic sagas and Homeric legends that show us that minds were keen in ancient times. Science is what's different. The technology that it has produced with antibiotics and electronics and architecture — this is where we are different. Science teachers are the ones who convey this to the young people. And if a young person connects with science, we've got another 70 years of productivity from them."

In February, Agre went back to Theodore Roosevelt High School in Minneapolis to talk to students about careers in science. It was the first time he had been in one of his old high school classrooms since he dropped out 37 years ago. His first message: "If you don't get into a good college, you won't be a failure," he says, chuckling. His second: "Learning is fun and exciting and the answers are not always known."

Maria Blackburn is a senior writer for Johns Hopkins Magazine.

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