Hopkins MedicineHopkins Medicine Winter 2004

  Current Issue
  Top Story
  Medical Rounds
  The Learning Curve
  Post Op
  Past Issues
  Talk To Us
  Site Index
  Search HMN
  Front Door

Waterway to Stockholm

Peter Agre credits his chemist father with sparking his fascination for science.
A tear-jerker movie. A mouth-watering aroma. The human body’s ability to suddenly release water is so commonplace that few of us give it a second thought. But to biochemists, physiologists and others studying the movement of molecules into and out of cells, the phenomenon presented a first-class stumper for generations. Diffusion, a kind of slow-motion seepage through the cell membrane, offered one explanation. Yet it couldn’t account for how quickly our eyes can well up, for example, or the gallons of water our kidneys handle every day.

Some researchers suspected that ion channels—the proteins that make a cellular doorway for calcium, potassium, sodium and chloride—did double duty by also acting as a water sluice. Others said, no, water must have its own, specialized gate. But how do you find such a thing? In cells that are already more than two-thirds water, where do you fish for a water channel?

In the 1980s, Peter Agre had heard of neither the debate nor the quest. He was, however, well steeped in the unexpected twists a line of scientific inquiry can take. A 1974 Hopkins medical school graduate and board-certified internist who’d trained in hematology and oncology, Agre (pronounced ogg-ray) had been examining the structural proteins of red blood cells when he encountered the case of two sisters with a debilitating anemia. He not only showed that their hereditary spherocytosis—a rare disease of misshapen blood cells—was a previously unknown form caused by a recessive gene, he found at the molecular level that the culprit was an insufficient amount of the very protein he’d been studying.

And so, when Agre embarked on his next research project, he already had the prepared mind that chance was about to favor. This time he set out to study the substance in the blood that can sometimes cause maternal blood to attack the fetus. No doubt some scientists would have ignored the gooey molecule that kept fouling Agre’s solutions of purified Rh protein. But he followed the urge that said, Take a closer look. What he found was the long-sought water channel. And it was that discovery that brought Peter Agre at the age of 54 the 2003 Nobel Prize in Chemistry.

Walking along the hallway of Agre’s lab on the fourth floor of Hopkins’ Preclinical Teaching Building, you can’t help but notice the images of Native Americans that adorn the walls. Born and raised amid southern Minnesota farmland, in what he calls “an idyllic little Norwegian town,” Agre and his five siblings are 100 percent descended from the low-key Scandinavian settlers who began populating the area after the Civil War. “If I fail to make my grants, I plan to write for Garrison Keillor,” Agre jokes, referring to the author whose humorous tales of life in the Minnesota town of Lake Wobegon have garnered a huge following. (He told a roomful of reporters that his mother cautioned him, “Don’t let it go to your head,” when she heard he’d won the Nobel.) As a boy, Agre remembers sitting on a hillside and waving the Norwegian flag when the King of Norway visited. But he also became intrigued by Minnesota’s other residents—the American Indians who lived nearby. “I would go to pow-wows,” he says, “and I spent hours and hours making a re-creation of an ancient Sioux belt. There’s an obsessive-compulsive side when I get fascinated with something.”

Agre credits his father, who died in 1995, with sparking his fascination for science. Courtland Agre worked his way through college during the Depression by selling shoes at J.C. Penney. He was a professor of organic chemistry, first at St. Olaf College and later at Augsburg College in Minneapolis. “Dad would invite us kids to his lab and have us do little experiments,” says Agre. “We were very proud of him. In third grade, the teacher asked us to draw a picture of what we wanted to do when we grew up. I drew a chemist with test tubes.”

Peter Agre and King Olaf of Sweden at the Nobel award ceremony. Dean/CEO Edward Miller, who attended the festivities, said Agre had the best bow.
Agre never really abandoned that dream, though at one point he toyed with the idea of becoming a journalist. He earned a B.A. in chemistry, with honors, at Augsburg, then decided to go to medical school. “I wasn’t confident that I had the ability to cut it in basic science,” he says. “I wasn’t an exceptional student. I was diligent. But as a medical student at Hopkins, the lights really went on. If I had gone anywhere else, I would have gone in a different direction. Here, I met people who were so interested in science that it made me think it would be fun.”

After earning his M.D. in 1974, Agre stayed on for a year as a pharmacology fellow, headed to Cleveland for his residency in medicine at Case Western Reserve University, then opted for a second postdoctoral fellowship at the University of North Carolina at Chapel Hill, where he quickly was promoted to clinical assistant professor of medicine. But the lure of the lab never deserted him, and when Hopkins offered him a dual appointment in the departments of Medicine and Cell Biology and Anatomy, he headed straight back to Baltimore.

It was a colleague, from Agre’s days at UNC, “a superb basic physiologist,” who suggested to him that the gooey contaminant that kept disrupting his Rh study might be the elusive water channel. At first, Agre had thought it might actually be the substance he’d been studying—the antigen that made the blood in some women attack their unborn child. But a bit of delving proved the molecule to be a protein in its own right—and one that was widely expressed. Agre came upon the protein not only on the membranes of red blood cells but in kidney cells and blood vessels, and related proteins in tear ducts, salivary glands, even plant cells. The sheer abundance of the stuff tugged at his curiosity. More intriguing still, the protein didn’t resemble any other known biological molecules except a distant relative in the lens of the eye.

Still, demonstrating that the mystery protein was the water channel took nearly a year. To devise the experiment that would make the case, Agre enlisted his colleague, physiologist William Guggino, an expert in how water moves in and out of eggs. In the 1970s, Guggino had begun exploring why fish eggs laid in salt water don’t shrivel, and frog eggs laid in pond water don’t explode. His and Agre’s guinea pig, Guggino decided, would be a frog oocyte, “one big cell, visible to the human eye, that’s very promiscuous at expressing membrane proteins on its surface.”

Sure enough, each egg doctored with Agre’s protein and placed in fresh water would swell up and burst within seconds, squirting yolk out one side. But did that alone prove the protein caused a previously impervious cell wall to suddenly sprout openings that admitted water? What if the injection itself had somehow damaged the membrane? Two refinements removed all doubt. When the researchers injected control eggs with a protein for a different kind of channel (chloride), those eggs remained intact. Even more ingeniously, they tapped the fact that mercury inhibits water movement to show that, in the presence of that element, their experimental eggs didn’t swell either. There was no longer any doubt. Agre’s protein was the water channel. He named it aquaporin.

“We put in our thumb and pulled out a plum,” he says. “It completely changed the focus of my lab. Within a week, we were getting calls from all over the world.”

It would be easy to assume that at an institution like Johns Hopkins, Nobel laureates inhabit every floor. Yet, only two full-time School of Medicine faculty members have ever received the call from Stockholm. In 1978, Daniel Nathans and Hamilton Smith shared the prize in medicine for their discovery of restriction enzymes, the so-called chemical scissors that laid the groundwork for mapping the human genome.

To a select few in the know, there were hints that Agre might be the one to break the 25-year dry spell. “Peter had been invited several times to Stockholm, including being asked to speak at the Nobel centennial in 2001,” says Dan Lane, who headed biological chemistry from 1978 to 1997, and convinced Agre in 1993 to switch to his department. “Then a member of the Nobel committee dropped in a few months ago just to chat with him. When the chemistry committee chair called to ask me if Peter was going to be here on Oct. 8, well, it certainly seemed a possibility.”

On the night of Oct. 7, Agre simply turned in as usual. “I was sleeping fine,” he says. “It’s not as though it was likely that I would win.” This time, Agre’s instinct was wrong. And throughout Hopkins ever since, the mantra has been, “It couldn’t have happened to a nicer guy.”

Notorious for downplaying his achievements, for pointing only to the serendipity of his discovery and not the years of shrewd work that preceded and followed it, Agre prefers to deflect praise with humor. He doesn’t hesitate to bring up the D he got in high school chemistry. Told that the New York Times was clamoring for an interview, he quipped, “Is my subscription overdue?” Asked about Roderick MacKinnon, the biophysicist at New York’s Rockefeller University with whom he shares the 2003 chemistry prize, Agre replied, “He’s a serious scientist. I’m hanging on.” And in response to an introduction by Chi Dang, Hopkins’ vice dean for research, Agre said, “Chi made a technical error. It was the young people in my lab who did the work. I just made the coffee.”

Don’t you believe it, says Dang. “I know Peter from way back when. I came here as an assistant professor when he was in the hematology division. I was next door when he was trying to clone this thing. Peter has this sixth sense—he captures opportunities, he’s very persistent, he does science with great depth. Young scientists today are very energetic, they want to do a hundred things. Peter wants to understand something from 3,000 miles up all the way down to the atomic level. He solved the structure of aquaporin so we really understand it. That’s the depth. That’s why he was recognized.”

Since the paper proving the existence of the water channel appeared in 1992 in Science, Agre and others have identified 11 mammalian aquaporins. The channels have turned up, not surprisingly, in the more water-permeable parts of the body: salivary, tear and sweat glands, kidney tubules, the choroid plexus of the brain where spinal fluid is produced, the ciliary epithelium of the eye where aqueous humor is formed, the moist surface tissues of the alveoli in the lungs.

What most excites physicians, though, is that aquaporin research has shifted from merely finding where else the proteins are expressed to exploring how this knowledge can be harnessed to prevent or treat disease (among the current targets: glaucoma, nephrogenic diabetes insipidus, asthma, cystic fibrosis, brain edema and congestive heart failure).

To that end, Agre has spent years studying aquaporins’ structure, and in 2000 he and others produced the first high-resolution images that show how they do what they do. “They’re shaped like an hourglass,” he says, “the first such example in nature. Nothing else is smaller than water. Aquaporin is a machine with no moving parts that lets water go through without resistance and repels everything else.”

“One of Peter’s greatest strengths is recognizing what’s important and saying, This is where we should focus,” says pulmonologist Landon King, who has worked with Agre since 1989. “It’s not blind luck. He sees things earlier than many of us. He also has this ability to take complete stories and make them understandable to almost any audi-ence. He’s uniquely qualified—and now pedigreed—to be an ambassador for science.”

And if that is a role he is to assume as a Nobel laureate, it suits Courtland Agre’s son just fine. “These things come with an obligation,” he says, “to share with young people and get them excited about science. Dad would have loved this."

Mary Ann Ayd

[Return To Top]

Hottest Show on Broadway


Geographically speaking, the amorphous School of Medicine has always been hard to pinpoint. But now that the $140 million research building on Broadway (already nicknamed the BRB), under construction for the past three years, is open, the School has a bona fide front door at 733 N. Broadway.

A circular drive arcs the ground-level entrance. Directly inside, the School of Medicine’s admissions office occupies its finest quarters ever. Up one flight sit the offices of the registrar, student affairs, financial aid, research administration, the five School of Medicine vice deans and the business office connecting to the dean’s suite in the Traylor Building.

Levels three through eight of the BRB house laboratory programs for comparative medicine, medicine and the basic sciences, plus two elite research groups: the Institute for Cell Engineering and the McKusick-Nathans Institute of Genetic Medicine. In all, 31 principal investigators will soon have moved their labs into this airy new space, designed to encourage collaboration.

“The building brings to life the interdisciplinary approach,” explains Chi Dang, who as vice dean for research has been involved with the project from the start. “It introduces a whole new period for Hopkins.”

Anne Bennett Swingle

[Return To Top]

Patient Safety (Executive-Style)


JHU President William Brody (far left) makes safety rounds in the cardiac sugery intensive care unit.
When a team of physicians and other caregivers from the cardiac surgery intensive care unit told University President Bill Brody that surgical site infections were a problem in their unit, he wanted to know why. One surgeon whipped out photos of the operating room and pointed to a major culprit: dust-coated light fixtures. Brody immediately challenged the group to take responsibility for removing every such risk that put patients in jeopardy. He’d support whatever they needed to do, right down to canceling operations, he said. From that day forward, the ORs have been meticulously cleaned.

As patient safety has become a mantra at hospitals across the nation, in East Baltimore, leaders like Brody and Dean/CEO Edward Miller have adopted intensive care units around the Hospital in a program called executive safety rounds. In the two years since the program started, safety climate scores have risen in several of the ICUs.

During their once-a-month safety rounds, the executives ask touchy questions: “When was the last time a patient was put in harm’s way on your unit?” was a recent one. They’ve discovered that discussing such topics openly can be challenging. During Miller’s first meeting on the neuro critical care unit, a physician rebuked the unit’s safety team for airing dirty laundry. The dean quickly made clear that that was exactly the point. He wanted to hear directly from frontline staff about problems, knock down barriers to change and encourage problem-solving.

Brody, who preaches zero tolerance for risktaking when it comes to patients, says other industries have done a much better job at absolute performance quality. When the patient safety team in the cardiac surgery ICU set its sights on getting unit infection rates below the national average, he challenged them to aim higher. “You’ve got to keep driving the process,” he said, “until you’ve eliminated infections.

“Not only should health care be tracking medical errors,” Brody asserts. “We should be publishing them. Maybe that’s how we enforce a culture of change."

Patrick Gilbert

[Return To Top]

One Great Big Front Door

A patient calls for an appointment with a specialist at Hopkins Bayview, only to discover the physician is booked for six weeks. Worse, the scheduler can’t determine if another doctor—perhaps at White Marsh or the Johns Hopkins Outpatient Center—has an earlier opening. The reason? Hopkins Medicine’s various outpatient locations use scheduling systems that are incompatible with each other. The upshot is that frustrated patients are forced to call all over the system to find an available specialist. Staff physicians, meanwhile, can find themselves scheduled to see patients simultaneously at different clinics.

To cure the morass, the Johns Hopkins Clinical Practice Association is looking into creating a universal front door. A single computer system and entry point would not only streamline access to faculty physicians, but also increase revenues and decrease costs. Studies show that the multimillion-dollar investment could be recovered in as little as two years.

Patrick Gilbert

[Return To Top]

Meanwhile, in Singapore

For the first time in its history, the School of Medicine is setting up a division outside Baltimore. To be called the Johns Hopkins Medicine Division of Biomedical Science in Singapore, the new entity represents the latest step in a collaboration that began five years ago. Johns Hopkins Singapore, originally formed as a research unit and medical oncology clinic, now will also offer graduate training in basic and clinical research. Students will be able to earn a Ph.D. from either JHU or the National University of Singapore. The new division gets under way early this year with 12 full-time Hopkins faculty members who will focus on immunology, cancer biology and experimental therapeutics.

- Mary Anne Ayd

[Return To Top]

What is Conflict?

Medical schools have long assumed that patients would be leery of joining a clinical trial if they thought the researchers running it stood to gain financially. Not so, according to results of a recent Hopkins study. What motivates people to sign themselves up is the hope that they’ll benefit from a new treatment. Whether the study investigators have a monetary stake in the therapy or device being tested turns out to be beside the point.

To discover what patients think about physician conflict of interest, cardiologist Joel Braunstein and his colleagues Steven Schulman and Neil Powe approached 1,132 patients from 13 cardiology and internal medicine outpatient clinics about joining a hypothetical study of a drug to help prevent heart attack. They randomly told the patients either that there was no conflict of interest for the physician, that the physician would receive $2,000 for each patient in the study or that the physician held a patent on the study drug.

Of the 789 patients who completed a questionnaire on participating, about a third said they’d join the trial whether or not there was a disclosed conflict of interest. And more than half said they felt it wasn’t very important for investigators to disclose such information during trial recruitment.

“There’s been an incredible push by academicians and health policy-makers to make sure conflicts of interest are minimized,” says Braunstein. “While I believe this is ethically justified, our study surprisingly indicates patients don’t really care about these relationships.”

Patrick Gilbert

[Return To Top]

The Robot is In

It may sound like science fiction, but for two dozen patients who’ve received a new kind of postoperative checkup, the experience has been, well, a virtual hit. They actually like having their surgeon, Louis Kavoussi, roll into their hospital room looking like a Star Wars-esque droid. If Kavoussi can’t be there in person, his patients say, getting a visit from him as Dr. Robot is the next best thing.

A pioneer in robotic surgery, Kavoussi and some of his Department of Urology colleagues recently became the nation’s first hospital physicians to test drive the latest concept in doctor-patient video teleconferencing. Billed by its manufacturer as the world’s first remote-presence robot, the 5-foot, 200-pound device originally was developed to help nursinghome physicians cover more than one facility. The robot includes a flat-screen monitor, microphone and video camera that allow the doctor and patient to see and talk to each other in real time. Using a joystick and Internet hookup, the physician can operate the robot from almost anywhere.

Kavoussi, who’s used Dr. Robot to check on patients he’s already seen in person, to answer their questions and even inspect their surgical sites, says the machine isn’t meant to replace a hands-on physical exam. But he thinks one reason hospitalized patients give it high marks is because it helps them feel they’re getting more time with their physicians.

Furthermore, he says, the robot has other potential uses. “Many health care facilities and long-term care communities can’t maintain a staff of all the medical specialists they need. The robot could allow consultations whenever and wherever they’re needed, including military operations and disasters.”

Eventually, however, Kavoussi envisions the Hospital equipping every patient room with interactive monitors. “The robot itself,” he says, “is completely incidental. But for now, it’s definitely a cool thing.”

Mary Ann Ayd

[Return To Top]

Cites for More Eyes

Bert Vogelstein: The world's most influential scientist
Not all superstars live in Hollywood. According to the Philadelphia-based Institute for Scientific Information, Hopkins oncology researcher Bert Vogelstein tops the list of the world’s 50 most influential scientists in the past 20 years. The ISI list, published in its newsletter Science Watch, was compiled using detailed analysis of citations in journal articles from 1983 to 2002. Vogelstein’s work was referenced by other researchers 106,401 times, head and shoulders above all others. Nabbing the No. 3 spot on the list is Director of Neuroscience Solomon Snyder, with 63,106 citations. And Oncology Professor Kenneth Kinzler’s 48,277 citations put him at No. 19. Other Hopkins faculty who figured in the top 250 are Larry Lichtenstein, Jack Griffin, Pat Walsh, Dan Drachman, Tom Quinn, Ted Dawson, Andy Feinberg, Don Price and David Sidransky.

Mary Ann Ayd

To The Waterfront

This Hopkins Medicine employee now kayaks to her office in Fells Point
For 300 years, Baltimoreans have been settling in Fells Point. Now Hopkins is putting down a few roots of its own on those historic, cobblestone streets. To provide more clinical space on the crowded East Baltimore campus, the institution has transferred almost 400 employees who don’t work directly with patients to the waterfront district, many of them to the renovated Bond Street Wharf.

By all accounts, employees are enjoying their quite uncampus-like digs in the six-story building at the foot of Bond Street, where they have spectacular views of the surrounding harbor. (The office space is part of a new, mixed-use development that includes a park, restaurants, residences, retail and a 760-car garage.) For many, though, the inconvenience of being located away from the medical hub tempers their enthusiasm.

Backs and forths between the two sites become unavoidable. To cut the travel time and also the inconvenience, Hopkins runs a shuttle between Fells Point and the East Baltimore campus every 30 minutes.

Anne Bennett Swingle

[Return To Top]

Who’s applying?

The number of would-be doctors usually far outstrips the available openings in U.S. medical schools. Even so, trend watchers inevitably blanche when the applicant total takes a dip and rejoice when there’s an uptick.

For the last few years, as medicine appeared to become less desirable to college graduates nationally, the School of Medicine’s applications numbers held pretty steady. And last year, for the first time ever, more women applied (and were accepted) for the first-year class than men. This year, Assistant Dean for Admissions Paul White says, Hopkins saw somewhat of a market correction.

Around the country, applications to medical schools spiked 3.4 percent to 35,000, reversing a six-year decline. And for the first time, the majority of applicants nationally were women. At Hopkins, meanwhile, when the second round of applications was tallied in December, there were 44 more applicants than last year, but 95 fewer women than in 2002. Nineteen more applications, however, came in from minorities.

And in another turnaround, 2002 marked the first year more American women than American men earned Ph.D.’s. In that same year, at the School of Medicine, the split (49 men and 32 women) held a more traditional line. But by 2003, the picture had shifted. Last spring, the School awarded doctorates to 35 women and 25 men.

Mary Ann Ayd

[Return To Top]