PORES, FOR WHEN IT RAINS|
Agre Shares Insights of Lifetime of Water Studies
In a Sept. 9 Wednesday Afternoon Lecture that he aimed squarely at young scientists, Agre, 66, told a most agreeable story: a life rich with intellectual and social camaraderie spanning the globe—from Oslo to Tokyo to Malawi—with friendships yielding a natural harvest of discovery, in an almost secondary way.
“I started out as one of you,” he told youthful investigators in Masur Auditorium, which was hosting a concurrent blood bank symposium, “and branched out.” He counseled newcomers to scientific careers to be persistent: “It’s hard to perceive how far things can go.”
Water has been called the universal solvent, or, as Nobel laureate Albert Szent- Gyorgy called it, “the solvent of life,” said Agre. But it “brings problems when in disequilibrium,” which can include hurricanes and monsoons as well as failed kidneys.
Water will diffuse through anything, of course, but when it meets an aquaporin, it is selectively chaperoned in a way unparalleled in biology.
This chance finding grew out of studies of the Rh blood group antigen; a 28-kilodalton molecule was thought to be a contaminant, but appeared so abundantly in nature that Agre and others decided to “clone it out” in order to discover its function. After all, “a protein without a function is like a scientist without a grant,” he quipped.
Agre, a native Minnesotan, had been in the habit of going tent camping in national parks with his family. They had enjoyed Yosemite, Grand Canyon, the Everglades and others. But one year his kids insisted on Disney World in Orlando.
Agre had spent 3 years as a postdoc at the University of North Carolina at Chapel Hill (coincidentally, at a time when NIH director Dr. Francis Collins was training at UNC) and dropped in on his way back to Baltimore from Orlando to visit Dr. John Parker, an old friend.
The two got to talking about what this naturally abundant molecule could be, with Agre wondering if it could be an oxygen channel. Parker thought it was the long-sought water channel molecule and turned out to have had the correct hunch.
“Discovery is the reward in science,” said Agre, noting that Parker deserves credit for the key insight.
“Water is an interesting molecule,” he said. “Every living organism has one or more aquaporins.”
“It’s amazing the power that science has when people work as colleagues,” said Agre, who counted former NIH director Dr. Elias Zerhouni as a key contributor, for his technique for evaluating water in the lung via CT scan. Agre admitted, “I felt a little overwhelmed by the international interest in aquaporins.”
Not long after AQP1 was discovered, AQP2 was cloned in Tokyo, in intracellular vesicles, Agre said. The race was on. Defects in the AQP2 gene were found to cause severe diabetes insipidus, but occur only rarely. Defects in AQP0, found in the eye lens, cause cataracts in small children, some of whom go blind. AQP4 is found in the blood/brain barrier and can accelerate damage in post-stroke brain edema; counteracting that function can benefit victims of stroke, the third leading cause of death in the U.S.
Agre disclosed that his wife, Mary, was the beneficiary of this insight, and is now fully recovered.
AQP5 is found in sweat and secretory glands and saliva. “We believe aquaporins are tied to the stress response,” said Agre, adding that AQPs likely play a role as environmental response modifiers. He surmises that this function went awry for some of the 15,000 people who died when a major heat wave swept Europe in the summer of 2003.
Another class of AQP known as an aquaglycoporin plays an important role in skin hydration and provided Agre with an amusing anecdote. Cosmetic firm Christian Dior hoped Agre would endorse its product that ostensibly took advantage of this molecule’s salutary effect on skin. A full-page ad in a French magazine alleged that the product was built on Nobel laureate science.
“My 80-year-old mother, back in Minnesota, saw the advertisement and said, ‘Finally, you’re doing something useful.’”
Agre’s usefulness nowadays is in directing the Johns Hopkins Malaria Research Institute, where insight into aquaporins is focused on ameliorating blinding cerebral malaria in the small children of sub-Saharan Africa, 600,000 of whom died last year; millions more suffer complications.
In other global work, basic research on the functions of AQP 7 and 9, found in fat and liver, respectively, may be able to counter the effects of arsenic-contaminated groundwater in India, which has been associated with an epidemic of liver cancer.
Agre said the AQPs found in all plants also present scientific opportunities: “The challenge is to do something useful.”
At the end of his talk, Agre shared the excitement of the pre-dawn call from Stockholm that heralded his Nobel Prize in 2003. “I wondered, ‘Do I tell them that I got a D in high school chemistry?’’’ he recalled. “I could just envision my teacher, Mr. Thornton, aspirating his corn flakes.”
Agre’s mother warned Agre’s wife, “That’s very nice, but don’t let this go to his head.”
Displaying a photo of Nobel congratulations posted on a suburban Baltimore liquor store sign, Agre noted, “It wasn’t because I was their best customer.”
His final slide, offered by his last postdoc as he closes his laboratory, featured two Chinese letters, wei and ji, which combine to form the symbol for crisis. They stand, he said, for danger plus opportunity.
The full lecture can be viewed at http://videocast.nih.gov/summary. asp?Live=16898&bhcp=1.