APRIL 2000
Pioneers of Discovery
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Mental Illness's Public Enemy #1
By Marjorie Centofanti

I pick up my phone and recognize Sol Snyder's low-decibel voice, one a Baltimore Sun reporter said "exudes an air of calm most people only attain when they're on vacation."

"I have something interesting you might want to know," he tells me. As a sometime press officer for Hopkins, I'd written any number of news releases on work issuing from Snyder's neurosciences labs, and the calls all began like this. "Something interesting" could be engineering the first human brain cells able to grow and reproduce in laboratory dishes--a feat most scientists had thought a pipe dream. It could be finding that the body keeps a pinprick's pain from becoming excruciating by releasing its own version of morphine. It might be incontrovertible evidence that warped, aggressive behavior in animals can follow from warped brain chemistry.

From Snyder's arrival at Hopkins 35 years ago as a psychiatry resident to his present third decade as head of one of the world's most productive departments of neuroscience, his quiet manner belies what he's accomplished. Attesting to that is a 12-inch pile of clippings and news releases about discoveries he and a bright-eyed coterie of pre- and postdocs have made, even though the file lacks his 976 scientific journal articles, his books, or pieces for The New York Times.

Snyder's energies have focused on research about neurotransmission in the brain, on the brief liaisons between the transmitter molecules that nerve cells release and their protein receptors anchored in cell membranes. This fleeting attachment is the basis for all brain activity. And Snyder, who trained to be a psychiatrist but discovered early on that he could do more to thwart mental illness by staying in the laboratory, has long understood that the major drugs that affect mental well-being act through this process. "Understand neurotransmission at a molecular level," he explained, "and you know how drugs act; you see how to develop new ones."

Over the years, he and his students have contributed to science the discovery of both novel neurotransmitters and, as he says, "a slew" of receptors. You could call Sol Snyder the Godfather of synaptic chemistry for his lab's findings on the GABA receptor where Valium attaches; the adenosine receptor that links caffeine and the brain; the bradykinin receptor that's key to the transmission of pain; and several receptors for serotonin, neurotransmitter of mood and appetite. His lab co-discovered the dopamine receptor and tied its dysfunction to schizophrenia. Discovering that human brains contain receptors to opiates such as heroin or morphine was another significant find. It led him and others to "natural" opiates, the enkephalins and endorphins that form the basis of the "runner's high." In 1978, the opiate work won Snyder a shared Lasker Award, this country's highest medical research honor.

It's no hyperbole that principles coming from Snyder's labs have led to the psychiatric drugs that millions take, such as Prozac. Moreover, by enabling companies to work with receptors in bits of tissue, rather than in animal studies, Snyder lab techniques have greatly speeded the pace of drug development worldwide.

How do you get such results? My visit with Snyder following his call is instructive. Snyder welcomes me to a tasteful office, probably the only one in Basic Sciences with actual wallpaper. The "something interesting" proves just that: It's a simple yet elegant study, about discovering that a rare form of a common amino acid may be a fail-safe mechanism, a second key, to turn on a brain receptor. This receptor (called NMDA for N-Methyl-D-Aspartate) is, Snyder says, "arguably the most important to our humanity" because it is crucial to learning and memory. It's also the receptor overstimulated during a stroke, and Snyder found value in the idea that you could turn off a stroke's cascade of damage in the brain by turning off the second key.

No one's postulated this sort of fail-safe system before, but it makes sense to Snyder. "The NMDA receptor is so delicate, so crucial to us," he explains, hands flying, "that some safeguards to turning it on are in order."

But, Snyder asks rhetorically, who would consider a bizarre form of an amino acid as the second key? Scientists had thought the amino acid, called D-serine, nonexistent in humans and active only in insects and bacteria.

Snyder remembers finding a paper several years earlier, however, from an obscure Japanese group that noted the peculiarity of finding D-serine concentrated in the human brain. Snyder tucked that away. "Why don't you map this?" he later suggested to student Michael Schell and, using fluorescent antibodies as tracers, Schell did. D-serine glowed in exactly the same brain locations as NMDA receptors--a clue that the amino acid must play some part in their function.

A second bit of information clinched this idea. Snyder also knew of a study, decades earlier, in which pioneer biochemist Hans Krebs found the enzyme that destroys D-serine."At the time, people said, 'How ridiculous!'" Snyder explains, that Krebs claimed an enzyme existed in humans to break down something only found in bacteria and biological lowlifes. But Snyder's students resurrected Krebs's enzyme a half-century later, using it to destroy D-serine in the brain. "Lo and behold," Snyder says, "with D-serine gone, neurotransmission through the NMDA receptors stopped." Just what you would expect if you lost one of your keys. NMDA receptors, the Snyder lab proved, require the strange amino acid to work.

All this is vintage Snyder. For one thing, it confirms Snyder has "yard sale eyes." He scans scientific literature--religiously-- and assimilates what others overlook. An article showing that a gas, nitric oxide (NO), could relay messages to smooth muscle prodded Snyder and postdoc David Bredt to seek it in the brain. They found yet another neurotransmitter.

Not only did finding a gas used this way in the brain shock neuroscientists, but to Snyder's delight, it's gone on to uplifting applications. At a recent high-profile press conference, a Pfizer chemist credited the neuroscientist's NO work for the chemist's discovery of Viagra.

The interview itself tells much. After my preliminary questions, Snyder looks uneasy. I stop. "Let me tell you the whole story," Snyder beseeches. So he narrates for the next hour, stopping when I ask for applications of the discoveries--which there always are--until I am totally caught up and suggest directions his work could take, much to his encouragement and my delight.

"He has this marvelous way of drawing you in," says one of his first students, Joseph Coyle (MD '79), now head of psychiatry at Harvard. "He really lets you develop your own ideas. You feel a sense of ownership and urgency about designing your work. When I started in Sol's lab, it was the most exciting thing I'd ever done!"

Snyder is blessed with a narrative sense of his research: He's telling the story of his domains in the brain. This provides, others say, both an unfailing sense of what's important and a gift at weeding out the extraneous. His students pick this up. When their research is ripe for journal submission, for example, everyone in the lab meets at the appointed hour and tells their piece of the story. Snyder listens and distills it into the article, which he writes then and there, with feedback from all. "Amazingly, the rough drafts are usually the final drafts," says Coyle.

Snyder describes himself as a "klutz" at the lab bench; his colleagues doubt that, but, still, from early on he's been an instigator and collaborator rather than a lab bench regular. "The real science in Sol's labs occurs over discussions," says Hopkins neuroscientist Ted Dawson. "He wanders into your lab to talk and next thing you know, four or five people are brainstorming."

"Very few scientists do all their research with their own two hands," Snyder says. "I believe I'm here to be a mentor."

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