PROFILE : SOLOMON H . SNYDER

The Reward of Ideas That Are Wrong age of 1 9 , he was giving guitar lessons, and one of his pupils was a scientist at the National Institutes of Health who needed a technician for the summer. Snyder took the job. "I realized that research was not at all like science. Science means you take these mea­surements and numbers and analyze them-yuk . But research is really cre­ative," Snyder says. "You're discover­ing, composing."

T he soft-backed chair is too small for him. With his long legs and arms extending at odd angles,

Solomon H. Snyder shifts and stretch­es, crossing and uncrossing his legs while he plays with the Johns Hopkins University I . D . card strung around his neck , moving his hands now across his face, now down to his ankles to pull up his socks. "You've got to be an op­timist because you have got to have ideas you are pretty sure are wrong," says Snyder, first picking up and shuf­tling the coasters on his office coffee table, then stuffing his fingers under his belt as if to keep them still for a few mo­ments. "And , as you know, you have to be relatively relaxed to be enthusiastic . "

The only thing that seems relaxed about Snyder, one of the country's most prolific and creative neuroscientists, is his voice . In a near drawl , Snyder discusses his research and his personal interests, while his hands and eyes, perhaps ea­ger to get back to the business of designing experiments, con­tinue to wander.

The 5 2 -year-old researcher is best known for his work in the 1 9 70s on isolating the opiate receptor and the body's own opiates, the enkephalins and en­dorphins. But Snyder's contri­butions to other areas of neu­roscience, including the devel­opment of techniques to study receptors, the elucidation of as­pects of neuronal communica­tion and of olfaction, the in

ments. His mentor, Nobel laureate Juli­us Axelrod, a biochemist at the Nation­al Institute of Mental Health, thinks otherwise : " It sounds good; he likes to say that, but he really isn't a klutz."

For his part , Snyder compares re­search to musical composition and al­most calculatingly-as though he wants his interviewer to use the colorful metaphor-describes how music is a recurring theme in his work . His office, which resembles a comfortable living room, is filled with pictures and models

Several years later, after medical school , Snyder spent a year as an intern in San Francisco, where a personal ex­periment with the hallucinogen LSD un­derscored his strong interest in psy-

chopharmacology. Although he reached a state of panic after many hours of the drug's in­fluence, Snyder says the expe­rience made him "realize that there is more to awareness than ordinary awareness and that there are incredible things go­ing on in the brain."

He continues to value drugs as probes to study brain func­tion. "Most of what we know about neurotransmitters comes from · the drugs that affect them," he explains. In fact , Sny­der sees pharmacological igno­rance among many neuroscien­tists today as a shortcoming in the field . " They are missing a terrific tool . "

vitro cultivation of continually dividing human neurons and,

NEUROSCIENTIST Solomon H. Snyder insists that he is just a "klutz. " Photo: Chris Usher/Black Star.

Snyder himself has wielded these tools with consummate skill . His early fame came from his work on the actions of opi­ates in the brain. In 1 9 7 1 , dur­ing President Richard M. Nix­on's war on drugs, the feder­al government began to fund research to clarify the neuro­chemical basis of heroin addic­tion in the hope of finding a cure. Snyder, who had worked

most recently, the discovery of what may be a novel class of neurotransmitters, has kept him at the forefront of the rapidly expanding field.

Like some senior researchers, Sny­der clearly prefers thinking up new ideas to the grind of conducting experi­ments. As a result , the dozen or so stu­dents working with him do most of the hands-on research, according to Sny­der. He claims that he is a klutz and that leaving laboratory work to his stu­dents ensures the success of the experi-

of his instrument , the guitar. Although Snyder's parents encouraged him to become a musician, he resisted: "I was more conservative than my mother and father. " Instead Snyder wanted to be­come a psychiatrist . Hoping, he says, to muddle somehow through the science required for his chosen profession , he entered Georgetown Medical School .

Snyder credits the guitar with lead­ing him to his first research job. At the

in Axelrod's laboratory study­ing neurotransmitters and the

effect of drugs on the nervous system, was by then a professor of pharmacol­ogy and psychiatry at Johns Hopkins.

By designing a straightforward ex­periment , Snyder and Candice Pert , a graduate student , were able to isolate the opiate receptor in 1 9 7 3 . Their work opened up the field of psychopharma­cology : it promised the potential of binding receptors to alleviate pain with­out causing addiction and of treating

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addiction and, perhaps, mental disor­ders as well.

The technique that the two tailored to study the brain's receptors-reversible ligand binding-is still pivotal to neu­roscientific research. Snyder and Pert used opiates labeled with highly radio­active isotopes to bind to the receptor. They then washed the cells quickly so that only the opiates that bound to the receptors remained. With the indis­criminant opiates that stuck loosely to any tissue flushed away, the research­ers could then identify the binding sites and characterize the receptor.

Elegant experiments are the key to good research, Snyder believes. "If you can do an experiment in one day, then in 1 0 days you can test 1 0 ideas, and maybe one of the 1 0 will be right. Then you've got it made. " He says this ap­proach to research was one of the most valuable ideas Axelrod taught him.

Shortly after the discovery of the opiate receptor, the body's own natu­ral painkillers were identified by John Hughes, now at Parke-Davis in England, and Hans W. Kosterlitz of the University of Aberdeen. Pert and Snyder published the same results several months later, but they had been scooped. In 1 9 78 Snyder, Hughes and Kosterlitz shared the Albert Lasker Award for basic bio­medical research for their work on the opiate receptor and the enkephalins.

Pert, who was not so honored, lev­eled charges of sexism because she was first author on the 1 9 7 3 opiate recep­tor paper. Although Pert says she great­ly respects Snyder as a mentor, she re­mains convinced that "there was defi­nite sexism going on. Women are low on the scientific hierarchy and that has not changed. "

Snyder shrugs off questions about Pert. "Actually, it was sort of a noncon­troversy," he says, speaking in a soft monotone. Snyder lauds Pert's work and matter-of-factly describes how many students and colleagues are in­volved in every discovery. Citing Axel­rod, who won the Nobel Prize in 1 9 70, as an example, he says "it is not unrea­sonable to say that Dr. Axelrod gets credit for what Dr. Axelrod's laboratory turned out. "

Snyder has continued to pursue clas­sical receptor-based research. For in­stance, his laboratory is now studying the benzodiazepine receptor, the site where valium binds. And in 1 982 he and venture capitalists David and Isaac Blech founded the biotechnology firm Nova Pharmaceutical in Baltimore. Al­though the company has not yet pro­duced any drugs based on receptor technology, Snyder says several such compounds are in clinical trials.

But what most excites him at the mo­ment is an entirely new idea. Snyder explains that he and his students are exploring what may be a new kind of neurotransmitter-one that does not act on traditional receptors. Certain highly reactive chemicals, such as nitric oxide and carbon monoxide, may be more than just common air pollutants. They appear to diffuse from one nerve cell to another to deliver messages, by­passing the classical receptor model.

A decade or so ago nitric oxide was identified in the endothelial, or inner, cells of blood vessels. Originally called endothelial-derived relaxing factor, ni-

"Jfyou can do an experiment in one day, then in 1 0 days you can test 1 0 ideas, and maybe one of the 1 0 will be right. "

tric oxide diffuses from the blood ves­sel wall to the adjacent muscles, caus­ing the muscles to relax and the blood vessels to dilate, Snyder explains. The compound, which has a half-life of five to 1 0 seconds in the body, was also found to be the active metabolite of ni­troglycerin, a fact that might account for the efficacy of that substance in treating heart disease.

"We couldn't help but study it," says Snyder of himself and his student Da­vid S. Bredt. "I mean, Jesus, it's a new kind of messenger. " The two decided to determine whether nitric oxide is made in the brain-an idea that had been sug­gested by John Garthwaite of the Uni­versity of Liverpool and Salvador Mon­cada of Wellcome Laboratories in En­gland-and, if it is, what role it plays.

Again, by devising a simple assay, Snyder says he and Bredt were able to measure levels of a by-product of the creation of nitric oxide, a substance with a much longer half-life than that of nitric oxide. They discovered that nitric oxide is indeed present in the brain and that it binds with iron in an enzyme that makes cyclic guanosine monophosphate (cGMP), a compound involved in the chain of events that oc­cur after a neurotransmitter binds with a receptor. They recently identified spe­cific neurons that produce another en­zyme, nitric oxide synthase.

"Who ever heard of a receptor as iron? Iron as a receptor? " asks Sny­der, like a comic delivering a line. It is "a completely novel concept in neuron­al communication, " he says, his hands roaming ever more quickly over his

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chair, his temples, his hair. "This is the most fascinating thing I have seen in maybe 1 0 years: a new biological prin­ciple about how things act. "

Snyder can barely rein in his enthusi­asm. Since nitric oxide clearly plays a role in regulating blood pressure, what better candidate for a genetic abnor­mality responsible for hypertension, he asks. And recently, he notes, his labo­ratory has found evidence that carbon monoxide may work in a fashion analo­gous to that of nitric oxide.

Snyder says the idea of looking for nitric oxide in the brain is a perfect ex­ample of taking discoveries in other areas of science and applying them to neuroscience, a process he credits as a source of ongoing inspiration along with the insights and ideas of his stu­dents. "When I read something about the heart, I think ' Does that fit into the brain? ' When I read about cancer genes, I think 'Do they fit into the brain? ' " he says. "Some of the finest advances come from jumping fields. "

Another recent discovery that for now is not as well understood as nitric oxide is the continued cultivation of human neurons in vitro. Four years ago researchers in Snyder's laboratory ob­tained cerebral cortex tissue from an 1 8-month-old child who was undergoing an operation for megalencephaly. Normal­ly, neurons do not reproduce, or divide, but these neurons did and still are, although no one knows why or how. "We've mailed the cells to more than 200 laboratories so far," Snyder says. "They have all the properties of neurons; they do everything that neurons do. "

Snyder, enthusiastic but hardly re­laxed as he describes his vision, fore­sees using these neurons for brain transplants. "I mean, all this fuss about fetal brain transplants, " he scoffs. In­stead a surgeon could just implant these neurons in a certain region of the brain that has been damaged or possibly even ravaged by Alzheimer's disease and watch them grow, Snyder says. He adds that researchers in his laboratory have already done successful transplants in rats and plan to move on to monkeys in the next few months.

The thought of a new, elegant exper­iment never seems far from Snyder's mind. When asked about a possible connection between the mental impair­ment that can accompany iron defi­ciency and the importance of iron in binding sites for nitric oxide, Snyder's hands and eyes suddenly slow down­but his voice speeds up. Out loud, he quickly runs through the biochem­ical intricacies of iron, nitric oxide and cGMP. "Oh," he muses, "you could test that very easily. "-Marguerite Holloway

© 1991 SCIENTIFIC AMERICAN, INC