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What was your path into research?
SNYDER: When I first started studying medicine, I just wanted to be a psychiatrist—I didn’t have any interest in research or in being a scientist at all. Growing up, the one thing I really did well was playing and performing classical guitar, a career path I seriously considered, especially as my mother, a ”stage mom,” was encouraging. Less adventurous than she, I chose to be like “the other guys” and became a premed at Georgetown College followed by medical school also at Georgetown. I worked my way through college by giving guitar lessons. My guitar student Donald Brown, subsequently a world renowned molecular biologist, was in the very first research associate class at the National Institutes of Health. I worked in his lab the summer after college, and I realized that this science wasn’t anything like the “science” at school; it was creative work, and I loved it. He was a wonderful mentor and we’re still close friends. So I worked there all my summers, hung around in all my spare time and found that I loved research.
Nowadays, young M.D.’s get research training through the M.D./Ph.D. program. But back then, there was the Doctor Draft, wherein every doctor served in the military for two years. In the late 1950s, the NIH initiated the Research Associate program in which you could spend your military service researching at the NIH. As you would expect, everyone and their brother wanted to work there. I wouldn’t have been able to get in, even though I’d worked there summers. Luckily, though, I’d worked across the hall from the eminent neuropharmacologist Julius Axelrod. A Harvard graduate was to serve as a research associate with Julie but dropped out of the program. I got to take his place.
Working with Julie at the NIH, I went from loving research to adoring it. He was such a wonderful research mentor: when you came to the lab he’d talk about how we might approach problems, he’d make suggestions, but eventually he weaned each of us away, encouraging our independent ideas.
I started my psychiatry residency at Johns Hopkins in 1965 and I never left. Although I liked being a resident, and I liked treating patients, the laboratory work became so successful that the other stuff gradually melted away. Working in Julie’s lab really cemented my focus on lab work.
You yourself have trained many successful scientists. What’s the secret to being a good mentor?
SNYDER: A good mentor has to really care about the boys and girls in the lab as human beings, not as machines to generate data. You have to want them to build independent careers. I’ve found that if you just give them a lot of love, the science takes care of itself. Large doses of genuine caring and positive reinforcement—it’s like raising children. You have to encourage them to do their own thing. When someone starts in the lab, we brainstorm potential projects. Figuring out what to work on and how to approach it is the most important question in research. Just as Julie worked with me, my students and I usually start by looking at unfinished questions in the lab, but as they get new ideas I encourage them to follow their own paths.
Tell us about your latest research.
SNYDER: My lab’s goal is to study various molecular mechanisms in the brain, with a view toward the bottom line: understanding what’s gone awry in disease, especially mental illness, and what we can do about it.
One recent focus has been Huntington’s disease. It’s an amazing condition because it’s genetically dominant, so if the mother or father has the disease there’s a 50 percent chance of the child getting it. It also appears to come from just one single change in the DNA code that results in repeated copies of the amino acid glutamine in the protein that it makes, which is called huntingtin. This mutation gets passed down through generations, unlike most diseases, which come from several genes. It’s thought that it started with one person, hundreds of years ago, and everybody with the disease has the exact same mutation. The conditions are ideal for finding out what’s going on and then finding the cure.
What have you learned about the disease?
SNYDER: Over time, Huntington’s disease leads to degeneration of several parts of the brain. However, far and away the most pronounced degeneration takes place in the corpus striatum, the part of the brain that controls motion, which shrinks as much as 90 percent. Certain other brain areas, though, are not affected at all. In 1993, the aberrant gene was found, along with the protein huntingtin that it produced. However, huntingtin uniformly expressed throughout the body, not just in the specific parts of the brain affected by the disease, so we couldn’t connect it to the degeneration.
We eventually found that the protein huntingtin, when mutated by adding all the extra glutamines, binds to another protein that is selectively concentrated in the corpus striatum, the area of the brain most affected by the disease. This protein, Rhes, was so obscure that I’d never even heard of the journal that published its discovery. Our research revealed two things: one, that Rhes bound to mutated huntingtin, but not normal huntingtin, and two, the bound proteins together were toxic to the brain, although each alone was not.
If we had a drug that blocked the binding of Rhes to huntingtin, we might be able to stop or delay the onset of the disease. Working together with the Cure Huntington’s Disease Initiative, we’re screening drugs to find one that might block the binding between the two proteins with few side effects.
--Interviewed by Vanessa McMains, written by Sarah Lewin
Solomon Snyder on understanding how Huntington's disease damages the brain:
- Brain Degeneration In Huntington’s Disease Caused By Amino Acid Deficiency
- Johns Hopkins Scientists Uncover Molecular Roots Of Cocaine Addiction In The Brain And Reveal A Promising New Anti-Addiction Drug
- Johns Hopkins Neuroscientists Win National Academy of Science Awards
- Blocking Previously Unrecognized Links Between Inflammatory Systems Could Make COX-2 Inhibitors Safer
- Hopkins Scientists Uncover Cause Of Antipsychotic Drug Weight Gain
- Mystery Solved: Johns Hopkins Scientists Say Tiny Protein-Activator Responsible for Brain Cell Damage In Huntington Disease