Stopping Parkinson's: A Conversation with Rob Edwards, Physician-Scientist

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Robert Edwards

Translational science is a hugely popular term these days in part because it captures both the promise and the accountability of biomedical research. A generation ago, the favored term was "bench to bedside." And in the intervening years, "breakthrough science" and "high tech to high touch" each had their day in the sun.

Robert Edwards, MD, prefers the old-fashioned term "disease-related research," but not because he is nostalgic. In his mind, it best explains what he does, and who he is — that increasingly rare hybrid known as a physician-scientist.

"There are not too many of us around at UCSF, and after you consider other academic research centers like Harvard and Johns Hopkins, there are few places that have any at all," says Edwards.

So what exactly is a physician-scientist, and what is it about the career choice that keeps their numbers so small?

As to the first question, the best and shortest answer is anyone with a MD or MD/PhD degree who undertakes basic biomedical research.

And as to what explains their small numbers — there are now only about 2,000 MDs doing basic science research in the United States — cultural reasons often surface. Physician-scientists must be able to defend against the neither-nor prejudice, which hints that their "double major" has made them neither this nor that. They must also constantly maintain their credentials with colleagues on both sides of the research-patient care aisle, a test that can grow wearisome.

And then there are the grueling years of work. To qualify as an MD/PhD, for example, recently minted MDs defer their clinical training, and instead detour into a research laboratory to study the building blocks of disease as it arises within and among cells — a process that, coupled with the clinical rotations completed after their doctoral dissertation, can sometimes take seven, eight or even nine years.

Some clinical researchers skip the PhD part of the equation and devote themselves to patient-oriented research right out of the box, a decision that places them in or around clinics where the patients are. Recent estimates put their numbers at about 14,000.

Edwards, a neurologist who both heads up a research laboratory at UCSF Mission Bay and regularly sees patients, believes there is a single characteristic that unites all the variants.

"People like me like to bang away at one problem. Not everyone does. You really have to want to have the answer to a problem," he says.

Edwards' particular problem is the neurodegenerative disease known as Parkinson's, which afflicts an estimated 1 million Americans.

What causes Parkinson's? Rob Edwards explains.

Edwards came to Parkinson's through a back door of sorts. A UCSF neurology resident between 1981 and 1984, Edwards did his postdoctoral work in the lab of the legendary William Rutter, PhD, where he studied nerve growth factor.

What ultimately captivated him, though, was what happens at synapses — the junctions on a nerve cell where nerve cells communicate. This led him to the chemical messengers known as neurotransmitters and their elegant release-and-respond transformation from electrical impulse to chemical reaction — and back again.

"All the interesting stuff occurs at synapses," Edwards exults. "It's where information is processed, where memories form, where all cognition is based."

It was while still a postdoctoral fellow in the mid-1980s that Edwards first learned of a group of young intravenous drug users in nearby Santa Clara County. The drug users were distinctive because they were developing Parkinson's-like muscle tremors and weakness, the result of poisoning by a byproduct of heroin manufacture known as MPTP. MPTP kills neurons, particularly those responsible for producing dopamine, a chemical that influences muscle control.

Why was that important? Parkinson's disease starts when the brain cells that produce dopamine begin to die. "What these unfortunate drug users had done," Edwards explains, "is to turn themselves into human experiments." By studying what makes MPTP toxic, Edwards and his colleagues ultimately found a gene that protects against it. How so? "The transporter would sequester the toxin inside the vesicles, where it couldn't do any damage to the host cell. We used a clinical observation to understand the science," says Edwards.

Which is wonderful news, except that don't we give those with early-stage Parkinson's a dopamine replacement drug known as L-dopa? And based on Edwards' work with MPTP, is dopamine then a toxin too?

Yes and yes are the answers, Edwards explains. Dopamine is an internal toxin, but evolution has equipped us with protective measures that enable its benefits without causing serious consequences. "L-dopa does slow the progression of Parkinson's for five to 10 years, which is why we prescribe it," Edwards adds. "But there are some who wonder if the drug might be making the underlying disease worse."

Learn more about Rob Edwards' Parkinson's disease research.

Finding answers to the Parkinson's riddle will take time, Edwards insists, knowing the frustration of patients who bristle at the slow pace of progress. He has high hopes that work on the nerve terminal protein known as synuclein, discovered by recent UCSF recruit Robert Nussbaum, MD, will speed things along.

Nussbaum has noted that synuclein accumulates in large amounts in the brains of nearly everyone with Parkinson's disease. Synculein also hangs out at the synapses, the same part of the cell implicated in Edwards' other work on neurotransmitter release. And that could be a good thing, since Edwards can now use his experience from basic research on the synapse to help understand Parkinson's disease.

In the meantime, Edwards will continue to teach, see patients and keep trying to understand how a brain goes wrong (and stays right). He doesn't expect any special thanks. He just loves what he's doing.

Photo by Majed

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