An Odd Man Out Wins in Medicine

THE BALTIMORE SUN

Almost 25 years ago, Martin "Marty" Rodbell had a hunch.

Last week, that hunch earned the Baltimore native a Nobel prize in medicine.

The honor ushers Dr. Rodbell -- and Dr. Alfred G. Gilman of the University of Texas Southwestern Medical Center, who shared the prize -- into a tiny club of savants who form the core of the globe's science establishment.

But Dr. Rodbell's prize demonstrates how the establishment can be wrong.

It shows how our fundamental understanding of our world and ourselves is often shaped by mavericks who stray from the fold. And it suggests the importance of letting scientists follow their noses, not the crowd, in searching for answers to fundamental questions.

In 1967, Dr. Rodbell -- a graduate of City College, Johns Hopkins and the University of Washington -- was a career biologist at the National Institutes of Health, studying the internal machinery of the cell.

He didn't buy the standard view of how the body's billions of cells respond to signals from other cells and the outside world.

By then, biologists already knew a lot about cells.

They knew that poking through the surface, or membrane, of each cell is an array of switches called receptors. Each type of cell -- heart cells, intestinal cells, liver cells -- has a unique set of these receptors.

Hormones and other chemical messengers in the blood work by inserting themselves in a specific receptor, the way one piece of a jigsaw puzzle fits another.

Biologists knew that a hormone's docking with a receptor triggered a burst of chemicals inside the cell. And those chemicals told the cell to grow, divide, or do whatever else the rest of the body needed it to do.

But biologists didn't know some crucial things. One was what happened between the time a receptor was triggered and the cell responded. Many assumed -- incorrectly, as it turned out -- that a receptor acted as a pump that flooded the cell with the appropriate chemical.

Dr. Rodbell thought he saw a trickier response.

Molecular go-between

He guessed that a receptor, when stimulated, dispatched a molecular go-between or middleman -- which he called a "signal transducer." "It was a means of taking information in one form and converting it into another form," he said in an interview last week.

So he performed experiments that showed that those signal tranducers must exist, although he couldn't pluck it out of the cell membrane. They came to be called G-proteins, because they seemed to bind to a molecule called GTP.

At first, many of his colleagues were dubious.

"It wasn't that Rodbell was searching for a missing link," said Dr. Donald L. Gill, professor of biochemistry at the University of Maryland at Baltimore, who worked with Dr. Rodbell at the NIH in Bethesda from 1980 to 1982. "Nobody knew there was a missing link."

Dr. Rodbell ignored the skeptics and kept working. Some scientists were intrigued. Dr. Arthur G. Gilman, an energetic pharmacologist now at the University of Texas Southwestern Medical School in Dallas, joined the hunt.

"Rodbell knew there were proteins involved," said Dr. Gill. "He knew that every receptor he could study coupled to the same fundamental process. Al Gilman was the one who really got a whole team of people to tease these proteins out of the membrane. He was able to purify them and show they really existed."

The first G-proteins were discovered in the cell membrane. Later, another type was found inside the cell itself.

Fundamental processes

"Now there are thousands of people working on these proteins," said Dr. Gill. "They're finding new ones all the time, and new fundamental processes they control."

How does a G-protein work?

Take, for example, adrenalin -- a hormone that floods your body when you're challenged to a fistfight or cut off by a careless driver.

Your muscles need extra sugar in the bloodstream, to provide a source of energy if you need to punch someone or scamper to safety.

Sugar is stored in liver cells as glycogen -- a polymer, or very long molecule, that can't easily be shuttled through the blood. The liver cell has to be stimulated to snip the glycogen into shorter pieces, transforming it into glucose.

Adrenalin is pumped through the bloodstream. An adrenalin molecule snags an adrenalin receptor on the surface of a liver cell. The part of the receptor that sticks below the membrane, into the cell itself, changes shape.

With its new shape, the receptor couples with a G-protein.

This prompts the G-protein to eject a tiny molecule called GDP, a depleted version of an energy-rich molecule called GTP, for guanine triphosphate.

The GTP molecule, now inserted into the G-protein, causes its host to separate into three pieces. The largest of these pieces changes shape, and docks with an enzyme -- in this case adenylate cyclase.

The enzyme, in turn, churns out a second set of messenger molecules.

Other messengers

Those molecules trigger other messengers, which trigger others, and so on through a chain reaction that amplifies the cell's response. Finally, enzymes are produced that snip glycogen into glucose.

These short sugar particles spurt out into the bloodstream, where they are ready to feed other, hungry cells.

The body is ready to boogie.

Meanwhile, the G-protein slices a phosphate off the GTP molecule, turning its triphosphate into a diphosphate -- GTP into GDP. The G-protein assumes its original shape, uncoupling it from the adenylate cyclase.

The G-protein is once again fueled up and sitting on the tarmac, ready for takeoff.

Dr. Ronald L. Schnaar, a professor in the department of neuroscience of the Johns Hopkins School of Medicine, said only after Dr. Rodbell began his work did scientists "begin to make meaningful progress in linking receptors in a sensible series of steps to a final action" of the cell.

From his original hunch, Dr. Rodbell said last week, the study of G-proteins has become "one of the biggest fields, if not the biggest field, in biomedicine today."

Dr. Gill's lab, located in the second floor of a research building on Greene Street, is working on G-proteins that interact with calcium found in trace amounts inside the cell.

Affect sense of smell

Dr. Randall R. Reed, a professor of molecular biology at the Johns Hopkins School of Medicine, worked with Dr. Gilman in the late 1980s. He helped find that G-proteins play the same role in a person's sense of smell that they play in the release of sugar from the liver and hundreds of other processes.

G-proteins play a role in asthma. In diabetes. In high blood pressure. In how neurons -- brain cells -- communicate with each other.

Particles of light, called photons, strike cells inside the eye and activate G-proteins. It's one of the first steps the body takes in translating light into an image in the brain.

Cholera stimulates G-proteins in the gut, leading cells there to pump out water and sodium -- killing victims of the disease through severe diarrhea and dehydration.

Recently, scientists discovered groups of G-proteins called RAS proteins that have been linked to certain forms of cancer.

Basic research slighted

At a news conference last week, Dr. Rodbell, 68, said he quit in March as director of the NIH's environmental health center in Research Triangle Park, N.C., because the federal grants that supported his work had been cut several times.

He has always investigated basic cell processes, working on the assumption that his curiosity-driven research had as good a chance as any of finding new ways to control or cure disease.

The study of G-proteins has so far yielded no treatments. There are no guarantees it ever will. But it seems logical to think that the better the understanding of how cells work, the better the chance of finding ways to fix them.

Washington, meanwhile, seems increasingly unwilling to finance work with no prospect of an immediate, practical payoff.

"Now everything is targeted, bottom line, how to make a buck," said the scientist, thought to be the first graduate of City College ever to win a Nobel Prize.

"The attention of the Congress and the executive branch always has been toward the end goal. They are not as willing to take a chance now on people like me exploring the unknown."

Which means fewer scientists with hunches, and the chance to test them.

Douglas Birch is a reporter for The Baltimore Sun.

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