The Biological Switchboard
The Gods of science smile fondly on those who take what is messy and make it crisply elegant. They still sigh over rumpled old Murray Gell-Mann, the physicist who in the 1960s tamed the zoo of subatomic particles into a manageable three quarks. But the gods do not take kindly to Young Turks who would muck up what is already streamlined and uncomplicated. Martin Rodbell discovered that in the 1970s, when he challenged a simple, two-step explanation -- one awarded a Nobel Prize in 1971 -- for how living cells respond to messages from beyond their walls. ""I would go to meetings and people would say, "Oh, Marty, not again','' recalls Rodbell, 68, who retired last May from the National Institute of Environmental Health Sciences, part of the National Institutes of Health. ""Each step [in the research] met resistance.''
But the evidence was undeniable. Over time, his idea that something like the transducers in a telephone are crucial to cell communication became a central paradigm in cell biology, explaining processes as diverse as human cognition and sex in yeast. Last week the sages at the Karolinska Institute in Sweden finally caught up, announcing that Rodbell and Alfred Gilman of the University of Texas Southwestern Medical Center at Dallas, who extended Rodbell's work, won this year's $930,000 Nobel Prize in Physiology or Medicine.
It was the very elegance of the model he would supplant that attracted Rodbell to his field. How, he wondered, do living cells communicate with and respond to each other when few of the hormones or neurotransmitters that act as messengers even enter the cell on the receiving end? Say adrenaline, stimulated by a scary sight, arrives at the liver. Receptors, which span the outer membranes of liver cells like antennas on a roof, grab on to the adrenaline. The receptors, according to the old model, directly convey the message ""The adrenaline is here!'' to an enzyme inside the cell. The enzyme stimulates the liver cell to release glucose, allowing the body to fight or take flight in response to whatever caused the adrenaline surge.
Rodbell found that nature wasn't this efficient. Rather than using this two-step system to communicate, Rodbell discovered, cells need a third step. After the receptor catches the adrenaline or other messenger, it changes shape; like a rider shifting position on a packed bus, that changes the shape of next-door molecules now known as G proteins (diagram), which the old model never even suspected existed. The G proteins then activate a molecule that will, for example, cause the liver to release glucose. Not everyone bought this model. Rodbell recalls being challenged at virtually every scientific meeting where he presented his conclusions in the 1970s. Partly that reflected scientists' resistance to a cumbersome model. Partly it reflected their ""show me'' temperament: Rodbell had only indirect evidence for G proteins. He hadn't isolated any.
Gilman could. He set out to identify the unknown proteins that Rodbell had shown must exist. He succeeded in 1977, purifying the first of what are now at least 20 G proteins. One of them is activated when a particle of light falls on the retina; it relays this information to an enzyme that starts a cascade of steps causing an electrical signal to be relayed to the brain. The result: sight. Other G proteins respond to odors, increase the production of sex hormones or change the electrical activity of brain cells. ""This is a ubiquitous system,'' says Gilman, 53.
But not one that lends itself to new therapies. In the quarter century since the discovery, researchers have not worked out which receptors stimulate which G proteins and what cellular changes those proteins cause. One reason for the slow progress is that more than 300 receptors communicate with the 20-odd G proteins. Figuring out which protein is connected to which receptor and, at the other end, to what else within the cell is like straightening out an old-fashioned telephone switchboard whose wires are a tangled mess. Still, researchers have linked abnormal G proteins to pituitary tumors, leukemia and other cancers (part of the cell machinery is stuck in the ""on'' position, causing uncontrolled cellular proliferation). G proteins also explain why cholera is so deadly: the toxin exuded by the disease-causing bacteria binds to G proteins in intestinal cells, keeping the proteins in a perpetual ""on'' position; the cells keep churning out water into the gut, causing often-fatal diarrhea. But even though G proteins have explained diseases, they haven't led to cures.
In the bottom-line '90s, that's a problem. ""When I first came to NIH,'' recalls Rodbell, ""I never felt that someone was going to ask me, "What do these G proteins do for mankind?' '' But grant agencies did start asking, and Rodbell's funding shrank. To sustain his research, he retired four months ago; the institute agreed to funnel what would have been his salary back into his lab to pay for staff and supplies. ""It was a sad climax to a long career,'' says Rodbell. But one that might just have been jump-started.
In a mark of the slim pickings in chemistry and physics lately, the Nobel committee reached back half a century to find this year's worthies. George Olah, 67, of the University of Southern California won the chemistry award for figuring out, in the 1960s, how to disassemble and then recombine hydrocarbon molecules, a technique central to industrial processes. Clifford Shull, 78, retired from the Massachusetts Institute of Technology, and Bertram Brockhouse, 76, of McMaster University in Ontario, shared the physics prize for discovering how to use neutrons as atomic X-rays. Shining a beam of neutrons at matter, they found in the 1940s and '50s, can reveal the structure of such complex materials as semiconductors and superconductors.
Cells reach out but never touch each other. How, then, do they communicate? By a four-step process that scientists are still exploring.
Messages in the form of hormones, neurotransmitters or outside events, like a ray of light, reach cells.
The receiving cell is studded with molecules called receptors, which work like satellite dishes on a roof. The receptors grab hold of the message, which changes their shape.
The receptor then jostles the molecules that Rodbell and Gilman discovered: G proteins. This wake-up call causes the G protein to activate or inhibit an enzyme.
The enzyme spurs a chemical or electrical reaction: an adrena-line message for example, directs a liver cell to release glucose.