The ‘G’ Man The ‘G’ Man UW honors Nobel Prize winner with top alumni award

It's the little things in life that can turn out to make big differences. Take the case of Martin Rodbell. His encounters with a friend's chemistry set, an algebra teacher's extra assignments, a father's resistance to French literature, a Ph.D. project at the UW gone wrong—and perhaps he never would have won the Nobel Prize for Medicine in 1994.

“I think of this more and more as I get older,” says the 70-year-old Nobel laureate, who received his doctorate from the UW biochemistry department in 1954 and now lives in Chapel Hill, N.C. “A person’s experiences—the total life experiences—are really important to carrying something through to its logical conclusion.”

The logical conclusion to Rodbell’s experiences came in a phone call from Sweden at 6 a.m. in the morning on Oct. 10, 1994. The voice told him he was sharing the Nobel Prize with Alfred Gilman of the University of Texas Southwestern Medical Center at Dallas, for work they had both done on how cells communicate through G proteins

In recognition of his outstanding work in the world of science, the University of Washington and the UW Alumni Association have named Rodbell the 1996 Alumnus Summa Laude Dignatus, the highest honor the UW can bestow upon any graduate.

Rodbell is currently scientist emeritus at the National Institutes of Health (NIH). Though these honors come in his name, Rodbell modestly credits those who have touched his life both inside and outside of the lab. “It is not an individual that really does something. It takes a community of effort to make things really work,” he declares.

It is a series of communities—a blue-collar section of Baltimore; the academic environments of Johns Hopkins, Illinois and the UW; the wartime Navy; and the research labs of the NIH—that molded an affable grocery delivery boy into a Nobel prize laureate.

Born in 1925, Rodbell lived above his father’s small grocery store in Baltimore. “I worked in the store when I was old enough, filling shelves, writing orders and delivering groceries with my little red wagon,” Rodbell recalls. His parents were not intellectuals and had never attended college, but they instilled in him a yearning for knowledge, he says, and a respect for teachers.

At school, “Marty was not a teacher’s pet and he wasn’t a grunge, but he was regarded as one of the smart kids,” recalls Rodbell’s childhood friend, Neal Zierler. “He was just a great kid, a warm and charming fellow.”

Rodbell, Zierler and a third friend, Angus McDonald, gradually became interested in science and math. Rodbell couldn’t have a chemistry set in the basement—it was the storeroom for the grocery shop. “Neal had all the equipment,” he says. “We used to try to blow up things and watch mixtures change colors in his basement sink.”

“Angus and I were very interested in math and science, Marty less so,” Zierler recalls. “Maybe it rubbed off a little bit on him.”

In junior high, a math teacher took a liking to the threesome. “Mr. Lundberg knew the three of us could do algebra. He had us come in after class every day and gave us lists of algebraic problems to do,” Rodbell remembers. “The three of us weren’t that competitive. We just enjoyed doing those problems.”

The three attended a boys-only, public high school patterned after Eastern prep schools. There was a great emphasis on languages and hardly any science—there wasn’t even a physics course. Rodbell was torn between his love of languages—especially French—and his love of science.

“There were economic and cultural pressures that prevented me from going into French,” Rodbell says. “My father probably would have kicked me out of the house if I had told him I was going to be a French professor. It was always, `Why don’t you become a doctor?’ ”

That decision had to be delayed anyway. In 1943, Rodbell enrolled at Johns Hopkins as a sophomore, thanks to high school work that was worth almost two years of college. But he got his draft notice soon after he turned 18. “They realized because of my eyesight I should not be put on active duty. Anyone who saw me on a firing range said, `That guy shouldn’t have a gun in his hands,’ ” Rodbell recalls.

Being a Jew, he felt the first priority was to fight Hitler. But the Navy sent him to the Pacific instead. He graduated at the top of his class in radio school and thought he would have a cushy job aboard a ship or in the rear lines.

“Instead I was posted to the Marines. I was loaded with radio equipment—it must have weighted 100 pounds on my back—and told I was going in on the second or third wave.”

He was part of a landing in the Philippines, not under direct fire from the Japanese, but in a dangerous place. “I can tell you it was pretty scary to be in the middle of a jungle, especially for someone coming from Baltimore,” he says.

In that jungle he got malaria and after his recovery spent the rest of the war in ships’ radio rooms. Like most World War Il veterans, it was experience that changed his world view. “It had an enormous impact on me. We were a collection of people from all walks of like and backgrounds. There was a real sense of comradeship,” he says.

At the war’s end his ship docked in Seattle, where he spent a month before he was discharged. “I spent time in California too. I found that I really liked the West.” He kept those impressions in mind when he returned to Johns Hopkins.

His family still wanted him to be a doctor, so Rodbell started in pre-med. But he found the atmosphere too competitive. “I wasn’t so easy to get in, especially if you were a Jew,” he says. A turning point was a class in biology that set his course in biological research instead of a medical practice. A professor told him to specialize in biochemistry and he spent an extra year at Hopkins taking every advanced chemistry course available.

Martin Rodbell and his wife, Barbara, in their Chapel Hill, N.C. home. (Photo by Dan Sears)

It was during that time that he met his future wife, Barbara Lederman Rodbell. She was a Dutch refugee from Europe who somehow ended up in Baltimore. Her family was part of the Jewish community in Amsterdam and neighbors of the family of Anne Frank. Barbara was close to Margot Frank, while Barbara’s sister, Suzanne, was one of Anne Frank’s playmates and is mentioned in the famous diary.

Barbara Lederman survived the war in the Dutch underground, but lost her family to the Holocaust. After the war, Anne Frank’s father, Otto, offered to take care of her. “Barbara was too old for that; she wanted to get on with her own life,” Rodbell says, so she left for America. She remained in touch with Otto Frank until his death. Her memories of the Frank family and the Amsterdam Jewish community are preserved in the archives of the U.S. Holocaust Memorial Museum in Washington D.C.

At the time she met Rodbell, Barbara was selling hairbrushes in a department store and acting in a drama group at Hopkins. “She had to fill in at the last moment in Moliere’s School for Wives, and she was wonderful,” Rodbell recalls.

Others thought she was wonderful too, especially one of Rodbell’s fraternity brothers, who started dating her. But then the fraternity brother had to leave for graduate school, so he asked Rodbell to “keep an eye on” his girlfriend. “I looked in on her and found her in bed, terribly ill. She couldn’t get up. My mother made a big pot of chicken soup and I spoon-fed her. I had to nurse her back to health,” Rodbell says.

The romance blossomed. Barbara was a cultured European, accomplished in acting and ballet. Through her, Rodbell’s world expanded to include the performing arts.

Barbara Lederman and Martin Rodbell were married in 1950 (Barbara’s former boyfriend was best man) and the next day they flew to Seattle so that Rodbell could begin his graduate studies. Geography played a large part in his decision to come to the University of Washington. “I wanted to get far away from Baltimore,” he says.

His graduate advisor was Donald Hanahan, who now is professor emeritus at the University of Texas Health Sciences Center in San Antonio. “I knew someone at Hopkins and I called him about Marty,” Hanahan recalls. “I got good vibrations about him.”

Biochemistry was a new department at the time, but it had an outstanding core of faculty members, including Edwin Krebs and Edmond Fischer, who would win the Nobel Prize for Medicine in 1992.

“We had a relatively small group of graduate students,” says Biochemistry Professor Emeritus Hans Neurath, and Rodbell made an impression. “You don’t forget your students who are bright, alert and really know where they are going. His mind is turned on all the time.”

“We lived in Union Bay Village, which was a bunch of old Army barracks at the time, for $32 a month,” Rodbell says. “We were all in the same boat, beginning to have families. Our first child, Paul, was born there. We were all poor, but it was a great life.”

Barbara Rodbell continued her interest in the theater. She found an abandoned auditorium and started her own theater group, the Great Plays Company. Rodbell even turned up on stage once, as the truck driver in e.e. cumming’s Santa Claus.

The company was doing well when a director absconded with all the money. “That was the end of it,” Rodbell says, though his wife continued to perform, including in a UW drama school production of Chekhov’s Uncle Vanya.

The central stage in his life was Hanahan’s lab. Rodbell was trying to work out how the liver made a lipid cell that formed part of the cell membrane. Through trial and error, he found that the molecule ATP greatly accelerated the synthesis of the lipid.

“I was about to publish this when a professor at Harvard published a paper that showed it was a molecule called CTP that was responsible for the production of the lipid,” Rodbell says. He was crushed. Where did he go wrong, he asked himself. The Harvard professor called him and they discussed the research. “Well, what you’ve found,” the professor said, “is that ATP can be contaminated.” In this case, some CTP got into the compound.

It was a lesson he’d never forget. ATP comes from rendering houses—often it is derived from horse muscle—and is unlikely to be 100 percent pure. The pitfalls of impure ATP would factor into his later, Nobel prize-winning discoveries.

“There were a number of things he learned at the University that were of value to him,” says Hanahan. “He learned the value of research and its pitfalls. He learned the precise way to go about it. And he learned that if 10 percent of your work gets good results, it’s great.”

In 1954 Rodbell got his Ph.D. and left Seattle for the University of Illinois, where he spent two years as a postdoctoral fellow. Then he joined the National Institutes of Health in Bethesda, Md.—a relationship that would last for 38 years. Three more children came along, Suzanne, Andrew and Phillip, who got his B.S. in forestry management from the UW in 1982.

Eventually Rodbell had his own lab. His specialty was hormones and cell physiology, particularly working with fat cells. “He came up with a process that—45 minutes after knocking off a rat—you had a very clean test tube of fat cells. You had a single cell sample that would respond to hormones such as insulin and adrenaline,” says Constantine Londos, who worked under Rodbell at NIH and now heads his old lab there. “It’s still is one of the most widely cited papers in hormone research.”

Londos recalls the informal atmosphere of the early days fondly. Rodbell would often commute to work on a bicycle, wearing a precursor to a Walkman called a “bone phone.” On a spring day, Rodbell would sometimes close the lab, get everyone to hike down a canal towbath and then relax at a Georgetown café. He always wrote a poem for special occasions, a practice he continues to this day.

At that time scientists—including the UW’s Edwin Krebs and Edmond Fischer—had begun to unravel the way enzymes within the cell cause the cell to release molecules, such as glucose, into the bloodstream. A key to this cycle was a molecule called cyclic AMP. But theories on how information goes through the cell walls and gets to the AMP was limited and unproven.

Rodbell’s breakthroughs came in 1970 and 1971. With his fat cells, he tried to prove the theory of a “single messenger” molecule. But he couldn’t get the result that would confirm this theory.

Cell walls have receptors that detect a specific hormone from the outside. “It dawned on me, what if each receptor had different molecules to couple with the enzymes (inside the membrane),” he says. Instead of a simple cause and effect, there was an intermediate step in the messenger process.

Working with a colleague in a Washington, D.C., bar, Rodbell postulated a process with three parts: the discriminator (the receptor in the cell wall), a transducer (what it was he didn’t know), and an amplifier (which regulates the cyclic AMP).

“We actually drew it on the tablecloth,” he recalls. Rodbell presented his idea to an NIH conference the next day. “I felt, if this were the case, then you would get a more complex set of communication components. It would make the cells able to do many more types of things.”

But Rodbell’s colleagues were unimpressed. “There was silence,” he recalls. “It didn’t cause any huzzahs.” When his thesis adviser, Hanahan, heard about the theory, he remembers that he thought it was “a really far-out idea.”

Rodbell went back to his lab. Could he prove that there was this intermediary step, what he called signal transduction? In a classic series of five papers published in 1970 and 1971, using the standard scientific method of trial and error, Rodbell felt that he proved that there was a signal transducer and that it required a molecule called GTP (guanosine triphosphate).

One of the keys to his breakthrough was the contaminated compound that Rodbell had first encountered as a graduate student at the UW—ATP. The results he needed in one step only came when he added ATP to his experiment, but it didn’t make sense that the ATP caused the required reaction.

“Marty was well aware of the contamination of ATP by nucleotides from his work as a graduate student,” Londos says. In a day or two, after testing many nucleotides, Rodbell found that GTP, or its cousin GDP, caused the reaction.

To confirm that it was GTP and not the ATP itself, Rodbell synthesized a pure form of ATP in his lab, one that he could be sure was free from contaminants. When he added that pure form to his experimental system, liver membranes, the reaction was very weak. But when he then added just a trace of GTP to the same soup, the results were dramatic. “We knew we had discovered something,” he says.

“It was a very seminal discovery,” says Biochemistry Professor Emeritus Neurath. “He is one of the discoverers of a very important and very complicated physiological process.”

But at the time Rodbell’s work was not well received. “People didn’t believe it,” Londos recalls. “People said it was an aberration of the liver.”

“For five or six years I’d go to a conference and they’d say, `Marty, you’re not going to talk about that GTP again, are you?’ ” Rodbell says.

Gradually minds were turned around, especially after Rodbell’s lab came up with a stable form of GTP that gave huge effects that nobody could ignore. Also, Alfred Gilman in Texas began to unravel the biochemistry of GTP and a host of related molecules—called G proteins. And Rodbell’s lab and others confirmed that signal transduction went beyond hormones. “As it turns out, there are many, many other systems that are responsive to this signaling process,” Londos says. “Even our sense of light uses the same system.”

As of yet, no one has defeated a disease or cured cancer because of the discoveries of Rodbell and Gilman. But with a better understanding of how the cell operates, medical science is closer to a breakthrough. We already know that the cholera toxin alters G proteins. There are signs that G protein malfunction may cause diabetes and alcoholism, perhaps even some forms of cancer.

Ask Rodbell to predict the future, and he’ll decline the invitation. “I’m not much of a PR man,” he says. “To say that in the last 100 years, this is the greatest thing since Ivory Soap… I don’t like that kind of thing.”

In the years after Rodbell’s breakthrough, he continued to work on the nature of G protein action in cells and membranes. In the early 1980s he was offered a position at Tufts University in Boston and almost took it. “My colleagues at NIH kept telling me, `We need you.’ There was a job opening as scientific director at the National Institute of Environmental Health Sciences in North Carolina. There was a cabal. `Just go down there,’ they told me. So I did.”

He took the job at the Chapel Hill, N.C. research center. Rodbell’s mission was to strengthen the basic research side of the institute, known then for its work in toxicology. “I worked very hard at it and recruited many fine people,” he says.

The institute’s basic research activity is now highly respected. “People are impressed with how much good basic research is going on here,” says James Putney, chief of the institute’s cellular and molecular pharmocology lab, “and that’s due mainly to Marty’s service as scientific director.”

But NIH was suffering from budget cuts and Rodbell’s area was not immune. In frustration, he resigned as scientific director and went back to his lab. In June 1994, he retired from the institute and was named scientist emeritus, a rare distinction in the world of NIH. “I was very happy about that,” he says. “I still have a budget and a lab and we go on in our research.”

Martin Rodbell (left) receives the Nobel Prize in Medicine from Swedish King Carl XVI Gustaf in a Stockholm ceremony Dec. 10, 1994 (AP photo).

Retirement was hardly the end of the road, however. Only four months later came the call from Sweden, and his life has been in turmoil ever since. “The day of the award was just bedlam,” he recalls. “I was amazed that I got through it.”

It hasn’t stopped. This month he flies to Seattle to become the UW Alumnus Summa Laude Dignatus and two days later, he must be in Geneva, Switzerland, to receive an honorary degree from the University of Geneva.

Despite all the accolades, Rodbell retains the same likable personality he had as a grocery delivery boy. “There is not a whit of snobbishness in him. That’s just the way he is,” says Putney.

The Nobel prize winner has taken the occasion to preach an important sermon—the value of basic scientific research. “Knowledge is the greatest gift to humanity,” he says. “The role of science in human society is knowing. It is the culmination of human development and evolution. We should take pride in that.”

He decries the tendency to look at practical outcomes and the bottom line. “Knowledge is eternal. It reminds people of who they are and what they can accomplish,” he says.

Rodbell’s own life is a reminder of what we all can accomplish. As he explained so clearly in his Nobel address, “My career and my experiences with people and events have been seamless in that I cannot separate one from another. Without doubt, the thread of one’s life should be within the matrix of the total human experience.”

Turning it on: How G proteins communicate in the cell

During a summer hike in the Cascades, you are strolling along when suddenly, around the bend, you spy a huge grizzly bear. Your body goes on red alert. Instantly adrenaline is pumped throughout your blood system, prompting your liver and muscles to release energy-producing glucose. Your heart beats quickly, your lungs breathe faster, and you are ready to run as fast as you ever have in your entire life.

At this particular moment, you may not be wondering how this all works inside your cells, but it’s been a question for scientists since hormones were first isolated. In the early part of this century, scientists knew that a hormone, such as adrenaline, would signal a response in the cell—”release glucose into the blood.” But how exactly that message was translated through the cell wall was unclear—at the time they thought it worked in one turn, like a lock and key.

But the Nobel-prize winning work of Martin Rodbell proved that there is a lot more going on—a series of switches have to be thrown chemically in order for the message to get passed along. A key to those chemical switches are G proteins.

And if something is wrong with this process, such as leaving the switch “on” or “off” for too long, there is trouble. Scientists now know that cholera alters the G proteins, leaving the switch “on” for too long, which prevents the normal absorption of salt and water in the intestines—leading to dehydration or even death.

Diabetes and alcoholism are thought to be caused, in part, by G protein malfunction, and scientists have also traced a form of pituitary cancer to impaired G proteins. While G protein research has not yet let to a miracle cure, the discovery may lead to eventual treatments.

The system itself is a complex series of reactions. When you see the bear in the woods, your adrenal gland releases adrenaline. The hormone races throughout your body, but only the cells that need the signal, such as your heart muscle, have the receptors that can detect it. The hormone molecule “tickles one of the receptor outside the cell wall, and inside the wall, the other end giggles,” explains Rodbell’s NIH colleague Constantine Londos.

The “giggling” side of the receptor changes its shape, turning into an irresistible docking site for a G protein. Once snuggled into its site, the G protein itself undergoes a change. It had been holding on to a molecule called GDP. Now it releases that and grabs onto a related molecule called GTP.

But that’s not the end of the transformation. With GTP in its grasp, the G protein now works on other membrane processes, such as enzymes and ion channels. These enzymes can now make a new messenger molecule, called cyclic AMP. What follows is an “enzymatic cascade,” where the cyclic AMP causes a protein reaction. In the case of your liver and muscles responding to the sight of the grizzly, the enzymes release glucose from the cells, giving you the energy to run away.

The part G proteins play in the communication process happens in a instant. As you turn and run, all you can hope is that the grizzly’s G proteins aren’t working as well as your own.