Rodbell's Inspiration:
In the mid-1960s, Rodbell was studying enzymes. At that time, the only test medium available was crude chunks of fat tissue. To get more precise results, Rodbell developed a method for isolating single fat cells from the fat tissue. Because fat floats, Rodbell first put the minced tissue in a liquid and then treated the floating cells with a substance called collagenase to separate the fat cells from other cells.
"Great," he shouted, but are they viable cells?"
- –Bernardo Houssay
Martin Rodbell, 1966 Courtesy of the Rodbell Family
Fat cells isolated by Rodbell's method. Courtesy of Dr. May-Jan Zarnowski and Dr. Joseph Brzostawski, NIDDK
Rodbell's 1980 commentary on his 1964 paper, which became a "Citation Classic."
Reproduced with Permission from ISI (R). Original material published in Current Contents, Number 45, November 10, 1980
To confirm for the Nobel laureate Bernardo Houssay, who was visiting Rodbell's laboratory, that these cells were viable, Rodbell showed that the cells reacted normally to the hormone insulin. This was a turning point in his career—Rodbell's focus shifted from studying the metabolism of fat to examining the actions of hormones.
"Apparently, it often happens that a simple idea can engender consequences that are far beyond the intent."
- –Martin Rodbell
The procedure for isolating fat cells was a boon to hormone research, because fat cells respond to a wide variety of hormones. No one before had been able to study hormones' effects on cells this way. Many researchers began using Rodbell's method, making his paper "The Metabolism of Isolated Fat Cells" one of the most widely cited in the field.
What causes that surge of energy you get when you are frightened?
Martin Rodbell, 1967 Courtesy of Robert O. Scow, NIDDK
Before the work of Earl W. Sutherland, scientists knew that the adrenal gland produces a hormone called epinephrine, which travels to the body's cells and causes an increase in blood sugar. The sugar gives your body energy to react to stressful situations. But no one understood exactly how this hormone produced such an effect.
In the late 1950s, Sutherland investigated the effect of epinephrine on liver tissue. He and T.W. Rall discovered that the hormone—the "first" messenger—stimulates formation of a "second messenger" within cells. It is this second substance, cyclic adenosine monophosphate (cAMP), that stimulates the breakdown of stored carbohydrate into sugar. Sutherland suggested that the actions of many other hormones could be explained in the same way.
In 1965, Martin Rodbell was inspired when Sutherland spoke at the NIH. Rodbell realized that his isolated fat cells were the perfect medium for further investigation of the mechanism of hormone action.
Sutherland's model of hormone action
A receptor accepts a hormone and stimulates adenylyl cyclase (AC) to convert adenosine triphosphate (ATP) inside the cell to cyclic adenosine monophosphate (cAMP). The hormone is the first messenger; cAMP is the second. Sutherland won a Nobel Prize for this work in 1971 Courtesy of NY Academy of Sciences - G.A. Robinson
Discovering the Role of GTP
Rodbell knew that a number of different hormones increased cAMP (the second messenger) in his purified fat cells. Together with postdoctoral fellow Lutz Birnbaumer, he discovered that each hormone acts through a specialized receptor, but all hormones stimulate the same adenylyl cyclase (AC) molecule. This has been called the "ping pong ball model."
Rodbell thought it unlikely that so many receptors could interact directly with a single AC molecule. He predicted that there must be a go-between that carries the signal from each receptor to the AC molecule. Rodbell used the word "transducer" for this go-between, using a term from computer science.
"We are working hard in the lab these days with a sense of excitement that we may shortly have some important answers to the question of how hormones activate adenylate cyclase systems"
- –Letter from Martin Rodbell to Mr. Anil Joshi, November 15, 1973
To find the transducer that he predicted, Rodbell turned from fat cells to liver cells. Two things made this work possible. First, David Neville, of the National Institute of Mental Health, devised a method for isolating large amounts of liver cell membranes. Second, Rodbell developed a technique for measuring the binding of the hormone glucagon to its receptor in those membranes. With the liver cell membranes and a method to test them in hand, Rodbell and his team (Lutz Birnbaumer, H. Michiel J. Krans, and Stephen L. Pohl) tested the response of the cell membranes to the hormone glucagon. Their experiments proved that a molecule called guanosine triphosphate (GTP) was necessary for the transmission of a message from a glucagon-bound receptor to AC. Although Rodbell did not identify and isolate the transducer, he proved that it existed, was dependent on GTP, and was an integral feature of all receptors that increase the activity of AC. Alfred G. Gilman shared the Nobel Prize with Rodbell for finding the transducer, called the "G-protein."
"It was a period in which my life's experiences had kaleidescoped into a wonderful sense of creativity shared not only with my immediate colleagues but with scientists from all over the world."
- –Martin Rodbell
Rodbell also developed strong evidence for a second type of transducer—one linked to receptors that inhibit functions within the cell. He accurately predicted that other pairs of transducers and receptors would be found that regulate molecules other than AC.
Ping Pong Ball Model
Each hormone acts through a specialized receptor, but all hormones stimulate the same adenylyl cyclase (AC) molecule
3-Part Transducer Model
Rodbell's model of signal transduction: The signal from the hormone is transduced and amplified inside the cell
Typed protocol for AC assay
solutions
In April 1966, Rodbell typed this protocol, which describes the first measurements of AC done in his laboratory
Hand-sketched graph #3
Rodbell drew this graph on January 5, 1970. These results culminated a series of experiments that showed for the first time that hormone receptors were regulated by a transducer that required GTP
In this experiment, glucagon was first bound to its receptor on liver membranes. Then different concentrations of GTP (shown on
the curves) were added. The data showed that very low concentrations of GTP caused glucagon to dissociate from the receptor
First and Second Images: Courtesy of NIDDK
Third Image: Courtesy of Ann Butler Jones
Fourth Image: Courtesy of the Rodbell Family
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