Almost a century after mass spectrometry was first used to analyze small molecules, a Yale doctoral alumnus and former professor has shared in the 2002 Nobel Prize in Chemistry for his pioneering efforts to apply the technique to large molecules, such as proteins.
His discovery, electrospray ionization (ESI), allows scientists to gauge the weight of large molecules and determine quickly and accurately what proteins are in a sample. John B. Fenn, Ph.D. ’40, professor emeritus of chemical engineering at Yale, described his technique in a paper in Science in 1989. Evidence of his method’s significance is clear: last year alone more than 1,700 scientific papers that relied on ESI were published.
“What really gave it a kick in the pants was the advent of proteomics,” Fenn said when reached by phone three weeks after he heard the news. “It turns out that ESI is one of the most sensitive ways of getting accurate values of the mass of protein molecules. With the right instruments it has got such tremendous resolution that you can distinguish individual protein molecules even though they are in with a whole bunch of others in the sample.”
In its citation, the Royal Swedish Academy of Sciences said Fenn’s work has led to “increased understanding of the processes of life,” quickened the pace of drug development and led to faster diagnoses of cancer.
Fenn received the news of the award at his home in Virginia, where he is a professor of analytical chemistry at Virginia Commonwealth University in Richmond. He shared the award with two other researchers, Koichi Tanaka, an engineer from Japan, and Kurt Wüthrich, Ph.D., of Switzerland. Tanaka worked on other applications of mass spectrometry and Wüthrich used nuclear magnetic resonance to determine protein structures.
“It’s like winning the lottery,” Fenn says. “I’m still in shock.”
The technique he described in his 1989 paper solved a problem that had bedeviled scientists since 1912, when mass spectrometry was first used to analyze small molecules. Mass spectrometry worked only for molecules that weighed up to 1,000 times as much as a hydrogen atom. Using ESI, Fenn turned large molecules into smaller ions, without causing them to decompose. He created charged droplets by spraying molecules with water in an electrical field. As water evaporated from the droplets, only protein ions remained. Their mass could be determined by setting them in motion and measuring how long they took to travel a set distance.
Fenn, who received his doctorate in chemistry from Yale in 1940, returned to his alma mater in 1967 as a professor of chemical engineering, after stints in the chemical industry and on a U.S. Navy jet propulsion project. In 1978, with colleagues in chemistry and medicine, he began the work that led to the development of ESI.
Fenn left for Virginia in 1994, after his wife’s death and disagreements with the university over lab space. (His daughter, Barbara Fenn Reif, retired in December as director of student and alumnae affairs at the School of Nursing.) He’s still teaching and doing research, concentrating on the “conformation problem” of proteins. “How they fold and why they fold and what they fold to are extremely important problems because they determine what chemical reactions they do,” he says. “We are trying to pursue that.”
And, of course, his main tool is ESI.