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At ASMS, Nobel Laureate John Fenn Tells the History of Electrospray



John Fenn


Professor of Analytical Chemistry, Virginia Commonwealth University, since 1994.
Won the Nobel Prize in Chemistry, 2002.


Since 1987 Professor Emeritus, Yale University
1967-87 Professor of Chemical Engineering, Yale University
1959-67 Professor of Aerospace Sciences, Princeton University
1952-62 Director, Project SQUID (Navy program of basic and applied research in jet propulsion), Princeton University
1945-52 Experiment Inc., Richmond, Va.
1943-45 Sharples Chemical, Mich.
1940-43 Monsanto
1940 PhD in Chemistry, Yale University
1937 BA in Chemistry, Berea College, Ky.

Since John Fenn won the Nobel Prize in Chemistry last year along with fellow mass spectrometrist Koichi Tanaka and NMR researcher Kurt W thrich, he has been in great demand as a speaker. Last week at the American Society for Mass Spectrometry annual conference in Montreal, he gave not one but two lectures, in very different settings: the first at a small technical forum organized by Agilent Technologies on Saturday night, and the second in front of many hundreds of conference participants on Monday afternoon. In both talks, Fenn — who turned 86 on Sunday and didn’t seem to mind his late-in-life stardom manifesting itself in frequent requests from younger colleagues to sign their conference programs and to have their picture taken with him — told the story of electrospray ionization, and of the various people who contributed to its development.

Flying Droplets

Fenn started his trek into mass spec history in 1940, when he was a graduate student at Yale. The physics faculty at that time included John Zeleny, the first person to carry out planned research on the electrostatic dispersion of liquids. Zeleny passed a small stream of liquid through a thin needle that was at high potential relative to an opposing electrode. The resulting field at the tip dispersed the emerging liquid into a fine spray of charged droplets.

Zeleny observed that at a certain stage the droplets in the spray would break up into smaller droplets. He recognized that this disruption was a phenomenon which had been anticipated and characterized by a British scientist, Lord Rayleigh, back in 1882. (In an aside, Fenn remarked that many people have become lords because of their scientific achievements, but “to my knowledge, he is the only person that was ever born a lord and then became a great scientist.”) Rayleigh reasoned that if the droplet shrinks as solvent evaporates, the charges on its surface get closer and closer together, finally reaching the point where the Coulomb repulsion between them exceeds the surface tension that holds the droplet together, causing it to break up into offspring droplets.

Zeleny’s discovery, Fenn recounted, was followed by that of Malcolm Dole at Northwestern University in Evanston, Ill., who in 1968 proposed that a succession of such evaporation disruption sequences should ultimately produce droplets so small that each one contains only one molecule of solute. As the last bit of solvent evaporates, that residual solute molecule would retain some of that droplet’s charge to become a gas phase ion.

Several years later, meteorologist Julio Iribarne at the University of Toronto and his graduate student Bruce Thomson proposed a different mechanism for ion formation. They suggested that before the droplets become small enough to contain only one solute molecule, the field at their surfaces would become strong enough to lift a surface ion into the ambient gas.

“These two mechanisms are much debated in the field today, and the field pretty much splits 50/50 down the middle,” Fenn said. “My own feeling is that sometimes it’s one and sometimes the other.”
Dole’s and Fenn’s paths might have crossed much earlier than in the 1980s, as Fenn explained. After graduating from college in 1937, Fenn decided to go to graduate school and received offers for teaching assistantships from Northwestern University, where Dole was on the faculty, and Yale, where Zeleny was a professor. Though he first decided to move to Evanston — because the offer paid more, and because Northwestern’s chemistry department had a better reputation than Yale’s — he was swayed in the end. The reason? It happened that the treasurer of Fenn’s college in Kentucky, who had a son who was entering Yale as a freshman that same fall, offered him a free ride to New Haven with all his gear. “That delayed my meeting Malcolm Dole for 40 years,” Fenn said.

It was not until 1968 that Dole published the results of his attempt to produce ions by what is now known as electrospray ionization. Unfortunately, his results were not convincing enough to persuade other investigators to repeat those experiments. That is, not until Fenn, who had just moved from Princeton to Yale, got hold of the paper. “I spotted right away what one of his problems was, because what Dole didn’t take into account is that when the gas expands into vacuum, it cools like mad,” Fenn said. This cooling effect resulted in resolvation of the ions so that their apparent masses were much greater than the true masses of the bare ions, giving Dole measurements that were higher than predicted.

From Vitamin B to Proteins

Fenn and his graduate student Mike Labowsky decided to repeat Dole’s experiment and showed that they could get much better results if they removed the solvent vapor from the gas ion mixture before it went into the vacuum of the mass spectrometer. They did this by applying a counter current flow of dry gas going upstream against the droplets and ions, which were driven by the electric field. However, because of problems with the equipment they soon abandoned further work on the experiment.

Several years later, Masamachi Yamashita, a postdoc in Fenn’s lab, picked up the project, studying smaller molecules. Among other things, he analyzed the content of vitamin B tablets, getting a clean peak for each species that — according to the label — was in the tablet. When they later obtained a better mass spectrometer with a higher mass range, Fenn and his students worked their way up to bigger molecules, including cyclosporin A, gramicidin, and polyethylene glycol. They found that with increasing molecular weight, each species gave rise to a growing number of peaks in the mass spectrum, representing multiply charged ions, which for large molecules were so close together that individual peaks could no longer be resolved with their instrument. “We put these results in a paper that we submitted to Analytical Chemistry, and the reviewer wrote back and said, ‘This is not a mass spectrum, it’s dirt in the system,’” Fenn remembered.

Looking for molecules with a well-defined molecular weight — unlike polyethylene glycol samples — Fenn and his coworkers then turned their attention to proteins, such as insulin. The results showed several well-defined peaks for each species, but the reviewers were still not impressed, saying that the scientists were dividing their signal for each species up among a number of peaks. But Fenn suggested to his graduate student, Matthias Mann, that each one of those peaks represented an independent measure of the molecular weight of the same parent molecule, and that there ought to be a way to average over these values to get a more reliable value for the true mass. “Two days later, he walked back to me with an algorithm” that could deconvolute the spectrum into a single peak, Fenn said.

The rest is history: Since Fenn presented those protein results in 1988, the number of papers using electrospray ionization has exploded from one or two per year to 1,700 in 2002 alone, and still seems to be rising.

But the use of electrospray ionization is not restricted to protein analysis, and Fenn pointed out a number of emerging applications: For example, his lab developed an electrospray-based device to measure particles in gases, which could provide a simple way to analyze the quality of air samples for environmental studies.

The Future: Electrospray in Space

Moreover, electrospray might soon be going to space. NASA is planning to build an array of microsatellites to use as a very large radio telescope to study objects far away in the universe. These microsatellites have to be positioned very carefully, and the proton flux from the sun has enough momentum to move them away from their desired position. Electrospray droplets of non-volatile liquids, Fenn said, can be electrostatically accelerated to produce thrust to put the elements of the array back into position. A three-person company in New Haven, Conn., called Analytical is currently developing these microthrusters with support from NASA.

Finally, electrospray may find applications in medicine: a related process known as electrospinning can produce very fine fibers of polymers that can be woven together into scaffolds to support new tissue growth.


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