1 May 2009

Alan Marshall: A scientist and a gentleman

Meet one of the greatest innovators in the history of mass spectrometry, hard at work.

By KRISTEN COYNE

Alan Marshall, Kasha Professor of Chemistry at Florida State University and director of the Ion Cyclotron Resonance Program at the National High Magnetic Field Laboratory, is ensconced in his favorite armchair. He’s dressed for comfort in khaki shorts and a button-down jean shirt, his sneakered feet propped on an ottoman. Smiling, he absent-mindedly twirls a white tuft of sideburn with one hand and cradles a yellow coozy in the other, appearing as chilled-out as the drink inside.

Alan Marshall.Alan Marshall.Meet one of the greatest innovators in the history of mass spectrometry, hard at work.

Marshall, though in his gracious North Tallahassee home, the pool and a well-stocked cooler just outside the door, truly is hard at work, surrounded by a score of scientists, postdocs and students from his lab. Actually, deleting “hard” from that sentence would make it ring more true – but not because the much-honored chemist is slacking off. Rather, the words “work” and “hard” are never, in the syntax of Marshall’s career, juxtaposed. Adjectives such as “enjoyable” or “engrossing” partner much better with “work,” as he sees it. For Marshall is someone who draws no boundary between work and the rest of his life, a scientist whose lab spills over into his white brick house a dozen miles away, a renaissance man of many interests, but none of which compete with his life’s greatest passion: Fourier transform ion cyclotron resonance (FT-ICR).

“He works seven days a week because it’s the most fun thing he can think to do,” says Chris Hendrickson, former director of instrumentation for the lab’s ICR program.

His passion is a key ingredient in his success, which began early in his career when he co-invented FT-ICR, a type of mass spectrometry that relies on powerful magnets. It has proven an extremely productive tool for scientists trying to figure out the composition of complex molecules such as proteins and petrochemicals. The technique has been a boon to oil companies, the pharmaceutical industry, counterterrorism efforts, medical research and biotechnology, among other areas, and scientists are constantly finding new applications. It’s the type of high-impact achievement for which Nobel Prizes are handed out.

Alan Marshall, left, and ICR scientist Chris Hendrickson with the 14.5 tesla ICR magnet.Alan Marshall, left, and ICR scientist Chris Hendrickson with the 14.5 tesla ICR magnet.At the forefront of the innovation is Marshall’s program at Magnet Lab headquarters in Tallahassee, Florida. The lab boasts some of the most powerful ICR equipment available; the gem of this collection is a spectrometer featuring a superconducting ICR magnet with a field of 14.5 tesla – the highest field in the world for such an instrument. (Tesla is the unit of measure of magnetic field strength). Scientists come from all over the world to use these machines and benefit from the unparalleled expertise found in Marshall’s team.

These visitors know Marshall from his reputation before they actually meet him: The insight that fueled an invention, the dedication that has produced more than 450 refereed journal articles, the passion that brings him into the office every single day, except Christmas and business trips. But many are surprised to discover that kindness is part of the package. In connection with this top scientist, one hears a word not often invoked these days, in the sciences or any other field, a way of being that has fallen out of fashion: Gentleman.

“It’s rare to have somebody be that brilliant and that nice,” said Hendrickson, who has worked with Marshall for the past dozen years. “It’s really rare.”

Defender of Science

Back in his Tallahassee home (dubbed “the White House” by friends and colleagues), Marshall is playing host to students and scientists from his lab. This is a weekly occurrence chez Marshall, a group meeting that is part mixer, part team-building exercise, part training. Each week, one lucky researcher makes a presentation on recent work that is scrutinized and debated by the rest of the group.

Example of a mass spectrum:  Detail from an analysis of crude oil.Example of a mass spectrum: Detail from an analysis of crude oil.In the hot seat this particular evening in the summer of 2007 is postdoctoral associate Sudarslal Nair, presenting his research on proteins.

His 6-foot-1-inch frame splayed across his beige armchair, Marshall settles in as if for a show. During Sair’s PowerPoint, he interrupts frequently, pressing for details, pointing out holes, cracking jokes and laughing at them with his gruff, throaty laugh. Though Marshall looks very much the part of the distinguished scientist, there’s a bit of Groucho Marx mixed in … the unruly hair and eyebrows, the moustache, the humorous asides. It’s not hard to picture a cigar dangling from the corner of his mouth.

Some of Nair’s answers prompt Marshall to nod approvingly. Other times he is less satisfied, voicing concern about data or methodology before prodding “Onward!” with a wave of a hand. Marshall’s questions become most pointed when he wants to know why Nair chose FT-ICR to investigate his problem. The greatest strength of this tool is its high resolution and sensitivity; it is very good at telling molecules apart by mass, even when there is not much difference between them. (Each type of molecule has a unique mass, determined by its chemical make-up; FT-ICR machines measure all the molecules in a sample and then count them all up to determine what particles are in there, and how much of each.) The results are displayed in a mass spectrum that resembles the peaks and valleys of a heart monitor and shows what molecules are in a sample, and in what quantity.

“You’re fishing here. We don’t like to fish. It takes forever.”

“We’re an ICR lab; why are we doing this?”

“So I say again: What good does it do to have high mass accuracy?”

Nair seems to sweat a little. But the twinkle never leaves Marshall’s blue eyes, nor does a smile leave his face. He’s not making sport of Nair (a valued team member who will soon advance to his first faculty position); he just finds the science so much fun. He loves what he does and does what he loves. The laugh lines on his face are deep.

Nair knows Marshall too well to take it personally and calls him a “true scientist and a great human.”

“I am really happy that I got a mentor like Dr. Marshall,” says Nair. “He never pressures anybody. Still, all of us work to our maximum potential to produce good data. I never saw him angry with any of his lab members or criticize unnecessarily. This attitude substantially improves the lab atmosphere and increases productivity.”

WHAT DO YOU KNOW?

Three decades after the invention, researchers at universities and companies across the globe are making important discoveries with more than 700 FT-ICR mass spectrometers.

Marshall interrogated Nair like a seasoned trial lawyer not just to make a better scientist out of him, but to defend a technique on which he has built his career. FT-ICR is an extremely powerful tool that has shown researchers how drugs bind to proteins, what oil deposits are worth drilling in, and could even track down terrorists by fingerprinting the compounds used in chemical or biological warfare. But applying the technique to a topic that doesn’t really benefit from its high accuracy and resolution is a bit like using an MRI machine to diagnose a cold; it’s a waste of a money, talent and skill that advances neither science in general nor FT-ICR as a field.

“We want to make sure we’re working on problems that require it,” said Marshall. “If there’s a cheaper way of doing it, we should be doing it that way.”

Marshall has always felt a deep responsibility and diligence toward the things and people he values, says his wife of 42 years, lawyer Marilyn Marshall. He always came home to eat dinner with his wife and children, now adults. And after the dishes, he often turned around and went back to the office.

“He has a servant’s heart in a sense,” she said, “in that he feels an obligation to his family and doing a good job to his profession.”

From Red Wagons to Stanford

Alan George Marshall was born in Northwest Ohio in 1944, the only child of Herbert Marshall and Cecile Marshall (later Cecile Rosser), a farmer and a school nurse. Even as a lad he helped out on the farm by ferrying crops from the field to the packing shed in his little red wagon.

Alan and Marilyn Marshall, with daughter Wendy, in Vancouver in 1970.Alan and Marilyn Marshall, with daughter Wendy, in Vancouver in 1970.He was 7 when the family moved to San Diego, Calif., where his dad took an engineering job. Because young Alan skipped second grade and his growth spurt was late in coming, he was smaller than most of his classmates and an easy target for bullies. But as the boy began to distinguish himself – in seventh grade, he was the proud winner of the junior high school spelling bee and set a school record for the standing broad jump the following year – he gained confidence and recognition. His interests were broad: Though his greatest love was science, he also played the clarinet and was on the track and cross country teams. He learned that focusing too much on one thing can work against you: He beat out his closest rival to be named outstanding male scholar of his graduating class because he’d earned better grades in gym. When Marshall left for Illinois’ Northwestern University in 1961 for a six-year medical program, scholarship money paved the way.

It did not take long for Marshall to realize that he chose medicine for the wrong reasons.

“I still like medicine, but I hated medical school,” he recalled. “It was all memorization.”

He switched to chemistry and never looked back. Lesson learned: to achieve success and happiness, you must love what you do.

While in college Marshall took another critical step toward securing future success and happiness when he set his sights on English and political science major Marilyn Gard. The two met in November 1964 and were engaged by Christmas.

“He had a wonderful sense of humor,” said Marilyn Marshall. “And of course I thought he was very handsome.”

The newlyweds moved to California the following year, where Marilyn finished her undergraduate degree at Stanford University and Alan worked toward his Ph.D there. Marshall continued to cultivate other interests, both scientific and otherwise, reading broadly about a wide range of topics. In an echo of his choice to quit medical school, he dropped his initial thesis topic, in which he used Nuclear Magnetic Resonance (NMR) to study how drugs bind to receptors. The topic failed to inspire him, so he cut his losses and switched to calculating shapes of ICR spectra. His unconventional decision to do two thesis topics – one in NMR, one in ICR – would have huge implications for both his future and the future of analytical chemistry. He will be forever grateful that his thesis advisor, John Baldeschwieler, allowed Marshall to follow his curiosity.

“I spent a lot of time working on topics other than the assignment he gave me,” Marshall recalled.

Another event that would greatly shape the young scientist’s career was his friendship with Mel Comisarow, a Stanford postdoc. Both men shared an interest in science and electronics, and paired up to build color TVs with Heathkits. When Marshall moved his family to Vancouver to launch his teaching career at the University of British Columbia in 1969, he encouraged Comisarow to join him. Two years later, he did.

It was during long campus strolls and late nights at the lab that the duo hatched and developed an idea that other chemists would have dismissed as either impossible or inconsequential: combining Fourier Transform with Ion Cyclotron Resonance.

History in the Making

When Marshall initially mentioned the idea to Comisarow, Marshall recalled, even Comisarow was skeptical, listing all the reasons it couldn’t be done. But Marshall convinced him it could.

The key ingredients for a novel scientific breakthrough were at hand.

“A lot of people think that science occurs by brilliant intuition coming out of blue sky,” said Marshall. “Really what is much more the case is that somebody knows something in one area and transfers it to another.”

The first FT-ICR spectrum, obtained by Alan Marshall and Mel Comisarow, December 17, 1973.The first FT-ICR spectrum, obtained by Alan Marshall and Mel Comisarow, December 17, 1973.With such a challenge, two heads were far better than one. Comisarow brought to the partnership expertise in ICR, a tool first developed in the 1930s, while Marshall offered expertise in NMR along with a his strong ICR background. Marshall’s knowledge of NMR was important in part because Fourier Transform (a centuries-old mathematical algorithm that converts signals detected over time into a spectrum of usable data) had recently been combined with NMR; in fact, Swiss researcher Richard Ernst went on to win the Nobel Prize in Chemistry for developing this tool.

“It wasn’t accidental that it took two people,” Marshall said of FT-ICR.

What helped set this effort apart was Marshall’s unique conflux of qualities: an ability to approach a problem with a broad command of science, a confidence in his abilities, a gift for teamwork, and the diligence to put in long hours, do the tedious calculations and write up the results.

Naresh Dalal, professor of chemistry at FSU and a researcher with the Mag Lab’s Electron Magnetic Resonance program, remembers the night in December 1973 when Marshall and Comisarow first hit pay dirt with the help of a 2-tesla magnet that Comisarow had configured into the world’s first FT-ICR spectrometer. Dalal, a UBC postdoc at the time, was working late in his second floor lab when an exuberant Marshall came in waving a piece of graph paper at him.

“We just created a new technique,” Marshall, a few months shy of his 30th birthday, told Dalal. “This is the world’s best mass spectrum.”

It looked like just a bumpy line on a scrap of paper. But Marshall recognized it for an achievement of exceptional promise.

“The peak was very narrow, and that’s what was better,” said Marshall.

The peak represented the mass spectrum of a methane gas sample the men had tested using the new technique. Determining the mass spectrum of a simple, well-known substance was of no particular note. But, as Marshall then boasted to his friend Dalal, the resolution they had achieved was so high that if they were to examine a sample containing 50 different compounds, they would get 50 distinct peaks. While it was possible at the time to identify that many molecules within one sample by using existing ICR techniques, the resolution was not nearly as high as with this new approach. And while existing techniques required an hour for such results, Marshall and Comisarow had achieved theirs in seconds. Their instrument allowed them to measure all the molecules at once, rather than one type at a time, as instruments did at the time.

It was, in fact, the beginning of a revolution in analytical chemistry. But nobody told that to the editors of the prestigious International Journal of Mass Spectrometry and Ion Processes, who rejected Marshall and Comisarow’s paper reporting the news. Fortunately for science, Chemical Physics Letters did accept it. While the paper created a stir, it hardly changed the field overnight.

“I felt like it had to work,” said Marshall. “It took a while to convince everybody else.”

WHAT DO YOU KNOW?

Back in 1973, identifying 50 compounds simultaneously was impressive. Today, thanks in large part to Marshall, FT-ICR can now identify a mixture containing 50,000 compounds.

While conducting most of his research on NMR, Marshall continued to develop the new invention while waiting for technology, equipment and the mindset of scientists to catch up. More than anyone, Marshall saw the potential in the invention, and devoted his intellect, hard work and passion to developing it.

“Smart isn’t enough,” observed his wife. “He’s also diligent. He works more hours than anyone else in his lab and everyone knows it.”

Michael Bowers, a chemistry professor at the University of California at Santa Barbara who has known Marshall for some 35 years, said Marshall is king of the field. “He’s innovative in that he’s continually trying to develop new methods to improve FT-ICR,” said Bowers. “There have been a lot of good people working there, but he stands above the rest in developing the method.”

A Career Takes Wing

Recognizing a rising star, The Ohio State University hired Marshall in 1980 as professor of analytical chemistry and biochemistry and director of the new Chemical Instrumentation Center for NMR and Mass Spectrometry. OSU lured Marshall with the promise of new tools, and in 1983 the National Institutes of Health delivered with a 3-tesla FT-ICR instrument. State of the art for its time, the tool finally allowed Marshall to show the world the great potential of the technique. He devoted his attention to developing new instrumentation, new applications and new theories. It was during this period that Marshall came up with a method for exciting and detecting ions in a sample called stored waveform inverse Fourier transform (SWIFT) that has found widespread use in the field. Although he could not bring grant money from Canada, he began attracting more and more funding to his new university.

The number of FT-ICR instruments in the world has soared since its invention in 1973.The number of FT-ICR instruments in the world has soared since its invention in 1973.A huge break came in 1988, courtesy of John Fenn. The American chemist discovered an ionization method called electrospray ionization (ESI) which allowed scientists to use FT-ICR for large biological molecules. (Before particles can be measured and counted with FT-ICR, they must be turned into ions – charged particles – so they will interact with the magnet’s field.) Fenn’s Nobel Prize-winning work created new opportunities for the pharmaceutical industry to use FT-ICR to explore how drugs bond to proteins.

“That’s when the growth really took off,” recalled Marshall.

Down in Tallahassee, Florida, Jack Crow took note.

Crow was the founding director of the Magnet Lab, which had been relocated by the National Science Foundation from the Massachusetts Institute of Technology in 1990 due in large part to Crow’s efforts. He courted Marshall aggressively. Marshall would not be wooed, and his wife didn’t want to leave her successful legal career. But in 1993, lured in part by a half-million dollar grant from the state of Florida to build a 9.4 tesla FT-ICR instrument (the biggest in the world at the time), Marshall agreed.

“I decided that if I didn’t come here, I would have to compete with the person who did come,” he said.

Since then Marshall has built a world-renowned program. He is directly responsible for attracting more than $20 million in outside funding to the lab and has been instrumental in securing an additional $10 million in grants for other FSU scientists. (With his most recent grant – $1.3 million from the National Institutes of Health – Marshall is researching the structural mapping of protein complexes.) He and his team have racked up records for mass resolving power, mass resolution and mass accuracy. The scientific establishment has noticed, bestowing a heap of prestigious awards on Marshall, including the Thomson Medal (given by the International Mass Spectrometry Society in 2000), the American Chemical Society Award in Analytical Chemistry (2002) and the Chemical Pioneer Award from the American Institute of Chemists (2007), to name a few. He is a fellow of the American Physical Society, the American Association for the Advancement of Science, and the Society for Applied Spectroscopy; In 2004, the International Journal of Mass Spectrometry devoted a special issue to his work on the occasion of his 60th birthday.

Marshall relentlessly pushes the envelope, in the process taking on some of the most challenging problems in the field, such as analyzing crude oil – the most complicated chemical mixture known to scientists.

“It was viewed as virtually impossible because of the huge number of components that make up crude oil, and how to unravel that,” said chemist Bowers.

But thanks to the work of Marshall, his team and their collaborators, the field of petroleomics has grown extensively, helping to locate, drill for and refine oil. Oil companies contributed half a million dollars to build his lab’s world-record 14.5 tesla magnet, commissioned in 2004. Petroleomics is the subject of one of the three books he has written in recent years.

Marshall is nothing less than a missionary when spreading the word about this technique, its application, and its continued promise.

Over the course of his career he has presented more than 1,400 talks and conference posters worldwide, both within and outside his field, to scientists as well as general audiences, explaining FT-ICR and inviting researchers to send their samples to the Mag Lab. He is always seeking new ground to cover, new territory to conquer, new applications for his instruments. It’s not unusual for a scientist to come to the lab, learn about the instruments and techniques, get exciting results with them, and return to his or her home institution to acquire his or her own spectrometer and continue probing.

“We basically build the field as part of the mission,” explained Marshall.

Marshall is well suited for this kind of missionary work. The zeal is a given; he is also charming. He impresses with the depth of his expertise, a confidence both easy and self-effacing, and a handsomeness that has grown from dashing to avuncular with the years. The Australian bush hat he sports out of doors adds panache.

Bowers recalls how Marshall kept his cool in front of an audience of thousands when he Bowers presented him with the special issue of the international journal of mass spectrometry, and a short this is your life presentation in front of thousands. “I’ve never seen him once in my whole life where he hasn’t been actually immediately present and real,” said Bowers. “He has excellent oral, presentation and organizational skills, which are critical to making the level of impact that Alan has made. … He has a certain presence about him, a certain confidence, a certain ease.”

Nice Guys Finish First

Those who work with Marshall are in awe of his encyclopedic intellect. Despite the quantity and breadth of his work, he fields questions about it quickly, pulling details from the prodigious file cabinet of his brain.

“You could go and ask him about any of his hundreds of papers and he’ll know exactly the equations in there, the details in the experiments. He just has it all in his head,” said Kristina Håkansson, a former postdoc in his lab who is now an assistant professor of chemistry at the University of Michigan. “Some people who have been working in the field as long as he has, you ask them about a paper they published in 1975, they won’t remember. He will.”

Alan Marshall (far right, sporting bush hat) with his group at his Tallahassee home. Alan Marshall (far right, sporting bush hat) with his group at his Tallahassee home. Marshall has made the most of his gifts not just by working a lot, but by working effectively. Those who have worked with and for him praise his ability to manage a team, to get the most out of people by encouraging and supporting them, to accord his staff the freedom to flourish. One fact underscoring how easy he is to work with: about a quarter of his refereed papers are results of collaborations.

Along with this is an ethic of service. By attending meetings, writing letters and making phone calls, he does more than his share to support the work of the chemistry department, the mission of the Mag Lab, and the future of his staff members. Dozens of hours every month are devoted to writing hundreds of letters recommending someone for a job, an award or grant. Common are the stories of his benign intervention in others’ lives. Håkansson was headed in another direction when Marshall recognized her talents and recruited her. When it was time to move on, she hadn’t even considered a job in the U.S. until Marshall convinced her she could land a plum post and helped pave the way.

FSU chemist Dalal has felt that guiding hand more than once himself. He was a grad student at UBC when he first met Marshall, heading toward a career in photoelectron spectroscopy. But after taking Marshall’s class in magnetic resonance Dalal changed course to focus in that area. (The choice was propitious: In 2007, Dalal was honored with the 2007 Southern Chemist Award based on his three decades of research in magnetic resonance.) Marshall again intervened in his career by recruiting Dalal to leave West Virginia State University and join FSU’s Department of Chemistry and Biochemistry in 1996.

“To me he’s a teacher, friend, mentor,” said Dalal, a highly respected and accomplished chemist himself who chaired his department for eight years. “I wish I could be like him. It’s a feeling of awe.”

Marshall leaves the type of mark that shapes a life. “Alan” has become a popular name for the sons of people who work with him.

Marshall knows how much it meant to him when mentors encouraged him: He still remembers his eighth grade science teacher as well as the freshman physics professor to whom he dedicated his thesis. He appreciates the people along the way who took a chance on him. UBC hired him even though he didn’t have a postdoc. OSU hired him even though he had little funding and had never run a facility. The Mag Lab’s Crow hired him even though his funding was up for competitive renewal.

Certainly all of those people have been pleased with their investment. The ripple effect of FT-ICR on analytical chemistry over the decades has been enormous, and continues as more and more instruments go online and more applications are discovered.

According to UC chemist Bowers, the invention is, “certainly in the top quarter of all things ever done in science, and probably in the top 10 to 15 percent.”

But, Bowers quickly added, “His best stuff may be ahead of him.”

Dalal agrees. “This is just the tip of the iceberg,” he said. “Better electronics and bigger magnets will only improve the technique.”

Marshall hopes to get one of those bigger magnets soon. The Mag Lab has designed a 21 tesla FT-ICR magnet for which they are currently seeking funding.

With it added to his impressive arsenal, Marshall will forge ahead with research technique development. In the lab’s future he foresees progress in identifying biological biomarkers for diseases such as Alzheimer’s and kidney disease, which could tell scientists more about the diseases and help doctors identify them sooner.

And at the end of the day, Marshall will leave his office, don his bush hat, climb into his red sports car (license plate: FT-ICR) and head home to the white house, where he will be sure, as he does every night, to toast his wife’s good cooking and, after their meal, clear the dishes.

Celebrating an Inventor

Marshall was a 2016 inductee into the Florida Inventors Hall of Fame. View a video made to commemorate the honor below.

Video by Stephen Bilenky