Renowned Stanford microbe hunter Stanley Falkow to receive a 2008 Lasker Award

- By Krista Conger

STANFORD, Calif. - Stanley Falkow has spent his life studying how bacteria cause human disease. But ask him whose side he's on, and he's likely to pause. Or maybe not. Actually, it's been pretty clear all along - as evidenced by an experiment in graduate school that required him to feed hapless bacteria to a hungry slime mold.

Credit: Krista Conger falkow window

Stanford professor Stanley Falkow will receive the 2008 Lasker-Koshland Award for Special Achievement in Medical Science.
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"I felt like a traitor," recalled Falkow, PhD, the Robert W. and Vivian K. Cahill Professor in Cancer Research at the Stanford University School of Medicine. He was supposed to be learning more about the mold. Instead, he trained his microscope on the lucky bacterial survivors, exhibiting an affinity for microbes that has lasted more than 50 years and spawned the careers of nearly 100 students, postdocs and fellows.

The breadth and depth of Falkow's career is being recognized with the 2008 Lasker-Koshland Award for Special Achievement in Medical Science. Sometimes referred to as "America's Nobels," the Lasker Awards are this country's most distinguished honor for researchers in basic and clinical medical sciences. The Special Achievement award, which has been renamed in honor of the late biochemist Daniel Koshland Jr., is given only once every two years to commemorate a life of scientific contribution and service. The awards will be announced Sept. 13 by the Lasker Foundation and then officially presented at a ceremony Sept. 26 in New York City. Falkow's award carries a cash prize of $300,000.

Falkow's colleagues, collaborators and students couldn't be happier about the recognition.

"Dr. Stanley Falkow is one of the most remarkable and respected scientists of our time," said Stanford medical school Dean Philip Pizzo, MD. "His elegant research contributions to the field of bacterial pathogenesis, which he fathered, have been enhanced by his incredible leadership as a teacher and mentor for a generation of physicians and scientists worldwide."

"There's an irreverent, playful joyfulness to the way Stanley does science," said David Relman, MD, a Stanford professor of infectious disease and of microbiology and immunology, who was a postdoctoral scholar in Falkow's lab in the late '80s. "Everyone who meets him feels like they have a personal connection."

Falkow's fascination with his chosen field began when, at about 11 years old, he happened upon Paul de Kruif's Microbe Hunters - a classic story dramatizing the earliest discoveries of micro-organisms by Leeuwenhoek, Koch, Pasteur and others - in his local library in Rhode Island. After reading the book, he was hooked. He arranged a deal with a nearby toy store to work in exchange for a small microscope, and promptly became a member of what was then a relatively small group of bacterial paparazzi.

Although Falkow, now 74, went on to experience most of the transformative technological breakthroughs in science, from ultracentrifugation to DNA sequencing to microarrays, he still has a soft spot for microscopy. He's most well-known for his work on extrachromosomal elements called plasmids and their role in antibiotic resistance and pathogenicity in humans and animals, but he's continued throughout his career to explore the microbe's-eye view that can only be afforded by getting down to their level.

In particular, he's fond of promoting the idea that many of the adverse effects of microbial infection are the fault of the host as much as the bacteria. "Disease is a distraction that keeps us from understanding the biology of the relationship between the two organisms," said Falkow, who is also a professor of microbiology and immunology. "I never met a microbe I didn't like."

His enthusiasm is hard to resist. One of his most recent postdoctoral students, Manuel Amieva, MD, PhD, credits Falkow with turning him on to the study of infectious disease. "Stanley is very funny and witty, and he always has a different perspective or twist on things" said Amieva. "It was very refreshing to hear him describe infectious disease from the point of view of the microbe. For the first time, I began to think of humans as basically just a landscape for microbes to inhabit."

"He's given more to science than just stellar ideas and new insights," added Relman. "His legacy includes a community of over 100 trainees who view each other as family and who have learned a unique way of looking at the world and of doing science."

Amieva, then a medical student and now an assistant professor of pediatrics and of infectious disease at Stanford, and others in the Falkow lab were fair game for Falkow's charm. But the inveterate fisherman with the easy grin tends to net followers from an even larger pool.

"Although we were drawn together because of a mutual love of trout fishing," said Marshall Bloom, MD, who has known Falkow for more than 20 years, "he has since become a devoted member of my family. My two sons call him zeyde, the Yiddish word for grandfather, and I am confident that Stanley's wonderful personality was a major influence on their love of science and their decisions to pursue biomedical careers of their own."

Credit: Krista Conger falkow blue

Looking back at his career, Falkow says he 'never met a microbe I didn't like."
To download a high-resolution version of this image, click here.

Bloom is the associate director of Rocky Mountain Laboratories in Hamilton, Mont., a division of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Word is that Falkow was lured to become a part-time resident of the Bitterroot Valley because of the area's excellent fly fishing after first visiting the lab in 1984. He'll tell you it was the opportunity to pursue his first love - the microscopic examination of the human pathogens studied at the labs.

Falkow's unassuming nature may have been shaped in part by his mother, now 98 years old. When informed of her son's Lasker Award she responded, as she has in the past, "Well, Stanley, better you than some stranger I don't know."

She's had a lot of opportunities to hone her delivery: Falkow's previous honors include the 2000 Robert-Koch Award from the Robert-Koch Foundation in Germany, considered one of the most prestigious awards in the field of microbiology; an election to the Institute of Medicine, an honorary society whose members are selected by their peers for making major contributions to health, medicine or related fields; membership in the National Academy of Sciences and the Royal Society; and a former presidency of the American Society of Microbiology.

In some ways, Falkow's career can be described as a series of fortunate coincidences. He learned medical bacteriology during summers off as an undergraduate at the University of Maine by working in a laboratory at Newport Hospital in Rhode Island. He met sick patients by rounding with the doctors, identified patients' bacterial infections by culturing them on plates, and even helped with autopsies when treatment was unsuccessful. The experience filled him with a lasting desire to understand why some bacteria made people sick, when others coexist with us peacefully.

When Falkow pursued this study as a graduate student in the early 1960s, first at the University of Michigan and next at Brown University, and then as an independent researcher at Georgetown University, he learned the biochemical and microbiological techniques necessary to deduce how bacteria transmit antibiotic resistance to one another by sharing circular extrachromosomal elements called plasmids. In particular, he found that some bacteria were resistant to antibiotics to which they had never been exposed, which at first confounded the researchers.

"Bacteria are smart, but they're not that smart," said Falkow, who subsequently discovered that bacteria gained their resistance by sharing their genes much more promiscuously then had been thought possible.

Although few scientists at the time were skilled in both bacteriology and microbiology, his colleagues did not support his drive to determine why some bacteria are more dangerous to humans than others.

"At the time, there was a kind of euphoric feeling that infectious disease had been mostly conquered," said Falkow, "so I was encouraged to abandon my focus on pathogenicity." As a result, Falkow switched gears to focus on understanding plasmids that confer antibiotic resistance, called R factors. His research came full circle, however, when learned that some bacteria carry plasmids encoding toxins that can wreak havoc on their hapless hosts. When Falkow arrived at Stanford in 1981, he set aside his study of plasmids to concentrate fulltime on how organisms as diverse as cholera, plague and whooping cough cause disease in humans.

In addition to experiencing a fortuitous intersection of bacteriology and molecular biology, of plasmids and pathogenicity, Falkow participated in the first discussion of recombinant DNA, or the splicing together of genes from different organisms.

"As soon as we proposed the idea, it was immediately clear that it would work," said Falkow, who provided one of the plasmids used in the first recombination experiments. "All great experiments in science are simple. When we hear of one, we all say, ‘Why didn't I think of that?'"

Such creativity and free thinking in science resulted primarily from an influx of funding for research in response to the Soviet Union's Sputnik program, according to Falkow. "In the '50s and '60s, the philosophy was to fund the best and the brightest, no matter what," he said. "The idea was that creativity was very important and should be encouraged, and that paid off in the explosion of genomic research findings in the '90s."

In contrast, the current structure of government funding allows little leeway for trial and error, Falkow believes. "Students today talk about proving a hypothesis, rather than testing it," he said. "It's a subtle, but very real difference. But very creative people often don't really follow the same drum. There may be an argument for going from A to B to C to D, but some people go directly from A to F. There has to be room for both of them."

Mentoring students and fostering their creativity is something Falkow takes seriously. He insists that the relationship is a learned skill. "You listen carefully to a student and let them finish talking it out. And then you tell them to do what they said they wanted to do. And then they think you are very wise. I might ask them, ‘How long are you going to do this?' if I'm not convinced, but I would let them do it."

"He is incredibly generous," added Amieva. "He never keeps anything for his own research when his students leave to start their own careers. He's never afraid of running out of new ideas."

He's also willing to speak out. "I got to get to know Stanley in 1977 when I was the commissioner of the Food and Drug Administration," said Donald Kennedy, PhD, who went on to serve as the president of Stanford University and is now the Bing Professor of Environmental Science, emeritus. "Stanley, who was on an advisory committee for the agency, was very concerned about the overuse of antibiotics in animal feed. I needed a world-class science expert to help with this issue, and I was very fortunate to find Stanley."

Not only did Falkow testify before Congress in an effort to ban the practice, he also argued against a proposal in 2003 to censor the publication of scientific information, such as the sequence of the polio virus, that could possibly be used for bioterrorism.

"My wife and I have become great friends with Stanley and Lucy," said Kennedy. Falkow is married to Lucy Tompkins, PhD, a professor of infectious diseases and of microbiology and immunology at Stanford. "He has a wonderful, and sometimes outrageous, sense of humor."

"I've been privileged to see a series of really extraordinary discoveries in my scientific life," said Falkow. "From centrifugation to Southern blots to PCR to microarrays - things have progressed so quickly. One of the last students I had in my lab devised a way to use microarray technology to screen for mutations that were important in mice and macrophages. When I looked at her data, it suddenly struck me: she had recapitulated the last decade of research in her field in just one or two experiments."

This fast pace is exciting, but Falkow believes it should also be approached with caution. "It's mind-boggling, the amount of information that you can get from one automated DNA sequencing run," he said. "I remember when I had a TRS80 computer from RadioShack. I had to learn BASIC, and I'd wait at home at night for someone to call me on the phone and read me the 60 nucleotides they'd gotten that day. I'd key them in, and we'd look for restriction enzyme sites. Now we're very close to having the sequencing drive the biology rather than the biology driving the sequencing. But you always, always have to do an experiment."

Since closing his lab in 2006, Falkow's life has assumed an only slightly more relaxed pace. In addition to fishing, he's learned to pilot small aircraft. Asked what he looks forward to, he responds promptly, thinking of a missed opportunity that morning. "Flying." But, as might be expected, the joy of both pastimes stems as much from the process as from the outcome. Bloom, who takes extended fishing trips with Falkow, describes a typical excursion. "Well, I'm right-handed, and Stanley is left-handed. So he catches all the fish looking one way, and I catch the ones looking the other way. But neither one of us catch all that many."

This willingness to accept what comes is another Falkow hallmark. "One of the difficulties we deal with is the attitude that, if you pour enough money into a project, you can come up with a vaccine or a treatment," said Falkow. "I think that's not true. You have to understand the fundamental biology behind the question. Finding a biological law that doesn't have an exception or a variation is very, very difficult. And the idea that humans can come up with something that is better than what happens naturally is extremely daunting. Very often, people can't."

But they can have fun trying. When Falkow told his mother he wanted to be a bacteriologist, she wondered, "A man can make a living doing this?"

Indeed he can.

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