Stanford scientist wins Kyoto Prize for developing revolutionary cell-sorting technology

STANFORD, Calif. - A search for life on Mars, the first ink-jet printer and nuclear weapons testing seem unlikely inspirations for a machine that changed the face of science and medicine. But to hear developer Leonard Herzenberg tell it, it all makes perfect sense. The Stanford researcher's feat of improbable alchemy, as well as his strong commitment to share his scientific and social accomplishments with others, has garnered him a 2006 Kyoto Prize, Japan's equivalent of the Nobel Prize.

"I'm extremely pleased and excited to receive the award," said Herzenberg, PhD, an emeritus professor of genetics at the Stanford University School of Medicine who in the late 1960s directed the development of the first fluorescence-activated cell sorter, or FACS. "I only wish it were possible to be shared with my wife and lifelong colleague, Leonore Herzenberg." Leonore Herzenberg, PhD, is also a professor of genetics at Stanford.

Kyoto Prizes are presented annually by the Inamori Foundation to individuals and groups worldwide who have contributed significantly to human progress in one of three areas: advanced technology, basic sciences, and arts and philosophy. This year's winners were announced June 9. The official award ceremony will take place Nov. 10 in Kyoto, Japan, where each winner will receive a 20-karat gold medal and a cash gift of approximately $446,000.

Herzenberg, 74, won the advanced technology award for developing the sorter, which can tease individual living cells out of population of trillions based only on their protein fingerprints. The sorter jump-started the fields of modern immunology, stem cell research and proteomics, and made invaluable contributions to clinical care, including treatment of diseases such as cancer, AIDS and other infectious diseases. FACS machines are now ubiquitous in research and clinical laboratories around the world.

"The FACS is one of the most important medical devices ever developed," said Philip Pizzo, MD, dean of Stanford's School of Medicine. "In the early 1980s, it provided fundamental insights into the impact of HIV on the immune system and it has been a valuable tool for diagnosing, monitoring and treating HIV/AIDS, cancer and infectious diseases. Professor Herzenberg is truly one of the leading innovators in human biology of the 20th century."

Like a coin sorter that separates a jumble of change into neat stacks of quarters, nickels, dimes and pennies, the FACS makes sense out of chaos. But rather than separating by size, it divvies up cells according to fluorescent tags attached to their surface during experiments. For example, it can shunt green-tagged cells into one tube, red into another and untagged cells into yet another. Because researchers can couple the tags to antibodies that home in on and attach to proteins found only in certain cell types, the sorter can pluck out rarer-than-rare immune stem cells for further study or identify populations of cells that are waxing and waning in such diseases as cancer or HIV. The possibilities of the technology, also known as flow cytometry, are limited only by the creativity of the users.

"As an immunologist, I have often had cause to bless Len for his foresight and commitment," said Nobel laureate and president of the California Institute of Technology David Baltimore, who has known Herzenberg for more than 30 years. "So many experiments in modern immunology are possible only because of the FACS."

Those sentiments were echoed by Garry Nolan, PhD, a former Herzenberg graduate student and current Stanford faculty member. "Entire industries have sprung from the Herzenbergs' efforts," he said. Nolan pointed out that in the 1970s the couple astounded many researchers by making their highly specific monoclonal antibodies (specialized immune molecules that recognize only one protein) available to anyone who asked, even their scientific competitors. "One of the most valuable lessons they taught me was that you build better bridges between scientists by sharing rather than withholding information."

The Herzenbergs, known to colleagues as Len and Lee, have collaborated since Len Herzenberg entered graduate school at the California Institute of Technology in 1952. After completing a postdoctoral fellowship with Jacques Monod at the Pasteur Institute in Paris, he served as a public health service officer at the National Institutes of Health in Harry Eagle's laboratory from 1957 until 1959, when he was recruited to Stanford. In addition to the Kyoto Prize, he also received the prestigious Novartis Prize in Immunology in 2004.

The Herzenbergs have also been devoted to spanning the academic gap between the advantaged and the disadvantaged. Together they conceived the first effort to bring local high school students from the then-predominantly African-American community of East Palo Alto to the Stanford campus to learn about medicine and biology. Lee Herzenberg started a tutoring program complete with a college counselor to encourage the students to continue their schooling and help them with college admissions.

"These kids actually did very well," said Len Herzenberg. "They got into good schools, and a couple even became college deans or administrators. Later I was appointed to head a faculty committee formed to help get African-American students into Stanford's medical school and to provide programs to help them succeed." Translating ideals into action, whether scientific or social, is a Herzenberg trademark that dovetails neatly with the university's reputation.

"Stanford is known for its bold and original thinkers willing to tackle problems and teach solutions. Leonard Herzenberg reflects the best of that tradition," said Stanford University President John Hennessy.

The scientific problem in the 1960s that initially set Herzenberg on his path toward the cell sorter was pretty mundane: his eyes hurt. "I was sitting in the lab one day counting immunofluorescent cells under the microscope, and I said, ‘There's got to be some kind of machine that can do this.'" He found that scientists at Los Alamos National Laboratory in New Mexico had developed a machine to sort cell-sized particles by volume in order to analyze the lung contents of mice and rats exposed to fallout from atomic bomb testing. With characteristic zeal, he headed to New Mexico.

The Los Alamos scientists weren't interested in modifying their system to detect fluorescent and live cells, but after a day and a half they allowed Herzenberg to bring blueprints of their machine back to Stanford. At the time, Herzenberg was stationed near the laboratory of former chair of the genetics department Joshua Lederberg, who had received funding from NASA to devise instruments to detect extraterrestrial life. Scientists in the two labs got to know each other while sharing a pingpong table set up in the stairwell, and Herzenberg capitalized on that relationship by convincing Lederberg engineers Russ Hulett and William Bonner to help him modify the Los Alamos plans. Together they and their colleagues cobbled together the predecessor of the first FACS, affectionately dubbed "The Whizzer," in the basement of the medical school for about $14,000. They published their success in Science in 1969.

By the early 1970s the group had incorporated a laser to make the cells fluoresce more brightly, and invited the inventor of the ink-jet printer, Dick Sweet, to hone the machine's droplet-sorting technique. By 1971 the FACS was up and sorting 5,000 live, functional cells per second and, although they may not have known it at the time, history had been made.

Fortunately, Herzenberg's career was far from over. He went on to collaborate with Becton-Dickinson to commercialize production of the FACS machine, and he was the first to realize how the newly emerging monoclonal antibody technology could make FACS analyses and sorting experiments reproducible among basic and clinical laboratories. Herzenberg's commitment to equal opportunity has persisted during his nearly 50-year tenure at Stanford. He established the first flow-cytometry core at Stanford to ensure that everyone had access to the new technology, and, during the early days of the AIDS epidemic, both Herzenbergs concentrated their research on the strange immune deficiency when many were turning their backs on infected gay men.

"The Herzenbergs have a ferocity to see that things are done right," said Nolan, "both scientifically and socially. Len is one of the most amazingly ethical and concerned people that I've ever had the opportunity to work with. He deserves to win the Kyoto Prize not just because of all he's accomplished, but because of what others have been able to accomplish because of him."

After some hemming and hawing, Herzenberg admits to feeling a bit proud. "It is an awfully good feeling to open almost any scientific journal and find articles referencing the FACS technology," he said. "It's even being used to analyze plankton from the depths of the ocean and to perform experiments on the space shuttle."

Who knows? Someday researchers may turn to the FACS to investigate particles from outer space. Maybe they'll even find evidence of life on Mars or on planets outside our solar system.

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2023 ISSUE 1

How social factors make or break us