Harvard University - Department of Molecular & Cellular Biology

MESELSON WINS LASKER AWARD

by Carol Cruzan Morton

October 12th, 2004


Matthew Meselson
(PhotoBureau, Inc./Joe Vericker)
Matthew Meselson, a Harvard molecular biologist whose famous experiment substantiated the newly discovered double-helix structure of DNA and who prompted the United States to drop its biological and chemical weapons programs, has won a Lasker Award, a scientific honor sometimes referred to as "America's Nobel."

Meselson won the Lasker Award for Special Achievement in Medical Science "for a lifetime career that combines penetrating discovery in molecular biology with creative leadership in public policy aimed at eliminating chemical and biological weapons," according to the citation.

The awards were announced on Sept. 26 by the Albert and Mary Lasker Foundation in New York. Other winners include three scientists sharing the basic medical research award and one researcher in the clinical medical research category.

The scientist and author Lewis Thomas once observed that the history of the Lasker Awards since 1946 can be read as an accurate record of the progress of biomedical science. Likewise, on a smaller scale, Meselson's research motored along as a kind of pace car for the young field of molecular genetics.

"In the early days of molecular biology, Matthew Meselson laid the biochemical groundwork for several key areas: DNA replication, DNA repair, DNA recombination, and DNA restriction," says a statement from Joseph Goldstein, chair of the Lasker jury committee and a Nobel laureate at the University of Texas Southwestern Medical Center at Dallas.

Goldstein singled out a 1958 paper. It describes what others have called "the most beautiful experiment in biology." In it, Meselson and Franklin Stahl, a postdoctoral fellow at the California Institute of Technology, reported that DNA replicates itself by making new double-stranded twins, each containing one strand of the original parent molecule and one newly formed strand. The findings substantiated Watson and Crick's proposed mechanism and their double-stranded helical model of DNA.

"To perform this experiment, Meselson and Stahl first grew bacteria in broth that contained heavy nitrogen and then switched the microbes to broth that contained light nitrogen," according to the award citation. "Because the cells incorporate nitrogen into DNA, this scheme allowed the scientists to distinguish between old (heavy) and new (light) strands. To analyze the DNA generated during the experiment, Meselson invented a technique called equilibrium density gradient centrifugation, which allowed him to distinguish between DNA molecules that differed slightly in density. In this way, he and Stahl showed that a parental helix made of two heavy strands duplicates to give two molecules, each composed of one heavy and one light strand."

At the time, Meselson was a graduate student of Linus Pauling. The Meselson-Stahl experiment had begun as a side project and made up the second half of his thesis project. Meselson's powerful method has also resolved other key issues in molecular biology, notes the award citation. "In 1961, Sydney Brenner and Francois Jacob, working with Meselson at CalTech, used this procedure to establish the existence of messenger RNA, the genetic intermediary between genes and proteins," the citation reads. "That same year, Meselson used the density gradient method to learn how two DNA molecules produce new ones that contain a mixture of the parents—a process known as genetic recombination—and that recombinant molecules result from the breaking and joining of the two parent DNA molecules. Density gradient centrifugation has since been used by scores of scientists to answer a variety of biological questions."

From CalTech, Meselson moved to Harvard University in 1961, where he is Thomas Dudley Cabot Professor of the Natural Sciences. There, he isolated the first known restriction enzyme, a protein that bacteria use to chop up and destroy DNA from foreign strains. "A related group of enzymes turned out to be invaluable for manipulating DNA because they cut at defined sequences," notes the citation. In his Nobel account of his work on restriction and modification, Werner Arber acknowledges building upon Meselson's work.

"In other pioneering studies," the Lasker citation continues, "Meselson correctly predicted the sequence of methyl-directed mismatch repair, a process by which cells correct mistakes in their DNA."

Most recently, Meselson and his colleagues have challenged the notion that sex is necessary for evolution—at least in the case of translucent little moss-loving creatures known as bdelloid rotifers. Prevailing theory calls for sexual reproduction in order to generate diversity by recombination of parental DNA sequences to form progeny genomes, but no male bdelloid rotifers have been found despite 300 years of scientific study. Yet, they have defied science by not going extinct. They may have done without sex for 80 million years in part by virtue of having no retrotransposons, promiscuous genetic elements that insert themselves willy nilly into chromosomes and can damage genes, researchers in Meselson's laboratory have found.

Soon after he came to Harvard, Meselson embarked on what became a 40-year campaign to prevent the production and use of biological and chemical weapons. It began in 1963 when he was invited to spend a summer at the U.S. Arms Control and Disarmament Agency in Washington. He found a large development and production program in biological weapons, which was potentially devastating but relatively inexpensive.

The 2004 Lasker awardees and Foundation executives (from left to right: Jim Fordyce, Trustee Chair; Dr. Neen Hunt, President of the Lasker Foundation; Pierre Chambon; Ron Evans; Ann Kelman, on behalf of her late husband Charles; Elwood Jensen; Matthew Meselson; and Dr. Joseph L. Goldstein, chair of the Lasker Awards jury)
(PhotoBureau, Inc./Joe Vericker)
The richest country in the world should not want to pioneer or endorse cheap weapons of mass destruction, he reasoned. "This rationale propelled him to persuade the government to abandon biological and chemical weapons, in part by writing papers for Henry Kissinger when Kissinger was Richard Nixon's national security advisor," the Lasker citation reads. "Nixon unilaterally ended the biological weapons program in 1969 and subsequently extended the ban to weapons based on toxins, poisonous chemicals produced by living creatures."

Meselson traveled on several scientific expeditions to resolve other issues of military and strategic importance, the Lasker citation notes. President Nixon ended U.S. herbicide operations in Vietnam based on findings by a scientific team led by Meselson that the United States was mistaking civilian rice fields for enemy soldiers' crops. In another trip to Southeast Asia, Meselson investigated the "yellow rain," which purportedly was a poison that the Laotians and Vietnamese, with Soviet assistance, were spraying on anti-government tribespeople. He identified the substance as bee droppings—pollen eaten by the insects, which they then excreted in massive showers.

In another international mystery of the cold war era, Meselson led a team to Russia in 1992 and 1993 to determine the cause of a 1979 anthrax epidemic that killed more than 60 people in Sverdlovsk. For years, the Soviets blamed tainted meat, which Meselson had described as plausible in Congressional testimony. But he insisted an on-site inquiry was needed. After repeated attempts to bring independent investigators to Sverdlovsk, Meselson and his wife, medical anthropologist Jeanne Guillemin, were allowed to lead a team to probe the cause of the epidemic. After many interviews with victims' families, it became clear that nearly all of the people who died worked or lived within a long narrow zone downwind of a military microbiological facility suspected of developing biological weapons. With local meterological records, Meselson pinpointed the day the germs escaped.

Now, Meselson co-directs The Harvard Sussex Program, which promotes science-based scholarship to inform public policy on biological and chemical weapons. The Lasker Award also cites a proposed treaty to ban biological and chemical weapons under international criminal law drafted by Meselson and co-director Julian Perry Robinson of the University of Sussex. Under this pact, participating countries would have jurisdiction to prosecute any individual found on their territory who orders the use of or purveys these weapons—much like the existing international agreements that govern airline hijacking, torture, and hostage-taking. The organization is trying to persuade governments to adopt the treaty.

A native of Denver, Meselson showed an early affinity for chemistry and physics. "When I was still in grammar school, the basement of our house in Los Angeles became a sizeable laboratory where I built radios, spectroscopes, and other instruments, purified radium and rare-earth elements from carnotite and monazite ores by fractional crystallization and ion-exchange chromatography, and synthesized for neighbors the recently discovered insecticide DDT," he wrote in a commentary in the October 2004 Nature Medicine.

For all of his academic achievements, Meselson did not graduate from high school, because he was missing the full three years of physical education credits mandated by California state law. Fortunately, he found a college that did not require a high school diploma: The University of Chicago. The school offered undergraduates only a general liberal arts cirriculum. Still shy of graduation but needing science credits for graduate school, he entered CalTech as a freshman, where he met Pauling and did a research project for him. Dissatisfied with undergraduate life in Pasadena, Meselson returned to Chicago to finish his bachelor of philosophy degree and spent a year as a physics graduate student at the University of California, Berkeley. He was invited to a party at Pauling's home that summer, where Pauling invited him to join his lab. He received his doctoral degree from CalTech in 1957 and stayed on for three years as a research fellow and Assistant Professor.

The Lasker citation also notes Meselson's mentoring of graduate students and postdoctoral fellows who have achieved their own measures of fame, including Mark Ptashne, 1997 Lasker award winner at Memorial Sloan-Kettering Cancer Center in New York;  Susan Lindquist, director of the nearby Whitehead Institute;  Steven Henikoff, investigator of the Howard Hughes Medical Institute at Fred Hutchinson Cancer Research Center, Seattle;  and Sidney Altman, 1989 Nobel laureate in chemistry at Yale University.

In addition to Ptashne, a former MCB faculty member, the department has been well represented in the Lasker Awards. Other past Harvard MCB winners include Raymond Erikson, Wally Gilbert, Jack Strominger, Don Wiley and James Watson.

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