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Meselson, Matthew

Matthew Meselson

Harvard University

For a lifetime career that combines penetrating discovery in molecular biology with creative leadership in public policy aimed at eliminating chemical and biological weapons.

The 2004 Albert Lasker Award for Special Achievement in Medical Science honors a researcher who has made world-class contributions to two different aspects of the scientific enterprise: molecular biology and public policy. Matthew Meselson has deciphered fundamental biological problems and has helped to prevent the manufacture and spread of biological and chemical weapons.

In 1958, Meselson (then a graduate student of Linus Pauling at the California Institute of Technology in Pasadena) and Franklin Stahl showed that DNA duplication produces two identical daughter molecules, each containing one parental and one newly formed strand. This work provided compelling support for Watson and Crick’s proposed mechanism of DNA replication and for 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. 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.

This powerful method has also resolved other key issues in molecular biology. For example, in 1961 Sydney Brenner and Francois Jacob, working with Meselson at the California Institute of Technology, used this procedure to establish the existence of messenger RNA, the genetic intermediary between genes and proteins. 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. In this experiment, he infected cells with distinct viruses, one labeled with heavy nitrogen and heavy carbon and the other unlabeled. By showing that recombinant molecules contained discrete segments from both parents, Meselson established in this and additional experiments that the 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.

Later, Meselson (by then on the faculty at Harvard University) turned his attention to another scientific issue. Researchers knew that bacteria destroy DNA from foreign strains by chopping it up. He found the first known protein to perform this feat — called a “restriction enzyme” because of its ability to restrict, or reject, DNA. A related group of enzymes turned out to be invaluable for manipulating DNA because they cut at defined sequences. The discoverer of that class of restriction enzymes, Hamilton Smith, credited Meselson’s influence on his work in his 1978 Nobel Prize lecture. In other pioneering studies, Meselson correctly predicted the existence of methyl-directed mismatch repair, a process by which cells correct mistakes in their DNA.

In the past several years, Meselson has been tackling another central question: How does sexual reproduction contribute to evolution? Mixing two parents’ characteristics produces offspring with new combinations of traits, and prevailing theory asserts that asexual animals and plants are doomed to extinction. Meselson and his colleagues have provided strong evidence that rotifers of the Class Bdelloidea, a group of tiny aquatic invertebrates, have evolved for tens of millions of years without sex — a conclusion that challenges current evolutionary thinking.

Alongside his work in molecular biology, Meselson has devoted much effort toward preventing the production and use of biological and chemical weapons. In 1963, he was invited to work at the Arms Control and Disarmament Agency in Washington, where he began exploring the US biological weapons program. He reasoned that the United States had no need for such weapons and that pioneering them would only stimulate other countries and groups to acquire them. 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. 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 helped to resolve other issues of military and strategic importance. During the Vietnam War, he led an expedition to Vietnam at the request of the American Association for the Advancement of Science. His group showed that the United States was mistaking civilian rice fields for enemy soldiers’ crops. Meselson’s findings prompted President Nixon to end US herbicide operations in Vietnam.

Meselson’s scientific fieldwork also helped solve two contentious puzzles of the Cold War. He investigated the “yellow rain” in Southeast Asia during the 1980s, purportedly a poison that the Laotians and Vietnamese, with Soviet assistance, were spraying on anti-government tribespeople. Meselson traveled to Southeast Asia, where he and his colleagues identified this substance as bee droppings — pollen eaten by the insects, which they then excreted in massive showers.

Another international controversy brought Meselson to Russia. In 1979, an anthrax epidemic killed more than 60 people in Sverdlovsk, USSR The Soviets blamed tainted meat, whereas US intelligence agencies suspected an airborne leak from a biological weapons facility. Meselson stated in Congressional testimony that the Soviet explanation was plausible, but that an on-site inquiry was needed. He repeatedly attempted to bring independent investigators to Sverdlovsk. Finally, in 1992, the Russian government allowed him and his wife, medical anthropologist Jeanne Guillemin, to bring a team to Sverdlovsk and probe the cause of the epidemic. The group examined preserved tissue samples, talked to city officials to learn how they responded to the outbreak, and initiated interviews with family members of those who died. The next year, Guillemin and Meselson returned to Sverdlovsk to conduct additional interviews. The victims lived in scattered locations, but the discussions revealed that their workplaces fell within a long narrow zone, with one end at the suspicious facility. Because bad meat doesn’t travel in straight lines but wind often does, the researchers concluded that an airborne leak had caused the outbreak. Using local meteorological records, Meselson was able to pinpoint the day the germs had escaped.

With Julian Perry Robinson of the University of Sussex, Meselson directs The Harvard Sussex Program, which aims to increase the contribution of scholarship to the formation of public policy on issues involving biological and chemical weapons. Aided by experts in international law, Meselson and Robinson drafted a treaty in the late 1990s that would prohibit biological and chemical weapons under international criminal law. This pact would give courts of participating countries jurisdiction over any individual who orders the use of 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, which would make purveyors of biological and chemical weapons international criminals.

While engaged in these policy-related activities, Meselson has maintained an active laboratory. His graduate and postdoctoral students include numerous scientific stars: Mark Ptashne (Lasker Basic Research Award, 1997), Susan Lindquist (Director of the Whitehead Institute), Steven Henikoff (Investigator of the Howard Hughes Medical Institute), and Sidney Altman (Nobel Prize in Chemistry, 1989). The contributions of these investigators highlight Meselson’s mentorship talents.

Meselson is widely respected for his penetrating intellect and innovative insights. Among his scientific peers, he stands out as one whose talents and contributions have spanned molecular and international events alike.

by Evelyn Strauss

Key publications of Matthew Meselson

Meselson, M., Stahl, F.W., and Vinograd, J. (1957). Equilibrium sedimentation of macromolecules in density gradients. Proc. Natl. Acad. Sci. USA. 43, 581–583.

Meselson, M. and Stahl, F.W. (1958). The replication of DNA in E. coli. Proc. Natl. Acad. Sci. USA. 44, 671–682.

Brenner, S., Jacob, F., and Meselson, M. (1961). An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature. 190, 576–581.

Meselson, M. and Weigle, J.J. (1961). Chromosome breakage accompanying genetic recombination in bacteriophage. Proc. Natl. Acad. Sci. USA. 47, 857–868.

Meselson, M. and Yuan, R. (1968). DNA restriction enzyme from E. coli. Nature. 217, 1110–1114.

Wagner, Jr., R. and Meselson, M. (1976). Repair tracts in mismatched DNA heteroduplexes. Proc. Natl. Acad. Sci. USA. 73, 4135–4139.

Nowicke, J. and Meselson, M. (1984). Yellow rain: A palynological analysis. Nature. 309, 205–206.

Meselson, M., Guillemin, J., Hugh-Jones, M., Langmuir, A., Popova, I., Shelokov, A., and Yampolskaya, O. (1994). The Sverdlovsk anthrax outbreak of 1979. Science. 266, 1202–1208.

Welch, M. and Meselson, M. (2000). Evidence for the evolution of Bdelloid rotifers without sexual reproduction or genetic exchange. Science. 288, 1211–1215.

Award presentation by Thomas Maniatis

Award presentation by Thomas ManiatisI am honored to introduce Professor Matthew Meselson, the recipient of the 2004 Albert Lasker Award for Special Achievement in Medical Science. Matt was the mentor of Mark Ptashne, a Lasker Award winner in 1997, who was my mentor. Matt is therefore my scientific grandfather. I have known Matt for over 30 years, and have marveled at his ability to remain at the forefront of science and at the same time serve his country as an advisor at the highest levels of government. His secret is simple — he is incredibly smart. Matt is being recognized for his extraordinary contributions to two different areas of the scientific enterprise: molecular biology and public policy.

In 1958, as a graduate student at Caltech, Meselson conceived the theoretical basis of a technique called equilibrium density gradient centrifugation, and showed that this method could be used to separate macromolecules that differ only slightly in their densities. He and Franklin Stahl then used the method to address the question of how DNA replicates. They designed an experiment so elegant and so decisive it became known as the most beautiful experiment in biology. They showed that DNA duplication produces two identical daughter molecules, each containing one parental and one newly formed strand. This work provided compelling support for Watson and Crick’s proposed mechanism of DNA replication and for their double-stranded helical model of DNA.

In 1961, Sydney Brenner and François Jacob, working with Meselson at Caltech, used density gradient centrifugation to establish the existence of messenger RNA, the genetic intermediary between genes and proteins. That same year, Meselson used the method to learn how two DNA molecules produce new ones that contain a mixture of the parents — a process known as genetic recombination.

Later, as a faculty member at Harvard University, Meselson predicted and demonstrated methyl-directed mismatch repair, a process by which mistakes in DNA are corrected, and he was the first to purify a bacterial enzyme that destroys the DNA of invading bacterial viruses. A related group of enzymes turned out to be invaluable for mapping, cloning and sequencing DNA because they cut at defined sequences. The discoverer of that class of restriction enzymes, Hamilton Smith, credited Meselson’s earlier work as being the key to his Nobel Prize-winning discovery.

In the past several years, Meselson has been tackling another central question: How does sexual reproduction contribute to evolution? Meselson and his colleagues have provided strong molecular-genetic evidence that an apparently all-female group of tiny aquatic invertebrates has evolved for tens of millions of years without sex — a conclusion that, if true, would put Woody Allen out of business.

During the same time that Meselson made these extraordinary contributions to the understanding of fundamental biological mechanisms, the remainder of his seemingly limitless intellectual energy was directed towards preventing the production and use of biological and chemical weapons. Beginning in 1963, he worked at high levels of government as a scientific advisor. Meselson’s effectiveness in this position was based on his ability to approach issues from a strictly scientific basis. Thus he not only understood the efficacy and dangers of biological and chemical weapons, especially to civilians: he also studied the military strategies for their use. He convincingly argued that the United States had no need of these weapons and that its pursuit of them would only stimulate other nations and groups to acquire them. His cogent analysis was influential in persuading President Richard Nixon in 1969 to end the US biological weapons program, and to renounce biological and toxin weapons.

This same approach led to the resolution of other issues of military and strategic importance. During the Vietnam War, Meselson led an expedition to Vietnam that concluded that the United States’ herbicide program was based on the false assumptions that crop destruction could distinguish civilian rice fields from fields maintained by enemy soldiers, and that wide-scale defoliation of the forests was reducing US battlefield casualties.

Meselson’s scientific fieldwork also helped solve two contentious puzzles of the Cold War. He investigated the ‘yellow rain’ in Southeast Asia during the 1980s, purportedly a poison that the Laotians and Vietnamese, with Soviet assistance, were spraying on anti-government tribespeople. Meselson traveled to Southeast Asia, where he and his colleagues identified this substance as bee droppings — pollen eaten by the insects, which they then excreted in massive showers. During the 1990s, after earlier attempts to bring independent scientists to the Soviet Union to investigate a controversial anthrax outbreak that took place in 1979, Meselson and his team traveled to Russia and conducted a meticulous epidemiological study that proved the outbreak was caused by an aerosol release from a suspected biological warfare facility.

As you might imagine, all of Matt’s accomplishments have led to recognition through awards, lectureships, and even appearances on CNN news. However, I will only mention two of his most notable honors: First, Matt was once listed by a local newspaper as the most eligible bachelor in Boston. They must have been right, considering that a short time later he married the talented and attractive Jeanne Guillemin, who is here with Matt today. Second, although President Nixon was grateful for Matt’s advice, Matt was honored by being placed on the Nixon’s political enemies list, which includes luminaries such as Mike DeBakey; Derek Bok, the President of Harvard University; and Joe Namath, the New York Jets quarterback. In spite of these two notable honors, I believe that Matt will cherish the Lasker prize above all, which recognizes his lifelong accomplishments in science and public service.

Acceptance remarks by Matthew Meselson

Nature Medicine Essay

Acceptance remarks, 2004 Lasker Awards Ceremony

Many scientists became intrigued with science while still quite young. For me, as a schoolboy in Southern California, it was chemistry and the thought that perhaps chemistry and physics could eventually explain how living things replicate themselves. Except for the guiding framework of classical genetics and some general insights from structural chemistry, the subject was then almost totally mysterious.

In 1953, I was accepted into a graduate program at the University of Chicago called “Mathematical Biophysics.” These were attractive key words to a young person wanting to apply chemistry and physics to biology before DNA had set the agenda. Intending to leave for Chicago, I was invited to a swimming pool party at the Pauling house in Sierra Madre. Linus, whose course in General Chemistry I had taken as a Caltech undergraduate, came out of his study, looked down at me in the water and said, “Well, Matt, what will you do next year?” Hearing my plan, his response was, “But that’s a lot of baloney. Why don’t you come be my graduate student?” Of course, that’s what I did.

That happy chance led to much else: going to Woods Hole in 1954 as Jim Watson’s summer research assistant; meeting Frank Stahl there; coming under the intellectually rigorous influence of Max Delbrück and the Caltech phage group; density-gradient centrifugation; semi-conservation; Brenner, Jacob, and messenger RNA; phage lambda recombination with Jean Weigle; and unending talk about science with Caltech house mates Frank Stahl, Jan Drake, Howard Temin, and our regular dinner partner, John Cairns.

And then at Harvard many superb students and post-docs; more recombination; DNA mismatch repair; class I restriction and modification enzymes; and now trying to understand why males and meiosis exist.

I was extraordinarily fortunate in starting research just when the structure of DNA was discovered. For all of us, the structure itself posed the important questions and hinted at the answers: How it replicates; how it recombines; how it mutates; how it carries information for protein sequence; and since only nucleic acids can read it, a hint about how information gets out of the nucleus to specify proteins in the cytoplasm. A guidebook to the previously secret garden of life!

Still more good fortune provided the funds for molecular biologists to pursue these problems long before any practical application came into view. That was in substantial part because of the insight and dedication of those individuals at the NSF and the NIH who believed that the most basic science must be supported regardless of potential application and were independent-minded enough to buck the bureaucracy when necessary.

So to my teachers, colleagues, and students, to those whose support has been essential, and to the Albert and Mary Lasker Foundation for its fostering and recognition of biological research, many thanks.

Interview with Matthew Meselson