March 22, 2004

Pioneer In Interferon Research
Lauded For Career Achievements

In a career that has spanned more than 50 years of scientific research, Philip Marcus, professor of molecular and cell biology, has enjoyed his share of significant results and papers regarded as 'classic'.

Philip Marcus, Board of Trustees Distinguished Professor of Molecular and Cell Biology, works in his lab in Torrey Life Sciences. Marcus has spent about half a century researching viruses and the interferon system. Photo by Dollie Harvey

His achievements were recognized when the University named him a Board of Trustees Distinguished Professor, the highest honor for faculty, citing his pioneering interferon research. Marcus is also interim director of the Biotechnology Bioservices Center; a member of the Center for Excellence in Vaccine Research; and has been chair of the Institutional Biosafety Committee for 27 years.

It's the thrill of the chase for new knowledge about viruses and the interferon system that motivates Marcus, at 76, to don his blue lab coat, write new papers, and hint to a visitor - without revealing his secret - that his latest work will shake some people up when published.

"I don't think it's fun to do work that a lot of other people are doing - and science should be fun," he says, quoting a scientist he greatly admires, the late Leo Szilard. Szilard was one of the Manhattan Project designers, who abandoned physics for biology after the atomic bomb - for which he received a patent - was dropped.

Marcus was a graduate student of Szilard's at the University of Chicago, where he received his master's degree in microbiology in 1953. He then moved to the University of Colorado for his Ph.D., where he worked under biophysicist Theodore T. Puck.

Marcus's first research breakthrough was a paper he wrote with Puck in 1954 for the Proceedings of the National Academy of Science, describing a technique they developed for cloning mammalian cells - the first time this had been done. They invented the technique after Szilard offhandedly sketched on a napkin his idea for the project, inspiring Marcus to pursue a new method.

That method is still used. A history of somatic cell genetics written in 1995 called it a "technological revolution" that "provided the essential basis for what rapidly became the standard methodology for cloning animal cells."

Marcus's next significant work was a demonstration of cell surface migration of proteins in the early 1960's. During a summer course at the Cold Spring Harbor Laboratory headed by Nobel laureate James Watson, Marcus - by then a junior faculty member at Albert Einstein College of Medicine in the Bronx - described for the first time the dynamics of the movement of virus molecules on the surface of cells.

An "intrinsic interference test" Marcus developed at Einstein made it possible to quantitatively detect rubella virus, the cause of an epidemic in the 1960's.

Interferon has occupied much of Marcus's research since 1966. He was even introduced at one scientific symposium as 'Mr. Interferon.'

Interferon, discovered in 1957, the year Marcus earned his Ph.D., is a protein produced by humans and other animals that activates a cell's anti-viral response. How a virus kills a healthy cell has long been one of his interests; how interferon stops it is another. Which virus molecules induce interferon production, and, more recently, which molecules suppress interferon induction, are also subjects of his research.

The chills or fever often experienced during a viral infection such as the flu are caused not by the virus, but by interferon going to work. Interferon was once touted as a "miracle drug" cure for cancer, but its workings and effects have proved to be more complex than first thought. Interferons are now produced by genetic engineering and used as an adjunct therapy for some types of cancer and for treating certain forms of hepatitis.

Much of Marcus's research on what makes viruses and interferon tick has been conducted together with his research associate for 30 years, Margaret Sekellick, a UConn alumna who is now a professor-in-residence.

Marcus's laboratory in the Torrey Life Sciences Building is a center of information about viruses. The lab has developed assays, or measures, for quantifying the properties of viruses, such as their ability to cause infection, induce interferon, kill cells, and suppress interferon induction.

The lab is the leading proponent of the theory that double-stranded ribonucleic acid, or dsRNA, is the inducer of interferon, Marcus says. In what he describes as a "serendipitous insight" in 1975, when he and Sekellick were studying how vesicular stomatitis virus - a virus that causes a disease in cows - kills a cell, they began to study dsRNA produced by a defective particle of that virus.

Working on chick embryo cells, they determined that just one molecule of dsRNA was enough to induce interferon production in a cell. Andrew Ball, a professor of microbiology at the University of Alabama who was a colleague of Marcus and Sekellick when the work leading to the one-molecule theory was in progress, has described the scale envisaged by the theory: "When you compare the size of a molecule and the size of a cell, it's like a pea up against the Cathedral of Notre Dame."

Yet strangely, while a cell would respond with incredible sensitivity to one molecule of dsRNA, cells that got two or more molecules produced little or no interferon, Marcus noted, and no one knew why. Despite considerable skepticism by reviewers about their one-molecule theory, a paper by Marcus and Sekellick describing it appeared in Nature in 1977.

"I think it is fair to say that the full implications of this pioneering work have yet to be fully appreciated by the scientific community," says Ball.

One area of focus in Marcus's lab has been avian interferon. In 1994, Sekellick cloned chicken interferon for the first time. Another former student of Marcus's, Charles Weissmann of Biogen, became the first to clone the human interferon gene.

Over the years, Marcus's work has been funded by the NIH, the National Science Foundation, the U.S. Department of Agriculture, and Connecticut Innovations. Recently, he and Sekellick have been working on a procedure to overcome interferon resistance by some viruses.

Marcus is in his 28th year of teaching virology, a class that used to attract a fairly stable population of 30 or so juniors, seniors, and graduate students and has nearly doubled that enrollment this year. In 1980, he introduced information about HIV to the class. He has also taught students about ebola and influenza, viruses they might read about in the newspaper as well as in their class notes. And this year, he will talk about the SARS virus.

While he bridles at the question of when he will retire from teaching, Marcus did retire just over a year ago after 18 years as editor-in-chief of the Journal of Interferon and Cytokine Research (interferon is a member of the cytokine family of proteins). During his tenure as editor, he processed more than 2,000 papers.