HARVARD GAZETTE ARCHIVES

Maniatis Named First Thomas H. Lee Professor

The work of Thomas Maniatis, the first Thomas H. Lee Professor of Molecular and Cellular Biology, perfectly embodies the benefits of research science. At a time when funding for basic research is under scrutiny, his accomplishments in the field of genetics -- and that of his colleagues -- are proving extraordinary.

"An exciting aspect of biology today is that much of what we learn through basic research has direct applications to fighting disease and improving human health," said Maniatis. "I never dreamed that my laboratory research would have an impact on society in my lifetime, and to see that projects we undertook just 10 years ago are benefiting people now is very gratifying."

The University Governing Boards recently approved Maniatis' appointment to a chair established thanks to Thomas H. Lee '65, who gave $22 million to the University last year.

The president and founder of the private Boston-based Thomas H. Lee Co., Lee is widely regarded as a pioneer in growth company buyouts. Active at Harvard as well as numerous other educational, medical, and arts organizations, he is a member of the Committee on University Resources Campaign Executive Committee, the Visiting Committee to Harvard College, the Boston Major Gifts Steering Committee, and the Faculty of Arts and Sciences Financial Aid Council.

Lee offered Dean of the Faculty of Arts and Sciences Jeremy R. Knowles the discretion of allocating $9.5 million of the gift. Knowles directed some of this to establish the new professorship and to create a fund for the recruitment of new biology faculty. Lee sees the sciences as critical components of liberal education and is particularly interested in the Human Genome Project and its impact on civilization.

Knowles added the remainder of the gift to the Thomas H. Lee AB '65 Scholarship Fund, which provides financial aid to undergraduates.

Lee also gave President Neil L. Rudenstine the discretion to allocate $9.5 million of the gift, which Rudenstine will do after further discussions with him. Lee asked that the remaining $3 million support programs at the Graduate School of Education and various affiliated institutions.

Chair to honor Knowles

While Lee's name now identifies the chair, it ultimately will be known as the Jeremy R. Knowles Professorship of Molecular and Cellular Biology.

"I wanted to honor Jeremy and recognize his achievement not only as an effective dean but also as an eminent scientist," said Lee.

It is the University's practice to refrain from naming a chair for a current dean, so the designation will change after Dean Knowles steps down from the deanship.

Maniatis added: "I am so pleased to hold a chair that will carry the name of such a distinguished scientist and dean."

Dean Knowles said: "I am most grateful to Tom Lee for providing the Faculty of Arts and Sciences with such a wonderful opportunity to boost our research and teaching in molecular biology. Harvard is fortunate to have an outstanding faculty member -- Tom Maniatis -- whose creativity and scholarship are of the highest quality and make such a difference for so many, to hold this chair. Personally, I am deeply honored that Tom Lee, such a thoughtful friend and generous alumnus, should wish to endow this chair in my name."

Understanding genes

Maniatis and his research team pioneered the development of molecular cloning methods and their application to the study of gene structure and expression. These methods have had a profound impact on biology, from the advancement of basic knowledge, to the identification of mutations that cause human genetic diseases such as cystic fibrosis and certain forms of cancer.

Maniatis and his team were the first to isolate, or "clone," a human gene, and to identify mutations in genes isolated from patients with a genetic disease. Specifically, they cloned the human hemoglobin gene, which encodes the red blood cell protein that carries oxygen from the lungs to the rest of the body. By comparing genes obtained from normal individuals with those from individuals with a genetic disease called thalassemia, the researchers were able to precisely pinpoint mutations that cause the disease. This general approach was subsequently adopted by others to identify the genetic basis of scores of other human diseases.

In 1982, Maniatis coauthored a laboratory manual for genetic research entitled Molecular Cloning, which can be found on students' desks from Boston to Beijing (and, in earlier days, on Knowles'). This manual has played a pivotal role in training students and in the practice of recombinant DNA research over the past 15 years.

Maniatis' objective in developing gene cloning technology was to obtain tools for studying gene regulation, the process by which genetic information encoded in the DNA of the gene is translated into protein, the basic building blocks of cells. This process involves transcribing DNA to produce a similar molecule called RNA, which in turn is translated into protein. However, the gene contains regions that cannot be decoded. These nonsense sequences are transcribed into RNA, so they must be removed by a process called RNA splicing. This mechanism is analogous to editing a piece of film, where unwanted sections are cut out and the remainder spliced together. The primary focus of the Maniatis laboratory is to understand gene expression at the level of RNA transcription and RNA splicing. Many genetic diseases emerge as the consequence of defects in these processes.

Maniatis and his colleagues have identified complex arrays of proteins required for gene expression, and have cloned the genes that encode them. These proteins can then be produced in large amounts employing recombinant DNA methods and then used to reconstitute transcription and splicing in a test tube. These studies have led to a better understanding of how these processes occur, and how they are regulated during normal cell growth and differentiation.

Recently, the Maniatis lab has focused on understanding how the beta-interferon gene is regulated. This gene is normally silent, but is activated when cells are infected by viruses, such as those that cause colds and flu. The interferon gene produces a protein that binds to surrounding, uninfected cells and protects them from virus infection. In the course of understanding how this regulation works, Maniatis's lab showed that proteins required for interferon regulation also play a key role in inflammatory diseases such as asthma and arthritis. In collaboration with a Cambridge biotechnology company, ProScript, which Maniatis cofounded, he and his co-workers are studying the function and activation of these proteins with the ultimate goal of identifying inhibitors that could be used in the treatment of inflammatory diseases.

Most of Maniatis's work, however, entails basic research. For example, the sex of fruitflies is determined by how a particular RNA molecule is spliced. If it is spliced one way the fly is female, while a different splice produces a male. Maniatis and his coworkers have succeeded in reconstituting this differential RNA splicing reaction in a test tube and have determined the mechanisms involved. Remarkably, the same mechanisms used for controlling RNA splicing in the fruitfly also function in human cells.

Distinguished Career

Maniatis began his research career as a postdoctoral fellow at Harvard in 1971. A Denver native, he earned bachelor's and master's degrees from the University of Colorado and, in 1971, a doctorate in molecular biology from Vanderbilt University.

Exchanging Cambridge, Mass., for Cambridge, England, he spent one year at Britain's Medical Research Council of Molecular Biology. After returning to Harvard, he left again to become senior staff investigator at Cold Spring Harbor Laboratory, where he and his coworkers developed a method called cDNA cloning, in which RNA transcripts are converted back into DNA and cloned. The researchers used this method to obtain the cDNA clone of the RNA that encodes hemoglobin. This development presented a major breakthrough which allowed the RNA encoding any gene to be cloned. At the time this work was being done, Maniatis held a joint appointment between Harvard and Cold Spring Harbor, but the research was undertaken at Cold Spring Harbor because the Cambridge City Council had passed a moratorium on his area of biotechnological research -- making this the only place in the world that prohibited the work. As a result, Maniatis accepted a position at the California Institute of Technology, where his lab devised methods for directly cloning genes rather than their RNA transcripts. The lab produced the first "library" of human genes, a major advance in gene research. Using this library, it was possible to isolate virtually any human gene, and this library has been used by researchers worldwide to isolate and study new human genes.

Following the lifting of the moratorium on recombinant DNA research in Cambridge, Maniatis returned to Harvard as professor of biochemistry and molecular biology. He served as chairman of the department from 1985 to 1988, and has held the Mallinckrodt Professorship in Molecular and Cellular Biology since 1995.

Among the many honors bestowed on Maniatis are the Eli Lilly Award in Microbiology and Immunology from the American Society of Microbiology in 1981, and the 1985 Richard Lounsbery Award for Biology and Medicine from the U.S. and French national academies of science. He is a member of the U.S. National Academy of Sciences and a fellow of the American Academy of Arts and Sciences.

Maniatis is a cofounder of Genetics Institute, a leading Cambridge biotechnology company, and served as a member of its board of directors and scientific advisory board for more than 17 years. The company has developed protein-based drugs such as blood-clotting factors, and growth factors that stimulate the production of red blood cells and the cells of the immune system.

One of Genetics Institute's most significant accomplishments enables people with hemophilia A or B to live normal lives; they previously were at constant risk of infection, and many contracted AIDS because the clotting factors they require were purified from blood. "The Genetics Institute scientists cloned the genes that are defective in individuals with hemophilia A or B, and then reinserted them into specially designed cells that could be used to produce the clotting factors in large amounts. Thus, highly purified proteins could be made in large amounts from a source free of any infectious agents," said Maniatis.

Maniatis's teaching duties have for many years included the basic undergraduate course in molecular biology. During the past few years, he has focused on senior honor students and graduate students with an advanced course on gene regulation.