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Destroying Dogma: the Discovery of Reverse Transcriptase

The central dogma of molecular biology that evolved in the 1950s and 1960s was that a cell's genetic information travels down a one-way street, from DNA to RNA to proteins. In 1970 David Baltimore (1938- ) made a profound discovery that contradicted this conventional wisdom: he found an enzyme, reverse transcriptase, that used an RNA template to catalyze the synthesis of DNA. Baltimore was studying a tumor virus originally discovered at Rockefeller called Rous sarcoma virus (RSV), and the finding had far-reaching implications for cancer research and for molecular biology more generally. In 1975 he was awarded a Nobel Prize for the work, shared with Howard Temin and Renato Dulbecco.

Baltimore, David

Baltimore had spent a decade studying how animal viruses replicate. He focused his work on viruses such as polio and vesicular stomatitis virus (VSV), which store their genetic information in RNA. Baltimore and his colleagues had found an unusual enzyme in VSV that allowed it to copy its genomic RNA to make messenger RNA. This led them to search for similar enzymes in RNA tumor viruses. Another researcher-Howard Temin at the University of Wisconsin, Madison-had suggested that the replication of RNA tumor viruses involves a DNA intermediate. So Baltimore and his colleagues searched for an enzyme that could make DNA from RNA. Looking first in Rous sarcoma virus (RSV) and then in Rauscher mouse leukemia virus, they found the enzyme-reverse transcriptase. Simultaneously with Baltimore, Temin and Mizutani found evidence of DNA synthesis in RSV. Papers from the two research groups were published together in the journal Nature in 1970.

The discovery of reverse transcriptase reshaped the science of molecular biology in many ways. It launched a new era in cancer research, because with this enzyme it became possible to unravel the genetics of tumor viruses and to find oncogenes-cancer-causing genes-using copies of RNA as probes for DNA sequences. Reverse transcriptase also opened the field of biotechnology: with this enzyme it was possible to make DNA from all sorts of RNA, not only from viral RNA, and then insert genes into vectors and manipulate them. Reverse transcriptase also made possible the discovery of HIV, the virus that causes AIDS, which was identified by the activity of this enzyme. In addition, when coupled with the polymerase chain reaction, it made it possible to use mRNA to detect genetic defects in human disease much more efficiently. Reverse transcriptase continues to yield new insights. It turns out that much of the human genome comes about through reverse transcription. In addition, telomerase, the enzyme that prevents the ends of chromosomes from fraying, is a reverse transcriptase.

In the late 1970s Baltimore reoriented the focus of his laboratory to a mix of immunology and virology. Among many significant findings, his research group identified the protein pair that rearranges immunoglobulin genes, the so-called RAG proteins. They also discovered the key transcription factor NF-KB. In addition, Baltimore's identification of unique enzymatic activity in the process by which the Abelson mouse leukemia virus causes cancer laid the groundwork for the development of the successful anti-cancer drug Gleevec.

David Baltimore received the BA from Swarthmore College (1960) and the PhD from The Rockefeller University (1964), for work under Richard Franklin in the laboratory of Igor Tamm. After postdoctoral fellowships at the Massachusetts Institute of Technology, in the laboratory of James E. Darnell, Jr., and Albert Einstein College of Medicine, in New York, he became a research associate at the Salk Institute for Biological Studies, working in association with Renato Dulbecco, with whom he later shared the Nobel Prize. In 1968 he joined the faculty of MIT. His appointment in 1982 as the founding director of MIT's Whitehead Institute marked the beginning of a notable administrative career for Baltimore, carried out alongside his continuing research. From 1990 to 1991 he served as president of The Rockefeller University, and he remained a member of the Rockefeller faculty until 1994, when he returned to MIT. Baltimore was president of the California Institute of Technology from 1997 to 2006. Today he is the Robert A. Millikan Professor of Biology at Caltech. Baltimore has been a leader in science policy for more than 30 years, starting with his 1975 participation in the Asilomar Conference on Recombinant DNA Molecules, which brought molecular biology into the public arena. He has also served as head of the National Institutes of Health AIDS Vaccine Research Committee, and in 2007 he was president of the American Association for the Advancement of Science.

The discovery of reverse transcriptase was acknowledged by several awards: in 1971 Baltimore received the Gustav Stern Award, the Warren Triennial Prize, and the Eli Lilly Award. He was honored with the Gairdner International Award in 1974, and in 1975 he shared the Nobel Prize in Physiology and Medicine with Howard M. Temin and Renato Dulbecco. In recognition of his long ties to Rockefeller, the University awarded Baltimore an honorary degree in 2004. He is a member of the U.S. National Academy of Sciences and its Institute of Medicine.

Selected Publications

Huang AS, Baltimore D, and Stampfer, M. Ribonucleic acid synthesis of vesicular stomatitis virus. 3. Multiple complementary messenger RNA molecules. Virology, 1970, 42:946-957

Baltimore D, Huang AS, and Stampfer M. Ribonucleic acid synthesis of vesicular stomatitis virus, II. An RNA polymerase in the virion. Proc Natl Acad Sci USA, 1970, 66: 572-576

Huang AS, Baltimore D. Defective viral particles and viral disease processes. Nature, 1970, 226:325-327

Baltimore D. RNA-dependent DNA polymerase in virions of RNA tumour viruses. Nature, 1970, 226:1209-1211

Temin HM and Mizutani S. RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature, 1970, 226:1211-1213

Temin H and Baltimore D. RNA-Directed DNA Synthesis and RNA Tumor Viruses. In Advances in Virus Research, vol. 17. Smith KM, Lauffer MA, and Bang FB, eds. New York: Academic Press, 1972, pp. 129-186

Links

The Nobel Prize in Physiology or Medicine, 1975
http://nobelprize.org/nobel_prizes/medicine/laureates/1975/index.html

An Interview With David Baltimore
http://nobelprize.org/nobel_prizes/medicine/laureates/1975/baltimore-interview.html

The Baltimore Laboratory
http://baltimorelab.caltech.edu/

DNA from the Beginning: Chapter 25, Some viruses store genetic information in RNA
http://www.dnaftb.org/dnaftb/

Hospital Centennial

Destroying Dogma: the Discovery of Reverse Transcriptase

Selected Publications

Further Reading

Links