David Baltimore
David Baltimore was an American biologist, university administrator, and 1975 Nobel laureate in Physiology or Medicine. He was a professor of biology at the California Institute of Technology, where he served as president from 1997 to 2006. He founded the Whitehead Institute and directed it from 1982 to 1990. In 2008, he served as president of the American Association for the Advancement of Science.
At age 37, Baltimore won the Nobel Prize with Renato Dulbecco and Howard M. Temin "for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell", specifically the discovery of the enzyme reverse transcriptase. He contributed to immunology, virology, cancer research, biotechnology, and recombinant DNA research. He also trained many doctoral students and postdoctoral fellows, several of whom have gone on to notable and distinguished research careers. In addition to the Nobel Prize, he received a number of other awards, including the U.S. National Medal of Science in 1999 and the Lasker Award in 2021.
Early life and education
Baltimore was born on March 7, 1938, in Manhattan, New York, to Gertrude and Richard Baltimore. Raised in the Queens neighborhoods of Forest Hills and Rego Park, he moved with his family to suburban Great Neck, New York, while he was in second grade because his mother felt that the city schools were inadequate. His father had been raised as an Orthodox Jew and his mother was an atheist, and Baltimore observed Jewish holidays and would attend synagogue with his father through his Bar Mitzvah. He graduated from Great Neck North High School in 1956, and credits his interest in biology to a high-school summer spent at the Jackson Laboratory's Summer Student Program in Bar Harbor, Maine. It was at this program that he met Howard Temin, with whom he would later share the Nobel Prize.Baltimore earned his bachelor's degree in chemistry with high honors at Swarthmore College in 1960. He was introduced to molecular biology by George Streisinger, under whose mentorship he worked for a summer at Cold Spring Harbor Laboratory as part of the inaugural cohort of the Undergraduate Research Program in 1959. There he also met two new MIT faculty, future Nobel Laureate Salvador Luria and Cyrus Levinthal, who were scouting for candidates for a new program of graduate education in molecular biology.
Luria and Levinthal invited Baltimore to apply to the Massachusetts Institute of Technology. Baltimore's future promise was evident in his work as a graduate student when he entered MIT's graduate program in biology in 1960. His early interest in phage genetics quickly yielded to a passion for animal viruses. He took the Cold Spring Harbor course on animal virology in 1961 and chose to move to Richard Franklin's lab at Rockefeller University to complete his PhD research on animal virology. There he made fundamental discoveries on virus replication and its effect on cell metabolism, including the first description of an RNA replicase, finishing his PhD in only two years.
Career and research
After his PhD, Baltimore returned to MIT for postdoctoral research with James E. Darnell in 1963. He continued his work on virus replication using poliovirus and pursued training in enzymology with Jerard Hurwitz at Albert Einstein College of Medicine in 1964.Independent investigator
In February 1965, Baltimore was recruited by Renato Dulbecco to the newly established Salk Institute for Biological Studies in La Jolla as an independent research associate. There he investigated poliovirus RNA replication and began a long and storied career of mentoring other scientists' early careers including Marc Girard, and Michael Jacobson. They discovered the mechanism of proteolytic cleavage of viral polyprotein precursors, pointing to the importance of proteolytic processing in the synthesis of eukaryotic proteins. He also met his future wife, Alice Huang, who began working with Baltimore at Salk in 1967. He and Alice together carried out key experiments on defective interfering particles and viral pseudo types. During this work, he made a key discovery that polio produced its viral proteins as a single large polyprotein that was subsequently processed into individual functional peptides.Massachusetts Institute of Technology
Reverse transcriptase
In 1968, he was recruited once more by soon-to-be Nobel laureate Salvador Luria to the department of biology at MIT as an associate professor of microbiology. Alice S. Huang also moved to MIT to continue her research on vesicular stomatitis virus. They became a couple, and married in October 1968. At MIT, Huang, Baltimore, and graduate student Martha Stampfer discovered that VSV replication involved an RNA-dependent RNA polymerase within the virus particle, and used a novel strategy to replicate its RNA genome. VSV entered a host cell as a single negative strand of RNA, but brought with it RNA polymerase to stimulate the processes of transcription and replication of more RNA.Baltimore extended this work and examined two RNA tumor viruses, Rauscher murine leukemia virus and Rous sarcoma virus. He went on to discover reverse transcriptase – the enzyme that polymerizes DNA from an RNA template. In doing so, he discovered a distinct class of viruses, later called retroviruses, that use an RNA template to catalyze synthesis of viral DNA. This overturned the simplified version of the central dogma of molecular biology that stated that genetic information flows unidirectionally from DNA to RNA to proteins. Reverse transcriptase is essential for the reproduction of retroviruses, allowing such viruses to turn viral RNA strands into viral DNA strands. The viruses that fall into this category include HIV.
The discovery of reverse transcriptase, made contemporaneously with Howard Temin, who had proposed the provirus hypothesis, showed that genetic information could traffic bidirectionally between DNA and RNA. They published these findings in back-to-back papers in the journal Nature. This discovery made it easier to isolate and reproduce individual genes, and was heralded as evidence that molecular and virological approaches to understanding cancer would yield new cancer treatments. This may have influenced President Richard Nixon's war on cancer, which was launched in 1971 and substantially increased research funding for the disease. In 1972, at the age of 34, Baltimore was awarded tenure as a professor of biology at MIT, a post that he held until 1997.
Asilomar conference on recombinant DNA
Baltimore also helped Paul Berg and Maxine Singer to organize the Asilomar Conference on Recombinant DNA, held in February 1975. The conference discussed possible dangers of new biotechnology, drew up voluntary safety guidelines, and issued a call for an ongoing moratorium on certain types of experiments and review of possible experiments, which has been institutionalized by recombinant DNA advisory committees established at essentially all US academic institutions conducting molecular biology research. Baltimore was well aware of the importance of the changes occurring in the laboratory: "The whole Asilomar process opened up to the world that modern biology had new powers that you had never conceived of before."MIT Cancer Center
In 1973, he was awarded an American Cancer Society Professor of Microbiology that provided substantial salary support. Also in 1973, he became one of the early faculty members in the newly organized MIT Center for Cancer Research, capping a creative and industrious period of his career with nearly fifty research publications including the paradigm-shifting paper on reverse transcriptase. The MIT CCR was led by Salvador E. Luria and quickly achieved pre-eminence with a group of faculty including Baltimore, Phillips Robbins, Herman Eisen, Philip Sharp, and Robert Weinberg. Baltimore was honored as a Fellow of the American Academy of Arts and Sciences in 1974. He returned to New York City in 1975, for a year-long sabbatical at Rockefeller University working again with Jim Darnell.Nobel Prize
In 1975, at the age of 37, he shared the Nobel Prize for Physiology or Medicine with Howard Temin and Renato Dulbecco. The citation reads, "for their discoveries concerning the interaction between tumor viruses and the genetic material of the cell." At the time, Baltimore's greatest contribution to virology was his discovery of reverse transcriptase which is essential for the reproduction of retroviruses such as HIV and was discovered independently, and at about the same time, by Satoshi Mizutani and Temin.After winning the Nobel Prize, Baltimore reorganized his laboratory, refocusing on immunology and virology, with immunoglobulin gene expression as a major area of interest. He tackled new problems such as the pathogenesis of Abelson murine leukemia virus, lymphocyte differentiation and related topic in immunology. In 1980, his group isolated the oncogene in AMuLV and showed it was a member of a new class of protein kinases that used the amino acid tyrosine as a phosphoacceptor. This type of enzymatic activity was also discovered by Tony Hunter, who has done extensive work in the area. He also continued to pursue fundamental questions in RNA viruses and in 1981, Baltimore and Vincent Racaniello, a post-doctoral fellow in his laboratory, used recombinant DNA technology to generate a plasmid encoding the genome of poliovirus, an animal RNA virus. The plasmid DNA was introduced into cultured mammalian cells and infectious poliovirus was produced. The infectious clone, DNA encoding the genome of a virus, is a standard tool used today in virology.
Whitehead Institute for Biomedical Research
In 1982, with a charitable donation by businessman and philanthropist Edwin C. "Jack" Whitehead, Baltimore was asked to help establish a self-governed research institute dedicated to basic biomedical research. Baltimore persuaded Whitehead that MIT would be the ideal home for the new institute, convinced that it would be superior at hiring the best researchers in biology at the time, thus ensuring quality. Persuading MIT faculty to support the idea was far more difficult. MIT as an institution had never housed another before, and concerns were raised that the wealth of the institute might skew the biology department in directions faculty did not wish to take, and that Baltimore himself would gain undue influence over hiring within the department. The controversy was made worse by an article published by the Boston Globe framing the institute as corporate takeover of MIT. After a year of intensive discussions and planning, faculty finally voted in favor of the institute. Whitehead, Baltimore, and the rest of the planning team devised a unique structure of an independent research institute composed of "members" with a close relationship with the department of biology of MIT. This structure continues to this day to attract an elite interactive group of faculty to the Department of Biology at MIT and has served as a model for other distinguished institutes such as the Broad Institute.The Whitehead Institute for Biomedical Research was launched with $35 million to construct and equip a new building located across the street from the MIT cancer center at 9 Cambridge Center in Cambridge Massachusetts. The institute also received $5 million per year in guaranteed income and a substantial endowment in his will. Under Baltimore's leadership, a distinguished group of founding members including Gerald Fink, Rudolf Jaenisch, Harvey Lodish, and Robert Weinberg was assembled and eventually grew to 20 members in disciplines ranging from immunology, genetics, and oncology to fundamental developmental studies in mice and fruit flies. Whitehead Institute's contributions to bioscience have long been consistently outstanding. Less than a decade after its founding with continued leadership by Baltimore, the Whitehead Institute was named the top research institution in the world in molecular biology and genetics, and over a recent 10-year period, papers published by Whitehead scientists, including many from Baltimore's own lab, were the most cited papers of any biological research institute. The Whitehead Institute was an important partner in the Human Genome Project.
Baltimore served as director of the WIBR and expanded the faculty and research areas into key areas of research including mouse and drosophila genetics. During this time, Baltimore's own research program thrived in the new Institute. Important breakthroughs from Baltimore's lab include the discovery of the key transcription factor NF-κB by Dr. Ranjan Sen and David Baltimore in 1986. This was part of a broader investigation to identify nuclear factors required for lg gene expression in B lymphocytes. However, NF-κB turned out to have much broader importance in both innate and adaptive immunity and viral regulation. NF-κB is involved in regulating cellular responses and belongs to the category of "rapid-acting" primary transcription factors. Their discovery led to an "information explosion" involving "one of the most intensely studied signaling paradigms of the last two decades."
As early as 1984, Rudolf Grosschedl and David Weaver, postdoctoral fellows, in Baltimore's laboratory, were experimenting with the creation of transgenic mice as a model for the study of disease. They suggested that "control of lg gene rearrangement might be the only mechanism that determines the specificity of heavy chain gene expression within the lymphoid cell lineage." in 1987, they created transgenic mice with the fused gene that developed fatal leukemia.
David G. Schatz and Marjorie Oettinger, as students in Baltimore's research group in 1988 and 1989, identified the protein pair that rearranges immunoglobulin genes, the recombination-activating gene RAG-1 and RAG-2. this was a key discovery in determining how the immune system can have specificity for a given molecule out of many possibilities, and was considered by Baltimore as of 2005 to be "our most significant discovery in immunology".
In 1990, as a student in David Baltimore's laboratory at MIT, George Q. Daley demonstrated that a fusion protein called bcr-abl is sufficient to stimulate cell growth and cause chronic myelogenous leukemia. This work helped to identify a class of proteins that become hyperactive in specific types of cancer cells. It helped to lay the groundwork for a new type of drug, attacking cancer at the genetic level: Brian Druker's development of the anti-cancer drug Imatinib, which deactivates bcr-abl proteins. Gleevec has shown impressive results in treating chronic myelogenous leukemia and also promise in treating gastrointestinal stromal tumor.