David Baltimore

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,[9] pointing to the importance of proteolytic processing in the synthesis of eukaryotic proteins.[10][11] He also met his future wife, Alice Huang, who began working with Baltimore at Salk in 1967.[11][12] 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.[10][11]

In 1968, he was recruited by soon-to-be Nobel laureate Salvador Luria to the department of biology at MIT as an associate professor of microbiology.[13] Alice S. Huang also moved to MIT to continue her research on vesicular stomatitis virus (VSV). They became a couple, and married in October 1968.[12] At MIT, Huang, Baltimore, and graduate student Martha Stampfer discovered that VSV involved an RNA-dependent RNA polymerase within the virus particle, and used a novel replication 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.[11][12][14]

Baltimore extended this work and examined two RNA tumor viruses, Rauscher murine leukemia virus and Rous sarcoma virus.[11][15] He went on to discover reverse transcriptase (RTase or RT) – the enzyme that polymerizes DNA from an RNA template. In doing so, he discovered a distinct class of viruses, later name retroviruses, that use an RNA template to catalyze synthesis of viral DNA.[16] 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.[15][17][18] 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.[12][16]

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 prestigious journal, Nature.[19][20] This discovery was heralded as evidence that molecular and virological approaches to understanding cancer would yield new cures for the dreaded disease. 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.

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.[3] 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."[7]^:111

In 1973, he was awarded a prestigious 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 capping a creative and industrious period of his career with nearly fifty research publications including the paradigm-shifting paper on reverse transcriptase. The MIT CRC was led by Salvador E. Luria and quickly achieved pre-eminence with a remarkable group of faculty including Baltimore, Phillips Robbins, Herman Eisen, Philip Sharp, and Robert Weinberg, who all went on to illustrious research careers.[13] Baltimore was honored as a Fellow of the American Academy of Arts and Sciences in 1974.[6] He returned to New York City in 1975, for a year-long sabbatical at Rockefeller University working with Jim Darnell.

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."[21] At the time, Baltimore's greatest contribution to virology was his discovery of reverse transcriptase (Rtase or RT) which is essential for the reproduction of retroviruses such as HIV and was discovered independently, and at about the same time, by Mizutani and Temin.[10]

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 (AMuLV), 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.[22] 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.[9] 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.

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.[23] They devised a unique structure of an independent research institute composed of "members" with a close relationship with the department of biology of MIT. The Whitehead Institute for Biomedical Research (WIBR) was launched with $35 million to construct and equip a new building located across the street from the MIT cancer center in Cambridge Massachusetts. The institute also received $5 million per year in guaranteed income and a substantial endowment in his will (for a total gift of $135 million). 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.[24] Whitehead Institute's contributions to bioscience have long been second to none. 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 were the most cited papers of any biological research institute.

After establishing the institute in a beautiful newly constructed research building across the street from the MIT cancer center, he served as director of the WIBR serving to expand the faculty and research areas into key areas of research including mouse and drosophila genetics. The Whitehead Institute has been rated as doing "World leading research in genetics and molecular biology",[25] and was an important partner in the Human Genome Project.[26]

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.[27] Their intention was to identify nuclear factors required for lg gene expression in B lymphocytes. What they discovered, NF-κB, turned out to have much broader importance. 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."[28]

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."[29] 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.[30] this was a key discovery in determining how the immune system can have specificity for a given molecule out of many possibilities,[31] and was considered by Baltimore as of 2005 to be "our most significant discovery in immunology".[6]^{:Addendum, May 2005}

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 (CML). 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 (Gleevec), which deactivates bcr-abl proteins. Gleevec has shown impressive results in treating chronic myelogenous leukemia and also promise in treating gastrointestinal stromal tumor (GIST).[32][33][34]

Baltimore served as the director of the Whitehead Institute until July 1, 1990, when he was appointed the sixth president of Rockefeller University in New York City. He moved his research group to New York and continued to make creative contributions to virology and cellular regulation. He also began important reforms in faculty management and promoted the status of junior faculty at the university. After resigning on December 3, 1991, Baltimore remained on the Rockefeller University faculty and continued research until spring of 1994. He then rejoined the MIT faculty as the Ivan R. Cottrell Professor of Molecular Biology and Immunology.

From left: JPL Director Charles Elachi, La Canada-Flintridge Mayor Greg Brown, Baltimore and JPL Deputy Director Eugene Tattini (2006).

On May 13, 1997, Baltimore was appointed president of the California Institute of Technology (Caltech).[35][36][37][38][39] He began serving in the office October 15, 1997 and was inaugurated March 9, 1998.[40]

During Baltimore's tenure at Caltech, United States President Bill Clinton awarded Baltimore the National Medal of Science in 1999 for his numerous contributions to the scientific world. In 2004, Rockefeller University gave Baltimore its highest honor, Doctor of Science (honoris causa).[41]

In 2003, as a postdoctoral fellow in David Baltimore's lab at Caltech, Matthew Porteus was the first to demonstrate precise gene editing in human cells using chimeric nucleases.[42]

In October 2005, Baltimore resigned the office of the president at Caltech[43] (see Luk van Parijs case). Former Georgia Tech Provost Jean-Lou Chameau succeeded Baltimore as president of Caltech.[44] Baltimore remains the Millikan Professor of Biology at Caltech and is an active member of the institute's community.[45]

His laboratory at Caltech is focused on two major research areas: understanding the mammalian immune system and creating viral vectors to make the immune system more effective in resisting cancer. Understanding the diverse activity of the NF-κB transcription factor is one focus. NF-κB is now known to activate as many as 1000 genes in response to various stimuli. It is also known to play different roles in different cells.[45]

Another focus is understanding the functions of microRNA. MicroRNAs provide fine control over gene expression by regulating the amount of protein made by particular messenger RNAs.[45] In recent research led by Jimmy Zhao, Baltimore's team has discovered a small RNA molecule called microRNA-146a (miR-146a) and bred a strain of mice that lacks miR146a. They have used the miR146a(-) mice as a model to study the effects of chronic inflammation on the activity of hematopoietic stem cells (HSCs). Their results suggest that microRNA-146a protects HSCs during chronic inflammation, and that its lack may contribute to blood cancers and bone marrow failure.[46]

Baltimore recently joined with other scientists to call for a worldwide moratorium on use of a new genome-editing technique to alter inheritable human DNA.[47] A key step enabling researchers to slice up any DNA sequence they choose was developed by Emmanuelle Charpentier, then at Umea University in Sweden, and Jennifer A. Doudna of the University of California, Berkeley.[48] Reminiscent of the Asilomar conference on recombinant DNA in 1975, those involved want both scientists and the public to be more aware of the ethical issues and risks involved with new techniques for genome modification.[47]

In addition to his influence on public policy for recombinant DNA research, Baltimore has influenced national policy concerning the AIDS epidemic. In 1986, he and Sheldon M. Wolff were invited by the National Academy of Sciences and the Institute of Medicine to coauthor an independent report: Confronting AIDS (1986), in which they called for a $1 billion research program for HIV/AIDS.[3][49] As of 1996 he was appointed head of the National Institutes of Health (NIH) AIDS Vaccine Research Committee (AVRC).[50]

Baltimore is a member of the National Academy of Sciences USA (NAS), 1974;[51] the American Academy of Arts and Sciences, 1974; the NAS Institute of Medicine (IOM), 1974;[52] the American Association of Immunologists, 1984.[53] He was elected a Foreign Member of the Royal Society (ForMemRS) in 1987;[54][55] the French Academy of Sciences, 2000;[56] and the American Association for Cancer Research (AACR).[52] He is also a member of the Pontifical Academy of Sciences, 1978.[57] In 2006 Baltimore was elected to a three-year term as president of the American Association for the Advancement of Science (AAAS).[52]

Baltimore is a member of the USA Science and Engineering Festival's Advisory Board[58] and an Xconomist (an editorial advisor for the tech news and media company, Xconomy).[59] Baltimore also serves on The Jackson Laboratory's board of trustees,[60] the Bulletin of the Atomic Scientists' Board of Sponsors,[61] Amgen, Inc.'s board of directors,[62] and numerous other organizations and their boards.

During the late 1980s and early 1990s, Thereza Imanishi-Kari, a scientist who was not in Baltimore's laboratory but in a separate, independent laboratory at MIT, was implicated in a case of scientific fraud. The case received extensive news coverage and a Congressional investigation. The case was linked to Baltimore's name because of his scientific collaboration with and later his strong defense of Imanishi-Kari against accusations of fraud.

In 1986, while a professor of biology at MIT and director at Whitehead, Baltimore co-authored a scientific paper on immunology with Thereza Imanishi-Kari (an assistant professor of biology who had her own laboratory at MIT) as well as four others.[63] A postdoctoral fellow in Imanishi-Kari's laboratory, Margot O'Toole, who was not an author, reported concerns about the paper, ultimately accusing Imanishi-Kari of fabricating data in a cover-up. Baltimore, however, refused to retract the paper.

O'Toole soon dropped her challenge, but the NIH, which had funded the contested paper's research, began investigating, at the insistence of Walter W. Stewart, a self-appointed fraud buster, and Ned Feder, his lab head at the NIH.[64] Representative John Dingell (D-MI) also aggressively pursued it, eventually calling in U.S. Secret Service (USSS; U.S. Treasury) document examiners.[65]

Around October 1989, when Baltimore was appointed president of Rockefeller University, around a third of the faculty opposed his appointment because of concerns about his behaviour in the Imanishi-Kari case. He visited every laboratory, one by one, to hear those concerns directly from each group of researchers.[64]

In a draft report dated March 14, 1991 and based mainly on USSS forensics findings, NIH's fraud unit, then called the Office of Scientific Integrity (OSI), accused Imanishi-Kari of falsifying and fabricating data. It also criticized Baltimore for failing to embrace O'Toole's challenge. Less than a week later, the report was leaked to the press.[66] Baltimore and three co-authors then retracted the paper; Imanishi-Kari and Moema H. Reis did not sign the retraction.[67] In the report, Baltimore admitted that he was "too willing to accept" Imanishi-Kari's explanations, and felt he "did too little to seek an independent verification of her data and conclusions."[68] Baltimore publicly apologized for not taking a whistle-blower's charge seriously.[69]

Amid concerns raised by negative publicity in connection with the scandal, Baltimore resigned as president of Rockefeller University[70] and rejoined the MIT Biology faculty.[71]

In July 1992, the US Attorney for the District of Maryland, who had been investigating the case, announced he would bring neither criminal nor civil charges against Imanishi-Kari.[72][73] In October 1994, however, OSI's successor, the Office of Research Integrity (ORI; HHS) found Imanishi-Kari guilty on 19 counts of research misconduct, basing its conclusions largely on Secret Service analysis of laboratory notebooks.

An HHS appeals panel began meeting in June 1995 to review all charges in detail. In June 1996, the panel ruled that the ORI had failed to prove even one of its 19 charges. After throwing out much of the documentary evidence gathered by the ORI, the panel dismissed all charges against Imanishi-Kari. As their final report stated, the HHS panel "found that much of what ORI presented was irrelevant, had limited probative value, was internally inconsistent, lacked reliability or foundation, was not credible or not corroborated, or was based on unwarranted assumptions." It did conclude that "The Cell paper as a whole is rife with errors of all sorts ... [including] some which, despite all these years and layers of review, have never previously been pointed out or corrected. Responsibility ... must be shared by all participants." Neither OSI nor ORI ever accused Baltimore of research misconduct.[74][75] The reputations of Stewart and Feder, who had pushed for the investigation, were very damaged.[75]

Baltimore has been both defended and criticized for his actions in this matter.[76][77][78][79][80][81][82] In 1993, Yale University mathematician Serge Lang strongly criticized Baltimore's behavior.[83] Historian of science Daniel Kevles, writing after the exoneration of Imanishi-Kari, recounted the affair in his 1998 book, The Baltimore Case.[84][85] Horace Freeland Judson also gives a critical assessment of Baltimore's actions in The Great Betrayal: Fraud In Science.[86] Baltimore has also written his own analysis.[87]

In October 2005, Baltimore resigned the office of the president of Caltech,[43] saying, "This is not a decision that I have made easily, but I am convinced that the interests of the Institute will be best served by a presidential transition at this particular time in its history..."[88] Soon after, at Baltimore's request, Caltech began investigating the work Luk van Parijs had conducted while a postdoc in Baltimore's laboratory.[89] Van Parijs first came under suspicion at MIT, for work done after he had left Baltimore's lab. After van Parijs had been fired by MIT, his doctoral supervisor also noted problems with work van Parijs did at the Brigham and Women's Hospital, before leaving Harvard to go to Baltimore's lab.[90] The Caltech investigation concluded in March 2007. It found van Parijs alone committed research misconduct, and that four papers co-authored by Baltimore, van Parijs, and others required correction.[91]

• Warren Alpert Foundation Prize (2000)
• National Medal of Science (1999)
• Golden Plate Award of the American Academy of Achievement (1986)[92]
• EMBO Member (1983)[1]
• Nobel Prize in Physiology or Medicine (1975)
• Fellow of the American Academy of Arts and Sciences (1974)
• NAS Award in Molecular Biology (1974)
• Canada Gairdner International Award (1974)[93]
• Gustav Stern Award in Virology (1971)
• Warren Triennial Prize (1971)
• Eli Lilly Award in Immunology and Microbiology (1971)