David Baltimore

Dr. David Baltimore’s (DB) (b. 1938- ) career has spanned nearly four decades and rightly distinguished him as one of the preeminent biologists of his generation. He was awarded the Nobel Prize in 1975 at the remarkable age of 37 (1), and since then has been a leading force in molecular biology, virology, immunology (2), and science policy (3). His later work on viral oncology and immunology has led to speculation that another Nobel Prize is in his future (4). Dr. Baltimore has over 600 peer-reviewed papers to his credit, is a member of the National Academy of Sciences, recipient of the National Medal of Science (1999), and is currently President of the California Institute of Technology (5).

DB’s early scientific research focused on the molecular processes that underlay the ability of poliovirus to infect cells (5). This naturally led him to work on other RNA viruses. He was particularly interested how RNA viruses caused cancer. In 1969, DB and Howard Temin published the discovery of retroviruses and reverse transcriptase (9). They would later share the Nobel Prize (along with Renato Dulbecco for related research) for their work (7).

Retroviruses are RNA animal viruses that replicate through a DNA intermediate (7). They were the first viruses shown to cause cancer, and include the well known virus HIV, as well as avian leucosis, murine leukemia, chimpanzee foamy virus, as well as many others. The genome of a mature virus contains only three genes that encode proteins. Gag (group-specific antigen) codes for core and structural proteins. Pol (polymerase) codes for reverse transcriptase, protease, and integrase. Env (envelope) codes for the retroviral coat (7). A shared feature of all retroviruses is a lipid coating that surrounds their capsid. It should be noted that the reverse transcription that copies the RNA back into DNA is not unique to retroviruses. Hepatitis B and cauliflower mosaic virus (in plants) also utilize reverse transcriptase.

There are seven steps in retrovirus replication:

1) Entrance

2) Uncoating of the virion

3) Reverse transcription

4) Integration

5) Transcription

6) Assembly and encapsidation

7) Budding (7)

By elucidating the role of reverse transcription, Baltimore not only made major advances in scientists ability to understand (and combat) retroviruses, but added a new addendum to the Central Dogma of molecular biology. First articulated by Francis Crick (no slouch himself) in 1958, the statement is as follows: DNA makes RNA makes protein (8). A common misconception is that the discovery of reverse transcriptase invalidates the Central Dogma. However, the idea is that once information reaches the protein state it cannot go in reverse (i.e. back to RNA or DNA). In this sense the Central Dogma remains, but it is true that through reverse transcriptase, retroviruses can go from RNA to DNA, back to RNA, and then on to a protein. Or, in some cases, can go from RNA to protein (7).

In addition to his contributions to understanding retroviruses, DB developed the Baltimore Classification Scheme for viruses, based on the relationship of the viral genome to its mRNA (7). It is listed as follows:

Class I – double-stranded DNA genome

Class II – single-stranded DNA genome

Class III – double-stranded RNA genome

Class IV – single-stranded RNA genome of plus sense

Class V – single-stranded RNA genome of minus sense

Class VI – single-stranded RNA genome of plus sense that replicates with a DNA intermediate

Class VII – double-stranded DNA genome that replicates with a RNA intermediate

The above classification is very effective and covers most viral possibilities, however, there are exceptions. An example is the ambiviruses, which contain a single-stranded RNA genome, half of which is plus, the other half minus (7).

In 1974, DB was one of a group of scientists who published a letter urging caution with regards to recombinant DNA (10). In the letter, they recommended that scientists defer from creating microorganisms with novel genes, and also from inserting cancer causing genes from viruses into bacterial cells. They called on the U.S. government to set up rules of conduct for this type of research and attempted to organize scientists to discuss the issue. This latter suggestion eventually resulted in the Asilomar Conference, where the participants recommended a one year moratorium on genetic engineering (11).

Although DB’s career as a biologist is quite distinguished, it is not free of controversy. A colleague and co-author of a paper that had been published in the journal Cell was accused of scientific misconduct. Although Dr. Baltimore was never implicated, his handling of the matter was seen by many as arrogant to the extreme, and eventually cost him the position of President of Rockefeller University (12). Baltimore had been unwilling to retract the paper; he was content to let the scientific community determine if there were any flaws to be criticized. DB firmly believed that the self-correcting nature of science would determine the truth of the matter.

Many scientists disagreed, in particular, Paul Doty of Harvard University. He and DB exchanged several tense letters in the journal Nature of the ethics of science (12). A rumor circulated that several Harvard professors, including James Watson, were attempting to convince the Noble Committee to strip DB of his prize. Watson firmly denied this (13), and it is probably untrue. After two university investigations, two NIH investigations, and Congressional hearings, it was determined there had been no wrong doing, but the taint of the affair persisted for many years.

Dr. David Baltimore is still an active scientist, a vigorous proponent of improved federal science policy, AIDS vaccine research, and head of a major university.

References

1. Vella, F. 2002. Ahead of the Curve: David Baltimore’s Life in Science. Biochemistry and Molecular Biology Education 30(5): 336-337.

2. Klausner, R.D., Fauci, A.S., et al. 2003. The Need for a Global HIV Vaccine Enterprise. Science 300: 2036-2039.

3. Baltimore, D. 2004. Science and the Bush Administration. Science 305:1873.

4. Roizman, B. 2002. Ahead of the Curve: David Baltimore’s Life in Science. Perspectives in Biology and Medicine 45(2): 294-296.

5. California Institute of Technology. 2002. Dr. David Baltimore. http://president.caltech.edu/bio.html. Retrieved on: 8 June 2005.

6. Culliton, B. 2003. Book Reviews. Bull. Hist. Med. 77: 474-475.

7. Madigan, M.T. and J.M. Martinko. 2006. Brock Biology of Microorganisms, 11^th Ed. Pearson Prentice Hall, Upper Saddle River,NJ.

8. Crick, F. 1958. Central Dogma of Molecular Biology. Nature 227: 561- 563.

9. Baltimore, D. 1970. Viral RNA-dependent DNA polymerase. Nature 226: 1209-1211.

10. Berg, P., et. al. 1974. Potential biohazards of recombinant DNA. Science 185: 303.

11. Wade, N. 1975. Genetics: Conference Sets Strict Rules to Replace Moratorium. Science 187: 931.

12. Hall, S.S. 1991. David Baltimore’s Final Days. Science 254: 1576-1579.

13. Watson, J.D. 2001. No campaign to strip Baltimore of his Nobel. Nature 411: 131-132.