Marshall Nirenberg and the Genetic Code

My friend and colleague Franklin Portugal has written a  biography of Marshall Nirenberg, entitled “The Least Likely Man: Marshall Nirenberg and the Discovery of the Genetic Code,” (MIT Press, 2015).   Nirenberg won the Nobel Prize for Physiology and Medicine in 1968 for solving the genetic code.   Frank worked in Marshall’s lab during that time, from 1967-70, and remained friends with him, and so he is an ideal biographer.  Marshall died in 2010 and his family gave Frank access to his private “lab diaries” that shed light on the specifics of his work and thinking.

After the discovery of the structure of the genetic substance DNA by Watson and Crick in 1953 (see “A Century of DNA” by Portugal and Cohen, MIT Press, 1977), scientists still faced seemingly insuperable problems.  The most important of these was how the information encoded in the linear sequence of chemical bases (A, G, C, T) in the DNA molecule was translated into the linear sequence of amino acids in proteins that were produced in the cell by genetic expression?

Watson, Crick and their colleagues formed an exclusive club, “The RNA Tie Club” with only 20 members, who among themselves set out to solve this problem.  The name of the club implied that they thought that RNA, another nucleic acid like DNA but with a different sugar component and a different structure, was intimately involved in the process of genetic expression from DNA to protein.  However, their mainly theoretical approaches did not succeed.

A completely unknown and in fact obscure scientist, Marshall Nirenberg, working at the National Institutes of Health (NIH), did in fact solve the problem and elucidated the genetic code, with his assistant Heinrich Matthaei, using mainly experimental approaches including a “cell free system,” which they published first in 1961.  A cell free system is a mixture of all the required components from the cell that is used to test the expression of synthetic RNA’s into proteins (or polypeptides).

 Nirenberg was born in New York City in 1927, but grew up in Orlando, Florida, where his father purchased and ran a dairy farm.  He did his PhD at the University of Michigan and moved to NIH in 1957.   He would certainly have never been considered a rival by the then great names of Molecular Biology.  But his name is still little known compared to Watson and Crick, yet the elucidation of the genetic code was one of the greatest and most important discoveries in history.

Since there are 4 bases in DNA and there are 20 common amino acids (aa’s) in proteins, the code could obviously not be one base per aa, neither could it be 2 bases per aa since there are only 16 binary combinations.  Most people assumed that the code consisted of three bases per aa (allowing 64 possibilities), but it was Nirenberg using his cell free system who proved the three-base codon.

Questions arise, why was Marshall Nirenberg unknown, how did he manage to overcome his isolation and solve the most significant problem then facing molecular biology, and why has his name been largely forgotten?  Partly it was because he was very reserved and not self-promoting, partly because he changed his area of research to neurobiology after solving the code and partly because he accepted his Nobel Prize with humility.

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