by PhilipJ on 5 March 2006
You can think of a gene as a section of DNA, made up of a sequence of nucleotides — the familiar adenine, thymine, guanine, and cytosine (A, T, G, and C, respectively). In the central dogma of molecular biology, this sequence gets transcribed by RNA polymerases into RNA (where the nucleotide uracil, U, takes the place of thymine), which is then translated by the ribosome into a particular protein, itself made up of amino acids. It turns out that to get from the four-letter alphabet of bases to the 20-letter alphabet of amino acids, sets of three bases form codons, each of which specify either a particular amino acid (for example, the nucleotide sequence AGG codes for the amino acid argenine) or for the ribosome to start or stop translating.
(don’t worry about introns and exons — perhaps we’ll go over those in another post)
DNA, however, is not an invincible molecule. There are a variety of ways in which it can become damaged, leading to mutations, additions, or deletions in the sequence of bases. This, in turn, leads to a mutation in the amino acid sequence of the protein encoded by the gene, and even a single amino acid substitution can ruin a protein in terms of folding or function. A misfolded or otherwise unfunctioning protein can be fatal, or lead to visible changes in the host organism.
Intragenic suppression (finally getting to the point!) is an interesting phenomenon where, after a single mutation knocks a particular gene out, a second mutation in the same gene restores the gene’s proper function. This can happen in a variety of ways, for example, disruption of protein structure that is “fixed” upon a second mutation, or frameshift mutations which disrupt the reading frame of the ribosome. Here’s an example of a single frameshift mutation (taken from here), wild-type DNA which codes for specific amino acids is shown below:
If there is an insertion of a single guanine nucleotide (shown in red), the entire sequence after that insertion, now shifted to the right by a single base, codes for drastically different amino acids and even a premature stop (also shown in red):
An intragenic suppression would then be a second mutation in that same gene which would either restore the sequence to its original form, or change the sequence again in such a way that the gene is able to once again function in some fashion. At the time of intragenic suppression’s discovery (the early 60s), the mechanism for reading the genetic code was still unknown, but Francis Crick at Cambridge correctly surmised that a single mutation added or deleted a unit of DNA which put the entire message out of phase, and a second mutation of the opposite type was able to put the message back in phase, turning the gene on again. This led his team to conclude that the genetic code was read in a linear fashion from beginning to end, which we now know to be largely true. By the mid 60s, Crick declared, “The story of the genetic code is now essentially complete.”
So, where does Richard P. Feynman, QED wizard, bongo player, half-genius, half-buffoon that he was, fit into this story? He very nearly discovered it all.*
Convinced by Max Delbruck, himself a physicist-turned-genetics professor at Caltech, Feynman took a sabbatical year to study genetics in Delbruck’s lab (joking that it was time to do some “real work” now). Delbruck’s lab studied the genetics of the bacteriophage T4, another virus which attacks E. coli. A particular mutation of the T4 virus called rII enabled it to infect E. coli strain B — but not its normal host of strain K. By infecting strain K with the T4 mutant, normally no copies of the virus would be found. If any were, some backmutation must have occured to revert the virus to its original form — a rare event. If such a mutation did occur, it was possible to collect the virii and re-infect some strain B to see what happened.
Feynman found that odd-looking plaques appeared. These “idiot r’s” weren’t growing as they should, and Feynman’s guesses as to what was happening at the DNA level were that either another mutation had occurred at the rII site, or a second mutation occurred elsewhere on the DNA which partially counteracted the original rII mutation. Through a lot of hard work, Feynman was able to show that it had to be the latter — two mutations were working against each other in a kind of self-suppression, and that the second mutation was another of the same rII type. While persuaded to write up this finding (colleagues in the Delbruck lab called the mutually supressing mutations “Feyntrons”), he never did. It was discovered independently elsewhere, and became known as intragenic suppression.
Andre and I are in good company — Richard P. Feynman was Biocurious.
* Most of the Feynman details are from James Gleick’s Feynman biography, Genius.