Chemistry Nobel for “directed evolution” (2018)

  1. Very nice. Congratulations! But where is the “directed evolution” oxymoron in this story? The process used is simple organism breeding as done by mankind for thousands of years, in this case sped up by advanced technologies. “Random mutations” are not entirely random as the mutations desired had to converge towards a clear, specified target. Random generator devices also generate within specific ranges, say 0 to 9, rejecting outright any “randomness” outside that range (‘a’, ‘#’, ‘21’ will all be rejected). “Natural selection” is also missing as the selection has been clearly done by qualified researches pursuing a specific goal. At best this would be called “artificial selection”, but even that is misleading since organism breeding is a human activity that goes well beyond simple ‘selection’.
  2. The researchers induced mutations in proteins and selected those that best met the goals of the research. The winners were Frances Arnold of the California Institute of Technology, George Smith of the University of Missouri and Gregory Winter of the MRC molecular biology lab in Cambridge, England.
  3. Smith showed in 1985 that inserting DNA into these viruses would make them display proteins linked to that DNA on their surfaces. It was a way to find an unknown gene for a known protein. Winter adapted the approach to create useful antibodies, proteins that target and grab onto disease-related targets. Winter introduced mutations to make antibodies progressively better at binding to their targets. In 1994, for example, he developed antibodies that grab onto cancer cells.
  4. Arnold was seeking ways to make improved enzymes, which are proteins that encourage chemical reactions to occur. In 1993, she showed the power of “directed evolution” for doing that. First she created random mutations in DNA that lets cells produce an enzyme. Then she slipped these mutated genes into bacteria, which pumped out thousands of different variants of the enzyme. One variant did a particularly good job at a certain task, so she made a new round of mutations in this variant. That produced another variant that worked better. When she made mutant versions of that variant, she got an even better version. It contained a combination of 10 mutations that nobody could have predicted would work so well, the Swedish academy said.
  5. This process also resembles a mechanism of the immune system: though antibodies are very similar, a small region at the tip of the protein (hypervariable region) is extremely variable, allowing millions of antibodies with slightly different tip structures, or antigen-binding sites, to exist. The large and diverse population of antibody paratope (antigen-binding sites) is generated by random recombination events of a set of gene segments, followed by random mutations in this area of the antibody gene, which create further diversity (VDJ or VJ recombination). During antibody production, one allele of V, one of D, and one of J is chosen and joined together using random genetic recombination to produce the paratope.
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