2018 Nobel prize in chemistry

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2018 Nobel prize in chemistry

Post by Petter » Thu Oct 04, 2018 7:45 pm

Congratulations to Frances H. Arnold for her Nobel prize in chemistry!

Arnold developed a method for using directed evolution to modify enzymes for our needs. The procedure is very similar to the solution to challenge "Breeding II" so I will describe in some details what she and did in her seminal work (she has since repeated this for other enzymes and environmental challenges). I describe this while making parallels to what we do in "Breeding II", which I find a pretty close analogy.

They used bacteria that produce the enzyme subtilisin. This enzyme is a protease, the type of enzyme our cell lab secrocyte can secrete to break bonds between cells. Generally proteases break down proteins and specifically this subtilisin breaks down casein. These bacteria live in environments with mostly water and also the enzyme works in environments with mostly water. They wanted to make the enzyme work in an unnatural environment with a high concentration of the solvent DMF where the original, "wild" type, subtilisin doesn't work.

They started with a population of these bacteria where they had copied and inserted the gene coding for subtilisin using a method that introduces a lot of errors - mutations.
In the cell lab analogy this corresponds to the collection of green photocytes we start with. In the "Breeding II" challenge hint we mention that there is a "mutagen present on this substrate" - this corresponds to the mutations they introduce through the error prone copying. Note that their method is more efficient in this way, we introduce mutations all over the genome. For us that is not a big issue since the cell lab cells are quite robust-but i can imagine that introducing a useful amount of mutations in the subtilisin gene might kill all cells if that amount of mutations are also introduce throughout the genome.

Next they observe the cells in a solution of water and casein. Some cells still produced functional subtilisin and this starts to break down casein in the cells' surroundings. This showed up as a visible halo. They then took some of this subtilisin and moved to a solution containing some DMF and casein and they could see if it still produced a halo meaning it could break down some casein in the DMF environment. Note that the cells themselves were not in a DMF solution (I think the Frances Arnold wikipedia page is inaccurate in this regard).

In the cell lab analogy this corresponds to how after some mutations we look for cells that are closer to red one, our goal is a completely red cell. Once we have found a slightly redish cell we are however not finished, we want completely red cells. And similarly Arnold and coauthor Keqin Chen were not finished, they wanted subtilisin that worked faster and in even higher DMF concentrations.

They then went back to the cells producing the most potent subtilisin, the ones with the largest halo in the DMF solution. They once again copied the gene with some errors and introduced it in bacteria.

This corresponds to how we remove the less red cells and help our most redish cell reproduce. Mutations are added automatically from the mutagen on the substrate (also called radiation elsewhere in the game).

Then they repeated the steps, checking for halos around the cells, moving the subtilisin to a DMF solution, and noting what cells' subtilisin now produced the largest halos. In doing this they found mutated versions of subtilisin working even better in the DMF solution. Just like we have to rinse and repeat several times in the "Breeding II" challenge, they repeated this cycle four times. While doing this they kept increasing the DMF concentration. Starting with the highest concentration of DMF wouldn't work since so little casein is broken down that the halos can not be compared.

In the end they made using directed evolution cells that create subtilisin able to break down casein 256 times faster than the wild type in a DMF solution.
We on the other hand, using directed evolution, made a completely red cell.

Proposal of this method (1991): http://sci-hub.tw/https://www.nature.co ... t1191-1073
Presentation of the working method (1993): http://www.pnas.org/content/pnas/90/12/5618.full.pdf

Also congratulations to George P. Smith and Gregory P. Winter who share the other half of this year's prize for developing a technique called phage display.

Please let me know if I got something wrong.
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Re: 2018 Nobel prize in chemistry

Post by Wilcz » Wed Nov 07, 2018 1:57 pm

That's pretty smart and amazing how we can do similar things in this game.
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