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Caltech
Evolution is a powerful creative force: just look at the life around you to find evidence. And humanity has exploited this creative process to produce an extraordinary variety of animals and domestic crops. But this has been a long-term project, involving many generations and the many years they occupy.
This year, the Nobel Prize in Chemistry is awarded to three researchers who have discovered how to obtain effective evolutionary processes for us at the level of individual molecules and accelerate them to the point that results are available in a matter of weeks or months rather than in the future. years. The results include proteins that catalyze the formation of chemical bonds that life has never created and antibodies that can bind to any molecule of our choice. These results have already found their place in industrial production and medical treatment.
Catalysts
Half the price goes to Frances Arnold of Caltech for the development of the directed evolution of enzymes. The goal of directed evolution is to create an enzyme, or a catalyst, that achieves a chemical reaction of our choice, even if this reaction is totally useless for the organism in which the enzyme evolves. Arnold has developed a process that, in retrospect, seems obvious not always done before his work.
This starts with choosing the appropriate enzyme to use as a scalable raw material. Arnold recognized that even in cases where the reaction was not caused by any known living being, there were often related reactions catalyzed by known enzymes. In many cases, these enzymes may have a tiny catalytic activity that we want, providing the starting point for evolution.
From there, you have to make random modifications to the DNA encoding the enzyme in order to improve the functions. Arnold's laboratory has developed two methods for this. One was to make them really random, which was accomplished by copying DNA using an error-prone enzyme (its ability to recognize when it was using the wrong base was removed). Another solution was to focus the random mutations where they were most likely to have an effect – on the active site that binds to the chemicals and catalyzes the reactions. Another research group has developed a third one: mixing and sorting parts of several related enzymes belonging to different species.
These approaches provide the variations on which evolution can work. But the key to evolution is the selection: find these few examples in an ocean of variations that do what you want. To demonstrate his approach, Arnold chose a simple goal: to digest a colored protein. As a result, any bacteria carrying a variant of the enzyme that digests the protein would be surrounded by a clear and colorless halo. These bacteria can then be selected as the starting material for another cycle of evolution, with additional random modifications introduced, followed by another round of selection.
Arnold has shown that this could bring a variety of changes. During repeated cycles of selection, enzymes capable of operating at higher or lower temperatures were developed. In one case, both and low temperatures. By gradually increasing the concentrations of a powerful industrial solvent over several generations, another enzyme has been developed, which could still work in a mixture with 60% solvent and 40% water. Another enzyme has been generated that could form carbon-silicon bonds, something that has not been seen in any living organism.
Thanks to Arnold's pioneering work, other researchers have figured out how to perform the process without resorting to bacteria, accelerating it even more. And if the process still requires people to come up with a smart system to select the catalytic activity that they want, this has not proven to be a major hurdle. The artificially implicated enzymes are now used to produce biofuels, detergents, chemicals and pharmaceuticals. In some cases, entire pathways of advanced enzymes have been assembled to pass from a simple starting material to a useful end product in several chemical steps.
Selection and display
George Smith of the University of Missouri, Colombia, shares the other half of the award for explaining how to perform a related type of evolutionary selection. His technique is called "phage display" and relies on viruses (called phages) that infect bacteria. It is one of the biggest challenges in Arnold's approach: many of the proteins we would like to work with are stored inside the bacteria in which we make them. The chemicals we want to interact with are, however, kept outside of the bacteria.
The presentation of phages overcomes this problem by ensuring that the protein and the genetic material that codes for it are shipped outside the cell and stored together in the same virus. The main advance in this area has been to identify a protein normally embedded in the layer that covers the virus and to find a spot capable of tolerating large scale changes. The point is essentially a loop on the surface of the protein, and you can greatly enlarge the loop without interfering with the virus. Smith realized that this allowed researchers to insert just about any protein of their choice into that part of the gene, and that the protein would be displayed on the surface of the virus that was coded.
Smith then created a phage presentation variant called "biopanning", named after the pans that prospectors would use to separate the rare gold pieces from an extensive collection of pebbles. In biopanning, large groups of phages are made of different inserted proteins, then passed on a material containing a molecule that interests you. Any phage with a protein that adheres to your molecule will be retained and can be used to infect new cells. After several passages of this selection (with or without mutation), the phages obtained will all code for proteins having a high affinity for the molecule of your choice.
This can be useful for a variety of things, from research to the production of useful proteins. But medicine has found much use in using human antibodies to bind to specific proteins because the immune system considers these antibodies to be normal proteins and not foreign proteins to attack. Gregory Winter shares this half price for explaining how to change phage display to work with antibodies.
The antibodies are actually large complexes of four molecules, two light proteins and two heavy proteins. The part that binds to a foreign material lies at the interface between a light protein and a heavy protein, which makes the work difficult because the key element of most antibodies – their specific targeting – is usually divided into two proteins. Smith figured out how to take key parts of genes from these regions, combine them into a single gene, and then insert them into a phage protein. The resulting hybrid gene would ensure that the key portions of the antibody are exposed to the outside of the phage, available for the types of selection developed by Winter.
Isolating useful antibodies usually involved working with mice and multiple cycles of immunization over the course of months, followed by numerous immune cell cultures of mice. Now, an equivalent process could be done in a week using the phage display. Once isolated, key portions of the modified gene could be cut and spliced to form a normal human antibody gene, thus forming the entire complex used by the immune system.
Naturally, the drug quickly recognized the potential for producing antibodies that could bind to any molecule it wanted to target. (Monday, Medicine Nobel, provided some excellent examples of these useful targets.) The first antibody-based drug developed with the help of this technique came on the market in 2002 and was joined by others since.
By reading all of the above on evolution, bacteria and viruses, you may wonder how this work could have been attributed to chemistry. It is therefore useful to take a step back and think about what is really accomplished thanks to the techniques developed by the winners. If you did not use the evolution to do so, the design of a chemical that could bind to an arbitrary molecule of your choice would usually end up being called "materials science". And if you offered a chemist the opportunity to develop a catalyst for one of the many chemical reactions – a reaction that would work at the temperature and with the solvent of his choice – you would make this chemist extremely happy.
All this is resolutely chemistry. It's just that evolution has solved a lot of chemistry problems well before us.
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