Directed Evolution Wins Nobel Prize

From left to right: Dr. Frances Arnold, Sir Gregory Winter, Dr. George Smith
(Credits:Beavercheme2, Aga Machaj, Univ. Missouri-Columbia)

Yesterday, the Royal Swedish Academy of Sciences announced that the Nobel Prize in chemistry will be shared among three scientists who all used directed evolution to engineer proteins that solve problems. A reader who saw a news story about the announcement asked me to explain what “directed evolution” means, and I am happy to oblige. In directed evolution, scientists use the concepts of variation and selection to take a molecule that already exists in nature and adapt it to do something that they want it to do. Using a concrete example that comes from the research of Dr. Frances Arnold (one of the recipients) is probably the best way to explain the process.

Dr. Arnold’s lab started with a naturally-occurring enzyme charmingly named P450 BM3. Enzymes speed up specific chemical reactions, and P450 BM3 speeds up the reaction in which an oxygen atom is inserted between a carbon atom and a hydrogen atom in a fatty acid molecule. This is an important step in the process by which a living organism breaks down fatty acid molecules. Dr. Arnold’s lab was interested in doing the same kind of reaction, but on a different type of organic molecule: a small alkane. The enzyme P450 BM3 couldn’t initially do that. However, it could weakly speed up that reaction on large alkanes.

Since the enzyme could at least do that, Dr. Arnold thought that she could “tweak” it until it did exactly what she wanted it to do. However, enzymes are absurdly complicated molecules, and human science isn’t very good at making or understanding them. So she decided to let better organic chemists (bacteria) do the heavy lifting. Her lab took the gene that tells bacteria how to make P450 BM3 and subjected it to mutations. They then saw whether or not the resulting enzyme made by bacteria was any closer to being able to do what they wanted it to do. Maybe it did a better job speeding up the reaction on a large alkane, or maybe it was able to speed up the reaction on a shorter alkane. If that was the case, they saved that gene and allowed it to mutate more, seeing if any more progress could be made. If not, they threw it away and tried again.

This is why the process is called “directed evolution.” Dr. Arnold’s lab induced mutations (which are a source of genetic change in organisms) and then selected any enzyme that ended up being better at what they wanted it to do. With enough of those steps, they were able to get what they wanted: an enzyme that inserted an oxygen atom between a carbon atom and a hydrogen atom in a small alkane. In the end, the process had changed just over 2% of the molecule, but that was enough to change it from an enzyme that acted on fatty acids to one that acted on small alkanes.

Why go through this process? Why not just look at the molecule, decide what needs to be changed, and then change it? Because that’s beyond the reach of our technology and understanding. We just don’t understand chemistry well enough to decide what changes would have to be made and then do them. However, we can make random changes using mutations, and then use bacteria to build the mutant enzymes. We can then see how the mutant enzymes behave and either keep them or throw them away, depending on how they function.

To me, what’s really interesting about this result is that the change produced is incredibly limited. It’s not that the lab starts with an enzyme that speeds up one kind of reaction and produces an enzyme that speeds up a completely different reaction. The lab doesn’t even start with an enzyme that speeds up the same kind of reaction on a different type of molecule. They start with an enzyme that already does what they want it to do, just on a larger version of the molecule and not very well. They then tweak it to do the job better and on smaller versions of the molecule.

No don’t get me wrong. I am not saying this isn’t a great accomplishment. It most certainly is! However, I do think it helps to demonstrate something that creationists have been saying for a long, long time. Yes, evolution can produce change. However, that change is severely limited. Through the process of evolution, I can “tweak” an enzyme to be better at a job it doesn’t do very well. In addition, I can slightly alter the kinds of molecules it will act on. However, I can’t start with one enzyme and then produce an enzyme that does a completely different job. That’s beyond the scope of laboratory-based directed evolution.

Can natural evolution do what directed evolution cannot? I doubt it. Consider what Dr. Arnold points out:

Clearly, natural proteins are subject to additional constraints not present in most laboratory experiments, because they must function in vivo while minimizing deleterious interactions with other cellular components or pathways. In addition, laboratory evolution experiments usually impose a very strong selection for the target protein property, such that mutations that benefit the target property may be selected even to the detriment of other properties.

So while directed evolution is free to mutate things like crazy, natural evolution operates under a lot more constraints. To me, that means natural evolution is even more limited than directed evolution.

9 Comments

  1. Paul says:

    Thanks. I heard (yesterday) the Prize was related to directed evolution and wanted more information. I expected something from you.

  2. Erik T says:

    Do you think a process like this could be used to create new drugs?

    1. Jay Wile says:

      Yes. The other two winners are doing directed evolution in a slightly different way, and they are making drugs.

  3. John D says:

    Do you think it will ever be possibke to produce an organ using directed evolution?

    1. Jay Wile says:

      I am not sure what you mean. Directed evolution requires variation and selection. How can that be done on an organ?

      1. John D says:

        I mean taking this to the next level and coaching the prodcution of an organ where none existed before… or where a partial “step” exists.

        For instance, Dawkins always talks about the eye developing from a light sensitive cup. Could you see directed evolution in the lab producing something like an insect eye starting with the light sensitive cup on a flatworm?

        1. Jay Wile says:

          I don’t see how. There is a HUGE step from chemicals to cells. Then there’s the big step from cells to tissues, and then there’s the step from tissues to an organ.

  4. Nicolás Vera says:

    So basically they have done enzyme optimization through artificial selection.

    1. Jay Wile says:

      That is correct.

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