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Synthetic Biology versus Total Synthesis

From a series of paintings by David Cordes at Pacific University, Oregon.

I think most would agree that synthetic chemists can now make just about any non-protein/non-polysaccharide natural product if enough time, resources and manpower are brought to bear.[1] But that's not to say that the field is yet mature, or stagnating, as there still remain so many challenges to make our science more efficient, practical, and free from its current over-dependence on rare metals and petrochemical feedstocks. Recently, synthetic biology has started to emerge as a serious alternative to total synthesis when large amounts of complex natural products are required. Just think how many total synthesis papers start with a desultory line about 'the dearth of natural material', before recounting an arduous one- or two-yearlong quest to make a few more milligrams of the compound in question. Perhaps it sometimes makes more sense to try a different approach and ask 'can't we just improve the natural source?'. We synthetic chemists like to think we're special because we have the ability to make new compounds never seen in Nature, but with an increasing understanding of enzymes and the genes that encode for them, organisms can now be coaxed into producing compounds that have never been seen before. If you're interested in reading further debate over the future of the two fields then you should definitely read this short piece in Nature, in which champions of synthetic chemistry Phil Baran and Abraham Mendoza duke it out with Jay D. Keasling, a strong proponent of synthetic biology.

Reaction Vessels

From Nature, 492, 188.


1.  Of course, there still exists the question of 'should we?'. Aside from the importance of total synthesis in structural determination, and ignoring for the moment the oft quoted reason of solving supply problems, the other main justification offered by the practitioners of the art is the development of new methodology. I'd love to find a way to test this claim, but my feeling is that few generally useful reactions are discovered in long synthetic campaigns. Let me know in the comments if I'm wrong about this.

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  1. It’s adorable how Baran defends total synthesis by lumping it in with materials chemistry synthesis…

    Also: it’s easy to oversell synthetic biology. See for instance polyketide synthesis. It was thought that understanding polyketide synthases (PKSs) would be the key to combinatorial biosynthesis. That hasn’t played out quite so nicely, despite people like Khosla developing a pretty thorough understanding of the mechanistic workings of their gigantic, modular enzyme complexes. They’re not as malleable as we thought.

    Still, Taxol. Semisynthesis beat out a generation of testosterone-driven total synth guys.

    • Yeah, synthetic biology is still quite limited, but it’s very early days; the field is what? a decade or two old at the very most. What were organic chemists making back in the 19th century? or the 1940s or 50s, for that matter? I’m inclined to agree with Big Phil and say that biology’s the place to go for natural products (especially if you want grams), but it’s still very limited in what you can make. It’s also very time consuming to re-engineer organisms – I can’t imagine that compound libraries will be made by synthetic biologists for some time. I think for the foreseeable the best routes to natural product-based drugs will probably make use of both fields in semisyntheses like those of Taxol and artemisinin.

      Until we can make our own enzymes, synthetic biology won’t ever match the freedom of target choice that total synthesis has. I think it’s good for very efficient solutions to very specific problems.

      • Some of these biosynthetic enzymes aren’t fully specific, for example, accepting 2 or more different amino acids at a particular step. Many natural products are compound libraries containing a whole series of variants (i.e., milbemycins).

  2. I love how enzymatic reactions are *racemically pure*!
    Is there a better way to demonstrate you don’t really understand what you are talking about?

  3. Every tool has it’s strengths.

    Synthetic biology seems somewhat akin to process chemistry. It’s strengths lie in producing a single known compound cheaply and in large quantities. Total synthesis/medicinal chemistry is best when it explores chemical structures, making hundreds or thousands of closely related compounds. As time consuming as it is to make methyl/ethyl/butyl/futile analogues, that’s nothing compared to manipulating genes to do the same.

  4. ok, so I’m coming to this late… I’m a synthetic biologist with some training in synthetic chemistry, but mostly I do molecular biology, trained as a chemist in undergrad, and I had a lot of tot. syn friends in grad school.

    First: It is incredibly, incredibly embarassing how much “basic chemistry” biologists don’t understand. They really think they can just cut and paste genetic sequences and get a molecule out the end. Right now, I’m making modifications to an electron transfer enzyme (at the amino acid level) and I have discussions with my boss about midpoint potentials of iron-sulfur clusters and sometimes I get a blank face.

    Second: It’s also embarassing sometimes how little basic chemistry technique biologists know – in my last postdoc where I was doing a mutasynthesis of a natural product, I had to basically rewrite from scratch the isolation – the biologist postdoc before me was running silica gel chromatography columns packed 60 cm high, and wondering why his columns were such a pain in the butt – I was like, dude – you get diminishing returns and it’s almost never a good idea to run a column more than about 10-12 cm. Then when we took an NMR, we noticed twice the number of peaks, and he thought there was an impurity – I had to calm him down and explain that there was a diastereomeric mixture where the solvent methanol was reversibly attacking an electrophilic imine.

    I think in the end there are no good generalizations about the interplay between synthetic biology and synthetic chemistry. In some cases, synthetic chemistry will pilot the product at a small scale and enable validation and provide initial analytical standards. In some cases, chemistry (but probably not synthetic chemistry) will provide building blocks that are fed into a biological process to produce a variant of the molecule (mutasynthesis). In some cases, synthetic chemists will take a complex biological isolate and perform finishing reactions. And sometimes for stereochemical validation you just might need to build the molecule to be sure.

    In any case – we need to work together and appreciate the skillsets that both sides bring.

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