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> ...optimized factories... > Feed them sugar & water, and out pops specialty chemicals. Even if your culture contains microbes that produce the specialty che

> ...optimized factories... > Feed them sugar & water, and out pops specialty chemicals. Even if your culture contains microbes that produce the specialty chemical you're interested in, natural selection in the reactor favors the populations that use the least sugar and water and multiply the most. In other words, reactors are very good at growing microbes: surprise! They're quite bad at selecting for much else. Just doing what you described is called the Evolvenator. That discovery described how to build and test the microbe, but not necessarily how to design it. There's a fix: what if we make the interesting chemical a side effect of the kind of more efficient metabolism that's expressed by the highest-surviving population in your culture? In other words, the microbes that multiply the most make the interesting stuff by accident, usually as a consequence of the media in their reactor and a small tweak to their genetic code. It turns out that designing a chemical pathway that is metabolically superior to a natural one and as a side effect, produces an economically valuable product, is crazy hard. It is usually harder than designing an industrial process to manufacture the economically valuable product in the first place. That's why the article mentions that these other biotech firms "specialize" in making certain kinds of chemicals. In reality, they experiment with maybe two targets a year, and they land one that works out of 10. You'd be wrong to judge them on their hit rate: rather, I'm just pointing out how there isn't some kind of "optimization" magic to discover efficient chemical pathways. It's incredibly hard research! And I'm always surprised (though pretty delighted) that VC finds its way to these people, because VC avoids actual science projects like the plague. PS: The $13 million will buy things like the Sartorius bio reactor, a $1 million up front + $1-2 million a year machine capable of running automated experiments on yeast cultures in bioreactors. If you're in the business of making pickaxes instead of trying to strike gold, clearly you should make a better bioreactor. If you agree, just e-mail me.

Retric 10y ago
Why can't you just design organism / insert DNA to make X. Grow organism in 1,000 little reactors, measure output of X, keep top y% and repeat? Yield may drop over time, but this way evolution is somewhat on your side. PS: I don't expect that to work, but I am not sure what the issues are.
- kingjacob 10y ago
  Alot of companies do exactly that. Using systems like: http://www.tapbiosystems.com/ http://www.tapbiosystems.com/ But it's not cost effective when producing millions of liters.
  - doctorpangloss 10y ago
    TAP Biosystems is the manufacturer of what is now called the Sartorius. Also, if you look carefully at the Lygos website photos, you'll see the Sartorius.
- doctorpangloss 10y ago
  Let's say you had such an organism. Naturally, all the yeast individuals in your population have slight genetic variations. Maybe millions of them. Most have your plasmid to make X. Due to natural selection, the competing priority—let's call it the "Y" product—is reproducing * surviving as much as possible. The yeast genes that make the yeast reproduce as much as possible and survive as well as possible will eventually be the largest population in your reactor. So if X doesn't also achieve Y, the only thing that will be left in your reactor is a population that achieves Y. The worst thing (which is true most of the time) is that achieving X is opposed to Y. Processing some chemical in the media that doesn't translate to food for the organism is wasted metabolic resources. So for most applications you can think of, your X population will die or reproduce away its X genes. There's nothing you can parameterize to fix this! Like Y will happen regardless of what temperatures you use, or what media you use, or how much oxygen you give the reactor. By virtue of growing something, you're optimizing for Y. Either design X to also achieve Y, or fail. Evolution is opposed to you, not on your side! In practice today, we don't understand the biological systems design well enough to make X also achieve Y. So what happens is you grow the yeast until you have a population with maximum metabolic efficiency (i.e., maximally achieves Y), and THEN modify the yeast to do X. It dies quickly, and your left with a little bit of product. This works, but it's not viable.
  - CN7R 10y ago
    So from my understanding, bacteria is competing to reproduce the fastest, and the chemical that we want is simply a byproduct of its metabolism or pathway for reproduction issue is, however, the byproduct has to either be the most efficient factor for reproduction, or else by natural selection it will be removed my question is, can we use the same techniques found in tree grafting to prevent or delay natural selection, and grow our byproduct?
polyomino 10y ago
What if you added a lot of "error-checking" code that kills the host when it doesn't produce enough of the valuable chemical? I'd guess this is very difficult in practice. Or also add a competing organism that "triggers" when the concentration of byproduct is too low?
- 88e282102ae2e5b 10y ago
  For the first idea, you'd have to have some lethal protein or something that's specifically inhibited by the chemical of interest. Coming up with that might be even harder than the original problem. And even if you could, evolution wouldn't favor cells that produced it, since it confers no advantage. There's an energetic cost to making that protein. For the second idea, again, evolution ruins everything. The competing organism would do just that - compete.
- dnautics 10y ago
  Because "you get what you select for". Instead of getting more of the chemical, you'll get a host that has hacked and disabled your error checking code.
sjg007 10y ago
just another iteration of biofuel..
w1ntermute 10y ago
Here are two great articles on the challenges of biofuels: 1. The Rise And Fall Of The Company That Was Going To Have Us All Using Biofuels: https://www.fastcompany.com/3000040/rise-and-fall-company-was-going-have-us-all-using-biofuels https://www.fastcompany.com/3000040/rise-and-fall-company-wa... 2. A Biofuel Dream Gone Bad: http://fortune.com/kior-vinod-khosla-clean-tech/ http://fortune.com/kior-vinod-khosla-clean-tech/
pinot 10y ago
FWIW, in a past life, I bought (4) 2L Sartorius reactors used for $75k, built out my lab for <$50k and had an operating budget of $450k w/ 2 fully-burdened RAs. I agree with much else of what you've said. I worked in biosynthetics with some of the Lygos teammates at another company. All-in-all it's not a bad idea, but the development time is _so_ long, especially in yeasts. It's analgous to writing assembly w/o documentation, and debugging takes months per code-change.

Retric 10y ago

Why can't you just design organism / insert DNA to make X. Grow organism in 1,000 little reactors, measure output of X, keep top y% and repeat? Yield may drop over time, but this way evolution is somewhat on your side. PS: I don't expect that to work, but I am not sure what the issues are.

kingjacob 10y ago
Alot of companies do exactly that. Using systems like: http://www.tapbiosystems.com/ http://www.tapbiosystems.com/ But it's not cost effective when producing millions of liters.
- doctorpangloss 10y ago
  TAP Biosystems is the manufacturer of what is now called the Sartorius. Also, if you look carefully at the Lygos website photos, you'll see the Sartorius.
doctorpangloss 10y ago
Let's say you had such an organism. Naturally, all the yeast individuals in your population have slight genetic variations. Maybe millions of them. Most have your plasmid to make X. Due to natural selection, the competing priority—let's call it the "Y" product—is reproducing * surviving as much as possible. The yeast genes that make the yeast reproduce as much as possible and survive as well as possible will eventually be the largest population in your reactor. So if X doesn't also achieve Y, the only thing that will be left in your reactor is a population that achieves Y. The worst thing (which is true most of the time) is that achieving X is opposed to Y. Processing some chemical in the media that doesn't translate to food for the organism is wasted metabolic resources. So for most applications you can think of, your X population will die or reproduce away its X genes. There's nothing you can parameterize to fix this! Like Y will happen regardless of what temperatures you use, or what media you use, or how much oxygen you give the reactor. By virtue of growing something, you're optimizing for Y. Either design X to also achieve Y, or fail. Evolution is opposed to you, not on your side! In practice today, we don't understand the biological systems design well enough to make X also achieve Y. So what happens is you grow the yeast until you have a population with maximum metabolic efficiency (i.e., maximally achieves Y), and THEN modify the yeast to do X. It dies quickly, and your left with a little bit of product. This works, but it's not viable.
- CN7R 10y ago
  So from my understanding, bacteria is competing to reproduce the fastest, and the chemical that we want is simply a byproduct of its metabolism or pathway for reproduction issue is, however, the byproduct has to either be the most efficient factor for reproduction, or else by natural selection it will be removed my question is, can we use the same techniques found in tree grafting to prevent or delay natural selection, and grow our byproduct?

polyomino 10y ago

What if you added a lot of "error-checking" code that kills the host when it doesn't produce enough of the valuable chemical? I'd guess this is very difficult in practice. Or also add a competing organism that "triggers" when the concentration of byproduct is too low?

88e282102ae2e5b 10y ago
For the first idea, you'd have to have some lethal protein or something that's specifically inhibited by the chemical of interest. Coming up with that might be even harder than the original problem. And even if you could, evolution wouldn't favor cells that produced it, since it confers no advantage. There's an energetic cost to making that protein. For the second idea, again, evolution ruins everything. The competing organism would do just that - compete.
dnautics 10y ago
Because "you get what you select for". Instead of getting more of the chemical, you'll get a host that has hacked and disabled your error checking code.

sjg007 10y ago

just another iteration of biofuel..

w1ntermute 10y ago

Here are two great articles on the challenges of biofuels: 1. The Rise And Fall Of The Company That Was Going To Have Us All Using Biofuels: https://www.fastcompany.com/3000040/rise-and-fall-company-was-going-have-us-all-using-biofuels https://www.fastcompany.com/3000040/rise-and-fall-company-wa... 2. A Biofuel Dream Gone Bad: http://fortune.com/kior-vinod-khosla-clean-tech/ http://fortune.com/kior-vinod-khosla-clean-tech/

pinot 10y ago

FWIW, in a past life, I bought (4) 2L Sartorius reactors used for $75k, built out my lab for <$50k and had an operating budget of $450k w/ 2 fully-burdened RAs. I agree with much else of what you've said. I worked in biosynthetics with some of the Lygos teammates at another company. All-in-all it's not a bad idea, but the development time is _so_ long, especially in yeasts. It's analgous to writing assembly w/o documentation, and debugging takes months per code-change.