7 ms·

Synthetic biology startup Lygos raises $13M to make cleaner chemicals

65 points by sethbannon 10y ago

sethbannon 10y ago
We're learning more and more that microbes are essentially radically optimized factories. They've evolved for millions of years to be really good at producing stuff. Typically, though, it's not stuff we want. But if we edit the genetic code of the microbes we can direct that productive capacity towards making things we do want. That's exactly what Lygos is doing for industrial chemicals. And the beauty of the microbes Lygos is engineering -- specifically yeast -- is that they feed on sugar & water. Feed them sugar & water, and out pops specialty chemicals. This allows Lygos's microbial factories to produce industrial chemicals with sustainable inputs and with no toxic outputs. I'm incredibly excited by the potential for synthetic biology to reinvent the way we produce all sorts of things we like to eat, wear, or make things with in the decade ahead.
- doctorpangloss 10y ago
  > ...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.
- lvs 10y ago
  So, Dupont has a production-scale microbial process for 1,3-propanediol. What is the market for malonic acid if Dupont can already go directly to 1,3-propanediol? http://www.dupont.com/products-and-services/fabrics-fibers-nonwovens/fibers/brands/dupont-sorona/articles/how-dupont-sorona-is-made.html http://www.dupont.com/products-and-services/fabrics-fibers-n...
  - philipkglass 10y ago
    Malonic acid and its derivatives have their own demand as esters and neat acid apart from conversion to 1,3 propanediol. It's possible to catalytically oxidize 1,3 propanediol to malonic acid, so they are somewhat competing in the same space. The "clean" advantage of these fermentation processes is IMO greater than the "sustainable" part. You could use renewable energy to synthesize all the upstream precursors of traditionally-synthesized malonic acid (e.g. monochloroacetic acid, hydrogen cyanide) from air and seawater and it would be perfectly sustainable. But the intermediate products are hazardous to handle and there's a large waste stream of aqueous salt solutions and organic solvents. Eliminating hazardous intermediates and producing waste streams that can be handled by simple wastewater treatment makes it cheaper to build and operate facilities for these chemicals.
    - lvs 10y ago
      Agreed. Just pointing out that they're going up against an established DuPont process.
  - entee 10y ago
    Also that process has been around for at least 10 years: https://www.ncbi.nlm.nih.gov/pubmed/14580573 https://www.ncbi.nlm.nih.gov/pubmed/14580573 I met the guy (Charlie Nakamura) who developed the process. It took a hell of a long time to get everything working at useful efficiency, then a fair amount of development to get it working at scale. Also see others in this space: Amyris (older synthetic bio company) Zymergen (newer synthetic bio company that seems to be doing some of the same things Lygos wants to do)
- jjschm 10y ago
  Agree- our startup (www.Librede.com) does biosynthesis of cannabinoids in yeast from sugar. Much more environmentally sustainable and economical. Further, the modularity of the cannabinoid synthesis pathways in cannabis allows production of specific cannabinoids by substitution of single enzymes.
  - dekhn 10y ago
    I just want to say thank you for making a startup from an idea my friends had in college. For some reason we just never managed to get our shit together to the point of doing this. I can't remember why...
tsomctl 10y ago
Imagine warehouses filled with growing tomatoes. They wouldn't have leaves or roots. The plants would be directly injected with sugars and nutrients to grow. There wouldn't be any wasted energy due to the inefficiency of photosynthesis, or the need to grow leaves that will just be thrown away when the fruit is harvested. There'd be no pesticides, herbicides, or fertilizer running off into the water ways. No more habitat destruction. We would have delicious tomatoes in our grocery store, picked only a day before, full of nutrients and flavor. I'm aware that Monsanto is a terrible company, but GMO is going to help save the planet. Lygos is the first step towards the above scenario happen. At its heart, a cell is basically a huge finite state machine. It is programmed both through dna and proteins. Some day (and maybe Lygos already has something like this) we'll have a programming/description language to describe what a cell does/how it works. It would start with the basics. (When you see this molecule, attach this other molecule to it. When concentration of this gets too high, start doing this.) It would also have a basic support structure (nucleus/ribosomes) needed to be a functioning call. On top of this, you could program it to produce what you needed. I never supported Trump, but I'm severely disappointed in the direction his administration is going. If he wants to make America great again, lets start researching projects like what I described above. There was a pdf posted in yesterdays posting on Germany's fusion reactor, talking about the private companies that were helping to build it. They had to come up with new manufacturing skills and tools, and are now able to use those in other jobs. That is how you make America great again.
- searine 10y ago
  >Imagine warehouses filled with growing tomatoes. The fact is, even with a perfectly engineered tomato, it's hard to beat the low cost of dirt+sun.
- doctorpangloss 10y ago
  > There wouldn't be any wasted energy due to the inefficiency of photosynthesis... Honestly, tomatoes are really efficient as is. They grow huge amounts of fruit per acre; they grow in preposterous conditions, like people's windowsills, greenhouses, fields across the world, etc. I don't mean to pick on your particular choice of example, but you really got to get into the weeds to really understand the efficiencies of agriculture. Indeed, there's consensus that the greatest threat to agricultural efficiency are all the weaknesses of a highly-engineered monoculture. Imagine the devastation of the Florida orange harvest a few years ago due to frost, but due to a single weed. > a cell is basically a huge finite state machine There is a huge amount of research to create an "algebra" of synthetic biology, which is really fascinating stuff. You'd love it! You're right that a lot of what you're describing is inevitable, but there's a huge grind to get there, solving engineering problems totally orthogonal to the theoretical biology of it all.
mrob 10y ago
Some other organic acids are already made by bacterial fermentation. It's standard practice for lactic acid, and an uncommon method for succinic acid. More information: http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-lactic-acid http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemical... http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-succinic-acid http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemical...
- dekhn 10y ago
  Heck, Britain almost lost WWII because they couldn't make acetone. Chaim Weizmann invented a technique to make bacterial produce acetone.
  - mrob 10y ago
    The Acetone–butanol–ethanol process: https://en.wikipedia.org/wiki/Acetone%E2%80%93butanol%E2%80%93ethanol_fermentation https://en.wikipedia.org/wiki/Acetone%E2%80%93butanol%E2%80%... Obsoleted by cheaper petrochemical processes, but there's renewed interest now that environmental considerations are getting more attention, so maybe it will return to commercial use some day.
jgamman 10y ago
This is why I walked away from my field of chemistry...
bitwize 10y ago
That's so cool. I recognize the name Lygos because it's where Kristy Hawkins[0] was a chief scientist until the middle of last year. They probably wouldn't have made it to this stage without her yeast-engineering expertise. [0] Yes, this Kristy Hawkins: http://www.bodybuilding.com/contest_media/2542/22122/d/img_43021204324703.jpg http://www.bodybuilding.com/contest_media/2542/22122/d/img_4...

65 points by sethbannon 10y ago

We're learning more and more that microbes are essentially radically optimized factories. They've evolved for millions of years to be really good at producing stuff. Typically, though, it's not stuff we want. But if we edit the genetic code of the microbes we can direct that productive capacity towards making things we do want. That's exactly what Lygos is doing for industrial chemicals. And the beauty of the microbes Lygos is engineering -- specifically yeast -- is that they feed on sugar & water. Feed them sugar & water, and out pops specialty chemicals. This allows Lygos's microbial factories to produce industrial chemicals with sustainable inputs and with no toxic outputs. I'm incredibly excited by the potential for synthetic biology to reinvent the way we produce all sorts of things we like to eat, wear, or make things with in the decade ahead.

doctorpangloss 10y ago
> ...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.
lvs 10y ago
So, Dupont has a production-scale microbial process for 1,3-propanediol. What is the market for malonic acid if Dupont can already go directly to 1,3-propanediol? http://www.dupont.com/products-and-services/fabrics-fibers-nonwovens/fibers/brands/dupont-sorona/articles/how-dupont-sorona-is-made.html http://www.dupont.com/products-and-services/fabrics-fibers-n...
- philipkglass 10y ago
  Malonic acid and its derivatives have their own demand as esters and neat acid apart from conversion to 1,3 propanediol. It's possible to catalytically oxidize 1,3 propanediol to malonic acid, so they are somewhat competing in the same space. The "clean" advantage of these fermentation processes is IMO greater than the "sustainable" part. You could use renewable energy to synthesize all the upstream precursors of traditionally-synthesized malonic acid (e.g. monochloroacetic acid, hydrogen cyanide) from air and seawater and it would be perfectly sustainable. But the intermediate products are hazardous to handle and there's a large waste stream of aqueous salt solutions and organic solvents. Eliminating hazardous intermediates and producing waste streams that can be handled by simple wastewater treatment makes it cheaper to build and operate facilities for these chemicals.
  - lvs 10y ago
    Agreed. Just pointing out that they're going up against an established DuPont process.
- entee 10y ago
  Also that process has been around for at least 10 years: https://www.ncbi.nlm.nih.gov/pubmed/14580573 https://www.ncbi.nlm.nih.gov/pubmed/14580573 I met the guy (Charlie Nakamura) who developed the process. It took a hell of a long time to get everything working at useful efficiency, then a fair amount of development to get it working at scale. Also see others in this space: Amyris (older synthetic bio company) Zymergen (newer synthetic bio company that seems to be doing some of the same things Lygos wants to do)
jjschm 10y ago
Agree- our startup (www.Librede.com) does biosynthesis of cannabinoids in yeast from sugar. Much more environmentally sustainable and economical. Further, the modularity of the cannabinoid synthesis pathways in cannabis allows production of specific cannabinoids by substitution of single enzymes.
- dekhn 10y ago
  I just want to say thank you for making a startup from an idea my friends had in college. For some reason we just never managed to get our shit together to the point of doing this. I can't remember why...

tsomctl 10y ago

Imagine warehouses filled with growing tomatoes. They wouldn't have leaves or roots. The plants would be directly injected with sugars and nutrients to grow. There wouldn't be any wasted energy due to the inefficiency of photosynthesis, or the need to grow leaves that will just be thrown away when the fruit is harvested. There'd be no pesticides, herbicides, or fertilizer running off into the water ways. No more habitat destruction. We would have delicious tomatoes in our grocery store, picked only a day before, full of nutrients and flavor. I'm aware that Monsanto is a terrible company, but GMO is going to help save the planet. Lygos is the first step towards the above scenario happen. At its heart, a cell is basically a huge finite state machine. It is programmed both through dna and proteins. Some day (and maybe Lygos already has something like this) we'll have a programming/description language to describe what a cell does/how it works. It would start with the basics. (When you see this molecule, attach this other molecule to it. When concentration of this gets too high, start doing this.) It would also have a basic support structure (nucleus/ribosomes) needed to be a functioning call. On top of this, you could program it to produce what you needed. I never supported Trump, but I'm severely disappointed in the direction his administration is going. If he wants to make America great again, lets start researching projects like what I described above. There was a pdf posted in yesterdays posting on Germany's fusion reactor, talking about the private companies that were helping to build it. They had to come up with new manufacturing skills and tools, and are now able to use those in other jobs. That is how you make America great again.

searine 10y ago
>Imagine warehouses filled with growing tomatoes. The fact is, even with a perfectly engineered tomato, it's hard to beat the low cost of dirt+sun.
doctorpangloss 10y ago
> There wouldn't be any wasted energy due to the inefficiency of photosynthesis... Honestly, tomatoes are really efficient as is. They grow huge amounts of fruit per acre; they grow in preposterous conditions, like people's windowsills, greenhouses, fields across the world, etc. I don't mean to pick on your particular choice of example, but you really got to get into the weeds to really understand the efficiencies of agriculture. Indeed, there's consensus that the greatest threat to agricultural efficiency are all the weaknesses of a highly-engineered monoculture. Imagine the devastation of the Florida orange harvest a few years ago due to frost, but due to a single weed. > a cell is basically a huge finite state machine There is a huge amount of research to create an "algebra" of synthetic biology, which is really fascinating stuff. You'd love it! You're right that a lot of what you're describing is inevitable, but there's a huge grind to get there, solving engineering problems totally orthogonal to the theoretical biology of it all.

mrob 10y ago

Some other organic acids are already made by bacterial fermentation. It's standard practice for lactic acid, and an uncommon method for succinic acid. More information: http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-lactic-acid http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemical... http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemicals-factsheet-succinic-acid http://www.nnfcc.co.uk/publications/nnfcc-renewable-chemical...

dekhn 10y ago
Heck, Britain almost lost WWII because they couldn't make acetone. Chaim Weizmann invented a technique to make bacterial produce acetone.
- mrob 10y ago
  The Acetone–butanol–ethanol process: https://en.wikipedia.org/wiki/Acetone%E2%80%93butanol%E2%80%93ethanol_fermentation https://en.wikipedia.org/wiki/Acetone%E2%80%93butanol%E2%80%... Obsoleted by cheaper petrochemical processes, but there's renewed interest now that environmental considerations are getting more attention, so maybe it will return to commercial use some day.

jgamman 10y ago

This is why I walked away from my field of chemistry...

bitwize 10y ago

That's so cool. I recognize the name Lygos because it's where Kristy Hawkins[0] was a chief scientist until the middle of last year. They probably wouldn't have made it to this stage without her yeast-engineering expertise. [0] Yes, this Kristy Hawkins: http://www.bodybuilding.com/contest_media/2542/22122/d/img_43021204324703.jpg http://www.bodybuilding.com/contest_media/2542/22122/d/img_4...