
Synthetic biology startup Lygos raises $13M to make cleaner chemicals - sethbannon
https://techcrunch.com/2016/12/13/synthetic-biology-startup-lygos-raises-13-million-from-os-fund-and-ia-ventures-to-make-cleaner-chemicals/?hn
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sethbannon
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
> ...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
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.

~~~
doctorpangloss
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.

~~~
sandGorgon
question - so why does agriculture work? why are we able to grow tomatoes year
after year.

is the entropy at the cellular level versus at a plant level so different that
the processes are "locked" in place.

does it make more sense to try and grow plants that produce malic-acid
tomatoes? sure it might be harder to geow one... but once grown, you can scale
it infinitely.

~~~
archgoon
I suspect that it's that you can manually select which tomatoes you want. It's
a bit harder to select individual microbes.

So essentially, the difference between the trait you want, X, and the trait
that survives, Y, doesn't exist. Every Y is an X, since generations of farmers
are the ones manually doing the selection.

~~~
sandGorgon
that makes a lot of sense. so in case of tomatoes, the survivability of the
plant has no correlation with actual survival. it is being engineered by the
farmers.

what we really need is a way to select and ensure survival of the yeast that
we want.

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tsomctl
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.

~~~
lvs
A cell is absolutely not a finite state machine, and anyone who tells you this
either has no clue about biology or has no idea what a finite state machine
is. A cell's "state" is governed by a highly parallel set of probabilistic
interactions, not logic gates. No two cells given the same inputs can be
guaranteed to enter the same state. Populations of cells always exist in a
distribution of states.

~~~
tsomctl
And those probabilistic interactions perform no logic at all? Obviously a real
cell isn't identical to a silicon circuit, but I feel it is a useful
abstraction. If you want, look at proteins as being the finite state machine.
These people agree:

> We propose a theoretical formalism, molecular finite automata (MFA), to
> describe individual proteins as rule-based computing machines.
> ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070173/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070173/))

A textbook I read several years ago on cellular mechanics inspired my thoughts
on this, unfortunately I'm not able to find it right now. I was blown away at
the time, the chapter on dna transcription strongly reminded me of
programming.

~~~
entee
Logic is the wrong way to look at it, cells have no logic. They have an
impossible array of equilibria, random interactions, chaotic mixing, and
things we don't understand at all, along with others we may not even know
exist.

People like to think of blobs interacting and not interacting, but really a
cell is more of a crowded mess, see this image for a sense of scale:

[http://media.tumblr.com/525082e14ba810bc539c61a646fdba93/tum...](http://media.tumblr.com/525082e14ba810bc539c61a646fdba93/tumblr_inline_mr0qxaIAcz1qz4rgp.jpg)

Now picture everything in that image swirling around incredibly fast, with
some parts of it (the yellow fibers) more stationary and everything else
randomly zooming/bouncing around. There is no equivalent in computation.

A logic may appear to emerge from that jumble, but it's not going to behave
very predictably. It takes years of work to be able to predict mechanistically
just a tiny aspect of one system, much less the whole cell.

The DNA example you describe is a fascinating area, but it took ~30-50 years
to get that understanding, and we still find out new things about it all the
time! Now that's a really easy system to study, you can isolate its
components, you have clean readouts (new DNA generated, sequencing etc.). How
about everything upstream of that? The signaling chain going from the cell
surface to the DNA to turn on a gene is quite long, picture at least 3 links
with yet another 3 links each, which themselves have separate, independent
links back into the DNA.

That's not to say we can't make assumptions and make some progress, see Marcus
Colvert's lab:

[https://covert.stanford.edu](https://covert.stanford.edu)

But it's really, really hard, and an FSA is a quite incomplete way of
describing it. Looking at the paper you sent, a useful MFA would have to be
insanely large to be useful, and defining all the terms is just an impossibly
large task.

------
mrob
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-
chemical...](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)

~~~
dekhn
Heck, Britain almost lost WWII because they couldn't make acetone. Chaim
Weizmann invented a technique to make bacterial produce acetone.

~~~
mrob
The Acetone–butanol–ethanol process:

[https://en.wikipedia.org/wiki/Acetone%E2%80%93butanol%E2%80%...](https://en.wikipedia.org/wiki/Acetone%E2%80%93butanol%E2%80%93ethanol_fermentation)

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.

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bitwize
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_4...](http://www.bodybuilding.com/contest_media/2542/22122/d/img_43021204324703.jpg)

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

