March 25, 2022 • 51 mins
In Bio2040’s latest episode we had the chance to talk to Sam Lee, a long-time veteran of the biotech space.
This episode covers some of the history and fundamentals of the synthetic biology and biomanufacturing space.
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Episode Transcript
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Flavio (00:01):
Yes hello and welcome to another exciting episode of bio
2040, where we speak withthought leaders and experienced
researchers, entrepreneurs,investors, to uncover the
biggest opportunities in thebiotech space.
And I'm very excited today tohave Sam Lee with me, Sam Lee is
a very experienced veteran ofthe chemistry, pharma, health
(00:25):
tech, biotech space, and I'mvery excited to have you here,
Sam.
Good day.
Good day.
Sam (00:31):
Pleasure to be here.
Flavio (00:33):
Awesome.
Sam why don't we start off byyou giving us a little bit of
your background experiences whatyou've been doing in your
career.
Sam (00:42):
Sure.
I'll start from the beginning.
I'm a Canadian.
I got my PhD in chemistry,polymer chemistry from the
university of Toronto.
And my first job was as aresearch scientist at DuPont.
So that was where I started inthe division of.
Packaging and industrialpolymers.
So anything that's plastic.
And I did that for three yearsand then I had the pleasure or
(01:05):
opportunity to move into thebusiness development side.
And when I did that, I saw muchmore of the company.
Specifically the life sciencedivision, which they call the
life sciences enterprise thathad DuPont pharma, as well as
something they called bio basedmaterials.
They started to make throughsynthetic biology, which it
(01:26):
wasn't called that at the timefermentation to make a bio based
chemical.
That ended up being used to makesome fibers.
So I found that veryinteresting.
And as a result of that, I quitthe company and inside to get
into life sciences.
The first job I found in thatdirection was actually in a
biopharmaceutical company.
(01:46):
It was called NPSpharmaceuticals, which is based
in the U S and Toronto.
Which was a company that endedup developing two medicines that
are on the market today.
Then I went and worked with acardiologist to start help start
his biopharmaceutical companywith a medicine he invented for
cardiovascular.
(02:07):
Did that for a bit.
And then I joined a genericpharmaceutical company.
This is the genericpharmaceutical companies are
companies that make medicinesafter they expire, the patents
have expired.
And this is called Dr.
Reddy's Laboratories is one ofthe largest ones in the world
that was based in India, but Ispent the next eight years
working out of their us officeso it was really quite an
(02:29):
interesting range ofexperiences.
And in that process, I justbefore I ended up back up in
Canada, I worked with I becamethe founding partner with a
venture firm called SOSV.
That set up an accelerator forlife science companies in New
York called Indie bio New York.
I spent a little bit of timejust before the pandemic started
(02:53):
to get that going because it wasinvesting in life science,
startups particularly wheresynthetic biology was a field
that they were interested in.
So I've had an interestingcareer as I'm back in Toronto,
right now.
I'm actually working forBioNTech, which is the company
that invented the first COVID mRNA vaccine.
(03:14):
And and that's where I am.
But I have the pleasure ofmeeting you Flavio and
continuing this conversation andmy interest in synthetic.
Yeah, thanks.
Thanks for the introduction.
I think at this point, everybodyknows, BioNTech which produce
these wonderful vaccines thathave prevented probably millions
of deaths at this point.
Flavio (03:31):
So that's a, that's an exciting point.
We could probably spend anentire episode just talking
about that.
And then also Indie bio I'vebeen familiar with, it's a very.
Sort of incubator.
I was more familiar with the onein San Francisco, I think maybe
that was the first one.
And so you've really had a veryinteresting and illustrious
career across the wholespectrum.
I think that's also why ourconversation today is going to
(03:53):
be really interesting becauseyou can draw from all these
different aspects andexperiences.
So I think maybe for people toget situated.
Would it make sense to a littlebit talk about, today we have
this field called syntheticbiology, but and as you said in
your introduction, it wasn'teven called like that a while
ago.
So does it make sense for us togo and give somewhat of a
(04:16):
history?
Where did it start and where arewe today?
Sam (04:20):
Sure.
So what, where I, my experience,I did not include this when I
was giving my introduction isthat I did have the opportunity
10 years ago, back in 2010 to2011 to meet the CEO of a
pharmaceutical company.
And he contracted me to do somework for him and his family
(04:41):
office to look for investmentsfor him.
And I was so grateful for thatopportunity.
He must've seen in me my variedbackground that I could put a
lot of things together, myunderstanding and experience in
life sciences, but also groundedin my original background at
DuPont.
And so this was to look atthings in sustainability and
(05:02):
energy.
And this was to look forstartups that he could invest in
or new technologies that him andhis family office could invest
in.
This was just a side job.
I had a regular day job.
This was something I could do atnights on weekends.
So of course, when you get anopportunity like that you do it.
And we started looking at solarenergy, for example, at
(05:22):
Greentech of various types.
And then he came to me and said,why don't you look into
synthetic biology?
And this was 2011.
And I thought, what does thatmean?
And that's where I started tolearn about this space and
investigate it.
I did that by looking athigh-impact journals.
(05:44):
And I also did that because ofwe're looking at startups.
I started looking at patents andthrough that search, that's
where I started to see the firstiteration or first-generation of
companies, which I felt werewhat one could call synthetic
biology companies.
So just to be clear it's a bigspace.
(06:05):
It certainly is now, but evenback then, you could define it
by, by just about many differentcriteria.
We I broadly categorized it intwo broad buckets.
One of them would betherapeutics and the other would
be non therapeutics.
And most of the real-worldapplications as to where one
could go, one could arguably saythat there were products in that
(06:26):
space in a therapeutic areaalready.
So I looked at the nontherapeutic areas, which is a
huge space, but very quickly Inarrowed down on a number of
companies that were.
Being funded at the time.
Which we're getting some quitefar along with various products
and it turned out that thesewere they would call them
(06:46):
building block chemicals orpetrochemicals.
And that's when I stumbled uponthis connection that these were
products that they weredeveloping that were connected
to products that otherwise couldbe made from crude oil.
And so that was, it appeared tobe the first idea that drove the
first generation of companiesto, to make products as
(07:09):
substitutes or bio basedsubstitutes to petrochemicals.
Flavio (07:16):
So was that at the time was the idea there to fight
climate change was more of acost driver?
We could make a cheaper whatwere what was the idea and that
first sort of wave of syntheticbiology in the sustainability
area?
Sam (07:31):
It's a good question.
And that's when it at that pointin my life and my career, I
would have that moment where,when I look back, it all makes
sense and it all comes backtogether because by then I had
already left DuPont many yearsago.
And at the time I was at DuPontand in business development,
(07:51):
there was a big initiative inthe DuPont life sciences
enterprise.
They called it bio-basedmaterials.
And for all the scientists whowere in the traditional
chemistry area we felt, I feltleft out because all of the
spotlight and careeropportunities were going to
these biologists and what theywere doing was taking
(08:11):
fermentation to make a certaincompound.
It was called one,1,3-Propanediol is basically for
the organic chemistry.
So propane with two alcoholicgroups on either end.
And that would be the feedstockfor polyester.
And as I learned the businesspremise as to why they wanted to
do this well, polyester has beenaround for a long time.
(08:33):
And when in the early days whenpolyester was first developed
there, DuPont had figured out awhole range of different types
of polyesters.
You could make one of the bestpolyesters that they could make
was actually based on you.
This one, three propane dial,the reason they never chose
that.
And they ended up using theethane version of it.
(08:56):
The two carbon one is becausethat was the one that was
readily available from crude oilas a feedstock that was much
cheaper.
And now they found that in orderto provide a competitive product
let's make 1,3-Propanediol.
We have a way to do that throughfermentation and we could make a
new polyester fiber that wouldbe much more elastic, much more
(09:18):
durable, much stronger and soon.
And that was what drove it.
So basically the story otherthan that, you had a performing
fabric was that the cost pointbecame accessible because of
synthetic biology, which wasn'tcalled synthetic biology at the
time, it was just basically afermentation technology that
(09:39):
they through engineering E.
Coli was what they started with.
So that was the connection.
And then that was back in 1999,2000 when that product was being
developed and as it is on themarket in 2011, I began to see
that there was a whole bunch ofother products made by other
companies with that samepremise, that there were a lot
(09:59):
of products that the, thesewould be petrochemicals
chemicals that are 2, 3, 4carbons in size that would be
produced at petrochemicalrefineries.
And they would be the feedstockto go into.
Other materials downstream,mostly plastic but also a lot of
other materials and this firstgeneration of bio based
(10:20):
materials that were coming out,these synthetic synthetic
biology companies were basicallymaking that as a route alternate
as an alternative frompetrochemical.
So part of the storyline was tosay, this is a sustainable
material because they come from.
Fermentation, which is basicallyfrom sugar rather than
petrochemicals.
Flavio (10:42):
So in this scenario, we were essentially harvesting some
kind of sugar.
That we have was grown in somefield maybe sugar cane or some
other source of carbon whichthen the net CO2 would be zero.
Versus if we, obviously, if wetake a petrochemicals, these
products are then producedconsumed and ultimately
(11:04):
oftentimes either end up inwaste types or burned, which
then adds.
CO2 to the atmosphere.
Is that the correct way to thinkabout it?
Sam (11:12):
That's how they expressed it at that they, there was an
environmental element to this.
But the interesting thing washere's where the price of oil
comes in.
And this was, remember, this isthinking that's 10 years, 10
years old.
Yeah.
So where it is today and the, inthe storyline and the business
case are different, but it'sgood to know the past.
So this is 2011.
(11:33):
We just had the global financialcrisis in 2008.
And there was a little, if youjust look at the price of oil
between through the 1980s,1990s, it's been relatively flat
in us dollars.
Let's say about 40,$50.
And then it started to go up and60, 70, 80, 90 over a hundred
dollars a barrel.
(11:54):
We had the global financialcrisis.
There was a little blip, wentdown a bit, but it went back up.
So it was at an all time high.
And so oil as a feed stock intopetrochemical refiners is very
high.
Oil itself was the burning of itis contributing to carbon
dioxide.
And so both the price as well asthe environmental premise was
something that.
(12:14):
And the first-generation inthinking about this problem.
Those were undesirable elementsand what's going on then is
okay.
You've got a petrochemicalrefinery that's being the source
of these building blockchemicals that you need to.
What if we actually use thebio-based source?
So instead of using crude oil,let's just say it turns out to
(12:36):
be corn which provides theglucose to do fermentation to
make a bunch of materials.
It could be Propanediol.
It could be succinic acid.
It could be isobutanol,butanediol.
So these were the types ofmaterials that those first
generation of companies made.
They also the thought of makinga biofuel.
Because that's pretty there's abroad range of different oils
(12:59):
you could make from that.
So that's what they were doing.
And that was possible alsobecause the price of oil was
high.
So you had this tailwind in thebusiness case, tailwinds are
forces, which helped drive yourcompany or in business model.
But it's not a tailwind that'ssustainable.
If you take that away.
A big part of your business casefalls apart.
(13:20):
But at the time that tailwindwas the high price of oil and
then there was subsequently inthe U S at least there was a lot
of government incentivesprovided for green chemistries
that at that time was the Obamaadministration that provided
this.
And those were funds that wouldgo into helping.
The green chemicals industry asone way to call it evolve and
(13:44):
grow.
So that was what constituted,the first-generation the
companies they received a lot ofinvestment and at the same time,
they also ended up gettingproducts that were being
developed and hoping tocommercialize.
Flavio (13:59):
So what happened with these companies?
Both the biofuels.
I know if I remember correctly,there was a big hype back then,
but now it doesn't seem to havegotten as much traction as it
could have.
I think in Brazil, it's used forexample, as a gasoline
replacement, but other thanthat, it hasn't made these broad
impact that maybe some peoplewere wishing for.
(14:21):
So what did what happened withbiofuels and.
What happened with these otheruses that you are touching on in
and where are we today?
Is this now the price of oil hasgone back up.
Changing the game again, or somaybe if you can touch on the
unit economics a bit more indetail, that could also be
interesting.
Sam (14:39):
Sure.
Okay.
So biofuels is one segment.
These building block chemicalsis another segment.
If we just look at biofuels as asegment itself, it just
basically comes down to price.
We've got a lot in terms of theactual value chain or supply
chain of how these things aremade.
You do need to grow the cropsthat provide the glucose whether
(15:01):
that's corn or sugar beet orsugar cane.
You, you have that part, youhave to harvest that you have to
bring it into a location toconcentrate it.
That has to go into a fermentor.
And so when you compare thatwith the existing infrared
trucks, infrastructure thatexists for.
With with fuel itself it just isnot sustainable unless the price
(15:25):
of fuel was extremely high andyou got government subsidies
once the government subsidies goaway which basically happened as
the After effects of the globalfinancial crisis were away.
That was one leg that got pulledaway.
The other was that we neverexpected that shale oil and the
(15:47):
whole fracking technology cameinto play and it became a major
source of cheap oil as well.
The price of oil by around 2015,2016 had dropped.
Considerably because of this bigsupplier of cheap oil that was
enabled by another interestingtechnology, fracking technology
(16:07):
that brought it down.
So that, that whole aspect ofbiofuels was, had basically had
its legs kicked out of out ofit.
And it became unsustainable.
It's there, there is a bit stillin existence and I wouldn't call
it biofuels.
It could be ethanol which isadded.
But that's the remnant of whatthat part of the industry is.
The other part it's thesebio-based chemicals and it's
(16:31):
suffered the same effectsbecause your feedstock is very
high priced oil at the time,which no longer is the.
The other is the, so that's theThe input side of it the what
your costs are the output is, oris what your market is.
So if it's if it's going intoplastic let's say it's
(16:53):
polyester, or there has to be amarket that's large enough to be
able to make your unit economicswork.
As I indicated, Propanediol wasone of the first ones and it's
still a product that, that isstill made and it's integrated
in into the product supplychain.
(17:14):
So that's still sustainable.
It's not an industry in itself.
It's a product that's madein-house by the company that
used to be called DuPont as aproduct.
Succinic acid was one of theother ones that was a product
that was made by syntheticbiology.
It, they first started byfermentation of, e-coli and then
(17:34):
also by ferment, they switchedto a yeast based fermentation
for higher yields.
But still the price could not godown enough.
And at most you needed about40,000 metric tons to even start
to get there in unit economics,but you, and you would need to
have much higher levels.
So the problem there is that themarket demand the market size is
(17:59):
not high enough.
So, and that was the case of alot of these other products like
Butanediol.
So that's when we, when yourinput and output side are, the
economics don't work out,basically those companies don't
are not really that viable.
Flavio (18:20):
I think at this point it might be interesting also for
people to realize a little bitmore like where these
petrochemicals are used.
We talked about biofuels but inplastics, but there are other
areas as well.
Could you give us a quickoverview of what are the main
other from all the transport andheating, which is, people
(18:41):
probably most associated withoil and gas also, where else are
petrochemicals used?
Sam (18:48):
Well, actually predominantly it is plastics.
And this is where that was thefirst generation I would call of
synthetic biology companies isthat they are making the
building blocks for plastics,mostly polyesters.
And polyesters arebiodegradable.
So if it actually breaks downyou will have a some sort of
closely, hopefully sustainablesupply system and.
(19:10):
Degradation of those plastics.
The problem is that you'retreating these first-generation
of companies we're treatingtheir products as commodities.
And if one looks at it now eh,today, 10 years, Price of oil is
high again, but the the industryand the world has changed and we
(19:32):
are no longer, I feel working ina globalized world where
products can be shipped anywherearound the world.
We are going to be in marketsthat are more closed and
therefore the production thatyou make of any material.
Plastics for example, and you'dwant these plastics to be
recyclable or degradable, theywould serve a local market.
(19:52):
And so the companies that I seeevolving today, nevermind
synthetic biology for a moment.
These companies make materialsthat are degradable for
disposable wrappers, disposablecutlery, and so on as a very
simple example they serve verylocal markets.
And if that's the case, if we gointo bio-based materials what
(20:14):
one would make are a whole newsupply?
What I would think is as anidea, I'm not saying that I have
the right answer here where Ithink things are going is that
you would have to create a wholenew supply chain based on a
whole new set of materials.
So right now, what are the kindsof plastics that exist?
There's polyethylene.
(20:35):
Polyester which is there's manytypes of polyester, but
polyethylene terephthalate is orPET is the most common type of
polyester.
You would look at differenttypes of polyester.
And you would continue to dothat.
And basically you're developinga whole new set of materials to
replace the plastics that are inexistence today.
(20:57):
That's one way to do it anotheror second-generation is that
what are the other materialsthat you could make?
Another set would be.
Surfactants so these are morecomplex compounds.
They are originally come fromthey don't actually come from
some of them.
They come from petrochemicals.
Most of them come from othersources and including
agriculture.
(21:18):
The agricultural supply chainthis is becoming of interest and
they're used in soaps anddetergents which is a niche in
itself Another is to make thingsI one area I like and have been
watching for a long time as Palmoil, because Palm oil is used in
not just in a whole lot offoods, but in a whole lot of
other consumer products,cosmetics.
(21:41):
And they all come from Palmtrees, which really come from
mostly Indonesia.
And that comes at an incredibleenvironmental costs.
So where we are with generationto generation three, Is to make
a lot more complex systemsrather than just building block
are petrochemical likecompounds.
Flavio (22:04):
Yeah.
So there's a whole new businessarea really propping up.
There's companies like likeGingko Bioworks and many others
Amarys that are working oncreating.
Sometimes they're making lesstoxic or they're using less
toxic waste to make certainindustrial compounds that are
(22:27):
needed other times they'remaking you compounds right.
So one example is the flavorsand fragrances industry, for
example, vanillin, and I thinkis a classic example.
That's the sort of the moleculethat gives vanilla it's vanilla
taste and it's expensive togrow.
It only grows in certain regionsof the world, for example,
French Polynesia and then itneeds to be sourced and treated
(22:48):
and all that.
And at the end that the amountof work that goes into making.
The vanillin needed is quitegreat compared to us.
If you can have a fermentationbased system that makes the
exact compound, you need somepeople also call that precision
fermentation then potentiallyyou might have a much more
sustainable and also morepredictable supply chain.
(23:08):
Maybe I dunno if you havethoughts on that, where, the
plants and crops can be subjectto.
Both to pests climate disaster.
And now as we're learning alsogeopolitics starts playing a
role.
So instead of having to bedependent on.
Molecule being able to besourced only from a certain
region of the world.
We may want to have or countriesaround the world may want to
(23:30):
have a, as you were alluding toearlier their own sort of bio
manufacturing hubs, or they canmake the desired compounds,
where they needed and also beless dependent on both climate,
pests and geopoliticalperturbations.
Is that something you also seethat way or.
Sam (23:49):
That's right.
So Amyris, is, is a very goodexample of that.
That was one of the very first,Synthetic biology companies out
in California, back in the earlytwo thousands, mid two thousands
that got founded.
And it's been an interestingcompany to observe because
they've been trying to find theright business model for them to
stick.
And a very good example of that.
(24:10):
That was one of the very firstthe very first iteration of the
company was to create biofuels.
They had a way to, to, there wasto make a different fatty acids,
which are would therefore beoil.
That turned out not to besustainable for reasons which I
mentioned it's too high costscompared to what you could
(24:31):
actually purchase as regularFuel from petrochemical sources.
And then they started to pivotin a number of different ways.
One was in pharma ingredients.
Another was like you said in, infragrances these would be fine
chemicals.
Each one of those, it could bean industry is an industry in
itself.
And so this is where a one way Ithought about it was let's just
(24:54):
look, let's just look at theevolution of the chemical
industry which began long beforethe industrial revolution you
had companies that startedmaking fine chemicals which went
into pharmacy pharmaceuticalingredients you had from that
company.
These were all based in Germanyand Switzerland companies that
went into specialized in flavorsand fragrances.
(25:14):
You had companies that ended upgoing into dyes and pigments and
so all of those industries arestill I would have thought of
viable as approaches to thefirst generation and second
generation of synthetic biologycompanies instead of using
traditional chemical routes,most of which comes through
petrochemicals go throughsynthetic biology route and we
(25:36):
ended up we've been seeing that.
But now we're starting to seemore advanced versions of that.
So Amyris, I think never endedup catching on because they
never caught the right businessmodel.
So the way I would position itis that generation one are these
building block industrialchemicals that, that these
companies attempted to.
(25:57):
And their failure is that thoseare your, those are commodities
and you've positioned themcompeting against
petrochemicals.
Version 1.1 I would say is tostart to produce these specialty
chemicals and build a whole newsupply chain.
And that's a possibility ifthere's some entrepreneur out
there that wants to have thisvision of doing it, I think
(26:19):
that's a very interestingpremise.
Version two is instead of usingpetrochemicals as a, as an
input, why don't we considersome other carbon source, such
as carbon dioxide or methane,and we're starting to see
companies like that where yourfeedstock is not a sugar, which
is extremely expensive.
You've got to go through theagricultural supply chain is
(26:41):
secure that, but basicallyhooked your chemical your
company up to an industry that'ssupplying either carbon dioxide
or methane and or natural gas,some form of natural gas, and
we're starting to see that.
And that's driven by okay.
If you have that input, what canthe organisms that you've
engineered.
(27:03):
Make that's high value.
So that's another generation.
There are other companies thatcan make dyes most of these
dyes, again, come from finechemicals through a
petrochemical routes.
Many of these dyes are notbiodegradable, they end up
polluting riverways and yoursewer systems with these
intensely colored, sometimescarcinogenic dyes.
(27:25):
And so there are companies thatare thinking of, can we look at
dyes that are sourced fromorganisms, which are not just
therefore sustainable, but alsonot so toxic.
And that's another set ofcompanies.
We have companies that are usingsynthetic biology to, to make
compounds that really arevaluable.
So one of the ones I found thatwas very interesting was ways to
(27:50):
make human milkoligosaccharides.
These are sugars found in humanbreast milk and sugars in breast
milk are unique to.
the the mammal.
So the, one you find it inhumans is different from what
you find in Whales and what youfind in marsupials and so on.
And there were many companiesthat had a technology to
(28:10):
engineer E.
Coli to make these there'sabout.
Over 200 of these human milkoligosaccharides.
And why is the baby eating thesethings?
And nature and evolution musthave designed it in a certain
way.
And there have been studies toshow if you're actually having
breast milk with these humanmilk oligosaccharides there, you
do have lower incidents ofinfection.
(28:31):
You do have a better growthimproved brain development
marginally.
And it would be best for infantformulas too, to actually have
these ingredients in them aswell.
But you can't make these they'revery complicated by chemical
routes.
You'd have to use a biologicalroute.
And there was a company inGermany that, that figured it
(28:53):
out.
Two very brilliant brothers,Jennewein Biotechnologie, what
it's called and that's anexample I love as a citing as an
example of a synthetic biologycompany that made a very useful,
very high value product.
And just a year ago they wereacquired by a major specialty
chemical company for I think,400 million Euro.
(29:16):
So hats off to them.
That's a win that's a very goodexample of a, of an application
that, that actually is veryuseful.
Flavio (29:27):
Yeah.
So I love what you weredescribing, how, like the
version 1.0, these sort ofbuilding block chemicals really
turns out that you too closelycompeting with petrochemicals.
Oil, actually, is an incrediblycheap material in compared to
many other for the amount ofversatility did you can do and
(29:48):
the amount of energy that'sstored inside, right?
So it's a sort of very hard tocompete with that.
And then now we're learningthat, as I guess our tool
becomes better, our tools becomebetter.
Be in the synthetic biologyfield, the sequencing costs have
come down.
We have better assays.
We have high throughput assaysto test different to really do
(30:08):
cell engineering, cell lines andso on.
And so we can start engineeringmore complex pathways.
I think that's what you'retalking about now to make more
complex molecules,oligosaccharides or proteins
that are larger proteins thatalso maybe have a
post-translational modificationsand so on.
So it's really a whole new fieldthat's emerging now as both the
(30:31):
wet lab and dry lab come better.
There's a whole new field ofthings that they're opening up.
And I certainly love the exampleyou just mentioned with the
human breast milk.
I think that would be a boon.
If these infant formula all hadthese sort of healthier
compounds.
Yeah I think that's a veryinteresting way to think about
everything.
(30:51):
Maybe for people we can, getslightly technical here in just
explain a little bit more thesynthetic biology we've talked
about, how does it actuallywork?
What do people how do you gofrom an E.
Coli you find in nature toactually, making the compound.
Okay.
(31:11):
So there's many different waysto do it, but I'll just cite the
and that's why the field is sobroad.
And I'll just cite theindustrial biochemicals that
bio-based chemicals that westarted this conversation with
where originally the upstreamthe feedstock is sugar glucose.
And there's a number of pathwaysand these are ones that our
fundamental to two organisms asto how to they metabolize in
(31:34):
this case, sugar for energy.
And as I, what I noticed is thatwhen I looked at the patents,
the evolution or the timeline ofwhat, when these companies and
when these things came outclosely matched the, how far you
are going down each of thesepathways.
Sam (31:50):
So the very first one is the glycolysis pathway.
Which takes sugar and breaks itor builds that up into
Phosphoenolpyruvate and Pyruvatewhich, which are energy sources
that go on into other pathwayswithin the organism.
And when you look at thatPhosphoenolpyruvate is one that
(32:11):
can be engineered further.
By that, the pathways as towhere it goes to make succinic
acid.
And so that was one of the firstapproaches and early companies
using technology based onengineering, the organism to
take sugar.
And as it goes through the theglycolysis pathway gets to
phosphoenolpyruvate ends upmaking succinic acid.
(32:31):
Now if one takes the glycolysispathway further, it goes into a
number of other pathways whichare possible.
And this concept of metabolicengineering is about how do you
engineer the organism to steerthe direction of the pathway to
maximize the yield while keepingthe organism highly productive.
So another direction it could gois this aromatic amino acid
(32:56):
pathway.
So after you go through theglycolysis pathway, if you steer
it towards the aromatic aminoacid pathway, And, aromatic is
basically means benzene typecompounds and where you go then
may allow you to makebenzene-like compounds and
that's useful to maketerephthalic acid, which is a
(33:19):
building block, for example forpolyester.
And so there was a one or twocompanies that actually started
doing that because they managedto the professors that did that
work managed to find an optimalmetabolic engineered system to
do that.
Another direction you could gois after the glycolysis pathway,
(33:39):
you could go towards themevalonate pathway and that's
gets interesting because you itgoes into a lot of other
different products.
You could make fatty acids from.
You can make 1,3 Propanediol,which is the example I
personally saw in DuPont.
Fatty acids, those were in factthat's where Amyris, their,
their expertise was themevalonate pathway.
(34:00):
And I think the professorsoriginally came from UC Berkeley
and developed the expertise inthat to create a system and a
set of products that, thatdeveloped that could be used to
develop these fatty acids.
And then furthermore, afterthat, as you go further
downstream, you could end upengineering a lot of other
pathways towards the they'recalled phosphates drain your
(34:23):
phosphate, farnesyl phosphate,pyrophosphate.
And it's so on.
And that leads to a whole rangeof more complex compounds.
And when you get that far down,you're starting to make
compounds that could go intoflavor, instruct precursors
flavors and so on.
So that's the first generationof these industrials chemicals.
And they're all driven by howyou optimize that.
(34:45):
And they're all done in e-coli.
Eventually they will be switchedto yeast because you get a more
productive system.
And that's one way.
Flavio (34:54):
Okay.
Yeah.
So it seems like just tosummarize a bit more from a
layman's perspective, youessentially have sugar coming
from essentially, either corn orsugar beet or some other type of
plant.
And in this sugar gets turnedinto various compounds via
pathways, which are really justenzymes modifying these
(35:17):
compounds from one step to thenext.
And you have these very complexbranches of pathways things can
flow into.
And then the idea is here, if Iunderstood this correctly.
So finding out that the productyou desire to make finding out
chemically, where are you in?
Close in the natural wild typesort of pathway and then
(35:38):
engineering adding enzymes ormodifying enzymes and so on to
steer the flux, the metabolicflux into the direction that you
desire and it, and ideally haveat the end of the organism that,
has a hijacked pathway nowmaking the product that you
want, and then you, there's awhole bunch of downstream
(35:59):
processing that needs to happenafter that.
But is that's the high-levelgoal here and then synthetic
biologists companies like Amirysand Gingko and others have
specialized.
In doing these metabolicengineering tasks there's a
whole bunch of high throughputscreening going on sequencing
understanding the naturalpathways and in testing various
(36:21):
biological components swappingout promoters and enzymes and so
on to optimize the yield andthe.
titer your that your host canmake, whether it's E.
Coli, yeast or other, even morecomplex hosts like filamentous
fungi and so on are starting tobe used.
Sam (36:40):
Yeah, exactly.
You define that quite well.
That's, what's going on.
And it's there's a lot ofresearch ultimately to create an
organism, which you could use todrive this.
Now one thing, I think that'simportant is that many
technologies cannot produce aproduct on their own.
You need a lot of paralleltechnologies.
And I think one of the bigproblems is that this is taking
(37:01):
place in an organism and you gotto extract the product out of
that.
On the engineering side, I thinka cell-free system is something
that will be needed in thefuture to support a more
efficient production.
But the steps you've describedis exactly what's going on.
In the case of human milkoligosaccharides, as I
described, that was in factfinding the right enzyme and
(37:23):
where the patents are concerned.
It's whether you choose thatenzyme from one organism and you
patent that or an enzyme fromanother organism and you insert
it into your E.
Coli or ultimately a yeast orsomething in other organism
that's where you getintellectual property position.
And have the engineered organismproduce your human milk
oligosaccharide that way.
(37:44):
There are many different typesof human milk oligosaccharides,
some are more complex thanothers.
And of course the more complexones require more enzymes and
you'd have to find the genes forthat and figure that out.
And that's still a work inprogress.
It's that's still veryinteresting.
Flavio (37:59):
You mentioned the cell-free systems.
Can we dig into a little bitabout that?
What are the main advantages andthen maybe also current
challenges with establishingcell-free systems to make
compounds?
Sam (38:09):
Quite simply it's because when you create the product,
it's still in the cell, you'vegot to actually extract.
There, there are ways to dothat.
And the simplest is is basicallyhave a transporter that exports
it out of the cell.
And in that way, that's how youcatch, you get a labeling of
non-GMO at least for foodingredients, for example.
(38:30):
And, but the thing is if it wasnot in the cell itself then you
don't have for example, an E.
Coli, there may be the potentialpyrogens, these are toxins that
could, if you're going torupture the cell, could present
a safety issue for humanconsumption and so on.
Finding a cell-free system isengineering a number of
requisite enzymes.
(38:51):
And whether they're inimmobilized onto beads or done
in other ways, there's many waysto do this.
There's many differentapproaches to it.
A lot of people say, oh, there'speople already doing it but
having a cell-free system tocreate proteins is different
than having a cell-free systemto create a specialty
carbohydrates or cell-freesystem to make fatty acids.
(39:12):
So there's a lot ofopportunities there.
Flavio (39:15):
So I haven't thought about this very deeply.
So just, can you draw the linemaybe between like classical
more chemical synthesis and thenthe cell-free system.
And then I guess the bio-,cell-based system, where, what
are the clearest distinctionsand what is need, I guess I'm
trying to figure out for thecell-free system.
(39:36):
What is needed to make it work,that's maybe challenging.
Why hasn't it proliferated more?
Sam (39:43):
If we look at just the chemical side of it and again,
this is where my pharmabackground comes in useful, is
that you can only createrelatively simple chemical
structures through synthesis.
Now those are still fairlyexpensive and time-consuming to
do because they're done in bigchemical reactors and they're
done in several sequentialstages.
(40:03):
And where that industry is goingnowadays is to go through
continuous processing.
So that you're not cleaning outvessels, you're not transporting
the products of reaction, A plusB to C, and then you have
another vessel C plus D plus Eand so on to make F you're just
going to run this through anumber of columns and other
(40:24):
systems to ultimately put, havethe product made at the end of
that.
You can do that for relativelysimple compounds.
But when you start to makeproteins, when you start to make
complex carbohydrates when youstart to make a specialty fatty
acids, I think that's where puresynthetic chemistry is going to
(40:45):
be a lot more costly, and that'swhere you would want a
biological system becauseenzymes can do that much more
exquisitely.
They can do that the yield andthen the rate of reaction much
faster.
And that's where you'd want abiological system to do that.
Now right now, that takes placein cells because the cell has to
produce the enzyme as well asany necessary co-factors to
(41:07):
actually do that in a cell-freesystem, that's the genius or the
innovation that's required toliberate all of these processes
from a cellular system.
Flavio (41:18):
So just to understand what the would the enzymes
required in the cell-freesystem?
They would've probably stillbeen made biologically a cell at
some point, then you would howdo I imagine this?
It's a big soup of differentenzymes and then you add like
you're starting products to it,or how do I imagine this
(41:39):
working?
Sam (41:40):
Yeah, correct.
So that's, many enzymes are madethrough, through a cell based
system, originally, that'sanother opportunity in synthetic
biology is there a way to makeenzymes more effectively, more
efficiently, cost-effectivelyand there are companies that do
that as well.
Flavio (41:59):
Okay.
Are there any cell-free systemsthat are already up and running
today in a large scale?
Or is it, is this still in theearlier phases?
Sam (42:10):
It's early.
So there's lots of opportunitiesthere.
And I'm stunned at how quicklythe field is evolving.
I went to I, one of the jobs Ihad earlier was to actually look
for companies that hadtechnologies like this, and I
would go to certain conferencesand see who is actually
presenting at the investorpitches to see if it's
interesting.
(42:31):
And I would flag thesecompanies.
I would go after them as acorporate development kind of
approach.
And what surprises me is that,about one year after I
approached these companies,they're getting major rounds of
financing from variousinvestors.
Which shows how quickly they'regoing.
Because if you're running astartup company, you know how
long it takes.
But these are getting intoseries A or even series B which
(42:52):
is in the millions ormulti-millions of funding
because they've actuallydeveloped some proof of concept
of their technology.
And it could be something assimple as just finding one or
two enzymes.
Being able to immobilize it ontosome column and doing some proof
of concept doing that.
That's where I see some of this.
There, there are, there is maybea handful or one or two
(43:14):
companies that, that are alreadydoing this at scale.
Much longer, but these are verytraditional companies.
These are there's one verytraditional company doing this
Novozymes.
Ah, there's another that'snewer, Carbios and so on.
But I wouldn't say that they'veby a long shot sewn up the
market.
Flavio (43:33):
Okay.
So just to make sure that Iunderstand this correctly.
So in the cell-free system themain advantage is that we're
saving the downstream processingthat we'd have to do in the cell
based system.
Is that correct?
Sam (43:50):
Exactly.
So cost and waste because youremove a source of a lot of the
waste that ends up...
Flavio (43:57):
the whole biomass and all the things the cell makes
that we're not interested in,but it needs to survive like.
Sam (44:03):
Because usually in a fermentation, what happens is
you don't start making theproduct right away.
You start by charging thereactor and then you have to
build the biomass up so that thecells are propagating and
growing to a certain level.
And then you transition theactivity of the cell towards
making whatever it is you wantto make.
(44:23):
So there is a lag time.
And then after that, if even ifit's excreting it, you still got
to extract your product out ofthat soup.
Flavio (44:32):
Yeah.
And sometimes the intermediaryproducts could be toxic to cells
and there's various ways...
Cells are very complex things.
And so you have to get it justright.
In many areas for this to work.
And then I guess once you have acell-free system, as you said,
it seems like ultimately thatwould be a lot more efficient
(44:53):
and you wouldn't have to dealwith toxicity.
Probably then you would have todeal if you do a cell based
system.
Sam (45:00):
Like E.
Coli (45:00):
phages is for example, a major issue.
The other thing is there's aregulatory one.
If you're going into feedadditives or whatever, there are
certain countries that will notgive you the right labeling if
it's out of out of the E.
Coli system.
So you would need yeast system.
So what I've seen is mostcompanies while they may have
started with Ecolab, becausethat was the first organism that
they actually optimized to makethe product, they would
(45:23):
eventually switch to yeastanyway at some point and then.
The other issue is you're stillin an organism.
You still have to extract itout.
And then what's dependent is allyour engineering downstream
engineering to actually clean,wash, polish or whatever.
the the, the.
crude material into your finalproduct.
Flavio (45:42):
So are cell-free system sort of the future, is that the
final, is that the, or I don'tknow if the final frontier, but
that sort of the next frontieris do you see, how do you see if
we zoom out a little bit wheredo you see the synthetic biology
space going?
What are maybe some of thecurrent major challenges and
maybe where do you see also someopportunities?
Sam (46:04):
Right.
So a lot of enablingtechnologies would be important
and that's where cell-freesystems, I would call them
enabling technologies toactually help improve the the
efficiency, the cost efficiency,as well as the yield efficiency
of these systems.
That's one space.
I think the area, you mentionedGingko Bioworks as a company
there are a number of companiesout there, do this early stage
(46:25):
tools as some people call it thepickaxes of the gold rush.
Those fundamental tools, thosecompanies there are, they are
there there's always room formore, but that's usually you see
companies like that in the earlystages of a new a segment of an
industry.
Another area that.
We haven't touched on this atall, which is what I would call
cultured proteins, which is nowwe're going to foods area.
(46:45):
We've seen meat-free products.
The first group of those wouldbe alternatives to beef
products, and that's really bigin the United States and I'm
seeing it worldwide.
And that's a different approach.
We talk mostly about metabolicengineering, but those companies
have looked at cell culture andusing stem cells, for example.
(47:06):
And so now we're looking at muchmore complex systems and it's
not simply metabolicengineering.
It's now we're looking at cellbased growth.
So they take stem cells out ofmuscles and use that to create a
meat-like product.
And there's some of the issuesthere are, first of all,
isolating the stem cell.
So you're basicallybioprospecting.
(47:28):
That's a simple way to describethat.
And then the other is you've gotto grow these things, which
means there are media anyonewho's worked in a lab growing
cells the media to grow thecells is an extremely expensive
input or a reagent that you needto buy.
So there are technologies,that's another enabling
technology that you would needto bring the costs down.
Flavio (47:52):
Yes, the media seems to be the, one of the main or maybe
the main bottleneck in gettingcultured meat to the masses is
definitely an area I've beenvery interested in and following
for for quite a while.
Oh Yeah, it seems like there's alot of a lot of exciting things
going on.
We could probably spend anothercouple hours talking about this
and maybe we will.
But I think for today we havegotten a very interesting
(48:14):
overview, a little bit of thebackground.
And where some of the currentchallenges are, cell-free
systems.
Definitely a, an interestingsort of enabling tech and yeah.
Do you have any last words, lastthoughts you'd like to share
with us today?
Sam (48:31):
I've got a lot of thoughts, but I'll keep it to, to just two
of them.
One of them is that theopportunity to get into these
new areas is just huge now.
I mentioned that I, at one pointin my career, I was looking at
venture capital and I did astint in a life science startup
accelerator.
I don't think that that is theonly way to do it now.
And nowadays you get startuphubs all over the world.
(48:53):
And it, 10 years ago, I used tolook at various methods of like
patent searches and looking atprofessors to find these
opportunities.
Now they can come from anywherebecause technology has gotten to
a point where it's hit andreached above critical mass.
So I think that there's,hopefully there's somebody
(49:13):
listening here and would beinspired to be able to do this
and look at this as"I can doit".
It's just not something thatyou, you have to be in Silicon
Valley or in some hotspot inSwitzerland, somewhere to do
this.
The other is that based on whatI saw when we started this
conversation about commoditychemicals, we're in a new
industry now.
And if you make a product it'sbest not to think about it as a
(49:37):
drop-in place replacement forsomething that's already in
existence.
You're creating a whole new setof products.
So don't bother to make apetro-based chemical, a
petroleum-like chemical based ona, on a biological source to
replace something that's alreadyexisted.
Create a whole new product likelike what we saw with cultured
(49:57):
foods now.
Flavio (49:58):
Yeah, no, that I think I agree.
And I think we could also spendmore time talking about the
entrepreneurial opportunitiesand maybe what skills are
required.
And what kind of skills peoplewho are interested in getting
into the field may want to learnabout?
And there's definitely a widevariety of range Wet lab to a
more dry lab, kind ofcomputer-based.
(50:20):
There's a downstream processing.
We touched upon fermentation,making bioreactors.
There's many interesting fieldsand, or enabling tech, as you
said, all of these differentskills will be required to bring
about this revolution ofsynthetic biology and it is
happening, but it's probablyonly going to grow over the next
decade.
It seems like you and I aredefinitely very interested and
(50:42):
passionate about it.
And it's been a great pleasureto have you on the show today.
If people want to find youonline, maybe reach out or just
follow what you're up to.
What's the best way for peopleto get in touch?
Sam (50:57):
So right now I just have a LinkedIn profile.
I used to have my own website,but the world's changed so much.
We had COVID we have theglobalization I think is
changing.
And so I just have a LinkedInprofile, but what I may suggest
is why don't we go through yourwebsite, where we're posting
this and have a conversationthere.
And if I'm looking there, wecould I could answer questions
(51:17):
or stimulate new conversationthreads of conversations.
Flavio (51:20):
Absolutely.
We'll definitely post it on thewebsite and people can leave
comments or reach out to medirectly.
And then we'll hopefully keepthe conversation going and it
would be, it was very excitingto have you Sam.
Thanks a lot for coming on theshow and hope to talk soon.
Sam (51:34):
Likewise.
Thank you very much.
Yes hello and welcome to another exciting episode of bio
2040, where we speak withthought leaders and experienced
researchers, entrepreneurs,investors, to uncover the
biggest opportunities in thebiotech space.
And I'm very excited today tohave Sam Lee with me, Sam Lee is
a very experienced veteran ofthe chemistry, pharma, health
(00:25):
tech, biotech space, and I'mvery excited to have you here,
Sam.
Good day.
Good day.
Sam (00:31):
Pleasure to be here.
Flavio (00:33):
Awesome.
Sam why don't we start off byyou giving us a little bit of
your background experiences whatyou've been doing in your
career.
Sam (00:42):
Sure.
I'll start from the beginning.
I'm a Canadian.
I got my PhD in chemistry,polymer chemistry from the
university of Toronto.
And my first job was as aresearch scientist at DuPont.
So that was where I started inthe division of.
Packaging and industrialpolymers.
So anything that's plastic.
And I did that for three yearsand then I had the pleasure or
(01:05):
opportunity to move into thebusiness development side.
And when I did that, I saw muchmore of the company.
Specifically the life sciencedivision, which they call the
life sciences enterprise thathad DuPont pharma, as well as
something they called bio basedmaterials.
They started to make throughsynthetic biology, which it
(01:26):
wasn't called that at the timefermentation to make a bio based
chemical.
That ended up being used to makesome fibers.
So I found that veryinteresting.
And as a result of that, I quitthe company and inside to get
into life sciences.
The first job I found in thatdirection was actually in a
biopharmaceutical company.
(01:46):
It was called NPSpharmaceuticals, which is based
in the U S and Toronto.
Which was a company that endedup developing two medicines that
are on the market today.
Then I went and worked with acardiologist to start help start
his biopharmaceutical companywith a medicine he invented for
cardiovascular.
(02:07):
Did that for a bit.
And then I joined a genericpharmaceutical company.
This is the genericpharmaceutical companies are
companies that make medicinesafter they expire, the patents
have expired.
And this is called Dr.
Reddy's Laboratories is one ofthe largest ones in the world
that was based in India, but Ispent the next eight years
working out of their us officeso it was really quite an
(02:29):
interesting range ofexperiences.
And in that process, I justbefore I ended up back up in
Canada, I worked with I becamethe founding partner with a
venture firm called SOSV.
That set up an accelerator forlife science companies in New
York called Indie bio New York.
I spent a little bit of timejust before the pandemic started
(02:53):
to get that going because it wasinvesting in life science,
startups particularly wheresynthetic biology was a field
that they were interested in.
So I've had an interestingcareer as I'm back in Toronto,
right now.
I'm actually working forBioNTech, which is the company
that invented the first COVID mRNA vaccine.
(03:14):
And and that's where I am.
But I have the pleasure ofmeeting you Flavio and
continuing this conversation andmy interest in synthetic.
Yeah, thanks.
Thanks for the introduction.
I think at this point, everybodyknows, BioNTech which produce
these wonderful vaccines thathave prevented probably millions
of deaths at this point.
Flavio (03:31):
So that's a, that's an exciting point.
We could probably spend anentire episode just talking
about that.
And then also Indie bio I'vebeen familiar with, it's a very.
Sort of incubator.
I was more familiar with the onein San Francisco, I think maybe
that was the first one.
And so you've really had a veryinteresting and illustrious
career across the wholespectrum.
I think that's also why ourconversation today is going to
(03:53):
be really interesting becauseyou can draw from all these
different aspects andexperiences.
So I think maybe for people toget situated.
Would it make sense to a littlebit talk about, today we have
this field called syntheticbiology, but and as you said in
your introduction, it wasn'teven called like that a while
ago.
So does it make sense for us togo and give somewhat of a
(04:16):
history?
Where did it start and where arewe today?
Sam (04:20):
Sure.
So what, where I, my experience,I did not include this when I
was giving my introduction isthat I did have the opportunity
10 years ago, back in 2010 to2011 to meet the CEO of a
pharmaceutical company.
And he contracted me to do somework for him and his family
(04:41):
office to look for investmentsfor him.
And I was so grateful for thatopportunity.
He must've seen in me my variedbackground that I could put a
lot of things together, myunderstanding and experience in
life sciences, but also groundedin my original background at
DuPont.
And so this was to look atthings in sustainability and
(05:02):
energy.
And this was to look forstartups that he could invest in
or new technologies that him andhis family office could invest
in.
This was just a side job.
I had a regular day job.
This was something I could do atnights on weekends.
So of course, when you get anopportunity like that you do it.
And we started looking at solarenergy, for example, at
(05:22):
Greentech of various types.
And then he came to me and said,why don't you look into
synthetic biology?
And this was 2011.
And I thought, what does thatmean?
And that's where I started tolearn about this space and
investigate it.
I did that by looking athigh-impact journals.
(05:44):
And I also did that because ofwe're looking at startups.
I started looking at patents andthrough that search, that's
where I started to see the firstiteration or first-generation of
companies, which I felt werewhat one could call synthetic
biology companies.
So just to be clear it's a bigspace.
(06:05):
It certainly is now, but evenback then, you could define it
by, by just about many differentcriteria.
We I broadly categorized it intwo broad buckets.
One of them would betherapeutics and the other would
be non therapeutics.
And most of the real-worldapplications as to where one
could go, one could arguably saythat there were products in that
(06:26):
space in a therapeutic areaalready.
So I looked at the nontherapeutic areas, which is a
huge space, but very quickly Inarrowed down on a number of
companies that were.
Being funded at the time.
Which we're getting some quitefar along with various products
and it turned out that thesewere they would call them
(06:46):
building block chemicals orpetrochemicals.
And that's when I stumbled uponthis connection that these were
products that they weredeveloping that were connected
to products that otherwise couldbe made from crude oil.
And so that was, it appeared tobe the first idea that drove the
first generation of companiesto, to make products as
(07:09):
substitutes or bio basedsubstitutes to petrochemicals.
Flavio (07:16):
So was that at the time was the idea there to fight
climate change was more of acost driver?
We could make a cheaper whatwere what was the idea and that
first sort of wave of syntheticbiology in the sustainability
area?
Sam (07:31):
It's a good question.
And that's when it at that pointin my life and my career, I
would have that moment where,when I look back, it all makes
sense and it all comes backtogether because by then I had
already left DuPont many yearsago.
And at the time I was at DuPontand in business development,
(07:51):
there was a big initiative inthe DuPont life sciences
enterprise.
They called it bio-basedmaterials.
And for all the scientists whowere in the traditional
chemistry area we felt, I feltleft out because all of the
spotlight and careeropportunities were going to
these biologists and what theywere doing was taking
(08:11):
fermentation to make a certaincompound.
It was called one,1,3-Propanediol is basically for
the organic chemistry.
So propane with two alcoholicgroups on either end.
And that would be the feedstockfor polyester.
And as I learned the businesspremise as to why they wanted to
do this well, polyester has beenaround for a long time.
(08:33):
And when in the early days whenpolyester was first developed
there, DuPont had figured out awhole range of different types
of polyesters.
You could make one of the bestpolyesters that they could make
was actually based on you.
This one, three propane dial,the reason they never chose
that.
And they ended up using theethane version of it.
(08:56):
The two carbon one is becausethat was the one that was
readily available from crude oilas a feedstock that was much
cheaper.
And now they found that in orderto provide a competitive product
let's make 1,3-Propanediol.
We have a way to do that throughfermentation and we could make a
new polyester fiber that wouldbe much more elastic, much more
(09:18):
durable, much stronger and soon.
And that was what drove it.
So basically the story otherthan that, you had a performing
fabric was that the cost pointbecame accessible because of
synthetic biology, which wasn'tcalled synthetic biology at the
time, it was just basically afermentation technology that
(09:39):
they through engineering E.
Coli was what they started with.
So that was the connection.
And then that was back in 1999,2000 when that product was being
developed and as it is on themarket in 2011, I began to see
that there was a whole bunch ofother products made by other
companies with that samepremise, that there were a lot
(09:59):
of products that the, thesewould be petrochemicals
chemicals that are 2, 3, 4carbons in size that would be
produced at petrochemicalrefineries.
And they would be the feedstockto go into.
Other materials downstream,mostly plastic but also a lot of
other materials and this firstgeneration of bio based
(10:20):
materials that were coming out,these synthetic synthetic
biology companies were basicallymaking that as a route alternate
as an alternative frompetrochemical.
So part of the storyline was tosay, this is a sustainable
material because they come from.
Fermentation, which is basicallyfrom sugar rather than
petrochemicals.
Flavio (10:42):
So in this scenario, we were essentially harvesting some
kind of sugar.
That we have was grown in somefield maybe sugar cane or some
other source of carbon whichthen the net CO2 would be zero.
Versus if we, obviously, if wetake a petrochemicals, these
products are then producedconsumed and ultimately
(11:04):
oftentimes either end up inwaste types or burned, which
then adds.
CO2 to the atmosphere.
Is that the correct way to thinkabout it?
Sam (11:12):
That's how they expressed it at that they, there was an
environmental element to this.
But the interesting thing washere's where the price of oil
comes in.
And this was, remember, this isthinking that's 10 years, 10
years old.
Yeah.
So where it is today and the, inthe storyline and the business
case are different, but it'sgood to know the past.
So this is 2011.
(11:33):
We just had the global financialcrisis in 2008.
And there was a little, if youjust look at the price of oil
between through the 1980s,1990s, it's been relatively flat
in us dollars.
Let's say about 40,$50.
And then it started to go up and60, 70, 80, 90 over a hundred
dollars a barrel.
(11:54):
We had the global financialcrisis.
There was a little blip, wentdown a bit, but it went back up.
So it was at an all time high.
And so oil as a feed stock intopetrochemical refiners is very
high.
Oil itself was the burning of itis contributing to carbon
dioxide.
And so both the price as well asthe environmental premise was
something that.
(12:14):
And the first-generation inthinking about this problem.
Those were undesirable elementsand what's going on then is
okay.
You've got a petrochemicalrefinery that's being the source
of these building blockchemicals that you need to.
What if we actually use thebio-based source?
So instead of using crude oil,let's just say it turns out to
(12:36):
be corn which provides theglucose to do fermentation to
make a bunch of materials.
It could be Propanediol.
It could be succinic acid.
It could be isobutanol,butanediol.
So these were the types ofmaterials that those first
generation of companies made.
They also the thought of makinga biofuel.
Because that's pretty there's abroad range of different oils
(12:59):
you could make from that.
So that's what they were doing.
And that was possible alsobecause the price of oil was
high.
So you had this tailwind in thebusiness case, tailwinds are
forces, which helped drive yourcompany or in business model.
But it's not a tailwind that'ssustainable.
If you take that away.
A big part of your business casefalls apart.
(13:20):
But at the time that tailwindwas the high price of oil and
then there was subsequently inthe U S at least there was a lot
of government incentivesprovided for green chemistries
that at that time was the Obamaadministration that provided
this.
And those were funds that wouldgo into helping.
The green chemicals industry asone way to call it evolve and
(13:44):
grow.
So that was what constituted,the first-generation the
companies they received a lot ofinvestment and at the same time,
they also ended up gettingproducts that were being
developed and hoping tocommercialize.
Flavio (13:59):
So what happened with these companies?
Both the biofuels.
I know if I remember correctly,there was a big hype back then,
but now it doesn't seem to havegotten as much traction as it
could have.
I think in Brazil, it's used forexample, as a gasoline
replacement, but other thanthat, it hasn't made these broad
impact that maybe some peoplewere wishing for.
(14:21):
So what did what happened withbiofuels and.
What happened with these otheruses that you are touching on in
and where are we today?
Is this now the price of oil hasgone back up.
Changing the game again, or somaybe if you can touch on the
unit economics a bit more indetail, that could also be
interesting.
Sam (14:39):
Sure.
Okay.
So biofuels is one segment.
These building block chemicalsis another segment.
If we just look at biofuels as asegment itself, it just
basically comes down to price.
We've got a lot in terms of theactual value chain or supply
chain of how these things aremade.
You do need to grow the cropsthat provide the glucose whether
(15:01):
that's corn or sugar beet orsugar cane.
You, you have that part, youhave to harvest that you have to
bring it into a location toconcentrate it.
That has to go into a fermentor.
And so when you compare thatwith the existing infrared
trucks, infrastructure thatexists for.
With with fuel itself it just isnot sustainable unless the price
(15:25):
of fuel was extremely high andyou got government subsidies
once the government subsidies goaway which basically happened as
the After effects of the globalfinancial crisis were away.
That was one leg that got pulledaway.
The other was that we neverexpected that shale oil and the
(15:47):
whole fracking technology cameinto play and it became a major
source of cheap oil as well.
The price of oil by around 2015,2016 had dropped.
Considerably because of this bigsupplier of cheap oil that was
enabled by another interestingtechnology, fracking technology
(16:07):
that brought it down.
So that, that whole aspect ofbiofuels was, had basically had
its legs kicked out of out ofit.
And it became unsustainable.
It's there, there is a bit stillin existence and I wouldn't call
it biofuels.
It could be ethanol which isadded.
But that's the remnant of whatthat part of the industry is.
The other part it's thesebio-based chemicals and it's
(16:31):
suffered the same effectsbecause your feedstock is very
high priced oil at the time,which no longer is the.
The other is the, so that's theThe input side of it the what
your costs are the output is, oris what your market is.
So if it's if it's going intoplastic let's say it's
(16:53):
polyester, or there has to be amarket that's large enough to be
able to make your unit economicswork.
As I indicated, Propanediol wasone of the first ones and it's
still a product that, that isstill made and it's integrated
in into the product supplychain.
(17:14):
So that's still sustainable.
It's not an industry in itself.
It's a product that's madein-house by the company that
used to be called DuPont as aproduct.
Succinic acid was one of theother ones that was a product
that was made by syntheticbiology.
It, they first started byfermentation of, e-coli and then
(17:34):
also by ferment, they switchedto a yeast based fermentation
for higher yields.
But still the price could not godown enough.
And at most you needed about40,000 metric tons to even start
to get there in unit economics,but you, and you would need to
have much higher levels.
So the problem there is that themarket demand the market size is
(17:59):
not high enough.
So, and that was the case of alot of these other products like
Butanediol.
So that's when we, when yourinput and output side are, the
economics don't work out,basically those companies don't
are not really that viable.
Flavio (18:20):
I think at this point it might be interesting also for
people to realize a little bitmore like where these
petrochemicals are used.
We talked about biofuels but inplastics, but there are other
areas as well.
Could you give us a quickoverview of what are the main
other from all the transport andheating, which is, people
(18:41):
probably most associated withoil and gas also, where else are
petrochemicals used?
Sam (18:48):
Well, actually predominantly it is plastics.
And this is where that was thefirst generation I would call of
synthetic biology companies isthat they are making the
building blocks for plastics,mostly polyesters.
And polyesters arebiodegradable.
So if it actually breaks downyou will have a some sort of
closely, hopefully sustainablesupply system and.
(19:10):
Degradation of those plastics.
The problem is that you'retreating these first-generation
of companies we're treatingtheir products as commodities.
And if one looks at it now eh,today, 10 years, Price of oil is
high again, but the the industryand the world has changed and we
(19:32):
are no longer, I feel working ina globalized world where
products can be shipped anywherearound the world.
We are going to be in marketsthat are more closed and
therefore the production thatyou make of any material.
Plastics for example, and you'dwant these plastics to be
recyclable or degradable, theywould serve a local market.
(19:52):
And so the companies that I seeevolving today, nevermind
synthetic biology for a moment.
These companies make materialsthat are degradable for
disposable wrappers, disposablecutlery, and so on as a very
simple example they serve verylocal markets.
And if that's the case, if we gointo bio-based materials what
(20:14):
one would make are a whole newsupply?
What I would think is as anidea, I'm not saying that I have
the right answer here where Ithink things are going is that
you would have to create a wholenew supply chain based on a
whole new set of materials.
So right now, what are the kindsof plastics that exist?
There's polyethylene.
(20:35):
Polyester which is there's manytypes of polyester, but
polyethylene terephthalate is orPET is the most common type of
polyester.
You would look at differenttypes of polyester.
And you would continue to dothat.
And basically you're developinga whole new set of materials to
replace the plastics that are inexistence today.
(20:57):
That's one way to do it anotheror second-generation is that
what are the other materialsthat you could make?
Another set would be.
Surfactants so these are morecomplex compounds.
They are originally come fromthey don't actually come from
some of them.
They come from petrochemicals.
Most of them come from othersources and including
agriculture.
(21:18):
The agricultural supply chainthis is becoming of interest and
they're used in soaps anddetergents which is a niche in
itself Another is to make thingsI one area I like and have been
watching for a long time as Palmoil, because Palm oil is used in
not just in a whole lot offoods, but in a whole lot of
other consumer products,cosmetics.
(21:41):
And they all come from Palmtrees, which really come from
mostly Indonesia.
And that comes at an incredibleenvironmental costs.
So where we are with generationto generation three, Is to make
a lot more complex systemsrather than just building block
are petrochemical likecompounds.
Flavio (22:04):
Yeah.
So there's a whole new businessarea really propping up.
There's companies like likeGingko Bioworks and many others
Amarys that are working oncreating.
Sometimes they're making lesstoxic or they're using less
toxic waste to make certainindustrial compounds that are
(22:27):
needed other times they'remaking you compounds right.
So one example is the flavorsand fragrances industry, for
example, vanillin, and I thinkis a classic example.
That's the sort of the moleculethat gives vanilla it's vanilla
taste and it's expensive togrow.
It only grows in certain regionsof the world, for example,
French Polynesia and then itneeds to be sourced and treated
(22:48):
and all that.
And at the end that the amountof work that goes into making.
The vanillin needed is quitegreat compared to us.
If you can have a fermentationbased system that makes the
exact compound, you need somepeople also call that precision
fermentation then potentiallyyou might have a much more
sustainable and also morepredictable supply chain.
(23:08):
Maybe I dunno if you havethoughts on that, where, the
plants and crops can be subjectto.
Both to pests climate disaster.
And now as we're learning alsogeopolitics starts playing a
role.
So instead of having to bedependent on.
Molecule being able to besourced only from a certain
region of the world.
We may want to have or countriesaround the world may want to
(23:30):
have a, as you were alluding toearlier their own sort of bio
manufacturing hubs, or they canmake the desired compounds,
where they needed and also beless dependent on both climate,
pests and geopoliticalperturbations.
Is that something you also seethat way or.
Sam (23:49):
That's right.
So Amyris, is, is a very goodexample of that.
That was one of the very first,Synthetic biology companies out
in California, back in the earlytwo thousands, mid two thousands
that got founded.
And it's been an interestingcompany to observe because
they've been trying to find theright business model for them to
stick.
And a very good example of that.
(24:10):
That was one of the very firstthe very first iteration of the
company was to create biofuels.
They had a way to, to, there wasto make a different fatty acids,
which are would therefore beoil.
That turned out not to besustainable for reasons which I
mentioned it's too high costscompared to what you could
(24:31):
actually purchase as regularFuel from petrochemical sources.
And then they started to pivotin a number of different ways.
One was in pharma ingredients.
Another was like you said in, infragrances these would be fine
chemicals.
Each one of those, it could bean industry is an industry in
itself.
And so this is where a one way Ithought about it was let's just
(24:54):
look, let's just look at theevolution of the chemical
industry which began long beforethe industrial revolution you
had companies that startedmaking fine chemicals which went
into pharmacy pharmaceuticalingredients you had from that
company.
These were all based in Germanyand Switzerland companies that
went into specialized in flavorsand fragrances.
(25:14):
You had companies that ended upgoing into dyes and pigments and
so all of those industries arestill I would have thought of
viable as approaches to thefirst generation and second
generation of synthetic biologycompanies instead of using
traditional chemical routes,most of which comes through
petrochemicals go throughsynthetic biology route and we
(25:36):
ended up we've been seeing that.
But now we're starting to seemore advanced versions of that.
So Amyris, I think never endedup catching on because they
never caught the right businessmodel.
So the way I would position itis that generation one are these
building block industrialchemicals that, that these
companies attempted to.
(25:57):
And their failure is that thoseare your, those are commodities
and you've positioned themcompeting against
petrochemicals.
Version 1.1 I would say is tostart to produce these specialty
chemicals and build a whole newsupply chain.
And that's a possibility ifthere's some entrepreneur out
there that wants to have thisvision of doing it, I think
(26:19):
that's a very interestingpremise.
Version two is instead of usingpetrochemicals as a, as an
input, why don't we considersome other carbon source, such
as carbon dioxide or methane,and we're starting to see
companies like that where yourfeedstock is not a sugar, which
is extremely expensive.
You've got to go through theagricultural supply chain is
(26:41):
secure that, but basicallyhooked your chemical your
company up to an industry that'ssupplying either carbon dioxide
or methane and or natural gas,some form of natural gas, and
we're starting to see that.
And that's driven by okay.
If you have that input, what canthe organisms that you've
engineered.
(27:03):
Make that's high value.
So that's another generation.
There are other companies thatcan make dyes most of these
dyes, again, come from finechemicals through a
petrochemical routes.
Many of these dyes are notbiodegradable, they end up
polluting riverways and yoursewer systems with these
intensely colored, sometimescarcinogenic dyes.
(27:25):
And so there are companies thatare thinking of, can we look at
dyes that are sourced fromorganisms, which are not just
therefore sustainable, but alsonot so toxic.
And that's another set ofcompanies.
We have companies that are usingsynthetic biology to, to make
compounds that really arevaluable.
So one of the ones I found thatwas very interesting was ways to
(27:50):
make human milkoligosaccharides.
These are sugars found in humanbreast milk and sugars in breast
milk are unique to.
the the mammal.
So the, one you find it inhumans is different from what
you find in Whales and what youfind in marsupials and so on.
And there were many companiesthat had a technology to
(28:10):
engineer E.
Coli to make these there'sabout.
Over 200 of these human milkoligosaccharides.
And why is the baby eating thesethings?
And nature and evolution musthave designed it in a certain
way.
And there have been studies toshow if you're actually having
breast milk with these humanmilk oligosaccharides there, you
do have lower incidents ofinfection.
(28:31):
You do have a better growthimproved brain development
marginally.
And it would be best for infantformulas too, to actually have
these ingredients in them aswell.
But you can't make these they'revery complicated by chemical
routes.
You'd have to use a biologicalroute.
And there was a company inGermany that, that figured it
(28:53):
out.
Two very brilliant brothers,Jennewein Biotechnologie, what
it's called and that's anexample I love as a citing as an
example of a synthetic biologycompany that made a very useful,
very high value product.
And just a year ago they wereacquired by a major specialty
chemical company for I think,400 million Euro.
(29:16):
So hats off to them.
That's a win that's a very goodexample of a, of an application
that, that actually is veryuseful.
Flavio (29:27):
Yeah.
So I love what you weredescribing, how, like the
version 1.0, these sort ofbuilding block chemicals really
turns out that you too closelycompeting with petrochemicals.
Oil, actually, is an incrediblycheap material in compared to
many other for the amount ofversatility did you can do and
(29:48):
the amount of energy that'sstored inside, right?
So it's a sort of very hard tocompete with that.
And then now we're learningthat, as I guess our tool
becomes better, our tools becomebetter.
Be in the synthetic biologyfield, the sequencing costs have
come down.
We have better assays.
We have high throughput assaysto test different to really do
(30:08):
cell engineering, cell lines andso on.
And so we can start engineeringmore complex pathways.
I think that's what you'retalking about now to make more
complex molecules,oligosaccharides or proteins
that are larger proteins thatalso maybe have a
post-translational modificationsand so on.
So it's really a whole new fieldthat's emerging now as both the
(30:31):
wet lab and dry lab come better.
There's a whole new field ofthings that they're opening up.
And I certainly love the exampleyou just mentioned with the
human breast milk.
I think that would be a boon.
If these infant formula all hadthese sort of healthier
compounds.
Yeah I think that's a veryinteresting way to think about
everything.
(30:51):
Maybe for people we can, getslightly technical here in just
explain a little bit more thesynthetic biology we've talked
about, how does it actuallywork?
What do people how do you gofrom an E.
Coli you find in nature toactually, making the compound.
Okay.
(31:11):
So there's many different waysto do it, but I'll just cite the
and that's why the field is sobroad.
And I'll just cite theindustrial biochemicals that
bio-based chemicals that westarted this conversation with
where originally the upstreamthe feedstock is sugar glucose.
And there's a number of pathwaysand these are ones that our
fundamental to two organisms asto how to they metabolize in
(31:34):
this case, sugar for energy.
And as I, what I noticed is thatwhen I looked at the patents,
the evolution or the timeline ofwhat, when these companies and
when these things came outclosely matched the, how far you
are going down each of thesepathways.
Sam (31:50):
So the very first one is the glycolysis pathway.
Which takes sugar and breaks itor builds that up into
Phosphoenolpyruvate and Pyruvatewhich, which are energy sources
that go on into other pathwayswithin the organism.
And when you look at thatPhosphoenolpyruvate is one that
(32:11):
can be engineered further.
By that, the pathways as towhere it goes to make succinic
acid.
And so that was one of the firstapproaches and early companies
using technology based onengineering, the organism to
take sugar.
And as it goes through the theglycolysis pathway gets to
phosphoenolpyruvate ends upmaking succinic acid.
(32:31):
Now if one takes the glycolysispathway further, it goes into a
number of other pathways whichare possible.
And this concept of metabolicengineering is about how do you
engineer the organism to steerthe direction of the pathway to
maximize the yield while keepingthe organism highly productive.
So another direction it could gois this aromatic amino acid
(32:56):
pathway.
So after you go through theglycolysis pathway, if you steer
it towards the aromatic aminoacid pathway, And, aromatic is
basically means benzene typecompounds and where you go then
may allow you to makebenzene-like compounds and
that's useful to maketerephthalic acid, which is a
(33:19):
building block, for example forpolyester.
And so there was a one or twocompanies that actually started
doing that because they managedto the professors that did that
work managed to find an optimalmetabolic engineered system to
do that.
Another direction you could gois after the glycolysis pathway,
(33:39):
you could go towards themevalonate pathway and that's
gets interesting because you itgoes into a lot of other
different products.
You could make fatty acids from.
You can make 1,3 Propanediol,which is the example I
personally saw in DuPont.
Fatty acids, those were in factthat's where Amyris, their,
their expertise was themevalonate pathway.
(34:00):
And I think the professorsoriginally came from UC Berkeley
and developed the expertise inthat to create a system and a
set of products that, thatdeveloped that could be used to
develop these fatty acids.
And then furthermore, afterthat, as you go further
downstream, you could end upengineering a lot of other
pathways towards the they'recalled phosphates drain your
(34:23):
phosphate, farnesyl phosphate,pyrophosphate.
And it's so on.
And that leads to a whole rangeof more complex compounds.
And when you get that far down,you're starting to make
compounds that could go intoflavor, instruct precursors
flavors and so on.
So that's the first generationof these industrials chemicals.
And they're all driven by howyou optimize that.
(34:45):
And they're all done in e-coli.
Eventually they will be switchedto yeast because you get a more
productive system.
And that's one way.
Flavio (34:54):
Okay.
Yeah.
So it seems like just tosummarize a bit more from a
layman's perspective, youessentially have sugar coming
from essentially, either corn orsugar beet or some other type of
plant.
And in this sugar gets turnedinto various compounds via
pathways, which are really justenzymes modifying these
(35:17):
compounds from one step to thenext.
And you have these very complexbranches of pathways things can
flow into.
And then the idea is here, if Iunderstood this correctly.
So finding out that the productyou desire to make finding out
chemically, where are you in?
Close in the natural wild typesort of pathway and then
(35:38):
engineering adding enzymes ormodifying enzymes and so on to
steer the flux, the metabolicflux into the direction that you
desire and it, and ideally haveat the end of the organism that,
has a hijacked pathway nowmaking the product that you
want, and then you, there's awhole bunch of downstream
(35:59):
processing that needs to happenafter that.
But is that's the high-levelgoal here and then synthetic
biologists companies like Amirysand Gingko and others have
specialized.
In doing these metabolicengineering tasks there's a
whole bunch of high throughputscreening going on sequencing
understanding the naturalpathways and in testing various
(36:21):
biological components swappingout promoters and enzymes and so
on to optimize the yield andthe.
titer your that your host canmake, whether it's E.
Coli, yeast or other, even morecomplex hosts like filamentous
fungi and so on are starting tobe used.
Sam (36:40):
Yeah, exactly.
You define that quite well.
That's, what's going on.
And it's there's a lot ofresearch ultimately to create an
organism, which you could use todrive this.
Now one thing, I think that'simportant is that many
technologies cannot produce aproduct on their own.
You need a lot of paralleltechnologies.
And I think one of the bigproblems is that this is taking
(37:01):
place in an organism and you gotto extract the product out of
that.
On the engineering side, I thinka cell-free system is something
that will be needed in thefuture to support a more
efficient production.
But the steps you've describedis exactly what's going on.
In the case of human milkoligosaccharides, as I
described, that was in factfinding the right enzyme and
(37:23):
where the patents are concerned.
It's whether you choose thatenzyme from one organism and you
patent that or an enzyme fromanother organism and you insert
it into your E.
Coli or ultimately a yeast orsomething in other organism
that's where you getintellectual property position.
And have the engineered organismproduce your human milk
oligosaccharide that way.
(37:44):
There are many different typesof human milk oligosaccharides,
some are more complex thanothers.
And of course the more complexones require more enzymes and
you'd have to find the genes forthat and figure that out.
And that's still a work inprogress.
It's that's still veryinteresting.
Flavio (37:59):
You mentioned the cell-free systems.
Can we dig into a little bitabout that?
What are the main advantages andthen maybe also current
challenges with establishingcell-free systems to make
compounds?
Sam (38:09):
Quite simply it's because when you create the product,
it's still in the cell, you'vegot to actually extract.
There, there are ways to dothat.
And the simplest is is basicallyhave a transporter that exports
it out of the cell.
And in that way, that's how youcatch, you get a labeling of
non-GMO at least for foodingredients, for example.
(38:30):
And, but the thing is if it wasnot in the cell itself then you
don't have for example, an E.
Coli, there may be the potentialpyrogens, these are toxins that
could, if you're going torupture the cell, could present
a safety issue for humanconsumption and so on.
Finding a cell-free system isengineering a number of
requisite enzymes.
(38:51):
And whether they're inimmobilized onto beads or done
in other ways, there's many waysto do this.
There's many differentapproaches to it.
A lot of people say, oh, there'speople already doing it but
having a cell-free system tocreate proteins is different
than having a cell-free systemto create a specialty
carbohydrates or cell-freesystem to make fatty acids.
(39:12):
So there's a lot ofopportunities there.
Flavio (39:15):
So I haven't thought about this very deeply.
So just, can you draw the linemaybe between like classical
more chemical synthesis and thenthe cell-free system.
And then I guess the bio-,cell-based system, where, what
are the clearest distinctionsand what is need, I guess I'm
trying to figure out for thecell-free system.
(39:36):
What is needed to make it work,that's maybe challenging.
Why hasn't it proliferated more?
Sam (39:43):
If we look at just the chemical side of it and again,
this is where my pharmabackground comes in useful, is
that you can only createrelatively simple chemical
structures through synthesis.
Now those are still fairlyexpensive and time-consuming to
do because they're done in bigchemical reactors and they're
done in several sequentialstages.
(40:03):
And where that industry is goingnowadays is to go through
continuous processing.
So that you're not cleaning outvessels, you're not transporting
the products of reaction, A plusB to C, and then you have
another vessel C plus D plus Eand so on to make F you're just
going to run this through anumber of columns and other
(40:24):
systems to ultimately put, havethe product made at the end of
that.
You can do that for relativelysimple compounds.
But when you start to makeproteins, when you start to make
complex carbohydrates when youstart to make a specialty fatty
acids, I think that's where puresynthetic chemistry is going to
(40:45):
be a lot more costly, and that'swhere you would want a
biological system becauseenzymes can do that much more
exquisitely.
They can do that the yield andthen the rate of reaction much
faster.
And that's where you'd want abiological system to do that.
Now right now, that takes placein cells because the cell has to
produce the enzyme as well asany necessary co-factors to
(41:07):
actually do that in a cell-freesystem, that's the genius or the
innovation that's required toliberate all of these processes
from a cellular system.
Flavio (41:18):
So just to understand what the would the enzymes
required in the cell-freesystem?
They would've probably stillbeen made biologically a cell at
some point, then you would howdo I imagine this?
It's a big soup of differentenzymes and then you add like
you're starting products to it,or how do I imagine this
(41:39):
working?
Sam (41:40):
Yeah, correct.
So that's, many enzymes are madethrough, through a cell based
system, originally, that'sanother opportunity in synthetic
biology is there a way to makeenzymes more effectively, more
efficiently, cost-effectivelyand there are companies that do
that as well.
Flavio (41:59):
Okay.
Are there any cell-free systemsthat are already up and running
today in a large scale?
Or is it, is this still in theearlier phases?
Sam (42:10):
It's early.
So there's lots of opportunitiesthere.
And I'm stunned at how quicklythe field is evolving.
I went to I, one of the jobs Ihad earlier was to actually look
for companies that hadtechnologies like this, and I
would go to certain conferencesand see who is actually
presenting at the investorpitches to see if it's
interesting.
(42:31):
And I would flag thesecompanies.
I would go after them as acorporate development kind of
approach.
And what surprises me is that,about one year after I
approached these companies,they're getting major rounds of
financing from variousinvestors.
Which shows how quickly they'regoing.
Because if you're running astartup company, you know how
long it takes.
But these are getting intoseries A or even series B which
(42:52):
is in the millions ormulti-millions of funding
because they've actuallydeveloped some proof of concept
of their technology.
And it could be something assimple as just finding one or
two enzymes.
Being able to immobilize it ontosome column and doing some proof
of concept doing that.
That's where I see some of this.
There, there are, there is maybea handful or one or two
(43:14):
companies that, that are alreadydoing this at scale.
Much longer, but these are verytraditional companies.
These are there's one verytraditional company doing this
Novozymes.
Ah, there's another that'snewer, Carbios and so on.
But I wouldn't say that they'veby a long shot sewn up the
market.
Flavio (43:33):
Okay.
So just to make sure that Iunderstand this correctly.
So in the cell-free system themain advantage is that we're
saving the downstream processingthat we'd have to do in the cell
based system.
Is that correct?
Sam (43:50):
Exactly.
So cost and waste because youremove a source of a lot of the
waste that ends up...
Flavio (43:57):
the whole biomass and all the things the cell makes
that we're not interested in,but it needs to survive like.
Sam (44:03):
Because usually in a fermentation, what happens is
you don't start making theproduct right away.
You start by charging thereactor and then you have to
build the biomass up so that thecells are propagating and
growing to a certain level.
And then you transition theactivity of the cell towards
making whatever it is you wantto make.
(44:23):
So there is a lag time.
And then after that, if even ifit's excreting it, you still got
to extract your product out ofthat soup.
Flavio (44:32):
Yeah.
And sometimes the intermediaryproducts could be toxic to cells
and there's various ways...
Cells are very complex things.
And so you have to get it justright.
In many areas for this to work.
And then I guess once you have acell-free system, as you said,
it seems like ultimately thatwould be a lot more efficient
(44:53):
and you wouldn't have to dealwith toxicity.
Probably then you would have todeal if you do a cell based
system.
Sam (45:00):
Like E.
Coli (45:00):
phages is for example, a major issue.
The other thing is there's aregulatory one.
If you're going into feedadditives or whatever, there are
certain countries that will notgive you the right labeling if
it's out of out of the E.
Coli system.
So you would need yeast system.
So what I've seen is mostcompanies while they may have
started with Ecolab, becausethat was the first organism that
they actually optimized to makethe product, they would
(45:23):
eventually switch to yeastanyway at some point and then.
The other issue is you're stillin an organism.
You still have to extract itout.
And then what's dependent is allyour engineering downstream
engineering to actually clean,wash, polish or whatever.
the the, the.
crude material into your finalproduct.
Flavio (45:42):
So are cell-free system sort of the future, is that the
final, is that the, or I don'tknow if the final frontier, but
that sort of the next frontieris do you see, how do you see if
we zoom out a little bit wheredo you see the synthetic biology
space going?
What are maybe some of thecurrent major challenges and
maybe where do you see also someopportunities?
Sam (46:04):
Right.
So a lot of enablingtechnologies would be important
and that's where cell-freesystems, I would call them
enabling technologies toactually help improve the the
efficiency, the cost efficiency,as well as the yield efficiency
of these systems.
That's one space.
I think the area, you mentionedGingko Bioworks as a company
there are a number of companiesout there, do this early stage
(46:25):
tools as some people call it thepickaxes of the gold rush.
Those fundamental tools, thosecompanies there are, they are
there there's always room formore, but that's usually you see
companies like that in the earlystages of a new a segment of an
industry.
Another area that.
We haven't touched on this atall, which is what I would call
cultured proteins, which is nowwe're going to foods area.
(46:45):
We've seen meat-free products.
The first group of those wouldbe alternatives to beef
products, and that's really bigin the United States and I'm
seeing it worldwide.
And that's a different approach.
We talk mostly about metabolicengineering, but those companies
have looked at cell culture andusing stem cells, for example.
(47:06):
And so now we're looking at muchmore complex systems and it's
not simply metabolicengineering.
It's now we're looking at cellbased growth.
So they take stem cells out ofmuscles and use that to create a
meat-like product.
And there's some of the issuesthere are, first of all,
isolating the stem cell.
So you're basicallybioprospecting.
(47:28):
That's a simple way to describethat.
And then the other is you've gotto grow these things, which
means there are media anyonewho's worked in a lab growing
cells the media to grow thecells is an extremely expensive
input or a reagent that you needto buy.
So there are technologies,that's another enabling
technology that you would needto bring the costs down.
Flavio (47:52):
Yes, the media seems to be the, one of the main or maybe
the main bottleneck in gettingcultured meat to the masses is
definitely an area I've beenvery interested in and following
for for quite a while.
Oh Yeah, it seems like there's alot of a lot of exciting things
going on.
We could probably spend anothercouple hours talking about this
and maybe we will.
But I think for today we havegotten a very interesting
(48:14):
overview, a little bit of thebackground.
And where some of the currentchallenges are, cell-free
systems.
Definitely a, an interestingsort of enabling tech and yeah.
Do you have any last words, lastthoughts you'd like to share
with us today?
Sam (48:31):
I've got a lot of thoughts, but I'll keep it to, to just two
of them.
One of them is that theopportunity to get into these
new areas is just huge now.
I mentioned that I, at one pointin my career, I was looking at
venture capital and I did astint in a life science startup
accelerator.
I don't think that that is theonly way to do it now.
And nowadays you get startuphubs all over the world.
(48:53):
And it, 10 years ago, I used tolook at various methods of like
patent searches and looking atprofessors to find these
opportunities.
Now they can come from anywherebecause technology has gotten to
a point where it's hit andreached above critical mass.
So I think that there's,hopefully there's somebody
(49:13):
listening here and would beinspired to be able to do this
and look at this as"I can doit".
It's just not something thatyou, you have to be in Silicon
Valley or in some hotspot inSwitzerland, somewhere to do
this.
The other is that based on whatI saw when we started this
conversation about commoditychemicals, we're in a new
industry now.
And if you make a product it'sbest not to think about it as a
(49:37):
drop-in place replacement forsomething that's already in
existence.
You're creating a whole new setof products.
So don't bother to make apetro-based chemical, a
petroleum-like chemical based ona, on a biological source to
replace something that's alreadyexisted.
Create a whole new product likelike what we saw with cultured
(49:57):
foods now.
Flavio (49:58):
Yeah, no, that I think I agree.
And I think we could also spendmore time talking about the
entrepreneurial opportunitiesand maybe what skills are
required.
And what kind of skills peoplewho are interested in getting
into the field may want to learnabout?
And there's definitely a widevariety of range Wet lab to a
more dry lab, kind ofcomputer-based.
(50:20):
There's a downstream processing.
We touched upon fermentation,making bioreactors.
There's many interesting fieldsand, or enabling tech, as you
said, all of these differentskills will be required to bring
about this revolution ofsynthetic biology and it is
happening, but it's probablyonly going to grow over the next
decade.
It seems like you and I aredefinitely very interested and
(50:42):
passionate about it.
And it's been a great pleasureto have you on the show today.
If people want to find youonline, maybe reach out or just
follow what you're up to.
What's the best way for peopleto get in touch?
Sam (50:57):
So right now I just have a LinkedIn profile.
I used to have my own website,but the world's changed so much.
We had COVID we have theglobalization I think is
changing.
And so I just have a LinkedInprofile, but what I may suggest
is why don't we go through yourwebsite, where we're posting
this and have a conversationthere.
And if I'm looking there, wecould I could answer questions
(51:17):
or stimulate new conversationthreads of conversations.
Flavio (51:20):
Absolutely.
We'll definitely post it on thewebsite and people can leave
comments or reach out to medirectly.
And then we'll hopefully keepthe conversation going and it
would be, it was very excitingto have you Sam.
Thanks a lot for coming on theshow and hope to talk soon.
Sam (51:34):
Likewise.
Thank you very much.
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