Hey everyone, many of you know that in
between debunking science denying
charlatans, I like to highlight new and
innovative research being done by the
scientific community. You may have seen
headlines regarding a synthetic cell
named Spud cell. What's that all about?
Let's go over some information and then
chat with the scientist behind it all.
Kate Adamala is a synthetic biologist
working at the University of Minnesota.
For anyone who is unfamiliar with this
field, it essentially entails using
modern knowledge in a variety of
scientific fields in order to physically
construct biological systems from an
engineering perspective. This could mean
redesigning existing organisms or even
creating totally new systems completely
from scratch. It's an incredibly bold
field which promises a wide variety of
potential applications. Most obviously,
this includes the capacity for
engineered microorganisms to synthesize
useful compounds such as life-saving
drugs, biofuels, plastics, and more, all
in eco-friendly sustainable manner. In
fact, we have highlighted research in
this area in other content when
discussing genetically modified
microorganisms that can express a
desired set of enzymes which allow them
to synthesize certain materials in as
straightforward a manner as brewing
beer. But beyond these applications, the
field inevitably brushes up against
territory of a philosophical nature,
given that one of the stated goals of
the field involves creating life from
non-living materials. In other words,
life from non-life. Given my extensive
efforts combating anti-science
propaganda surrounding origin of life
research, it's worth noting that
synthetic biology has only some overlap
with the notion of abiogenesis. Methods
that can be devised to synthesize life
in a modern lab, as remarkable as they
may be, are very unlikely to bear any
resemblance to the processes by which
life initially evolved on Earth several
billion years ago. And those are the
specific processes that origin of life
researchers are hunting for. It's a
question of what is possible versus what
specifically happened. Nevertheless,
illustrating a variety of potentiality
for the assembly of a living cell does
help us better understand the
possibilities that are available to
natural systems and which ones are more
probable than others. So, what is this
so-called spud cell? In short, it's some
water enclosed in a fatty membrane that
is filled with DNA and other cellular
components, which is capable of growth
and cell division. Not quite to the
degree of an actual living cell, but it
exhibits select behaviors that are of
the nature of a living cell. So, we
would not call it alive, but on a
physicochemical continuum that spans
from the completely inert to the
completely alive, it sits somewhere in
the middle and it is almost certainly
the closest we have come to building a
living cell from scratch. Other highly
publicized achievements in this field,
such as Craig Venter's synthetic
organisms, have involved designing and
synthesizing a novel million-base pair
genome from scratch and then
transfecting it into an existing
bacterial cell. So, the genome was
synthesized, resulting in a totally
novel organism that had never existed
before, but no other aspect of the
bacterium was synthesized. Demonstrating
that a living organism could be
sustained by synthetic genome was an
incredible milestone. Whereas, Kate's
spud cell appears to be a milestone of a
different nature. Spud cell is not a
pre-existing cell at all, but rather
involves droplets forming, fusing, and
replicating of their own accord. Cell
division is not reliable over many
generations, so the process is clearly
not as robust as what occurs in even the
simplest extant living cells. But, it is
a remarkable result that can be regarded
as a stepping stone towards a more
concretely viable fully synthetic
organism. Spud cell's genome consists of
only 36 genes taken from various
existing species across several domains,
making it much simpler than the simplest
bacterium. Some of these genes encode
molecular tags that present on the
surface of the droplet, kind of like
membrane surface proteins. Some of these
tags act as attachment points for feeder
vesicles or smaller liposomes that
contain enzymes and other crucial
molecules for the core droplet, which is
incapable of biosynthesizing its own
building blocks. Other tags bind to a
protein named streptavidin, which
creates enough repulsion among the
surface molecules to force cell division
in a crude and inefficient manner. One
obvious barrier to extended division and
replication involves the fidelity of
genome replication. Living cells have
systems in place to segregate replicated
chromosomes such that each new cell has
a full copy of the genome. Spud cell
can't do that, so only 30% of spud cells
carry the full genome after five
division cycles. But it remains the
first achievement of its precise kind,
the first instance in which a complete
cell cycle has been demonstrated by this
sort of bottom-up system, which is
totally unlike the more common top-down
approach of deconstructing an existing
microorganism. This means that the door
is wide open for iterative improvement
of this approach.
Kate's team's work on spud cell
currently exists in the form of a
preprint on bioRxiv and thus has not yet
been peer-reviewed or formally
published. It's nearly 200 pages with
all the data, so it's not a short read,
but it is linked below should anyone be
curious to get a closer look. And
indeed, the intention is to make all of
this methodology publicly available for
other groups to mimic. For our purposes
here, we can simply take a moment to
examine some of the key figures. Figure
one depicts the complete cell cycle that
was observed, including replication of
the multi-plasmid genome, gene
expression, nutrient uptake and waste
removal, as well as division and
selection. Figures three and four depict
five generations of the cell cycle and
selection in populations of synthetic
cells, respectively. But as this will
get quite esoteric very quickly, we will
do best to move along and speak with
Kate directly. Enjoy this conversation
now. Kate, thanks so much for joining
us. So, we're going to talk a little bit
about spud cell today, but maybe just to
start, can you tell us a little bit
about your background? How did you
arrive at this research interest that
you have currently?
>> Hi and hi everyone. Thanks for having
me. I I am a synthetic biologist, which
means I am interested in biology, but I
recognize the limitations of biology. I
I'm trained originally as a chemist.
And I really like to know where
molecules go when I work with something.
And then when I started learning
biology, I realized that biologists
don't really know where their molecules
go.
A natural cell is like a black box. We
don't have a full
chemical ingredient list. We don't have
full blueprints of it.
So,
I wanted to call myself a bioengineer,
but I really can't with a straight face
because what kind of engineer doesn't
have like the full plans of what they're
working with.
So, that was that that was what really
motivated um
my field, motivated my my work in this.
And
I ended up wanting to build a synthetic
cell for two reasons. Um one, to show
that we can, to show that we can
assemble molecules into something that
looks like a cell, that there's nothing
magical about life as a phenomena, that
we can assemble those molecules and they
start performing certain functions of
life.
And that's the scientific kind of a big
picture philosophical motivation. And
then there was the practical motivation.
And um
that motivation basically um
came from the fact that
if you think about it, the invention of
an electrical light didn't come from a
continuous improvement of a candle.
That's a quote that's very overused, but
it explains our motivation really well.
If we want to improve biology, we want
to build bioeconomy, we want to have a
carbon neutral economy that allows us to
produce everything we need, everything
the civilization needs, using renewable
biosynthesis methods with biology. And
we're not going to get there by
improving a natural heavily evolutionary
constrained cell.
I do believe it's possible to run world
economy on bioproduction, but I don't
think it's possible to do that with
natural cells, the cells that evolved in
nature cuz they evolved for very
different purpose.
>> Right.
>> So that was that practical motivation
behind wanting to make a synthetic cell.
>> Yeah, I I totally feel you on the I I
studied chemistry as well and so for me
in learning biology, there is sort of
that chasm when you get all even the
most the simplest extant cell. I I think
that a lot of people right there's a lot
of heavily publicized stuff in synthetic
in synthetic biology where I think the
general public doesn't fully understand
that it is very top-down just sort of
the redesigning of a genome or something
like that. This is totally bottom-up. So
let's let's dig into Spud Cell. Please
tell us a little bit about uh I we
really want to understand the
composition of Spud Cell, the functions
it can perform, and how it compares to
something like a modern prokaryotic
cell. So maybe starting with like the
genome, let's talk about that.
>> The genome is um multiple plasmids that
contain all the proteins you need for
DNA replication,
protein expression, so transcription, um
making
all the um
copies of the mRNA that you need, making
some of the ribosomal proteins, although
we do not make ribosomes in a Spud Cell
yet.
Um all the proteins you need for growth,
so the growth is genetically encoded,
it's coupled to the genome, and all the
proteins you need for uh replication,
which also is genetically encoded. And
that's pretty much it. Um there's some
helper proteins like um reporter
proteins that tell us something about
the healthy that that
organ that I don't know if you could
call it organism that thing is.
Uh but that's the minimal absolute
minimal amount of genes you need to to
be able to complete a cell cycle.
>> Right. Yeah, so I mean, I know that
there's this sort of like
>> [clears throat]
>> fear theoretical minimum genome length
for a living organism, and this is
dramatically less than that, but but
perhaps that's not surprising because
it's not considered alive formally.
>> Yes. Um, I [clears throat]
I'm I strongly believe it is not alive
because it's not robust enough, and also
it doesn't continuously replicate. Um,
it can go through a few replication
cycles and then it stops. And I think
that's where the gap comes from in the
genome size. Our genome is still smaller
than that theoretically predicted um
smallest genome size, and I think that
gap will be filled by the proteins we
need to be able to continuously
indefinitely replicate.
>> Right. So, so would that be some kind of
cellular machinery? Like obviously in in
accident life, there there might has to
be a way to kind of segregate the
chromosomes to ensure that each uh
daughter cell has the full So, you'd
need to design some kind of apparatus,
whether it be natural or something
completely of your own invention, that
would successfully perform that
function. Is that kind of one of the
main barriers?
>> That's correct. That's my personally the
biggest obstacle right now is that we
don't have something called
cytoskeleton. Like every cell has this
protein structure inside it that acts
like a skeleton, and we don't have that
in a cell cell.
It's significant that we've achieved
replication without cytoskeleton,
but it's also notably poor replication.
I think it's really important to
introduce cytoskeleton, which is going
to be some of those missing genes, and
that's going to help with two things.
One is the
indefinite growth and ability for the
cell to be more rigid and robust, and
the other one will be the segregation of
the cellular components, and most
notably the genome.
>> Mhm. Mhm. Yeah, it would be very
fascinating if you could install
something like that and then you had
continued replication with full fidelity
of the genome. Would that then be alive?
And if not, why not? And what would be
the next
uh you know, what issue metabolically
would be preventing it from being called
alive or something like that? Um
yeah.
>> That's a tricky question because we
don't really have a good definition of
life.
>> Yeah.
>> There is no scientific definition of
life that I would find sufficient.
>> I mean, I I find the I find the
definition sufficient in in its ability
to describe
extant life. But when you get really,
really granular, we're talking about
systems that we've never observed
before, then there is a point where it
breaks down, obviously, because we've
never seen the simplest possible thing
that could possibly be considered alive.
We don't know what that is, you know. So
>> Exactly. And we might There might not be
a line, you know, it might be a
continuum.
>> Yeah.
>> It's possible that there is no like a
very clear boundary between life and
non-life, and I would actually be very
happy with that.
>> Yeah. I think that's probably the case.
Yeah.
Um
>> life isn't anything special. Life is
just behavior of molecules, so
>> That's right. Yeah.
>> Yeah.
>> It's an emergent property of of a
sufficiently complex system of
molecules, yeah. Um I I would I'd like
to know a bit about the membrane as well
because it's it's not like a
phospholipid bilayer or anything like
that, right? What is Oh, it is? Oh,
okay.
>> It is a very simple, plain phospholipid
bilayer, which is different than extant
cells because, as you know, in extant
cells, the the
membrane it's called a phospholipid
bilayer, but it really isn't. It's It's
a It's a protein, glycoprotein,
lipids,
sugar mix
membrane. It's It's more more like a
liquid crystal made
in part from lipids, but also a lot of
other things.
>> Yeah, teeming with with surface
proteins, obviously, right? But there
are But there are there are a small
handful of surface proteins in Smudge
cell, right? Can you tell us about
those?
>> They are Those proteins have three
functions. Um they're membrane channels,
so they allow us to uptake nutrients
from the growth media.
And they also present tags on the
surface, and those tags are used for
feeding, so inducing the process of the
the feeding and division, inducing the
process of division. And these are the
three functions of the membrane proteins
and nothing else.
>> Mhm. So, a channel protein so that it
can uptake substance just from its
surroundings, but then sort of a tag to
to fuse with these liposomes, which that
basically you you have to feed your
Smudge cell intentionally, essentially,
right? So, that that might also be
considered another barrier to it being
considered alive as it's it can't really
self-sustain without being fed the the
liposomes.
>> That's I mean, I I'm firmly that this is
not a living system, but I do have
problem with that feeding intentionally.
I mean, you have to feed intentionally,
too. It
Every organism has to feed
intentionally, so I I actually don't
think the feeding is a barrier. I think
that metabolism and replication are
bigger roadblocks towards aliveness.
>> Okay, yeah, let let's talk about
metabolism then. So, so we have the we
have metabolic processes that are
occurring. Obviously, the there's
there's protein synthesis happening.
Um what else in terms of like energy
production? What else is going on in
there?
>> Not much, really. It It makes It has
a very simple energy regeneration
pathway, but it also has to be fed some
amount of straight ATP and GTP.
And it has um ability to obviously make
RNA and proteins. It It's easier to to
to list what it can than what it cannot,
because it cannot do many things. It
cannot biosynthesize building most
building blocks. Um so, I mean acids and
nucleotides have to be fed from the
outside. And it also cannot break things
down. So, once you made a protein on
RNA, it's there to stay until chemical
degradation takes over. And that's
another big downside of that metabolism
is that it doesn't take its own trash
out. It doesn't recycle components.
>> Mhm. Mhm.
Okay, yeah. So, so certainly just like a
lack of enzyme diversity would probably
be one thing. Is that Which Which could
we summarize? Is it possible to distill
it into a short list of bullet points of
what prevents Spud cell from being
alive? We have the the lack of of
continuous cell division. What How would
you state that state this?
>> Yeah, to me it would be lack of
continuous cell division, lack of the
ability to evolve. The Darwinian
evolution right now is not possible
because the genome replication fidelity
is too high to induce correct rate of
spontaneous mutations, and lack of any
sort of
advanced robustness. So, there's no
biosynthesis pathways for most
metabolites, so it cannot really respond
to changes in the environmental
conditions. It cannot compensate.
>> Right.
Right. So, but I did read something
about
describing aspects of competition and
selection for Spud cell. So, does that
occur indeed? And And if so, in
why does it not qualify as Darwinian?
>> It does have competition and selection,
but it has to use mutations that are
artificially introduced. So, we've shown
that we can have competition. For
example, we have a gene that allows for
faster replication. And if you introduce
that gene into the population, after a
few generations that gene becomes more
prevalent, like it takes over the
population, which makes sense. That's
what a competition is, but it's been
introduced that mutation's been
introduced artificially by me.
>> Okay.
>> It's not arising spontaneously, which is
why it's not to me it's not a Darwinian
evolution.
>> Right. It's non-random mutation,
therefore, okay, that makes sense.
>> Yes.
>> Um interesting, but but yes, we could
see yeah, if if the the cell division
could be prolonged, then we might have
enough time to see because you're you're
I think you said it was about around
five cycles before it becomes untenable.
So, what if that could be extended to
several hundred, then then we start to
see uh random mutation and and what that
does.
>> That's what I'm hoping for. Yes, and I
think that's why that that list of what
it needs to be alive is is kind of all
of it is tied to each other. None of
those things by itself are going to do
it, but I think all of it arising
together will give this emergent
property of of increased complexity.
>> Mhm. Mhm.
What what would you say it would might
be the absolute next step in going from
Spud cell to something even closer to a
fully synthetic living cell?
>> Make cytoskeleton, make ribosomes, and
make better metabolism.
>> Mhm.
>> Um then add genome construction tool.
Right now, the genome is and I I'm
allowed to say that cuz I made it. The
genome's messy as heck. It's um it's a a
set of multiple plasmids and there are
practical research considerations why
it's like that cuz we had to iterate on
many of those genes. It's easier to do
it if they're smaller plasmids.
Eventually, I do want it switch to a
single mega plasmid like a bacterial
chromosome style.
>> Mhm. And that's that's more of a
technical than conceptual research step,
but I think that's going to help a lot
in division fidelity.
>> Right. If you're on if you just have one
circular chromosome and then you get
two, what each gets one, that seems a
lot simpler than how many is it seven
plasmids or how many
>> Depends on which version that's seven to
nine is
>> Seven to nine.
>> is is what we use.
>> Yeah, seems tricky seems like you'd need
some more sophisticated machinery. Yeah,
yeah, condensing into one could reduce
the complexity of the machinery you'd
need to install to segregate those.
>> the experimental complexity because one
giant plasmid is incredibly difficult to
make. It's
>> Right.
>> There are ways to make it but they're
pain in the lower back which is why
we've been using smaller plasmids but
it's on the on the to-do list.
>> Okay. Okay, that yeah, that makes sense
as kind of the next step here.
>> [snorts]
>> So I I have a question which you you may
or may not be able to answer.
My viewers know that I've done a lot of
work combating anti-science propaganda
in the field of origin of life research.
And so
among the propaganda peddlers there's a
lot of conflation between origin of life
research and synthetic biology where
obviously there is some overlap there.
But
work such as yours is not directly
pertaining to right your your quest to
build cell from scratch is not
necessarily specifically elucidating the
process by which life originally arose.
But um
Can you speak to what you might see as
potential overlap? Is there any kind of
like functional simplicity to spud cell
that you think
does have some application to features
of like early protocells? Is this
completely exclusively bioengineering or
or or do you think your work has
application to origin of life?
>> It definitely has conceptual
applications with origins. The spud cell
itself is not an origins model because
it uses modern enzymes. But it's a
platform that allows us two things. One
is you can imagine doing ancestral
protein reconstitution and using the
spud cell platform to for example test
how an ancestral ribosome or some other
ancestral pathway could work.
So, rebuild some of that earliest cell.
And it also is on a more kind of a
conceptual level, it shows you how
molecule behavior can lead to emergence
of life-like properties. So,
>> Mhm. Mhm.
>> even though it doesn't directly describe
the identity of the molecules that were
present 4 billion years ago on Earth, it
does help us kind of a conceptualize
that process, figure out, okay, we need
this pathway, that pathway together
in that order, in that kind of a
type of interactions to reconstitute how
early life could behave.
>> Mhm. So, we can we can elucidate some of
the emergent properties
that can more broadly apply to to to
different sets of molecules, including
the ones that would have been present in
in the first protocell.
>> Yes, that's correct. Even though I want
to make it very clear that the Spud cell
itself is not an origins model because
it is a modern
>> Yeah, I I mean, it has a DNA genome
already that disqualifies it, but
but yeah, it is yeah, it it is quite
interesting to see the propaganda
conflating synthetic biology with origin
of life research and then having to kind
of go in and and and and separate the
two without
without denying the conceptual
application, right? There is something
here. We have very very minimalistic
sets of
of molecules and we're seeing how life
can arise from that. So, obviously that
has some appli- cation, but just with a
totally different set of molecules.
Yeah.
Um what would you see I I think that
with synthetic biology in general, there
are a lot of applications. So, I'd love
to hear you talk more broadly about the
applications of of synthetic biology,
but also very specifically in terms of
Spud cell, what kind of practical
applications there could be beyond
simply the the the you know, the this
incredible task of synthesizing a cell.
>> Short term, it can be a platform to
create biologically active molecules,
mostly drugs, um high value added
molecules that use non-canonical
building blocks.
Um it runs on a translation system
called pure, which allows for
incorporation of many non-canonical
amino acids into proteins, for example.
>> Mhm.
>> And there's many drugs and drug
candidates that use those
building blocks and they're right now
difficult to synthesize because you have
to make them chemically. So, that's kind
of a short-term, in the few years time
scale, um when we start seeing first
applications of this technology.
Long-term, the our 2050 goal and beyond
is bioeconomy. It's being able to move
all the atoms that our economy needs
with biology instead of dead biology,
the petrochemicals.
>> Mhm.
I've done a little bit of work
elucidating how we use uh synthetically
or sorry, genetically modified
microorganisms to kind of install suites
of enzymes to then build So, what what
would be the difference here with a
bottom-up cell, like really on the on
the molecular level? How how would it
How would a spud cell-like
um system up approach synthesis
differently from like E. coli or
something like that?
>> It allows you to go farther. Um for
applications that are not toxic to
cells, so like products that are not
toxic or
>> Oh, okay.
>> or chemical transitions that biology
already knows how to do, E. coli is your
first choice because it grows the
fastest, it's the cheapest, we know how
to work with it.
>> Mhm.
>> But for there are many products that we
cannot access right now with with live
cell biosynthesis because they're either
toxic or there just are no enzymes in
biology to make those products.
>> Okay.
>> And
that's These are the two things that we
can do in a bottom-up cell is one is we
can develop new enzymes that use novel
non-canonical chemistries, novel
building blocks, and we can make
products that would be toxic to natural
metabolism because we can design the
metabolism around that toxicity.
>> Mhm. Mhm. Mhm. So, you won't be
constrained by what life knows how to
do, and you won't be constrained by
chemistry that doesn't kill a living
cell.
>> That's correct. That's These are These
are the things that I need I think are
absolutely needed to realize bioeconomy
because we won't be able to make
everything with natural cells.
>> Yes. Yes, that's true. And And yeah, so
so obviously just kind of the greening
of of of industry, right? If we're able
to make biofuels and
obviously drugs, but
all kind like are there any materials
that we're targeting that aren't so
hyped up in the news? Is there
Or is it pretty much just just those
couple?
>> Um
the high-volume things like certain
kinds of polymers, plastics, these are
the the things that are in the news. The
the one thing that sort of flies under
the radar is fertilizers. Um right now
we use fertilizers that use a
petrochemically derived
process to synthesize them. And those
fertilizers are absolutely necessary for
the crop yields we need to feed the
current population of of the world. And
that's Many people don't know that
that's why there is a direct link
between food prices and fuel prices and
oil prices. It's not just because fuel
prices, it's also because fertilizer
prices. Those directly are tied to oil
because that's a petrochemical process.
And those are compounds that are and
reactions that are toxic to natural
cells, which is why we don't have a
biosynthesis pathway for them. So, to to
this biologically accessible nitrogen
cuz that's basically what a fertilizer
is, um, into at the scale that we need
to fertilize the fields to get the crop
yield, right now we need oil, and that's
one of the things that is not very
media, like it's not it's not people
don't talk about it much, but that's a
huge thing when we think about carbon
neutral economy.
>> Understood. Okay. Yeah, that's the
really is the most, uh, incredible
science that which really pushes the
boundaries of of what we can know and
understand about the the natural world
while also having this incredible
economic application. It's kind of the
best of both worlds, which you you don't
you don't always see,
uh, in science.
Um, yeah, those are all the questions I
had. I, you know, uh, feel free to take
a moment if there's any anything you
want to direct the viewers to. I know
that, um, it's kind of a tumultuous time
politically with the future of, uh, the
funding of of science unknown. I'm not
sure exactly where your type of research
would fall on the chopping block with
what's going on with the OMB and just
generally with Trump with the Trump
administration, but, um, anything else
that that you'd like to share with the
viewers?
>> Um, that funding is definitely a concern
of ours and also the fact that this has
to be a technology that needs to belong
to an open source global community, and
that's why those two reasons, the
uncertainty of federal funding and the
need to keep the platform in the public
domain, is why we started a non-profit
organization called the Biotic that is a
funding organization that's going to
support this work and also steward the
open sourceness of it. Um, I if we're
right that this technology really will
be the basics of the next
economical revolution, the bioeconomy,
it has to belong to an open source
international global community, not a
single country, not a not a company
single company.
>> Mhm.
>> And that's what Biotic is intended to
do. So, to me, the research news is just
like step one. It's cool, we've done it,
but now we have to move on and actually
make it useful. And Biotic is what is
going to enable making it useful.
>> That's fantastic. Very noble and uh
yeah, I'll be sure to uh to uh provide
the appropriate links in the
description. Uh well
>> know. I Actually, I want to pull on that
thread. I don't know if it's noble. It's
more of a self-preservation instinct.
>> Sure.
>> And I think we're not going to have a
planet to leave to our kids if we don't
do it right now.
>> I suppose that's a pretty good point.
It's actually
>> [laughter]
>> as much more of of self-preservation
than than anything else. Where Where
does it become the point where where we
fight back for our our own survival? Um
Yes, well, my viewers know that I've
been talking about that quite a bit.
>> [laughter]
>> Um yeah, that that's all the questions I
had. Thanks so much for joining us.
>> Thanks for having me.
>> Pretty fascinating, no? While we're not
yet in a place where we can construct a
fully functional living cell that can
reliably sustain itself and replicate
indefinitely without any assistance,
Spud cell is undoubtedly a huge step in
that direction. As to the precise
applications synthetic biology will
succeed in offering and the degree to
which this science overlaps with origin
of life research remains to be seen.
But, I will be sure to update you with
any other breakthroughs present
themselves. As always, thanks for
watching. I'll see you next time.