- Welcome, everyone, to Wednesday Nite @ the Lab.
I'm Tom Zinnen. I work here at the UW-Madison Biotechnology Center.
I also work for UW-Extension Cooperative Extension,
and on behalf of those folks and our other co-organizers,
Wisconsin Public Television, the Wisconsin Alumni Association,
and the UW-Madison Science Alliance,
thanks again for coming to Wednesday Nite @ the Lab.
We do this every Wednesday night, 50 times a year.
Tonight, it's my pleasure to introduce to you John Yin.
He's a professor in chemical and biological engineering.
He also works at the Wisconsin Institutes for Discovery
across the street.
Tonight he's going to talk with us about COOL,
the Chemical Origins of Life.
He's been working on this since his life began, apparently.
That's how he likes to look at it.
And his life began in Boston, Massachusetts.
He also grew up for a time in LA.
He went to high school in Kensington, Maryland,
did his undergraduate work at Columbia University in New York
City, and got his PhD at UC Berkeley.
Then postdocked in Germany for a while and got his first
professor position at Dartmouth College.
And then he came here to UW- Madison to improve his
ice fishing potentials.
[laughter] I didn't hear any really cold areas there.
This is going to be pretty cool.
I love a cube as the central problem of biology. That's good.
A cube does have a center, does it not?
Please join me in welcoming John Yin toWednesday Nite @ the Lab.
[applause]
- Thanks very much for the kind welcome.
Can you hear me all right in the back?
Yes you can. Very good.
So, I'm delighted to be here.
I'd like to thank Tom Zinnen for inviting me,
and it's really fun to be able to share some of our interests.
This central problem of biology.
This is supposed to be a figure of the universe.
So apparently people who study the universe
make simulations of it.
And this creates a problem for biology,
and that problem is perhaps stated here.
How could purposeful systems have emerged from a universe
with no purpose?
This was a question raised by Jacques Monod,
a famous French biologist and part philosopher,
in his work "Chance and Necessity,"
an essay on the natural philosophy of modern biology.
So, it's a rather deep philosophical question, I think,
and we'll be trying in this next 50 minutes or so to try to
answer it a bit more concretely.
So, how do we do that?
Well, we have to say something about what we mean by
purposeful systems.
So, what I have in mind, and I think what Monod had in mind,
were systems like this.
Here's a jaguar chasing after its prey.
Or a Venus flytrap getting ready for dinner.
Maybe some colonies on a Petri dish of mold.
Or perhaps a snake finding its dinner.
Those aren't the only things of eating.
Here's a spider web.
Probably there's a spider waiting for its prey.
But there are also other systems that have particular purposes...
[laughter] such as reproducing.
And even bacteria in our gut are reproducing.
So, what we mean by purposeful systems here
are systems that are alive.
They have this property of living systems.
We can contrast this with purposeless, purpose free systems.
Systems that are not purposeful.
What do we mean by purpose free systems?
Well, ones that are not looking for dinner.
Right? Some minerals, quartz.
Or the moon.
Snowflakes.
Beautiful, nice symmetries, but we wouldn't assign particular
purposes to those.
Or to the universe.
Or even to a beautiful sunset.
We're not looking at systems that try to find dinner here
or try to reproduce.
And in this sense we might be considering
purpose free systems.
All right, so, we'd like to think about how living systems
might evolve.
And there is a framework for thinking about this.
So we can consider the simplest forms of life,
those of perhaps the friendly bacterium here, E. coli.
And the framework for thinking about how this might have
evolved is to think that it moved from simple life,
single cellular life, to complex life.
We can think of this as multicellular life.
And there's some process for describing that.
Elucidating by none other than Charles Darwin,
who thought about the various ways that accumulations
of slight modifications can proceed.
So, if you can't see it in the back, I'll read this.
"If it could be demonstrated that any complex organ existed
"which could not possibly have been formed by numerous
"successive slight modifications,
"my theory would absolutely break down,
"but I can find no such case."
So realize this was now 1859 in his "Origins of Species."
He had no idea of what we today call DNA.
So he's just thinking about slight modifications that he can
observe as expressed in particular biological organisms.
But he's imagining that there's some underpinning mechanism
that can facilitate this, and certainly in the last century
this is a major component of finding, at the molecular level,
what Charles Darwin was able to observe
at the macroscopic level.
So, this is how systems, living systems, evolved.
We'd like to try to extend this Darwinian theory from simple
life to complex life but now beyond life
and extending it backwards.
We might call that a biological phase.
If we want to extend it backwards,
we might imagine that prior to simple life there was something
we could call non-life and that there was a phase of change from
non-life to simple life, which we'll call a chemical phase.
So the idea here is that that red arrow consists of chemical
systems, not biological systems.
And that's what we're trying to elucidate a bit here.
So one way we'll take to do this is to imagine how we might
extend Darwinian theory beyond simple life or complex life
to chemical systems.
Could we imagine chemical systems that could exhibit
biological properties that could evolve?
That's what we'd like to try to do.
So, today we'll be focusing, then,
on this aspect of the transition from non-life to simple life,
and we'll take a couple of different approaches.
One is to start at simple life and try to deconstruct it a bit.
See if we can allow it to evolve toward
something almost chemical.
And then we'll come from the other side of non-life,
simple chemicals, and try to give them,
mix them in appropriate ways that they begin to exhibit
life-like characteristics.
So Darwin, in his own day, had no,
made no attempt to try to describe
how simple life would arise.
I think he would probably be delighted to see that his theory
might have some application beyond living systems.
So that's what we're trying to do today.
So, we can think of that to the right,
everything to the right of simple life as being purposeful,
and everything to the left of non-life being purpose free.
And I'll let you decide where purposeful comes in
in that transition chemical phase.
I'm not going to try to define that tonight.
So, the title of my presentation here is
"Chemical Origins of Life."
I kind of like that, COOL.
So this is the COOL research project.
I'm here in the Department of Chemical and Biological
Engineering, and I also lead the Systems Biology Theme
in the Discovery building.
So I'd like to start off by suggesting a nice book that I
read last September.
This is "What is Life?" by Addy Pross.
Some of you might know that the famous physicist
Erwin Schrodinger also wrote a book by this title.
Pross comes at it, though, from a perspective of a chemist,
a card-carrying organic chemist.
And I think he offers some real insights into how one can be
thinking about how biology could emerge from chemistry.
And one of the observations he makes is that there are, well,
at least two kinds of stability.
He focuses on two kinds.
One kind of stability is what one could call
thermal dynamic stability.
It's non-reactive. It's like this bottle of water.
There's no reaction going on here.
Or it could be a few stones there.
Nothing happening there.
But there's a different kind of stability which he calls dynamic
or kinetic stability.
And this is a highly reactive kind of stable system.
That might sound contradictory, so we have to try to unpack that
idea of what a dynamic stability could be.
Something that's constantly changing but somehow also
maintaining something about its behavior.
And here I have chosen a figure of a couple
of living cells here.
So those would be an example of systems
that exhibit dynamic stability.
Other examples might be-- This is a fountain in Mexico.
I was in Mexico last week, and so here,
what you see in the white here, are the water,
where the water is coming in.
And here's the stone or part of the fountain sculpture.
And what I'd ask you focus on is the water part.
And you have to imagine that this is spraying out and
creating this pattern of a couple of areas of water,
which appear to be quite stable, but any given water molecule
that you see at one instant in time you won't see for another
few seconds, perhaps after it circulates through.
Yet the pattern here is quite stable.
So this is one where the water is constantly changing,
yet the pattern of the water is maintained.
What are other sorts of examples of dynamic or kinetic stability?
This is a little bit hard to see.
I've got to find a better picture for this.
But you have to imagine kind of a conveyor belt here where this
conveyor belt is moving from top to down here.
And these objects here are cookies.
So this is a process if you go to the cookie factory.
Way way upstream, up there, is where they mixed up the batter
and the sugar and all the ingredients.
And they put it on this conveyor belt,
and the conveyor belt goes through a continuous oven.
It's got openings at the entrance where the cookies move
in, and an opening at the end where the cookies come out.
And here they're starting to leave this conveyor belt
and then go on to a cooling rack.
And this is, I would claim, an example of dynamic stability
because if you stare at this and you take pictures of this at
every instant, it'll look something like this.
There'll be different cookies, but the same pattern will be
reproduced over and over again.
If you bake cookies at home, you might be more akin to something
like this where you only have one door.
And we might call this a certain kind of--
What do we call this for cookies?
- Batch. - Batch. B-A-T-C-H.
That is not an example of dynamic kinetic stability.
We put the batch into the oven. It's constantly changing.
When we peek in the oven at different times,
we see it's brown to different extents.
So, over time, that is not an example
of dynamic kinetic stability.
What might be another-- Oh, this one.
So, you look at me up here and you might think this guy is--
How is this guy an example of dynamic kinetic stability?
Well, I do have to inhale in order to speak.
So as I am inhaling. I'm taking in oxygen.
Fortunately there's oxygen in this room.
And as I exhale and speak, I'm producing these words for you.
So I am also a dynamic stable system.
Some of my family members may have some questions
about the stable part. [laughter]
But I am taking in the oxygen
and producing carbon dioxide.
So I too am an example of a dynamic stable system.
Now, I come from the area of chemical engineering,
so I have to teach you at least a little bit
about chemical engineering.
So this would be an example of a reactor,
which we call a continuous stir tank reactor.
It's stirred tank because we've got a little mixer here,
and you can think of that as a propeller.
And when that propeller is spinning around,
that means everything in the tank is well mixed
and of the same composition.
This tank also has some feed here.
Those of you who might be from the more quantitative sciences
might see something that looks like changing
of velocity with time.
So this would be a volumetric flow rate.
So many gallons per hour might be the flow rate
into this vessel.
And this might be also at some concentration of some component,
concentration in.
And then within the tank we have a concentration
of that component.
Maybe it's sugar within the tank.
And then there's a volume of the fluid in the tank.
And then coming out there's some flow rate--
volumetric flow rate coming out.
Now, if the flow rate coming out is the same as the flow rate
going in, the volume within the tank will not change.
And this will be an example of dynamic stability,
in the sense that the volume is constant even though the
contents of the tank are constantly being renewed
and being drawn off.
Notice that the composition of what comes off will always
reflect whatever the composition was in the tank.
If we take it even another step further for the mathematically
inclined, we can try to think about things
that might grow in the tank.
So if it's sugar water, I might introduce some bacteria in
there, and the bacteria might grow or the yeast might grow,
if I'm interested in fermentations.
So we can call those bacteria or yeast replicators.
That's a more generic term.
Something that replicates or grows.
And one way we might represent how that concentration of
replicator changes as a function of time in here
is this is a term called a derivative.
Something we teach our undergraduate students
in calculus.
And we're saying how rapidly or how this concentration changes
depends on two kinds of terms.
Terms of growth, and the growth terms depend on how much
replicator we already have in there as well as what is this M.
This M is the food. Concentration of food.
If we have zero food in there, there's no growth.
But if we have some non-zero positive value for M.
This is positive.
And k is a rate of replicator formation given the presence
of replicators and food.
So all of those are positive values.
Likewise, g is a positive value.
It's a rate of decay or death.
And that would include not only if these cells are dying in
here, but also it would include some kind of accounting for how
they're leaving the tank.
So that g combines both those kinds of terms.
g is positive and X is positive.
So the term minus gX would be a negative term.
And what happens in cases of dynamic stability?
Then this equation simplifies.
Do we have any mathematicians or engineers in the audience,
or physicists, perhaps some chemists,
who could tell me how this equation would simplify?
- dX/dt will be zero.
- dX/dt will be zero Thank you.
Let's hear an applause.
[applause]
I want you in my class. [laughter]
All right, so that means that's zero,
and if that's zero, then that means we have a balance between
the growth and death, or we have a balance between
growth and decay.
Those are equally balanced, and that means if we sit
and look in this tank at any given point in time,
there is no change in the concentration of our replicator,
even though it is growing and it also dying.
It's just that those are balanced, quantitatively balanced.
I could take it a step further and put tank
inside of a process.
Don't look at the details here.
Just realize that there are a bunch of tanks connected
together with other things, and there are arrows here.
The main thing is in this process
there are inputs to the process.
This happens to be a biomass process.
So you put in biomass and you get some fuel out of this thing.
But this has inputs and outputs, and if we look at any component
within this process, it'll be like this one in the sense that
it'll be a dynamic stability.
Likewise, I can look at a big chemical plant where there are
many more of these operations, we might call them unit
operations, where somewhere in this plant there's a feed,
there are a bunch of distillation towers,
there are a bunch of other processing components,
and then there's some outlet.
Essentially, somewhere in here there's a way to feed in raw
materials, and there's a way to pull out products.
And when this plant is running, then it's also an example
of dynamic stability.
All right?
So that's your chemical engineering for the day.
Now we need to move on a little bit.
And we'll just emphasize the point, from process perspective,
Darwin's theory of natural selection should extend to
replicator chemistry.
So now we're trying to look at the chemistry,
and we need to say something a little bit about chemistry.
So just a little bit of chemistry.
I want to introduce a few terms.
So, one kind of chemical compound that you can find is
a polymer or polyethylene.
It's a very common plastic.
And you can find your ice cream perhaps distributed
in polyethylene containers.
And I already alluded to this term,
that if you look at the plastic and ask what is the technical
term for the plastic, you might encounter this term polymer,
which is made up of monomers.
So the monomers are single units,
and the polymers are stitched together.
Chemically stitched together monomers
to make what we call this polymer.
And the process of chemically linking together the monomers to
make this chain is called polymerization.
So that's a little bit of chemistry.
And the process of polymerization-- So the
polymerization of monomers of something called ethylene,
which contains two carbon groups,
yields a polymer or plastic that we call polyethylene
That's what we had over here.
In the chemical formulas, you have carbons
with hydrogens connected to them.
And the polymerization process, which chemical engineers like to
do, is to link together these monomers to make long chained
polymers, and then process those polymers into nice shapes
that can be useful.
So that's polymerization. That's unnatural polymerization.
You won't go into nature and find polyethylene,
at least-- Well, I should be a little careful.
[laughter]
These days you might find some plastic out there,
but not naturally formed polyethylene.
Perhaps released by some living form.
But there are also polymers that exist in living systems.
And here we should say something about DNA.
You've heard of DNA.
For our purposes, DNA is indeed a polymer
and it's made up of monomers.
Not the same single unit of monomer
as we see for polyethylene.
But now we have four unique monomers.
And we won't go into the chemical details.
They have different shapes, and they're made up of
different elements.
The purple is a common element shared by them, but the bases,
these other colors, represent how they differ.
And these are sometimes abbreviated A, T, G and C
for these chemical compounds.
Adenine, cytosine, guanine, and thymine.
We don't need to worry about those details.
The main point is DNA is a polymer.
So you imagine somehow stringing these together.
Chemically linking them together.
And chemically linking then I could make something out of
solely A or solely C or mixtures of A and C.
What is important here is that I can begin to encode information
using the different monomers.
I could do the same if I had just monomers of ones and zeros.
And that's what you have in your computer.
Ones and zeros essentially encoding information,
except they're not chemical ones and zeros;
they're electronic forms of ones and zeros.
All right, so this is just to iterate or emphasize the point
that all life uses the same monomers.
So they're the same monomers of DNA.
What differs from the DNA
of these various different organisms?
Well, it all boils down to every organism has its own compilation
of total DNA, which we call its genome.
And the corn plant has a genome.
You have a genome that was provided to you by your parents
as when you started off as a fertilized human egg.
And that genome then defines the various processes of development
that ultimately result in a mature corn plant when these
seeds are placed in the appropriate environment,
or when this fertilized egg is allowed to develop in the
appropriate environment, to complex organism.
Key differences here are that the genomes have different
lengths and they have different sequences.
They are chemically identical, though.
So that's pretty remarkable.
That tells us we are somehow all related, all lifeforms.
Okay, so where are we now?
We've talked a little bit about how we are trying to extend
Darwinian theory beyond life to chemical, chemical systems.
And we've talked a little bit about what sorts of chemicals we
might be particularly interested in.
Some kinds of polymers that are made out of monomers,
where the monomers are different and able to encode information.
So, let's take the next step
and consider a particular biological system.
Recall we're going to go and take,
start from the simple life here and try to go backwards
to something simpler than simple life.
So, simple life is a single cell here, but it's being invaded.
And this is a virus particle.
So this touches a little bit on the sort of research we do.
The virus particle is a little bit of information.
It can be made out of DNA or that information could also be
made out of a similar polymer called RNA.
But the main point is that information is delivered to the
cell, and when that information is unpacked in the cell,
it can direct the resources of the cell to make more virus.
All right?
So the cell normally, when it's provided growth media,
the cell itself will divide in two.
It'll grow larger and divide in two.
When the virus finds such a cell,
it sees the cell as raw materials.
So here I am putting on my chemical engineering hat and
saying this is actually perhaps like those processes where we
have some raw materials being converted into products.
Except from the standpoint of the viruses,
it's putting in the information that's informing the raw
materials in this cell how to make viruses.
It's turning the cell into a virus manufacturing plant.
And you might make anywhere from a hundred to a thousand
or 10,000 viral progeny from a cell.
And this could take anywhere from 15 minutes to 15 hours or
15 days depending on the virus that you might be working with.
All right, so this is how a virus reproduces.
What we want to do is deconstruct this a bit
and reduce it to a little bit of its chemistry.
So I want to take a look at a little bit of what's going on
in the deconstruction and construction of viruses here.
So this goes back into thinking this approach was an early stage
of systems chemistry.
I would call this the chemistry of figuring out how biology
might have come about from chemical processes.
So when a virus enters the cell, I alluded to the virus genome,
and this is used as a template to make proteins.
Proteins then feed back on processes that allow the genome
to reproduce itself, and then the genome gets together
with these proteins and ultimately packages them up
and makes virus progeny.
So this does not show all the resources of the cell,
but it shows some of the components that are important
for the virus.
If we take even a greater simplification
and look at this virus genome,
then we can ask what is chemically happening there.
So this virus genome for a particular virus,
I'll be considering one called a phage,
the virus genome was made out of a piece of RNA.
So you should think of this as a polymer made out of
DNA or RNA like monomers.
So different monomers where they have a unique sequence.
And this plus strand, plus indicates that there's
a certain kind of polarity.
If you can think of--
Well, we could also think of this as ones and zeros.
And the monomers then are components that can stick to the
RNA and be stuck together, bound together by a particular enzyme
or catalyst that the virus brings into the cell.
The virus also encodes this enzyme.
So when the virus genome gets into the cell,
it instructs the cell to make this enzyme.
And what happens is the enzymes uses the genomic template that
the virus introduce into the cell,
and it uses monomers that are present in the cell to stitch
together a complimentary piece of RNA.
So the red was what came in with the infecting virus,
and the blue is something that is made within
the infected cell.
So you can imagine if we think of monomers as being 1-1-0,
the first few monomers here as being 1-1-0,
on this opposite strand, coding in the negative sense,
you would have-- Let's see, I said 1-1-0,
so across from 1 I would have 0, and it would be 0-0-1.
So you can imagine how strings of ones and zeros on the red
strand could be complemented by ones and zeros
on the complementary blue strand.
So either strand encodes the same information.
And what happens within the cell as these strands separate during
an infection, and the replicase can then operate the same way as
it did on the red strand to make another blue strand.
But the replicase can also now operate on the blue strand to
polymerize and make the complementary red strand.
So we started off with a single red strand,
we made a red and blue,
and now we have two each of the red and blue.
And this can continue on.
So you have the possibility for exponential,
or you could call it explosive growth.
What the virus does when it enters the cell is it
essentially sets off a chemical or a genomic explosion,
making many copies of the genome.
So, what happened in the 1960s was a biologist by the name of
Sol Spiegelman said this is a very interesting reaction,
I wonder if we could deconstruct it
and think of it more in chemical terms.
So what he did was he and his coworkers isolated this red
strand from infected cells and the polymerase, this enzyme,
and he put them into the test tube and he bought
from the store the monomers.
So chemical stores you can buy the monomers
and you can also put in there.
So we no longer have this reaction going on
during an infection inside of a living cell.
He's trying to reconstruct this process of amplification
in a test tube, in a little plastic tube here.
So he has a few strands of the RNA,
excess monomers or building blocks that he bought from the
store, and excess replicase which he isolated
from infected cells.
And the question was, well, would this run or not?
Maybe if you provide all the ingredients for the initial
strand here and the enzyme, the catalyst that stitches together
the monomers, and plenty of monomer,
then you could keep on doing this process
of molecular growth.
Would that be possible? Well, indeed he tried that.
This is Sol Spiegelman.
So at time zero he mixed the ingredients together,
incubated them at, I think, about 37 degrees C,
about a little warmer than room temperature,
and over time he was able to measure the concentration
of RNA in the tube.
You might notice that this scale here is on an log scale.
So this is one, that's 10, and that's 100.
So the RNA here is growing exponentially over time.
And this is over a period of two, three hours.
It just keeps on growing.
You see initially it starts off with the same slope.
So that's an exponential growth, but then it starts leveling off.
And you can imagine that it's leveling off
because it's using up those monomers.
As you use up the monomers, the growth slows down.
So what he did next was an interesting thing.
He took these RNA molecules that were made in the tube
and he introduced them back into living cells.
So, normally the virus would introduce these molecules
into the cell.
Here he had a way of introducing them into the cell so the cell
could still remain intact.
And what he found was the cells would make more viruses.
So he's taking RNA molecules that were made in the test tube,
introducing them into the cell, and the cell now makes viable
virus particles that he can take and put on other cells,
and they'll continue to grow.
So he's made, within the test tube,
this molecule that is infectious.
This is 1965.
There were no companies like Promega
selling these biological enzymes.
He isolated it from the infection and was finding,
essentially, that he could make something that was infectious.
People called these molecules Spiegelman's Monster.
[laughter] Because they're RNA molecules that in some ways
behave like life.
So he took the next step and said, "Well,
"what would happen if we didn't allow them to
"run out of materials?"
How could you do that?
Well, he wanted to ask the question.
So this is the-- This is a couple of years later.
Proceedings of the National Academy of Sciences.
An extracellular Darwinian experiment with a
self-duplicating nucleic acid molecule.
So this nucleic acid, that's the RNA.
Self-duplicating, you know how that works now.
And this is extracellular. It's outside of the cell.
And there's, well, potential for evolution maybe.
And the key point here is he was asking,
what will happen to the RNA molecules if only the demand
made on them is the biblical injunction: multiply?
So you want to see, if you give them the resources to multiply,
how they will do.
And that means that you don't want them to run out.
So how do you keep them from running out?
Well, here's how they set up the experiment.
They set up what is called a serial transfer experiment.
There's the tube initially where they had their goodies of the
strands of RNA and the monomers and the replicase,
but then they set up a series of tubes here that had plenty of
the monomers, excess monomers and replicase, but no templates.
So there's nothing going on in these tubes.
You have growth initially in this tube.
And before you're able to use up all of those monomers,
you transfer a small fraction of that tube into the next tube.
So, some of those molecules that grew come into this land
of excess monomers.
You can say this land of milk and honey.
They're ready to replicate.
So you do a serial transfer, and they start to grow.
They can grow, again, in this tube just as they did in the
first tube except they're in this tube with all
these fresh monomers.
And they're able to grow and before they grow and use up all
those monomers, you transfer them again.
So you're constantly transferring these molecules,
and you imagine those lucky molecules that happen to get
transferred from tube to tube, the lucky large molecules,
only see all this plentiful monomers.
So, what happens then?
Okay, so here's what happens.
You start off with transfer number 0,
and these are the various transfer numbers.
As he's doing the transfer numbers,
they're counting or doing an accounting of how much of that
monomer has been incorporated into the reaction.
So after one or a few transfers, you see there are more and more
monomers being incorporated.
And up through about nine transfers it seems like each
transfer is taking up about the same amount of monomer.
But around nine or 10 it seems like there's a change in this slope.
You're not continuing along the same pattern.
You're actually going a little bit faster,
taking up more monomers.
So the system seems to be changing.
Up here it looks like things have slowed down,
but actually that's a little bit of an illusion.
What we don't indicate here is now he's started transferring
even more frequently because these molecules were taking up
the monomers so rapidly they had to reduce the time that they
were allowed to take up the monomers.
So what appears to be slower here
is actually even faster growth.
All right?
So, something is changing as we are doing this.
You have to admit this is basically a chemical experiment.
We don't have any living cells here.
There's an enzyme, there's a catalyst, it's a protein,
and these RNA molecules, then some monomers.
Then what he did was also, as before,
he took these templates and he put them back into the cell.
So, up through passage number nine,
when he put these back into the cell, the cell was infectious.
It made plenty of virus just as before.
So the monster was intact during those first nine transfers.
But by transfer 10, and everywhere beyond,
none of those molecules when put back in the cell was able to
produce a viable virus.
Somehow this molecule, this system,
lost the possibility of making virus.
So the monster is dead.
But some way there's a different monster here
because it's growing faster.
What he did was to analyze what was finally coming out here.
And when he looked at that molecule,
he found that it was much shorter.
83% shorter than the original starting material, starting molecule.
The starting molecule was about 4200 monomers in length,
and this was only about 17% of that.
Much smaller molecule.
So, smaller and able to replicate or reproduce
much faster than the original molecule,
but now not able to instruct the cell to make virus.
It's lost the essential information needed to make
viruses, but it's gained some capability to replicate
very rapidly.
That's pretty neat.
And this, I would argue, is an example where the molecules are
doing this selection process.
There are mutations that are occurring.
The mutations happen to shrink the molecule.
When the molecule is shorter, it doesn't take as long to make it.
So when you've got resources and you can grow faster than those
that are growing slowly, then you get enriched,
and you have a better possibility of being transferred
to the next tube than the ones that are reproducing
more slowly.
So that's a nice example of Darwinian selection
at the molecular level.
So that's the example that we just considered.
Simple life, deconstructing it, putting it into the test tube,
and showing that as long as we can replicate and create perhaps
some kind of variation, then things can evolve.
Now I want to take it from this side,
a system that is clearly non-life,
and see if we can move it in this other direction.
How do we do that?
Well, my second son is coming up to 15 years old.
So he's in ninth grade.
And in his biology book he's got this nice description of this
experiment by Stanley Miller from way back in 1953.
Some of you might have heard of this.
The idea was to take what was thought
to be a primitive atmosphere.
Gases in the primitive atmosphere of Earth
had things like water, perhaps methane,
CO2, ammonia, hydrogen, nitrogen.
No oxygen though.
So the early planet was thought to lack oxygen
in the atmosphere.
But there was certainly water around,
so there's also water down here.
So the gas is able to communicate or exchange material
with the water.
And what Miller did as a graduate student,
23-year-old graduate student at University of Chicago,
was to put a spark in here.
And when he sparked it, he found that there were compounds
that were formed in the water.
And those particular compounds were amino acids.
So, amino acids, it turns out, have a special place in biology.
Amino acids are the building blocks of proteins.
And when I say building blocks,
another term for that would be...
- Monomers. - Monomers.
And so there are different-- Boy, you guys are great.
[laughter] There are different amino acids.
Some of you might know there are 20 some amino acids, typically,
that we use to build up the proteins in our hair
or skin or muscles or tears.
We're just chalk full of proteins,
but those proteins are all made up of amino acid monomers.
And the proteins of all lifeforms are made up
also of amino acids.
So this was a huge triumph to go from these very simple gases
and to realize that the building blocks of biology
could be produced.
So I was very curious to turn the page and see what was next
in my son's biology textbook,
and they move onto the next topic.
[laughter] Okay.
That leaves you in suspense.
But it says to me also that maybe this field hasn't really
moved a lot since 1953.
And that's both a challenge but maybe it's also an opportunity.
So we've begun to think about this a little bit,
but we also have some help from some giants in the field to
think about how can we start stitching together these amino
acids, maybe to make proteins and maybe to move a little bit
from non-life in the direction of simple life.
So, if you look at the problem, then you immediately hit a wall,
and here's what the wall is.
I have to go a little bit more into the chemistry here.
The main point here is I have two amino acids.
They're both the same amino acid.
There's an amine group and there's an acidic group,
or acid group.
There's the acid group and amine group on this other amino acid.
And what happens, in order to chemically stitch
these together, we have to take a water.
You might know water has a chemical formula H2O,
and if we steal away H2O from these two,
then they can stitch together and form a bond.
Notice this has CCN and this has a CCN,
and if we read all along the line here, we have CCN and CCN.
We just formed a bond here, and that's called a peptide
or amide bond.
And in the process of making that bond,
we kick out the water.
So the water appears down here.
Now, there's a problem here in that if you go to your freshman
chemistry student and ask, "What direction is this chemistry
"favored if your amino acids are in water?"
If you have lots of water present,
then the chemistry favored is in the hydrolysis direction,
or moving upwards rather than moving downwards.
Moving downwards is what we want.
We want to stitch together these monomers to make two amino acids
joined together.
But what is favored in actual chemistry is, in water at least,
is a hydrolysis or a lysis or lysing or splitting of a
molecule by inserting a water.
So the water gets inserted here to make the two
separate amino acids.
So each of us is very unstable.
If you go to the swimming pool and sit there long enough,
this is what's going to happen.
You will be decomposed into your amino acids,
as long as there aren't other bacteria there.
But the chemistry at least favors your decomposition
back to your monomers.
All right, so this is a problem, and this is a serious problem.
In your body, you routinely stitch this together.
And this is happening as we speak.
You are digesting, you are making proteins,
but the machinery to do this is many orders of magnitude
larger than the amino acids.
So something the size of this room is the enzyme that helps to
stitch together amino acids of this size.
So a highly evolved, very complex machinery made of
both protein and RNA.
That we don't have present on the primitive Earth.
So we've got to figure out a way of trying to do this chemistry
in a much more primitive way.
And that's where I allude to the giants.
One of the giants in the field is Bernd Rode.
So he is an emeritus professor now from Vienna, Austria.
He's a theoretical chemist.
But he thought, you know, there's this problem of
stitching together the monomers, I wonder if we could do it in a
simple way by putting in some copper chloride.
So this is a little hard to see.
I'm sorry the color is a little washed out here.
But the copper here is indicated by this little trapezoid here.
And the amino acids now are shown by the circles here.
So it turns out that if you put some copper chloride into
solution, it forms a nice blue solution,
but the coppers have this tendency--
Well, copper is positively charged.
It has a two-plus positive charge.
The amino acid could have a little bit of positive
and negative charge.
It has enough negative charge so opposites attract,
and that amino acid may become associated with the copper.
Not only that, another amino acid might associate
with the same copper.
So now you have two amino acids, two monomers
brought into close proximity.
You can think of the copper as kind of a matchmaker for the two
amino acids, and they're sitting down to lunch here.
[laughter] Now, if the appropriate conditions are such
that it's not too acidic, then these two potential partners
jockey around, look at each other in the eye,
and realize that they might like to come together.
And if they actually come together,
if you could remove a water at this point,
then you can actually drive the chemistry so that these two
monomers come to the same side of the table and form that amide
or peptide bond.
The trick here is that you've got to remove the water.
So, maybe we've just shifted, maybe it's just a semantic point
here, but a key aspect here is that you brought these guys
in close proximity.
And the removal of the water is where Rode, I think,
was particularly clever.
One thing he did was to have very high concentration of
sodium chloride, salt, table salt, which, in solution,
likes to pull on water.
Sodium chloride likes to have water around it.
So it can be stripping away water.
These are water molecules around here.
But what he also did was leave the tube open
to the environment, so the water could just evaporate.
So he said, all right, leave the tube open to the environment,
allow the water to evaporate, and maybe you can get the
chemistry to go so now there are some di-mers.
These are two unit now monomers.
We'll call it a di-mer.
So, that allows you to--
It shows you how you can go from monomer to di-mer.
And then you can imagine the next step might be, well,
if you add backwater, and then these guys,
this di-mer can go back into solution.
But it can associate over here on the side.
So you could have a di-mer over here,
and then the next guy adding here could be either
a monomer or a di-mer.
If you go around the whole cycle again, evaporate,
then you could form two di-mers coming together would give you a
tetra-mer, or a di-mer and a monomer coming together
would give you a trimer.
So, by just going around here, essentially drying and then
rehydrating and then drying again,
we have a machine to be able to stitch together these monomers.
Here we've considered monomers that are all the same.
But you can imagine that we can now put in different monomers.
Any drawn for those natural 20 amino acids.
And you could imagine that, depending on their particular
chemical affinities for copper, that we might have any array of
different kinds of polymers that could be formed
from different monomers.
So, we had to try this on our own.
Back about 10 years ago, I had a master's student,
and I said why don't you give that a try and mix some amino
acid, in this case alanine, with some copper chloride and water.
You form this nice blue solution.
And let's just heat it to dry it.
So you bring it to 60 degrees C. You just put in on a block.
And you leave it open so it evaporates.
But to make sure we could do some kinds of measurements on
what's going on, I said, well, let's weigh this thing.
So here's the mass of the water.
We started off with half a gram of water in there at time zero
when we initially mixed this together.
And then over a period of, oh, what, four to eight hours,
took periodic samples, weighed it,
and because it's open to the environment,
you can imagine this water level just dropping, dropping,
dropping as you're evaporating,
and that's what you're seeing right here.
Mass of water in there is decreasing.
At the same time, we were sampling that water and doing
some analysis, some chemical analysis to say do you got any
dialanine in there.
And so the dialanine axis is over here,
and during that drying process as the water is dropping
and evaporating, we don't see any dialanine.
We don't see any dialanine after eight or 12 hours,
but if we incubate this now 16 hours and then we rehydrate it
and analyze, lo and behold
there's a little bit of dialanine.
And if we incubate even longer, there's more dialanine.
So this solid here is reacting.
That condensation reaction is actually occurring in the solid.
We're making polymers in here.
We're not making any polymers over here,
but we are doing that here, as we incubate this solid.
And we don't have to stop at 20 hours.
We could go out to 200 hours, and it keeps on going.
If we go out to 400 hours or so,
it doesn't maintain the same pattern.
This reminds us that maybe we're starting to use up those
monomers, as we saw with the RNA experiment.
So you can imagine other sorts of serial transfer experiments
you might want to do.
That's as far as we went in 2006,
but Rode did a series of other experiments
that were very intriguing also.
What they did was to put in other amino acids.
So, histidine is another amino acid.
This has some interesting side chemistry.
It's able to become acidic or basic depending on its side.
It has some more interesting chemistry than the alanine
that we are considering.
And the main point here is when you put in that additional amino
acid, this particular amino acid, it has a catalytic effect.
That means that it accelerates the reaction
without being consumed.
So you imagine bringing in that histidine.
Somewhere the histidine might associate a little bit over here
or over here or maybe in the solid phase.
The key point is if I've got histidine in that system,
then this growth curve of dialanine will be even steeper,
will make much more dialanine in the same amount of time
than we made in the absence of histidine.
So histidine is not being consumed.
It's serving as a catalyst.
Those of you who have studied some biology or biochemistry
know that enzymes or proteins that have histidine,
oftentimes the histidine will play a catalytic role,
that it can actually do some chemistry in the enzymes.
So maybe it's not surprising that the histidine alone in this
particular system could do some chemistry.
What was really surprising, though,
was when they took glycine.
So glycine happens to be the simplest amino acid you can imagine.
It's chemistry is just--
It's side group is just this H, a hydrogen.
And inside of you there's no enzyme.
I've found no-- We've got a great biology department,
biochemistry department here.
No one-- None of my biochemistry colleagues can tell
me of an enzyme in nature where glycine is active as a catalyst.
All right, it's boring chemistry.
All right?
But here, it's catalytic.
How could that possibly be?
So you've got this boring amino acid that normally, in our body,
doesn't do anything interesting, but in this particular scenario
can do something interesting.
And we have some thoughts on what's going on here
because when we look at these solids,
we see at least two kinds of solids.
One kind of solid looks kind of crystalline,
like if you pour a little salt out of your salt shaker.
It's kind of crystalline.
Another kind of solid is kind of glassy.
So it's kind of amorphous.
And it looks like melted glass.
In that case, it turns out that the reactive solid is more
reactive when it's glassy than when it's crystalline.
And we would hypothesize that when glycine is present,
perhaps it acts as a bit of a plasticizer and allows the
material to even flow a little bit and do some chemistry.
So that's a guess at this point.
We haven't demonstrated that, but we think that even the most
boring amino acid, a single monomer, can now be an enzyme,
and that's really quite remarkable.
Okay, so where do you go from there?
Well, we're starting to mix amino acids together and cycle
them and do all sorts of things.
And we've talked about how we started from the simple life
and move down towards non-life.
And hopefully I've convinced you that maybe non-life could be
moving in this evolutionary direction.
Maybe I have to elaborate a little bit more
on how that would work.
I've shown you how non-life, how the monomers can be brought
together to make polymers.
And I've suggested that certain monomers can be catalytic,
even the most boring ones.
If that's the case, then you could imagine any set of
polymers could possibly be catalytic.
So let's assume we have some building blocks,
and here I've shown the building blocks are monomers
in several different colors.
Red, blue, and green.
So we have-- We've considered three different monomers.
And just imagine that I put in the copper and do some chemistry
and allow these monomers to form di-mers.
We already saw that for alanine, that you could form
a homo di-mer made of the same monomers.
Or you could imagine maybe in some cases you'd form a hetero
di-mer made out of two different monomers.
Or if we cycled a few times, maybe you could make penta-mers
or even some-- I'm sorry.
This is mislabeled.
This should be-- What should this be?
This should be quatra-mer or tetra-mer.
So, of course, I purposefully did that just to see
if you were awake.
[laughter] All right, so you could imagine in this soup,
depending on how many times one of these molecules has been gone
through the process of being dried out and rehydrated,
that we might have some di-mers or tetra-mers or penta-mers,
and there might be some variation.
There's no kind of template copying here as we had
in the RNA case.
So there's no template copying.
So you could imagine any number of different kinds
of polymers arising.
And I just indicated a few variants here.
Now, what's interesting to think is that maybe this di-mer
could be like glycine.
It could be a catalyst.
And when I say a catalyst, that means maybe if this is present,
then it helps to make one of these B polymers.
So A could serve as a catalyst to enable B to be made
more readily, one of these B molecules to be made more
readily, more easily, without being incorporated,
but just facilitate that chemical synthesis.
The same could be said of B.
Maybe B, one of these B molecules could help a C,
and a C could help an A.
That's the interesting part.
If you have the possibility of somehow this loop closing
because then if A enhances B and B enhances C and C enhances A,
this is a positive feedback.
And a positive feedback has a capability then of growing out
where these molecules enhance their own synthesis,
while the ones that don't contribute so much to the
chemistry are left behind.
So you might imagine the red variant here does a little bit
better job than the blue variant.
And it would be perhaps enhanced by the chemistry here and allow
certain members of each of these penta-mers, di-mers,
or tetra-mers and di-mers to grow out.
So here, this is just an arm waving,
but I'm trying to make the case that it's plausible at least
that we could see some synthesis of polymers,
hetero polymers made up of different monomers,
enhanced in their synthesis and contributing to the bigger
picture of self-replication.
So, I've tried to make the case that under different
environments we might form different monomers, or, sorry,
different di-mers or polymers, and these might react on
themselves under different conditions.
If we make things a bit more acidic or change the
temperature, you can imagine the chemistry is favoring some
molecules over others.
So maybe there's an opportunity also for adaptation or evolution
in this kind of system.
So there are a few broader impacts or extensions of what
I've tried to elucidate here.
I've showed it for amino acids, thinking about how amino acids
might come together and become functional,
enable their own replication.
We're very interested in also doing this with
the RNA monomers.
For those of you who follow the biology--
I'm sorry, this got a little bit scrambled here.
But we're testing the RNA world hypothesis.
Some people believe that RNA was actually the first biopolymer to
be formed, and there are good reasons for that.
We're not convinced yet, but we think this might be a way to
show that or find RNA molecules that are able to contribute to
their own replication and evolution.
We could imagine taking the RNA monomers and mixing them with
amino acids and doing this kind of cycling and perhaps allowing
both kinds of polymers to arise.
I mentioned that the machinery that stitches together proteins
in living systems is very much more complex.
That machinery is called a ribosome,
and it's made up of RNA and amino acids or peptides.
Peptides being amino acids strung together.
So maybe it'd be possible to evolve that kind of machinery in
a test tube, where these kinds of cooperation where there's a
cooperation of RNA and peptides or proteins.
You don't have to stick with the amino acids or RNA,
the monomers that nature gave us.
There are many kinds of fascinating amino acids
that do not exist in nature.
We're not restricted to the ones that exist in nature.
We could carry out the same chemistry
using non-biological monomers.
And we imagine that they could conceivably also replicate.
So you could imagine making polymers that are reproducing
and are evolving and adapting but not made out of anything
that arises in living systems.
So we don't have to also restrict ourselves to the
specific kind of polymerization chemistry that I've shown here.
There are many kinds of polymerization chemistries.
So one could branch out to things that are not just
hydrolysis condensation chemistries.
Alternatively, we could stick with the 20 amino acids,
and just say let's repeat the experiment several times and see
if we get the same monomers condensing to form
the same polymers.
How reproducible is evolution?
Or if we do it at a slightly higher temperature,
will we get a very different kind of distribution
of molecular species?
Perhaps so.
So, what role does environment play on the evolution?
This is that idea of rewinding the tape.
We are also very interested in computational chemistry.
So, the things that happen in the solution phase,
this forming of amino acids coming together with copper,
is very well studied.
It's been known how that happens for more than 50 years.
So people who want to try to simulate that behavior
in computers have no problem with that.
It's just that when you dry and remove all that solvent and form
that solid that's reactive, that's a complete unknown,
and it would be a fabulous frontier, I think,
of computational chemistry to try to compute how living
systems or information containing systems could arise.
So that's something we're also currently working on.
So I try to make the point here that spreading these ideas of
Darwinian selection from living systems to chemical systems
might give us some insights into ways that life might have
originated from chemistries.
I'll end with this particular quote from Richard Feynman:
"What I cannot create, I do not understand."
Thank you.
[applause]