Guten Tag und Wielkommen und ich wir der Sagen, es freut mich Söfähle glückliche Gesichter
zu sehen.
Avich sehr nicht fähle Gesichter und ich wir der mein no maule Frägerstellen wie Waren
die Farien.
und sie wür nann worten Wielke Farien.
Ok schweissnicht ob profs Eigner Tovar und Wilsen, ere för leisungen auf Deutscher
der English halten werden, für like Wechsler ich sur English.
So this course is about RNA and this lecture is historically the first lecture in the course
because it's about the start of life and the role that RNA played and we will do nothing
less than answer the questions as to why are we here, what does it all mean, what is life
and how did life start.
Obviously we won't really answer all of those questions but I will get to in a few seconds
the definitions of life and evidence that life on earth started with a world that had
nothing but RNA in it.
Of course this is all rampant speculation and there are lots of problems with this idea,
nobody knows how life started so we talk about problems and at the end let me mention
an alternative viewpoint that maybe there was no RNA world and you can debate this topic
endlessly and nobody will ever say that you are right or wrong.
So how did this story start off?
So a few words of history, a few decades ago people looked at life on earth and they said
well the way modern life works is proteins enzymes are the catalysts of life and you
need them to copy DNA.
So it sounds like proteins are the most important but at least you could say a very important
component until in 1986 the first RNAzymes were found and this is really where the idea
of an RNA world started.
This was a radical idea in 1986, until then everybody said that all catalysis in all forms
of life is done by protein catalysts enzymes and then came the first good experimental
evidence and later a Nobel Prize that actually RNA could be an important catalyst as well.
So this topic is actually a surprisingly hot topic, it's pretty much purely academic but
there is this constant stream of papers in real good journals, so I'm talking about science
or nature chemistry and so on, where people every so often claim they may have found how
life started or the original oooh-a-zoopa and so on.
This is a popular sport.
Now if you look at life today you think about proteins and nucleotides working together,
so we have proteins, these do amongst their roles, the proteins do the copying or catalyze
the copying of nucleotides.
The nucleotides are mostly information storage, so people say when they're looking for a terrible
cliche, DNA is the book of life, you can say that, but basically it's information storage.
So we've got two, we could say separate roles and this is a term I'm going to use later.
This kind of life cycle is known as templated life, so if we look at the nucleotides, one
strand of DNA is a template for the other strand, Chablon, and DNA, so this side, contains
the codes necessary for that side, that you knew already.
Now what if we have life without proteins, so we're really talking about the oooh-a-zoopa,
so think as early on as life when you may not even have real kinds of cells, so just
some kind of self-reproducing soup.
Now could we have life without proteins?
This would mean we have a life cycle like this, so we've got some early molecule, maybe
RNA, and it does catalysis and it holds the information, and there are many possibilities,
so this molecule here could be protein-like, and I'll show you that that's really possible,
it could be RNA or something like modern RNA, some other kind of nucleotide, or of course
it could be something completely different.
The problem with saying that it's something different is that then you have to propose
a plausible method for how something else could evolve into the modern world where we
have both proteins and nucleotides.
Back to this word templated.
In this picture here, we only have one kind of molecule, but it's also templated, so that
means that this early molecule has the information necessary to copy itself or its complement,
and at the very end of this lecture, I'll bring in a newish idea that in fact maybe
you do not need templated life.
But the reason this is so important is that when you're talking about a system that could
evolve into modern life, we're talking about a system which has the ability or has built
in the idea of templates, Chablons, or a code, as well as catalysis.
Okay, first question we have to answer if we're talking about the oolazoopa, so the
primordial soup, is what's life?
And I'm going to be practical, not philosophical.
So if we're talking about practical life, we're talking about people and trees and bacteria.
Every year I ask the students, what do you think about viruses?
And some years they say, oh yes, viruses are alive, and some years they say no.
We could go a little bit further and say, what do you think about infectious DNA and
RNA agents?
What do you think about transposons, whose only mission seems to be to copy themselves?
But let's just be practical and agree that people, trees, bacteria, and a few other things
are real life forms.
What we're going to need to define life is some ideas, or some concepts.
The first one is that life has to consume energy, and as I'll say in a moment on the
next slide, life avoids equilibrium, and it needs energy, and it consumes entropy.
Think about that for a second.
Life removes disorder from the world.
If you are a tree and you are fixing carbon dioxide, you are reducing the entropy in the
world, which is thermodynamically legal, because in terms of free energy we use energy to reduce
the entropy.
Okay, so the first thing is, life consumes energy.
Second idea, which I cannot prove, is that life has to be able to evolve.
So first of all, equilibrium.
Why do I say that life does not exist at equilibrium?
This is a simple reaction where we have A and B going to C and D, and as in first year
chemistry lectures, we can write down the equilibrium, or write down the free energy
change of this reaction as a function of the concentrations of C and D up here, and take
the logarithm and so on.
If we are talking about even something simpler, the decay of something, so it is Erfal, from
A breaking down into B and C, we can write down the free energy change of this reaction
as well.
If you have a closed system, and the ratio of the concentrations of B and C divided
by A, so for this reaction, if that is zero, it means that there is nothing happening,
your reaction is not going forwards or backwards, which means that you are dead.
So life never reaches the equilibrium values, there would be no chemistry happening.
So you are either dead or you are in an extremely deep sleep, let us say you are dead.
So the consequence is that for life, we are not in Gleichgevit, we are in a steady state.
So our definition of life means that you are in a stationary state and not at equilibrium.
Let us consider some steady state systems and whether or not they are living.
So the first one up here is a professor, it is a photosynthetic professor who is taking
sunlight from here, so it has an energy source, drinking beer, nutrients in here and pinkling
out some waste products.
So this is obviously a very high level living system and it is in a stationary state.
Professors do not grow or get smaller, so this part never changes, but we are processing
products through the system here.
So this system is maintaining order, sorry, it might grow and it is doing a whole lot
of catalytic and specific chemistry.
Let us look at a lower life form.
So this is a bucket and it has some bacteria in it and it is being fed sugars in here
and waste is going out here and you would say, ok, bacteria in a bucket, they are also
in a stationary state, so there is stuff going in and coming out and this is a living system.
Now let us go to another not quite life form.
So I have got a bucket here and I am feeding it with iron and water and the iron gets oxidized
to make rust, water is reduced and I have got hydrogen gas coming out.
Would you say that this is a living system?
Most people would not.
So I have a system with iron and rust, it is doing something a bit close to an station
out at Sustand, I guess it is growing so it is not really stationary, but it is consuming
stuff and it is not at equilibrium and it is excreting stuff and the really fun thing
about this system here is it is reducing entropy.
The entropy of rust is less than iron and free water, so it is maintaining water, grows,
it is doing some very specific chemistry and the really fun thing about this system here
is rust is actually catalytic for the production of more rust.
So it really is a system that likes to reproduce itself.
Rust is not a very good catalyst, but it is certainly faster, the reaction goes faster
if you have some rust already present.
So this system is not living, so it is not enough to define life, we are going to need
some more.
Rust catalyzes the production of rust, but it does not do some of the other things that
life does.
It does not adapt and it does not evolve and there is no real selection in this system.
We can make some further arguments and say that the information content in rust is very
low.
I will show you what I mean by that in a moment and rust does not have general copying machinery.
So what do we mean by order?
How much information does rust have?
Not very much, but look at bacteria and people.
It is a bit arbitrary how you define information, but we can make some quantitative statements.
We could say let us look at the DNA sequences that we could have.
So you and I have got about 10 to the 9th DNA bases.
So there is 4 times 4 times 4 possibilities.
So it is 4 up to 10 to the 9th possible sequences of which a relatively small number are actually
used in the human population.
Remember, that is an extremely big number, that is a crazy big number.
Let us look at a dumb virus, so a little baby virus with about 6,000 bases.
Even this thing has got 4 up to the 6,000th power possible sequences and only a few of
these sequences are used to make the virus, it is not like 4 up to the 6,000th.
If you consider a virus like HIV, there is a finite number of sequences which lead to
a viable organism if you call a virus an organism.
So in some way, there is a lot of information being stored and selected in these kinds of
systems and whatever the details are, however you feel about my estimates of information,
we have much more information than rust.
So let us say living systems should also have the ability to store and take advantage of
information.
Let us summarize some of these ideas and the comparison of life and non-life.
So here are some properties and here are bacteria, all professors and here is a bucket with rust.
So are the systems at equilibrium?
No, neither system is at equilibrium, so the bacteria are not the winners here.
Do we have catalytic activity?
Yes, so bacteria are not yet the winners.
Do we have variation and selection?
Yeah, definitely.
This bacterial cell is not identical to that bacterial cell after they mutate fast enough,
so we have variation and the better ones, the ones that reproduce faster will get selected.
In the bucket with rust, we do not have much possibility for variation and selection.
After copying, the idea that an A is a U, the complement of a cytosine is a guanosine
and so on, that we have in bacteria.
In the bucket with rust, I am not sure because rust does tend to provoke more rust forming,
so you could argue that that is self-templating if you want to argue that way.
But do we have general copying machinery?
Here bacteria and professors are the winners because you can take almost any old DNA, put
it into a bacteria and it will get copied.
I know I oversimplify the molecular biology, but the bucket with rust does not have general
copying machinery.
If you throw DNA into this bucket, it is not going to get copied.
Then we have the information difference that bacteria have a lot of information and the
bucket with rust has very little.
So why did I go through all of these properties?
Because what I want when I am talking about the start of life is a system which has more
of these properties in common with bacteria than with rust.
So the ursupa should have the properties that bacteria have or at least something very close
to them.
Next thing is, are we talking about the start of life or life as it could be?
This is a common argument that the evolution of life is very unlikely and there are good
reasons not to believe those people.
What are we looking for?
Are we talking about life on earth?
Today we are talking about life on earth.
So the question is, is there a system, can you imagine a system which could have started
off and turned into modern life with proteins, RNA, lipids, cofactors and so on?
A different question and an easier question is, could some other self-copying system have
started?
So not with amino acid based proteins and nucleotides as we know them, but can you imagine
some other kind of self-copying system which has the potential for errors and that means
selection and could it have been based on some different chemistry?
And the answer is probably yes.
So life on earth has grown in a certain direction, but it is well possible that there would be
other ways to construct life using rather different chemistry.
So some other kind of chemistry which might also be based on forming heteropolymers and
compartmentalised reactions.
So this question of any kind of life, I will not talk about much today, but I will mention
it at the end of the lecture, it does come back and it is used as an argument against
the RNA world.
Today I am focusing on how did life as we know it start?
So if we agree that we are going to talk about life on earth as opposed to other possible
life forms, we can put some restrictions on the more likely theories.
So life on earth is based on mostly on the chemistry of carbon, oxygen, nitrogen, little
bit of phosphate, sulphate and then all of the so-called trace elements.
You can conceive that there are other possibilities here, but that is what we do not talk about
today.
We are talking about the nice word carbon-based life forms and any theory that you propose
for the start of life should be able to turn into proteins and lipids and carbohydrates
and nucleotides which could be quite different on some other planet.
We also want to talk about systems which lead to enzyme catalysis, the property of
modern life.
In general, so what is not restricted to life on earth, what we generally want is a system
which can introduce order and a system which can be self-replicating, copying and repairing
itself in the most general sense.
Life on earth is templated.
That may not be the case for a more general definition of earth, but when I talk about
how did life on earth start, I am more interested in templated explanations.
The other thing, some of this is not so obvious, let us go to this one first.
In general, when I talk about life, I would like to be talking about a system with variation
and selection, so a system that can evolve.
That I think is obvious.
What is not obvious is the idea of one preferred chirality, so we talk about D and L and we
only have on earth one chirality of amino acids, for example.
Do you think that is important?
This is a good question because the answer is not so obvious.
Why is all biochemistry based on just one chirality, whether we are talking about amino
acids or sugars?
There is a good reason for this.
If you look at, here is the simplest possible picture of a chiral system in three dimensions
anyway, so we have got grey connected to red atom, to a blue atom, to a green atom and
here is the chiral image.
These two are distinct molecules, although the bonds are exactly the same.
If you follow it through, the green is connected to the blue in both cases and then to the
red and then to the grey.
So they are very similar, but imagine you have a polymer, so a protein, for example,
that is built from one isomer, that is going to work very well, that is life on earth.
Now imagine you say, do we care about chirality?
Why cannot we have a racemic mixture of D and L isomers?
What that would mean is if you consider a longer heteropolymer like a protein or for
people who like them, even polysaccharides, but let us stay with proteins.
If you look down the way things are connected, it always goes in a certain direction.
So it goes down and then it curls around to the left.
If I had a racemic mixture, it would go down and curl around off to this side here and
what that would mean is if I build a heteropolymer from a mixture, sometimes the chain will go
to the left and sometimes it will go to the right.
So we would not get properly nicely defined structures.
So you really need, again, I cannot prove this, but it looks very convincing that we
absolutely need to pick one chirality for life to start.
So we need monomers with defined chirality.
This is where enzymes start to become really useful.
So I have some reaction.
So I've got X and Y could go over to produce this product or it could go over to produce
this product.
And it's enzyme selectivity that tells me or determines am I going to get the D or the
L isomer.
There are, of course, isomer specific catalysts, but they're pretty rare.
If you talk to an organic chemist, they have to fight really hard to do a separation based
on D or L isomers.
The next thing is, imagine we have alternative products for some kind of reaction.
So we've got some molecule here, which looks to me to be an oxygen, a hydroxyl here.
So carbon, oxygen, hydrogen.
We could do an esterification at this site here or at this site here.
The energy difference may not be very big between them, but it's enzyme selectivity
that determines in biochemistry, in modern biochemistry, do we get more of the A product
or more of a B product.
So if the free energy difference between these alternatives, between this and this, is not
very big, that means you would always be getting 50-50 mixtures.
And so we need some kind of molecule, like an enzyme or an RNA catalyst, which can send
our reaction going in one preferred path.
And again, you might say, does it matter if I get both?
It does matter for the reasons I mentioned that chirality matters, but it also matters
if you want to control biochemical pathways.
You want to be able to pick one pathway and send your reaction preferentially down one
specific pathway.
So this is where enzymes of whatever kind, protein or RNAzymes, seem to be so essential
to life and have to have been there from very early on.
When we're talking about the chemistry of life, we are often not talking about equilibrium
and free energy, but instead we're talking about kinetics.
So I have a reaction, X and Y might go and produce A at this site, or they might produce
B with a reaction at that site.
What determines what I see is probably not free energy considerations, but it's the rate
constant for this reaction, so Ka, compared to the rate constant for this reaction here,
Ka, B. So if I have some kind of catalyst, which is selective, it changes the ratio of
Ka to Ka, B, so maybe molecule A is formed faster.
And the second thing is, I have to be able to remove this A molecule here because otherwise
I'll get an accumulation of A, which would then start to go back in the reaction in the
wrong direction.
So I need some kind of additional step that removes A from my equilibrium.
So it turns A into something else, call it Z.
So the point of all of this is that it's very hard to imagine life without some degree of
selective catalysis, or something very much like enzymes.