Now that we know exactly what life is, let's get to the RNA world.
So what exactly do I mean by the RNA world?
Well, what we're talking about is a couple of properties.
Genetic continuity from generation to generation via RNA.
So we're not allowed to talk about DNA just yet.
And Watson-Crick base pairing.
Why is that important?
You might say, yeah, what about the other kinds of base pairs?
At the moment, we're talking about a system which stores information and likes templated
copying.
So we'll say we would like to have Watson-Crick base pairing.
And in the RNA world, we do not have any genetically coded proteins.
So did such a thing exist?
Why would you believe in an RNA world?
I'll give you five reasons of varying quality.
So first one to do with phenotype and genotype.
The roles of nucleotides, then something called a Clex, then biosynthesis, and finally
the ribosome.
So in more detail, these five points.
In the current world, we have very separate phenotypes and genotypes.
So we would say that proteins are phenotypic.
They don't carry information.
That's in the genes.
And proteins are usually catalysts, or at least the enzymes are usually catalysts, but they
don't contain genotypic information.
They don't code for other proteins, although I'm going to change that a little bit later.
If we look at RNA, it can be catalytic, and it does carry information for DNA molecules
or RNA molecules.
Think of RNA-dependent DNA polymerases or RNA-dependent RNA polymerases.
So RNA has both catalytic properties, and it carries information.
So we will pray to the god of parsimony, the simplest explanation.
And so we like the idea that life started with one kind of molecule.
And then you'd say, OK, it should be RNA, because that can be both catalytic, and it
can carry information.
So that's one way of thinking about it.
The point I mentioned was the various roles of nucleotides.
Now if you look at all of the biochemistry pathways that you met in biochemistry lectures,
a huge number of them use nucleotides in a very fundamental way.
So the energy carrier within the cell is usually ATP.
The molecules used in most redox chemistry are FAD, FADH, and NAD, NADH, sometimes phosphorylated
NADP.
Similarly, we have molecules like coenzyme A and acetenocylmethionate.
But when you look at these, you could say that each one of them is actually a modified
nucleotide.
And that really is a modified.
That's just a phosphorylated nucleotide, or that is adenosine with, here's the sugar ring,
with some more odds and ends put on the side.
But the point is, nucleotides don't seem to have turned up late in biochemistry.
They are in the most fundamental of metabolic roles.
It is hard to imagine any kind of modern biochemistry, which is not based on nucleotides.
Based on nucleotides, which uses nucleotides at a fundamental level.
So it seems like nucleotides have been around as long as organisms have been burning things
up to make energy or photosynthesizing to store energy.
So all the cofactors, nucleotides, energy metabolism, really uses a modified nucleotide
at a low level.
So RNA, like molecules, are in a lot of very universal biochemistry.
So you'd say, okay, RNA looks like it has been around as long as life.
That's not proof.
That's just a little bit of evidence.
The next thing is a technique called C-LEX, which you may not have heard of.
It used to be a bit more popular.
There was one group working on it in Hamburg.
It also used to be the topic of 90 minutes in the RNA course.
Now I'm going to attempt to summarize it in 90 seconds and then say why it is relevant
to the start of life.
So firstly, what is C-LEX?
The name stands for selection and expression or enhancement, something like that.
But it's a technique where you use RNA.
You start with a soup of very different RNA sequences, and we're talking about a lot of
sequences that might have been generated by some kind of random synthesis.
So we have a soup with 10 to the 12th, 10 to the 15th different sequences here.
What we want to do is get RNA that binds to something specifically.
So you might say, I want to build an RNA molecule that binds to something on cancer cells.
That's a real old classic application.
Or maybe I want to build something that binds to the transition state in reaction.
I'll say why that's important in a moment.
What you do is you fix your cancer cells or whatever to something solid.
You wash your pool over your cancer cells or whatever else you are using, wash away
all the stuff that didn't bind, and then you're left with a few RNA molecules that did bind.
So you take these molecules here, and now you use some harsh conditions to wash them
off, and these binding molecules, perhaps weak binding, you then copy them back to DNA,
do some kind of error-prone copying so you get mutations.
Use an RNA polymerase and generate back to a new RNA pool.
And what you will have is a bunch of molecules which perhaps weakly bind to your target.
You take these molecules, wash them over the target, select out the binding ones, copy
and amplify back and get a new round of molecules in the pool here.
And as you go around and around and around, you get more and more RNA molecules that bind
better and better.
Those are the ones you select.
And this works pretty well.
So this is actually how the things called RNA aptamers are sometimes made.
What's the relevance to the start of life?
Look at this pool for a minute that was initially 10 to the 15th, let's say, different sequence
differences.
What we have found, I don't find these things, what has been found is that if we have a soup
of RNA molecules, you find some which have got some kind of binding ability or some kind
of activity.
Imagine you find some that bind to a transition state in a reaction.
That would mean that they lower the free energy of the transition state.
And that's almost the definition of a catalyst.
So what people have learned from C-LEX is you can also find catalysts for different
kinds of reactions.
The interpretation is what's important.
The way people have interpreted these results is to say that if you have a big soup of random
molecules, there will be some activities present, some useful activities.
And that means you can say the start of life was just a big selection and amplification
experiment.
So that's actually, that's an interesting thought.
If you have enough molecules, you will find some with some of the desired properties.
Okay, the next argument for the RNA world comes from people who know about biosynthesis.
If you look at the way that by modern biochemistry builds nucleotides, there are long synthetic
pathways devoted to RNA biosynthesis with various enzymatic steps.
But when you make DNA, that's just a little modification afterwards, or at least the basis
for DNA.
Looked at from that point of view, it seems that RNA is the older molecule.
And then DNA was something of an afterthought, or at least DNA evolved later on.
That's actually a pretty good argument that RNA is a little bit older.
Now comes what the RNA world people call the smoking gun evidence.
So it comes from the ribosome.
And you will hear lots about ribosomes from Prof Wilson and Bertrand from his group.
Now the thing about the ribosome is that it's incredibly conserved.
It's just amazingly conserved.
There are so few things you can look at that are in common in everything ranging from people
to bacteria and archaea.
All of them have got ribosomes, and you can pretty much do sequence alignments over every
ribosome on Earth.
There's not many molecules you can talk about in that way.
So ribosomes are in some sense truly ancient things.
Now around 2000, the first ribosome structures were solved by crystallography.
There were some Nobel prizes for that.
This is a picture from Tom Stutz.
So this is a ribosome.
And even in 2000, what they noticed immediately was if you take the ribosome coordinates,
you can computationally remove all of the RNA.
And then you're left with the accessory proteins that are part of the ribosome.
When they did this, the active site is easy to find in the coordinates.
When they did this, they found that the nearest proteins to the active site were about more
than 18 angstroms away.
And that means that you would say proteins are not involved in the catalytic activity
of the ribosome.
And that is a really important fact because if that's true, and it seems to be true, it
means that the ribosome is actually a ribosome.
The catalytic activity of the ribosome is due to RNA because there aren't any protein
atoms nearby.
And that means that the most fundamental aspect of making proteins requires an RNA catalyst.
That would suggest that RNA catalysis evolved first.
And then later on, more effective protein catalysts evolved and took over various functions.
So the fundamental operation of making proteins from a template is done by an RNA catalyst.
So that's taken as the strongest single piece of evidence that the first biochemistry on
Earth living system, self-reproducing system, self-sustaining system was based on RNA biochemistry.