Thank you for
coming to see me in the morning.

I'm going to I thought I would start by
introducing a little bit of the context of

what we're doing you know Georgia Tech has
a lot of people working in this area of

the origin of life and ancient
biochemistry we have two federally funded

centers one is funded by NASA and the.

Head of that center and the other one is
is funded by N.S.F. which is the director

of that center this guy right here and
so I think we have probably

more people working on origin of life in
Georgia Tech probably than anywhere in

the world I think we're sort of one of
the international centers in this area.

And I'm going to talk about the work
of a lot of the people here and

maybe I'll introduce them if they're OK So

first I want to talk
about something a little.

Foreign to Georgia Tech which is sort of
our oath of it motivation which has to

do with the difference between
applied in basic research so

probably most people in
Georgia Tech are familiar with.

Applied research or translational research
or whatever you talk about because I mean

that's what engineers really like they
identify some problem like green energy or

individual medicine or drug delivery and
then they just really go after it and

try to solve the problem and that's
that's actually not at all what we do

in my lab that's sort of our philosophy.

We do basic research and so
we basically sort of sit around and

think about what we find really
interesting and then we work on

those problems and we don't really worry
about whether there is an application for

them or not we just sort of do
what we find most interesting and

we try to think about what is the most
sort of scientifically impactful

question we can ask and we don't worry
about whether we can patent it or

start a company or make money off of it.

So we're not worried about
some specific problem and.

Why would we do this why would anybody
do this because it seems a little bit

self-indulgent but actually it's really
not if you think about the really big

things in our lives and
I've made a list of them X. rays and

M.R. statens biggest drug on the market.

The Internet.

Cisplatin you could list
a lot of drugs here or

even all the technology
of molecular biology.

Restriction enzymes solid things we use
all of these things come out of basic

research in fact the idea of basic
research really is that if you want to

invent the future or you want to do
something that is that you can imagine

something it is just that sort of except
that you can't imagine the future and

you're not going to be able to predict
that and just do the most important thing

that you can then something
good will come out of it and

that's basically how the really big things
in science all happen none of these things

if you would have you know rock and when
he was working on cathode ray tube he had

no idea he could not conceive of what was
going to come out of the discovery of X.

rays and in fact all of these if you think
about the people working on early M.R.

what they were doing and what's happened
with magnetic resonance you know they

had no I had no they could not conceive of
of what they were doing to the world and

that's that's basically what.

Basic research is and it's a little bit.

People don't like it because you sort of
have to accept that you don't know and

that you can't predict and
that you and you can't plan for

the future universe administrator really
don't like it because they like to have

programs you know nanotechnology or
something and predict the future and

some certain area and they don't like to
admit that really they have no idea and

that's a really big questions in the
future are things that they can imagine so

it's a little bit hard.

To rationalize this but but it's something
that I really believe in quite strongly

and it's really what motivates us so

I'm saying in the end don't ask me why
I'm doing this this is why I'm doing it.

OK We're not trying to cure cancer
we're not directly we're not

trying to fight drugs we're just trying
to understand really the most fundamental

important problems that we
think we can address so.

We're studying the translational
system which is.

This is.

An image I got out of Wikipedia and
so it's incorrect.

Shows are in a with a means instead of
your skills sorry about that but anyway.

Let me tell you what this is
this is the messenger R.N.A.

this is genetic material this
is our informational polymer and

this is our functional
polymer which is protein and

what happens in the ride the zone in
the core of the translational system

is information is stripped transduced
between this kind of polymer and

this kind of polymer and this is not
a simple task because generally in biology

we have something called Direct template
where you have base pairing where you have

direct molecular interactions and you can
have a reaction go for that that's helpful

Emirates is work etc OK this is not direct
him flipping This is very indirect very

complicated there's no molecular
recognition between an amino acid and

nucleotides here OK so it's a very
indirect recognition process and

it's extremely complicated and
the machinery that does it is gigantic.

OK So we have these are charged T.R.

Knight is this is a tiara NE has an amino
acid so there is a system of enzymes

that puts the right amino acid on each
T R N A which has a different and

I code on here each so specific and
I code and this is this is called the.

Net a code this relationship between
this amino acid and that code and

that's the genetic code so the genetic
code is established by a series of

proteins that charge these two year and
it's.

Then the ribozyme is sort of what
carries out the code this T.R.

ne interacts with the message and
this peptide or

polypeptide synthesize the sequence of it
is dictated by the sequence of the M.R.

in it so the ribozyme is a very
sort of strange enzyme in that it

doesn't care about the sequence of the
message really it will make any protein

any sequence pretty much you
run any sequence of M.R.

in a here and
it will synthesize a protein.

With that sequence.

And there's two parts of it this
is called the small subunit.

And the large subunit and
you have this division of labor here

the small subunit does the decoding So
there's a there's a elaborate machinery

this whole thing actually it was correct
would be down here in the small so

if you get the recognition between
the tyrannies and the amp and the M.R.I.

is all down in the small subunit.

So that's that's actually called Decoding
and then the other part which is.

The chemical could Palace's that happens
up here in the large sub you know and

that's where this covalent bond we call
this capital transfer where this amino

acid is transferred up to that valium so
we have a valium attached to this

alanine And then there's a translocation
where this thing moves over there OK So

that's and that's in a separate
sub you know and these subunits.

If they're not actually doing translation
if they're not doing this reaction

are separate they don't interact with
each other they're stable independently

of each other.

They come together just to do this job and
they fall apart so

if you isolate ribozymes.

From a cell it's not really doing anything
you'll get the subunits independently

of each other if you isolate.

Ribozymes from its cell that's making
a lot of protein they will be assembled

into one of these machines.

OK so.

The translation system has a really
special place in biology and

I just want to introduce this is
a really amazing letter written by

Carl Woese to Francis Crick in one
thousand nine hundred eighty nine and

Carl Woese was just setting up his
lab at the University of Illinois and

he's he's kind of asking Francis Crick for
advice or he's not real he's sort

of telling him what he's going to do he's
saying this is the future of my Lab This

is my idea of what to do and
he is soliciting Francis Crick advice.

Here and if you look carefully in
this letter Carlos this is a really

amazing letter I think this is one of
the most important sort of things in

twentieth century science right here where
Carlos says if we want to understand our

knowledge of evolution
backwards a long time.

We can use this thing called
the internal fossil record.

Of the cell and in order to do that we
have to use the translational machinery.

And he says what more ancient lineages
are there the translational machinery is

a direct lineal and
they're all the way back R.N.A.

components if you really want to
understand the most ancient things

the most fundamental things in biology
you've got to look at the translation

system and how we knew this I have no idea
it's really it's kind of amazing I think

the vast majority people at this time
would have looked at transcription or

replication or something like that but
somehow Carl was some deep insight

that allowed him to focus on
the translational machinery.

And so and that's OK this is you
guys this is nineteen sixty nine.

And then in nineteen.

Seventy seven he published this P.N.

I asked paper in which
they basically rewrote.

Biology textbooks they discovered
the third branch of the Tree of Life so

basically modern biology as we
know it has a bacterial branch and

our kit and our kale branch and
you carry out a branch and

basically by studying
the translational machinery.

Carl Woese and George Fox who is our
current collaborator on this project

were able to understand this and
only the translation of machinery has

the information that would
allow you to understand this so

this is this is really not an accidental
discovery this is something basically they

went after this they had the insight
to know how to do it and

they did it I find this this is really one
of the most amazing stories in science

to me.

OK But so now we know a lot
more obviously than Carl Woese

know we have the sort of modern science of
phylogeny with all the sequencing and so

there are sixty proteins that are
represented by orthogonal everything alive

and fifty of those are components of the
translational machinery so the translation

translation that you can say it's
the universal biology it is a thing in

biology that every cell has if you want
to say what does what is this process

that defines biology it's not
replication it's not transcription

metabolism it's translation is
the thing that unites all of us with

all of our brothers and sisters
meaning all of us bacteria you carea

everything we all have these sixty sixty
proteins This is the thing that really

defines life.

So.

Let's just look at this to try to
understand what this really means these

are two ribozymes X. is a large
subunit from a bacterium in our lab.

Bacteria means red and
our care means blue.

I think because the bacterium we use
is thermos the office and it's hot.

And the R.K. we.

Sodium is blue or something like that so
anywhere we use that color scheme red and

blue so these are to arrive as.

One from R K one from bacteria there's a
larger view of it and we have superimposed

them on top of each other and my students
are long who's now graduated and

gone on to become a professor and
I won did this incredible it really seems

trivial now but the superimposition took
him about six months because it's a global

superimposition of you know the molecular
weight of this thing is a million and

to get the superimposition to work and
to be sort of statistically correct

defensible was no small thing and
so this is a global superimposition

of these two ribozymes one
from bacteria and one from.

OK And if you look up and zoom up.

So little busy here but you can see
the difference between bacteria and

our can see the red in the blue and
you can sort of see the difference and

one thing you can see is the differences
are very subtle right these I mean this

is a coarse grained representation but you
can see that the atoms are basically on

top of each other here and
if you look up even closer.

Here.

This is what it really
looks like in the middle.

Like I said the bacterial.

Is is red and they are kale is blue so
think about this these are two.

These were brother and sister at what we
call the last universal common ancestor

about four billion years ago and

what we're looking at is the differences
over four billion years of evolution and

you can see how much the atoms have
moved in that four billion years and

the idea is not very much OK this is about
that's maybe a couple hundred seven X.

from there and

so the sequence you can sort of see
the sequence of the bases the sequence

is essentially the same positions of
the atoms are the same this is the R.N.A..

In the writers' room this is part of the
ride was almost protein you can see the.

Protein and one of things illustrated here
is that actually the structure is more

conserved than the sequence So
for example this is Allen in.

And this is a Proline and the sequence is
different but the backbone atoms are still

on top of each other so the sequence can
vary a little bit but the structure so

if you want to look really far back in
time you use three dimensional structure

you don't use sequence because structure
changes more slowly over time in sequence

that's one of the sort of principles of
our lab for want understand deep deep

questions going all the way back we use
three dimensional structures not sequences

so these things are magnesium ions So
not only is the R.N.A. invariant over time

the protein is invariant over time the
positions of magnesium are invariant and

in fact these Magnesium is are hydrated
with water molecules and those water

molecules are not showing they're in
the same place in fact the water molecules

are oriented in the same place as
the hydrogen atoms in the water molecules

have not moved between of basically over
about four billion years of evolution

these hydrogen atoms are in the same place
so this is one of the most permanent

things in the known universe that is
not a very low temperature probably So

I think it's safe to say that so
biology basically really doesn't

change much its core we like to think
of you know elephants and giraffes and

hippopotamuses and all these things and
all this diversity in biology but

that's all an illusion deep at its
core biology is totally invariant

nothing happens nothing changes and if you
want to really see that you've got to look

at the translation have there's no
such thing as evolution basically.

No that's really not it that.

Evolution can't touch this OK evolution
can't touch translation it's not allowed

there is evolution but

it's all in the margins so really what
we're talking about is this this is

something that we call the last universal
common ancestor this is where speciations.

Started OK we broke
into these two branches

one of them became you carry an archaic
one became bacteria and we're basically

saying we're comparing this bacterial
rival zone with this our kale arrived and

we're looking at the differences
over about four billion years and

basically there are no differences.

So.

What we know is that the modern right
which is the right design that everything

alive has was basically
done it was evolutionarily

mature at Lucca all the proteins
all the amino acids everything we

have now we think about is really the core
of biology was already done at this point

everything else up here
is kind of a detail.

OK So how did this is how we
interpret this we use a computing

analogy which is maybe a little dangerous
because biology is not computing but

we say every living cell has all protein
is made in ribozymes the rival zone is

transmitted vertically Now I don't really
go into that but one of the ways to think

about this is that OK we're over here we
got our metabolism through what are called

horizontal processes which is we stole
them horizontally from bacteria so

so you know our in a lace in
these things we didn't inherit

them from our ancestors we got
them horizontally from bacteria.

Our translational system we got vertically
we inherited it along this line we didn't

there's no there's no horizontal sort of
movement of translational components so

there's there are special rules on.

How.
Things happen with translation which do

not apply to other sort of biological
components and the canonical Tree of Life

in fact this is what this is what Carlos
did they establish this tree of life and

they did this by looking out
translational machinery right they should

the when we talk about the tree of life
like this you're saying really where does

your translation of machinery come from
but that's basically what the Tree of.

Life is where did your ribozymes
come from they came from Luca.

Through this path.

The core of the right was known as
universally conserved it really doesn't

change.

And the central core of the ribozyme
the deepest part was established

basically at the origin of life and
in fact is is even much older than Luca So

what we say is that the ribosome is the
operating system of life it is the thing

it's like Das you know even now when
you buy a Windows machine Das is still

down in there you know it is they
can they have never taken it out and

Das is this invariant thing that
can't change because like it why can

Microsoft not changed because if
they change it everything breaks and

they they don't know how to change it
because too many things depend on it OK So

it really is a way one of the ways
to think about it is dependencies

there are so many dependencies
on the computer operating

that if you change the operating system
the computer crashes OK So translation or

the ribozyme is the operating system
of life or you can say it's also maybe

the compiler of life that's another way
you know you can have your code in your

and your executable and
you can change your code but

if you change the compiler everything
goes crazy so you can't change

your compiler and expect your program
to run so you can say the translate to

the right of the translational system is
maybe the operating system of life or

the compiler of life and you the problem
is there are so many dependencies on that

soon as you change everything breaks.

OK so this explains a lot of things
actually once you start think

about biology you know we're all
used to think about biology in terms

of replication you know if you think
of evolution and replication and

you think about the selfish gene and
the little replicators and

all of that logic.

I'm telling you throw all that away and

think about biology in
terms of translation.

Explains a lot of things so for
example there's this thing called the C.

value paradox which is look at
this is the amount of D.N.A.

in the nucleus of various organisms maybe
the biologists are familiar with the C.

value paradox.

And this is something has disturbed people
because you have something like there's

this lungfish there and this is look
at this is a log scale there's a there

are there are long fishes that have like
ten or one hundred times more D.N.A.

than we do we like to think of humans or
vertebrates as complicated and

elaborate So why does this lungfish
need two hundred times more D.N.A.

than we do and there are.

Look at this there's plants there's some
plants that have amazing amount of D.N.A.

So really what is D.N.A. Why do.

In fact we have way more D.N.A. that has
seems like we need the vast majority of

our D.N.A. doesn't make doesn't do
anything we know I mean even when you look

about non-coding R.N.A. and all this stuff
still the vast majority of our D.N.A.

as far as we know doesn't we
don't know what it does so

what is all this D.N.A. thing look
at these protozoa how much D.N.A.

I mean just massive really simple
organisms with massive amount of D.N.A..

So this is actually really has disturbed
biologists actually because it

kind of it doesn't fit with what we think
about biology why is the amount of D.N.A.

random and I'll tell you why because
D.N.A. is spam Basically it's

like trying to understand the Internet by
looking at the amount of spam you get and

you say this is an important person
because they get a lot of spam as

an unemployment person because they don't
get a lot of spam and that obviously

that's not going to get you very far right
this is spam that's really what it is if

you want to look at biology and understand
it you have to look at the translational

system here we have the OK so what I
have here this is the phylogenetic tree.

And we're on top you know that's you know
Anyway this is just this comes out of

a computer you put rivals almost sequences
into some code it calculates distances and

makes this tree you don't bias
that in any way this is just

the standard phylogenetic
tree if you carry out.

And we've mapped a bunch of things on
here the collar is the amount of D.N.A.

So look at it and the ones that are way
off scale are black so this is a.

Some kind of birch tree here I think and
this is this long fish and

so the idea is that the amount of D.N.A.
doesn't really tell you very much but

the sizes of the circles
are the sizes of the ribozymes And

if you want to look at complexity
in biology the best way or

the best proxy is basically to
look at the translational system.

And systems that have complicated
translational systems are complicated so

if you think back to my Internet you know
the translation system is like the IP

protocol and all the hardware of the
Internet is the things that really does it

I did D.N.A.
is just spam filters through and

really most of it is of no consequence so.

That's what this is showing you D.N.A.
is spam.

The translational system is the hardware
or the it's a fundamental important part

of biology that in fact if somebody
said What does it mean to be

human what you know what it means to be
human means to have the largest drives

omes in the known biological world
that's basically what distinguishes us

from monkeys were it's a little bigger
I mean these are primates up here and

things like that I mean we all have huge
drive themselves because they have to do

a lot of complicated things they have
to regulate and deliver and do all so

many roles I mean look at these
are bacteria down here in our.

Little tiny red zones.

OK So initially I said there I was
always the same in everything alive and

I'm sure you that.

It's different because I want
to just go over the whole

put this in the proper context.

And Jennifer glass will probably correct
me on some details here hopefully later.

But anyway this is the history
this is our history here.

So the Earth started you
know something like four and

a half billion years ago when
there was liquid water about.

So the Earth was about five billion
years ago there was evidence for liquid

water about four and a half billion years
we have liquid for we have evidence for

liquid water and life originated some
time around four billion years ago.

And.

Something kind of bad happened late heavy
bombardment there was a time I think when

geologists and astronomers thought that
this was a sterilising phenomenon here but

apparently now they say no so
life could be.

Considerably older now that they found
microbes down in gold mines in really deep

down in the earth it seems like life could
have survived this late heavy bombardment

so life could have originated before it

we definitely have microbial
fossils at four and.

Three and a half billion years and so.

Microbes kind of dominated and then they
bring basically they transform the earth

by producing oxygen took away all
the iron oxidized everything that sort of

happened here three point eight
billion years something like that.

So about two point four billion years ago
then we got you carry outs multicellular

organism animals dinosaurs and
look we are not on this the reason we're

not here is because if you put us the
scale we don't even show up on the whole

sort of I calculated you know humans
are this is this is five billion years and

humans are maybe a couple
hundred thousand years and

if you calculate it's like we don't
even show up on this thing so in this

history of the earth scale we don't
even we're not even here OK so

how do we know all this we have
a his we have you know nature Rick.

It's history all these craters on
the moon are caused but basically

in a really short period of time they come
from this delayed heavy bombardment so

the moan hasn't been steadily impacted

these impact craters are essentially all
in a pretty short period of time and

we have a good record of them the moon
is a really good recording device for

things that happened in that time
period so we know about that.

And then we have.

We have of course the sort of mineral
record you know of the biological mineral

record which is fossils so
these are stromatolites X.I.V.

there's this guy Roger Buick at
the University of Washington and I

was actually in his lab and he let me take
pictures of various things the house so

he has these fossils from Australia of
straw Matta lights that are about three

point five billion years old and a stream
out the light is this is these are modern

dramatic lights and sharks pay I think in
Australia that's what they look like and

there are these kind of there are these
might weird microbial mats that kind of

mineral eyes and so these are fossils so
this is basically I think the earliest

fossils we have some of the earliest
fossils we have biological fossils so

we know we have basically stromatolite
like structures three and

a half billion years ago
there's a good record of that.

We can look at the weather in
the atmosphere these are some of Roger's

fossils of raindrops this is really
amazing I think this is see this little

indentation here that's a raindrop that
struck there was some volcanic event so

something was laid down raindrops struck
and then something else was laid down so

that rain drops the fossil
of that rain drop from.

You know about three billion
years ago is preserved so

think about this took
you know milli second or

something and three billion years ago
we still have a record of that so

that sort of the time resolution of
some of this is really fantastic.

From the fossil record.

And but biology actually does the best for
us as far as preserving and

maintaining records and you know you're
all familiar with this I'm sure but

a tree to us a tree is a really good
analogy for what's going on in the right

I think of the ribozyme really as a tree
because the tree records its history in

a lot of detail in a lot of ways and so if
you look at this tree you know basically

you can see there was some bad years there
right where the things are small and

there were some good years and and the
history of this tree has been recorded and

the tree grows by a creation basically
once this layer gets laid down and things

move beyond it this doesn't get touched so
this is a really this is this is I'm going

to show you this is how the writers on
evolves also there's an accretion process

where once something happens the next
layer goes on and that preserves and so

there's this preservation process that
goes on as ribozymes get bigger and

bigger the thing underneath gets frozen so
a treat this

is this is frozen until
the tree gets burned or

something this inner part
this has been a created and

frozen and doesn't change and it maintains
that record so something happened to this

tree here you know a car into it or
something and it remembers.

OK so.

So we can read a lot of information out of
a tree and this is basically the a really

strong analogy between a tree and
the result.

But you know word of used to looking at
these things and it's we look at them so

much as just sort of instinctive to us but
if you look at a tree and

you do this automatically you know what's
new and what's old right if you look at

the tree the newest things on this tree
are the green leaves and then the small

branches so you could walk back I could
say make me a map of the age of everything

on this tree and you could do it right
this is the oldest part in this or

you could really in very detailed
way you could walk through a tree.

And establish sort of relative
ages of things in this tree.

The ribozyme works in exactly
the same way actually it is.

Really exactly the same way now you can't
do it because you have not looked at

ribozymes as much you
have looked at trees but

if you have I've looked at them as much as
I look at trees so I can just look at it

and I can read the age of things well
Antonovich out in the people my lab can do

this better than me but we can just look
tell by looking I mean it's really obvious

once you're used to it you can just look
at a rival zone and you can read in and

say what's old and what's now it's
very simple one of the easiest way and

I'll show you this in some detail
this is a bacterial right as I am.

And this is us we have
these really weird sort of.

Octopus like things coming
out of our representatives.

But.

Because of the common ancestry.

There is a century there is a bacterial
right inside of a yeast and

there is a yeast inside of us OK It
all goes back to common ancestry but

because of this accretion process
basically things got added to yeast but

they didn't touch the underlying thing OK
and it's really I mean this rule is so

strong in the Rye bizarre.

That really there truly is a fully
functioning bacterial right inside a yeast

and there is truly a fully functioning
yeast inside a human so I'll show you.

Sort of what that means so
this is the same one bacteria and human.

So in the first just look at that
little structure there in that little

structure there I mean I change the scale
a bit on these because humans are big and

I had to get them on the same scale but
everything here is here and

everything here is here but
there's stuff that gets added on so for

example if we look at that little bump
right there it's there and it's there and

if you look at that little bump right
there it's there and it's there and

then you say What's different I have this
little bump here this is he looks twenty

five and he looks twenty five is still
there but it grew it got bigger.

And that yeast thing here is still here
but then it grew and it got bigger OK So

this is sort of in a two
dimensional representation.

How this accretion process works.

This helix I'm going to show you this in
three dimensions so you can see what this

really looks like never goes away
it's always there in everything but

it gets added on and when it gets added on
that never goes away and then more gets

added on to that so it's just like a tree
the ribozyme grows like a tree so.

This is this is sort of the same thing and
this is human and eco ally.

Just sort of showing you in greater detail
ever everything you see here you can find

here there's nothing that has been
taken away I mean nothing you can.

They're represented a little different
they see this some stuff got added on in

here but
this element here is that element.

Look at this this we have a long helix
there we have a long helix there

stuff got added on.

But the underlying
structure stays the same.

OK So think about that what this really
means and it's not that yeast did

not come from bacteria right this actually
is because of common ancestry you know you

have to always think about it like that
but as the ribozyme was established and

things happened to it basically
the bacterial rival for

some reason we don't understand
basically throws out Luca and

it really you can look all
over the bacterial world and

the ribozyme is basically the same there
is no there is no diversity here and

that essentially applies to our then in
Karia Fortunately for us we have a lot

of diversity in the ribozymes there's all
kinds of changes that have happened and

and that allows us to see this accretion
process OK So let's let's look at how this

works so this is a bacterial ribozyme
which basically is the loop so

this is we're looking back here about four
billion years ago and fact this is the.

Helix twenty five I'm not sure I
knew the whole ride was on is that

one helix I showed you and then.

Wrong way and then something gets
added to it this is the Ark A and

it's a little bigger and so this is the
Ark and Helix twenty five now we have to

give it a different name and then this is
East you can see the thing is there and

something else and these are all from
crystal structures this is not made up or

modeled or anything these are from
known three dimensional structures so

what you can see is that
things have grown out of.

The Ark A and structure but
basically everything is there and then so

this is east and
then we have a fruit fly zone and

you can see the yeast all the elements
of yeast are there see how similar they

are except a lot of things have been added
on and then if you look at the next step

we have we have structures of human
arrives on everything in fruit fly is

there in human except a lot of
stuff has been added on but

this is a original helix twenty
five it's still here OK So

things really it is like a tree things
get added on they get added on and

added on but
the underlying structure is frozen.

So this is how we describe this we
say the structural integrity of old

already components are preserved
when you add new R.N.A. and

the surface layers are buried and
subsumed into a frozen core and

the scores getting bigger and bigger and
bigger in fact you know I can I can make

a prediction I make a very firm
prediction if we wait two billion years.

That you carry on will get bigger but

the underlying core will not change so.

In fact I'll bet money on that.

You have to take a long time to
think about these experiments.

So these two things are the same
to us we can read we.

In really sort of the pathway of evolution
of this this is the human resume.

And what this means though this is this
is the frozen this idea of growing and

freezing what it means is that it's just
like the tree where the where you can look

into a tree and we can say all
right I know what the weather

was like in one thousand nine hundred
twenty five in one nine hundred twenty six

we can do the same thing we can
say I know what biology was like.

Way back before Luca right
because the ribozyme grew by

this freezing process all the way from
the beginning from before Luca and so

we can look deep into the core of the Dr
as well so this is the Luke arrived and

we can look into this core and we can ask
what was happening OK so the arrival zone

has remembered the history of biology for
us and one of the things we can see for

example protein was there
protein in ancient biology no

there was not this is a relation
of the amount of R.N.A.

to the amount of protein and
we just basically

add up the number of nucleotides and
the amount of amino acids and say and so

this is a this is the history of
protein in biology in the beginning in

the core of the there was no protein and
then we got a little bit of protein and

we got more and more and more so
basically the rival has totally tracked to

the history of biology I mean really
deep and important events for example

the arrival of protein in biology
is frozen into the ribosome.

And then we can look at those
proteins I think the next one and

we say what were these proteins like these
ancient like these are the first proteins

in biology what were they were they
are our heel this is were they enzymes

What were they no they were not they
were they were unstructured but

they were non-canonical they were
non folded so this is basically.

Sort of what we would call canonical.

Protein structure and what you can see the
formal proteins up here if you look you

know the average protein there are about
sixty percent seventy percent of Felix and

datasheet these things in the core
basically they have not learned to fold

yet OK So this is protein before it
had learned to fold so what what does

that mean how does a molecule learn to
fold anyway what we really think is.

This really wasn't protein I mean it
wasn't pure procure wasn't approach

it was a Rassam A Probably it was

it was contaminated with Esther's it
wasn't chemically it had learned to forget

because it wasn't really
refined protein so this.

Interpretation of this is that you know
not just the arrival of protein really

the chemistry of the polymers is kind
of trapped into the ribozyme and

if we can figure out you know what kind of
polymers fold in this way we can figure

out what the precursors of protein
were that's one of the things we're

working on along with Nicholas.

OK so.

You know I told you the right
was almost a tree and.

And I showed you how when we move forward
you know from bacteria to yeast through

flight a human we can see all these branch
points I really tell you but we can

walk backwards because once we've done
that we can recognize how it branches.

And just like you can look at a tree and
you can you don't have to cut the tree

down in order to say this branch is
older than that branch you can just tell

by looking I'm not going to tell you how
we do it but it's really well grounded

in easy to do we can look in the in
the corner of the right is on and

do the same thing OK So
these are all the little elements this is

this is basically a map of how
the look of a group OK and

it's complicated and Chad really worked
this out but you know there was there was.

This red thing is older than that
green which is older than that so and

we can see really distinctively I'm not
going to tell you how we did it if you

don't have to do it I've already done
it for you but it's very easy to read

how the right design grew and
we can go back into the right design and

read it backwards into time OK So
this is the part that's conserved and

everything alive but we can basically
read back and figure out how it grew and

this is this is a lot of information and
it's kind of too detailed So

what we did was we kind of
group get into these phases so

we have six phases here that
we grouped these things and so

basically this is the initial This is
the oldest part of the ribosome here and

then this and then things grew from there
so we get it's like when you look at

the tree you can see that trunk and you
say this is the oldest part of the tree.

That's what that is that's the oldest part
of the right but so right there and so

what we have done this is Main
experimental part of our lab so

OK Well let me show you so
this this little section right

here.

That's that's I've sumed up into it OK so
now this red.

I haven't really explained you how we
did that you just have to believe me but

this red part here is
the oldest part of the river.

And that's what it looks
like in three dimensions so

this is what we do we make them and
we bring it back from the dead and

we study it in the lab and we have all
these steps as this thing grew in fact

we basically have five steps here in
order to get to this structure here and

we think we've made all of these
structures and we have them and

we're studying So basically what
we're doing is we're recapitulating

the deepest oldest evolutionary
steps in the right result and

this to us is the origin of life
the way to think about it this.

Part of the ride is older than protein it
comes from before there was protein in

biology it's it's from some world that
we don't even know what it was and

yet we have it because of this accretion
process is freezing process it got frozen

in time for so we can go back and
pull it back out and look at it and

study it and so
we have all these steps and I mean we

if you go back we have a lot right this is
enough to keep graduate students busy for

a very long time we have so
many steps in ribozyme of evolution and

the nice thing is you know we can
it's not that hard to make R.N.A.

right we order the gene express that
we can make this piece of art and

we have all these pieces of R.N.A. we're
studying what they do we have ideas this

this here we believe this is the exit
door this has the a say in the piece and

we think this should be the smallest
catalytic element right there but

so we make it and we can figure out if
that's true we believe that this thing

should be more active in iron then with
magnesium because the ancient Earth was

rich with iron before oxidation So
you know we have a lot of predictions

basically this we're studying the origin
of life but it's just experimental science

like any other kind of science where we
have we have models we make molecules

we test them and then half the time
more than half the time we're wrong and

we have to remake them and
revise our model so

there's nothing different from this and
any other experimental science.

OK I think that I well.

You guys are looking bleary
eyed Here let me just

tell you that Jessica who introduced
me is the manager of our lab and

she has you know kind of done
a lot of experiments but

also keeps everything working for
us really well and is technically

you know she is probably trained more
people to do good molecular biology than

anyone I know I mean just the number
of people she is trying to get going.

Unbelievable and
she's also a really good scientist and

does a lot of it was one of my papers and
Anton.

I'm not seeing him here there is we have
so we have sort of division of labor we

have a bioinformatics group that whole.

Cutting the ride his own
thing is done by Chad and

Anton and Nick and
they basically we have sort of new

bioinformatics tools that we have invented
to help us understand the writers and

I think we're probably the only people
really looking at the ribozyme in

an integrated way we don't we I mean we
want to we're studying the ribozymes of

everything most people who study
the ribozyme are doing like eastern

bacteria or something we're
studying all right zones and

it's not easy because you know these are
molecular weight millions you know there's

there's hundreds of thousands of sequences
there's just the amount of data you have

in fact we call the ribozyme the most data
rich volume of space in the known universe

it's you know you could just just dealing
with all the data is really daunting and

so these guys have basically developed
a whole bunch of new tools actually and

people all over the world use their
tools now for studying the rub them.

And then.

Here you see someone who really got
us going I should always mention him

he helped us write the original
proposal and original experiments and

really got the whole project going.

OK Thank you guys appreciate
you coming thanks and

I answer questions if you have any.

Well OK this is just a question
like this I ever get asked about it

I see here I know you did these.

Or you.

So you were just a little a little.

Just.

If I had to guess.

I would say that R.N.A.
what there's a way I would say that R.N.A.

is kind of a frozen accident in that
if you started life again you might get

a different polymer but
that protein is not the protein I think.

I think protein is probably if I had to
guess on something being universal to life

I would say protein the made
the reason I say that is number one

amino acids are everywhere in the world
and nucleus sides of nucleotides are not

I think R.N.A. is really a creation of
biology but even though it didn't kind of

make sense from what I said it because I'm
saying that protein came late but I think

it was much more natural I think you know
if you I mean amino acids are raining down

on our heads right now from outer
space they're just made everywhere and

they're very easy to polarize and R.N.A..

You know it's really not
clear where it came from.

You know it's it's really difficult
to understand it so I think R.N.A.

I didn't say it is also a creation of
biology in that the vibe the original

ribosome was not necessarily
made from R.N.A. So that's.

Another level of complexity here.

Gary.

Yes.

Very well but yes we do have our ancestral
called our ancestral A.P.C. which.

Will transfer a center Yes you know and
we haven't published it and

we probably won't for a while because
the yields are really low we can only see

the product by mass spec and you know what
we would really like to do is get as.

And running so we can do kinetic.

Sort of thing and we're not there yet for

sure.

Well we optimize it in fact that
the last thing I showed which is

we call a S one through five which
is on the bottom of that thing.

That is our second generation and.

We actually have not tested that yet
the ass's are not so

easy and
you know if our center is renewed if it's

not I don't know why well so you know.

Yeah we iterate it by you
know in fact every year and

fact even we can we can come up with
models faster than we can test them

that's our problem and so we have
a working model we have a reaction but

we have we now know that's wrong
it's wrong in so many ways but

we you know haven't we can just it's so
slow and so laborious

to test them that our actual testing
of the models is way behind our models.

So yeah.

This.

Gets bigger you know that's a really good
question and we don't know totally and

actually so that's one of things
we're trying to figure out but

if you think about it you carry out
a gripe a zone versus a microbial you know

you have docking on all these organelles
and delivery of proteins and you have

a lot more sophisticated regulation
you know it's not you know the human.

Have these octopus arms that come out.

And those are exactly what
those do is not known but

it's not that they might provide some
communication between the exit tunnel and

the decoding region so there's some kind
of very long range communication maybe.

Fluctuations between those things but
that's just not known but

it's just if you really think about what
the right design is doing it's not just

making protein it's regulating and
it's delivering you know and

ribozymes are transported and you know
that there's so many roles it plays and so

all the complexity of it you carry out
Excel gets kind of wrapped up into that.

Yeah.

Yeah.

What do you mean that's what I
showed you isn't it what do you mean

You mean chemically how it

happens.

No this is what it is if you look here
this is the first expansion that we know

about and basically this is like a tree
this is a trunk this grows out and

in fact we call this an insertion
fingerprint it's a very specific

kind of confirmation fingerprint
that allows us to identify it and

really unbelievable the kind of
reproducible is that an arm comes out and

then it grabs on there's something
called an A minor interaction here so

an arm sprouts actually we think
something you know are in a can so

we think an R.N.A. cell fly gated here and
grabbed on there and

in fact if you look over here we have the
same kind of thing and then the A minor

interaction is there so yeah we have
a really good idea step by step for and

even this growth process you know
you can make self like gating R.N.A.

we believe one of the things we're going
to try to do is actually put small pieces

of R.N.A. together and grow the zone
the ancestral home actually in

vitro because we think actually that's how
this grew it was actually chemically at

the level of chemical ligation.

And R.N.A.
is really good at that kind of thing yes.

Functions.

So what kind

of.

Structure.

Do.

You like you've found as.

Usual.

This season he's So I mean.

We.

Were kind of actors.

OK I think I'm in the OK so the function
of protein has changed we think

the original what was happening is
the right bizarre had some very primitive

catalytic ability to do nonspecific
condensation and some of

the products this is our model some of the
products of that stuck to the right and

stabilized and conferred advantage OK So
that's our model for

the origin of protein so those products
of the ribozyme stuck to it and

they originally did not have to be
polypeptide because they weren't making

I'll feel a season because she's They
were just sticking to the right zone.

Just conferring stability Yeah I
wouldn't I would say more of

a yeah they just cooperated with
the R.N.A. and the peptide in the R.N.A.

together were more
chemically stable in and.

Then either it separately.

So that's our idea for the origin
of protein where it comes from and

Intel you know protein is fine as Ester
there's nothing wrong with Ester Intel

you need to make an alpha helix or a beta
sheet and then you cannot do it OK so

the original products of the ribozyme
were not making alpha helix these

invaders sheets they were just sticking to
the ribozyme and they're in the all these

whacked out confirmations so and there's
a lot of oxy acids in a biopic systems and

so we think probably the original primary
product of the right design was polyester

not polypeptide but as soon as you
want to form a globular struck.

That Esther won't do it.

So clearly biology there's a lot of.

Translation.

Yes.

But it's not.

Right yeah right so complex and.

Transcription.

So why those systems.

Yeah.

Right that's a really good question and
I don't know the answer one of the things

we're trying to understand is yes what
what what are the nature of the forces

evolutionary forces on the right that seem
to be different than other structures so

what Eric is saying if you make
a phylogenetic tree of D.N.A.

polymerase is you you don't you can't
trace it back I mean there's no signal

going all the way back and so that somehow
you know there presumably was a D.N.A.

pool in mice or something at Lucca but
it's divergent somehow the evolutionary

pressure on it is not sufficient to you
know maintain it to the extent that

we can see it all the way back so
what is different about translation.

I don't know well think about it
like this it in the limiting sense

if you mess with the translation system
let's say you change the genetic code

you're instantly dead right because that
changes every single protein and so the.

I mean if you just think about it in that
limiting sense the evolutionary pressure

on the translation system is just the
ments because nothing else has that kind

of consequence in that way right and I
mean that's the limiting kind of thing but

there's you know you're
basically evolution does not a.

Cataclysmic changes you can
only do incremental changes and

when you mess with the right
design it's just a catastrophe so

you can you can it's
just something like that.

I'm not really sure but
it's something like that.

This work force.

This is before there was no D.N.A.
we think at this point there was no D.N.A.

there were no problem races there were
none and none of that there was no coding

in fact we believe this is the first
enzyme in biology the very first

time in biology is this and so you're
asking us what you have to realize and

this is a hard concept but evolution has
evolved this is from the days of chemical

evolution not biological evolution
right so you know if you think about

about biological evolution where you
have genetics and poem arises and

all of that stuff it had to come from
something right it didn't just bring up so

there was a chemical evolutionary
process that got us to genetics and

all of that that's what got us this and
we can talk about that but

ideas but it's it's a mysterious world
that we don't know but there have to be

evolution before genetics because
genetics had to come from somewhere right

it didn't just pop up the novel so
that's a chemical evolution.

Process.

Yes.

Well.

You know what we haven't made them I mean
all what we want to do is make we have

ideas for what they are you know we
think they could be Rasta mates.

And various things like that.

But you know synthetically to make
these things is no joke and so

and that's kind of Nicads world anyway so
it's his job to make those for

us but what we would really like to do
is make those some of those molecules

I mean we can model them and put them
in the writers on and say you know in

an empty simulation you know do they
behave in the way we think they should but

then ultimately you need
to do the experiment and

that's something that we would
like to do both with the R.N.A.

we believe that actually this was not
necessarily R.N.A. it was a precursor and

we have ideas on what it was but for
right now experimentally we just

got to stick with our new because
it's easy to make fountain you know.

But the we believe is older than R.N.A.
and older than proteins really is

the core of it was made
from their predecessors.

Other questions.

All right well thank you guys for
coming on thank you.