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Defending the Christian Worlview, Creationism, and Intelligent Design » Origin of life » The RNA & DNA World » The RNA world, and the origins of life

The RNA world, and the origins of life

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26The RNA world, and the origins of life - Page 2 Empty Re: The RNA world, and the origins of life Mon Mar 23, 2020 10:41 am



our good evening ladies and gentlemen
having shown you a few photographs of
Steve Benner in his lab it's now my
pleasure to introduce the man in the
flesh so my name is Paul Davies I'm
director of the Beyond Center for
fundamental concepts in science and as
many of you know motto is confronting
the big questions and the sort of big
questions we like to confront I often
say are the things you love to talk
about over dinner parties things like
how did the universe come to exist how
did life come to exist is time travel
possible what is the destiny of mankind
where do the laws of physics come from
all that sort of stuff and the question
about how did life begin is of course
one of the most fundamental that people
can ask for the thousands of years human
beings have dreamed about being able to
create life the physicist Richard
Feynman famously wrote what I cannot
create I do not understand creating life
might be a dream but people also fear
its consequences as Mary Shelley's
famous story of dr. Frankenstein's
monster so graphically Illustrated today
we no longer believe that life is some
sort of magic matter but rather an
exquisitely fine-tuned and complex
physical and chemical system that can be
understood by the scientific method but
still the prospect of designing and
creating new forms of life remains both
thrilling and in some ways troubling and
no person is better qualified to address
this topic than tonight's speaker who's
come closest to attaining that goal
Steven Benner established the foundation
for applied molecular evolution in
Gainesville Florida after a
distinguished career in academia he has
a PhD from Harvard University in
chemistry I was tempted to say he's not
merely a chemist
but some of my best friends are chemists
as stevie's is much more than a chemist
I think his works has impacted fields
with tongue-twisting names like
paleogenetics evolutionary
bioinformatics planetary biology and
astrobiology but especially the
burgeoning new field of synthetic
biology his life his book life the
universe and the scientific method takes
a penetrating look at the problem of
what is life and how would you know if
you found it for example on Mars copies
of the book will be for sale after the
lecture and dr. Benner has kindly agreed
to sign copies one last announcement
please turn off your cell phones and
ladies and gentlemen now join me in
welcoming the 2004 beyond and your
lecturer dr. Steven Benner surprised to
see so many people here on a Friday
evening it speaks well I guess of the
intellectual atmosphere in Tempe Arizona
and surrounding communities I'm hoping
I'm not going to just disappoint how are
we doing can people hear me would you
like it louder
all right excellent so what is life and
the problem is my next slide is going to
be perhaps no perhaps it won't work at
all hmm no but it seems like this is the
kind of question that should be
approachable using what we teach in
middle school as the scientific method
right because after all if we're gonna
go search for life on Mars should we not
know what we're going to be searching
for and it seems to me therefore that
the scientific method should be brought
to bear to answer the question what is
life now who here did a science fair
project when they were in middle school
raised their hand who enjoyed it see the
problem is that you know we're not going
to get a lot of information for this
of a big question from the science fair
middle school paradigm because you know
if you're in in in this game what you
are supposed to do is ask the question
then you do like background research and
then you construct hypotheses which you
test with an experiment a deathly design
experiment so even a negative result
tells you something informative you
analyze results draw conclusions and if
the hypothesis is true or partly Razoo
you're supposed to report the results
and if not you're supposed to go back
and think and try again no that's fine
but it's a skill there's no question
that it's like playing chords on a piano
right if you're going to try to learn
how to play the piano or if you're
trying to learn how to do science
presumably you have to be able to do
something like this but it really
doesn't do much for these big questions
like what is life or how did life
originate or how might we recognize life
oh we were to encounter it on Mars and
so I thought I would sort of weave these
two questions together tonight with sort
of a sort of semi philosophical look at
what we do as scientists to try to ask
some of these big questions and of
course the very first thing that we do
is we observe and this is certainly true
for our friend the biologist who is
observing a moose that it was a
biological living entity and there's no
question that he is going to consider
that moose the subject matter of his
discipline certainly a moose is within
biology of course one of the problems
already is that you have two kinds of
biology there's the so called natural
history biology which means that you
observe biology you observe animals you
observe moose maybe you might look at
the fossils and somehow you maybe you
might probe them a little bit so a good
friend of mine Gary bull offski would go
out into the Montana Plateau pick up
moose droppings figure out what the
Moose had been eating and then make an
energy balance trying to predict how the
moose would be you know walking around
next step the next week or the next
month in response a to environmental
stress of course the biologist has this
choice he can also do something
different he can shoot the moose right
this is why this is a Jake Fuller
cartoon of decisions that biologists
make because if you kill the living
things you can analyze its pieces you
might be able to go further of course
the natural historian biologist doesn't
think the
this is biology any longer at all right
of course this is no love lost between
these people Harvard's biology
department divided into two there's the
two groups of people those who observe
the Moose and the people who shot the
Moose could not really get along but the
bottom line is that observation alone in
biology has not turned out to be
particularly productive in going past
the sort of bulk descriptive describe
the Mo's you can describe what he eats
what he does but and it doesn't really
answer the why of the moose
so there's analysis okay and so the
analysis of course is starts with
unfortunately Killingly the the the
organism it's then dissected the
dissection is to the level of the organ
and then of course the cell but
eventually to the level of the molecule
we have of course the historical
beginnings of analysis in modern biology
where they're trying to look at the
Mastodon Otis I was to do with the
pieces but at some point you get all the
way down to molecular representations of
what is in the moose or the Macedon in
fact you're looking at this here this is
a structure of a something that you have
in your bodies it's called the ribosome
it is actually the molecular machine
that makes proteins you're making
proteins all the time from the food that
you are presently digested of course
that's you ate protein is protein is
being broken down into amino acids and
they're being reassembled into new
proteins your proteins not the mastodons
that you had for dinner and so the
bottom line here is at some point
analysis gets to the point where you're
actually looking at individual atoms and
that's where these little bumps are each
one is a different atom and that's the
section roughly to the level of the
molecular system which makes most
biology today associated with a chemical
description almost everybody will talk
about metabolism they'll talk about the
chemistry of metabolism you talk about
vitamins I'll talk about the molecules
that are vitamins I talk about genetics
they talk about the DNA that's part of
genetics and so that's a very popular
area because it's also an explanation
for why we do not find aliens among us
because as any alien will tell you if
you a scientists near an alien what does
the scientists want to do to the alien
they wanted to sect them and there's 12
Steven Spielberg movies embedded in
that observation great now keep in mind
that analysis plus observation together
has been quite productive we do have
theories for life and I've represented
three of them here by the appropriate
statues there's a cell theory of life
roughly 1838 this is a guy named Sean
who is a man who said hey maybe actually
it's kind of amusing if you read his
original papers he's trying to unify
botany and zoology noticing that both
animals and plants have something in
common that is that they are made up of
cells and so this is the cell theory of
life and one of the leading journals in
modern biological science is called cell
simply cell of course this is Charles
Darwin as a young man much more handsome
than those pictures that you see of him
as an old man and he has evolutionary
theory which is of course a very central
theory in biology as well of course
eventually here's Watson and Crick
talking about the gene theory there is
their famous structure of DNA I've
expanded some of the DNA into chemical
structures here and so we do actually
have from analysis we have from
observation these theories exists and
people talk about them people teach them
in classes um and so you can come up
with sort of this idea that sort of
combines them if this is actually a
definition that was suggested by none
other than Carl Sagan which is being
used among other things as NASA goes out
and looks for life in the cosmos that
life is a self-sustaining chemical
system capable of Darwinian evolution
what we mean by self-sustaining is not
that you can live without anybody else
around you you have to eat things but
you were able to go out and get your own
food right and of course capable of
Darwinian evolution Darwinian evolution
is a big term with lots of baggage it
means being able to have children the
children are mutants sometimes in some
detail actually many people think they
always are but they say they are always
and then of course the having a survival
of the fittest and natural selection to
operate on it that's all embedded in
those two words well excellent so Watson
Crick tomorrow I'm gonna be this
dangerously close to chemistry but I
want to try to help you out here there
you go I mean Watson Crick model
for DNA almost everybody saw this it's
something put in there okay so who saw
this at some point in their high school
education raise your hand you see now
that's a good response that shows the
robustness of the American education
fair enough a pairs with T G pairs with
C in this double helix where replication
and veneers the double helix over here
replication involves separating the
strands and then making a complementary
strand by putting in G opposite C and T
opposite a and a opposite T and so on
you get two copies of the same thing
occasionally there's a mistake that's
the mutation which if it's not repaired
ends up being the the playground of
evolution but it's a relatively
straightforward model and it's actually
60 years old roughly so now you can ask
the question so how has observation and
analysis and these theories of biology
served us when we actually needed to do
something with them like look for life
on an alien planet
in this particular case bars now in 1976
about 40 years ago Viking mission
actually was to duplicate missions
landed at two separate sites on the
surface of Mars they were at the time
roughly the most expensive experiment
scientific experiments that were ever
done and they carried with them life
detection experiments and in fact there
were three of them and you can think
about this for a minute because the
first one they were going to sprinkle
food on the surface of Mars and see if
carbon dioxide is emitted and that's the
Purple Line um second they were going to
water the surface of Mars and see if
oxygen was released now the third thing
they were going to do is they're gonna
put carbon dioxide on the surface in the
atmosphere above the surface of Mars a
little bit of carbon monoxide trying to
reproduce the actual atmosphere of Mars
they're gonna see a carbon entered the
ground it's fixed as we like to say
these experiments actually are not
applying any of those three theories of
life that I've told you about they don't
apply a cell theory they don't apply an
evolutionary theory they don't even
apply a gene theory of life what they
are doing actually is constructively
applying what we would call a metabolism
theory of life and the reason why is
because if I go out and feed you some
food you will release carbon dioxide if
water the ground outside where something
is growing the photosynthesis will take
place and they will release oxygen and
of course tearing organisms at the
bottom of the food chain will actually
fix carbon dioxide that's how the plants
get their carbon right they have carbon
dioxide in the atmosphere which they
suck up and make in the plant
no you can look at that you can say this
is what we call terror eccentric or
Earth eccentric right we are making the
design the tests looking for life on
Mars we're designing it for expecting
the life on Mars to be very much
like the life on Earth and for those of
you who are not aware of these results
all three tests for life on Mars were
positive 1976 this is Gil Levin he's the
man who designed the Raible release
experiment he will still tell you he's
still living he will still tell you that
he is the man who discovered life on
Mars the conclusion therefore all the
co2 was released when they sprinkled
food on the oxygen was released when
they watered the surface of Mars and
carbon dioxide was fixed when they put
radioactive carbon on the on the surface
the conclusion life is present if you
going to interpret these tests on their
own terms there's life on Mars and so
the question you probably are wondering
it was why the hell haven't I even told
about this right who thinks that there
is life on Mars raise your hand
who's Gilda's Grill in the audience I
don't Sam right yes a yes absolutely
he's has got great associations so the
bottom line is that those experiments
were tested so the question is why
haven't you heard about it why I get
many more hands up when I say who's seen
the structure you know double helix and
I get by having somebody who's heard
that these three tests for positive on
Mars the reason for this is because they
did another experiment all right it took
a little while this is a gas
chromatography mass spectrometer for
those of you who are in the business you
know exactly what this guy does they
scooped up a little bit of Martian soil
they entered it into a cup they heated
it up to various degrees of temperature
and what they're looking for is gas
coming out which they flow into hydrogen
tube and then they have a palladium
separate and all the rest of it
but what they're looking for is reduced
organic molecules Oh like glucose or its
products if I heat glucose up to four
hundred degrees I get something off for
protein if I heat protein up to 400
degrees I'll get organic comments off
what did they find well they found
nothing they found no organics all right
so we have three positive tests our
metabolism and now we've got one test on
the other side so there's no organic
model so no one said anything about an
organic molecule theory of life but
about the evolutionary theory of life
the cell theory of life a genetic theory
of life but now we know that they're
operationally constructively using the
organic or reduced carbon theory of life
and we know it Trump's actually a
metabolism theory of life because if you
got three positive tests for metabolism
and one sign there's no reduced organic
no reduced organic wins so you're
learning something about how these
scientists are thinking but here's even
worse this minute the minute the minute
they decided that there was no life on
Mars there could be no life on Mars
because there was no reduced organic
compound what did they do well the
minute that they decided that there was
no life on Mars by the GC mass spec they
went back and found explanations for how
you could get three positive metabolic
results out of the metabolism test and
of course the first thing they noticed
was a sort of Venn diagram which is the
red circle is all systems that transform
organic compounds and the blue circle is
all living systems including you
but of course outside the living system
circle but still within the transforming
organic species circle is your car and
no one thinks your car is alive so that
was saying that okay as soon as the
community decided that they needed
explanations to find non-life
explanation for the signs of Martian
life they found them and they were found
them within minutes days not weeks
months or years after the results came
in now you could have asked how come
they didn't think of these before and
right but that's a that's a separate
question which I will entertain in the
question answer card well this is water
by the way just for those of you who
want to know what they think happened
are they what they thought happened this
is continuing to evolve water is
hmm h2o many people know that
ultraviolet light comes to the surface
of Mars much more intensely than on
earth because it does not have an ozone
shield like the earth hats it will split
water into an H zero and an H oh and an
H dot an H dot these are two hydrogen
atoms each with their electrons and then
what happens is these two H dots can
recombine the of hydrogen and hydrogen
that may escape into space leaving
behind hydrogen peroxide which is a
reactive species is an oxidizing species
it's something you might have in your
bathroom or in a mouthwash why where you
swish your mouth with you know bubbles
of oxygen and of course this is a
reasonably powerful oxidant or it can be
and so the argument was that this is
what is actually oxidizing the food to
make carbon dioxide not metabolism this
is an inorganic oxidation process
getting its energy ultimately from the
ultraviolet light that is coming from
the Sun to Mars so there goes poor Gil
Levin's tests there is the food that
they sprinkled they put a couple of
amino acids like glycine a sugar like
lactic a glycolic acid or lactic acid is
not quite sugars but in point of fact
all of these are oxidized by hydrogen
peroxide in the presence of iron by the
way this is a reaction that was known in
1900 discovered by the german chemist
roof is called the roof a bow or the
groove degradation it's well known
species iron is the catalyst Mars is the
red planet and it's red presumably
because of iron in the surface so the
science is at and by the way just for
the record you know adding water is one
of the ways that was argued to activate
the hydrogen peroxide that's left behind
ultraviolet light was being used as an
argument as how the carbon dioxide was
fixed so I don't want to need to go
through the details I certainly don't
want you to walk out the door
remembering the details all that you
should know is it the minute you had a
theory the reduced carbon theory with a
result a gas chromatography mass
spectrometer instrument Trump the
metabolism metabolism Theory folded and
immediately people found ways of
actually explaining those results and I
don't dare go much farther than to say
results meaning what the culture needs
them to me that's sort of how it happen
so the community was despondent okay
life was not likely to be President on
um actually this is I should say this
book that Paul mentioned this out in the
lobby is we got the Gainesville Sun
political cartoonists to do cartoons for
us I must confess at all I say was that
the community was despondent before I
know it Jake Fuller has generated this
hour nice Martian is holding something
called the McKay report in 1996 then the
kay report came out but cheer up the
despondent scientists who were unhappy
that they were not going to go find life
on Mars and what was in the McKay report
well he actually by the way in case you
didn't know have pieces of Mars on earth
what happens is something slammed into
Mars ejects rocks some of them are
injected with enough speed to reach
escape velocity and then they travel
around the solar system for a little
while and some of them land in
Antarctica and then you go down and
scoop them off all the ice does anything
that's on the top of ice is likely to
have fallen in a small fraction of the
meteorites as you find where explained
as Martian derived and and there will
people look at atmospheric composition
in those shot glasses and them Marshall
made using these type of things this is
Alan Hill 84001 it's a meteorite from
Mars Dave McKay looked at it closely and
what he saw were cells how are you
getting somewhere right we do at least
have a cell theory of life yes and so
now that trumps the organic theory right
something was wrong with a GC mass spec
actually it turned out that there was an
entirely separate interpretation for why
that instrument did not find sure right
now Gil's pretty happy right because
after all now what you're saying is a
strong theory of life you're absolutely
observing cells so the cell theory of
life Trump's the carbon theory of life
which of course Trump's the metabolism
theory of light and so in 1996 Bill
Clinton went on television like if you
want to see the clip you can actually
see it in the movie contact where the
Carl Sagan excerpted Bill Clinton's
discussion of the discovery of maybe
life on Mars into the the discovery of
course by Jodie Foster of
extraterrestrial intelligence by their
radio signals for those of you
who have seen the movie so no man so I'm
now wearing it what I'm doing here is
we're being sort of anthropologists of
science right so we're looking at the
scientists and we're trying to make the
distinction between what scientists say
they believe and what they
constructively believe and remember a
constructive belief is driven from an
actual belief because you act on her so
who believes here that quantum mechanics
is true raise their hand yeah now who is
for whom is that a constructive belief
like what did you do today that actually
require that you believe that quantum
mechanics was correct nothing I mean
even Paul you didn't do anything today
that required to be correct well maybe
you did so so so you're looking at the
scientists and saying what they do know
for those of you who are students in the
room especially what did I forget to put
on this picture a scale bar thank you
you're not a student absolutely this is
a microscopy 101 what we forgot to put
on that picture is a scale bar um and so
I will do now here that scale bar is
roughly 1 micrometer 10 to the minus 6
meters there's a meter or a millionth of
a meter and so there's this size of an e
coli a typical bacterial cell given that
scale bar and people look at that and
all of a sudden they said that these
cells are too small to be life now you
know I don't know if that was a very
persuasive argument everybody was a cell
biologist but you know the only correct
response is what makes you think life
cells on Mars have the same constraints
that cells on earth have right so you
saved too small too small what well a
presumed volume needed for a presume set
of components well what could those
possibly be well there was an answer to
that question when it was race and the
answer is there's that ribosome again
that's that ribosome I showed you a few
slides earlier which is the machine that
you had to make proteins
there's the ribosome the Machine and
turn life that makes proteins if I scale
it down to here it's roughly that big
which is roughly the width of that cell
and so the argument is that this cell is
too small to be life now you know I try
to get the students to write out clean
Aristotelian syllogisms and so you when
you do so you are no
notice that you miss a premise right so
if you say the cell is too small for a
ribosome therefore the cell is too small
for life you're missing a premise right
because somewhere is tucked in there
there's got to be a premise sign that
proteins which are what's made by the
ribosome are required for life right so
maybe the cells too small for ribosomes
ribosomes are required to make proteins
proteins are required for life therefore
the cell is too small for life but you
can't you know just hum the words to
that you got to actually say it all the
way out because the question is big who
is the third person who talked about the
protein theory of life right we've
talked about the cell three of life we
talked about the genetic theory life
we've talked about the evolutionary
theory of life we talked about the
metabolism theory of life we talked
about the reduced carbon theory of life
we talked about the cell came back and
trumped the metabolism and now we're
saying ah life requires proteins there's
a problem with that um and that problem
is actually captured in the two colors
of that ribosome
okay the two cars of that problem I'm
now spelling this out for you we might
do some logic proteins are made by a
ribosome on earth today today the
information by the way in DNA is used to
make an RNA molecule catalyzing the in
carrying the information from the DNA
then RNA directs the ribosome to make
proteins of course presumably life had
to start sometime and you know if you
got a system which requires DNA and a
ribosome and an RNA molecule carrying
information that's a pretty complex
system and so it suffers from this
question as to how the system gets
started like what are the odds that a
DNA molecule emerged from Darwin's warm
little pond that's pretty low what's the
odds that a ribosome did at the same
time as well as all the translation
machinery this is what my creationist
friends called the irreducible
complexity problem right you just can't
get it started because there's just too
much and so but never mind the bottom
lines it turns out that the ribosome
which we understand the structure by
analysis is in fact it is the machine
that makes proteins but it's turned out
that it's not made of proteins mostly
the red orangey colors are proteins
that's our ER are actually RNA molecules
and the blue components are actually
proteins slapped on the surface so what
this says and by the way where the
tene is actually made is surrounded by
RNA it's the RNA part of the ribosome
that makes the protein so now all of a
sudden you say well if RNA is needed to
make proteins and RNA came before
proteins are you with me right hmm and
by the way some people have taken the
leap that is an early episode of life on
earth use RNA as the only encoded
catalyst at RNA in the early life-forms
did both genetics and metabolism one
molecule doing both that's actually a
nice way of solving the chicken and egg
problem because I if proteins are needed
to make RNA and RNA is needed to make
proteins which comes first or the answer
is RNA comes first and the ribosome
contains the evidence of that because in
the ribosome is the machinery that makes
proteins proteins before RNA now if you
think about that for 30 seconds in
context of your discussion of the
Martian meteorite right we said that the
meteorite was too small to hold
but if ribosomes are needed to make
proteins and it's the RNA of the
ribosomes that made proteins and the RNA
therefore came before proteins the
assumption then is that there was not
only is it possible for life to have no
proteins but that the earlier versions
of life on earth where organisms RNA
organisms that did not use proteins at
all well you don't have to walk with me
through this by the way just for those
of you who are into vitamins a lot of
the vitamins that you either in fact
cofactors that have a piece of RNA and
the argument has been it it's left over
from a time on earth where all the
catalysts all the metabolism that you
did was catalyzed by RNA species so if
you go out for example and buy yourself
a vitamin with a pantothenic acid in it
many of you do that's part of a cofactor
that has an RNA piece if you go in and
buy something which is a part of
coenzyme a it's a RNA piece ATP the
energy matter of life has an RNA piece
the reaction can go just as well without
the RNA piece um so the argument is that
these are vestiges as were moleculars
pandas thumb of a time where your
ancestors life on earth did everything
that life needed to do without proteins
is built into the historical analysis so
now work with me here okay an ancestral
form of life on earth that used RNA as
the only encoded bio Palmer is of course
a vestige of the thing that makes
proteins RNA before proteins means RNA
without life without proteins life with
only RNA so if the RNA part of the
ribosome is the part that makes the
therefore we go RNA became before
proteins double or ago life is possible
without proteins with RNA alone by the
way just for the record about 70% of the
volume of a big micron cell the ones
that cell biologists are used to looking
at the ones the same cell biologists who
think that the life that we see the
cells on Dave McKay's Allen hills
Martian Mirai are too small to hold life
about 70% of the non-solvent volume of a
bacteria living in your stomach is being
used to make proteins so if you can get
rid of the need to make proteins triple
ergo I went to slides right life based
on RNA alone can be much much smaller
can be in much much smaller cells in
life that needs proteins what Drupal
Argo therefore the Allen health
structures are not too small to be life
they just have to be life without having
this devote 70% of their volume to
making proteins which is what the e.coli
living in your stomach are doing how we
doing so there you are back we put the
scale bar in there the structures of
Dave McKay this cell a modern bacterial
typical cell is largely because it has
to make proteins therefore has to have a
lot of these the argument these cells
are not too small to be life based on
RNA only a kind of life that we think
was actually our own ancestor on earth
and that's because they don't have to
contain any of these guys because they
don't need proteins so keep in mind
we're constraining our prejudice of what
life is and of course it's just for the
record if you go out and there into the
galaxy and you ask you know if you
actually do believe that there was a
prebiotic world at life at some point
originated this is like a hitchhiker
guide you know
everybody agrees that this was a bad
idea but never mind
you make the RNA world it then takes
some time to invent the ribosome
okay the ribosome is eventually invented
and now you can start to have an RNA
protein world and of course at some
point intelligence is invented and
therefore you can actually go back and
use your RNA protein like to explore the
cosmos well what are you most likely to
find you're most likely to find life
that contains proteins like yourself are
you most likely to find the most
primitive form of life which only had
one biopolymer in it RNA and the answer
to that is it depends on how fast SAR is
able to invent the ribosome if it's slow
to invent the ribosome is it ribosome is
difficult to invent if it's difficult to
invent the machine that makes proteins
you go out to the cosmos you're gonna
find life that uses only RNA has its
genetics and metabolism molecule of
course if ribosomes are invented quickly
then of course early life is originated
and of course you'll find mostly
organisms that use proteins and of
course if you believe that intelligence
is fast or slow people have different
views on that but if you think that
intelligence is slow to invade you'll
mostly encounter on intelligent
organisms whereas if intelligence is
quickly an advantage you'll find mostly
intelligent organisms so again I happen
to think it's a little bit of a trouble
to invent this machine therefore I would
not be surprised if all of the life on
Mars were not in fact RNA life so are
you with me
by analysis right by dissecting the
moose by dissecting the Mastodon we've
come up with a ribosomal an RNA molecule
a ribosome it makes proteins from that
we say RNA which is the orange part
which actually makes the proteins is
more important for making proteins in
the protein part RNA came first proteins
came later therefore this kind of
structure is early proteins are late
life is possible with this kind of
structure only and not with proteins
being required now sadly the Martian
cells turned out to be mineral ridges
you turn the rock on its side you look
at a different way and so the question
of Martian life shift back to the
despondent side but later what good
water was found on Mars and of course
that's the water theory of life where
you have water you have I mean the water
theory of life sort of trumps any other
things there I mean clearly this saw and
so on I mean clearly the science is not
supporting us as we would like
especially when we set out to seek weird
life right because we're constantly
going back and forth and back and forth
and back and forth the science we're
doing its job you expect to converge on
some sort of a solution you haven't done
them all right no problem but there's a
third thing that we can do besides
observation and analysis we can do
something called synthesis now what
synthesis is is a way of assembling
let me put things together in pieces
we've already done as I've explained the
sort of exploration as we try to find
examples of alien life that helps us
understand what life is we can already
do an examination of fossils and modern
life to try to understand what simpler
life might be this is this indeed going
backwards in time from the modern
ribosomes for example to more ancient
ribosomes I won't talk today about any
prebiotic chemistry where you try to get
life out of you know prebiotic soup in
the laboratory but I'm going to talk now
about the fourth approach which is to
actually try to construct life in the
laboratory right as there's sort of a
reason for this and Fineman was already
mentioned this evening because if we
truly understand what allows a system to
sustain Darwinian evolution we should be
to make one of our own right if you're
so smart right do it right if you
understand this and this is of course a
final remark that was already quoted
what I cannot create I do not understand
another one of my favorite fineman's
quotes as people are easy to fool and
the easiest person to fool is yourself
synthesis does a couple things for you
one of the things it does is not only
demonstrates that you understand
something but it prevents you from
fooling yourself into thinking you can
do something or from thinking you
understand something when you don't and
that is a really important thing because
in my view science is an intellectual
activity that it embodies a mechanism
Vence the scientists from always
reaching the conclusions that they set
out to reach I mean most of the time
we're gonna do that there's nothing we
can do about that but what science does
is has an experimental method or an
observation that is something that every
now and then once in a blue moon
it's the scientists to agree that he was
wrong at some point or she was wrong at
some point so synthesis is a mechanism
for preventing you from fooling yourself
if you're serious and adequate you
cannot fool yourself into thinking the
opposite if you try the synthesis fails
and it fails in a way that that cannot
be a boy my favorite example of this and
I really should not bring this up too
often right right keep in mind is this
Mars climate orbiter now keep in mind
that the human instinct and this is true
even if you're a human scientists what
do you do if the observation that you
have made contradict your hypothesis you
don't discard the hypothesis you discard
the observation right and in some cases

27The RNA world, and the origins of life - Page 2 Empty Re: The RNA world, and the origins of life Mon Mar 23, 2020 10:41 am


by the way that's entirely reasonable
right because if the spectrometer is
broken and doesn't give you right the
right answer because it's broken you
should discard that I mean this is the
classic example as to know if what's all
emeralds are greens you just observe an
emerald and you discover it's not in
green that does that violate the rule
well no you observe it under ultraviolet
light well okay I didn't mean all
emeralds are green when you observe them
under white light so then you somebody
comes along and looks at it under white
light he says it's not green he has
red-green color blindness they say okay
I didn't mean that way all animals are
green when observed in their eyes this
is the called Quine deulim paradox it's
the fact that you are always making
inferences based on a lot of assumptions
that you don't really think about all
the time and so a lot of times you know
you maybe should be discarding the
observation rather than the hypothesis
but that's not a good idea to do as a
general rule and one of the classic
examples is that the Mars climate
orbiter which is going out to Mars where
the guidance system Hardware was
operating under the English system no
feed pounds this type of thing the
guidance system software was being in
the metric system
all the way out if you read the mission
logs some people knew something was
wrong they were burning too much fuel to
correct it and and they were able to
rationalize it away and then of course
but some point you're targeting this
Grand Challenge the synthesis is forcing
these scientists across uncharted
grounds if you're wrong the rocket
crashes and there's no way around them
and so synthesis is able to drive
paradigm change in ways that an analysis
cannot because as you are happily
writing your grant applications do easy
hypotheses ignoring data the
contradicting them and publishing the
data to confirm them right if you're
trying to do synthesis it puts a wrap it
into it so what we'd like to say is that
synthesis sets this Grand Challenges is
also in biology now this is where
synthetic biology is you set this Grand
Challenge you drag scientists kicking
and screaming there Jake has the
scientists being dragged across
uncharted territory where they're forced
to solve unscripted questions okay
unscripted problems using available
theory when the theory is inadequate the
synthesis fails and it fails in a way
that that cannot be ignored
therefore synthesis drives discovery and
paradigm changes in ways of observation
and analysis not and so now we're on to
the next stage okay so we think we're
smart we think that RNA alone should
support a self-sustaining chemical
system capable of Darwinian evolution
that's a definition of life right and so
we ought to be able to do it if that's
all there is to it so there is a watson
crick base pair who here has ever taken
a course in organic chemistry raise
their hand who like the course I say
idear right Watson Crick base pairing is
easy to understand and I'll get it
easier in the next slide for those of
you who don't know chemistry but
basically there's a big piece two rings
and a small piece one ring big pairs was
small that's one of the rules of
complementarity well then hydrogen bond
donors which I have in red and pair with
hydrogen-bond acceptors I have in blue
so cytosine the C and DNA as a
small thing with a donor acceptor
acceptor red blue blue hydrogen bonding
pattern and it pairs with guanine which
is a big thing with a blue red red
hydrogen bonding pattern acceptor donor
donor and for those of you are not
chemists let me see if I can go to this
we can go to that structure which maybe
puts that a little bit more clearly
right it's putting together LEGO sets
right we have a big Lego piece a small
Lego piece the big Lego piece has prongs
and holes and C pairs with G because
it's got a prong hole hole complementary
to the poll prong prong right and
contrast T well God didn't get it right
and God even with adenine forgot to put
the prong on the bolo or Lego P so you
actually hold the a T base pair together
just with the top two hydrogen bonds but
that's a mistake that I assure you we do
not make in the laboratory as chemists
we will put that nh-2 group back but
never mind now one of the things that
you've got is a problem here because if
you think about this as for 30 seconds
we like the idea if we want to build our
own Darwinian system from scratch the
demonstrate understanding of course not
because we want to take over the world
like Mary Shelley was protagonist does
we like the idea that nucleic acids
alone might be sufficient for Darwin
right you liked because that means we
just have to design the nucleic acids
you don't have to also design proteins
so it's half the work that way we only
need to design one biopolymer not two
from scratch there's a problem people
have tried this I mean people tried to
take you know this relatively simple
system even missing why actually I put
already the amino group back in for the
chemists or in the audience
um people which actually tried to get
good function out of this system they've
largely failed um we say that RNA should
be able to support catalysis and
genetics that is metabolism and
inheritance without proteins but it just
has four building blocks DNA the same so
it's actually not so many I mean
proteins have 20 different building
blocks they have all course there's 20
kinds of stuff on them and the more
stuff the more you can do with a protein
so it's not terrible
surprising that proteins are much better
at doing metabolism much better doing
structure in some sense and so our knit
has much less to work with and so one of
the arguments why people have failed to
actually get I mean if you know you can
say if I think that life originated by
an RNA molecule crawling out of a test
tube or crawling out of a prebiotic soup
and asking me to dance right I ought to
be able to do it in a laboratory right
but people try and people fail and it's
not clear why but one possibility of
why's you only have four building blocks
and not much stuff to work with those
proteins got a lot of interesting
chemical stuff so the goal now is to
take this structure we've got a
hypothesis now so I am back in secondary
school middle school science fairs right
we have a hypothesis if we add more
building blocks to RNA and put more
stuff on them but the RNA will be a
better able to support Darwinian
evolution um so the question is are
there any suggestions as to how to add
more letters into the nucleic acid
alphabet now the people in the front row
to answer that question and I'm not
gonna get anybody to answer this
question until I start putting this back
there the two rules in cartoon form
big pairs with small gods mistake left
out of prong on this one we'll put it
back in but you'll notice that I have a
red dot eye prong and a red dot I have a
prong a red dot at a red dot I have not
even begun to consume all possible
designs of all Lego blocks right it
doesn't take much to say okay there's T
small dot prong dot C prong dot dot
complementary is a big thing right dot
prong prong and wrong dot well there's
God's mistake but I can also have a dot
dot prong which is complementary to a
prong dot dot I can make another piece
of Lego brick and they swill fit
together like this guy will fit together
with this guy this guy will fit together
this guy this guy will fit together with
this guy get Braille right you know
the--and all the ways you have dots and
prongs on these things so and so you
know i it's great we can also make up
new letters j v KX z p and my favorite s
be the bottom line is that you can do
all these structures in principle the
is now that right there you are again
now with the chemistry with instead of
prongs and dots we have of course actual
atoms and hydrogen bonding groups and so
yeah if it's so simple in fact that's
what the watson-crick theory is it's a
very simple model for how genetics works
we ought to be able to get DNA not with
four letters in it but twelve now that's
not quite 20 which is what proteins have
but it's more okay um and and and we
could with more stuff we can do more
useful things so what we're going to now
do is do a new kind of genetic system
that is not found anywhere in the United
are not that I know uh though Paul might
have some disagreement with that I mean
we I mean it's a fact by the way and and
and and Paul's written extensively and
they say there could very well be the
life I'm about to discover under
described under the carpet here and not
because we made it and put it there
right but it could be there naturally
and we all the tests that we would use
to look for it would not have found it
this is a Carol Cleland shadow biosphere
right which to get you the willies if
you haven't gotten them already a new
kind of genetic system and just for the
record I won't go through this details I
certainly will not bore you all those
molecules have been made actually Stefan
Lutz here is from Emory College he sees
one Emory University he sees one of the
compounds that he worked on which is
that one I guess think that Trudy ate it
if I recall for his par those days he
gave the chemistry seminar three o'clock
this afternoon so there you go we made
these molecules we put them in double
strands Anne Wong who provided from
Georgia State provide us with selenium
selenium nucleus sides to help us solve
a crystal structure and it looks just
like the big small hydrogen bond donor
hydrogen bond acceptor exactly the thing
but you say this happens to be the ZP
pair Chris Switzer has looked at the s B
pair and I won't go through all the
details but it really behaves like DNA
that's actually useful it turns out that
if I have a t and GC base pairs and I
put them into your body you got lots of
DNA and lots of RNA with a T or you G
and C and so almost all the nucleic
acids in your body will interfere with
DNA that you put in right and so we have
a very common thing what you want to do
detect nucleic acids in your body why
well because unwanted nucleic acid is
what an infectious disease is right if
you have an infection from HIV disease
comes from the unwanted disease HIV
nucleic acids same thing with anything
so so very often we would like to
something called a beacon which I'll
describe briefly it has a fluorescent
molecule but it's got this little
hairpin structure and because it has the
hairpin structure the fluorescent
compound is next to a quencher there it
is sort of in more double-helix form so
being the floor next to the quencher the
fluorescence is not displayed because
any times the fluorescence tries to get
started is quenched by the quencher but
if you have DNA here and you make a loop
say with TC CGA t knowing that t pairs
with a and C pairs with G and C pairs
with G & G pairs with C and a pairs of T
and T pairs with a the unwanted DNA say
from the virus is infecting you will
bind to this it will break the beacon
open and it will cause the floor to be a
long way away from the quencher and now
the thing will glow if you have green
DNA there well okay so the thing wrong
with this is of course if you've got a
lot of DNA and and your body and the
stem is holding the beacon together is
made out of GC TNA there's bound to be
some DNA somewhere floating around your
blood that's complementary to the stem
region and so the DNA will be invading
that stem and separating the floor on
the quencher causing the floor to glow
and that means that you will get what we
call in the business a false positive
which if you could imagine the only
thing more annoying than being told that
you have an HIV infection is to be told
you have an HIV infection when you do
not right and so this gives you
background and false positive and so by
putting funny bases and we are referring
to these as a component of an
artificially expanded genetic
information system Aegis that's what
what acronym comes from of course the
minute you have the stem held together
by PZ pairs or SB pairs or whatever you
don't have to worry about that beacon
being intubated and in fact that's
that's that's that's a remarkably useful
tool but this is actually a branched DNA
structure that is actually used to
measure viral load in patients bodies
people who have HIV hepatitis B
hepatitis C will actually use this assay
where people are trying to detect I say
8 molecules of the virus per milliliter
in blood and we actually put the
non-standard artificial nucleobases here
and here to improve the signaling of the
Nano structure suppressing noise just by
making this assembly which has many
signaling units per one capture of one
target DNA not be invaded by the natural
DNA this is a hundred-million-dollar
your product I don't want to encourage
any of you to get HIV or hepatitis but
if you do you might have the pleasure of
knowing of a small fraction of what your
healthcare provider pays a personalized
your care comes back to the Westheimer
Institute in the foundation for applied
microevolution to support our research
so we're actually quite happy about this
but again isn't so that's how the
artificially expenditure neck
information system pairs we gave crystal
structures of Farnsworth ugly it does
all the static things that you expect
from nucleic acids but remember life is
a self-sustaining chemical system
capable of Darwin and evolution so one
of the questions is whether a 6 8 10 or
12 letter DNA remember you just have a
four letter DNA so you're inferior 6 8
10 or 12 letter DNA can it evolve and
particularly can it adapt and while
we're at it we might as well get it to
evolve an adapt to do something useful
like buying 2 cancer cells and so here
is a relatively simple scheme it was
developed initially by people like Jack
szostak and Jerry Joyce and Larry Gould
and Andy Ellington where you start by
taking a library of many nucleotides
containing GAC T Z and P we're just
going to do the six letter version
tonight the eight letter version that's
too complicated for the evening and you
know that's a random variation well
we'll bring along some target cells say
cancer cells and we'll mix the library
with the cancer cells now of course most
of the library members have no function
so most of them do not bind to the
cancer cells but a few of them do
and so you can wash away the ones that
don't and when you do you recover a few
that do you separate them these are the
so called survivors now these are DNA
molecules built from a six-letter
genetic alphabet GAC tzp the Z has a
nitro group on it for the chemists
there's extra functionality we've got
more stuff on the extra letters so that
means they have more functionality they
are more likely to have some in that
library that bind and now the evolution
has fun right we made GAC tzp six
nucleotide we then had let them have
children remember DNA can be copied the
copies can be copied the copies of the
copies can be copied in the copies of
the copies of the car I'll stop there
you can make a lot of the copies of the
survivors with mutations sometimes where
the mutations are themselves
replicatable and now what you do is you
get a new library but this new library
is no longer a random library it's one
that has evolved under the selection
pressure that we must bind to the cancer
cell or else we'll get washed away
there's an in vitro laboratory evolution
experiment so the new library is the
descendants the kids the children if you
will of the survivors who survived the
selected challenge not avoided being
gored by the Mastodon but rather the
ones that have been able to stick to the
answer so okay so now what you can do is
repeat the cycle this time of course
with a library that is enriched in
molecules that bind to cancer cells and
of course in the next cycle what you
will happen will is they fit children
the ones more likely to survive the
selection the ones that are more likely
to bind to cancer cells will survive
even better if you do a number of these
cycles round and round around I won't
even go there after a while you'd begin
to see all of a sudden up comes some
cells some molecules with a six-letter
DNA that bind to cancer cells this is
after 11 rounds of selection but this is
quite fast with just standard cells
standard DNA for letters not a lot of
stuff right sorry no not a nitro group
but not a lot of stuff that we have one
Z and P it takes you to 18 or 20 rounds
of selection to even begin to see this
kind of so the six letter DNA is he
evolving faster or letter DNA and
eventually you can go back and get some
of these we can determine their sequence
there you go there's a sequence of a DNA
molecule which contains E and P which I
put in red which binds to cancer cell
this is a useful diagnostic more
important we make it this cell by this
is this I explained that what this plot
is this is the intensity of a cell and
this is the number of cells having
intensity what do I mean by intensity
well we put a little fluorescent marker
on a molecule that has evolved out of
the selection pressure and so if the
cell binds a lot of them the cell has a
very strong green glow um actually if we
now start removing the ZZZ and removing
the p's that is removing the funny bases
going back to just the four letters tend
to lose the binding to cancer cells that
is that they remove the Z and P the
binding goes away then Z and P is
important for the binding by the way we
can do more within this I mean we can
actually take extra letters in the
nucleotide alphabet and write extra
proteins in amino acids into the protein
lexicon this is actually work that was
done by Chris Switzer and Jim Bain now
close to a good grief I'm getting old
twenty years ago their horizon is really
unlimited with these extra cells and
remember reproduction isn't alone not
sufficient to support their winning and
it's got to be reproduction with
mistakes reproduction with errors where
the errors themselves are reproducible
that's the key element here so yes in
general a pairs of T G pairs with C Z
pairs with P your biochemistry course is
going to be a lot more complicated but
never mind
s pairs with PA v with JK with X most of
the time but sometimes mistakes are made
in this coughing those are the mutations
from which you can actually do evolution
or selection within this system and
that's of course what makes this
Darwinian well for those of you who are
science-fiction fans if you listen very
carefully the et you'll discover as et
is dying for the eighth or ninth time
and that Elmen being brought back to
life the kids crying each time you can
saying that et has a six letter in the
alphabet so this is actually has
precedence in the science fiction
literature not as old as Mary Shelley um
I should say that they then listen to
the chatter they say one is diamine of
purine and that dime you know purine and
the other is a perimeter in which we
cannot identify which means that these
videos were not very good scientists
this picture by the way I cost me five
hundred dollars I had to pay Steven
Spielberg to let me put it in the book
so then what about risk
okay what about risk okay so you say hey
we've got a six-letter genetic system
that is not quite self-sustaining in
terms of evolution but it's capable of
evolving and I'd love to put this risk
diagram up because this is actually Eric
Schmidt who is the biosafety coordinator
of the European Union who made its the
following point that if you dealing with
a organism which has a alien genetics or
an alien core molecular biology it
actually is not quite necessarily toxic
and he draws this Venn diagram okay
so within the red circle are all
organisms that you might construct that
have the standard Terran biochemistry
outside the red circle you do not have
standard terror and biochemistry so
these are interesting parasites remember
you and your I mean the most nutritious
food is the food that's most like you
right that's just because you are
looking for nutrients and and so you
have to get the nutrients from so meat
is more nutritious to you and by this
lighter than grass for example but the
argument now is that if you are using
standard chemistry right the organism
that uses it is a parasite because he
finds you tasty right so um we are of
course in our system entirely outside of
that we're making something unnatural
which is why Eric Schmidt says
xenobiotic and why it's a quote ultimate
biosafety tool you know within the green
system of course it's capable of
evolving outside the green system is not
capable of evolving of course the thing
is not capable evolving it really is
hardly at risk at all right because you
know they can't evolve in response to
we'll eventually die um inside the
circular here is self-sustaining outside
the surface it's not salt circle the
blue circle now is not self so saying
that means it needs to be fed um what
we're trying to do is of course going
back through the system where we're
trying to use unnatural stuff we're
trying to make a capable involvement of
course we're a long way from getting it
to be self-sustaining um craig venter
however as you may know with ham smith
produces cell which uses standard turn
biochemistry is self-sustaining it's
capable of evolving so it's right
squarely in the middle of the wrist
circle you just have to remember what
craig synthesized was really not
materially different from what is
already out there in natural biology so
it may be risky but it's not not a new
risk so there you go so i told you now
about observation and of course
exploration is part of that we've talked
about it analysis I have not talked
about origins we've talked about
synthetic biology what we can say is
that yes we can construct okay using a
scientific method that is more
complicated than what we were taught in
school where our biases are jarred by
exploration for sure no question about
um Natural History certainly is
expanding our view of what life could be
like as RNA life only before proteins
emerge that's a possibility
and Sciences of course is this human
intellectual activity which has a
process that is an appropriate way able
to dislodge the scientists from always
coming to the conclusion they set out to
conclude and synthesis in this respect
is the ultimate tool it it drags this
scientists across territory uncharted
territory where they're forced to solve
unscripted problems and if the series
inadequate it crashes and therefore
synthesis can drive discovery and
paradigm change as well better than
analysis and observation by themselves
so what is life well still don't know
but we seem to be able to get something
that we have value in life adaptation to
perform a function you're binding to
cancer cells as the example that I
showed you from a functionalized nucleic
acid with extra letters in the nucleic
acid alphabet design by synthesis made
by chemists able to replicate with
imperfections of course where the
imperfections are themselves replicable
and therefore able to evolve no you know
we talked about lighting as
sustaining chemical system capable of
Darwinian evolution you say but this is
not self-sustaining right but of course
that's what we emphasize system in this
case and of course the difference is
between this and that 12-letter
Darwinian in a system capable of
assisted DNA this is a Darwinian
evolution of tests it was are more than
obvious so with that let me stop I'll
thank you for your attention and I'll be
happy to answer any questions you might
well thank you thank you Steve for that
very thought provoking lecture we have
time for questions would you like to
moderate your own from IP is the one
thing that you should do though is to
repeat the question my last in case
people can't hear all right say be
running around with the microphone we've
got a hand right there yes say loudly
and I will repeat the question yes
where's your periodic table in this room
they don't have one absolutely well John
Barris and I wrote a book under the
auspices of National Academy of Science
oh yeah so the question is being asked
is whether or not I'm making the
assumption that carbon-based life is
what we're doing here I mean you saw a
lot of carbons are there and you saw no
silicones right well that's right so the
the the definition of life is a
self-sustaining chemical system capable
of Darwinian evolution is a theory of
life but it makes the assumption the
only way that matter can be organized
in a way that gives us properties that
we value in life is through Darwinian
evolution this process but it does not
make the assumption that you don't have
silicon right if you cannot mean
tellurium instead of sulfur there's all
sorts of analysis that you could
analogies that you can make I mean
arsenic instead of phosphorus is one
that was we were worried about a lot so
there's no question if you can construct
a working system which gives you
Darwinian evolution out of silicon that
will pass the muster for life by this
model it's a theory of life it's a
statement it's deeper than a definition
is basically a statement saying that
this is the only way we think it's
possible to get you know now keep in
mind that if you ever I knew presumably
as a human species are not far from this
point if you ever get to the point where
you're able to do germline manipulation
so that you anticipate future things and
change the DNA in the germ lines that
are producing your babies this is
something that is not allowed by
Darwinian evolution you're not allowed
to have prospective mutation this would
be called maybe Lamarckian evolution of
course the question is when the human
civilization adopts it or creates that
technology well it cease to be alive
right that's sort of the paradox of this
but but yes but yes no we've tried I
mean there was a john beerus and i we
put together a report with the National
Academy on a weird life as it was called
and it was published at about 2010 you
can get a copy from the National Academy
where we tried to come up with systems
based on silicon based on avoiding as
much carbon as possible and one can
conceive of these they have never
actually been synthesized but you a
synthetic chemist okay so it's going the
wrong direction
yeah another question no other question
Oh in the back oh well yes yeah I mean
absolutely if you go out and find data
so the question is whether a robotic
system right if you go out and find data
in the cosmos would you say that data is
life and that's of course the subject of
many Star Trek next generation lots and
the answer is we would probably say he's
a bio signature and as he was the
evidence is something that was life made
him if that's only because we can't
conceive in our feeble we're looking at
it of him coming out of a spontaneous
generation from a suit but that's just
that's just us but yes anything that's
capable of Darwinian evolution even if
it's a robotic structure would be called
life of this in the back yes cope in
unscripted hypothesis sure well I mean I
mean keep in mind that what we do is
science when we're doing routine
sciences we kept control over the
hypothesis that we choose and of course
anybody especially if you're trying to
write a grant application does not pick
a hypothesis that is difficult to test
so you would tend to have scripted
hypotheses and the science fairs are
well known for these right you use are
my cat left-handed or right left called
or right Paul this is a common thing but
what a synthesis right you know you
you're being driven by the goal and so
you don't have the option to pick and
choose your hypothesis the hypotheses
that you must deal with the theory
kellman's you must deal with are the
ones that you're relying on to get that
synthesis to work in so that's what we
mean by unscripted in that context yes
I absolutely know if you would like to
do that and there's a no we the problem
fundamentally is that with carbon
nitrogen oxygen and hydrogen as the only
elements from which you can build it is
actually very hard to build a small
thing with three prongs or three holes
without having a charge on that
particular molecule the big thing is
actually you can do so the reason why
you only see 12 bases and six base pairs
is set of 16 bases in eight base pairs 2
4 8 16 which is what you would expect it
has to do with the constraints of
chemistry associated with how many bonds
carbons oxygens nitrogen's and
hydrogen's make so it's very core to the
chemistry so you cannot get this from
the prongs story you have to go back and
look at those structures that's that's a
very good question however very
observing I have to worry about this
person yes
it's let me summarize that for those in
the back absolutely so the question is
right Miller and Urey made up a model
for what they thought the early earth
atmosphere was like and so they put a
lot of energy through it and got a lot
of goo out thar and then eventually they
could get out of that goose of amino
acids and that's a very important
initiation of pretty much modern
prebiotic chemistry so the question is
what we go to other planets as well and
we might be able to make models about
what their environments were do the same
kind of experimenting getting different
I mean we can go to a planet which is
dominated by silicon hydride in the
atmosphere and try to get silicon
silicon life out of this what should
people and your problem is yes I mean I
would love to do it keep in mind that
almost all of the problem has to do with
the uncertainty of the ancestral
atmosphere and the ancestral environment
so ASU has of course a wonderful
astrobiology organization which is very
much involved in this and you know they
will tell you I mean I don't know jack I
mean some days it's Mondays Wednesdays
and Fridays is that well if the
oxidation state is more and that's it
you know it depends on the model so
that's a large amount of uncertainty
meaning relatively little constraints on
what you can actually get now Titan for
example is a moon of Saturn it's got a
lot of organic stuff going around it and
you know I mean we've it's a rich source
of organic molecules and I love that you
forget a life-form that could live in
methane liquid at 95 Kelvin that's about
minus 200 yeah exactly so your earth
unfortunately has been poisoned by these
plants they put all this oxygen in the
atmosphere and then it really destroys
the ability to do good organic chemistry
that's anything that you put out onto
the table gets toasted right the butter
goes rancid the toast the bread becomes
toast eventually and so you have a
problem with this and and then of course
you know we don't we have a big fight
going right now so what minerals were
available in early Earth I mean I love
to have borate minerals I love to have
gypsum I would love to have molybdate
minerals we'd love to have these in a
dry desert environment not actually
unlike Death Valley and honest
I'm like Phoenix but then I got that
geologists assigned me that they're
models for early Earth have so much
water on them that there was no dry land
and so I can't have a Phoenix everything
submerged as a Kevin Costner Waterworld
and and so so you'll find that when you
try to model what the early Earth looked
like and then what early Venus look like
or what early Mars look like you'll get
consensus on the direction almost
everybody will be that Mars had more
water than than it has now
Venus was more habitable then than it is
now but you won't get a lot more
constraints than that until we do a lot
more work yes yes yes we're trying to
get them both in the same we're trying
to get the functional stuff and the
information the same mall and maybe I
missed it presenting it yes so the
question is knowing why do we how do why
do we take this chicken and egg problem
seriously so right now you have of
course a three biopolymer system you
have DNA that passes information from
you to your kids
you've got proteins which does most of
the stuff that needs to be done and you
have RNA which carries information from
the protein stops right from the DNA
molecule to the ribosome to make the
proteins and your problem now is the
creationist irreducible complexity
problem right no one no one knows how
DNA arose from prebiotic soup no one
knows how RNA arose from pre bases we
even have any problems getting proteins
out of pre but actually where those
these tend to be a little bit easier how
you would get all three of them at the
same time where one is performed the
genetic role one is performing the
functional role and ones the messenger
between the two is just a problem that
is a complexity irreducible origins
problem so everybody was very very happy
when Tom Cech and Sid Allman back in the
1980s discovered that RNA in addition to
being a genetic mom
and there are RNA viruses for example
could also do catalysis as we said hey
that problem is solved right we don't
have to get proteins and DNA and RNA and
ribosomes and machinery to all rise
immediately to get life going all we
need is an RNA molecule that will itself
be a catalyst that specifically catalyze
the tip with directed synthesis of
another RNA molecule it's son or
daughter and then life we get started is
that RNA enzyme that catalyzes the
synthesis of RNA from an RNA template
would be imperfect but the imperfections
would be replicable okay and so that's
where this story goes that's why we look
for a single biopolymer so it could be
proteins people have argued that
proteins were the primordial biopolymer
RNA came later the only problem is that
proteins don't have any easy
watson-crick big small prongs hole
replication potential and so you know
that's why RNA is better at least with
RNA I can imagine replication principles
so that's where that clear is that so we
are up against a chicken or egg problem
we have to this very complex system
which is your modern metabolism we had
to simplify it we had to simplify in a
way to get one molecule do both
catalysis and genetics and do stuff as
well as encode stuff and we get one
molecule then we had to where help out
that one molecule arose that so hard
enough problem without having two or
three yes yes so we're using the
property of a 12 letter or in this case
six letter genetic system putting it
under evolutionary pressure where for
part of it it's folding to bind to
cancer cells it's doing stuff like a
protein and then another part of that
cycle it is being copied like a genetic
yes sir shoot yeah I guess so yes yeah I
mean keep in mind that there's a to
questions you're asking the questions
whether they're more error-prone
intrinsically or whether they're more
error-prone in our hands yeah so
intrinsically actually they are probably
less error-prone because the 80 pair
joined by only two hydrogen bonds is
weak and all the funny ones that we have
are joined by three hydrogen bonds so
this is a very very very error-free
system when it's just coming to
hybridization the problem is that when
we make copies of it we actually use
enzymes which we get from natural
biology these are enzymes that have
evolved for billions and billions of
years to take ga CT and not Zee PSP or
any of these other things and so those
enzymes we mutate we evolve them we do
engineering on them we do all sorts of
stuff to try to get them to handle our
funny alphabet and so those are more
likely to make mistakes with our funny
stuff because they're unnatural not
because they're intrinsically bad yes
Paul so you raised the question about
whether making new forms of life is
risky and you've persuaded us that the
risks are very low and then the flipside
is is it useful and you've given us some
examples of what's been done but this is
presumably the tip of a huge iceberg and
the future of synthetic biology must
open up all sorts of wonderful
possibilities possibly further risks can
you just sit a few sentences say you
know what's next on the agenda for sure
I mean I was embarrassing because
there's a good chemist organic chemist
synthesis is what we do is not a field
so when I woke in 2004 was an article in
nature and in Scientific American
telling me that Pete Schultz and I at
both invented synthetic biology and
I called Pete said did you invent
synthetic biology without telling me and
he said no but we're gonna write into
the next grant application
so but synthesis of course is an old
field in chemistry almost all the
compounds that you have in your clothing
as dyes or synthetic and of course
biology became synthetic in 1970s with
the recombinant DNA technology and there
was a big concern at the time as to
whether or not this would lead to plants
that would escape the laboratory bugs
that would have saved a Leger Praetorian
be harmful there was a huge conference
in Asilomar in California where rules
were set out over the last 40 years
we've come to pretty much understand
that there's not a lot of risk
associated with this but there are still
some people who don't like genetically
modified organisms so right now they'll
make plants right which will be
resistant to herbicides you plant the
plant with herbicides you put herbicide
down all the weeds die and the plants
grow better and they're cheaper so and I
mean a good biochemists will tell you
and I will be one of them that this is
not materially different at all from the
plant that you get minute but the
futures are hard to say I mean the
future basically we are desperately
trying now to get a coli to metabolize
steps here that will enable us to get Z
and P for example made inside of an
e.coli so as tribe right that's gonna
ask you can you upload this stuff into
cells and take it away
your guests and the chemistry department
actually has contributed one of the
enzymes so one of the steps in that
metabolism so we have that metabolism
working in e.coli I have not did not
talk about it because it's a little
premature to speak up but yes again Eco
is able to maintain plasmas it contain
funny bases and of course the funny
bases now will be used in diagnostic
systems and so you will have an e.coli
package there's able to do a complete
diagnostic workup of you right now so
don't have to pay money for each and
that's certainly isn't it so unlike dogs
which are human creations after all but
very close to wolves we're dealing here
with truly novel
organisms that could in the very near
future be autonomous and that's that's a
big problem we we the autonomy of these
things especially it's also true with
just recombinant DNA organisms it's less
than we would like they're dying No
when we try to keep them alive but in
principle yes you could have all time
right so the problem that would be that
this poor guy he dropped now in the
world he wants to go find some Z to eat
that's right yes no chance yes not so
we've created a whole ecosystem yes like
the next step all right well I think
we're going to have to draw it to
conclusion not least because you need to
sign books outside so before we wrap it
these occasions take a lot of
organization and my staff particularly
Adriana Fontes who ought to be around
somewhere and Katie and Alisa at the
back there you all have met them on your
way in and several others who have
helped out over the weeks in in
promoting and dealing the website and
encouraging you all to come and so I
think a round of applause for them as
well as for our speaker
and see you all next time
drive safely

28The RNA world, and the origins of life - Page 2 Empty Re: The RNA world, and the origins of life Fri Apr 10, 2020 7:00 pm


1. Life uses only right-handed RNA and DNA. There is no selection process of only right-handed RNA and DNA on prebiotic earth.
2. RNA is thermodynamically unstable in water, and overall intrinsically unstable. It devolves to become more and more “asphaltic”, as the atoms in the mixture are rearranged to give ever more molecular species. In the resulting “asphaltization”, what was life comes to display fewer and fewer characteristics of life.
3. Systems of interconnected software and hardware like in the cell are irreducibly complex and interdependent. How could and would information processing machinery come to exist without the software and vice versa?
4. A certain minimum level of complexity is required to make self-replication possible at all; how was that achieved prebiotically?
5. RNA catalysts would have had to copy multiple sets of RNA blueprints nearly as accurately as do modern-day enzymes. how did that supposedly happen prebiotically?
6. In order a molecule to be a self-replicator, it has to be a homopolymer, of which the backbone must have the same repetitive units; they must be identical. How was that possible In the prebiotic world?.
7. Not one self-replicating RNA has emerged to date from quadrillions (10^24) of artificially synthesized, random RNA sequences.  
8. Over time, organic molecules break apart as fast as they form. How was that overcome on early earth?
9. How could and would random events attach a phosphate group to the right position of a ribose molecule to provide the necessary chemical activity? And how would non-guided random events be able to attach the nucleic bases to the ribose?  The coupling of ribose with a nucleotide is the first step to form RNA, and even those engrossed in prebiotic research have difficulty envisioning that process, especially for purines and pyrimidines.”
10. L. E. Orgel:  The myth of a self-replicating RNA molecule that arose de novo from a soup of random polynucleotides. Not only is such a notion unrealistic in light of our current understanding of prebiotic chemistry, but it should strain the credulity of even an optimist's view of RNA's catalytic potential. If you disagree, why?
11. Macromolecules do not spontaneously combine to form macromolecules. How do you think did it occur nonetheless prebiotically?
125. The transition from RNA to DNA is an unsolved problem.
13. To go from a self-replicating RNA molecule to a self-replicating cell is like to go from a house building block to a fully built house.
14. Arguably one of the most outstanding problems in understanding the progress of early life is the transition from the RNA world to the modern protein-based world.  
15. It is thought that the boron minerals needed to form RNA from pre-biotic soups were not available on early Earth in sufficient quantity, and the molybdenum minerals were not available in the correct chemical form.
16. Given the apparent limitation of double-stranded RNA (dsRNA) genomes to about 30 kb, together with the complexity of DNA synthesis, it appears dif¢cult for a dsRNA genome to encode all the information required before the transition from an RNA to a DNA genome. Ribonucleotide reductase itself, which synthesizes deoxyribonucleotides from ribonucleotides, requires complex protein radical chemistry, and RNA world genomes may have reached their limits of coding capacity well before such complex enzymes had evolved.

29The RNA world, and the origins of life - Page 2 Empty Re: The RNA world, and the origins of life Sun Jul 12, 2020 6:06 am


"The RNA World is a widely-embraced hypothetical stage of molecular evolution, devoid of protein enzymes, in which all functional catalysts were ribozymes. Only one fact concerning the RNA World can be established by direct observation: if it ever existed, it ended without leaving any unambiguous trace of itself."

Even this is a bit of an understatement. Because without the prior assumption of evolution, which can and has underwritten a wide range of speculation, there is precisely zero reason to believe this wild hypothesis. No organisms have ever been discovered that demonstrate the RNA World hypothesis in action. Nor have scientists ever constructed any such organisms in their laboratories. This is not too surprising because no one has even produced anything remotely close to a detailed design of how such organisms could function.

Wills and Carter also point out negative evidences such as catalysis (RNA enzymes lack the ability to function over a wide range of temperatures) and the “impossible obstacles” to the hypothetical yet necessary transition from the RNA World to something resembling today’s extant cells. As Carter explains:

"Such a rise from RNA to cell-based life would have required an out-of-the-blue appearance of an aaRS [aminoacyl-tRNA synthetase]-like protein that worked even better than its adapted RNA counterpart. That extremely unlikely event would have needed to happen not just once but multiple times — once for every amino acid in the existing gene-protein code. It just doesn’t make sense."

Indeed, it just doesn’t make sense. And yet in spite of these obvious problems, the RNA World has been a textbook staple, presented as a plausible and likely example of how early life evolved.

30The RNA world, and the origins of life - Page 2 Empty Re: The RNA world, and the origins of life Mon Nov 23, 2020 4:34 pm


Nucleic acid instability challenges RNA world hypothesis 26 SEPTEMBER 2016
RNA and DNA have very different abilities to withstand chemical changes like depurination, deamination, and hydrolysis. The chemical stability of these two nucleic acids should also be considered when thinking about how they could become incorporated into the earliest forms of life.

The stability of the RNA bases: Implications for the origin of life MATTHEW LEVY AND STANLEY L. MILLER , July 1998
High-temperature origin-of-life theories require that the components of the first genetic material are stable. We, therefore, have measured the half-lives for the decomposition of the nucleobases. They have been found to be
short on the geologic time scale. At 100°C, the growth temperatures of the hyperthermophiles, the half-lives are too short to allow for the adequate accumulation of these compounds (t1/2 for A and G ~ 1 yr; U = 12 yr; C = 19 days).
Therefore, unless the origin of life took place extremely rapidly (<100 yr), we conclude that a high-temperature origin of life may be possible, but it cannot involve adenine, uracil, guanine, or cytosine.

The evidence that is currently available does not support the availability of ribose on the prebiotic earth, except perhaps for brief periods of time, in low concentration as part of a complex mixture, and under conditions unsuitable for nucleoside synthesis.

Robert Shapiro:
The presumption that “the bases, adenine, cytosine, guanine and uracil were readily available on the early earth” is “not supported by existing knowledge of the basic chemistry of these substances. The RNA-world hypothesis faces an even more acute, but related, obstacle—a kind of catch-22. The presence of the nitrogen-rich chemicals necessary for the production of nucleotide bases prevents the production of ribose sugars. Yet both ribose and the nucleotide bases are needed to build RNA.

Dean Kenyon explains
“The chemical conditions proposed for the prebiotic synthesis of purines and pyrimidines [the bases] are sharply incompatible with those proposed for the synthesis of ribose.”

Shapiro concludes:
“The evidence that is currently available does not support the availability of ribose on the prebiotic earth, except perhaps for brief periods of time, in low concentration as part of a complex mixture, and under conditions unsuitable for nucleoside synthesis.”

Naturally occurring RNA molecules possess very few of the specific enzymatic properties of proteins. Science has shown that ribozymes can perform a few of the inumerous functions performed by proteins. Some RNA molecules can
cleave other RNA molecules (at the phosphodiester bond) (hydrolysis). Ribosomal (rRNA) performs peptide-bond formation in the peptidyl transferase center, though only in association with an additional chemical catalyst. Beyond that, RNA can perform only a few minor functional roles and then usually as the result of engineering in the laboratory. Claiming that catalytic RNA could replace proteins in the earliest stages of chemical evolution is not evidence-based.

How do you go from an RNA based world, to produce proteins? That is a huge, unsolved gap. In order to do so, you need the molecular machines that do so. The primitive replicator would need to produce RNA molecules capable of performing the functions of proteins involved in translation. These RNA molecules would need to perform the functions of the twenty specific tRNA synthetases and the fifty ribosomal proteins, among the many others involved in translation. How do you go to substitute supposed ribozymes with proteins, that later would do the same job? That's a far fetched just so scenario, which bears no evidence that such a transition could/would occur. In other words, the evolving RNA world would need to develop a coding and translation system based entirely on RNA and also generate the information necessary to build the proteins that later would be needed to replace it.

Determination of the Core of a Minimal Bacterial Gene Set
A bacterial cell depends upon a translation and coding system consisting of 106 distinct but functionally integrated proteins as well several distinct types of RNA molecules (tRNAs, mRNAs, and rRNAs) The minimal number of ribosomal proteins required for proper functioning of the ribosome corresponds to the gene set present in M. genitalium, which includes 31 proteins for the large ribosomal subunit and 19 proteins for the small one.

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