PROFESSOR: Good morning.
Come on down.
All right.
So last time, we talked about
the first couple of steps of
the central dogma.
The central dogma is this name
given to the statement DNA
goes to DNA by replication.
DNA goes to RNA by the process
of transcription.
We call it transcription because
it's such a direct
copying of letter to letter.
RNA goes to protein by a
process of translation,
because translation is the
kind of word we would use
between two different
languages.
And there are two different
languages--
the languages of nucleotides
and the
language of amino acids.
For what it's worth, it's name,
the central dogma, goes
back to Francis Crick, who
called this the central dogma.
He did it in a kind of a
light-hearted way, although
others since then have
criticized it, saying, oh,
this is dogmatic.
Actually, Crick said not
that DNA goes to
RNA goes to the protein.
He says that all information
flows from nucleic acids to
proteins and not back again.
Because even then, Crick knew
that in theory, there was no
reason you couldn't go back from
RNA to DNA, and as we'll
see today, that happens.
So sometimes people say, oh,
well, the central dogma was
proved wrong because RNA
can go back to DNA.
Well, actually, that was even
anticipated right then at the
very beginning, when they
realized RNA and DNA were
essentially equivalent
information.
The key step of converting
nucleic acid information into
protein information
is translation.
And that's the last bit
we have to fill in
and talk about today.
So let me start by just
reminding you-- because most
of you know it--
how translation works.
So, in translation, you have a
particular RNA that has been
made by the cell.
Here's my RNA.
It goes five prime
to three prime.
That's always the way we
write these things.
And it has some particular
sequence.
I'll make up a sequence here.
A, U, A, C, G, A, U, G, A, A,
G, A, G, G, C, C, C, dot dot
dot dot dot, U, A, G, dot dot
dot dot, three prime.
All right.
Somehow, that's going to be
translated into a protein.
It's translated according to a
fantastic look-up up table.
This look-up table is called
the genetic code.
And the rule, the algorithm--
and it's a fairly simple
algorithm, well, nothing's
ever really simple in biology,
but it's close to simple--
is you run along the sequence
from the beginning.
And you guys could write this.
Anybody who's taken basic
computer programming.
Run along the sequence and find
the first occurrence of
A, U, G. Why A, U, G?
Because A, U, G is the
place you start.
That's how life worked it out,
and that's what it does.
After that, you parse the
sequence in triplets.
These triplets get
the name codons.
And then you keep going
until you hit one of
three possible triplets.
U, A, G. U, A, A. U, G,
A. And you stop there.
Any MIT student should be able
to write an algorithm that
takes a string, finds the first
occurrence of U, A, G,
breaks it up into triplets
passed there, keeps going
until you encounter one of
these three triplets.
What do you do for
a given triplet?
You look it up against
the table.
How many triplets are there?
How many three-letter words
are there with the four
nucleotides?
AUDIENCE: 64.
PROFESSOR: It's 4 to the 3rd--
64 possible words.
I've used up three of them to be
stop, so there are 4 to the
3rd possible codons.
That's 64.
Three stops.
The other 61 possible codons
specify an amino acid.
That's it.
There's a look-up table.
The genetic code.
How many amino acids
are there?
20.
And there are 61 possible
codons, so that implies there
is some redundancy.
Some codons--
some amino acids are coded
for by the same codon.
Okay.
That's fine.
And in your book is the genetic
code that is the
look-up table here.
The genetic code translates
these codons into amino acids.
Or to stop, in the case of
the three stop signals.
So for example, this A, U,
G at the front is always
translated into methionine.
Met.
And if I've got it right,
this should be a lysine.
Here we go.
Arginine, proline, et cetera--
you just look it up.
That's it.
That's the order in which
you make the proteins.
So you send off an order written
in RNA, you send it
off to the factory, the factory
sends you back a
protein that is methionine,
lysine, arginine, proline,
blah, blah, blah, blah, blah.
That's it.
This genetic code is essentially
universal amongst
all of life.
That's pretty stunning.
What does that tell you?
The fact that all of life uses
virtually the identical
genetic code?
There's actually a tiny
difference between prokaryotes
and eukaryotes affecting a
codon and there's a tiny
difference somewhere else.
But essentially, it's the exact
same genetic code that
all of life uses.
It's very unlikely that this
genetic code is the only
possible way you could make
a genetic code, right?
So the fact that all of life
uses, essentially, exactly the
same code is pretty strong
evidence that all currently
existing life descends from
a common ancestor.
Because if these were evolved
independently, it's extremely
unlikely that you would have
gotten exactly the same
genetic code.
So that's an interesting point
that you can see from just the
fact that everybody uses
essentially the
same genetic code.
It's a universal genetic code.
All right.
So I've expressed this to you
in a completely computer
sciencey kind of way.
But, of course, the cell doesn't
do this by computer
science because cells are
unable to write C code.
The reason that cells are unable
to write C code is C
wasn't really developed until
the last several decades, and
cells, pretty sure, precede the
development of C code by
Kernighan and Ritchie.
So it's got to be the case that
it's done some other way.
How is it done?
Well, it's done like this.
And I'll just be very
schematic and you'll
get it in your book.
There's a big machine.
The big machine here is
called the ribosome.
It consists, itself, of proteins
and RNAs, and it's a
huge structure.
The huge structure needs
to read codons.
And this is a case where
Francis Crick
drove everybody nuts.
Francis Crick, back in the
1950s, just sat at his desk
and thought.
He was terrible at doing
experiments--
nobody really wanted to let
him do experiments.
Francis was a great thinker.
He thought.
He said, golly, how can this
sequence be translated into
amino acids?
Well, people at the time had
all sorts of nutty ideas.
Some of the nutty ideas was that
the sequence of the RNA
folded up into pockets that
just fit a proline.
And another pocket that
just an arginine.
And if you just think about the
constraints to get that to
work, it's nuts.
That the sequence itself would
form perfect binding pockets
for the necessary amino acids.
Crick said impossible.
He said the really sensible
way to do this, if I were
running life, what I
would do is I would
have an adapter molecule.
The adapter molecule would be
some kind of a nucleic acid,
and the nucleic acid would kind
of match the codon on one
end and have the amino acid
on the other end.
And then there'd be another
adapter, and the adapter would
have the next amino acid.
And then you would catalyze
a bond between them.
Therefore, I predict, says
Francis, there will be small
adapter molecules, probably made
out of RNAs themselves.
And Francis called this the
Adapter Hypothesis.
It drove people crazy because,
of course, he was right.
People found the adapters and
they would use transfer things
that transfer information--
get called transfer RNAs.
What happens is the ribosome
has pockets in which these
transfer RNAs basically come
in, match their sequence,
there's a codon each of these
transfer RNAs has a matching
anticodon that matches the
triplet, and it has already
attached to it an amino acid--
the right amino acid
for that anticodon.
How does that right amino
acid get attached
to the right tRNA?
There's an enzyme.
The job of that enzyme is to
attach this amino acid,
proline, to this transfer RNA.
It's a Prolyl-tRNA synthetase.
And its job is to put proline
on the right tRNAs.
There's another one that puts
arginine on the right tRNAs.
There's a whole business that's
set up to get the right
tRNAs, have the right amino
acids attached to them through
a bunch of enzymes
floating around.
So then these tRNAs with the
amino acid attached drop in,
they drop into the next
position, and a bond--
the peptide bond--
is catalyzed.
Interesting factoid.
The catalysis, this enzymatic
catalysis to join together
those amino acids is actually
carried out not by the
proteins in a ribosome,
but actually
by RNA in the ribosome.
The RNA is the enzyme.
You know why that's
kind of cool?
If this bothers you, just forget
it, but one of the
mysteries about how you ever go
from DNA to RNA to protein
and all of that is how the whole
thing ever got started.
How could you possibly have
gotten protein synthesis
started if the things that were
needed to make protein
synthesis were proteins?
So this is actually an echo of
an ancient world 3 billion
years ago, where this was all
probably carried out by RNAs.
RNA was probably the early
catalysts for most things, and
we still see evidence of the
fact that even today your
peptide bonds are catalyzed
actually by RNA and they're
doing the enzymatic work.
Anyway, it's kind of cool.
If you didn't get that, don't
worry about it, but
it's kind of cool.
So then what happens after
you attach the
first two amino acids?
Well, the ribosome chugs down
here and grabs the next code--
these two shift over.
You can either think about the
ribosome moving this way or
the RNA moving that way.
The next tRNA drops in, the
next bond gets made, chugs
over, the next one drops in,
the next one gets made, and
onward like that until it hits
a stop codon at which, it
releases it.
The ribosome knows
to release it.
There's actually a little factor
that drops in and tells
it to release it there.
And that's how you
make proteins--
kind of cool.
It works very well.
It chugs along in
that fashion.
For you computer scientists,
what you basically have is a
two-tape turing machine--
you're reading one tape and
writing to the other tape.
There's a nucleic acid
tape and there's
an amino acid tape.
If you're not a computer
scientist, forget I said that.
OK.
So it's basically a two-tape
tape turing machine where the
RNA is coming through here and
the protein is coming out that
way, but the amino acids
attach to each other
until it comes off.
In fact, actually, very
recently, a Nobel Prize was
awarded last year for beautiful,
beautiful work on
how this actually takes place--
the molecular details
of the ribosome.
Really gorgeous.
Any questions about that?
Yeah.
AUDIENCE: Is that not
susceptible to the same error
as replication is?
PROFESSOR: Oh, is that not
susceptible to the same error?
Does the ribosome ever
make mistakes?
It does.
What happens if you make
the wrong protein?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Oh well.
The answer turns out to be "oh
well" because for any given
DNA, you make lots of RNAs.
For any RNA, you use it
again and again to
make lots of proteins.
And if the occasional protein is
not so good, if the quality
control is not perfect, it's
much less serious than if your
master instructions in the
DNA were not perfect.
So the cell actually
devotes a lot less
attention to quality control.
Now.
That's not to say there isn't
important quality control.
There are quality control
mechanisms, but it doesn't
have to be as accurate as one
error in a billion, like you
want to be in copying
your DNA.
And that's really an important
point, is the archival copy
has to be really good, but
little yellow sticky notes--
what you make from it, which
are basically RNA or the
little yellow sticky notes you
copied down-- they don't have
to be perfect.
And each copy, the protein
doesn't have to be--
and if the protein is not
perfect, there are mechanisms
that take unfolded proteins
and degrade them.
So it turns out there are ways
to achieve quality control in
that sense.
It's a great question.
