So in the last lecture I spent quite a while trying to convey a sense of
how the structure of DNA was discovered. The crystallographic
data that led to it, as I said, was collected by Roslyn
Franklin. And I saw there was some confusion about this picture that I
showed you next. This is not a photograph of a
double helix. This is what happened when she
bounced the x-ray off the crystal of DNA. This is the diffraction
pattern that she saw. And then one works backwards from
that trying to figure out what kind of structure it was that would have
caused that diffraction pattern. And you have to be a pretty good
x-ray crystallographer to draw any kind of inferences from that.
And there people, including Francis Crick, who saw the implications
of it right away. But the point was she collected the
data and then two people that I told you about then whose name you know
so well, Jim Watson and Francis Crick, were the two individuals that
came up with the model that explained the diffraction pattern.
And therefore we learned the structure of DNA as a
double-stranded helix. I also tried to make the case that
it wasn't two geniuses who sat down in the room, took a look at this and
popped up with the model. It was a story of real people with
misadventures and mistakes and recovery from mistakes and so on
getting it. It was also a very small group. And I'm going to take
just a very small minute at the beginning of the class because I
have a colleague, Vernon Ingram who's sitting down
here in the front, who was a member of this very small
group with Jim Watson and Francis Crick. So here was there where all
this happened. And almost nobody in the world has
had a chance in your generation to hear directly from somebody who was
there when it happened. So asked Vernon if he would come
and just talk to you for a little bit just what it was
like to be there.
Well, thanks, Graham. You seem to be at a very exciting
state in 7.014. This structure of the secret of life,
no less. And it's interesting that immediately when Watson and Crick
put together a model of the DNA molecule that fit the x-ray data,
that was the point, how do you know a model is correct?
Because there are certain distances in the model, and those have to
correlate exactly with the distances of the x-ray spots in the
diffraction pattern that you saw. That's how you know that a model
that you've built to certain specifications corresponds to what
the molecule of itself in the crystal that you're examining
actually is composed of. It was by sheer accident that I
happened to be working as a biochemist in the MRC,
The Medical Research Council lab at the Cavendish Laboratory where
Watson and Crick were working. Sheer accident. It was a very
crowded lab, as Graham said. And that's something that you should
remember. When you're choosing a lab to work in,
always go to a lab that's overcrowded. Never go to a lab
where there's lots of space because a really successful lab attracts so
many coworkers, visitors that it rapidly gets
overcrowded. And that was the case in this
laboratory. The director was Max Perutz. Co-director John Kendrew
doing x-ray crystallography of proteins for almost the first time,
and solving the protein structure. Francis Crick was a graduate student
of Max Perutz's doing his PhD work. And the first thing I remember about
Francis was when I went there as a biochemist to work with Max Perutz,
when I went there, there was this tall gangling guy constantly
circulating between the top floor of the building, his office in the
middle and the x-ray machines at the bottom. He was constantly going up
and down. And in those days the buildings didn't have an elevators
or lifts as the English called them.
So he was in excellent physical shape. Very crowded,
a very modest lab. And what's usually forgotten is a key member of
that group, an engineer, Tony Broad, key person because he
invented what was then the world's best and most efficient x-ray
machine, a rotating anode x-ray machine.
And because to the x-ray crystallographers in that group this
machine was available, because of that they were the
preeminent x-ray structure group in the world. My job was as a
biochemist protein biochemistry putting a heavy atom,
mercury, very heavy atom into Max Parutz's hemoglobin crystals
in specific places. That has a predictable effect on the
x-ray pattern and that enables the Fourier diagram to be constructed
with real phase values for the x-ray diffractions, for the physicists
among you here. Are there any physicists here?
Yeah, I thought so. That was a big step forward and that was also a big
step in figuring out the structure of the DNA samples semi-crystals
that Professor Walker just referred to.
All dependent on the engineer Tony Broad who is never mentioned in any
of these histories, but without him this would not have
happened. So it was an exciting place to work in,
very exciting. We were all young in those days. And living the lives of
young men and young women with all the complications that arise when
you put a whole bunch of very energetic young men,
very energetic young women together. And by that I mean the interpersonal
relationships which when you're in a crowded, very active situation can
sometimes interfere. And always very entertaining,
I can tell you that. I could give you chapter and verse.
But it isn't really so very different from people
your age now, right? I mean I'm not saying it interferes
with you, sometimes it might. But it was an exciting lab, an
exciting time to be there because we were not the only group trying to
figure out the structure of DNA. A huge competitor was Linus Pauling
at Caltech who had beaten that same group once before,
quite recently, over the alpha helix, the crucial component of
protein structure. He got the right answer first,
1.5 angstrom reflection, the alpha helix. And our group,
Max Parutz and our group had been wrong. So the group was smarting
under that kind of defeat, if you like.
And competition is a wonderful spur, as long as you don't let it get out
of hand. Well, needless to say we didn't,
but the competition with the Pauling lab was certainly so severe that we
awaited the next letter. You see, in those days new
scientific information arrived not by publications,
that too much too long, but by personal letter. And,
in fact, the NIH has put together all these various letters in the
Francis Crick collection. And when you have time you should
look at those. They're quite interesting because
they tell you in a way a scientific paper does not tell you.
What I feel about my experiment results. What she feels about her
experiment results. What it means to me as a person,
to her as a person, to him as a person. So we were constantly
watching the mail and discussing the news as it came in,
mostly over a beer at the pub next door. It was very conveniently
located. But being a small group crowded
together made communication within our group very easy indeed.
And we had fights. I don't mean physical fights.
We had scientific fights. And as a biochemist I was able to
settle a crucial fight among the crystallographers Crick and Watson
who were building the model. Because, quite frankly,
they didn't know much chemistry. And were trying to build a model
with the wrong confirmation of the peptide bond. They didn't realize
that the peptide bond has two possible confirmations.
And they had at one point a terrible time trying to fit
everything together because they were using the wrong confirmation.
I'm talking about lactam-lactim for those of you who are organic
chemists and it means something, a confirmation. And once they got
the first confirmation then the model clicked into place.
So we all helped, that's what I'm trying to say.
We all helped with one great aim in mind. It was clear.
And you know from what Professor Walker said, that the DNA structure,
in its structure held the clue to crucial physiological
behavior of DNA. And Crick and Watson said this in
their first paper, the structure itself because of its
complimentarity gives you an immediate clue as to how it
replicates. And replication of DNA structure from generation to
generation is, of course, the crucial thing about
DNA. The copying, the precise copying
from generation to generation. And that fell out the of x-ray
structure. That's why the x-ray structure was so very important,
because it gave you an immediate understanding of the role of DNA in
modern biology. So that's what we did.
And eventually the people in the group, the group got so overcrowded
they built a huge lab that was beautiful, like any new lab is.
But the thing I remember most of all was the atmosphere in that place.
So remember, when you go and choose a lab, choose one that's overcrowded.
It will pay off. [APPLAUSE]
Thank you so much. That was really wonderful.
Thank you.
I don't know if some of you realized quite how rare that was,
this discovery of the structure of DNA. As I said,
probably one of the big discoveries of mankind. Because,
as Vernon said, you could see so many of the secrets of life as soon
as you saw that structure. Very few people have ever heard
from someone who was there at the time. Maybe you'll forget a bunch
of stuff down the line, but I hope you'll remember you heard
somebody who was there when Wesson and Crick were there and maybe his
extra piece of advice about choosing a lab.
To say one thing quickly, some of you I think understood what
I've been trying to do. I spent quite a bit of time talking
about science being done by real people doing real experiments.
Thanks for your comments. A few of you have gone out of your way to say
that this was a total waste of time and you didn't understand why I
didn't teach you something instead of doing something on the test.
Well, I'm making up the test. And if you don't think there'll be
something on scientific process on the second exam you'll
be surprised. So I'm spending a lot of time on
this, and the reason is because you are MIT student.
You know, you can go many places in the country to many high school
biology courses and you can memorize, someone will tell you to memorize
everything that's in the book, and you'll get tested whether you
can memorize it. You guys are at MIT because you
have the potential to be leaders in whatever you do.
I've made the transition from being an undergrad sort of trying to
memorize stuff in a textbook to working on a cutting-edge.
I've made some reasonably significant discoveries in science,
as have my other colleagues in the department, some of them making
greater than I. But nevertheless if you're on the
cutting-edge then you're dealing with all the stuff I'm trying to
tell you about in this thing. You're working as a part of a group.
There's competition. There are interpersonal
relationships. You make mistakes.
You recover from them. You're making inferences.
You're testing models. This is a very complex, very real,
very dynamic, very human interaction. I hope you got a little bit of
whiff of that from Vernon. And I wouldn't be,
I'm quite capable of reproducing diagrams from the textbook without
trying to give you a deeper understanding,
and that's what I'm trying to do here. And I hope if it hasn't made
sense to you by the end that at least a few more of you will get it.
And those of you who I think saw what I was doing I appreciate your
telling me that in the things. These are anonymous so I don't know,
but a couple of you are certainly trying to make it clear that you
didn't think it was worth your time coming to lecture.
I'm trying to tell you why I'm trying to do it.
I'm trying to teach you in a deeper way. And this is a required course.
It's important for your life. I hope some of you will see that or if
you don't see it now you'll see it later in your career.
OK. Now, we're going to talk about DNA replication.
I'm going to start to drive into some of the details that maybe are
more the kind of things you're expecting. I just want to make one
quick point here. I've talked about cell division and
we saw this, how cells come from other cells going to make more cells.
I showed you this little movie you've seen a few times of a yeast
cell dividing, but all cells divide.
Here's a cancer cell dividing. If you get a cancer it's a cell
that's forgotten how to stop dividing and is growing to make a
tumor. There's this cancer cell dividing. It looks not unlike a
yeast on a molecular level, very, very similar. But there's
another point. I told you how the structure of DNA
with the complimentary strands with G pairing with C and A pairing with
T immediately gave rise to an insight as to how the genetic
material could be replicated. And you guys know that it's held
together by hydrogen bonds between base pairs which are about
one-twentieth the strength of the covalent bonds.
So you're able to peel the strands apart without breaking the covalent
bonds. And then by pairing A with T and G with C and doing that on both
strands then you can end up with two identical copies.
And so if you do two identical copies and you do it again you get
eight. One of the things we've realized over the last two or three
years in looking through the exams is somehow, at least some of the
class, didn't connect the business about cells coming from other cells
and DNA duplicating to give daughter DNA. And I'm just trying to hammer
home the point that these are related. Every time a cell divides
it has to duplicate its genetic information.
That's why I'm going to be telling you about DNA replication.
Here's a picture of that same cancer cell, but watch over here.
This is the DNA. And you see it's doubled. And see how the DNA,
which is the chromosomes, has pulled apart so that at the end you now
have two cells and you've got identical copies of DNA.
So if you're studying cancer, for example, this sort of thing is
relevant to you. OK. So the issue of how --
Well, before I do that, I'm sorry. Just a couple of things
about DNA replication before I dive into this. So we all started out as
a single cell. I've got a lot more obviously
because I'm made up of a lot of cells. If I took all the DNA in my
body and I wind up all the molecules in it, do you guys have any idea how
long that would be? Who thinks it would reach let's say
across the room? OK. Across campus?
Across Cambridge? Around the world? To the moon? Anybody left?
To the sun? I've got ten to the fourteenth cells.
There's about a meter or two in each cell. 10 to 20 billion miles
of DNA in each of our bodies, human DNA.
They would go back and forth to the sun multiple times.
So that much DNA had to get replicated in order for the
fertilized egg we all started out as to become you.
Another thing, the accuracy of replication is about
ten to the minus tenth. Most people, including myself,
don't have a very good feel for exponents. So that's one
mistake in 10 billion. You know, it could be one mistake in
10 to the ninety-ninth. Well, what is one mistake in 10
billion mean? So let's relate it to something we know.
If I was typing let's say an eight letter word, 60 words a minute,
24 hours a day, 7 days a week, and I was as good as DNA replication,
how often would I make a mistake? So you can each think of how long
you think that is. But if I was good on average,
I would make a mistake once every 38 years.
So I'm about to tell you about a process that's absolutely
astonishing in terms of how fast and how much you can do and with an
accuracy that goes beyond what we're used to in our ordinary life.
So how does it do this? It has to be more than just pulling the
strands apart. And there's been some confusion as
to why I'm emphasizing 5 prime and 3 prime.
Well, each of these subunits, each nucleotide, this is a 3 prime
hydroxyl and this is the 5 prime position. If we were joining
together subunits that had a hook and an eye it would make a
difference because it's not the same on both ends. If we're going to
start hooking together it's exactly the same thing when we get to a
biochemical level, the 5 prime end is not the same as
hydroxyl at the 3 prime end because the whole thing is asymmetric.
So the enzymes that copy DNA are known as DNA polymerases.
And it was a very difficult challenge to figure out how they
operated, but Arthur Kornberg was the first person to solve
this problem. He was an extraordinarily gifted
biochemist. He's still at Stanford. And what he found was if we have a
5 prime end this would then be the 3 prime end, and there's a 3 prime
hydroxyl which is this one right here. And this was paired,
say, with a C and A paired with a T. And let's say a G paired with a C
here. And let's say the next template base was,
let's make it a T. What Arthur Kornberg was able to find was an
enzyme activity that catalyzed a template-dependent replication of
DNA. That was critical because he had to find, if you broke the cells
open, somewhere in that gamish of enzymes and things from
inside a cell. There had to be something that was
able to copy DNA. So in order to do that he had to
work out an assay. And he also had to have some kind
of guess as to what the cell would be using in order to carry out the
synthesis. But one thing that was sort of obvious was a DNA template
because that was being copies. But the other part was you had to
have energy to form a covalent bond.
So somehow there had to be something that was sort of activated with the
energy built into the molecule so that thermodynamically the whole
thing would slide downhill when you made a bond. And he knew that the
cell had triphosphates, just the same type that we talked
about when we talked about ATP.
So this would be a deoxyribonucleotide triphosphate.
And he was able to make a guess, because he had to try things until
he found something that would work, that this was what's used in DNA
synthesis. So this hydroxyl ultimately attacks
this phosphate here. And these two other phosphates then
come off as a leaving group. So if we thought of it as a pea
like this with two more peas here, these two come off and you get a new
bond formed to the phosphate. And so what Kornberg then was able
to find by using a DNA template that had this sort of structure and
[TTATA?] like this, that he was now able to get an A
added here. This hydroxyl here became the new hydroxyl.
And so the direction of synthesis, this strand is the other way, so the
direction of synthesis of a DNA polymerase, it's polymerizing in the
5 prime to two 3 prime direction. This was again an amazing discovery
because it was the first time that anyone had found an enzyme
that could copy DNA. Arthur Kornberg got a Nobel Prize
for it. But at this point actually genetics came in because there was a
scientist John Cairns who was at that point down at Cold Spring
Harbor, as I told you the other day. And John, in spite of the fact that
Arthur had found a DNA polymerase that had all the properties that you
would expect for copying DNA, didn't think that was the one that
actually copied the DNA necessary for cellular replication.
So he reasoned if he was right he'd be able to find a mutation that
would eliminate the activity of that enzyme and the cell would still live.
And so they did a screening, and it was a lot of work, but they
eventually found a mutant of E. coli that lacked this DNA polymerase
that Arthur Kornberg had discovered. And the cell was still alive and
was still replicating its DNA. So it told both John and then
Arthur there must be another enzyme in the cell.
And so Arthur went back. And now working in a mutant that
was missing this first polymerase he discovered he found the one that
really replicates the DNA. The first one is important,
too. It's needed for DNA repair. I'm going to talk to you about that
in next lecture, but it's not absolutely crucial for
life. And there's an interplay of genetics and biochemistry.
And you'll see I'm just sort of foreshadowing what we're going to
get to when we talk about the genetics of this.
And I know a couple of you clearly were frustrated about me showing you
pictures of the people who did this, but nevertheless since this was such
a historic event a couple of years ago at Cold Spring Harbor.
This you see the helix model down there. There was Jim Watson opening
the symposium. When I got up to talk I said,
well, I told my students that I'd let them know what it was like when
I was there, so I took out a camera and I took a picture of the audience.
And so there are a bunch of Nobel Laureates and types here who were
sitting there smiling for you guys in the class. And there was Arthur
Kornberg giving his talk. Now, these DNA polymerases are
incredible protein machines. The crystal structures of DNA
polymerases operating their template have been solved.
And you can solve, depending on how many diffractions
you can get, you can get a model that's more and more detailed.
And there have been very high resolution models of DNA polymerases.
This blue and white stuff is the surface of the protein,
and this is sort of a template and the various parts.
Just to give you an idea here are these tracings of the shapes of the
electron density. You can see how the
crystallographers have fit the nucleotides right in the crystal
into these electron densities. And here putting it together a bit
in the blue is the secondary structure of the protein and the
templates and whatnot. And I don't expect you to see very
much in that, but the point is I wanted to sort of just set you up to
show you this little movie. Because DNA polymerases are
incredible machines. They copy at about a thousand
nucleotides a second and their accuracy is really amazing.
And I'll tell you all the tricks to the accuracy in the next lecture,
but I want to show you this little movie because this is sort of a
simulation of what must happen every time a nucleotide is added.
Now, we'll see this over and over again so I'll take it in pieces.
The yellow and the orange are the secondary structures.
That's an alpha helix. And certainly one thing you can see
is happening, as we're looking at this, is the parts of the protein
are moving during this. So you can see this alpha helix
that's sort of swinging up and swinging back down.
Now, what's over here is the template base.
That's the base that correspondents to the T that I was just
showing you here. This is the incoming nucleotide.
There is the triphosphate coming down here. And,
in fact, you just see those two phosphates going.
So what's happening here, this is going to be the end of the
growing chain. It's going attack right there,
join the phosphate and the pyrophosphate will leave.
And if you'll take a look, when you see this movement of this
helix from the beginning state to up to here, you'll see what happens.
It's squeezing the template base and the incoming nucleotide together.
What it's really doing is testing for the correct shape.
Remember the shape of an A-T base pair and a G-C base pair is the same.
And if those of you who are confused about guanine and the
keto-enol thing, try to draw hydrogen bonds with the
enol form of guanine and see how you do. I think you'll begin
to understand a bit. So at the heart of life is something
that can copy DNA. And there are these exquisitely
beautiful machines. The replica machine in E.
coli has 18 proteins and the ones in our bodies are even more
sophisticated with even more parts. OK. But to replicate a DNA
molecule there's another problem that comes up.
Because DNA polymerases copy --
-- and grow chains in a 5 prime to 3 prime direction.
And they need a 3 prime hydroxy
terminus. So they won't work if you just gave it a single strand of DNA.
No DNA polymerase can handle that. It has to have something like this
where there's a template strand --
-- and there's what's known as the primer strand.
So there has to be something that has the 3 prime hydroxyl and there
has to be something that's going to provide the template that's going to
be copied. So if we pull strands apart like this with 5 prime to 3
prime then they'll be 5 prime to 3 prime running in the opposite
direction. If we have a template like this,
this is OK because the strand here can be copied 5 prime to 3 prime.
This is the new strand being synthesized by the DNA polymerase.
But what about the other strand? The replication fork is moving in
this direction, but if the -- So here is the 3 to 5 prime
direction here. So if the DNA polymerase is going
to be copying this strand it's going to be moving backwards to the
direction of the replication fork. Now, I guess evolution and nature
could have selected for two types of DNA polymerases,
one that copies 5 prime to 3 prime and one that copies in the opposite
direction. But it didn't. And there are a number of
theoretical reasons that we could discuss in a more advanced course
perhaps for why that is true. But, in fact, what it does is it
uses the same polymerase. So as these things peel apart the
polymerase works in the other direction, but there's another
problem. If I just peel it apart like this there's no 3 prime
hydroxyl. So it took people quite a few years to figure out the strategy
that's used in nature. Nature has a special enzyme that
makes a little piece of RNA. It's called an RNA primer. And
what it does is it provides a 3 prime hydroxyl.
And once you have the 3 prime hydroxyl at the end of the little
RNA chain then the DNA polymerase --
-- can be made 5 prime to 3 prime.
So as you peel open the replication fork then little pieces of RNA are
used to make a new strand of DNA and it goes this way.
Now that obviously doesn't give you a new intact DNA strand.
And part of the clue to this working out what was going on at DNA
replication was the recognition that newly synthesized DNA was made as
little pieces. And then later it got joined into
longer pieces. And the person who discovered this
was Okazaki. So these fragments of DNA that are synthesized initially
are called Okazaki fragments, after the person who discovered this.
It was rather puzzling because when you tried to look at the synthesis
of DNA you're looking at a long molecule, and you found some of the
newly synthesized material was in short pieces. And as you watched
over time it got longer. So the cell, I think you can sort
of see from first principles what has to happen here then.
That in order to come and make --
This strand is pretty easy to do, but what the cells have to do now is
they've got these little RNA primers.
And then they remove the RNA by an
enzyme that's capable of degrading the DNA or clipping it
at the junction. And that then leaves the cell in
this sort of situation where there are little tiny gaps in between
these pieces of DNA. But at the end of each one of these
is a 3 prime hydroxyl. So another polymerase or one or
another polymerase in the cell can fill those little pieces
of DNA out. And then there's one little nick
that needs to be sealed. And so what you finally end up with
is a 3 prime hydroxyl here, a 5 prime phosphate that's at the
other end, and then these are joined together. This is one nucleotide
here and the other here. These are then joined together to
give the ordinary phosphodiester bond that links --
-- the two nucleotides together like
that. And the enzyme that does that is an enzyme called DNA ligase.
You can almost think about it as DNA Scotch tape that will take a
little nick in DNA, if we've got a phosphate and
hydroxyl, and it will join them together.
So this process of replication, which can go at about a thousand
nucleotides a second with this amazing degree of accuracy,
uses two different DNA polymerases, both of which biochemically can only
go in one direction. But you can see they have to be
somehow oriented so that one of them is able to move in this direction
and the other one is able to move in that direction.
The key part in this sort of the course is to try and understand this
5 to 3 prime and to get this basic idea that nature had to do something.
It was fairly easy to copy one strand because that was sort of the
direction of the polymerase movement was the same as the replication for
it movement, but the other strand had to have been much
more a problem. And so when you get down to a
biochemical level, though, it's very conceptually easy
to say, oh, you've got complimentary strands so we just take it apart,
we take the photograph and the negative and we make the opposite
one and now we've got two copies. When you get down to the
biochemical details there is this major biochemical issue of whether
the polymerase can go in the 3 prime or the 5 prime direction.
And nature has chosen to do it all or has been selected to do it all
somehow with a polymerase going in one direction.
There are many other aspects to DNA replication. And one of the tricks
that I find most fascinating is that these polymerases,
once they get on DNA they stay on. And that's part of the secret
because it takes about a millisecond to add a nucleotide,
but if it comes off the DNA it has to get back on. Then it
takes about a minute. So the whole trick to being a very,
very fast DNA polymerase is to somehow hang onto the DNA.
So what biochemists did was they purified the actual enzymatic
activity that could carry out this process, and then they started to
look for other protein factors that would help the process to work
better. And they discovered something called a processivity
factor which made the polymerase stay on the DNA.
And people wondered for a lot of years how that worked and why did
this system work so well. And finally the crystal structure of
the processivity factor was discovered. And if I go back to
this sort of diagram where this is the piece of DNA that's copied,
what it turned out was that the processivity factor is basically a
doughnut that kind of gets clamped around the DNA like that.
So it's sort of like taking a washer with a place where you can
pry it apart opening it up, putting it around the DNA like this.
And then the polymerase, more or less since this is
topologically linked to the DNA, is like a washer sliding on a wire.
This DNA polymerase hangs onto that and it doesn't come off.
And I think there's a little picture of it.
Here's a little movie. There's the DNA going through and
this is one of these clamps. It's virtually the same structure
in a bacterium and inside of us. But, in fact, the amino acids are
almost all different. But the underlying structure of the
protein is almost identical. And there are special machines
called clamp loaders that pry open this clamps, clamp them around DNA,
and that's part of the secret to how these polymerases are able to
polymerize DNA so fast. There are a lot of other pieces of
this machinery. If you go on you'll hear more about
them. I just want to give you one of the most recent insights.
I mean this, as you might guess, since DNA replication is at the
heart of life it's been studied very, very hard, ever since the discovery
of DNA helix. My colleague, Alan Grossman, made quite a
discovery just probably three or four years ago.
He took that green fluorescent protein that we've seen a few times,
and he actually joined the gene encoding green fluorescent protein
to the backend of a piece of the DNA polymerase.
So wherever the DNA polymerase went now there was a little fluorescent
molecule. And he looked to see where it was in the cell.
And I, like many other people, had for years taught, and this is
why, you know, I have respect for the fact that I'm
just teaching you the current model. For much of my career I taught, so
DNA polymerase is sort of like a train going down the tracks a
thousand molecules per second. And we're doing all this stuff with
the leading and with the two strands. So let me just put those words up
while I'm up there. This one is called,
this strand that's easy to replicate is called the leading strand.
And this one where you have to do the primer and whatnot is called the
lagging strand. In any case, what I had taught was
that polymerase was like a train running on tracks.
You could calculate how fast it would move. What Alan,
to his amazing I imagine, found was when he looked to see
where the DNA polymerase was, it wasn't spread out all over the
cell as if you thought it was a thing running on tracks.
In fact, it was in the center of the cell. And then late in cell
division it split into two spots that went to the midpoints of what
would be the daughter cells. And so what he ended up realizing
from that was that instead it was more as if the polymerase was a
factory and it pulled the DNA through it rather than it traveling
down the tracks of the DNA. And that was a very surprising
discovery that went against all the dogma and all the pictures in the
textbook. And it was a discovery at MIT.
That was published in, I think it was 2001, something like
that, a very recent discovery. Things keep changing. That's again
why I keep emphasizing I cannot teach you a fact in biology.
I can teach you the best understanding we have that explains
the experiments to date. But somebody may make a discovery
tomorrow. That means we'll have to change our understanding.
OK? So good luck on the exam. I'll see you on Monday, OK?