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PROFESSOR: So here's
what we did.
We found mutants that
effect biochemistry.
That's one way to make the
connection between
function and gene.
But if we want to go the other
way, we now have to do the
biochemistry of genetics.
What's biochemistry about?
It's purifying things
in a test tube.
What's genetics about?
Heredity.
So what do we have to do?
We have to purify heredity
in a test tube.
But that's it.
That's what we have to do.
If we're going to make that
connection in that direction,
all we need is to take a cell,
grind it up, and purify not
the enzyme that digests
a sugar, but heredity.
We need to get a pure
tube of heredity.
You can imagine that this wasn't
an obvious thing to do,
how you get a pure
tube of heredity.
The problem is you
need an assay.
If you want to find an
enzyme that digests a
sugar, you have an acid.
You purify different fraction,
you make different fractions
of a cell you see which fraction
of the cell is able
to digest the sugar.
But if I make different
fractions of the cell, it's
not obvious how I figure out
which fraction of the cell has
heredity in it.
And yet, that's exactly
what was done, and
that's today's lecture.
So purifying heredity.
The discovery of the
transforming principle.
By the transforming principle,
I don't mean an
idea, like a principle.
I mean a substance.
This is an old medieval kind
of word, a principle.
It's kind of a Harry Potteresque
kind of word or
something like that of what is
the transforming principle,
the transforming substance.
It's the kind of word alchemists
would like to use,
but it was actually what's
attached to this, and it was
called at the time the
transforming principle, the
transforming substance.
And it really is the work in
1928 of a young scientist F.
Griffiths in London.
Griffiths was particularly
interested in studying the
bacteria pneumococcus.
Why was Griffith so interested
in studying the bacteria
pneumococcus?
Well, not so long before in
1918, there had been the
terrible Spanish influenza
epidemic that had killed
millions of people around the
world, the worst flu ever.
Millions of people died by
this flew, and one of the
reasons they died when they
have the flu was they got
pneumococcal infections.
Griffiths was trying to make a
vaccine against pneumococcus,
a pretty good idea trying to
make a vaccine against
pneumococcus.
Pneumococcus highly virulent
stuff, but particularly if
you're compromised
by the influenza.
So what did he do?
Well, Griffiths had a strain
of pneumococcus.
He didn't, by the way, infect
people with it.
He infected mice with it, that
being considered a somewhat
more ethical way to
do the experiment.
So he had a strain of
pneumococcus that had a
smooth, glistening coat.
When you looked at it, it
was smooth and white and
glistened, the colonies
that it made
smooth, white, glistened.
And it was virulent.
If you inject it into a mouse,
the mouse got pneumococcus
infection, and it died.
It turns out we now know
that it has a beautiful
polysaccharide coat around it
that provides resistance to
the host's immune system,
et cetera.
He also had a strain
of pneumococcus
that had a rough coat.
It was not glistening.
It was kind of dull looking,
and it was non-virulent.
He injected it into a
mouse, mouse lives.
It happens to be the case that
we now know that it had a
mutation in a gene that produced
that coat, but that
doesn't much matter.
It didn't produce that
polysaccharide, and therefore,
was more easily fought off
by the immune system.
So Griffiths does the following
experiment.
He takes his smooth, virulent
bacteria, he injects it into a
mouse, that's a mouse.
And what happens to the mouse?
AUDIENCE: Dies.
PROFESSOR: Dies.
Exactly.
That's a dead mouse.
And one of the easier assays
in molecular biology is the
feet up, feet down assay.
All right.
Dead mouse.
Now, what does he do?
He takes the rough,
non-virulent, he injects it
into a mouse, and
what happens?
Lives.
Right?
Lives.
Then what he does, he takes the
smooth, virulent and he
bakes it in an autoclave.
He heat kills this bacteria.
Now, this heat-killed, dead,
virulent bacteria when
injected into a mouse, what
happens to the mouse?
It's alive.
The mouse is fine.
The bacteria was dead.
And then he does the following
truly weird experiment.
He takes the absolutely
harmless, rough, non-virulent
bacteria but alive, plus the
smooth, virulent bacteria that
has been killed by heat,
heat-killed.
The rough stuff is harmless.
The smooth heat-killed
stuff, harmless.
Both are harmless.
We've shown the mouse can
live with this injected.
It can live with
this injected.
He injects it into the mouse,
and what happens?
Dead mouse.
Very surprising.
Not only that, when he takes the
blood of the dead mouse,
he can culture out of it.
He can culture on a Petri plate
from this dead mouse
live, smooth, virulent
bacteria.
How did that happen?
Somehow, we didn't have any
live, smooth bacteria.
We had dead, smooth bacteria.
We had live non-virulent
bacteria.
Somehow, the dead stuff
transformed the live harmless
stuff into virulence.
It transformed it.
The substance, the unknown
substance that transformed it
was referred to as the
transforming principle or
transforming stuff.
And now we have biochemistry
because we have an assay.
We could take the dead, virulent
bacteria and break it
up into fractions and see
which substance, which
fraction, is it a protein?
Is it a carbohydrate?
Is it nucleic acid?
Is it something, is the
transforming substance and
purify heredity because we
have seen the transfer of
heredity to the harmless
bacteria.
There is an assay.
The minute there's an assay,
you could do biochemistry.
Now, the problem was the assay
was painfully slow.
You had to grind up the dead
bacteria, you had to
demonstrate by mixing it
together, putting it into a
mouse, waiting months, and then
you had to get a further
sub fraction.
It was just painfully slow.
All this mouse stuff
and all that.
And Griffiths didn't make much
progress through the 1930s,
but he kept going at it.
And I suspect might have gotten
there except for the
fact that in 1941, his lab was
hit by a German bomb during a
blitz, and he died.
And so Griffiths never saw the
result of this, but he did
purify fractions and all that.
But thank goodness others
picked it up.
He was again, Griffiths
was a great guy.
He worked in World War I, worked
during World War II on
important public health
problems, and really lays this
foundation, but never really
purified what the final
substance was because he
died in a bombing.
But then you get in 1943, during
World War II, folks
working in New York City at
Rockefeller University, then
Rockefeller Institute, Avery,
McCarty, and MacLeod continue
this work, and they do
it without the mouse.
Because what they do is they
grind up the virulent stuff
and they sprinkle it on the
living stuff, the living
bacteria and played it out,
and just looked for the
appearance of colonies
that are transformed.
Skip the mouse.
Skipping the mouse makes it a
lot easier, because you can do
those experiments
pretty quickly.
Bacteria grow quickly.
Same basic idea.
Purify the stuff from the smooth
dead stuff, grind it
up, put it in different
fractions, apply them, and
then sprinkle them on a
plate, and look for
the occasional colony.
And now you're just going to
look for a fraction of the
material that has the capability
to produce some
smooth colonies.
Well, they did that, and they
purified it, and the purified
it, and they purified it, and
they purified it, and they
eventually found that the
particular type of molecule
that they purified appeared
to be DNA.
But when they purified fractions
containing DNA,
these fractions had the
ability to transform.
Wow.
You might immediately say,
that's the transforming
principle, DNA.
That's the transforming
substance.
What do you think the
reaction was?
Skepticism.
First, it should be
noted it's 1943.
People were busy at
the time, right?
We're in the middle
World War II.
It wasn't exactly top on
people's minds, but there was
enormous skepticism
scientifically of those people
who did follow the work.
Why?
Because the one thing they knew
was that DNA was truly a
boring molecule.
It was understood by all smart
people that DNA was an
incredibly boring structural
molecule that had none of the
fascinating diversity and
richness of proteins.
Proteins could do zillions
of different things.
DNA, you know, it's
just scaffolding.
Why?
What is the structure of DNA?
So let's turn to the structure
of DNA to see why it is that
people were not impressed.
Of course, when people are not
impressed, you purified
something and you show it
transforms, what do you say to
Avery, McCarty, and MacLeod?
How do you express
your skepticism?
You say, it's very good.
You've purified this and it
contains DNA, but is it
absolutely totally 100% pure or
is it possible that you've
carried along in the fraction
that you have purified some
other trace quantity of a highly
potent protein that is
really causing heredity?
And of course, that's the
problem is you can never prove
that there's not a teeny smidgen
of something in there.
You can only show how pure it
is, but you can never rule
something out.
So when people want to sort
of dis your biochemistry
experiments, it's always easy
to say, it was probably
something else in there too you
just don't know about it.
And that was what the
answer was to them.
But let's look at the
structure of DNA.
So DNA has three important
components
which we need to learn.
A, it has a sugar called
2 prime deoxyribose.
So ribose is a 5-carbon sugar.
A five-part carbon sugar
is a pentose.
So this is a sugar, in fact a
pentose, pentose of course
five, pentose meaning it's a
5-carbon sugar, but it lacks a
hydroxyl group.
So it's just slightly
different from
the 5-carbon sugar.
And we draw it in this
configuration where there is
the 1 prime carbon here, the 2
prime carbon here, the 3 prime
carbon here, the 4 prime carbon
here, the 5 prime
carbon here.
That's very important to know.
We've got an oxygen up here.
Here, we have an OH and an H.
Here, we have an H and an OH.
Here we have H. Here we
have our OH, H, H.
But here we should have
a hydroxyl off every
carbon, and we don't.
Only here are deoxy.
That's the only difference from
this being a perfectly
normal ribose, deoxy at
the 2 prime position.
Big deal.
Now, the next component of DNA
that you need to know about
are these nitrogenous bases.
So hanging off our
ribose is a base.
This base has carbons, oxygens,
hydrogens, and nitrogens.
And they come in four flavors,
adenine, A, guanine, G,
thymine, T, cytosine, C. A, T,
C and G, and we'll look at
their structure in
just a moment.
Then the next important part
if we look at this
conceptually, is that hanging
off here, we have a
triphosphate.
We have a triphosphate.
So this is the monomer for
making DNA, triphosphate.
We have a sugar, the sugar in
exactly the same place off the
1 prime carbon there has a base,
off the 5 prime carbon,
we have a triphosphate.
What's the triphosphate
good for?
Energy.
We're going to do a
polymerization, and that's
going to contribute the energy
for the polymerization, and
that's pretty much it.
That's the way to
think about DNA.
So when we do our polymerization
now, we
polymerize and we get base,
CH2, phosphate.
And then coming down this way
attached here, we have our
phosphate, and that attaches
to the 5 prime carbon here,
and onward that way.
So notice that our polymer goes
from a 5-prime carbon
here, 3-prime carbon here,
5-prime carbon here, 3-prime
carbon there.
And we go sugar, phosphate,
sugar, phosphate, sugar,
phosphate, sugar, phosphate,
5-prime attachment, 3-prime
attachment, 5-prime attachment,
3-prime
attachment.
That's DNA.
Pretty boring.
The same sugar, same phosphates
strung together,
totally boring.
The only difference
are these bases.
And there's only four of them,
and they're not very
impressive.
They're pretty boring,
these bases.
There are purines.
The A and G are purines,
and their ring
structure looks like this.
This is six-membered ring and
there's a five-membered ring.
There are pyrimidines, T and
C, and they just have a
six-membered ring.
They've got carbons, and
oxygens, and nitrogens, and
hydrogens, and they
don't differ
really in their charges.
By compared to the amino acids,
positive charges,
negative charges, hydrophobic
groups,
sulfurs that are reactive.
Amino acids, that's
impressive.
Those 20 different side chains
have wildly different chemical
properties.
These form measly bases, have
essentially, the same chemical
properties.
There's nothing very different
about their chemical
properties and therefore, all
smart right-thinking people
recognize the DNA
could not be a
particularly interesting molecule.
It had to be largely
a structural
molecule of some sort.
So when Avery, McCarty, and
MacLeod tell us ah, the
transforming principle of
DNA, nobody's impressed.
But of course, it's
World War II.
People are busy.
Lot of things going on.
And not that long afterwards,
not that long afterwards,
another really important
experiment gets done in the
early 1950s, the Hershey-Chase
experiment.
Hershey is not the candy bar.
It is Alfred Hershey
and Martha Chase.
Martha Chase and Alfred Hershey
do a cool experiment.
People were studying something
else at the time.
They were studying the viruses
that infect bacteria,
bacterial viruses.
So it turns out just like you
may get a viral infection, E.
coli gets viral infections
too.
It usually dies of them or at
least often dies of viral
infection, not necessarily
usually, I take that back,
sometimes dies of viral
infections.
So that is a virus, actually,
greatly magnified, glommed on
to E. coli, virus E. coli.
What happens is, if you mix
the virus with E. coli, it
gloms on, and then if you wait
a little while giving it a
happy medium to grow in, the E.
coli some time later, half
an hour later maybe, bursts
open, dead, and spews out
zillions of viral particles
which could go on
to infect new cells.
How does it do that?
How does it instruct E. coli
to make viral particles?
It must be bringing
information.
It's having progeny.
It is passing on heredity too.
It has some transforming
information.
Where is the transforming
principle in the little virus?
It gloms on to the cell somehow
gives something into
the cell, and poof, 20 minutes
later, half an hour later,
lots of viruses.
Where's the information
carried?
Now, this was a much
simpler system.
This system, you're asking
what's in the bacterial virus.
There's not a lot in
a bacterial virus.
It's not like a cell that
have zillions of things.
The bacterial virus is a
pretty simple particle.
The bacteria virus consists of
protein coat, proteins are on
the outside, DNA
on the inside.
That's it.
You don't have a lot to work
with, a limited number of
proteins, DNA in the middle.
These things just as an aside
were thought to kind of like
eat bacteria.
Because they were thought to
eat bacteria in a way by at
least the early things, they're
called bacteriophage,
bacteriophage.
The word phage means to eat.
So you may hear me talking about
bacteriophage, meaning
eaters of bacteria.
Indeed, actually there was some
nutty ideas in the 1920s
and 1930s when bacteriophage
were first discovered that the
way to cure a bacterial
infection was to drink a lot
of bacteriophage.
They would kill the bacteria.
It's a thought.
People actually tried
these things.
Anyway, it turns out not
to be such a good idea.
So Hershey and Chase decided
we're going to figure out
which is it?
Is it the DNA or is
it the protein?
How do you find out?
Yeah?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Put in only protein,
and see what happens.
So take the bacteriophage,
purify it from
protein verses DNA.
I've got a pure component of the
protein, I sprinkle it on,
nothing happens.
I take the DNA, I sprinkle
it on, nothing happens.
Neither works.
Why is that?
AUDIENCE: [INAUDIBLE].
PROFESSOR: The shape, those
little feet in the shape were
critical for the
pathogenicity.
So when we grind up the virus,
it doesn't work anymore.
It's a great idea.
If it worked, bingo, we'd have
it, and that should be the
first experiment we do
because it's so easy.
But it turned out not to work.
Yes?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Put a chemical marker
on the protein, put a
chemical marker on the DNA,
and see which one
goes into the cell.
What chemical marker?
How are we going to attach a
chemical marker to the protein
without messing it up?
We can't mess up the
protein, right?
It still got to function.
How do we get a chemical
marker on it?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Sorry?
AUDIENCE: [INAUDIBLE].
PROFESSOR: So what chemical
do you want me to put in?
Well, how am I going to tell
whether, DNA's got phosphorus.
How am I going to follow
the phosphorus?
AUDIENCE: Radioactive tag.
PROFESSOR: Radioactive tag.
Bingo.
What if I used radioactive
tags, and I made a
radioactively-labeled virus.
How can I radioactively
label the DNA?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Sorry?
AUDIENCE: [INAUDIBLE]
PROFESSOR: A radioactive base.
I could do that.
What else could I do?
Yup?
AUDIENCE: Phosphorus.
PROFESSOR: Phosphorus.
Phosphorus has the nice property
that phosphorus is in
my DNA, but it's not
an proteins.
So what do I use?
Phosphorus-32, P-32.
So I use P-32, and how do I
manage to chemically create a
virus that has P-32 in it?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Just throw it in the
solution with P-32, and
the virus will take care
that itself, right?
So simply grow virus for a while
in the presence of P-32.
Let's do that.
So grow virus in a test
tube with bacteria.
Here's my bacteria.
Here's my virus I've put in
there, and let me put in P-32,
and what I'll get is
P-32-labeled labeled virus.
How do I label my protein?
Someone said it already.
What elements can we
find that's in
proteins but not in DNA?
AUDIENCE: [INAUDIBLE]
PROFESSOR: Sorry?
AUDIENCE: Sulfur.
PROFESSOR: Sulfur.
Sulfur.
S-35 is a radioactive isotope of
sulfur, and if I grow it, I
can S-35 label the proteins
in my virus.
Nice.
This radioactive labeling
trick is very cool.
So I take it, I take some
P-32-labeled virus where these
P-32 was only in the DNA.
I got some S-35-labeled
label virus where the
S-35 is in the protein.
I could mix them together, now
do my experiment, wait 20
minutes and, or even wait last
10, 15 minutes, and see which
element has gone
into the cell.
How do I do that?
See I've got my cells here,
and I've got the viruses
attached to them, and they've
injected something in here.
They've either injected
a protein or
they've injected DNA.
What was injected?
I need to carefully go in there
and remove the virus and
look at just what's
in the cell.
I have to now separate the virus
glommed onto the outside
of the cell from the cell.
So do I use micro manipulator
tweezers to
pull off the virus?
AUDIENCE: [INAUDIBLE].
PROFESSOR: Well, if I
denature, I might
crack open the cell.
Centrifuge it.
If I centrifuge it, the whole
thing will spin down.
I need to kind of knock the
viruses off the cell,
physically.
I just got to agitate it so
I get them off the cell.
With enough kind of hydrodynamic
agitation, the
viruses fall off.
So a device was created that
was able to just perfectly
knock the viruses off.
It's referred to as the Waring
kitchen blender.
It turns on your kitchen blender
is perfect for this.
Take the viruses, add it to the
bacteria, sit for a little
bit, put it in your kitchen
blender, press puree.
And let's say on puree setting,
the viruses fall off,
and now you can spin it in a
centrifuge, the bacteria are
denser, they come down.
The viruses are lighter, they
stay in the supernatant, and
you can take the supernatant and
the pellet at the bottom
over your radioactivity counter
and see which one is
in the bacteria.
These were referred to as the
famous Waring blender
experiments.
They really are, actually.
So you put this in the Waring
blender, you knock off the
viruses, you spin it down, and
what happens is after you've
done it, there's a pellet here
of the bacteria that are spun
down in the centrifuge.
The virus particles
are still up here.
We take this pellet over to our
counter, and which element
do we find in great abundance,
S-35 or P-32?
AUDIENCE: P-32.
PROFESSOR: P-32.
The DNA is what's going in.
Bingo.
Nice experiment.
Now if you were churlish,
couldn't you say, yeah, look
it's mostly the DNA, but there's
a little smidgen of
protein maybe, that
came along too.
Do you think they found
absolutely zero S-35 in there?
No, because they don't perfectly
knock the virus off.
Some of it kind of sticks.
There's 1% S-35.
And if you're being really
churlish about this you would
say I still don't believe you.
But now you have it from two
different directions.
You have it from the
pneumococcus, this bacteria
experiment from Avery, McCarty,
and MacLeod Hershey
and Chase coming from two
different systems.
They're giving you
the same answer.
It's pretty clear.
It's in the air.
People know DNA is the stuff.
They're believing it now.
DNA is the stuff.
But how does it work?
How can this dumb molecule
possibly be the
transforming principle?
Well, smart, young people
want to know.
So an erstwhile ornithologist,
that is a college kid from the
University of Indiana who
particularly liked bird
watching got very enamored by
this problem, actually based
on some fabulous faculty at
the University of Indiana.
He got really intrigued by how
could DNA possibly do this.
But he recognized he didn't
know any chemistry.
He decided to go to Cambridge,
England to the Medical
Research Council lab, the MRC
lab in Cambridge, England
where he teamed up with someone
who did a lot of
talking and very few
experiments.
A physicist who had worked for
the British admiralty during
World War II on classified
things and had somehow gotten
interested in biology.
And because he had this kid,
this recently graduated
college kid, and you had this
35-year-old physicist who
nobody was quite sure what to
make of, they kind of hung out
with each other in
the same office.
And they didn't really do many
experiments, but boy did they
do a lot of talking, and
thinking, and looking at all
the data that were out there.
And that's pretty much what
James Watson and Francis Crick
were doing.
They knew this problem
was important.
And Jim and Francis would talk
every day about this stuff,
and they will talk to people
down the hall who really knew
about the chemistry
of nucleic acids.
And they went down to London to
Maurice Wilkins' lab where
crystals were being
made of DNA.
And Rosalind Franklin, who was
a fantastic scientist and had
managed to make crystals of DNA,
showed Crick and Watson
her crystals of DNA.
Francis Crick being a physicist
was very good at
understanding crystallography
and how crystal structures and
x-ray diffraction patterns
related to each other.
And Francis knew immediately
this thing had to be a helix.
He could tell it was a helix.
And they went back, and based
on Rosalind Franklin's x-ray
diffraction patterns, went and
made a model, a model for the
structure of DNA.
You all know the model.
You've seen the double
helix forever.
It's a cultural icon, but that's
how this came about.
And The Double Helix, the
Structure of DNA, April of
1953 is published.
The double helix has two
strands running an
anti-parallel directions, 5
prime to 3 prime, 5 prime to 3
prime anti-parallel directions,
and it has a
perfect base pairing between
purines and pyrimidines.
If you have a T, and
I'm just going to
draw this very quickly.
You can look in your book for
getting it just right.
You have two hydrogen bonds.
That's T and A, and if you
have a C, you have three
hydrogen bonds that perfectly
hold it to the G, et cetera.
So notice C and G fit perfectly
together to make
three hydrogen bonds.
A and T fit perfectly together
to make two hydrogen bonds,
and that was the key was to
recognize that when you stick
them together in that way, you
get exactly the same width.
They fit perfectly.
You couldn't match an A with a
G, an A with a C, you could
only match the A with
a T. That was it.
Brilliant.
Beautiful.
Now, you guys should read
Crick's book The Double Helix
in which he tells the stories
because it's just a
fascinating, fascinating
business.
He'll tell, or others will
tell actually, the story.
So you know what this
means by the way?
This means that the amount of
A should equal the amount of
T. And the amount of G should
equal the amount of C.
There should be a ratio, a
one-to-one ratio that the A to
T ratio should be one to one.
And the G to C ratio should
be one to one.
Although any organism might have
more As than Ts and Gs
than Cs, the ratio of these guys
should be one and these
guys should be one.
This actually was discovered
by a chemist at Columbia
called Chargaff.
These were called Chargaff's
rules.
Chargaff was a very
distinguished chemist who came
up with Chargaff's rules with
the As equals the Ts, and the
Gs equals the Cs, and
he didn't know
what to make of it.
By the way, Chargaff actually
visited Cambridge, England
while Crick and Watson were
there before their discovery,
and he had lunch with them.
And he related that Crick and
Watson seemed like Bozos to
him, because they couldn't even
keep straight the exact
structure of the four bases.
They always had to keep
looking it up.
They hadn't memorized the
structures the four bases, and
Chargaff was such a brilliant
chemist, he, of course, knew
this instantly, et cetera,
et cetera.
And he said, these guys are
never going to get anywhere
because they really don't even
understand the structure of
the bases, haven't
memorized it.
When Crick and Watson's
discovery turned out to be the
single most important biological
discovery of the
20th century, Erwin Chargaff who
lived a very long life was
sort of bitter because he's kind
of worked it out in a way
with the ratio and never figured
out what it meant.
And he said one of the
bitterest, cuttingest comments
I've have ever heard from a
scientist which is referring
to Crick and Watson as still not
being impressed even after
they won their Nobel
Prize for this.
He said that two such pygmies
should cast such giant shadows
only shows how late
in the day it is.
Anyway, he was not happy to
have missed this point.
Crick and Watson were
very happy to have
figured this out.
They, when they figured this out
in February of 1953, what
do you do in England when you
make a big discovery?
AUDIENCE: You have tea.
PROFESSOR: No, you
don't have tea.
You go to the pub.
They went to the pub.
They ran down to the Eagle Pub,
they brought everybody
drinks, and they told everybody
at the Eagle Pub,
we've discovered the
secret of life.
The people at the Eagle Pub
had no idea what they were
talking about, but were happy to
have a round of drinks, and
there you go.
They immediately raced to
write this up in Nature.
It appears in Nature in
April of 1953, and
it's a one-page paper.
And get it on the
web and read it.
It's the single best one page
that has been written in
biology in the 20th century.
And of course, what
did they say?
The title is kind of unassuming,
"A Structure for
the Salt of Deoxyribonucleic
Acid," nothing too exciting.
But Crick and Watson
realized something.
What do they realize?
Crick and Watson realized
why is this a big deal?
Why is this double helix
so important?
Well, the implication of the
double helix is that if I have
a double helix and those strands
were to separate, each
would be a template for a
double helix, heredity.
How do you pass information
to two daughter cells?
You got a double helix.
It's redundant.
If you know the A is on
one strand, you know
the Ts on the other.
Unzip it, copy, voila.
I now have two copies
of heredity.
What's a mutation?
Occasionally get it wrong.
Bingo.
They saw it.
They knew.
Now, they didn't have
time to prove this.
I mean, who has time
to prove this.
This is such an exciting
discovery secret of life.
Drinks for everybody, they write
it up, but in the last
paragraph, they certainly don't
want anybody to think
that they missed the point.
And they write the coyest
sentence in molecular biology.
They write, "It has not escaped
our notice that this
structure offers an
explanation for
heredity and mutation.
We'll address this in another
paper." Cute.
Very cute.
They put down their marker, they
knew what it meant, but
they got the thing off to
Nature very quickly.
It was a hot topic.
They were competing
with other people.
You'll read about the
competition with Linus Pauling
and other things like that.
It had not escaped their notice
that this pretty much
explains heredity.
Now, of course, are
you convinced
that it explains heredity?
It's a nice model, but don't
we require proof?
We do require proof.
It's an ex post facto model, we
need proof, It's a pretty
good ex post facto model,
but we need proof.
So the last step, which I'll
touch on very briefly, was
proof of what's called
semi-conservative replication.
Meaning that each strand
is used for the other.
And I might run two
minutes over.
We'll see.
I'll try to keep
it within time.
Out at Caltech, two graduate
students, Frank Stahl and Matt
Meselson hear of this.
Matt Meselson by the
way is still
working in Harvard Square.
He's at Harvard.
He's a wonderful guy.
Matt is there.
You could ask Matt about this,
young graduate student at
Caltech in the early '50s.
Obviously, this model looks
like it must be right.
How do you prove it?
Well, Matt and Frank, Meselson
and Stahl came up with a cool
experiment to prove it.
Meselson and Stahl, they take
bacteria, here's my DNA in
there, they want to show that
each strand, each, when we
make a new generation of
bacteria, the new DNA has one
old strand and one new strand.
That each old strand
is being used as a
template for a new strand.
How are we going to tell?
We gotta label it somehow.
We got a label the old strand
different than the new strand.
How do we possibly label and
they're the same chemical
composition?
What are we going to do?
AUDIENCE: Radioactivity.
PROFESSOR: Radioactivity or
some kind of isotope.
Well, they used an isotope.
What they did, super cool, they
grew this up, but not in
normal nitrogen, but in N-15,
not, by the way, radioactive,
but different weight.
They grew it up in N-15.
They added bacterias that had
grown up, and all of their DNA
had lots of N-15 in it
on both strands.
They then pour in a lot of
medium that has N-14.
Tons, they swamp it with
N-14 so what's this
strand going to be?
N-14.
So what can you tell me about
the difference between this
DNA and that DNA?
AUDIENCE: One's going
to be lighter.
PROFESSOR: One is going
to be lighter.
How do you measure how
much lighter it is?
They came up, they invented the
technique for this purpose
of centrifuging in
a salt gradient.
They put in the right amounts of
salt, cesium salt, and they
centrifuge it so hard that
there's a gradient of
densities, denser here,
lighter here.
And they find that this DNA
and this DNA centrifuge to
different places.
There's a difference
in their density.
The new DNA is half old,
N-15, half new, N-14.
It has the intermediate
density.
If I grow another generation,
I'm going to see some N-15
14s, and I'm also going
to see some N-14, 14s.
And that's what they found.
They invented this technique
it's isopycnic centrifugation
and Matt Meselson and Frank
Stahl provided an experimental
prediction of the beautiful
Crick-Watson model that was
fair to say the secret
of life.
Anyway, these are
the foundations.
Notice now, we've taken genetics
and used it to do
biochemistry.
We've taken biochemistry
and used it
to understand genetics.
And so finally, we are
making the bridge
of molecular biology.
Next time.
