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A Passion for DNA
James Watson helped discover the Double Helix, and fathered modern genetics.
Select text to jump ahead in the clip:
ALDA:
When we decided
to make a show about DNA--
the stuff genes are made of--
we naturally wanted to start
with some of the finest DNA
we could find.
So we came here to the DNA
Learning Center on Long
Island.
MAN:
The first thing
we're going to do
we're going to swoosh
our cheek pockets really
good.
Now, I have to tell you
you're going
to get the DNA
of the tuna
I had for lunch.
So my DNA's right there
in that little cup, huh?
Take a peek
under the microscope;
you'll see thousands
of cheek cells
that just sort of slough off.
I see.
That blue dot in the center
is the nucleus?
The nucleus.
This is my nucleus.
ALDA:
It's the nucleus
that houses the DNA
so we have to break it up
and shake it up
to release my genes.
Okay, I got it.
ALDA:
Unlike me, the high schoolers
whose class we've dropped in
on
aren't in the least amazed
that you can get your hands
on
your own genes and chop them
up
multiply them, even read
what they have to say.
They've grown up
during the years
when scientists
have pretty much deciphered
the entire human genome. . .
I'm a nervous wreck.
ALDA:
The three-billion-letter
instruction manual
for making a person.
You want more?
Science is hard,
I'll tell you.
ALDA:
Our show is about the people
who
are picking through the DNA--
not just of humans
but a strange menagerie
of other creatures--
to find out how this
unimpressive looking gook
has within it some of life's
most precious secrets.
What'll you give me
for this?
(chuckling)
ALDA:
One of the first people
to imagine
that DNA was worth anything
was Jim Watson
who, with Francis Crick
50 years ago, discovered
the double-helix structure
of DNA--
a structure now echoed
in this staircase
outside Watson's office
at Cold Spring Harbor
Laboratory
just down the street
from the DNA Learning Center
on the north shore
of Long Island.
(conversing quietly)
Jim Watson first came here
in the late 1940s
as a 20-year-old
graduate student
obsessed with finding out
what genes are made of
and how they work.
WATSON:
I thought it was the only
problem worth solving.
Of course, that wasn't true
but it was the only one
Ithought worth solving.
And, uh, luckily...
except for Francis Crick
I don't think there
was anyone who was, you know
as high about DNA as we were.
ALDA:
Hmm...
ALDA:
Watson and Crick discovered
their mutual passion for DNA
when Jim went
to Cambridge, England, in
1952.
But most biologists
didn't share their enthusiasm
and dismissed the pair
as arrogant and irrelevant.
Watson later wrote about this
period inThe Double Helix
his famously candid account
of their discovery.
WATSON:
No one predicted, you know...
thought we were ever
going to succeed.
And England is too polite
to have too much ridicule
but, you know, no one
was betting on us, and, uh...
you know,
our obsession about DNA...
You know... 'Prove it.'
You know, 'And why are you
so excited?'
And so... you've got
to be... nothappy
that other people
don't believe you, but
just...
I wrote inThe Double Helix--
and it still offends people--
that when you get into
science
you realize
that most scientists are
stupid.
(snickering):
And... because...
Hey, wait a minute,
now, come on...
Yes.
No, but yeah...
I think that's a correct way
of looking at it
because they don't see
the future.
You know, it's a relative
matter
whether you call them
stupid or not, but, you
know...
How can anyone
with a Ph.D. be stupid?
But most people with Ph.D.
aren't doing anything
you know, doing anything,
uh... breathtaking.
So... you have to be prepared
not to care
that most people think you're
going in the wrong direction
and that means you have to...
Well, one, it pays
to have someone else
who agrees with you, so
Francis
and I could talk to each
other
and we never tried
to persuade anyone else.
There was no point of trying
to persuade anyone else.
ALDA:
One Saturday morning
in early 1953
Watson was fiddling with a
model
of a possible DNA structure
based on a double helix.
That Saturday,
when things fell
into place
what piece was
missing from this?
What did you...?
Well, we
didn't have this.
This was missing.
We had the background
but we didn't know
how to fill in the center.
ALDA:
The center had to accommodate
the four different
chemical units, or bases
that DNA is made from, known
by
their letters as A, T, G and
C.
Watson was trying to make
matching pairs of bases
but they just wouldn't fit.
So you were pretty sure
it was a double helix
but you didn't know
how these base pairs
fit together, huh?
Yeah, yes.
And in the books
the chemistry
was written wrong.
In what way?
Well, they had
an atom in the wrong...
a couple atoms
in the wrong place.
And so someone said
'Well, the chemistry in
the books is wrong.'
Well, that must
have thrown you
for a few months.
Yeah, at first I said,
'No, I don't believe you.'
But then
the next day I thought
'Well, we'll see
what happens if you...'
you know...
Change it from the way
it is in the book?
Yeah, and then
the whole thing fell out.
So if we hadn't
had that chemist
in the room with us
he wouldn't
have been someone
to say 'Well, it's wrong.'
ALDA:
But it wasn't just that the
corrected As and Ts, Cs and
Gs
fit snugly in the center
of the double helix;
The structure immediately
suggested the answer
to the gene's central
mission:
carrying information
and copying it
from generation to
generation.
The information could be
carried
in the letters
and the copying achieved
by each strand of the helixes
becoming the template
for a new matching partner.
So in one stroke, Watson
and Crick had the answer
not only to how genes are
made,
but how they work.
WATSON:
This was just much bigger
than anyone expected
and... in a way,
it was so beautiful.
There wasn't
the usual jealousy of us.
You know, people could
rejoice
in the answer.
People just liked
that discovery.
They found it...
they found it so beautiful
that their natural
jealousy faded away
in the glare
of its beauty.
Yeah, I think it was, uh...
Everyone hoped it was right,
because if it was right
we finally had
the molecule of heredity
because, while
Francis and I were very...
believed strongly DNA was
going
to be the genetic molecule
most people didn't.
And it wasn't until people
saw
the double helix
that sort of the world
of science accepted DNA
as a genetic molecule.
And that then led to the,
you know, uh...
a lot of people suddenly
coming
in and following up our work
and the explosion
of molecular biology.
My office
was up there...
before I moved...
ALDA:
In the years that followed
many of which
Jim Watson spent here
as director of Cold Spring
Harbor Laboratory
he continued to play
a central role
in unraveling how genes work.
In the late 1980s
when a group of biologists
began to consider
the then outrageous idea
of deciphering all the genes
in the human body
it was to Jim Watson that
they
turned to lead the project.
WATSON:
I was in favor of it
because even though
it seemed premature
it seemed to be the only way
to understand a lot of
disease;
and, uh, I was then in my
50s.
By that stage,
when you're in your 50s
you're seeing
your parents die or dead
and you're conscious of
disease.
When you're 25, hopefully
you're
not, you're not thinking...
You're thinking in terms of
life, not death or sickness.
And, uh, so I saw getting
the human genetic information
as a big plus
toward moving medicine.
And, uh, that's how we
helped,
uh, sell it to Congress--
it was really disease.
Gene Reader
The Human Genome Project is being completed, one letter at a time.
Select text to jump ahead in the clip:
ALDA:
Back at the DNA Learning
Center,
I'm finding out for myself
why many biologists
originally
opposed the Human Genome
Project
even if it promised to
revolutionize our
understanding
of human disease.
Oh, there it is.
ALDA:
The techniques of handling
and reading DNA
were slow and cumbersome.
Reading three billion
letters' worth would involve
thousands of people working,
literally, for decades.
But then came a revolution.
This is the Whitehead Center
for Genome Research
the largest of the 16
laboratories around the world
collaborating on
the Human Genome Project.
There are people here
but they're far outnumbered
by machines.
ALDA:
Wow, this is amazing.
Look at this.
ALDA:
The director of the Genome
Center is Eric Lander.
This is some
kind of robot?
Yeah, over there
you got...
all those little spots
on the plates.
Those are each separate
bacterial colonies.
Every one of them has
a little piece of human DNA
that we've got to sequence.
It might have 2,000 letters
of human DNA.
The first thing
we've got to do
is we've got
to pick them up
and grow each
bacterial colony up
so that we get
enough DNA out of it.
I presume
this robot is
doing this
because it's doing it
a lot faster than humans
could.
We used to do this--
not so long ago,
ourselves, with toothpicks.
So this is simply a highly
automated toothpick
somewhat more expensive,
much more efficient.
Every one of those
is a different sentence
in the human genome.
And so we've got to go
collect
these random shreds of
sentences
and sequence them.
That's pretty much what the
entire operation here does.
ALDA:
The machines in this room
diligently prepare
100,000 sentences a day
of the three-billion-letter
book
that's the human genome.
The next trick
is to read those sentences.
That's done here
in another huge room
crowded with
bland-looking machines
tended by a handful of
humans.
The humans' job is to feed
the
sentences into the machines--
96 at a time--
in these little cartridges.
To read
the order of the letters--
the As, Ts, Gs and Cs--
in the sentences
the machines make use of a
process that sounds kind of
odd.
LANDER:
Well, it turns out
that little sentences
move faster
than big sentences
when you put
them through...
Jell-O, in essence.
I mean, now,
what is Jell-O?
Well, you have this...
you have this giant
scientific laboratory
devoted to putting
sentences through Jell-O.
That's roughly right...
I'm amazed I didn't
come up with that.
We'd like to use
fancier words
because it's impressive and
it costs a lot of money
but basically you're taking
little molecular sentences
and putting them
through Jell-O.
The point about Jell-O is
it's this very
complicated network.
The little sentences
can wiggle through
better than
the big sentences.
And in fact, what's
really cool about this
is that the guys
who are 50 letters long
get there just a little ahead
of the guys who are 51
letters
who are a little ahead
of the 52-letters.
Then the sentences
that are 75-letters
are lagging behind.
And there's
this little detector
that reads the letters
as they go by.
So in fact, if
we find a machine...
Guys, have we got a machine
where we can bring up
the letters as they're going
by?
TECHNICIAN:
Yeah.
Let's go take you
to see the letters
going by.
ALDA:
The letters, it turns out,
have
colored tags to identify
them--
red for a T, green for an A,
blue for a C and yellow for a
G.
So you can read out the DNA
sequence, 'G-A-T-T-C-G'
because we attached
the right colors
to the right letters
and we just read
their color.
It's a beautiful trick.
ALDA:
For me to understand the
trick
took about ten minutes
in front of
a nearby white board.
You've got some
DNA sequence here.
ALDA:
But to save time,
we'll summarize:
The DNA sequencing machine
is actually making copies
of the DNA sentence-- but
every
time one of those colors
is stuck on,
the copying grinds to a halt.
So there are lots of sentence
fragments of different
lengths
floating around in there,
each
one ending in a different
color.
A sentence that's
33 letters long
and is labeled red, for
instance
means there's a T
at position 33.
Reading all the different
fragments
eventually fills in
the whole sequence.
Number six
is purple.
Right, right.
And the number seven
is green
and the number eight...
that's it.
Mmm... okay,
thank you.
That's the end sequence!
That's all there is!
This whole place
is here
to stick in
these things.
All right,
well, let's go.
Yeah, I'll run one
of the machines now.
That's it.
You've got it.
(laughing)
That's freshman...
It takes an hour
in freshman biology
but you've got it,
that's it!
ALDA:
Well, that's a relief.
But there was still
one nagging question.
Just who exactly is the human
whose genome is being read?
ALDA:
If you took my blood cells
and went through
this whole process...
do you need to get a lot of
other people's blood cells
to get a comprehensive
picture
of human... the human genome?
Your DNA and my DNA
are 99.9% identical.
We differ at one letter
in a thousand.
So if what we're
trying to do
is find all the genes
in the genome
all the sentences,
we can do that just fine
whether it's your DNA, my DNA
or anybody else on this
planet.
Once you've read
one person's DNA
you then become interested
in this one letter
in a thousand variation.
And that matters.
I mean, between you and me
I said we're
99.95 identical
but we also have 30...
sorry, three million
differences...
And one of us might have
something that's off
that could cause disease,
is that right?
Oh, one of those letters
could be breast cancer
one of those letters
could cause
early onset
Alzheimer's disease.
You want to know
the differences.
But it's as if you had
many different editions
of the same book,
and they differed by, you
know
a comma here, or the British
spelling of some word here
instead of
the American spelling.
So when you say
'Well, what do we mean
to read the book?'
Anybody's copy
of the book will be fine
if you want to get
the story line down.
If of course we really care
about the punctuation--
and at the end of the day
in medicine
we really do care
about the punctuation--
then we've got
to read your book.
But the Human Genome Project
was about reading
the first copy of the book.
Right.
LANDER:
We're now in the age when
biology is about
information...
ALDA:
In February 2001,
Eric Lander was the lead
author
on the scientific paper
that announced the first
draft
of the human genome.
This laboratory
continues to pour out
50 to 60 million letters
of DNA code every day
as the details of the human
code book are filled in.
And unlike
the commercial companies
that are also
sequencing our genes
the data streaming out
of these machines are free.
Every 24 hours, the 50, 60
million letters we produce
here
get posted on the Web.
And they go flying around
to databases in Japan and
Europe
and Washington,
and then from there
to databases in tens
of thousands of biological
labs.
So in fact, there's this
huge information shuffling
going on, constantly
because if you were studying
a
particular thing about
diabetes
you could've searched
the world's databases last
week
to see if there was a gene
like what you were looking
for
and there was nothing.
You better make sure
you have an automatic program
searching again next week
because it might
have just shown up.
And so people have these
automatic 'demons'
running on their computer.
So they say,
'I'm interested in this.
Let me know
if you should see one.'
And then your
computer goes 'bong'
and says you've got...
'You've got G-mail.'
That's... you've
got G-mail.
That's right.
The thing you
were looking for
just showed up last night,
here it is.
ALDA:
Jim Watson, the first
director
of the Human Genome Project
was convinced it would
revolutionize medicine.
ALDA:
So... tell me about how
our lives will be different
now
medically, do you think?
I mean, how revolutionary
is this going to be?
Well, you know,
it's possible
to over-hype
all this stuff
and I think people sometimes
have outrageous expectations
that there are going to be
cures
next week from all of this.
It's certainly not
going to be like that.
What it is
that's really revolutionary
is for the first time we're
going to be able to
understand
the mechanism of how cells
work
organs work,
in a really detailed level.
See, we don't actually know
what's wrong in most
diseases.
We can describe
that when you have diabetes
you have high blood sugar.
That's great, but it doesn't
tell you what's wrong;
what part
of the machine is broken.
We haven't even had the parts
list of the machine.
Trying to practice medicine
would be like trying
to practice auto mechanics
when you didn't know what
the parts were in the car.
You'd never take your car in
to an auto mechanic
that didn't know
what the parts were
and how they
were connected.
Oh, I have many times,
actually.
Well, probably, yeah.
And you know
the results.
Paid through the nose
for it, too.
Well, but you take
your body in, to medicine
and for the last century, we
didn't know what the parts
were.
I mean, we knew what the
hearts
and the lungs were
but not the little molecular
machines and how they work
so how could we describe what
was wrong in diabetes
and what's wrong in asthma
and
what was wrong in
hypertension?
The real breakthrough
of the Genome Project
the real guarantee, is we're
going to be able to figure
out
what all those little
molecular
machines are doing
and what goes wrong in
disease.
It doesn't promise you you'll
be
able to fix it because of
that
but the understanding sure
beats
the ignorance we've had
and it's going
to transform medicine
because for the first time
we're going to have met
the enemy in disease.
Fishing for Baby Genes
How do genes create a baby? One scientist is using fish to find out.
Select text to jump ahead in the clip:
ALDA:
Our next story is also about
finding human genes.
Now, I always wash...
dip my hands here.
If you don't mind doing that,
that'd be great, because...
ALDA:
But Nancy Hopkins isn't
looking
for human genes in humans--
she's looking in fish.
These are all...
your fish here?
Yeah, yes.
How many
do you have here?
HOPKINS:
In this room alone...
I don't know,
we have maybe in here
about, I'd say, 75,000.
75,000?
100,000, maybe?
Yeah, we have a total
of about 150,000 fish.
How many did you
start with?
23.
23?
ALDA:
The fish are zebra fish
originally from
the Ganges River.
They're a popular choice
for home aquariums
for at least one of the
reasons
they're popular with Nancy--
they thrive in tanks
with the right care
and attention.
HOPKINS:
ere's only about
a thousand more to go.
ALDA:
But the main reason Nancy is
raising all these zebra
fish--
unlikely though it may seem--
is to find the genes
that make a baby.
HOPKINS:
Of course, we would
like to use humans...
ALDA (laughing):
Yes, right...
You can't fit them
into the tanks.
We haven't
had any volunteers.
ALDA:
How close are
their genes to ours?
I mean, how much
can we learn
about the development
of a baby human
from the development
of a baby fish
of this kind?
Alot.
Yeah?
Yes, we would betotally
crushed if it weren't...
didn't turn out that
the genes were almost
identical.
This is really hard
to understand
because if I made a list
on a piece of paper
of the features
that were identical
between those fish
right there and me...
You don't see...?
ALDA:
I mean, we have eyes;
our tails are very different
(laughing)
our gills are different...
HOPKINS:
But, they have a head end
and a tail end;
they have a heart that beats
they have a liver,
they have a gut
and at the cellular level
their cells have to do all
the
same things that your cells
do.
We really believe
that the genes
we're going to find
for making a baby fish
will be many, many
of the same
as making a baby human.
ALDA:
A zebra fish egg is mostly
yolk.
In this speeded-up shot
the cells that will become
the baby fish are at the top.
The cells divide and
multiply,
and then in just 24 hours
they form all the many
different
types of tissues
from which the baby fish
is made.
Under the microscope
the tiny embryos are already
wriggling vigorously
a day after the eggs
were fertilized.
So that's the tail, and
that's
wrapped right around the
yolk.
There it goes-- whoops.
This is the brain.
This is the middle of the
brain,
the hind brain.
Whoa, whoa.
ALDA:
It looks like a little
frisky anchovy.
Well, thank you
for pointing that out.
I'd never thought of that.
Where's the heart?
HOPKINS
Just sort of under the chin.
ALDA:
It's beating fast.
HOPKINS:
So you can see
why it's a terrific animal
to study early development
because in one day
you have that.
And one fish--
those little female fish--
can lay several hundred eggs
like that in a morning.
ALDA:
Nancy estimates that of the
tens
of thousands of zebra fish
genes
only about 2,400 are actually
involved in making a baby
fish.
Her goal is to find
as many of these baby-making
genes as she can.
She starts by injecting
early embryos with a virus
that invades the cells
and inserts its DNA randomly
into the fish's DNA.
If a piece of virus happens
to land in the middle of a
gene
that gene will be destroyed.
And if the gene was involved
in making a body part
then the descendants of the
fish
whose gene was damaged
will have a problem.
But because Nancy
can't know in advance
what genes the virus will hit
she has to bombard all the
genes
in thousands of embryos
in the hope that occasionally
she'll hit something
interesting.
Then she has to raise
and cross-breed
thousands of offspring
to find out if she did.
That's why
she needs so many fish.
And it's also why
much of her lab's time
goes into peering
at thousands of baby fish
looking for her
unfortunate victims.
It turns out that generally
the defects that occur
in these little tiny babies
actually result in death.
Oh, I see.
So you see a very specific
thing
go wrong
and then the fish is doomed.
ALDA:
So far Nancy Hopkins
and her colleagues
have found more than a dozen
specific defects
in their zebra fish embryos.
HOPKINS:
So here's a normal embryo
that's two days old.
And these two embryos
are also two days old
but they have a mutation
in just one out of maybe
their
30,000, 40,000, 50,000 genes.
And that one defect
is causing this embryo
to look like this
instead of this.
So whenever you take away
that gene
you get this
very specific result.
ALDA:
To track down the damaged
genes,
Nancy makes use of the fact
that they were damaged
in the first place
by having a bit of virus DNA
stuck into them.
Fishing out the virus
also fishes out the gene
it disrupted.
What do you
look forward to
as the end result
of this work?
Oh, well, I think there's
really two things, you know.
One is it has tremendous
medical potential, I think
because, you know, we're
looking
for genes through which
you really construct the body
parts of a vertebrate animal.
And so you can imagine
that if you have
something go wrong
with somebody and you
wanted to fix it
having the genes
that make organs grow
make tissues, specific
cell types grow, and so forth
could have tremendous
medical application.
So that would be terrific
if we found the gene
that cured some disease.
That would be wonderful.
But that's
sort of a random shot.
But in the meantime, you know
we're really collecting a
list
of genes that are essential
to build this animal,
and we hope in the end
to end up with
a set of, you know
bottles on the shelf
and there'll be the hundred
genes to make a heart
and the 75 genes
to make the blood
over here 50
for the ear, you know.
So it would be all
the body parts, in genes.
ALDA:
Nancy Hopkins
was already in mid-career
in a different field when she
laid everything on the line
to invent this way of using
fish
to look for the genes
that make a baby.
So perhaps it's no wonder
that to her zebra fish
are something special.
HOPKINS:
As scientists we're not
supposed
to get attached to our
animals
as individuals
but I do love my fish.
I must say I do, you know.
When I'm upset, I come in
the fish room and just...
When you're upset
you come in and...
Just look
at the fish, yeah.
That's interesting.
Hmm... very calming.
You can't help wondering what
they're thinking about,
really.
A Gene You Won't Forget
Scientists can use a gene to improve this insect's memory, and one day, perhaps ours.
Select text to jump ahead in the clip:
ALDA:
These are fruit flies--
about as unlike you and me
as it's possible for another
living creature to be...
unless you look at their DNA.
Then, as with Nancy Hopkins'
zebra fish, the similarity
between their genes and ours
is downright spooky.
For a hundred years
fruit flies have been a
favorite
with geneticists--
and never more so than today.
Scores, perhaps hundreds,
of human diseases
have their genetic
counterparts
in flies.
But of all the insights
into ourselves
we've gained from these
creatures and their genes
few are more dramatic
than the discovery
made by this man, Tim Tully.
Tully is fascinated by memory
and he's devised
an ingenious machine
to test the memory skills
of fruit flies.
He puts several dozen flies
into a chamber lined
with an electrical coil.
The flies are in for an
experience they won't
forget--
at least for a few minutes.
TULLY:
Now I'm attaching
the voltage source
where the flies will get
a slight little shock
to their feet.
They're only receiving
about five nano-amps of
current
which is nothing.
Just enough for them to
notice,
not enough to hurt.
ALDA:
While they're noticing
the tingle in their feet
the flies are also noticing
something else--
an unusual smell,
a chemical scent.
The purpose of the experiment
is to see
how well the flies remember
that the tingle and the smell
go together.
The flies are tapped
into a crowded elevator
where they wait
while Tim attaches two tubes
to the basement level
of his machine.
One tube is fed the odor
the flies experienced
while being shocked.
The other tube gets
a different odor.
Now comes the test.
Tim gently lowers the
elevator
to a point
between the two tubes.
The question is, which tube
will the flies choose?
If they remember the
unpleasant
experience upstairs
they'll avoid that smell
down here.
If they've forgotten,
they could choose either
tube.
With the experience
still fresh in their minds
these flies are indeed
avoiding
the shocking smell.
But what Tim really
wants to know is
how well the lesson stays
with them a week or so later
in their long-term memory.
It turns out it all depends
on how they were trained.
TULLY:
In order for a fly to form
a long-term memory
of this simple, little
odor-shock presentation
it has to practice
repeatedly.
And we've shown clearly
with our genetic experiments
that if you give the fly
ten training sessions
of odor-shock pairings
and you cram them all
together
it does not form
a long-term memory.
You have
to give them
the right amount of time
in between sessions, huh?
They have to be
spaced out in between.
Right?
The spaced training is
required.
There must be a rest interval
in between each of those
ten training sessions.
But is it true
that it mustn't be
too long a time?
Of course.
If we were to wait
24 hours between sessions
the flies would not form
a long-term memory
because obviously
the memory from one session
is completely gone
before the next session
and that's not going to help.
And for this particular task
in this fly
the optimum rest interval
appears to be
something like 15 minutes.
ALDA:
So like most of us,
normal flies can't cram
nor can they learn
from a single experience.
So is your needle sharp
enough to penetrate that egg?
We shall see.
ALDA:
But this fruit fly egg is
getting something extra:
a gene called creb.
Along with this extra creb
gene
the flies also get a gene
that turns their eyes red
so the extra-creb flies--
anesthetized
to keep them manageable--
can be easily identified.
All flies have a creb gene.
Its job is to help convert
short-term memories
into long-term memories.
And when the red-eyed flies
with the extra creb gene
were tested a week later
in Tim's memory machine
most of them crowded away
from the shock-associated
odor
no matter how badly
they'd been trained.
TULLY:
For the creb-on flies,
they can form a long-term
memory
after cramming, and even
