A PASSION FOR DNA
FISHING FOR BABY GENES
A GENE YOU WON'T FORGET
BYPASS GENES ON TRIAL
ALDA Somewhere down there could be the genes that construct
a baby, that grow new blood vessels, that help you remember
a kiss, or that make you grow old.
ALDA (NARRATION) I learn how to read a gene.
ALDA Mm, thank you.
ERIC LANDER That's all there is!
NANCY HOPKINS Of course we'd like to use humans…
ALDA (NARRATION) And what fish can tell us about babies.
In flies we discover a memory gene…and in worms a gene
CYNTHIA KENYON You change one gene and you
cure this disease of aging.
ALDA (NARRATION) But we also find out why using genes
to cure disease is still mostly hope.
JIM WATSON I'll
only be truly happy if we stop cancer or stop schizophrenia.
ALDA. Join me as we look for the genes that make us
or break us, on "The Gene Hunters."
PASSION FOR DNA
ALDA (NARRATION) When we decided to make a show about
DNA -- the stuff genes are made of -- we naturally wanted
to start with some of the best DNA we could find. So
we came here to the DNA Learning Center on Long Island.
INSTRUCTOR The first thing we're going to do is swoosh
our cheek pockets really good.
ALDA Now I have to tell you you're going to get the
DNA of the tuna I had for lunch a little while ago.
So my DNA's right there in that little cup, huh?
Take a look in the microscope, you'll see thousands
of cheek cells that just sort of slough off.
ALDA That blue dot in the center. That's the nucleus?
INSTRUCTOR That's the nucleus.
ALDA This is my nucleus.
ALDA (NARRATION) It's the nucleus that houses the DNA,
so we have to break it up and shake it up to release
ALDA OK, I got it.
ALDA (NARRATION) 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, 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…
ALDA I'm a nervous wreck.
ALDA (NARRATION) … the three billion letter instruction
manual for making a person.
ALDA You want more? Science is hard, I tell you.
ALDA (NARRATION) 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.
ALDA What'll you give me for this?
ALDA (NARRATION) 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.
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.
JIM WATSON I thought it was the only
problem worth solving. Of course that wasn't true, but
it was the only one I thought worth solving. And luckily,
except for Francis Crick, I don't think there was anyone
who was as high about DNA as we were.
ALDA (NARRATION) 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 in his famously gossipy
account of their discovery, The Double Helix.
No one predicted, you know, thought we were ever going
to succeed. And England is too polite to have too much
ridicule, but no one was betting on us, and… our obsession
about DNA… Prove it. And why are you so excited? And
so you've got to be not happy that other people don't
believe you, but just… I wrote in the Double Helix and
it still offends people that… when you get into science
you realize that most scientists are stupid. And… because…
ALDA Now, come on.
JIM WATSON Yes, 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 PhDs aren't
doing anything. You know, doing anything 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
ALDA (NARRATION) One Saturday morning in early 1953,
Watson was fiddling with a model of a possible DNA structure
based on a double helix.
ALDA That Saturday, when things fell into place, what
piece was missing from this? What did you…?
Well, we didn't have this.
ALDA This was missing.
JIM WATSON We had the backbone
but we didn't know how to fill in the center.
ALDA (NARRATION) The center had to accommodate the four
different chemical units, or bases, 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
ALDA So you were pretty sure it was a double helix,
but you didn't know how these base pairs fit together,
JIM WATSON Yes. And in the books the chemistry
was written wrong.
ALDA In what way?
JIM WATSON 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
ALDA Well that must have thrown you…
JIM WATSON 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
ALDA Change it from the way it is in the books.
JIM WATSON Yeah, and then the whole thing fell out. So if
we hadn't had that chemist in the room with us there
wouldn't have been someone to say, well, it's wrong.
ALDA (NARRATION) But it wasn't just that the corrected
As and Ts, Cs ad Gs, fit together 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 helix 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.
JIM 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.
ALDA They found it so beautiful that their natural jealousy
faded away in the glare of its beauty.
JIM WATSON Everyone
hoped it was right because if it was right we finally
had the molecule of heredity, because while Francis
and I were very… we believed strongly that 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, a lot of people suddenly coming
in and following up our work and the explosion of molecular
ALDA (NARRATION) 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. When in the late 1980s, a group of biologists
began to consider the then outrageous idea of deciphering
the all the genes in the human body, it was to
JIM WATSON that they turned to lead the project.
JIM 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 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 so I saw getting the human genetic information as
a big plus toward moving medicine. And that's how we
helped sell it to Congress. It was really disease.
ALDA (NARRATION) 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.
ALDA Oh, there it is.
ALDA (NARRATION) 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 are far outnumbered by machines.
ALDA Wow, this is amazing. Look at this.
ALDA (NARRATION) The director of the Genome Center is
ALDA This is some kind of robot?
ERIC LANDER Yeah, over
there are all these little spots on those 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 2000 letters of human DNA. The first thing
we've got to do, we've got to pick up and grow each
bacterial colony up so that we get enough DNA out of
ALDA I presume this robot is doing this because its
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 (NARRATION) The machines in this room diligently
prepare a hundred thousand 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 human's job is to
feed the sentences into the machines -- 96 at a time,
in these little cartridges. In order to read the order
of the letters -- the As, Ts, Gs and Cs -- in the sentences,
the machines make use of something extremely weird.
ERIC LANDER Well it turns out that the little sentences
are faster than big sentences when you put them through
jello, in essence. Now, what is jello?
ALDA You have this giant scientific laboratory devoted
to putting sentences through jello. I'm amazed I didn't
come up with that.
ERIC LANDER We like to use fancier
words because it's impressive, it costs a lot of money.
But basically you're taking little molecular sentences
and putting them through jello. The point about jello
is that it's this very complicated network, the little
sentences can wiggle through better than the bigger
sentences. And in fact what's really cool about this
is that the guys that are 51 letters long get there
just ahead of the guys that are 52 letters. And then
the sentences that are 75 letters long 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 go by? Let's take you to see the letters go
ALDA (NARRATION) 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.
ERIC LANDER So you
can read out the DNA sequence -- GATTCG -- because we
attached the right colors to the right sentence. It's
a beautiful trick.
ALDA (NARRATION) Understanding the trick took about
10 minutes in front of a convenient whiteboard.
ERIC LANDER I'm just going to make up some letters of DNA
ALDA (NARRATION) But to save time, we'll summarize.
The DNA sequencing machines are actually making copies
of the DNA sentences -- but every time one of those
colors is stuck on, the copying grinds to a halt. So
there are lots of sentence fragments floating around,
each one ending in a different color. By reading both
the fragment length and its color, you get the sequence.
ERIC LANDER So the number 6 is purple.
ALDA Right, right.
ERIC LANDER And the number 7 is green,
and the number 8… That's it.
ALDA OK, thank you.
ERIC LANDER That's it. That's all
there is. This whole place here is to stick in these
ALDA OK, OK, well let's go, I'll run one of those machines
ERIC LANDER That's it. You've got it. It takes
an hour in freshman biology. You've got it. That's it!
ALDA (NARRATION) 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 the human
ERIC LANDER 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 the planet. Once
you've read one person's DNA, you then become interested
in this one letter in a thousand variation. Now that
matters. I mean, between you and me I said we're 99.95
identical, but we still have three million differences…
ALDA And one of us might have something that's off that
might cause disease, is that right?
ERIC LANDER 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 you 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.
We're now in an age when biology is about information…
ALDA (NARRATION) 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 codebook are filled
in. And unlike the companies that are also sequencing
our genes, the data streaming out of these machines
ERIC LANDER Every 24 hours, the 50, 60 million
letters we produce here get posted on the Web. And they
go flying around the databases in Japan and Europe and
Washington and then from there to databases in tens
of thousands of biology laboratories. So in fact there's
this huge information shuffling going on constantly,
because if you were studying a particular thing about
diabetes, you could have 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 shown up. 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…
ALDA And then your computer goes bong, and says you've
ERIC LANDER You've got Gmail. That's right.
The thing you were looking for just showed up last night,
here it is.
JIM WATSON, the first director of the
Human Genome Project, was convinced it would revolutionize
ALDA Tell me about how our lives will be different now,
medically. I mean, how revolutionary is this going to
ERIC LANDER Well, it's possible to over-hype all
this stuff and I think people 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, at 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 don't know what the parts are
in the car. You'd never take your car into an auto mechanic
who didn't know what the parts were and how they are
ALDA Oh, I have many times.
ERIC LANDER Probably, yeah.
And you know the results.
ALDA Paid through the nose for it too.
ERIC LANDER Well, you take your body in, to medicine,
and for the past century we didn't know what the parts
were. I mean, 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 Program, the real
guarantee, is that 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 are
going to have met the enemy in disease.
FISHING FOR BABY GENES
ALDA (NARRATION) Our next story is also about finding
NANCY HOPKINS Now I always wash my hands,
dip my hands here. If you don't mind doing that.
ALDA (NARRATION) But
NANCY HOPKINS isn't looking for
human genes in humans -- she's looking in fish.
ALDA These are all your fish here?
NANCY HOPKINS Yes.
ALDA How many do you have?
NANCY HOPKINS In this room
alone -- I don't know-- we have maybe in here about,
I'd say, seventy five thousand?
ALDA Seventy five thousand?
NANCY HOPKINS A hundred
thousand maybe. We have a total of about a hundred and
fifty thousand fish.
ALDA How many did you start with?
NANCY HOPKINS Twenty
ALDA Twenty three?
ALDA (NARRATION) 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.
NANCY HOPKINS There's only
about a thousand more to go.
ALDA (NARRATION) 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.
Of course, we'd like to use humans…
ALDA Yes, but you can't fit them into the tanks.
NANCY HOPKINS But 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?
NANCY HOPKINS A lot, yes. We would be horribly crushed if
it didn't turn out that the genes weren't almost identical.
ALDA This is really hard to understand because if I
made a list on a piece o f paper of the features that
were identical between that fish right there and me…
I mean we have eyes, our tails are different, our gills
NANCY 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 (NARRATION) 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 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.
NANCY HOPKINS So that's the tail and it's wrapped around the
yolk. There it goes, whoops. There's the brain, the
middle of the brain, the hind brain.
ALDA Look, look. It's like a little frisky anchovy.
NANCY HOPKINS Well thank you for pointing that out.
I'd never thought of that.
ALDA Where's the heart?
NANCY HOPKINS Just sort of under
ALDA It's beating fast.
NANCY 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 (NARRATION) Nancy estimates that only about 2400
of the tens of thousands of zebra fish genes 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 descendents
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.
NANCY HOPKINS It turns out that generally the defects you
get in these little babies actually result in death.
So you see a very specific thing go wrong and then the
fish is doomed, it's going to die.
ALDA (NARRATION) So far
NANCY HOPKINS and her colleagues
have found more than a dozen specific defects in their
zebra fish embryos.
NANCY HOPKINS 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 30, 40, 50 thousand 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
ALDA (NARRATION) 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
ALDA What do you look forward to as the end result of
NANCY HOPKINS 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 with 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 tissue, specific cell types grow and so forth,
could have 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 that in the end to end up with a set of bottles
on the shelf; and there'll be a hundred genes to make
a heart and the seventy-five genes to make the blood,
over here fifty to make the ear, you know. So it would
be all the body parts, in genes.
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.
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. When I'm upset I come in the fish room
ALDA When you're upset you come in and…
Just look at the fish.
ALDA That's interesting.
NANCY HOPKINS Hmm. Very calming. You can't help wondering
what they're thinking about really.
A GENE YOU WON'T FORGET
ALDA (NARRATION) 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.
TIM 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 (NARRATION) 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 want 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
TIM TULLY In order for a fly to form a long-term memory
of this single 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 together, it does not form a long-term memory.
ALDA You have to give them the right amount of time
between sessions, huh?
TIM TULLY They have to be spaced
out in between. The spaced training is required. There
must be a rest interval in between each of those ten
ALDA But is it true that it mustn't be too long a time?
TIM TULLY Of course. If we were to wait 24 hours between
sessions, the flies would not form 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
ALDA (NARRATION) So like most of us, normal flies can't
cram, nor can they learn from a single experience.
TIM TULLY So is your needle sharp enough to penetrate that
egg? STUDENT We shall see.
ALDA (NARRATION) But this fruit fly egg is getting something
extra -- a gene called creb. Along with the creb gene,
the flies also got a gene that turns their eyes red.
So the creb flies -- anesthetized to keep them manageable
-- can be easily identified. All flies have a creb gene.
It's 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.
TIM TULLY For the creb-on flies, they can form a normal
memory after cramming or even after one training session.
So they have the functional equivalent of a photographic
ALDA (NARRATION) As you'll probably not be surprised
to learn by now, we too have a creb gene -- a gene that
functions like a switch to turn short-term into long-term
memories: the phone number you just looked up into the
phone number you remember all your life.
TIM TULLY This
switch works in both directions. And this is now what
we think is occurring normally, not in a genetically
engineered fly, but in each of us. The switch is set
somewhere between fully on and fully off. Now if we
can target that switch with a drug, in principle we
can find drugs that set the switch more toward on, and
that should facilitate the conversion of short-term
to long-term memory. We can think of that as a very
therapeutic treatment for those who suffer from Alzheimer's
disease and perhaps even for the age associated memory
loss that all of us are going to have eventually. Because
what we're doing is, we're turning up the gain on how
easy it is to convert short- term to long-term memory.
ALDA Yeah, but you know also, where were you for eleven
years when I was trying to learn all those lines on MASH.
I could have just taken one of these creb pills and I'd
have been fine.
TIM TULLY Exactly. And you know, as we move from considering
this kind of drug discovery from clinical applications
to lifestyle issues, then even the notion that someone
could use a drug like this to memorize lines is not
out of the realm of possibility.
GENES FOR YOUTH
ALDA (NARRATION) This is
CYNTHIA KENYON. And these are
ALDA Is that it?
CYNTHIA KENYON There they are. There
ALDA Wow! Look at them move!
CYNTHIA KENYON Aren't they
ALDA (NARRATION) If you thought studying fish and flies
was an odd way to find out about ourselves, what about
worms smaller than a grain of sand? But worms too may
contain human secrets -- in this case, how we age.
ALDA Most of us would think, How is that possible? How
could the way a worm ages be anything like the way we
CYNTHIA KENYON They have all the same kinds of
tissues in their bodies that we have in our bodies.
So for example, they have muscle cells that let them
move. They have a whole nervous system that lets them
go towards things they like, go away from things they
don't like. They have skin. They have an intestine that
looks a lot like our intestine. So at the level of individual
cells and tissues, these animals are very similar to
ALDA (NARRATION) Normal nematode lifespan is just 2
CYNTHIA KENYON This is a brand new adult worm.
This will be maybe a college graduate -- about that
ALDA How old is he?
CYNTHIA KENYON He's, in worm days,
he's three days old and he would be the equivalent of
a twenty year old person. So he's pretty frisky, moves
around, has nice muscle tone. You can see.
ALDA The worm has nice muscle tone.
CYNTHIA KENYON He
does! So he's moving through his food. This is bacteria,
that he's... a lawn of bacteria.
ALDA That's a nice sinuous movement. What does an old
guy look like?
CYNTHIA KENYON Okay, now I'll get an
old worm for you. Here's some nice old worms. Here's
a pair of them.
ALDA Boy, they're just sitting out in the sun!
CYNTHIA KENYON Look at them. Look at them. There are two of
ALDA They're on their lawn chairs.
CYNTHIA KENYON They
are -- or maybe even in the nursing home. This worm
is still a little bit active but it's nothing like a
young worm. And look at its body, you see this big gap
here and these little pock marks? So it doesn't look
young anymore. It looks very old now. And actually what
I think is really interesting is that anyone in the
world looking at these worms can see that they look
kind of old. So in other words, there is something about
the aging process that speaks to you, directly from
an animal of any type.
ALDA (NARRATION) In a series of experiments that became
instant classics, Cynthia has made worms that live twice
as long as normal. First she gave normal worms a bath,
in a rather unpleasant chemical that causes random changes
-- or mutations -- in the genetic material inside the
worms' cells. Next she laboriously placed thousands
of single worms onto their own individual dishes. Now
she could follow each worm over time, generation after
generation. Most worms died or lived shorter because
of their mutations. But in a few there was a single
change -- a change in one gene -- that led to longer
life. So now living in the incubator in Cynthia's lab
is a strain of mutant worm that lives 4 weeks, rather
than 2. It's astonishing to see a lively, young-looking
worm that's the same age as the old folks we'd seen
ALDA Oh my God that really is...
CYNTHIA KENYON …this
is a mutant worm. This is the exact same age.
ALDA The same age!
CYNTHIA KENYON It's the same age
-- I'm not kidding you. Look at that. I mean it doesn't
ALDA I never looked at these worms before but this looks
the same. To my eye this looks the same as the three
CYNTHIA KENYON Well it's a little different.
ALDA How is it different? Show me how it's different.
CYNTHIA KENYON It's a little slower. It's a little bit
bigger. But you know, it is much younger in spirit than
that one we just saw. That's for sure. Isn't that amazing!
ALDA It is amazing.
CYNTHIA KENYON I mean it's just
unbelievable -- you change one gene and essentially
you cure this disease of aging, if you want to put it
ALDA I'm taking this very personally here for a minute
CYNTHIA KENYON Uh-oh.
ALDA …well I'd like to live to about 106 -- at least
that's what I've always thought. But now I may switch.
Maybe I'm too modest - maybe I should go for 140 or
CYNTHIA KENYON Why not?
ALDA Yeah, well that is what I want to ask you, why
not? Because what I want to know is, this guy is 12
days old, he's still thriving at 12 days -- 12 out of
a 14 day usual life span. He's going to go on another
2 weeks, right?
CYNTHIA KENYON Yeah.
ALDA Now, in those two weeks, how much of those two
weeks will be vigorous like this? When is he going to
start to act like a 100 year old, or a 110 year old
person? What do you observe?
CYNTHIA KENYON I would
say that in about one more week this animal will be
still not looking as bad as the normal worms that I
just showed you, the normal 12 day old worms. But they
will be much slower. They'll be walking and not running.
ALDA (NARRATION) In other words, everything takes twice
as long -- youth, middle age and old age. This really
could happen with people some day, because Cynthia's
rapidly figuring out how the lifespan system works.
CYNTHIA KENYON Here it is.
ALDA What is this, like a thousand times bigger than
it ought to be?
CYNTHIA KENYON Even more than that I
think because the normal worm you can hardly see. So
this is a zillion times larger.
ALDA A zillion. Ah, I knew there was a number.
ALDA (NARRATION) In nematodes, lifespan is regulated
by hormone messengers that circulate in the body and
land on receptors -- like this blue mushroom.
CYNTHIA KENYON This red thing here is a cell. And the worm is
actually full of many cells and this is just one of
CYNTHIA KENYON The receptor sits in the edge
of the cell and its job in the animal is to receive
signals from the outside and the signals that it receives
are hormones. So this is a hormone…
CYNTHIA KENYON We have lots of hormones in
our bodies controlling all aspects of our growth and
our physiology. In the normal worm, where the hormone
is bound to the receptor, the consequence is that the
worms have a short life span.
ALDA (NARRATION) The mutation that extends life changes
the shape of the receptor so the hormone's blocked.
CYNTHIA KENYON And so the hormone can't fit in to its
normal spot -- see like that, it can't fit in there.
And as the consequence, the animal lives longer.
ALDA Do you know why?
CYNTHIA KENYON We don't know all
the details, but we do know that one thing that is very
important are these little orange balls here. These,
it turns out, we can call these fountain of youth balls.
ALDA (NARRATION) With the receptor blocked, the cell
makes more youth chemical -- and that's the stuff the
worm needs to live. But in normal worms with working
receptors, the fountain of youth dries up.
So here goes, I'm going to start shooting the laser
at it. Now the way I do that is with the little foot
ALDA (NARRATION) Cynthia has discovered a second lifespan
regulation system in nematodes, this time by disrupting
cells used in reproduction. She delicately knocks out
the cells, using a tiny laser.
CYNTHIA KENYON I think
I've killed it now, yes. Here's the cell I've been shooting
at. When I started off it looked a lot like this cell
with a nice dish shaped center, but now you see its
gone, there's no round circle.
ALDA (NARRATION) Worms with reproductive cells destroyed
also double their lifespans -- and the mechanism is
just like the first system Cynthia discovered. In this
case the worms no longer make a second kind of messenger
hormone, again resulting in more youth chemical being
made inside cells. So what happens when one worm has
both lifespan systems blocked?
CYNTHIA KENYON What we
found is that it lives twice again as long.
ALDA You're kidding!
CYNTHIA KENYON Yeah, it's a very
amazing result. So it lives now, instead of a human
living like not 90 years but 180, its like living 360
years. Do you see what I'm saying? You're doubling the
doubling of the life span.
ALDA (NARRATION) It's too soon to know if an anti-aging
pill for humans could one day be based on
old but sprightly worms. But she's hopeful.
ALDA Before you did this work did you have an age that
you thought you might live to, and now have you changed
your mind about what that age might be?
Ah, yeah, I'm much more, er... Well I have to tell you,
I have a retirement account. So that means that at some
level I think I might have to retire at some point.
So part of me is living in the real world. On the other
hand, I have an imagination that I might not have to
use it for a very long time. It could get really big!
GENES ON TRIAL
ALDA (NARRATION) So far in our show about genes, we
haven't seen many humans -- scientists excepted. And
so far, despite the immense promise of the genetic revolution,
its impact on most of us has been slight. Mall-walker
COOPER was an exception.
COOPER I started about 7 years ago, and I could walk
5 miles every morning. I don't want to be immodest,
but I was a good mall walker. I was usually at the head
of the group.
ALDA (NARRATION) But for the two years before we met
her, Lillian had been sidelined by a badly narrowed
artery in her left leg.
COOPER If I don't find a way to get it fixed, I'm gonna
lose the leg. I've been advised of that by two doctors.
And I'm not ready for that.
ALDA (NARRATION) In 1997, Lillian took part in an experiment
conducted by Dr
ISNER to see if a gene could help save her leg. As we'll
see, this form of gene therapy would later become engulfed
in controversy. But for Lillian, everything went smoothly,
as a dye injected through a catheter revealed the extent
of the blockage in her artery.
ISNER This is where the problem is. It takes a long
time for that dye to wind it's way all the way down
to her calf muscle and foot. That's why she's having
all the pain. And so the need here is to find a way
to somehow deliver a significantly larger volume of
blood flow down to the lower leg.
ALDA (NARRATION) Isner plans to employ a gene that make
new blood vessels grow -- in effect to create a bypass
around the blockage without the need for a surgeon.
ISNER The idea that people could grow their own bypass
is an intriguing one because there is nothing like letting
nature do the surgery.
ALDA (NARRATION) To deliver the gene, Isner employs
a narrow balloon that will be slid into Lillian's artery
to a point just above the blockage and inflated to squash
the gene into the blood vessel's walls. Hundreds of
millions of copies of the gene are coated onto the balloon,
then dried so that they stick there. As the balloon
is inflated, the hope is that at least some of the millions
of genes will go to work in the cells lining her artery.
Six weeks later, and Lillian at least is convinced that
the genes are doing their job.
COOPER Yesterday I walked from the hospital down the
main street - over a half a mile - and I kept going.
I feel that there have to be new blood vessels forming
because what else would cause this? My leg is better,
my foot is better, I can walk better. Has to be that.
NURSE We'll have to use that cane as kindling.
COOPER Ha, ha.
ALDA (NARRATION) Another test is done to measure blood
flow into Lillian's leg. The result at least partially
justifies her optimism. While before it took 15 seconds
for blood to reach her calf, now it takes only nine.
Since Lillian had her gene therapy, many others have
received -- and apparently benefited -- from
ISNER's blood-vessel-growing gene. Isner himself had
growing confidence in the technology.
ISNER Whenever you try something like this for the first
time, you always wonder: is it science fiction, or is
it going to be real therapy? A lot of things we try
turn out to be science fiction, make good movies, but
they don't help too many patients. I think this has
the potential to be great science fiction, but now we
are seeing a few indicators that suggest that it actually
might be useful.
ALDA (NARRATION) Our story now jumps ahead to the fall
of 1999. Again, Dr
ISNER is preparing to try to grow a new bypass with
his gene -- this time not in a leg, but in a heart.
The patient is
ALDA Good morning.
ALDA I hope this isn't too intrusive. I know it's got
to be intrusive to some extent. Are you a little groggy?
LENNON Yes I am.
ALDA How would you describe what shape your heart is
LENNON Well it's like a 50-pound block on me that's
sitting there. You know, the pressure, the breathing
ALDA Yeah. And internally what's happening? What's going
on inside your heart?
LENNON Well, I've had seven angioplasties, and three
bypasses, and four heart attacks.
ALDA (NARRATION) And so today, Joe is to get some genes
-- millions and millions of them, injected directly
into his heart. Or maybe not. Because it is also entirely
possible that all Joe will be getting in his heart is
a shot of salt water.
ALDA This is a double blind test, so you don't know
what's going in today.
ISNER No we don't.
ALDA Who does know?
ISNER We don't know, the patient doesn't know. The only
person who really knows is this young lady standing
right behind us,
CURRY, who's preparing the DNA, or the saline, the salt
water. Cynthia, you almost ready there? OK, great, I'll
be ready to go.
ALDA You have to leave?
ISNER Yes, we'll be ready to start.
ALDA Well, good luck with it.
ISNER Thank you very much.
ALDA (NARRATION) When not being filmed for Frontiers,
Jeff Isner comes nowhere near this lab. It's off limits
to everyone involved in the trial.
CURRY I have to be very careful about what I say to
the nurse coordinators and to the doctors. Just basically
I have to keep my mouth shut. And I guess that's OK
because I've always been good at keeping a secret.
ALDA You're part of a double blind trial, is that right?
LENNON That's right.
ALDA And you don't know if you're getting the real stuff
ALDA Is that… was that a hard decision to make?
LENNON I just hope that eventually, if I don't get it
this time, I'll get it the next time.
LENNON Anything to get rid of the chest pain. I figure
it's worth the risk.
ALDA (NARRATION) It's a risk several patients have taken
already -- though Joe will be one of the first to be
getting the injection into the inside of his heart.
The earlier patients were injected through a surgical
incision in their chests. Joe's injection will be via
a catheter snaked into his heart from his groin, using
a tiny needle that will stab into the heart's inner
ALDA How do you decide exactly where to put the DNA
ISNER Yeah. So the map on the right has a red zone.
And that red zone indicates an area where the heart
muscle is not contracting normally. And that's we presume
because there's not enough blood flow to that site.
ALDA Is it going in now, the DNA?
ISNER Yeah, this is going to be the first of six injections
that we're going to do. If you look carefully you'll
be able to see -- right about there -- the needle should
come poking out. You see it? It's very thin. And now
Dr Vale is going to be injecting the DNA. We don't want
to be doing this too quickly because we don't want any
of the solution to come squirting back at us. So we'll
sort of ease it into the muscle. So now Dr Lasorda has
moved the catheter to another site…
ALDA (NARRATION) It's the catheter injection method
that's really on trial here today. The previous tests,
in which the DNA was injected a surgical incision, had
promising results. The hope is that the more benign
catheter method will be as effective. The elaborate
double blind trial is to make sure that it isn't simply
the injection procedure itself but the DNA being injected,
ISNER How you doing Joe?
LENNON I feel a little like a warm feeling around my
heart. I don't know if that's natural or not but I do
feel a little something.
ALDA (NARRATION) What none of us in the catheter lab
that day knew was that the whole concept of gene therapy
was about to be put on trial -- and that both doctor
and patient would be caught up in the fall out. In September
1999, the news broke that a young man enrolled in a
gene therapy experiment at the University of Pennsylvania
had died. The case involved a different disease from
LENNON's, a different gene and a very different way
of putting the gene into the patient. But the Pennsylvania
incident triggered a sweeping governmental review of
all gene therapy experiments. While all this was going
on, Joe came back for a three-month check up -- concerned
much less with the potential risks of gene therapy than
he was with its potential benefits.
LENNON I still don't know if I got the DNA yet, but
we'll see. I've felt a lot of good days, but then I'm
back to where I was again. And them days I'm just, gee,
it's working slow, but when the bad days come again,
I don't know.
LENNON We were encouraged, and we're a little disappointed
that there hasn't been a big change. But there's still
time, and as Joe said, even if you didn't get the DNA,
you can always get it later. NURSE You're going to go
right under this camera. It's going to be really close…
ALDA (NARRATION) Joe signed on for the clinical trial
with the promise that -- should it turn out that he'd
not received the DNA -- he'd be eligible to get it later.
But as the follow up tests on Joe continued to show
little or no improvement, suddenly the rules changed.
In the review of all gene therapy trials conducted by
the Food and Drug Administration in the wake of the
Pennsylvania case, Jeff Isner came in for harsh criticism.
A few weeks later, his heart trial was shut down. One
LENNON's condition had worsened.
LENNON If I feel good during the day I try to walk and
putter around doing little things, but I seem to get
tired out. I get light headed, dizzy, and my heart starts
to race, so it's not getting better, it's getting worse.
I was upset about the trial being shut down. I figure
that was my last resort, so hopefully it'll begin again.
ALDA (NARRATION) But by the summer of 2001, Jeff Isner's
gene therapy trial was still on hold. And
LENNON was still waiting and wondering. Did he get the
gene? And if not, would he ever get his second chance?
For scientists working on the human genome, this is
an exciting -- even heady -- time. But for the man who
did so much to start it all, enthusiasm is tempered
with the reality that most of us, like
LENNON, are still waiting.
JIM WATSON People say, aren't
you very happy that the genome project's almost done?
And I say, ah, I'm not depressed. I mean it's going
good and it's great, but I'll only be truly happy if
we stop cancer or stop schizophrenia. I mean, there
were two motivations for the genome… One you want to
understand life and the other that you want to understand
disease. And when, you know, when I started out life,
science, I wanted to understand life. And you get older
you realize that what…
ALDA You want to understand death too…
JIM WATSON No
ALDA Or what leads to it.
JIM WATSON Yeah, you don't
want to study death. You want to stay away from it!