NARRATOR: One question: "Why is there such
a stunning diversity of life?"
One answer: "Evolution: Charles Darwin's brilliant
theory that explains how species adapt and
change." It's been called the best idea anyone
ever had. But there's one big problem: How
does it actually work?
Now, extraordinary science is answering that
question. It is uncovering the hidden mechanisms
inside creatures' bodies that can explain
astonishing transformations like how birds
can evolve from dinosaurs; why a fish was
once your ancestor; and above all, what makes
us human.
Right now on NOVA, you'll find out, What Darwin
Never Knew.
The 
tree of life on Earth, is one of stunning
diversity: 9,000 species of birds, 350,000
kinds of beetles, 28,000 types of fish; 2,000,000
living species and counting. And we are just
one of them.
But why is there such an amazing variety of
animals? Why are there so many types of fish,
so many different species of beetle? How did
this extraordinary profusion of life on Earth
come about?
Today we celebrate the man who would ultimately
answer that question: Charles Darwin.
He was born 200 years ago, and it is 150 years
since he published the work that has become
the bedrock of our understanding of life on
Earth.
CLIFF TABIN (Harvard Medical School): What
Darwin wanted to understand was how you get
this extraordinary diversity of life on Earth.
He was spot on. He really nailed it.
NARRATOR: Darwin's theory of evolution, his
account of why species adapt and change, has
been called the best idea anyone ever had.
But even Darwin admitted that his work was
incomplete. Vast questions were still unanswered.
And the biggest question was, "How?" How did
evolution take place?
SEAN B. CARROLL (University of Wisconsin–Madison/Howard
Hughes Medical Institute): He didn't know
any of the mechanics of that process. He didn't
understand the physical forces that would
actually change the way species appeared.
NARRATOR: But today we can answer the questions
that Darwin could not. We can look under the
hood of evolution, and see exactly how this
mysterious process gives rise to such astounding
diversity.
CLIFF TABIN: What's incredible about this
timing, from a scientific perspective, is
we're going to be able to understand that
diversity. And that just adds to the excitement.
It doesn't demystify it, it makes it all the
more magical.
NARRATOR: And this is the magic and mystery
of evolution: over eons of time a single species
gives rise to many. An ancient fish evolves
to become the ancestor of all four-limbed
animals, even us. And one species, our own,
develops a large and uniquely complex brain,
enabling us to dominate the planet.
This is the search for the answers to what
Darwin never knew.
Darwin began his love affair with nature when
he was a child, just like many of his modern
followers, including evolutionary biologist
Sean Carroll.
SEAN CARROLL: I developed my interest in animals
the same way I think most biologists did,
which was either going out in the backyard
or going to zoos.
And anytime I got a chance, I'd flip over
logs and look for salamanders and snakes and
frogs and things like this. And I was just
fascinated with their patterns and behaviors.
NARRATOR: So it was with the young Charles
Darwin.
Young Charles liked to traipse around outdoors.
He loved to collect beetles and things. He
was a completely ordinary kid. And he didn't
like school.
In fact he was such a poor student that his
father, a rather successful physician and
a pretty imposing figure, was worried about
Darwin's direction in life.
So his father packed him off to Edinburgh,
the finest medical school in Europe, to become
a doctor. But young Charles was just too squeamish.
SEAN CARROLL: He was really horrified by medical
school. He witnesses an operation on a child—and
this was in the era before anaesthetics—and
he fled the operating theater, vowing never
to return.
NARRATOR: Next his father sent him to Cambridge
to study for the clergy. He didn't succeed
at that either, but he did find his direction
in life, reviving his childhood interest in
nature.
SEAN CARROLL: Darwin starts on his path to
his divinity degree, and he starts to mature
as a student. He becomes more serious about
some subjects, particularly natural history;
and he learns a lot more about botany, and
about geology and these things. He's becoming
a pretty solid field scientist.
NARRATOR: His reputation as a naturalist gained
him a spectacular invitation.
SEAN CARROLL: Charles was offered a place
on the British Navy ship, The H.M.S. Beagle,
whose mission was to survey the waters around
South America. Now the captain of the Beagle
wanted a well-educated scientific person aboard,
and a dinner companion, somebody to share
conversation with. And Darwin fit the bill
perfectly.
NARRATOR: And so, Charles Darwin set off on
a fateful voyage that would revolutionize
our understanding of life's great diversity.
The voyage of the Beagle took nearly five
years. It wove its way from the Cape Verde
Islands and along the coast of Brazil. It
was in Argentina that he made his first important
discovery.
SEAN CARROLL: Early on in the voyage he found
some amazing fossils. He dug up some skulls,
some jaws, some backbones of what turned out
to be giant mammals. Now, these were clearly
extinct, and Darwin began to ponder. What
was the relationship of those fossils to the
living mammals of South America?
NARRATOR: But one port of call on Darwin's
voyage proved more important than all the
others: the Galapagos. This cluster of 13
isolated islands lies 600 miles off the coast
of Ecuador, in the Pacific Ocean.
These islands are home to unusual animals
found nowhere else on Earth: penguins that
live at the equator and swim in warm water,
instead of the frigid seas of the South Pole;
giant tortoises that weigh up to 600 pounds;
iguanas, huge lizards that swim and dive in
the sea—everywhere else, they dwell only
on land.
Traveling for the first time in the Galapagos,
Sean Carroll is seeing the same creatures
that so intrigued Darwin.
SEAN CARROLL: Of all the animals, I think
these marine iguanas are the greatest symbol
of the Galapagos, what I most wanted to see
here. And to see them in their native habitat,
blending against that black rock, just as
Darwin described it, is an absolute thrill.
CHARLES DARWIN (Evolutionary Theorist, Passage
taken from Darwin's diary) It is a hideous-looking
creature, of a dirty black color, stupid and
sluggish in its movements. They are as black
as the porous rocks over which they crawl.
NARRATOR: Darwin meticulously described the
iguanas in his diary, but he was far from
the scientific authority he would become.
SEAN CARROLL: The Darwin that arrived here
was not the great theorist that we know today.
He was a 26-year-old collector, collecting,
really, almost at random, any kind of plants,
any kind of animals, any kinds of rocks. He
didn't even know the meaning of what he was
collecting, until much later.
He was also fascinated by the giant tortoises,
which allowed him to ride on their backs as
they slowly lumbered around. CHARLES DARWIN
(Passage taken from Darwin's diary) I frequently
got on their backs, and then, upon giving
a few raps on the hinder part of the shell,
they would rise up and walk away. But I found
it very difficult to keep my balance.
NARRATOR: Darwin measured the creatures' extreme
slowness: about four miles a day, he calculated.
But the local people knew something else about
the tortoises.
SEAN CARROLL: They could tell which island
any tortoise came from just by looking at
its shell.
NARRATOR: Their shells differed depending
on which island they lived on. Some tortoises
had shells shaped like a dome; others had
shells arcing over their heads like a saddle;
others differed subtly in color or by how
much the bottom of the shell flared out.
Darwin had literally been sitting on a clue,
a way to understand the great diversity of
life. But he didn't yet realize it.
Instead Darwin turned his attention to birds.
The islands were full of what seemed to be
a familiar assortment of species. So he stuffed
his collecting bag with what he thought were
types of finches, grosbeaks, wrens and blackbirds.
And then, after five weeks in the Galapagos,
Darwin and the Beagle went to other ports
in the Pacific, and finally set sail for home.
On board he started to sort through the vast
number of specimens he had collected on the
five year voyage. But it was not until he
returned to Britain that he was able to make
sense of them.
It began with a startling revelation. All
the different birds he had collected actually
were variations of a single type.
SEAN CARROLL: He learns that those birds he
had collected on the Galapagos actually represented
13 different species of finch.
NARRATOR: What misled Darwin was that they
looked radically different: some had wide
tough beaks, others had long slender ones.
And these differences depended on which islands
they lived on.
SEAN CARROLL: Now why would that be? Why would
there be slightly different birds, slightly
different species, on different islands, all
in one part of the world?
NARRATOR: Darwin now thought back to the Galapagos
tortoises. They too differed from island to
island. His brain began racing.
SEAN CARROLL: Thoughts are starting to crystallize,
take shape in his mind, bit by bit by bit.
He starts this process he describes as "mental
rioting," just a stream of consciousness where
he's jotting down—note after note after
note—thoughts as they occur to him.
And finally they converge on this one idea.
NARRATOR: What Darwin now realized was that
somehow, for some reason, species change.
Originally, there must have been just one
type of finch on the Galapagos, but over time
it had diversified into many kinds, with different
beak shapes; the same for the tortoises. One
type of tortoise must have turned into many
kinds, with different shells depending on
which island they lived on.
With this great insight, Darwin entered dangerous
new territory. The standard view at the time
was that God had created every species, and
that what God had created was perfect and
could not change.
SEAN CARROLL: But Darwin said "No. Why would
the Creator bother with making slightly different
finches for each of these different islands
that all looked alike?"
NARRATOR: The prevailing view just didn't
make sense. But this was only the beginning
of Darwin's revolution. He turned his attention
to the fossils he had collected in South America.
One was of a giant sloth, another was of a
huge armadillo-like creature.
These animals were extinct, but little sloths
still existed in South America, and so did
smaller armadillos. What could this mean?
SEAN CARROLL: It dawned on him that they resembled
each other, so what he had found in the ground
were the buried ancestors of the living animals
of South America. So, again, here was more
evidence that species changed. Somehow these
ancient giants must have been transformed
into the smaller creatures we see today.
NARRATOR: But what Darwin would later find
out, took this idea of how species change
into a completely new league.
In Victorian times, scientists routinely studied
life forms at the embryonic stage. How these
tiny forms develop from just a single cell
into an entire creature has long been seen
as one of the wonders of nature.
MICHAEL LEVINE (University of California,
Berkeley): Watching a developing embryo is
truly the most glorious miracle of nature,
no baloney.
NARRATOR: What Darwin learned from studying
the embryos amazed him.
In snake embryos you could see tiny bumps,
the bony rudiments of legs. But these would
never develop in the adult snake. Darwin wondered:
"Were snakes somehow descended from animals
with legs?"
He learned that whales, which have no teeth
as adults, had them as embryos.
Those teeth disappeared before they were born.
To Darwin it had to mean whales were descended
from creatures with teeth.
But human embryos provided the most startling
evidence. Under the microscope, tiny slits
around the neck were clearly visible: exactly
the same structures were found in fish. But
in fish they turned into gills; in humans,
they became the bones of our inner ear. Surely
this showed that humans must be descended
from fish.
It's an astonishing thought.
OLIVIA JUDSON (Imperial College London): I
don't know about your ancestors, but mine,
you know, included, included priests and,
you know, the, the usual, the usual suspects.
But, but the idea that all of us have, have
fish in our family tree, I think it's amazing.
NARRATOR: And so Darwin arrived at an astonishing
conclusion, one that would become central
to his understanding of the great diversity
of life.
SEAN CARROLL: Darwin had this amazingly bold
idea: the tree of life—that all species
were connected. And what it meant was, if
you go far enough back in our family tree
of humans, you'll come to fish. If you go
far enough back in the family tree of birds,
you'll come to dinosaurs. So that creatures
that don't look anything at all like each
other are actually deeply connected. No one
came close to having this idea before Darwin.
NARRATOR: This seemed to be an explanation
for the vast diversity of animals. Beginning
with a common ancestor, over time, across
generations, species could change dramatically.
Some might add new body features, others might
drop them.
Ultimately one type of creature could be transformed
into something utterly different. It's a process
Darwin called "descent with modification."
But it all begged a question: why? What was
making creatures change? Darwin needed clues.
And he found them in a very surprising place.
Dogs: big, small, fat, tall. The British have
long been obsessed by them.
It was a full-blown love affair in Victorian
England. Even Her Majesty was dog-crazy.
That love affair still continues today, especially
among scientists like Heidi Parker at the
National Institutes of Health.
HEIDI PARKER (National Human Genome Research
Institute): One of the most interesting things
about working with the domestic dog is the
kind of variation that you have. We have sizes
that range from something the size of a groundhog,
up to dogs like Zeppie, here, who can get
to be the size of mule deer.
If we had that kind of size variation in humans,
we would have people running around the size
of Barbieâ„¢ dolls.
NARRATOR: In his day, Darwin knew this range
of sizes hadn't come about by chance. Through
a careful process of selection, dog breeders
mixed different dogs with different physical
traits to create new forms.
HEIDI PARKER: Darwin was intrigued by what
he was seeing breeders could do with domestic
dogs. They could select for individual traits,
such as size or shape, and they could actually
change the look of their breed.
NARRATOR: The Whippet, for example, had been
developed to chase rabbits. It was created
by mixing greyhounds for speed, with terriers,
used to hunt small game.
And then it hit Darwin. Was there a similar
form of selection going on in nature, but
without human interference? Could natural
selection explain the great diversity of life?
SEAN CARROLL: It was brilliant. He took something
very familiar and comfortable, for example,
animal breeding, and explained that the same
sort of thing was going on in nature, just
at a little bit different pace and with no
human guide.
NARRATOR: But what could be carrying out selection
in the wild? It was then that Darwin took
a completely fresh look at nature.
The Victorian view of nature was sentimental—lambs
lay down with lions—but Darwin's travels
on the Beagle led him to a different view.
For Darwin, nature was savage. Every creature
was locked in a desperate struggle for survival,
ultimately ending in death.
OLIVIA JUDSON: The scale of death in nature
is absolutely horrendous. And sometimes it's
not just there's a lot of death, but it's
very unpleasant death.
NARRATOR: But, in all this brutal chaos, Darwin
saw a pattern.
SEAN CARROLL: Darwin showed that nature was
a battlefield and that everything was in competition.
And this brutal battle, this war of nature
as Darwin described it, was actually a creative
process.
NARRATOR: The pattern that Darwin saw was
that the creatures that survived were those
best adapted to the specific environments
they lived in. For instance, some could handle
extremes of climate. Others were brilliantly
honed killing machines, perfect for catching
the available prey. Still others were perfect
to evade those who might be hunting them.
But how did this harsh view of nature explain
the finches on the Galapagos, where Darwin
observed that that the birds on different
islands had different beak shapes? Somehow
those different beaks must be helping the
finches survive.
CLIFF TABIN: The finches of the Galapagos
Islands have beaks of many sizes and shapes.
And there's a reason for that; they use their
beaks as tools. Now, if you think of the type
of tool you would want to crush a seed that's
very tough, but is the food that you really
like, you'd want a beak like this, which is
the type of beak the ground finch has.
NARRATOR: On an island where the only food
is seeds that are hard to crack, a short,
powerful beak will mean a finch will survive.
But on another island, the available food
isn't seeds but flowers.
CLIFF TABIN: On the other hand, if you wanted
to get into narrow spaces to get pollen and
nectar, that are very hard to get at, you
wouldn't need a big, strong beak, you'd need
a probing beak.
NARRATOR: So on a different island, where
you have a different food source, you have
a different beak shape. And this pattern was
repeated across the Galapagos.
It seems that the finches' beaks had altered
to fit the diet of each particular island.
And that was how one original type of finch
had been transformed into many. But how had
these changes come about?
Here Darwin had another clue. He could see
it in his own family. As every parent knows,
no two children are ever exactly the same.
Charles looked different from his brother
Erasmus, even though they shared the same
parents.
Charles's children looked a bit like him and
his wife Emma, but they, too, looked different
from each other. That was something he called
"variation."
SEAN CARROLL: He realized that not every individual
was the same, stamped out like a toy from
a press, but there was variation.
NARRATOR: Darwin realized that variation must
be the starting point for change in nature.
In any generation, the animals in a litter
are never quite the same. And in the wild,
such a tiny variation might make all the difference
between life and death.
Two penguins, for instance, might differ a
tiny bit in the thickness of their blubber,
a big factor if you live in extreme cold.
In a harsh climate, the environment will select
who will live and who will die. And slowly,
Darwin suggested, over many, many generations,
these tiny variations would allow the fit
to get fitter, and the unfit would vanish.
These variations accumulate and eventually
new species branch off. This is evolution
by natural selection. It is one of the keys
to how new species are formed.
And so, in 1859, after years of painstaking
research, Darwin finally published his masterwork,
On the Origin of Species. It is still impossible
to overstate its importance.
CLIFF TABIN: It was really a quantum advance
in understanding. It shook people up, it changed
the way people thought.
NARRATOR: Gone was the idea that all species
were created perfect and immutable, taken
as an article of faith. In its place, Darwin
provided proper scientific theory, based on
facts and observation.
OLIVIA JUDSON: It is much more than the presentation
of simply the idea of natural selection. It's
a vision of how evolution by natural selection
works.
NARRATOR: One-hundred-fifty years later, his
theory has stood the test of time.
SEAN CARROLL: What's amazing is that Darwin
got so much right. His ideas largely stay
intact today.
NARRATOR: But Darwin himself acknowledged
that there were holes in his theory. He didn't
actually know how it worked. What was happening
inside a creature's body that makes it change?
But now, at last, modern science is providing
the answers, through a hidden mechanism that
Darwin knew nothing about.
Arizona's Pinacate Desert is a harsh and brutal
place, especially if you're a rock pocket
mouse.
MICHAEL NACHMAN (University of Arizona): They're
the SNICKERS® bar of the desert. They really
are. They're probably eaten by foxes and coyotes
and rattlesnakes and owls.
NARRATOR: Weighing just half an ounce, this
mouse could never fight off these large predators.
Its best hope for survival is camouflage.
Not surprisingly, its fur matches the color
of the Pinacate rocks.
But in some sections of the desert, the environment
is different. Ancient volcanoes erupted, and
now the desert is a patchwork of dark lava
and light rock.
But of course a light mouse on dark rock is
easy pickings. So something has happened that
Darwin might have predicted. The mice now
living on the dark rocks have evolved darker
fur. Those that stayed on the light rocks
remain light.
Nachmann was fascinated. How had this happened?
To find out he first needed to catch some
mice. So, with Sean Carroll, he visits a line
of traps he set the previous night.
MICHAEL NACHMAN: All of the dark ones have
a white underbelly, and, presumably, there
is no selection for a dark underbelly, because
predators are coming from above.
NARRATOR: This much Darwin could have done:
find some mice and compare the color of their
fur to their environment. But Nachmann can
now do something that Darwin never could;
he can look inside the animals' D.N.A.
The study of D.N.A. is one of the great triumphs
of modern science.
It has taken our understanding of how creatures
evolve and develop to a level that Darwin
could never have dreamed of.
SEAN CARROLL: The D.N.A. molecule is one of
the real secrets of life. It's a perfect system
for storing the vast amounts of information
that's necessary for building all kinds of
creatures.
NARRATOR: D.N.A. consists of one long molecule,
spiralling around in a double helix. That
helix is, in turn, made up of four smaller
molecules, called by the letters G, A, T and
C.
D.N.A. can be found in the cells of every
living thing on Earth.
OLIVIA JUDSON: The thing about D.N.A. that
I think is remarkable is that the molecule
itself is so elegant: with a small number
of letters, you can say almost infinite words.
NARRATOR: And that is the key. D.N.A. is a
code, and its double strand contains all the
information to make living things grow and
develop. Lined along each D.N.A. molecule
arranged special sequences of this code that
form our genes.
Many genes get translated into proteins, and
these proteins make the stuff of our bodies.
One protein makes hair; another makes cartilage;
others make muscle.
SEAN CARROLL: What makes D.N.A. so amazing
is that contains just four letters but all
sorts of combinations of those four letters
contains all the information for making all
the creatures that are on the planet.
NARRATOR: It's a gene that determines whether
our eyes are blue or not. Another gives us
freckles. Another gives us dimples. But D.N.A.
has one other vital quality: it doesn't stay
the same.
When a baby is conceived, the fertilized egg
receives half its D.N.A. from the mother and
half from the father, creating wholly new
combinations. It's why we look a bit like
our parents, but also different.
Another way that D.N.A. can change is mutation.
SEAN CARROLL: Mutation is a critical ingredient
in the recipe for evolution. Without mutation,
everything would stay constant, generation
after generation. Mutation generates variation,
differences between individuals.
NARRATOR: Mutations can happen as our D.N.A.
copies itself when our cells divide and our
bodies develop. An A, for instance, can be
replaced by a G or a C by a T. This can cause
minute changes that no one is even aware of.
But when mutations occur in the cells we pass
down to our children, they can cause big changes,
like turning a light-colored mouse dark.
SEAN CARROLL: Mutation seems to mean that
something bad has happened. Well, mutations
are neither good or bad. Whether they are
favored, or whether they are rejected, or
whether they're just neutral, depends upon
the conditions an organism finds itself in.
So, for the pocket mouse, a mutation that
caused the mouse to turn black, that is good
if they're, you're living on black rock. It's
bad if you're living out in the sandy desert.
NARRATOR: It was that mutation, the one that
turned a light-colored mouse dark, that Michael
Nachmann was hunting for.
Back in the lab he began the painstaking business
of comparing the genes of the two types of
mice, trying to pinpoint any differences.
MICHAEL NACHMAN: Science is fun when you really
don't know what you're going to find.
NARRATOR: One by one, the genes in the two
mice proved identical. But then, in one gene,
he found something. There were four places
where the sequence of As, Ts, Cs and Gs were
different.
When a mouse is born with these mutations,
its fur grows dark. And that means it can
survive on the dark rocks when others would
not. Here was a clear example of evolution
and natural selection at work.
MICHAEL NACHMAN: I think Darwin would have
been delighted to know that we can find the
genes that are responsible for evolutionary
change.
NARRATOR: And this was just one of many links
that have been found between genetic mutations
and evolution.
Scientists can now pinpoint a range of examples
of evolution in action. The Colobus monkey
can see in color because of a mutation in
one gene; it can now tell nutritious red leaves
from tough old green ones. A genetic glitch
gave this Antarctic fish a potent antifreeze
in its blood, so it can survive in the icy
waters when others cannot.
So powerful was this link between genetic
mutation and evolution that an idea took hold:
to understand how evolution works, all you
need to do is compare creatures' genes.
SEAN CARROLL: One might think that you could
understand all of evolution, simply by mapping
the genes of every creature. Identify all
the genes, identify all the differences, and
you could explain the differences between,
say, a mouse, and monkeys and humans.
NARRATOR: So, when the human genome project
began, in 1990, the scientific world was on
tenterhooks. All three billion letters of
our D.N.A. were going to be identified, in
order.
In parallel, the D.N.A. of some animals and
plants was also being sequenced. Surely this
would be a quantum leap in our understanding
of how different life forms evolved?
With this came another idea: that complex
animals like us would have many more genes
than simpler ones.
SEAN CARROLL: Here we are, the most complex
and sophisticated animal on the planet, right?
You might think that would require a whole
lot more genetic information.
NARRATOR: The betting was on. Just how big
would our genome be compared to other life
forms?
OLIVIA JUDSON: There were estimates that humans
would have between, let's say, 80,000 and
120,000 genes.
NARRATOR: So when the final answer came in
2003, it was a shocker: 23,000 genes, the
same number as a chicken, less than an ear
of corn.
MICHAEL LEVINE: People were freaked out by
the relatively small number of genes. It's
down to something like 22- or 23,000 protein-coding
genes in a human genome.
The simple nematode worm has about that same
number. And there are plants that have considerably
more genes than the glorious human genome.
OLIVIA JUDSON: The whole human genome project
has been a humbling experience, as we've discovered,
that, actually, it doesn't take as many genes
to make a human as we had all hoped.
NARRATOR: And it wasn't just that we had so
few genes, but many of our key genes were
identical to those of other animals.
Huge though the breakthrough had been, the
genetic revolution had opened up a whole new
set of puzzles. As a solution to the mystery
of how evolution works, genes and their mutations
were only part of the story. There had to
be something else, more subtle and more mysterious
going on.
SEAN CARROLL: We have to explain, then, "How
do you get all these differences, if you have
really similar sets of genes?"
NARRATOR: The quest to uncover what Darwin
never knew would have to start again.
The first tantalizing clues would come from
those life forms that Darwin himself had studied,
embryos.
Look at these embryos. It is almost impossible
to tell, just days after conception, which
is the chicken, the turtle, the bat, the human.
They look almost the same.
Only as they grow, does it become clear which
is which. Darwin wondered, as scientists do
today: how could they start out so similar
and end up so different?
MICHAEL LEVINE: There is something profound
about what the embryo was telling us. And
we have rediscovered what Darwin was talking
about all along, that the embryo is where
the action is, in terms of animal diversity.
It is the platform for diversity.
NARRATOR: What fascinates modern biologists
is that all these different animals don't
just look the same, they are using virtually
the same set of key genes to build their bodies.
The body-plan genes determine where the head
goes; where the limbs go, and what form they
take: whether they are arms, legs or wings.
Another set of genes determines an animals
body patterning: the blotches, the stripes
and spots.
It is the same genes at work in every creature
from the leopard to the peacock to the fruit
fly, and yet they produce radically different
results.
This has led scientists to a crucial insight
about how animal bodies have evolved. It's
not the number of genes that counts.
SEAN CARROLL: It's not the genes you have
but how you use them that creates diversity
in the animal kingdom.
NARRATOR: Finding out just how these same
genes are used to create such amazing diversity
has been the work of Sean Carroll and an unlikely
hero of modern science: the fruit fly.
SEAN CARROLL: As much as I'd like to study
the mammals of the African savannah, they
make poor choices for laboratory animals.
They're large, expensive and then reproduce
very slowly. To get data, we have to find
the simplest examples of the phenomenon we
want to understand.
NARRATOR: But the humble fruit fly does weird
and wonderful things.
This fruit fly is dancing for sex. A rapt
female takes in the show. She's particularly
besotted by the dark spots on the male's wings.
Watching it all is an equally besotted Sean
Carroll.
SEAN CARROLL: You might think them to be just
annoying, but they're really charming. The
males of this species does a rather elaborate
courtship dance where he displays these spotted
wings in front of the female. To us, it's
as magnificent as what a peacock does.
NARRATOR: But in some species of fruit fly,
the males don't have wing spots.
SEAN CARROLL: There is another fruit fly species
that is different from the spotted species
in two important ways: it doesn't have spots
on its wings, and it does a lot less dancing.
NARRATOR: Here then is a classic evolutionary
puzzle. Why does one type of fly have spots
and the other doesn't? Sean Carroll wanted
to know what is going on in their genes that
makes them different.
SEAN CARROLL: So we wanted to take apart the
genetic machinery for making wing spots, to
understand how those wing spots evolved.
NARRATOR: Carroll began the process of sifting
through the two types of flies' D.N.A. He
had one clue to set him on his way. He already
knew the gene that codes for the black wing
spots. He calls it the paintbrush gene.
But surprisingly, when he compared the genes
of the two flies, they both had that gene,
and yet only one had spots.
SEAN CARROLL: When we look at that gene in
the two species, really, they both have this
paintbrush gene. So the big difference is
not having the gene, it's how they use it.
One species is using it to make spots, the
other one doesn't.
NARRATOR: So why did the paintbrush gene create
spots in one type of fly but not the other?
In search of answers, Carroll turned to one
of the least understood regions of D.N.A.
The vast stretches that were once known as
junk.
It has been called the dark matter of the
genome: mysterious, uncharted, strange.
The vast bulk of the double helix, some 98
percent of it, doesn't code for proteins,
which make the stuff of our bodies. The genes
which do comprise just two percent.
Even now, no one is sure what much of this
huge non-coding area actually does, but it
has long beckoned evolutionary detectives,
like Sean Carroll.
So that is the fragmented test?
Carroll had already learned that the paintbrush
gene itself was identical in the two types
of fly. So he extended his search through
their D.N.A. And in one place, just outside
the paintbrush gene, he found an important
clue: a stretch of D.N.A. that was different
in the fly with wing spots.
What could this mean?
So Carroll conducted an experiment. He decided
to put that mysterious stretch of D.N.A. that
he had found in the spotted fly in the unspotted
fly. To help him see if it had any effect,
he attached it to a gene from a jellyfish,
a gene that codes for a protein that makes
the jellyfish glow.
SEAN CARROLL: We cut the D.N.A. up into little
pieces, and we hook it up to a protein that
glows in the dark. And then we inject that
into the unspotted fly.
NARRATOR: And then something remarkable happened.
SEAN CARROLL: When we looked at those unspotted
flies, we see, now, their wings are glowing
in the dark with spots.
NARRATOR: Somehow that mysterious stretch
of D.N.A. had turned on the paintbrush gene
in the unspotted fly's wings. Once spotless,
now it had luminous spots.
SEAN CARROLL: Bingo. We had found the piece
of D.N.A. that mattered.
NARRATOR: Carroll had found something that
is revolutionizing our understanding of how
different animal bodies have evolved.
A piece of D.N.A. called a switch. Switches
are not genes. They don't make stuff like
hair, cartilage or muscle, but they turn on
and off the genes that do.
SEAN CARROLL: Switches are very powerful parts
of D.N.A., because they allow animals to use
genes in one place and not another; at one
time, and not another; and so, choreograph
the spots and stripes and blotches of animal
bodies.
NARRATOR: In the case of the fruit fly it
is a mutation, a change in just a few letters
of the D.N.A., that has caused the paintbrush
gene to be switched on. And so, a whole new
species with wing spots has been created.
But switches are now explaining far more than
that. They are helping to solve many perplexing
evolutionary questions, like how one creature
can become another creature by losing it legs.
It all goes back to what Darwin had seen in
the snake embryo: the rudiments of leg bumps.
This convinced him that a snake must have
evolved from some four-legged animal.
Over the years that same mysterious process,
the losing of legs, has been seen in other
creatures, like the whale. Its front flippers
have all the bones of a land creature's arm,
even the fingers. And further back in its
body, it has the vestiges of a pelvis. Clearly
it is descended from an animal that walked
on the land.
DAVID KINGSLEY (Stanford University, Howard
Hughes Medical Institute): Lots of animals
have evolved to slither through the ground,
like snakes. Other animals slither or swim
through the water, like, like whales. So if
you need a streamlined body, it's good to
get rid of these things that stick out from
the body, like limbs.
NARRATOR: Like the whale, the manatee is another
huge mammal that lives in the sea. And it,
too has lost its hind legs. How?
Darwin could never have answered that question,
but now, thanks to our understanding of how
D.N.A. is switched on and off, and a very
small fish, we are getting a little closer.
In this lake, in British Columbia, there is
a creature that really shouldn't be here:
a stickleback.
Most sticklebacks live in the ocean, but some
10,000 years ago, a few were left stranded
in this lake, cut off from the Pacific. And
over the years, they have evolved.
The ocean stickleback has a pair of fins on
its belly that are like spikes. They are for
defense. The spikes make the stickleback hard
to eat.
But the lake sticklebacks have lost those
spikes on their bellies. And it is this that
intrigues researchers David Kingsley and his
colleague Dolph Schluter.
To understand what's behind it, they first
identified the gene that makes the stickleback's
spikes. It's one of those key body-plan genes
and, not surprisingly, they found it to be
identical in both the ocean and the lake stickleback.
The question was, "Why hadn't it been turned
on in the lake stickleback, which had lost
its spikes?"
Kingsley felt the answer might lie in a switch.
DAVID KINGSLEY: We know these genetic switches
exist. But they're still very hard to find.
We don't have a genetic code that lets us
read along the D.N.A. sequence and say, "There's
a switch," to turn a gene on in a particular
place.
NARRATOR: But eventually, hunting through
the vast stretch of D.N.A. that does not code
for proteins, he found it, a section of D.N.A.
that had mutated in the lake stickleback.
These mutations meant that the switch was
broken. It didn't turn on the gene that makes
spikes.
But this work may have implications far beyond
sticklebacks. They are convinced that there
is a link between the stickleback losing its
spikes and other creatures, like a manatee,
losing their legs. And they have two tantalizing
clues.
One: the same body-plan gene that is responsible
for the stickleback spikes also plays a role
in the development of the hind limbs.
The second clue is more tentative. The lake
stickleback may have lost its spikes, but
evolution has left behind some tiny remnants:
the traces of bones. And they are lopsided,
bigger on the left than on the right.
DAVID KINGSLEY: We thought, "Wouldn't it be
amazing if, in fact, this classic unevenness
is the signature of using the same gene to
control hind-limb-loss in incredibly different
animal?"
NARRATOR: So Kingsley and his team went looking
in manatees, searching for this lopsided pattern.
And they found it. In box after box of manatee
skeletons they saw pelvic bones that were
bigger on the left and smaller on the right.
Right now, Kingsley and his team are looking
for the same switch in the manatee that caused
the lake stickleback to lose its spikes. And
if they find it, they will have a powerful
explanation for something that baffled Darwin:
how creatures like manatees, whales and snakes
can evolve away their legs.
But all this begs another question. If switches
can play such a profound role in the different
shapes and patterns of animal bodies, from
wing spots, to spikes, to hind legs, what
is throwing those switches in the first place?
Researchers would see the answer in animals
very familiar to Darwin: those Galapagos finches.
Arkat Abzhanov and Cliff Tabin have spent
years trying to find out exactly how those
Galapagos finches got their different beaks.
Their starting point was what they had learned
from Darwin himself: their beaks were vital
to the birds' survival.
On an island where the main food was seeds,
finches had short, tough beaks for cracking
them open. On an island where the main food
was from flowers, birds had long pointy beaks
for sucking up nectar and pollen.
And they knew something else: the finches
are born with their beaks fully formed. So
the answer to why they had such different
beaks must lie in something that happened
to the finches as embryos, in the egg.
CLIFF TABIN: Something amazing is happening
inside those eggs. Genes are turning on and
off. And depending exactly on how they turn
on or off will determine what type of finch
is formed.
NARRATOR: To find out just what was going
on, the researchers first had to collect some
eggs.
ARKHAT ABZHANOV (Harvard Medical School):
There she is...just got back and about to
lay some eggs. Quite likely that she already
has a batch. She's coming out.
NARRATOR: Abzhanov checks a ground finch nest
and finds a single egg. He won't remove it
because the mother might abandon the nest.
Another nest already has three eggs. He takes
one for his research, as he knows the mother
will lay a replacement.
The team collects several eggs, with embryos
at different stages of development. That way
they will be able to chart exactly how the
different beaks grow.
Back in the lab, they can begin the process.
This cactus finch embryo is well on the way
to its signature long, pointy beak. And this
ground finch embryo is growing a short thick
beak.
CLIFF TABIN: What we wanted to do was try
and understand the genes that were involved
in making the beak the way it was, making
a big, broad thick beak different from a long,
thin beak or a short, thin beak.
NARRATOR: They concentrated on a group of
genes known to control the growth of birds'
faces. As they looked, they saw something
intriguing.
One particular body-plan gene became active
in the ground finch—with the short, thick
beak—on the fifth day of development, but
it didn't go to work in the cactus finch—with
its long, slender beak—for another 24 hours.
This was a revelation. The same genes were
responsible for the beaks in all types of
finch. Any differences were in timing and
intensity.
CLIFF TABIN: We've got it; we've nailed it.
It's the same genes in making a sharp, pointy
beak or a broad, nut-cracking beak. What is
essential and makes the difference, and all
the difference, is how much you turn the gene
on and when you turn it on, when you turn
it off.
NARRATOR: And the revelations didn't end there.
There was something special about this gene.
Like all body-plan genes, it doesn't actually
make the stuff of our bodies. It didn't make
the cartilage for the finches' beaks. It throws
switches, and the switches then turn on or
off the genes that do make the beak.
SEAN CARROLL: These are a different type of
gene; they're the genes that boss other genes
around.
NARRATOR: Scientists now realize that not
all genes are created equal. Some make the
stuff of our bodies, and switches are needed
to turn many of these stuff genes on and off.
The body-plan genes are what throw these switches,
which tell the stuff genes what to do and
when.
This subtle choreography can have profound
effects on how different animal bodies are
formed.
And this knowledge is helping us solve perhaps
the biggest Darwinian puzzle of all: the mystery
of the great transformations.
It all goes back to Darwin's idea of the tree
of life, that all life-forms are ultimately
related, and from the earliest common ancestor,
over billions of years, they have changed
and diversified, so that creatures that started
out looking the same, evolved to become completely
different.
And scientists have made some amazing connections:
that dinosaurs share a common ancestor with
birds; and that a fish must have been the
ancestor of all four-limbed creatures, even
us.
Of all his ideas this was probably Darwin's
most astonishing.
SEAN CARROLL: It was one thing to grasp how
two species of finch could become different,
how their beak shape could change. That was
a small step. But what about the big differences,
the differences, say, between the fish that
swim in the sea and the animals that walk
on land? How did those changes take place?
NARRATOR: Over the years evidence for these
great transformations has been found. For
instance, just a year after Darwin published
On the Origin of Species, a fossil called
archaeopteryx was discovered. It had features
of both birds and dinosaurs.
And Darwin had seen equally persuasive evidence
in embryos. Those slits in the ear of all
land creatures, even humans...in us, they
become tiny bones in the inner ear, but in
fish, they become gills—a tantalizing hint
that land animals must be descended from fish.
But the stumbling block has always been how?
How could a fish develop legs and walk on
land.
Darwin had no idea, but Neil Shubin was determined
to tackle that problem.
NEIL SHUBIN (University of Chicago/The Field
Museum): It captured my imagination. I mean,
here's a fin, and on the other side was a
limb, and they looked different in many ways.
And I thought, "Well, what a first-class scientific
problem to devote my research to!" And I've
been devoting pretty much my research to it,
ever since—over 20 years.
NARRATOR: The first stage in Shubin's quest
was to find a fossil.
If Darwin were right, somewhere out there,
there had to be a transitional form, a fossil
that was part fish, but had the beginning
of legs. But where to look?
He had one clue. The fossil record shows that
creatures with legs first appeared some 365
million years ago. Before that, there were
only fish.
So, summer after summer, Shubin set up camp
on Ellesmere Island, just a few hundred miles
from the North Pole. It has exposed rock from
that crucial transitional time. The scientist's
own video shows how remote and bleak the place
was.
NEIL SHUBIN: It's cold; it's about freezing
every day over the summer. Winds are high;
they can get up to 50 miles per hour. There
are polar bears there. We have to prepare
ourselves by carrying guns. It's a beautiful
place. You've got to love it. It's my summer
home.
NARRATOR: Each expedition was costly, but,
after three of them, there was little to show
for their efforts. A fourth trip seemed pointless.
NEIL SHUBIN: I remember having a conversation
with my colleagues saying: "Well, should we
go? Is this really a waste of money?" This
was our do-or-die moment, and we almost didn't
go.
NARRATOR: But they decided to try one last
time.
After three days they still hadn't found anything.
Then, just when no one was expecting anything
to happen...
NEIL SHUBIN: A colleague was cracking rocks,
and I was working five feet away from him.
And I hear "Hey! Hey, guys, what's this?"
And sticking out of the cliff was the snout
of a fish—and not just any fish, a fish
with a flat head. And by seeing a flat-headed
fish in rocks about 375 million years old,
we knew that we had found what we were looking
for.
NARRATOR: A flat snout, with upward staring
eyes, the signature of an animal that pushes
its head out of the water. And for that, it
would have needed something like arms.
NEIL SHUBIN: What we did at that moment was
all jump around high-fiving. It was a, you
know, there were only six of us in the field
that time, so it was quite a scene.
NARRATOR: Back at home, Shubin and his team
got to work, examining their 375-million-year-old
fossil.
They named their new finding Tiktaalik, an
Inuit word for a freshwater fish.
Tiktaalik is a perfect transitional form.
Much of its body is that of a fish. It's covered
in scales. But it also had something very
un-fishlike,
an arm-like fin, or, perhaps, a fin-like arm.
Tiktaalik had the bone structure that is seen
in the arms and legs of every-four limbed
animal: one big bone at the top; two bones
underneath, leading to a cluster of bones
in the wrist and ankle.
It's the same pattern that is found in everything
from sheep, to sheepdogs, to Shubin himself.
NEIL SHUBIN: You now have an animal that can
push itself up off the substrate, either on
the water bottom or on land.
NARRATOR: One obvious question was, "Why had
Tiktaalik evolved to this new structure?"
One possible answer is suggested by other
fossils found near it.
NEIL SHUBIN: There are large predatory fish,
about 10 to 15 feet long, living alongside
Tiktaalik.
NARRATOR: Tiktaalik was prey. To survive it
had few choices.
NEIL SHUBIN: You can get big, you can get
armor, or you can get out of the way.
NARRATOR: Neil Shubin thinks Tiktaalik got
out of the way. With those arm-like fins,
it could have dragged itself to safety on
land or in the shallows, but this was only
half the answer.
NEIL SHUBIN: What it doesn't show us is the
actual genetic mechanism, the genetic recipe
that builds a fin into that which builds a
limb.
NARRATOR: At 375-million years old, Tiktaalik's
D.N.A. had vanished long ago.
Shubin needed a next of kin, a fish relative
that was still alive.
NEIL SHUBIN: What we needed was a creature
that was in the right part of the evolutionary
tree, but also a fish that had a very fleshy
fin. So the search was on.
NARRATOR: A number of fish fit the bill, but
Shubin favored one in particular: the paddlefish.
NEIL SHUBIN: The paddlefish is a really weird
fish. They have developed this really long
snout, and they are really voracious. They
eat each other. Oftentimes you will lose a
lot of your fish when they swim together,
because they will eat each other.
NARRATOR: Living in the shallow waters of
the Mississippi, it's also a living fossil.
Scientists have spent years working out the
relationships between different species of
fish, and they know that the paddlefish is
one of the last survivors of the class to
which Tiktaalik once belonged.
But unlike Tiktaalik, the paddlefish is in
plentiful supply.
NEIL SHUBIN: Paddlefish is a common source
of caviar, so we get our paddlefish from caviar
farms.
NARRATOR: Intriguingly, even though Tiktaalik
is extinct, the paddlefish is actually the
more primitive form. Its fins bear far less
relation to an arm or leg than Tiktaalik's.
And because they are related, the two kinds
of fish should share the same genes, so Shubin
began looking at paddlefish embryos, hunting
for the genes that built its fins. And soon
he zeroed in on one particular group of body-plan
genes called Hox genes.
Hox genes have been found in all complex animals,
from the velvet worm that dates back some
600 million years, to the modern human. And
in all that time, the letters of their D.N.A.
have remained virtually unchanged.
They are aristocrats of the gene community,
near the very top of the chain of command.
They give orders that cascade through a developing
embryo, activating entire networks of switches
and genes that make the parts of the body.
They are absolutely critical to the shape
and form of a developing creature.
SEAN CARROLL: These genes determine where
the front and the back of the animal's going
to be; the top, the bottom; the left, the
right; the inside, the outside; where the
eyes are going to be; where the legs are going
to be; where the gut's going to be; how many
fingers they're going to have.
NARRATOR: Shubin found that Hox genes had
a key role in the formation of paddlefish
fins. One set of Hox genes orders the first
stage of fin development, a sturdy piece of
cartilage that grows out from the torso.
Amazingly, in all four limbed animals, even
us, exactly the same genes create the long,
upper arm bone.
In the paddlefish, another set of Hox genes
command the next stage of fin development.
Again, exactly the same genes control the
growth of our two forearm bones.
Finally, the same genes, working in a different
order, make the array of bones at the end
of the fin. The same sequence of the same
genes makes our fingers and toes.
This was a massive revelation. Suddenly the
origin of creatures with arms and legs didn't
seem such a huge leap after all. If the same
genes were at work in Tiktaalik, then many
of the genes needed to make legs and arms
were already being carried around by prehistoric
fish.
All it needed was a few mutations, a few changes
to the timing and order of what was turned
off and on, and a fin could become a limb.
NEIL SHUBIN: Oftentimes, the origin of whole
new structures in evolution don't involve
the origin of new genes or whole new genetic
recipes. Old genes can be reconfigured to
make marvellously wonderful new things.
NARRATOR: So it is now possible to answer
what Darwin didn't know and explain how all
four-legged creatures could be descended from
fish.
Around 375-million years ago, a creature like
Tiktaalik was under attack, harried by predators.
But some random changes to the activity of
the Hox genes led to its fins developing a
structure like a limb.
Tiktaalik could now haul itself out of danger,
onto dry land. On land, it would have found
a world of plants and insects, a world ripe
for colonization, a world perfect for animals
with arms and legs.
And so, over millions of years, these new
limbs evolved, changed and diversified. Some
became adapted for running, others for flying;some
for digging, others for swinging. And so,
four-limbed creatures took over the world
in a multitude of different ways, and all
because of some changes to an ancient set
of genes.
And this is the true wonder of where our new
understanding of D.N.A. has led us to: there
are genes that make the stuff of our bodies,
switches that turn them off and on, and still
other genes that give those switches orders.
Together, in a complex cascade of timing and
intensity, they combine to produce the amazing
diversity of life on this planet. That truly
is something that Darwin never knew.
But can this new science also explain perhaps
the most fundamental question of all: "What
makes us human?"
The scope of human activity is simply astounding.
KATIE POLLARD (University of California, San
Francisco): What fascinated me were all the
crazy things that humans do. You look around
the world, and if there is something bizarre
and interesting that you could be doing, humans
are up to it somewhere in the world. And when
you look at all of this, you have to ask yourself,
what makes us so special. And what is the
basis for this humanness?
NARRATOR: For all nature's wonders, the achievements
of the human mind are truly unique. We are
the only species to think about what others
think about us; to punish those who have harmed
others; to create art, music, architecture;
to engage in science, medicine, the microchip.
Only we can destroy millions at the push of
a button.
Hardly surprising, then, that for centuries,
we thought that humans were different from
all other species: better, created in the
image of God.
But then Darwin began to draw conclusions,
from evidence like gill slits in human embryos,
that showed that we were descended from fish.
But it was when he drew parallels with other
close relatives that he got into real trouble.
SEAN CARROLL: Shortly after Darwin returned
from his voyage, in London, an orangutan named
Jenny went on exhibit. And this was a huge
sensation. This was the first great ape to
be exhibited in captivity. And Darwin was
absolutely taken with how she was, sort of,
childlike in her ways. And he saw a lot of
human behavior in the way this orangutan behaved.
NARRATOR: When Darwin suggested that human
beings must actually be descended from apes,
he was savaged. He was accused of attacking
that core belief that humankind had been created
in the image of God, above all other creatures.
But today, the idea that we share a common
ancestor with apes is completely accepted
in biology. Instead, as a result of having
sequenced the genomes of both humans and apes,
we face a very different puzzle.
Katie Pollard is an expert on chimp D.N.A.
KATIE POLLARD: Given all the obvious differences
between humans and chimps, you might expect
our D.N.A. to be really different. But, in
fact, it's more like 99 percent identical.
NARRATOR: Just a one percent difference in
the D.N.A. of humans and chimps.
The mystery facing modern science is not,
"How can such different animals be related?"
But, "How can such closely related species
be so different?" That really is something
that Darwin never knew.
But slowly, scientists are starting to find
the answers. And one answer begins with insights
into the genetics of a key human organ, our
hands.
The human hand is a marvel; nimble and dexterous,
nothing quite like it exists anywhere else
in nature. It offers us a unique combination
of precision and power, and much of that is
down to one particular digit, our thumb.
JIM NOONAN (Yale University): One of the features
of the human hand is our ability to touch
all four fingers with the thumb. And that
allows us to make grips like this, grips that
give us a lot of precision. The power grip
is the ability to put a lot of strength into
this sort of contact.
So if you're holding a ball, you're basically
pinching it, and we can put a lot of strength
into that.
NARRATOR: The better to throw a fastball with.
Finding out why we have such versatile hands,
compared to our nearest relatives, is the
task of Jim Noonan, at Yale University. He
began sifting through that vital one percent
of D.N.A. that is different in humans from
chimps.
JIM NOONAN: It's, kind of...one of the fundamental
questions in science is, "What makes us who
we are?" And that's really what we're trying
to get to—what makes humans human.
NARRATOR: It was slow work. One percent may
not sound like much, but it's still some 30
million of D.N.A.'s chemical letters: As,
Ts, Cs and Gs.
JIM NOONAN: The genome's a big place. And
just by looking at a sequence, it, you really
can't tell, for the most part, what is important
and what isn't.
NARRATOR: But eventually, in human D.N.A.,
he spotted something: a sequence that was
different in 13 places, compared to chimp
D.N.A. The trouble was, he had no idea what
this piece of D.N.A. actually did.
To find out, he inserted it into the embryo
of a mouse. To make the effects of the D.N.A.
easier to follow, he attached it to another
gene that gives off a blue color. That way
he could see where the gene became active
in the embryo.
As the embryo developed, the piece of D.N.A.
seemed to be active all over the place, but
most intriguingly, it was doing something
in the growing paw.
JIM NOONAN: I thought, "Wow, this is really
cool!" It was, it was a really striking image.
NARRATOR: What Noonan saw was that the human
D.N.A. became active in the mouse embryo's
thumb and big toe. It seems that Noonan may
have found a switch that helps form that key
human attribute, our thumb, the part of our
hand that gives us so much power and precision.
It's that power and precision that enables
us to hold a paintbrush, manipulate tools,
pilot a jet fighter, record our thoughts,
all those things that separate us from other
apes.
Of course having a nimble hand is one thing.
But you have to know how to use it. And for
that you need to have humankind's other signature
organ, our brain.
The human brain is vast—three times bigger
than a chimp's—and is structured very differently.
How this extraordinary organ evolved is central
to understanding why we are the way we are.
It is something that Darwin himself was at
a loss to explain, which is why many of his
critics remained unconvinced by his account
of human origins.
But now, part of the answer to why we have
such a remarkable brain may have come from
a surprising source.
Hansell Stedman is a dedicated athlete and
a medical doctor. He never imagined he would
come up with an answer to a profound evolutionary
mystery. He has devoted his career to trying
to cure muscular dystrophy, a distressing
and sometimes fatal degenerative disease.
His quest is very personal.
HANSELL STEDMAN (University of Pennsylvania
School of Medicine): My first exposure to
muscular dystrophy was inescapable. My younger
and my older brother both were born with muscular
dystrophy.
NARRATOR: Muscular dystrophy is a genetic
disease. Its sufferers have a mutation in
one gene that robs their muscles of the ability
to repair themselves.
HANSELL STEDMAN: ...typical workout, here
on the rocks, might blow through a few thousand
muscle cells, but they'll regenerate overnight,
and if anything, be a little stronger the
next day I come in, as a result of all of
that. Whereas, in muscular dystrophy, the
injury process is greatly accelerated, and
the injury process outstrips the body's ability
to repair.
NARRATOR: In search of a cure, Stedman is
investigating the hundreds of genes that control
the development of muscles. So when the human
genome project took off, Stedman seized his
chance.
HANSELL STEDMAN: When the horsepower of the
entire human genome project kicked in, we
knew exactly what to look for.
NARRATOR: Stedman was hunting for any new
muscle-making genes. And so, as the human
genome was sequenced, he began sifting through
the vast mountains of data.
Eventually he found what he was looking for:
a previously unidentified muscle-making gene.
But there was something strange about this
new gene. It didn't look like any other muscle-making
genes. Two letters were missing.
This gene should cause a disease.
HANSELL STEDMAN: It became very clear, early
on, that if you have a mutation of this type,
you get some serious muscle problem going
on.
NARRATOR: Here was a puzzle. Why would humans
carry a gene that was clearly damaged? Perhaps
it was simply a mistake in the data.
Stedman decided to dig a little deeper and
look in another human subject.
HANSELL STEDMAN: In the department of true
confessions, we do certain experiments first
on ourself, largely out of convenience. You
can swab your own cheek and get working on
some D.N.A.
NARRATOR: To his utter amazement, he found
the same damaged gene in himself.
HANSELL STEDMAN: I'm seeing this in my own
D.N.A., and it's suggesting that, "Wait a
minute. That means there's a muscle disease
here somewhere, a muscle disease that I'm
unaware of." And I thought it would be worth
checking this out in some other members at
the lab.
NARRATOR: A few swabs later and...
HANSELL STEDMAN: Sure enough, at the end of
the day, every single person had the same
glitch in their same D.N.A. at the same place.
NARRATOR: Here then was a real mystery. It
seemed that this peculiar muscle-making gene
was common in humans. But when he identified
the same gene in apes, it was just like any
other muscle-making gene.
Why was there such a difference? What did
this gene enable one species to do that the
other could not?
Stedman began to research the role of this
gene in apes. And he found it made one particular
kind of muscle. The muscle for chewing. In
fact, the muscle used to close the jaw. In
humans, that genetic glitch meant that we
chew with just a fraction of the force of
an ape.
This in itself was interesting, but where
Stedman went next was truly intriguing, and
highly controversial.
He drew a direct connection between the power
of our jaw muscle and the evolution of the
human brain. Stedman's thinking goes like
this: the skulls of apes and humans are made
of several independent bone plates. They let
our heads get bigger as we grow. The muscles
for chewing pull against these plates, and
in an ape, these forces can be enormous.
HANSELL STEDMAN: So in the gorilla, the muscle,
the size of a human thigh muscle, lives here
and has to go through this large space to
power the jaw moving back and forth. We're
not talking biceps, triceps here, we're talking
quad here. This is an enormous muscle that
has to come right through this hole here to
power the jaw-closing apparatus.
NARRATOR: Stedman contends that all this muscle
power forces an ape's skull plates to fuse
together at an early stage, and this puts
limits on how much the brain can grow.
HANSELL STEDMAN: In a chimpanzee, gorilla
or orangutan, those growth plates are pretty
much shut down, closed for business, by about
three, four years of age. In a human, they
remain open for growth to perhaps the age
30.
NARRATOR: This, Stedman believes, is the key.
A mutation in our jaw muscle allows the human
skull to keep expanding into adulthood, creating
a bigger space for our brain. And so our most
important organ is able to grow.
HANSELL STEDMAN: It's very cool, to us, to
think that some kind of muscle-altering mutation
might actually have been a signature event
in the evolution of what makes us a distinct
species. It might have been absolute prerequisite
for landing us where we are today.
NARRATOR: But having the space for a big brain
is one thing. What is needed to actually grow
one?
That is the question that Chris Walsh is trying
to answer. He's another scientist who never
expected to be taking on what even Darwin
didn't know.
CHRIS WALSH (Children's Hospital Boston):
I never thought that I'd be studying evolution.
I'm a neurologist, interested in the brain
and kids with neurological problems. And no
one was more surprised than us to find that
the study of kids with disabilities would
lead us into these fascinating evolutionary
questions.
Is he breathing generally good, during the
day?
MOTHER OF MICROCEPHALY PATIENT: Sometimes
it will go fast: huh, huh.
NARRATOR: Chris Walsh is a specialist in a
rare disorder called microcephaly. Children
with microcephaly are born with brains that
can be a half the normal size.
CHRIS WALSH: This disorder can be very devastating
for the kids that have it. They typically
will have severe mental retardation, and so,
will not be able to achieve normal language
and normal schooling. And so it's really an
event that defines the whole family. It defines
the lives not only of the child but of the
parents of that child. And these families
are desperately eager to try to understand,
at least, what caused the disorder in their
kids.
NARRATOR: The purpose of Walsh's work was,
initially, to help families that might be
carrying any defective genes causing microcephaly
to plan their lives.
CHRIS WALSH: We're able to offer those families
predictive testing, so that if they're planning
on having additional children, we can tell
them ahead of time whether that child is likely
to be affected or not.
NARRATOR: First Walsh had to decide where
to look in the vast genome to find any possible
microcephaly-causing genes. So he focused
on one particular area of D.N.A. Other research
suggested it contained a gene involved in
the condition.
That gene is known to control how and when
brain cells divide in animals such as fruit
flies and mice.
CHRIS WALSH: What this gene seems to do is
help control the fundamental decision that
the brain has to make, which is, "When do
I have to stop making cells? When is the brain
big enough?"
NARRATOR: Then his team began searching for
that same gene in a family with a history
of the disease. And sure enough they found
something: a gene that helps direct brain
growth. And, crucially, it was defective.
Walsh decided to check this finding in other
patients.
CHRIS WALSH: Once we found this gene, we sequenced
it in our kids with microcephaly disorder.
And we found that one family after another
had a disabling change in the gene that completely
removed its function.
NARRATOR: In total, he has found some 21 different
mutations responsible for microcephaly. Sometimes,
one of the D.N.A.'s chemical letters is replaced
with another letter, sometimes letters are
missing entirely, but whatever the defect
is, they all stop the brain cells from dividing
at a very early stage of development.
Walsh was now certain, thanks to his microcephaly
patients, he had found a gene key to the growth
of the human brain. Now he decided to compare
normal versions of the gene found in healthy
humans with the same gene in chimpanzees,
our closest relatives.
And what he found was astonishing. The gene
in humans was radically different from that
found in chimps. There had been a large series
of mutations.
It could be that these mutations were a major
factor in the evolution of our huge brains.
And this discovery came about only because
of Walsh's work with his patients.
CHRIS WALSH: I think one of the amazing things
for us was the extent to which studying human
disease can unexpectedly enlighten us about
something like human evolution.
NARRATOR: But this is only the beginning of
our understanding of the evolution of the
human brain. It's an area of research that
is now attracting scientists with a range
of skills that Darwin would have marvelled
at.
Katie Pollard is a biostatistician. Her life
is spent crunching numbers.
KATIE POLLARD: What I love about my work is
geeking out on a computer, writing programs
and thinking about biology. I'm actually working
on something that not just scientists care
about, but really every human being can relate
to and cares profoundly about: what makes
us human.
NARRATOR: Pollard has constructed an ambitious
computer program. It is designed to highlight
D.N.A. that is similar in apes and other animals,
but which is very different in humans.
KATIE POLLARD: Out of these 15 millions letters
that make humans different from chimps, we
need to try to figure out which ones were
important. And so we use a technique, which
is to look for places where human is different
from chimp, but chimp looks almost identical
to other animals.
NARRATOR: She, too, is looking for D.N.A.
relating to the human brain.
KATIE POLLARD: The brain is one of the things
that's changed the most during human evolution,
both in terms of its complexity and its size.
And so when we look to find the parts of our
genome that make us human, we're particularly
interested in finding out whether these are
things that are involved in the brain.
NARRATOR: It is a huge feat of number-crunching,
as Pollard loaded in D.N.A. sequences from
both humans and chimps.
KATIE POLLARD: You basically take a bunch
of computer hard drives and you stack them
up together.We were able to take a task that
would have run for 35 years on a desktop computer
and do it in one afternoon.
NARRATOR: And at the end of that afternoon,
they had a whole array of material charting
the differences between humans and chimps.
Importantly, many of those differences were
not in the actual genes. They were in switches.
KATIE POLLARD: It turns out that the vast
majority are not genes. Instead, they're pieces
of our D.N.A. that we can think of as switches.
They're pieces of D.N.A. that turn a nearby
gene on or off, that tell it where, in what
cells in our body, in what tissue, at what
time or at what level to be operating.
NARRATOR: And there was something even more
intriguing about those switches.
KATIE POLLARD: A large number of them, more
than half, were nearby a gene that was involved
in the brain.
NARRATOR: In Pollard's work, one particular
piece of D.N.A. stood out. It was a piece
D.N.A. that is known to be active in the development
of one of the key parts of the human brain
in the embryo: the cortex.
The cortex is that wrinkled outer layer of
our brain. It's vital for those defining human
capabilities like language, music, and mathematics.
When she looked at that D.N.A. in chimps and
compared it to the same D.N.A. in a chicken,
it was different in just two letters. But
in humans it was different by 18 letters.
A massive mutation.
KATIE POLLARD: This was about as great of
a "eureka moment" as you could have as a scientist.
NARRATOR: So here is another intriguing piece
of evidence suggesting how D.N.A. can shape
our distinctive human qualities.
We now know that D.N.A. works in many different
ways, through genes that make the stuff of
our bodies, through switches that turn those
genes on and off, and through sequences of
D.N.A.'s chemicals that throw those switches.
Taken together, what this all adds up to is
a way that we can, at last, understand how
small differences in D.N.A. can generate enormous
change.
KATIE POLLARD: Basically, you can make massive
changes, just changing those switches. So
a small change, a couple of D.N.A. letters,
could have a profound effect.
NARRATOR: And so that final Darwinian puzzle—how
a human can be so closely related to an ape
and yet be so different—is now, slowly,
being answered.
One-hundred-fifty years after Darwin first
put forward his grand theory to explain the
great diversity of life, the scientists who
carry on his legacy have advanced his work
in wondrous ways.
SEAN CARROLL: I think, if Darwin were here
today, he'd be absolutely stunned, delighted,
even moved, to see how much his theory has
grown.
CLIFF TABIN: What we now are able to understand,
on the one hand, would just blow him away.
But I also think it would give him enormous
satisfaction, because, ultimately, everything
we've been learning validates the things that
he said.
OLIVIA JUDSON: I think that Darwin was a remarkable
scientist and absolutely should be celebrated.
However, I do not think that he was the end
of evolution; on the contrary, I think he
was the beginning. He outlined the major points,
but we have discovered more than I think he
would have imagined possible.
NARRATOR: As we celebrate the 200th birthday
of Charles Darwin and the 150th anniversary
of his great work, there is still much more
to understand about how the endless forms
of nature have arisen.
And in rising to that challenge, it is likely
that we will continue to advance medicine
and come to a better understanding of ourselves
as well.
