Inside every living thing
is the most incredible molecule in the universe.
It's DNA.
It holds the code to make every single one of us,
and all other life on earth.
It's simply wonderful.
And in the last decade, our understanding of that genetic code
has undergone nothing less than a revolution.
We finally finished reading the human genome.
We made a list consisting of every single one
of the three billion units that make up human DNA.
You could say that, after 13 years and billions of dollars,
we had finally read the book of life.
But how does that book of life actually work?
How does this long list in our DNA make us unique?
How does it influence what we look like?
How smart we are?
How long we live, and our ultimate fate?
How does the genome make you, you?
My name is Dr Adam Rutherford.
After years in the lab as a geneticist,
I'm now a journalist who writes about how biology shapes our lives.
I believe that the defining science of the new century was born
almost exactly 10 years ago.
In February 2001, a multibillion dollar project,
that had united thousands of scientists from
around the world, finally published its first results.
We had read our entire genetic code.
Without a doubt, this is the most important, most wondrous map
ever produced by humankind.
Today we are learning the language in which God created life.
Whatever your religious views, that is a bold statement.
I believe that this endeavour DID change science and the world.
But maybe not quite as we thought it would.
So 10 years on, we have to ask ourselves,
just how far have we come?
How much does decoding our genetic make-up tell us about being human?
The human genome is the total of our hereditary information,
the complete list of every single one
of the three billion bases in our DNA.
Those bases are the chemical rungs inside the double helix.
There are four different kinds.
A for Adenine, T for Thymine,
C for Cytosine, and G for Guanine.
In 2001, we finally decoded the entire list for an average human.
And that became the reference
against which others could now be compared.
It ushered in a new era,
where the previously unimaginable was now quite easily possible.
For instance, we can now routinely dig into the very heart of DNA,
pretty well in the comfort of our own homes.
This is Hugh Rienhoff.
Hi, how are you? How's it going? Nice to see you.
His youngest daughter Bea was born in 2003.
At what point did you figure out
there was something not exactly right with your daughter?
The minute she was born,
when Bea was taken out of the womb by caesarean section
and I saw that she had very long feet
and she had contracted fingers
and she also had a port wine stain on her face.
Bea also had long, floppy legs, poor muscle coordination,
poor growth, and her eyes were set unusually far apart.
As a clinical geneticist,
Rienhoff figured his daughter's unique symptoms had a genetic cause.
The doctors couldn't work out what it was,
so, in a makeshift laboratory in their home in San Francisco,
he started to rifle through her genome,
her entire genetic code.
And because of the advances made in the human genome project,
the technology to do this is now commonplace.
This is the DNA kit which you can buy
and in there are the solutions that allow me
to purify all the things away from the DNA.
So, at the end of the day, when I add alcohol, just grain alcohol,
it causes the DNA to come out of solution
and it looks like a white piece of cotton,
which is just floating in a clear liquid.
But the next stages were totally unimaginable, even ten years ago.
He isolated specific stretches of Bea's DNA,
copied them and then set them off to a commercial lab to be read.
So what I've done, Bea Bea, is I've taken that piece of DNA from you,
and I'm looking for instances where your DNA sequence
does not match the sequence sets in the reference genomes.
But, using this new technology, and the dogged persistence of a parent,
Rienhoff located sections of code
that might be the key to Bea's condition.
We found one gene that was clearly not being made properly in Bea.
And one of them is involved in muscle development.
Excellent.
Rienhoff is confident that he may have found a direct link
between his daughter's DNA and her condition.
A, B, C, D, E, F, G...
It's not a cure, but it's without a doubt a huge insight.
There is some comfort in knowing exactly what's wrong,
even if you can't do anything,
even if you don't know what to expect in the future,
it's still nice to know what's wrong.
Just think for a moment what Hugh Rienhoff has achieved.
It's truly impressive.
Working alone, without the support of a university or a hospital,
he personally decoded the DNA that caused his daughter's
unique and unknown medical condition.
This is where genetics has taken us.
But to fully understand how far we have come,
we need to go back 50 years to the dawn of modern genetics.
Back then we had just worked out
that the mechanism of inheritance, and of life, itself lay in DNA.
But what DNA was and how it actually worked was still a mystery.
The long journey to unravelling just how our DNA made us who we are,
and also how it could go wrong,
began one summer morning nearly 50 years ago.
On the 8th of July, 1953,
an envelope arrived at an office in Cambridge University.
In it was a letter from America and it was addressed to Francis Crick,
who just three months earlier, along with his colleague Jim Watson,
had discovered that the DNA molecule was shaped like a twisted ladder,
the famous double helix.
The letter addressed a question
that Crick and Watson had been unable to answer.
How does the DNA code work?
Strangely, the letter wasn't written by a biologist,
but by a physicist called George Gamow, better known
for his theories on radioactivity and the Big Bang.
The letter was riddled with spelling mistakes and errors,
but it did contain an original insight,
something the biologists had not yet considered.
Gamow was looking past what had captivated everyone
about Crick and Watson's discovery, which was its famous twisted shape.
Instead he was looking INSIDE the double helix
at the rungs of the ladder.
Gamow saw information, where others just saw a twisted molecule.
He became fascinated by the four different molecules
that made the rungs of the spiral -
A, T, C and G -
and the patterns that they formed.
He guessed that the way DNA worked
was through a hidden code in the patterns
that these four different chemicals made inside the DNA spiral.
He was suggesting an entire cryptic language hidden in the DNA molecule.
Francis Crick himself said the importance of Gamow's work was
that it was an abstract theory of coding,
and was uncluttered by unnecessary chemical details.
Which is a polite way of saying his biology was terrible
but his insight was piercing.
Within a year, Crick, Watson, Gamow
and a handful of the most brilliant scientists of their generation
had formed a gang to try and decipher the code,
to try and understand
how the letters are rendered into flesh and blood.
Scientists already knew
that chemicals called proteins make living tissue.
All our body's organs - muscles, skin, heart and brain -
are all made of, or by, proteins.
And proteins themselves are made of
smaller building blocks called amino acids.
And, although there are millions of proteins, it only takes combinations
of just 20 amino acids to make every protein.
Think of it like a set of plastic bricks
in which there are only 20 different types of brick.
Each amino acid is represented by a different brick,
and, just like amino acids,
the bricks can be different shapes and sizes.
In order to make a protein, all you have to do
is build a length of different bricks.
But how did the DNA molecule,
with the secret code Gamov suspected was there,
actually make the proteins that make up our body?
Well, it was obvious that the DNA would have to
encode the amino acids, the building blocks of those proteins.
But discovering just how DNA could make particular amino acids
wouldn't come for another eight years,
until 1961 in Washington DC.
Two young and unknown scientists,
Marshall Nirenberg and Heinrich Matthaei,
believed they had figured out something that no-one else had.
How to find out which particular letters in DNA
encode which amino acids that make which proteins.
They laboriously tested combination after combination
of amino acids, proteins and pieces of DNA.
If they got the combination right, they would begin to reveal exactly
how the code in DNA actually worked.
Weeks passed with no end in sight.
Then, late one Saturday night, they had a go at an untried combination.
They put together a stretch of code that effectively spelt out only Ts.
And they discovered that this particular stretch code
made only one particular amino acid - phenylalanine.
It was the Rosetta Stone moment.
Nirenberg and Matthaie had cracked it.
They had shown that a string of Ts in the genetic code
was an instruction for the cell to go and get some phenylalanine,
and string it together into a protein.
And in doing so, they had taken the first step
in deciphering the genetic code.
They had translated the first word in the secret language of our genes.
But what no-one knew
was how DNA could make each of us so very different.
What bits of our DNA made us tall or blue-eyed, asthmatic or diabetic.
Could we isolate bits of DNA that make particular proteins,
and give us particular features and qualities
that we can all easily see.
To begin to understand that, there's another idea I need to explain.
If I told you that this family
have something in common on a genetic level,
you'd probably pretty quickly guess what it is.
They all have a ginger gene.
So what is a gene?
Well, a gene is a unit of inheritance.
Physically it is a small section of your DNA that influences a trait,
like gingerness, or eye colour, or even ear waxiness!
Genes spell out in our DNA the precise nature of a protein.
So this family has a pigmentation gene
that encodes a protein that makes their hair ginger.
The code in that gene is obviously different
from the code of people who are, for example, blond.
And this difference in code is called a variant.
But which bits of our DNA molecule hold the bits of code
that gives us ginger or blonde hair?
Finding these individual genes was an incredible challenge.
Our DNA molecules are both immensely long -
containing over 3 billion letters of code - and they're microscopic.
But what if those bits of code can give you not ginger hair
but a devastating disease?
Then, tracking them down is obviously hugely important.
And it was this that was the next challenge geneticists faced.
In the 1980s in Britain, the search to link diseases to specific genes
was led by Professor Kay Davies, a young ambitious researcher.
She focused on a degenerative disease,
Duchenne Muscular Dystrophy, or DMD, that affected boys.
Duchenne Muscular Dystrophy
is a progressive muscle-wasting disease,
so these boys tend to have difficulty walking and climbing up stairs,
about the age four or five.
They generally go into a wheelchair about the age of 12.
Many of them would be dead by 20.
We knew, for example, that Duchenne Muscular Dystrophy was a muscle gene.
We had no idea what it did. There were all sorts of theories,
but it was impossible because there were thousands of genes
expressed in muscles to decide which was the one that was mutated.
But how could she trace the suspect gene?
The technology of the time meant
she couldn't easily read the genetic code directly,
but she could look at huge stretches of the DNA, called chromosomes.
Chromosomes are lengths of bunched-up DNA,
hundreds of millions of base pairs long.
We humans have 23 pairs of chromosomes -
one of each pair from each of our parents.
With Duchenne Muscular Dystrophy, Professor Davies had a crucial clue
to help her find the abnormal variant.
She knew the disease only affected boys.
This meant she could trace the genetic fault
to one of the chromosomes relating to sex,
in this case the X chromosome.
So her first step was to collect a bank of X chromosomes
from families with a history of the disease.
We had to purify people's X chromosomes,
and then we could amplify the material
and put it in bacteria and grow it and look at it.
And we'd never been able to do that before.
Davies chemically chopped these chromosomes into small chunks.
She could now start to search through the DNA of affected families
for variations in their genetic code.
To do this, she made a family tree for each affected family,
showing the patterns of DMD
inherited through the generations.
Then she compared that tree
with a tree showing patterns of inheritance
from the pieces of X chromosome she had collected.
When one of those trees matched the tree showing the DMD inheritance,
she knew the piece of DNA she was looking at
was very close to the gene responsible
for Duchenne Muscular Dystrophy.
It was just a case, which was a challenge still, of then homing in.
We knew it was in that five million base pairs of DNA
and all we had to do was find the gene.
That painstaking search took several groups over ten years,
but finally the gene responsible for DMD was located.
So the eureka moment was when we found where the gene was.
We knew then we could develop prenatal diagnosis for the disease
which hadn't been available up to that point,
so it was a very exciting time.
It was the first time genetics had made a serious clinical impact.
We could now diagnose a crippling genetic disease in an unborn child.
We did, for example, diagnosis in a family
where a particular mother had had a couple of abortions
because she didn't want an affected male,
and that was quite frequent in DMD families
because it's such a distressing disease,
and then we were able to do a diagnosis.
We could predict whether the foetus was affected, and there were twins.
I remember it very well because the diagnosis came back
that she was going to have two normal twins.
In fact, one of the twins was a boy and other a girl.
So this lady then had an instant family.
These two twins were born, obviously normal,
and the female was not a carrier.
So that was just a wonderful story.
Professor Davies' discovery of the gene variant linked to
Duchenne Muscular Dystrophy was a genuine landmark.
Years of genetic research finally had a real effect on people
and it fired the starting gun for the race for understanding other
brutal genetic diseases, like Cystic Fibrosis and Huntingdon's Disease.
But being diagnosed with a genetic disease isn't necessarily
the easiest thing to take
because understanding its causes is not a cure.
Charles Sabine was a war correspondent for NBC,
working in Afghanistan, Iraq and Kuwait.
EXPLOSION
Then, in 2003, he was told he had the faulty gene
which causes Huntington's disease.
I had never, in all the experiences I had been through,
from being taken, captured, by Mujahedin guerrillas
and had a grenade held to my head...
None of those experiences scared me as much as Huntington's disease
because of the finality, the terrible finality of the disease.
This disease takes away your dignity
and right now it has a complete vacuum of hope.
So that is what makes it so impossible to deal with.
Huntington's is a genetic disease that attacks the brain,
and in all cases leads to mental and physical decline,
and then, without exception, death.
What I experienced was this sudden feeling,
first of all, of lack of control of any aspect of my life
because suddenly it was not me that was determining
the way my life was going to go,
but by 50/50 chance was going to be determined by this gene inside me
that I have no control of.
In the 1980s, using techniques like those developed by Kay Davies,
scientists finally located the gene
responsible for this devastating disease.
We found the Huntingdon's gene on chromosome four.
That revolutionised Huntingdon's because you could tell,
in instances where those individuals wish to know the information,
you could tell them whether they were going to be affected,
but more so you could protect them, if they wanted,
against having affected children in the future.
That was a huge breakthrough.
And although Charles may not be cured,
because of this breakthrough and genetic screening,
Sabine knows his daughter will never have to live through
this horrific disease.
Her existence and the fact that she does not have the gene
for Huntington's disease gives me probably more joy
than anything in the world.
The success of genetic screening made the '80s a crucial time
in our story of the genome.
But all the diseases isolated in the '80s have one thing in common.
They're all caused by just one gene - they are monogenic.
But monogenic diseases are unusual...
..because most diseases, and indeed most human traits,
are not simply linked to a single gene,
but to many, sometimes dozens of genes.
Just take height.
You, quite clearly, are the tallest so stand over this side here.
You, come in this gap here...
'At 5ft 10in, I am rather boringly an inch over the national average.'
But there is a large range around that mean.
So what determines how tall you are?
So if you think about height, it seems quite obvious
that height has an inherited component, and that means genes.
Tall parents tend to give birth to tall children.
But when we began to look comprehensively in the genome
for the genes which affect height, we found dozens of them.
Height is what's known as polygenic.
It's influenced by many genes.
Even though it's one measurement to us,
it's actually a mishmash of loads of components -
bone lengths, muscle growth, nutrition, and so on -
all combining into how tall you are.
And that would make the genetics very murky.
So, to understand polygenic diseases and traits, we'd have to link
each trait with every single possible influencing gene.
That would be a massively difficult thing to do
because, to find each gene,
we'd have to read and know more of our DNA sequence than ever before.
By the late '70s, a new invention was being developed
that would pave the way to unpack the whole genome
and ultimately read every single one of the 3 billion bases in it.
It's time to meet the man who cracked it, who finally figured out
how to read every single letter of any DNA molecule.
He was born in a small Gloucestershire village in 1918
and his name was Fred Sanger.
Sanger was a quiet, unassuming man
who spent the Second World War studying in Cambridge,
and there began his lifelong love for unpicking the molecules of life.
Fred Sanger's first great achievement was to discover
the chemical structure of insulin.
For that, he got a Nobel Prize in 1958.
That's impressive enough, but winning two Nobel Prizes?
Well, that's just showing off.
In 1977 Fred Sanger invented a technique which earned him
his second Nobel Prize, and for which he'll always be remembered.
Officially, it goes by the rather sinister title of
the Chain Termination Method.
But as a tribute, in the business,
it's better known as Sanger Sequencing.
So how does it work?
In us, our genomes are more than three billion letters long.
But for purposes of simplicity, I'm going to sequence a gene
of just six letters.
The problem is, what with DNA being so small,
is that we can't read it directly.
In other words, we can't see what the letters are.
So we need an indirect way of reading the cards,
and this is where Sanger's cunning technique comes into its own.
First, he got the DNA to start copying itself
into shorter fragments.
And here's the cunning bit.
So essentially, Sanger's technique is a chemical trick that allows you
to read just one card in your shortened fragment of DNA,
and that's the end card.
So what good does that do? You may very well ask.
How does knowing the end card in a shortened fragment
help you to read the entire sequence of your original DNA?
Well, the answer is it's a numbers game.
Sanger got the original DNA to replicate itself
millions of times at every possible length.
Now, there was an end letter,
a letter he could read, at every possible position in the sequence.
So you end up with a mix containing fragments of your original DNA
that terminates at every single position along the sequence.
So the final step
is that you read along the rows. A...A.
T, along the line...it's a T.
C, all the way along, it's a C.
T, T, A, A and G.
And bingo! There is your DNA sequence.
In real life, the results of sequencing look something like this.
Fans of forensic detective shows will recognise this.
It's a sequencing gel.
It's in four columns, one for each letter, A, T, C and G.
And by reading from the bottom upwards,
you can see that the actual sequence is...
A...
T...
A...
..C and so on.
When Sanger and his colleagues first came up with this technique
in the 1970s, it was manual and a painstaking slog.
Nowadays, the process has developed and is fully automated.
At a fraction of the cost, now in a matter of weeks,
we can sequence billions of letters of DNA.
But the basic technique is still that of Fred Sanger.
Over the next 30 years, as technology grew in sophistication,
the few thousand bases scientists could sequence grew to millions,
and in the '90s, the awesome potential of Sanger's technique
could finally be realised.
And then we set our sights on what I think is
the most ambitious scientific project of all time -
sequencing the entire human genome.
Upscaling Sanger's sequencing system for the human genome
was a colossal task.
A truly global collaboration that took over a decade...
..thousands of scientists and billions of dollars.
But in February 2001, the first results of all that work and money
hit the news stands.
So in February 2001, I was sitting in the lab doing my PhD
about a mile in that direction at Great Ormond Street Hospital
and the copy of Nature and the copy of Science landed on my desk
announcing that the human genome sequence was completed.
There was a big, grandstanding announcement saying,
"We've done it, we've sequenced the human genome,
"we've read the book of life." Great big phrases like that.
It will revolutionise the diagnosis, prevention and treatment
of most, if not all, human diseases.
In coming years, doctors increasingly will be able to cure
diseases like Alzheimer's, Parkinson's, diabetes and cancer
by attacking their genetic roots.
I have to admit that the President's words
left many of us in the business uneasy.
Just having the code still meant we were a long way from being able
to do anything clinically useful with it.
After all, reading the code is one thing,
but understanding all of it is something else.
In fact, as we started to look at the code and search for
all of the genes that made us, we were in for a big shock.
This is Dr Ewan Birney. At the tender age of 26,
he was one of the lead researchers on the human genome project.
With the human genome nearly decoded,
the best brains in the genetics world were asking,
how many genes does a human have?
Certainly, the consensus feeling, I can remember being told,
that it was somewhere between 50,000 and 100,000 genes
that seemed to make sense to most people.
What were these guys, who are the experts in their fields,
the top geneticists in the world,
where were they getting these numbers from?
There was a kind of textbook, back-of-the-envelope calculation,
where they took the average length of
a human gene on the bits of genomic sequence known at the time.
It was 30,000 base pairs
and they took the whole size of the human genome - 3 billion -
divided one by the other and you get 100,000.
And by a strange quirk, we know exactly
what the best brains in the genetics world actually believed back then,
because Ewan Birney got them to put their money where their mouths were,
he and got them to bet on how many genes they thought we had.
So I went round with a plastic beer thing and the book
and I bumped into people and said, do you want to bet?
If ever you want to see evidence of brilliant scientists
getting it really wrong, this is it.
You're in there first. Ewan Birney, number...
48,251. And the next number down...
It's John Quackenbush, one of the big, big betters
118,259.
Huge. Huge.
Absolutely huge, but kind of in the consensus.
Then, in early 2001, using the new complete Human Genome,
Ewan Birney was able to count the real number of genes in a human.
So when we got to the publication -
I can't actually remember the phrase we used.
I think we said something like we can confidently identify 25,000 genes,
and we believed that maybe up to 35,000 genes in the human genome,
and that up to 35,000 was because
people were frankly not happy about the smaller number.
Within a few years, scientists agreed on a rough figure.
They could only find around 24,000 genes in the human genome.
By far the majority of the code in our DNA seemed to be just useless.
It wasn't genes at all.
What most scientists in fact called "junk DNA".
Imagine that this building is your genome.
Three billions letter of DNA code.
Now, this is the amount that makes up genes.
So according to the classical genetics model, a tiny proportion,
just two or three per cent, make the proteins that make you.
And the rest is darkness.
This was a real shock.
98% of our genome is not genes and doesn't code for proteins.
There's an assumption in a lot of genomics
that a lot of the DNA is just junk, it's garbage, it's rubbish.
And I have to say, at first glance, that seems reasonable
because a lot of it just doesn't produce anything.
There are only about 24,000 genes
that go to make a mammal, a human being, say,
which is about the same number of bits you need
to make a double-decker bus. It's not very many.
I'd like to think I'm more complicated than a bus
and that is a surprise.
And what it tells you is something very important.
It's that we don't understand genetics at all.
We're in a situation that we've got a lot of boxes labelled
screws, washers, bulbs, and we don't even know
how to put them together,
let alone how to start the bus and drive it through the streets.
But because we were looking for genes that cause disease,
this low number had an unexpected upside.
It meant fewer genes to study.
Now this was crucial,
because at the time sequencing DNA was still colossally expensive.
So by narrowing down on just a small proportion of the genome,
it meant that large-scale studies were financially realistic.
And then scientists found something intriguing.
As we started to compare people's whole genomes,
we realised that everyone's DNA is almost identical.
If you compare one human genome with another
they would be identical at most positions,
they differ at about one position in a thousand on average.
Yet we know we are hugely different.
We are all unique.
So the challenge now was to find those relatively few
individual differences in genes, genetic variants,
that account for differences in people.
And more specifically to find the variants that cause disease.
So in 2005, the Wellcome Trust here in the UK
united many labs by launching a huge survey
to read half a million DNA letters,
within known genes, for not just one,
but thousands of ill and healthy people.
The hope was that half a million DNA letters would be sufficient
to identify the most significant common variants that link to disease.
Professor Peter Donnelly was part of the team
who actually crunched the massive amounts of data.
Some 10 billion pieces of genetic information were analysed,
harvested from over 10,000 people, at a cost of over £9 million.
The first experiment looked at seven illnesses
that, like height, were linked to many genes.
So here's an example from the large study we did initially
and the paper we published.
So this shows a row for each disease, and along each row we plot a measure
of the difference for each of the 500,000 variants we measured
between the sick people and healthy people.
The graph shows a summary of those results.
The half a million DNA letters are run from left to right,
divided up from chromosomes 1 to 22 and the X chromosome.
And when there is a noticeable difference
in the letters between sick and healthy people,
it shows up as a green peak.
You're saying that the green ones
are where a disease is associated with the genome?
Yes, the green ones are the ones where there's a genetic variant
which is considerably more common in the sick people
than the healthy people in a way which is associated with disease.
It was a huge breakthrough.
Now, for the first time, it looked like we could find diseases
that were caused by errors in more than just one gene in our DNA.
I still remember the first time we sat down and had a serious look.
It was an extraordinary moment, knowing it would deliver
and we'd get some insights into the genetics of those common diseases.
It was really exciting.
That excitement was felt well beyond the scientific community.
Good evening. British scientists unveiled a new era in medicine today,
when they announced they'd finally unravelled a genetic link
to seven major diseases,
raising the prospect of predicting a child's medical future at birth.
Well, it was an awesome breakthrough. But looking back,
perhaps the media machine got a little ahead of itself,
because what this genome survey actually says about the health
of individuals, of real people, is in fact rather limited.
Because what we have to remember
is that even though our genes may indicate that we are susceptible
to disease, it doesn't mean we will actually get that disease.
Mark Hurst is a senior lecturer in human genetics.
He has a strong family history of diabetes.
This is my mum and dad.
They got married just after the war.
I was aware that my dad had diabetes. He tests his sugar levels
and he was on various drugs to try and control it.
And it became obvious in the late '70s and '80s
that there was a genetic component
and so, as I was studying human genetics,
I sort of followed it with some interest.
The heritability of Type 2 diabetes
if you've got close relatives is very high.
Over the last 20 years, two of my sisters and one of my brothers
have all developed Type 2 diabetes,
so the genetic lottery says
I may have some of the genes, I might not, I don't know.
But Dr Hurst knows that even though he probably has variants in his DNA
which mean he is likely to suffer from diabetes,
it's far from certain he will actually get the disease
because other factors are important too.
There's a great...almost belief that you're a slave to your genes
and I think for some of the monogenetic disorders,
that probably is very much the case,
but for most complex diseases, multigenic diseases,
a large amount of environmental component,
so you can control large amounts of your environment
through things like exercise and diet.
Recent studies suggest that, simplistically,
diabetes is 70% genetic and 30% environmental.
There's this environmental component which was related to
your body weight, your waist size, your diet,
and I decided I can't control my genes, but I can at least
do something about the environment, so I started to run.
Hurst runs three miles a day.
This, he believes, has kept his diabetes at bay.
I suspect I would have been quite a lot heavier...
..and I think I would have probably developed
the signs of early diabetes by now.
Hurst's story reminds us that in most cases our traits and diseases
spring from our environment as well as our genetic code.
So now we have to ask ourselves a crucial question.
How much of a disease is to do with our genes at all?
It turns out we can make a guess at that
from a more traditional kind of genetic experiment.
The next questionnaire for you is a questionnaire about you.
This is Dr Claire Howarth.
And her unusual research tool?
Twins.
So why are twins so useful for any sort of genetic study?
It's a fantastic natural experiment, twins.
They provide the opportunity to investigate the roles
of nature - genes - and nurture - the environment,
so if a trait has a genetic influence
then you'd expect identical twins who share more genes to be more similar
than non identical twins, who share less of their genes.
Identical twins grow from one egg and one sperm,
so they are genetically the same.
There are quite a lot of similarities between us.
We look quite similar. We talk quite similar.
But I can't really say.
Same likes, dislikes almost, kind of mainly. Yeah.
What do you like that's the same?
We like the same music. Yep, music.
Like the same food. Sport.
You're about to go to university, right?
In two years. Two years, yeah.
You really do finish each other's sentences!
But non-identical twins are from different eggs and sperm,
and like normal siblings share only about 50% of their genes.
I'm very into my sport, like watching,
whereas Maddy's much more into playing.
I'm really, really musical. Caroline can't carry a tune in a bucket.
She doesn't play any instruments.
I love art and design more.
Studies like Dr Haworth's compare traits like height
between thousands of identical and non-identical twins.
We can break up the variance in a trait such as height, say,
and we can say how much that is due to genetic differences between people
and how much is due to environmental experiences they've had.
173.
These studies show that many common traits
are inherited much more than we thought.
Reading disability and reading ability are both highly heritable.
Somewhere between 50% and 70% of the variance
is due to DNA sequence that people have inherited from their parents.
And when Howarth started to test
for traits that genome surveys had looked at,
she got unexpected results.
Many traits were more heritable
than the genetic studies had previously revealed.
For height, twin studies say it's around 80% inherited
versus 5% that was found in the genome scan.
For Type 2 diabetes, it's 70% versus 6%.
There was a large proportion of the DNA's influence
simply not being seen.
Some have called this "the missing heritability".
We know there is missing heritability because twin studies have told us
that a lot of traits are very highly heritable,
so for example height is about 80% heritable,
so when we do a molecular genetics study of height,
what we find is the DNA variance that we've identified only explain
about 5% of the variance, so we have this mismatch
between 80% heritability and only 5% that's been identified in the genome.
This was an extraordinary result.
Where was this missing heritability coming from?
Could it be that something in the mysterious 98% of the genome
that doesn't seem to do anything,
is actually far more important than we thought?
And this seemed possible, when we compared the code of our genome
with the code of other animals,
looking for parts preserved over millions of years of evolution.
So if you look between human and chimpanzee, for example,
most of our DNA is the same.
Between human and mouse, a fair bit is still pretty much the same.
But by the time you go to chicken, it's very clear that,
if there's a piece of DNA that's the same between human and chicken,
then it's important for humans and it's important for chickens
and there's no real way of getting round that.
And there's quite a lot of this stuff and it's not all near genes.
So there are these big chunks of the genome
that don't seem to have any protein-coding genes,
yet is still conserved between human and chicken and human and mouse.
If these pieces of DNA were cropping up in many species
they were clearly important for life.
But many of them weren't in the genes.
They were in the so-called junk DNA, and that meant that this wasteland
was far more important than we had previously imagined.
We'd assumed genes would account for
the vast majority of our inheritance.
But the new message was this.
A good place to be looking for the missing heritability
was in the 98% of the genome that isn't made up of genes.
And now we have the technology to start hunting.
So in this room we've got six or seven
of the newest generation of machines. Each one of these runs
for about a week, and in that week,
it'll sequence well over 20 whole human genomes.
And that's about 300 billion bases.
Professor Mark McCarthy
at the Wellcome Trust Centre for Human Genetics
is harnessing this new technology
to sequence the entire genome of hundreds of diabetes sufferers.
And the hope is that this will reveal influential variants
that had slipped through the net of earlier, less accurate surveys.
So the big advance in the last year or two has been the ability
to sequence the whole genome with much higher accuracy
and much lower cost than has been possible before.
If you remember, the original genome sequence took many years
and many billions of dollars to complete.
It involved many scientists.
It's now possible to do experiments on that scale
in a trivial amount of time for a few thousand dollars.
It's now become possible to consider re-sequencing the whole genome
of many thousands of individuals to understand the differences
between for example those that have diabetes and those that don't.
His ambitious project intends to sequence
the whole genome of 3,000 people,
comparing every single one of the 3 billion bases
in diabetes sufferers and healthy people.
They will throw up new genes and regions
that we hadn't hitherto implicated in disease risk
and that will give us new ways of understanding
the biology of the disease.
And we may have much better prospects for using genetics
as a tool for predicting risk of disease and response to treatment
than is currently possible
with the common variants that we have identified so far.
Already McCarthy has begun to find many new variants
that are associated with diabetes
in the part of the genome that aren't made of genes -
the increasingly misnamed junk DNA.
And not just a few, but many.
It seems that, for common variants at least,
most of the action lies in that non-coding DNA.
That non-coding DNA, the 98% of our genome,
was turning out to be not just important, but critical.
I think McCarthy's technique is the way forward.
If we want to really understand how our genetics makes us
utterly unique, we need to sequence many more human genomes.
Maybe everybody's.
In 2003, Ewan Birney started a series of experiments
to find out exactly what this junk DNA actually did.
The project was called ENCODE, the Encyclopedia of DNA Elements.
Using the very best technology of the time,
hundreds of scientists from around the world
scoured sections of the junk DNA.
There's a really obvious question which I'm dying to ask,
which is what is it? What is it doing?
There isn't an easy answer to what these things do,
but our best understanding was the prediction going in -
and it's still what we think now -
is that a lot of this is switching where genes switch on and off.
The idea that genes switch on and off grew from my own field,
the study of the development of embryos.
As an organism grows, its cells decide to be organs,
brains, limbs and livers, and this means the genes that control them
have themselves to be controlled.
And the location of this system of gene regulation?
Well, not within the genes themselves,
but in the rest of the DNA.
There's this incredible choreography of molecules in each cell.
And so this dance of how all these different molecules inside the cell
work out is working on these parts of the genome,
many of them are not close to even protein-coding genes.
They're spread out in the big dark matter of the genome.
But the ENCODE project revealed yet another layer of complexity.
Not only was the dark matter of DNA actually very important,
but it was also becoming clear that the physical structure,
the shape of DNA, affected us too.
This is how we think about DNA,
the classic Crick and Watson double helix.
You can see in the middle, in the core, are the base pairs,
and outside, the twin backbones that spiral up
to give it that iconic shape.
But this is just a portrait
and portraits are not the same as people.
This is a much better representation of DNA in action.
The double helix here is in purple
but it's wrapped around a complex of proteins called histones
and they again wind up on each other
and the whole thing is covered in another protein.
It may look like chemical chaos and certainly
it's a far cry from the classic double helix model we're used to.
It's a complex world buzzing with activity.
Chemicals squeezing past other chemicals,
proteins constantly moving,
remodelling the shape of the DNA on the fly.
And this model shows only a tiny stretch of DNA,
about 150 bases long.
There are 100 million more of these in the full genome.
It should come as no surprise
but this is seriously sophisticated stuff.
The last 50 years has been a revolution
in our understanding of our genome.
From breaking the code in our DNA
to learning how mistakes in that code
lead to tragedies like Huntingdon's disease,
to glimpsing how our genome relates to complex traits
and diseases like diabetes,
and seeing how its effect can be mitigated
by changing our environment.
But it's only in the last ten years
since the publication of the full human genome sequence
that I believe we are seeing the biggest revelations.
Because the real breakthrough has been understanding
just how little we know about the genome.
That is true enlightenment.
There isn't going to be a moment where we can stand up and say,
that's it, we understand the human genome.
It is...
as complex as we are.
And we're pretty complex.
So I don't think it will be reached within my lifetime.
But I think we'll know so much more in five years than we do now.
And so much more in ten years than we do now,
that I think I'll be surprised.
I believe there never were going to be any easy answers.
Human beings are amazing, complex creatures.
Ten years on from completing the Human Genome Project,
we shouldn't be disappointed
that the results were different from what we expected,
nor surprised that we didn't come up with any definitive answers.
That's how science works.
It's a journey, a continuous exploration
of how things work and who we are.
And now, with the human genome complete,
we can finally see the road ahead.
To find out more about what makes your genome,
the Open University has created a set of free fridge magnets,
which you can order online at...
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