Unlocking the Code The Gene Code


Unlocking the Code

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Inside every living thing

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is the most incredible molecule in the universe.

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It's DNA.

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It holds the code to make every single one of us,

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and all other life on earth.

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It's simply wonderful.

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And in the last decade, our understanding of that genetic code

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has undergone nothing less than a revolution.

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We finally finished reading the human genome.

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We made a list consisting of every single one

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of the three billion units that make up human DNA.

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You could say that, after 13 years and billions of dollars,

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we had finally read the book of life.

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But how does that book of life actually work?

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How does this long list in our DNA make us unique?

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How does it influence what we look like?

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How smart we are?

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How long we live, and our ultimate fate?

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How does the genome make you, you?

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My name is Dr Adam Rutherford.

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After years in the lab as a geneticist,

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I'm now a journalist who writes about how biology shapes our lives.

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I believe that the defining science of the new century was born

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almost exactly ten years ago.

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In February 2001, a multi-billion dollar project,

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that had united thousands of scientists

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from across the world, finally published its first results.

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We had read our entire genetic code.

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Without a doubt, this is the most important, most wondrous map

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ever produced by humankind.

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Today, we are learning the language in which God created life.

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Whatever your religious views, that is a bold statement.

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I believe that this endeavour DID change science - and the world.

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But maybe not quite as we thought it would.

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So ten years on, we have to ask ourselves,

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just how far have we come?

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How much does decoding our genetic make-up tell us about being human?

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The human genome is the total of our hereditary information,

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the complete list of every single one

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of the three billion bases in our DNA.

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Those bases are the chemical rungs inside the double helix.

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There are four different kinds.

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A for Adenine, T for Thymine,

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C for Cytosine, and G for Guanine.

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In 2001, we finally decoded the entire list for an average human.

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And that became the reference

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against which others could now be compared.

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It ushered in a new era,

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where the previously unimaginable was now quite easily possible.

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For instance, we can now routinely dig into the very heart of DNA,

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pretty well in the comfort of our own homes.

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This is Hugh Rienhoff.

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-Hi, how are you?

-How's it going? Nice to see you.

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His youngest daughter Bea was born in 2003.

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At what point did you figure out

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there was something not exactly right with your daughter?

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The minute she was born,

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when Bea was taken out of the womb by caesarean section

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and I saw that she had very long feet

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and she had contracted fingers

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and she also had a port wine stain on her face.

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Bea also had long, floppy legs, poor muscle co-ordination,

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poor growth, and her eyes were set unusually far apart.

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As a clinical geneticist,

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Rienhoff figured his daughter's unique symptoms had a genetic cause.

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The doctors couldn't work out what it was,

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so, in a makeshift laboratory in their home in San Francisco,

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he started to rifle through her genome,

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her entire genetic code.

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And because of the advances made in the human genome project,

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the technology to do this is now commonplace.

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This is the DNA kit which you can buy

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and in there are the solutions that allow me

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to purify all the things away from the DNA.

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So, at the end of the day, when I add alcohol, just grain alcohol,

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it causes the DNA to come out of solution

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and it looks like a white piece of cotton,

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which is just floating in a clear liquid.

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But the next stages were totally unimaginable, even ten years ago.

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He isolated specific stretches of Bea's DNA,

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copied them and then set them off to a commercial lab to be read.

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So what I've done, Bea Bea, is I've taken that piece of DNA from you,

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and I'm looking for instances where your DNA sequence

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does not match the sequence sets in the reference genomes.

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But, using this new technology, and the dogged persistence of a parent,

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Rienhoff located sections of code

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that might be the key to Bea's condition.

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We found one gene that was clearly not being made properly in Bea.

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And one of them is involved in muscle development.

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Excellent.

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Rienhoff is confident that he may have found a direct link

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between his daughter's DNA and her condition.

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# A, B, C, D, E, F, G... #

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It's not a cure, but it's, without a doubt, a huge insight.

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There is some comfort in knowing exactly what's wrong,

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even if you can't do anything,

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even if you don't know what to expect in the future,

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it's still nice to know what's wrong.

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Just think for a moment what Hugh Rienhoff has achieved.

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It's truly impressive.

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Working alone, without the support of a university or a hospital,

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he personally decoded the DNA that caused his daughter's

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unique and unknown medical condition.

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This is where genetics has taken us.

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But to fully understand how far we have come,

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we need to go back 50 years to the dawn of modern genetics.

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Back then we had just worked out

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that the mechanism of inheritance, and of life itself, lay in DNA.

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But what DNA was and how it actually worked was still a mystery.

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The long journey to unravelling just how our DNA made us who we are,

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and also how it could go wrong,

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began one summer morning nearly 50 years ago.

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On the 8th of July, 1953,

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an envelope arrived at an office in Cambridge University.

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In it was a letter from America and it was addressed to Francis Crick,

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who just three months earlier, along with his colleague Jim Watson,

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had discovered that the DNA molecule was shaped like a twisted ladder,

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the famous double helix.

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The letter addressed a question

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that Crick and Watson had been unable to answer.

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How does the DNA code work?

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Strangely, the letter wasn't written by a biologist,

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but by a physicist, called George Gamow, better known

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for his theories on radioactivity and the Big Bang.

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The letter was riddled with spelling mistakes and errors,

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but it did contain an original insight,

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something that the biologists had not yet considered.

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Gamow was looking past what had captivated everyone

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about Crick and Watson's discovery, which was its famous twisted shape.

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Instead, he was looking INSIDE the double helix

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at the rungs of the ladder.

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Gamow saw information, where others just saw a twisted molecule.

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He became fascinated by the four different molecules

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that made the rungs of the spiral -

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A, T, C and G -

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and the patterns that they formed.

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He guessed that the way DNA worked

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was through a hidden code in the patterns

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that these four different chemicals made inside the DNA spiral.

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He was suggesting an entire cryptic language hidden in the DNA molecule.

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Francis Crick himself said the importance of Gamow's work

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was that it was an abstract theory of coding,

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and was uncluttered by unnecessary chemical details.

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Which is a polite way of saying his biology was terrible,

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but his insight was piercing.

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Within a year, Crick, Watson, Gamow

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and a handful of the most brilliant scientists of their generation

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had formed a gang to try and decipher the code,

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to try and understand

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how the letters are rendered into flesh and blood.

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Scientists already knew

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that chemicals called proteins make living tissue.

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All our body's organs - muscles, skin, heart and brain -

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are all made of, or by, proteins.

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And proteins themselves are made of

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smaller building blocks called amino acids.

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And, although there are millions of proteins, it only takes combinations

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of just 20 amino acids to make every protein.

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Think of it like a set of plastic bricks

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in which there are only 20 different types of brick.

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Each amino acid is represented by a different brick,

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and, just like amino acids,

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the bricks can be different shapes and sizes.

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In order to make a protein, all you have to do

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is build a length of different bricks.

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But how did the DNA molecule,

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with the secret code Gamov suspected was there,

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actually make the proteins that make up our body?

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Well, it was obvious that the DNA would have to

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encode the amino acids, the building blocks of those proteins.

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But discovering just how DNA could make particular amino acids

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wouldn't come for another eight years,

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until 1961, in Washington DC.

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Two young and unknown scientists,

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Marshall Nirenberg and Heinrich Matthaei,

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believed they had figured out something that no-one else had -

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how to find out which particular letters in DNA

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encode which amino acids that make which proteins.

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They laboriously tested combination after combination

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of amino acids, proteins and pieces of DNA.

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If they got the combination right, they would begin to reveal exactly

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how the code in DNA actually worked.

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Weeks passed with no end in sight.

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Then, late one Saturday night, they had a go at an untried combination.

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They put together a stretch of code that effectively spelt out only Ts.

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And they discovered that this particular stretch of code

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made only one particular amino acid, phenylalanine.

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It was the Rosetta Stone moment.

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Nirenberg and Matthaie had cracked it.

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They had shown that a string of Ts in the genetic code

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was an instruction for the cell to go and get some phenylalanine,

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and string it together into a protein.

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And in doing so, they had taken the first step

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in deciphering the genetic code.

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They had translated the first word in the secret language of our genes.

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But what no-one knew

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was how DNA could make each of us so very different.

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What bits of our DNA made us tall or blue-eyed, asthmatic or diabetic.

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Could we isolate bits of DNA that make particular proteins,

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and give us particular features and qualities

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that we can all easily see.

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To begin to understand that, there's another idea I need to explain.

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If I told you that this family

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have something in common on a genetic level,

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you'd probably pretty quickly guess what it is.

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They all have a ginger gene.

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So what is a gene?

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Well, a gene is a unit of inheritance.

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Physically, it is a small section of your DNA that influences a trait,

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like gingerness, or eye colour, or even ear waxiness!

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Genes spell out in our DNA the precise nature of a protein.

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So this family has a pigmentation gene

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that encodes a protein that makes their hair ginger.

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The code in that gene is obviously different

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from the code of people who are, for example, blonde.

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And this difference in code is called a variant.

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But which bits of our DNA molecule hold the bits of code

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that gives us ginger or blonde hair?

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Finding these individual genes was an incredible challenge.

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Our DNA molecules are both immensely long -

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containing over three billion letters of code - and they're microscopic.

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But what if those bits of code can give you not ginger hair

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but a devastating disease?

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Then, tracking them down is obviously hugely important.

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And it was this that was the next challenge geneticists faced.

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In the 1980s in Britain, the search to link diseases to specific genes

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was led by Professor Kay Davies, a young ambitious researcher.

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She focused on a degenerative disease,

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Duchenne Muscular Dystrophy, or DMD, that affected boys.

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Duchenne Muscular Dystrophy

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is a progressive muscle-wasting disease,

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so these boys tend to have difficulty walking and climbing up stairs,

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about the age four or five.

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They generally go into a wheelchair about the age of 12.

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Many of them would be dead by 20.

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We knew, for example, that Duchenne Muscular Dystrophy was a muscle gene.

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We had no idea what it did. There were all sorts of theories,

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but it was impossible because there are thousands of genes

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expressed in muscles to decide which was the one that was mutated.

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But how could she trace the suspect gene?

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The technology of the time meant

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she couldn't easily read the genetic code directly,

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but she could look at huge stretches of the DNA, called chromosomes.

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Chromosomes are lengths of bunched-up DNA,

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hundreds of millions of base pairs long.

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We humans have 23 pairs of chromosomes -

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one of each pair from each of our parents.

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With Duchenne Muscular Dystrophy, Professor Davies had a crucial clue

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to help her find the abnormal variant.

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She knew the disease only affected boys.

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This meant she could trace the genetic fault

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to one of the chromosomes relating to sex,

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in this case, the X chromosome.

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So her first step was to collect a bank of X chromosomes

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from families with a history of the disease.

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We had to purify people's X chromosomes,

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and then we could amplify the material

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and put it in bacteria and grow it and look at it.

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And we'd never been able to do that before.

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Davies chemically chopped these chromosomes into small chunks.

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She could now start to search through the DNA of affected families

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for variations in their genetic code.

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To do this, she made a family tree for each affected family,

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showing the patterns of DMD

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inherited through the generations.

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Then she compared that tree

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with a tree showing patterns of inheritance

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from the pieces of X chromosome she had collected.

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When one of those trees matched the tree showing the DMD inheritance,

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she knew the piece of DNA she was looking at

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was very close to the gene responsible

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for Duchenne Muscular Dystrophy.

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It was just a case, which was a challenge still, of then homing in.

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We knew it was in that five million base pairs of DNA

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and all we had to do was find the gene.

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That painstaking search took several groups over ten years,

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but finally the gene responsible for DMD was located.

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So the eureka moment was when we found where the gene was.

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We knew then we could develop prenatal diagnosis for the disease

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which hadn't been available up to that point,

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so it was a very exciting time.

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It was the first time genetics had made a serious clinical impact.

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We could now diagnose a crippling genetic disease in an unborn child.

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We did, for example, diagnosis in a family

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where a particular mother had had a couple of abortions

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because she didn't want an affected male,

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and that was quite frequent in DMD families

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because it's such a distressing disease,

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and then we were able to do a diagnosis.

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We could predict whether the foetus was affected, and there were twins.

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I remember it very well because the diagnosis came back

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that she was going to have two normal twins.

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In fact, one of the twins was a boy and other a girl.

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So this lady then had an instant family.

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These two twins were born, obviously normal,

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and the female was not a carrier.

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So that was just a wonderful story.

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Professor Davies' discovery of the gene variant linked to

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Duchenne Muscular Dystrophy was a genuine landmark.

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Years of genetic research finally had a real effect on people

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and it fired the starting gun for the race to understand other

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brutal genetic diseases, like Cystic Fibrosis and Huntingdon's Disease.

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But being diagnosed with a genetic disease isn't necessarily

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the easiest thing to take,

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because understanding its causes is not a cure.

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Charles Sabine was a war correspondent for NBC,

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working in Afghanistan, Iraq and Kuwait.

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EXPLOSION

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Then, in 2003, he was told he had the faulty gene

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which causes Huntington's disease.

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I had never, in all the experiences that I had been through,

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from being taken, captured, by Mujahedin guerrillas

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and had a grenade held to my head...

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None of those experiences scared me as much as Huntington's disease,

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because of the finality, the terrible finality of the disease.

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This disease takes away your dignity

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and, right now, it has a complete vacuum of hope.

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So that is what makes it so impossible to deal with.

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Huntington's is a genetic disease that attacks the brain,

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and, in all cases, leads to mental and physical decline,

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and, then, without exception, death.

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What I experienced was this sudden feeling,

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first of all, of lack of control of any aspect of my life

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because suddenly it was not me that was determining

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the way my life was going to go,

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but by 50/50 chance was going to be determined by this gene inside me

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that I had no control of.

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In the 1980s, using techniques like those developed by Kay Davies,

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scientists finally located the gene

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responsible for this devastating disease.

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We found the Huntingdon's gene on chromosome four.

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That revolutionised Huntingdon's, because you could tell,

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in instances where those individuals wish to know the information,

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you could tell them whether they were going to be affected,

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but more so, you could protect them, if they wanted,

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against having affected children in the future.

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That was a huge breakthrough.

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And although Charles may not be cured,

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because of this breakthrough and genetic screening,

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Sabine knows his daughter will never have to live through

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this horrific disease.

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Her existence and the fact that she does not have the gene

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for Huntington's disease gives me probably more joy

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than anything in the world.

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The success of genetic screening made the '80s a crucial time

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in our story of the genome.

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But all the diseases isolated in the '80s have one thing in common.

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They're all caused by just one gene - they are monogenic.

0:23:170:23:21

But monogenic diseases are unusual...

0:23:320:23:35

..because most diseases, and indeed most human traits,

0:23:370:23:40

are not simply linked to a single gene,

0:23:400:23:44

but to many, sometimes dozens of genes.

0:23:440:23:49

Just take height.

0:23:520:23:53

You, quite clearly, are the tallest, so stand over this side here.

0:23:580:24:03

You, come in this gap here...

0:24:030:24:05

'At 5ft 10in, I am rather boringly an inch over the national average.'

0:24:050:24:11

But there is a large range around that mean.

0:24:110:24:13

So what determines how tall you are?

0:24:160:24:18

So if you think about height, it seems quite obvious

0:24:180:24:22

that height has an inherited component, and that means genes.

0:24:220:24:26

Tall parents tend to give birth to tall children.

0:24:260:24:30

But when we began to look comprehensively in the genome

0:24:300:24:34

for the genes which affect height, we found dozens of them.

0:24:340:24:38

Height is what's known as polygenic.

0:24:380:24:41

It's influenced by many genes.

0:24:410:24:44

Even though it's one measurement to us,

0:24:490:24:53

it's actually a mishmash of loads of components -

0:24:530:24:55

bone lengths, muscle growth, nutrition, and so on -

0:24:550:24:59

all combining into how tall you are.

0:24:590:25:02

And that would make the genetics very murky.

0:25:020:25:05

So, to understand polygenic diseases and traits, we'd have to link

0:25:080:25:13

each trait with every single possible influencing gene.

0:25:130:25:17

That would be a massively difficult thing to do

0:25:170:25:20

because, to find each gene,

0:25:200:25:21

we'd have to read and know more of our DNA sequence than ever before.

0:25:210:25:26

By the late '70s, a new invention was being developed

0:25:270:25:31

that would pave the way to unpack the whole genome

0:25:310:25:34

and ultimately read every single one of the three billion bases in it.

0:25:340:25:39

It's time to meet the man who cracked it, who finally figured out

0:25:400:25:44

how to read every single letter of any DNA molecule.

0:25:440:25:48

He was born in a small Gloucestershire village in 1918

0:25:480:25:52

and his name was Fred Sanger.

0:25:520:25:54

Sanger was a quiet, unassuming man

0:25:570:26:00

who spent the Second World War studying in Cambridge,

0:26:000:26:03

and there began his lifelong love for unpicking the molecules of life.

0:26:030:26:08

Fred Sanger's first great achievement was to discover

0:26:110:26:14

the chemical structure of insulin.

0:26:140:26:17

For that, he got a Nobel Prize in 1958.

0:26:170:26:21

That's impressive enough, but winning TWO Nobel Prizes?

0:26:230:26:27

Well, that's just showing off.

0:26:270:26:29

In 1977, Fred Sanger invented a technique which earned him

0:26:290:26:33

his second Nobel Prize, and for which he'll always be remembered.

0:26:330:26:37

Officially, it goes by the rather sinister title

0:26:370:26:40

of the Chain Termination Method.

0:26:400:26:42

But as a tribute, in the business,

0:26:420:26:44

it's better known as Sanger Sequencing.

0:26:440:26:47

So how does it work?

0:26:490:26:52

In us, our genomes are more than three billion letters long.

0:26:520:26:56

But for purposes of simplicity, I'm going to sequence a gene

0:26:560:27:00

of just six letters.

0:27:000:27:02

The problem is, what with DNA being so small,

0:27:040:27:07

is that we can't read it directly.

0:27:070:27:09

In other words, we can't see what the letters are.

0:27:090:27:13

So we need an indirect way of reading the cards,

0:27:130:27:15

and this is where Sanger's cunning technique comes into its own.

0:27:150:27:20

First, he got the DNA to start copying itself

0:27:200:27:24

into shorter fragments.

0:27:240:27:26

And here's the cunning bit.

0:27:280:27:30

So essentially, Sanger's technique is a chemical trick that allows you

0:27:300:27:34

to read just one card in your shortened fragment of DNA,

0:27:340:27:39

and that's the end card.

0:27:390:27:41

So what good does that do, you may very well ask?

0:27:430:27:46

How does knowing the end card in a shortened fragment

0:27:460:27:49

help you read the entire sequence of your original DNA?

0:27:490:27:52

Well, the answer is it's a numbers game.

0:27:520:27:54

Sanger got the original DNA to replicate itself

0:27:560:28:01

millions of times at every possible length.

0:28:010:28:05

Now, there was an end letter,

0:28:050:28:08

a letter he could read, at every possible position in the sequence.

0:28:080:28:14

So you end up with a mix containing fragments of your original DNA

0:28:140:28:19

that terminates at every single position along the sequence.

0:28:190:28:24

So the final step

0:28:240:28:25

is that you read along the rows. A...A.

0:28:250:28:30

T, along the line...it's a T.

0:28:300:28:33

C, all the way along, it's a C.

0:28:330:28:37

T, T, A, A and G.

0:28:370:28:44

And bingo! There is your DNA sequence.

0:28:440:28:48

In real life, the results of sequencing look something like this.

0:28:490:28:53

Fans of forensic detective shows will recognise this.

0:28:530:28:58

It's a sequencing gel.

0:28:580:28:59

It's in four columns, one for each letter, A, T, C and G.

0:28:590:29:06

And by reading from the bottom upwards,

0:29:060:29:08

you can see that the actual sequence is...

0:29:080:29:11

A...

0:29:110:29:12

A...

0:29:140:29:15

T...

0:29:160:29:18

A...

0:29:190:29:20

..C, and so on.

0:29:210:29:23

When Sanger and his colleagues first came up with this technique

0:29:230:29:28

in the 1970s, it was manual and a painstaking slog.

0:29:280:29:31

Nowadays, the process has developed and is fully automated.

0:29:310:29:35

At a fraction of the cost, now in a matter of weeks,

0:29:350:29:38

we can sequence billions of letters of DNA.

0:29:380:29:41

But the basic technique is still that of Fred Sanger.

0:29:410:29:45

Over the next 30 years, as technology grew in sophistication,

0:29:470:29:50

the few thousand bases scientists could sequence grew to millions,

0:29:500:29:55

and in the '90s, the awesome potential of Sanger's technique

0:29:550:29:59

could finally be realised.

0:29:590:30:01

And then, we set our sights on what I think is

0:30:010:30:04

the most ambitious scientific project of all time -

0:30:040:30:08

sequencing the entire human genome.

0:30:080:30:11

Upscaling Sanger's sequencing system for the human genome

0:30:150:30:18

was a colossal task.

0:30:180:30:21

A truly global collaboration that took over a decade...

0:30:220:30:27

..thousands of scientists and billions of dollars.

0:30:280:30:32

But in February 2001, the first results of all that work and money

0:30:340:30:39

hit the news stands.

0:30:390:30:41

So in February 2001, I was sitting in the lab doing my PhD,

0:30:430:30:47

about a mile in that direction, at Great Ormond Street Hospital,

0:30:470:30:51

and the copy of Nature and the copy of Science landed on my desk,

0:30:510:30:55

announcing that the human genome sequence was completed.

0:30:550:30:59

There was a big, grandstanding announcement saying,

0:30:590:31:02

"We've done it, we've sequenced the human genome,

0:31:020:31:05

"we've read the book of life." Great big phrases like that.

0:31:050:31:08

It will revolutionise the diagnosis, prevention and treatment

0:31:080:31:12

of most, if not all, human diseases.

0:31:120:31:15

In coming years, doctors increasingly will be able to cure

0:31:150:31:18

diseases like Alzheimer's, Parkinson's, diabetes and cancer,

0:31:180:31:22

by attacking their genetic roots.

0:31:220:31:24

I have to admit that the President's words

0:31:270:31:30

left many of us in the business uneasy.

0:31:300:31:32

Just having the code still meant we were a long way from being able

0:31:340:31:37

to do anything clinically useful with it.

0:31:370:31:40

After all, reading the code is one thing,

0:31:420:31:45

but understanding all of it is something else.

0:31:450:31:48

In fact, as we started to look at the code and search for

0:31:480:31:52

all of the genes that made us, we were in for a big shock.

0:31:520:31:56

This is Dr Ewan Birney. At the tender age of 26,

0:32:030:32:07

he was one of the lead researchers on the human genome project.

0:32:070:32:12

With the human genome nearly decoded,

0:32:140:32:17

the best brains in the genetics world were asking,

0:32:170:32:20

how many genes does a human have?

0:32:200:32:22

Certainly, the consensus feeling, I can remember being told,

0:32:250:32:30

that it was somewhere between 50,000 and 100,000 genes

0:32:300:32:34

that seemed to make sense to most people.

0:32:340:32:36

What were these guys, who are the experts in their fields,

0:32:360:32:39

the top geneticists in the world,

0:32:390:32:41

where were they getting these numbers from?

0:32:410:32:44

There was a kind of textbook, back-of-the-envelope calculation,

0:32:440:32:48

where they took the average length

0:32:480:32:50

of a human gene, on the bits of genomic sequence known at the time.

0:32:500:32:55

It was 30,000 base pairs

0:32:550:32:58

and they took the whole size of the human genome - three billion -

0:32:580:33:02

divided one by the other and you get 100,000.

0:33:020:33:05

And by a strange quirk, we know exactly

0:33:070:33:09

what the best brains in the genetics world actually believed back then,

0:33:090:33:14

because Ewan Birney got them to put their money where their mouths were,

0:33:140:33:18

and got them to bet on how many genes they thought we had.

0:33:180:33:22

So I went round with a plastic beer thing and the book

0:33:220:33:26

and I bumped into people and said, "Do you want to bet?"

0:33:260:33:31

If ever you want to see evidence of brilliant scientists

0:33:320:33:36

getting it really wrong, this is it.

0:33:360:33:38

You're in there first. Ewan Birney, number...

0:33:380:33:41

-48,251.

-And the next number down...

0:33:410:33:46

It's John Quackenbush, one of the big, big betters,

0:33:460:33:49

118,259.

0:33:490:33:54

-Huge.

-Huge.

0:33:540:33:55

Absolutely huge, but kind of in the consensus.

0:33:550:33:58

Then, in early 2001, using the new complete Human Genome,

0:34:000:34:05

Ewan Birney was able to count the real number of genes in a human.

0:34:050:34:10

So when we got to the publication -

0:34:110:34:14

I can't actually remember the phrase we used.

0:34:140:34:17

I think we said something like we can confidently identify 25,000 genes,

0:34:170:34:23

and we believed that maybe up to 35,000 genes in the human genome,

0:34:230:34:27

and that up to 35,000 was because

0:34:270:34:30

people were frankly not happy about the smaller number.

0:34:300:34:34

Within a few years, scientists agreed on a rough figure.

0:34:350:34:39

They could only find around 24,000 genes in the human genome.

0:34:390:34:44

By far the majority of the code in our DNA seemed to be just useless.

0:34:440:34:49

It wasn't genes at all.

0:34:490:34:51

What most scientists, in fact, called "junk DNA".

0:34:510:34:55

Imagine that this building is your genome -

0:34:550:34:59

three billions letter of DNA code.

0:34:590:35:02

Now, this is the amount that makes up genes.

0:35:020:35:05

So according to the classical genetics model, a tiny proportion,

0:35:050:35:10

just two or three percent, make the proteins that make you,

0:35:100:35:14

and the rest is darkness.

0:35:140:35:17

This was a real shock.

0:35:200:35:23

98% of our genome is not genes and doesn't code for proteins.

0:35:230:35:30

There's an assumption in a lot of genomics

0:35:300:35:33

that a lot of the DNA is just junk, it's garbage, it's rubbish.

0:35:330:35:37

And I have to say, at first glance, that seems reasonable

0:35:370:35:40

because a lot of it just doesn't produce anything.

0:35:400:35:42

There are only about 24,000 genes

0:35:420:35:44

that go to make a mammal, a human being, say,

0:35:440:35:47

which is about the same number of bits you need

0:35:470:35:49

to make a double-decker bus. It's not very many.

0:35:490:35:52

I would like to think I'm more complicated than a bus

0:35:520:35:54

and that is a surprise.

0:35:540:35:56

And what it tells you is something very important.

0:35:560:35:58

It's that we don't understand genetics at all.

0:35:580:36:01

We're in a situation that we've got a lot of boxes labelled

0:36:010:36:05

screws, washers, bulbs, and we don't even know

0:36:050:36:07

how to put them together,

0:36:070:36:09

let alone how to start the bus and drive it through the streets.

0:36:090:36:13

But because we were looking for genes that cause disease,

0:36:130:36:17

this low number had an unexpected upside.

0:36:170:36:20

It meant fewer genes to study.

0:36:200:36:23

Now, this was crucial,

0:36:230:36:24

because at the time, sequencing DNA was still colossally expensive.

0:36:240:36:29

So by narrowing down on just a small proportion of the genome,

0:36:290:36:32

it meant that large-scale studies were financially realistic.

0:36:320:36:36

And then scientists found something intriguing.

0:36:380:36:41

As we started to compare people's whole genomes,

0:36:410:36:44

we realised that everyone's DNA is almost identical.

0:36:440:36:50

If you compare one human genome with another

0:36:510:36:54

they would be identical at most positions,

0:36:540:36:57

they differ at about one position in a thousand, on average.

0:36:570:37:00

Yet we know we are hugely different.

0:37:050:37:09

We are all unique.

0:37:090:37:11

So the challenge now was to find those relatively few

0:37:110:37:14

individual differences in genes, genetic variants,

0:37:140:37:18

that account for differences in people.

0:37:180:37:20

And more specifically, to find the variants that cause disease.

0:37:200:37:24

So in 2005, the Wellcome Trust, here in the UK,

0:37:250:37:29

united many labs, by launching a huge survey

0:37:290:37:33

to read half a million DNA letters,

0:37:330:37:36

within known genes, for not just one,

0:37:360:37:39

but thousands of ill and healthy people.

0:37:390:37:42

The hope was that half a million DNA letters would be sufficient

0:37:420:37:46

to identify the most significant common variants that link to disease.

0:37:460:37:51

Professor Peter Donnelly was part of the team

0:38:030:38:06

who actually crunched the massive amounts of data.

0:38:060:38:09

Some ten billion pieces of genetic information were analysed,

0:38:090:38:14

harvested from over 10,000 people, at a cost of over £9 million.

0:38:140:38:19

The first experiment looked at seven illnesses

0:38:200:38:24

that, like height, were linked to many genes.

0:38:240:38:28

So here's an example from the large study we did initially

0:38:280:38:31

and the paper we published.

0:38:310:38:33

So this shows a row for each disease, and along each row we plot a measure

0:38:330:38:38

of the difference for each of the 500,000 variants we measured

0:38:380:38:42

between the sick people and healthy people.

0:38:420:38:44

The graph shows a summary of those results.

0:38:440:38:47

The half a million DNA letters are run from left to right,

0:38:470:38:50

divided up from chromosomes 1 to 22 and the X chromosome.

0:38:500:38:54

And when there is a noticeable difference

0:38:540:38:58

in the letters between sick and healthy people,

0:38:580:39:01

it shows up as a green peak.

0:39:010:39:03

You're saying that the green ones

0:39:030:39:06

are where a disease is associated with the genome?

0:39:060:39:09

Yes, the green ones are the ones where there's a genetic variant

0:39:090:39:13

which is considerably more common in the sick people

0:39:130:39:16

than the healthy people, in a way which is associated with disease.

0:39:160:39:19

It was a huge breakthrough.

0:39:190:39:22

Now, for the first time, it looked like we could find diseases

0:39:220:39:26

that were caused by errors in more than just one gene in our DNA.

0:39:260:39:30

I still remember the first time we sat down and had a serious look.

0:39:300:39:33

It was an extraordinary moment, knowing it would deliver

0:39:330:39:36

and we'd get some insights into the genetics of those common diseases.

0:39:360:39:39

It was really exciting.

0:39:390:39:40

That excitement was felt well beyond the scientific community.

0:39:420:39:47

Good evening. British scientists unveiled a new era in medicine today,

0:39:500:39:54

when they announced they'd finally unravelled a genetic link

0:39:540:39:57

to seven major diseases,

0:39:570:39:59

raising the prospect of predicting a child's medical future at birth.

0:39:590:40:03

Well, it was an awesome breakthrough, but looking back,

0:40:030:40:07

perhaps the media machine got a little ahead of itself,

0:40:070:40:11

because what this genome survey actually says about the health

0:40:110:40:15

of individuals, of real people, is, in fact, rather limited.

0:40:150:40:19

Because what we have to remember

0:40:210:40:23

is that even though our genes may indicate that we are susceptible

0:40:230:40:26

to disease, it doesn't mean we will actually get that disease.

0:40:260:40:31

Mark Hurst is a senior lecturer in human genetics.

0:40:350:40:39

He has a strong family history of diabetes.

0:40:400:40:43

This is my mum and dad.

0:40:450:40:47

They got married just after the war.

0:40:470:40:50

I was aware that my dad had diabetes. He'd test his sugar levels

0:40:500:40:55

and he was on various drugs to try and control it.

0:40:550:41:00

And it became obvious in the late '70s and '80s

0:41:000:41:03

that there was a genetic component

0:41:030:41:05

and so, as I was studying human genetics,

0:41:050:41:08

I sort of followed it with some interest.

0:41:080:41:11

The heritability of Type 2 diabetes,

0:41:130:41:16

if you've got close relatives, is very high.

0:41:160:41:19

Over the last 20 years, two of my sisters and one of my brothers

0:41:190:41:23

have all developed Type 2 diabetes,

0:41:230:41:26

so the genetic lottery says

0:41:260:41:28

I may have some of the genes, I might not, I don't know.

0:41:280:41:32

But Dr Hurst knows that even though he probably has variants in his DNA

0:41:340:41:39

which mean he is likely to suffer from diabetes,

0:41:390:41:42

it's far from certain he will actually get the disease,

0:41:420:41:46

because other factors are important, too.

0:41:460:41:49

There's a great...almost belief that you're a slave to your genes

0:41:490:41:55

and I think for some of the monogenetic disorders,

0:41:550:41:59

that probably is very much the case,

0:41:590:42:02

but for most complex diseases, multigenic diseases,

0:42:020:42:06

a large amount of environmental component,

0:42:060:42:09

so you can control large amounts of your environment

0:42:090:42:12

through things like exercise and diet.

0:42:120:42:14

Recent studies suggest that, simplistically,

0:42:140:42:18

diabetes is 70% genetic and 30% environmental.

0:42:180:42:22

There's this environmental component which was related to

0:42:220:42:25

your body weight, your waist size, your diet,

0:42:250:42:28

and I decided I can't control my genes, but I can at least

0:42:280:42:32

do something about the environment, so I started to run.

0:42:320:42:35

Hurst runs three miles a day.

0:42:370:42:41

This, he believes, has kept his diabetes at bay.

0:42:410:42:45

I suspect I would have been quite a lot heavier...

0:42:470:42:50

..and I think I would have probably developed

0:42:520:42:55

the signs of early diabetes by now.

0:42:550:42:57

Hurst's story reminds us that in most cases our traits and diseases

0:42:580:43:02

spring from our environment as well as our genetic code.

0:43:020:43:07

So now we have to ask ourselves a crucial question.

0:43:130:43:18

How much of a disease is to do with our genes at all?

0:43:180:43:22

It turns out we can make a guess at that

0:43:220:43:25

from a more traditional kind of genetic experiment.

0:43:250:43:29

The next questionnaire for you is a questionnaire about you.

0:43:290:43:33

This is Dr Claire Howarth.

0:43:330:43:36

And her unusual research tool?

0:43:360:43:38

Twins.

0:43:380:43:40

So why are twins so useful for any sort of genetic study?

0:43:480:43:52

It's a fantastic natural experiment, twins.

0:43:520:43:55

They provide the opportunity to investigate the roles

0:43:550:43:59

of nature - genes - and nurture - the environment,

0:43:590:44:02

so if a trait has a genetic influence

0:44:020:44:05

then you'd expect identical twins who share more genes to be more similar

0:44:050:44:09

than non identical twins, who share less of their genes.

0:44:090:44:13

Identical twins grow from one egg and one sperm,

0:44:140:44:18

so they are genetically the same.

0:44:180:44:20

There are quite a lot of similarities between us.

0:44:200:44:22

We look quite similar. We talk quite similar.

0:44:220:44:25

But I can't really say.

0:44:250:44:27

-Same likes, dislikes almost, kind of mainly.

-Yeah.

0:44:270:44:32

What do you like that's the same?

0:44:320:44:34

-We like the same music.

-Yep, music.

0:44:340:44:37

-Like the same food.

-Sport.

0:44:370:44:39

You're about to go to university, right?

0:44:390:44:41

-In two years.

-Two years, yeah.

0:44:410:44:43

You really do finish each other's sentences!

0:44:430:44:46

But non-identical twins are from different eggs and sperm,

0:44:490:44:53

and like normal siblings, share only about 50% of their genes.

0:44:530:44:57

I'm very into my sport, like watching,

0:44:580:45:01

whereas Maddy's more into playing.

0:45:010:45:04

I'm really, really musical. Caroline can't carry a tune in a bucket.

0:45:040:45:08

She doesn't play any instruments.

0:45:080:45:10

I love art and design more.

0:45:100:45:13

Studies like Dr Haworth's compare traits like height

0:45:180:45:22

between thousands of identical and non-identical twins.

0:45:220:45:26

We can break up the variance in a trait such as height, say,

0:45:260:45:31

and we can say how much that is due to genetic differences between people

0:45:310:45:35

and how much is due to environmental experiences they've had.

0:45:350:45:39

173.

0:45:390:45:42

These studies show that many common traits

0:45:420:45:45

are inherited much more than we thought.

0:45:450:45:48

Reading disability and reading ability are both highly heritable.

0:45:480:45:52

Somewhere between 50% and 70% of the variance

0:45:520:45:55

is due to DNA sequence that people have inherited from their parents.

0:45:550:45:59

And when Howarth started to test

0:46:040:46:06

for traits that genome surveys had looked at,

0:46:060:46:08

she got unexpected results.

0:46:080:46:11

Many traits were more heritable

0:46:130:46:16

than the genetic studies had previously revealed.

0:46:160:46:20

For height, twin studies say it's around 80% inherited

0:46:200:46:26

versus 5% that was found in the genome scan.

0:46:260:46:30

For Type 2 diabetes, it's 70% versus 6%.

0:46:300:46:35

There was a large proportion of the DNA's influence

0:46:360:46:40

simply not being seen.

0:46:400:46:41

Some have called this "the missing heritability".

0:46:430:46:47

We know there is missing heritability because twin studies have told us

0:46:470:46:51

that a lot of traits are very highly heritable.

0:46:510:46:53

For example height is about 80% heritable,

0:46:530:46:56

so when we do a molecular genetics study of height,

0:46:560:46:59

what we find is the DNA variance that we've identified only explain

0:46:590:47:02

about 5% of the variance, so we have this mismatch

0:47:020:47:06

between 80% heritability and only 5% that's been identified in the genome.

0:47:060:47:12

This was an extraordinary result.

0:47:160:47:18

Where was this missing heritability coming from?

0:47:180:47:23

Could it be that something in the mysterious 98% of the genome

0:47:240:47:29

that doesn't seem to do anything,

0:47:290:47:31

is actually far more important than we thought?

0:47:310:47:34

And this seemed possible, when we compared the code of our genome

0:47:350:47:41

with the code of other animals,

0:47:410:47:42

looking for parts preserved over millions of years of evolution.

0:47:420:47:47

So if you look between human and chimpanzee, for example,

0:47:510:47:54

most of our DNA is the same.

0:47:540:47:56

Between human and mouse, a fair bit is still pretty much the same.

0:47:560:48:02

But by the time you go to chicken, it's very clear that,

0:48:020:48:05

if there's a piece of DNA that's the same between human and chicken,

0:48:050:48:08

then it's important for humans and it's important for chickens

0:48:080:48:12

and there's no real way of getting round that.

0:48:120:48:14

And there's quite a lot of this stuff and it's not all near genes.

0:48:140:48:18

So there are these big chunks of the genome

0:48:180:48:20

that don't seem to have any protein-coding genes,

0:48:200:48:23

yet is still conserved between human and chicken and human and mouse.

0:48:230:48:27

If these pieces of DNA were cropping up in many species

0:48:290:48:34

they were clearly important for life.

0:48:340:48:36

But many of them weren't in the genes.

0:48:390:48:43

They were in the so-called junk DNA, and that meant that this wasteland

0:48:430:48:47

was far more important than we had previously imagined.

0:48:470:48:50

We'd assumed genes would account for

0:48:590:49:01

the vast majority of our inheritance.

0:49:010:49:04

But the new message was this -

0:49:040:49:05

a good place to be looking for the missing heritability

0:49:050:49:09

was in the 98% of the genome that isn't made up of genes.

0:49:090:49:12

And now we have the technology to start hunting.

0:49:120:49:15

So in this room we've got six or seven

0:49:190:49:21

of the newest generation of machines. Each one of these runs

0:49:210:49:26

for about a week, and in that week,

0:49:260:49:28

it'll sequence well over 20 whole human genomes.

0:49:280:49:32

And that's about 300 billion bases.

0:49:320:49:36

Professor Mark McCarthy

0:49:380:49:40

at the Wellcome Trust Centre for Human Genetics

0:49:400:49:43

is harnessing this new technology

0:49:430:49:45

to sequence the entire genome of hundreds of diabetes sufferers.

0:49:450:49:50

And the hope is that this will reveal influential variants

0:49:500:49:54

that had slipped through the net of earlier, less accurate surveys.

0:49:540:49:59

So the big advance in the last year or two has been the ability

0:49:590:50:03

to sequence the whole genome with much higher accuracy

0:50:030:50:06

and much lower cost than has been possible before.

0:50:060:50:08

If you remember, the original genome sequence took many years

0:50:080:50:11

and many billions of dollars to complete.

0:50:110:50:14

It involved many scientists.

0:50:140:50:15

It's now possible to do experiments on that scale

0:50:150:50:19

in a trivial amount of time for a few thousand dollars.

0:50:190:50:22

It's now become possible to consider re-sequencing the whole genome

0:50:220:50:27

of many thousands of individuals to understand the differences

0:50:270:50:31

between for example those that have diabetes and those that don't.

0:50:310:50:35

His ambitious project intends to sequence

0:50:350:50:39

the whole genome of 3,000 people,

0:50:390:50:42

comparing every single one of the three billion bases

0:50:420:50:45

in diabetes sufferers and healthy people.

0:50:450:50:48

They will throw up new genes and regions

0:50:480:50:52

that we hadn't hitherto implicated in disease risk

0:50:520:50:57

and that will give us new ways of understanding

0:50:570:50:59

the biology of the disease.

0:50:590:51:01

And we may have much better prospects for using genetics

0:51:010:51:06

as a tool for predicting risk of disease and response to treatment

0:51:060:51:10

than is currently possible

0:51:100:51:12

with the common variants that we have identified so far.

0:51:120:51:15

Already McCarthy has begun to find many new variants

0:51:180:51:22

that are associated with diabetes

0:51:220:51:25

in the part of the genome that aren't made of genes -

0:51:250:51:29

the increasingly misnamed junk DNA.

0:51:290:51:33

And not just a few, but many.

0:51:330:51:36

It seems that, for common variants at least,

0:51:380:51:42

most of the action lies in that non-coding DNA.

0:51:420:51:46

That non-coding DNA, the 98% of our genome,

0:51:510:51:55

was turning out to be not just important, but critical.

0:51:550:52:00

I think McCarthy's technique is the way forward.

0:52:020:52:05

If we want to really understand how our genetics makes us

0:52:050:52:08

utterly unique, we need to sequence many more human genomes.

0:52:080:52:13

Maybe everybody's.

0:52:130:52:16

In 2003, Ewan Birney started a series of experiments

0:52:180:52:22

to find out exactly what this junk DNA actually did.

0:52:220:52:26

The project was called ENCODE, the Encyclopedia of DNA Elements.

0:52:260:52:33

Using the very best technology of the time,

0:52:330:52:35

hundreds of scientists from around the world

0:52:350:52:38

scoured sections of the junk DNA.

0:52:380:52:41

There's a really obvious question which I'm dying to ask,

0:52:410:52:44

which is what is it? What is it doing?

0:52:440:52:46

There isn't an easy answer to what these things do,

0:52:460:52:50

but our best understanding was the prediction going in -

0:52:500:52:54

and it's still what we think now -

0:52:540:52:56

is that a lot of this is switching where genes switch on and off.

0:52:560:53:00

The idea that genes switch on and off grew from my own field,

0:53:010:53:06

the study of the development of embryos.

0:53:060:53:10

As an organism grows, its cells decide to be organs,

0:53:110:53:15

brains, limbs and livers, and this means the genes that control them

0:53:150:53:19

have themselves to be controlled.

0:53:190:53:22

And the location of this system of gene regulation?

0:53:250:53:30

Well, not within the genes themselves,

0:53:300:53:33

but in the rest of the DNA.

0:53:330:53:35

There's this incredible choreography of molecules in each cell.

0:53:350:53:40

And so this dance of how all these different molecules inside the cell

0:53:400:53:45

work out is working on these parts of the genome,

0:53:450:53:49

many of them are not close to even protein-coding genes.

0:53:490:53:53

They're spread out in the big dark matter of the genome.

0:53:530:53:58

But the ENCODE project revealed yet another layer of complexity.

0:54:010:54:06

Not only was the dark matter of DNA actually very important,

0:54:060:54:11

but it was also becoming clear that the physical structure,

0:54:110:54:15

the shape of DNA, affected us, too.

0:54:150:54:18

This is how we think about DNA,

0:54:240:54:26

the classic Crick and Watson double helix.

0:54:260:54:29

You can see in the middle, in the core, are the base pairs,

0:54:290:54:33

and outside, the twin backbones that spiral up

0:54:330:54:36

to give it that iconic shape.

0:54:360:54:38

But this is just a portrait

0:54:380:54:40

and portraits are not the same as people.

0:54:400:54:42

This is a much better representation of DNA in action.

0:54:420:54:46

The double helix here is in purple

0:54:460:54:48

but it's wrapped around a complex of proteins called histones

0:54:480:54:52

and they again wind up on each other

0:54:520:54:54

and the whole thing is covered in another protein.

0:54:540:54:57

It may look like chemical chaos and certainly

0:54:570:54:59

it's a far cry from the classic double helix model we're used to.

0:54:590:55:04

It's a complex world buzzing with activity.

0:55:090:55:14

Chemicals squeezing past other chemicals,

0:55:140:55:17

proteins constantly moving,

0:55:170:55:19

remodelling the shape of the DNA on the fly.

0:55:190:55:24

And this model shows only a tiny stretch of DNA,

0:55:240:55:28

about 150 bases long.

0:55:280:55:30

There are 100 million more of these in the full genome.

0:55:300:55:35

It should come as no surprise

0:55:360:55:38

but this is seriously sophisticated stuff.

0:55:380:55:42

The last 50 years has been a revolution

0:55:500:55:53

in our understanding of our genome.

0:55:530:55:56

From breaking the code in our DNA

0:55:560:55:59

to learning how mistakes in that code

0:55:590:56:01

lead to tragedies like Huntingdon's disease,

0:56:010:56:04

to glimpsing how our genome relates to complex traits

0:56:040:56:08

and diseases like diabetes,

0:56:080:56:10

and seeing how its effect can be mitigated

0:56:100:56:13

by changing our environment.

0:56:130:56:15

But it's only in the last ten years,

0:56:150:56:17

since the publication of the full human genome sequence,

0:56:170:56:20

that I believe we are seeing the biggest revelations,

0:56:200:56:23

because the real breakthrough has been understanding

0:56:230:56:27

just how little we know about the genome.

0:56:270:56:30

That is true enlightenment.

0:56:300:56:33

There isn't going to be a moment where we can stand up and say,

0:56:330:56:37

"That's it, we understand the human genome."

0:56:370:56:41

It is...

0:56:410:56:42

as complex as we are.

0:56:420:56:44

And we're pretty complex.

0:56:440:56:48

So I don't think it will be reached within my lifetime.

0:56:480:56:52

But I think we'll know so much more in five years than we do now.

0:56:520:56:57

And so much more in ten years than we do now,

0:56:570:56:59

that I think I'll be surprised.

0:56:590:57:02

I believe there never were going to be any easy answers.

0:57:050:57:09

Human beings are amazing, complex creatures.

0:57:090:57:14

Ten years on from completing the Human Genome Project,

0:57:140:57:18

we shouldn't be disappointed

0:57:180:57:20

that the results were different from what we expected,

0:57:200:57:23

nor surprised that we didn't come up with any definitive answers.

0:57:230:57:27

That is how science works.

0:57:270:57:29

It's a journey, a continuous exploration

0:57:290:57:32

of how things work and who we are.

0:57:320:57:34

And now, with the human genome complete,

0:57:340:57:37

we can finally see the road ahead.

0:57:370:57:45

Subtitles by Red Bee Media Ltd

0:57:450:57:48

E-mail [email protected]

0:57:480:57:51

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