BBC Cura Milagrosa A Década do Genoma Humano parte 3

Uploaded by amilkerr on 09.08.2011

in the human body.
You're just changing one tiny one.
And the fact that that will then prevent
such a terrible condition
that will be with that person all their life,
I think it's justifiable.
As a parent, it must be very difficult
to see your child going through CF,
and to think that one... potentially one injection,
one dose of gene therapy whilst my mum was pregnant
could have prevented all of this.
I know that my parents, there's absolutely no doubt
that they would not want me to have had CF,
and have to go through everything I have.
So if it was an option for them,
I definitely think they would have taken it.
Ten years ago,
scientists were surprised by how few genes they discovered in our DNA.
But it quickly became clear that fewer did not mean less complicated.
It was the activity level of genes and how they worked together
that scientists had to understand.
Emma wants to see how scientists are changing
the way cancer patients will be treated,
as they extend their knowledge of our genes' activity.
I think having seen how far the cancer genome project has got,
I'm really excited to find out what's going to happen next with that information,
but also what's going to happen sooner rather than later for me.
Here at King's College, London, scientists are working on a method
that, if successful, will change the way they treat their patients.
It will allow them to predict how a patient's cancer will behave,
and with this knowledge, doctors will then know how best to treat it.
Overseeing this research is Professor Ghulam Mufti.
What's been developed at the present moment is, at the time of diagnosis,
you test the cancer cells
and identify what drugs are likely to work or kill those cells.
The hope is to use knowledge of a patient's genetics
to inform the choice of treatment
and ensure they get the best one available.
So for myself, I had a really difficult choice to make
when I had my chemotherapy.
It was either standard treatment or a clinical trial,
but nobody could really advise me that one was going to be
more successful than the other.
With the type of treatment you're offering now,
will that choice become easier for patients like myself?
Oh, definitely. And as time goes on, it's probably going to be the case
that the majority of cancers will have some kind of targeted therapy.
To find the right targeted therapy for the patient,
doctors need to know what's going on in their DNA.
To discover this,
they use a pioneering piece of technology known as a GeneChip.
This reveals the degree to which a gene is active - "turned on" -
or inactive - "turned off" - in a patient's cancer.
Believe it or not, in this little square,
this black box in the middle, it's got all the genes
that a human being has,
so this particular gene chip has over 28,000 genes.
The chip is divided into millions of microscopic squares
and each single square identifies a particular gene.
When molecules from a patient's cancer cell are squirted into it,
the squares are designed to light up
and reveal the level of gene "expression" - or activity -
in the patient's cancer cell.
On the screen is the genetic data taken from a chip.
What is shows you is that there are some of the genes
where the activity is more, and that is represented
by these shining areas, whereas in some areas
there is no activity of the gene at all,
so those are completely dark areas.
The hope is to group cancers by their pattern of genetic activity
and then use this information to take an informed decision
on which treatment will be most effective.
So how long will it be before this technology
is available for patients like me, so that, on an initial diagnosis,
we can be given more information about our treatment choices?
I think that's hard to speculate about,
but one thing is for sure,
that since the completion of the human genome project,
the advances have been absolutely phenomenal and, therefore,
I'm pretty sure that, over a period of time - say, the next decade -
we would be able to identify the right treatment regime
for a particular patient.
The future looks promising.
By studying the patient's genetics,
doctors believe they will be able to produce a targeted treatment
that's most effective for the individual patient.
Finding out that targeted treatment is going to be available is just...
it's amazing, really. My original thoughts
were that there isn't going to be available for 20 years or so.
So to find out that it's going to be within the next decade is brilliant.
Not just for me but also for Jamie as well.
Tom has come to a facility in Oxfordshire
run by the Medical Research Council.
He's here to meet a mouse,
one that should give him a remarkable insight
into his own condition.
What scientists here are trying to do is identify,
one at a time, the genes involved in complex diseases such as alcoholism.
This is Ward 6, where we do most of our work.
We've got about 2,500 cages in here...
They have recently identified one mouse
whose behaviour is unlike anything ever seen before.
So...Tom, this is one of the alco-mice.
This is the one, is it? This is our man.
As you'll know,
what makes us all individuals is the blueprint of life, our DNA,
which is a long genetic code of letters - A, T, G, C and so on -
and that codes every single protein and every single thing in our bodies.
What we've done is we've changed one single letter in that genetic code,
at random, in the animals
and we've looked to see which of them consume alcohol.
We've done that with a simple choice,
very much akin to if you and I went into a pub
and I said, "What would you like to drink?"
So the animals are living very happily in the cage.
And you can see we've got two bottles here - one with water,
and one which is 10% alcohol,
so the equivalent of a strong beer in terms of alcohol strength.
We know that the majority of mice will not touch alcohol at all
if given this choice.
But the alco-mice will take 85% of their daily fluid intake
from the alcohol-containing bottle. Oh, wow.
Which is equivalent to you or I taking, weight for weight,
round about two bottles of whisky a day.
Wow, that's heavy going.
They are, but the important thing is it's entirely free choice, you got no obligation
they can consume whatever they like.
And, as you can see, he's very happy there, having a little look around the cage.
He chooses the ethanol all the time, basically?
85% of the time, yeah.
Scientist have learnt from studies of identical twins,
and of adoption cases,
that around half of what makes people alcoholic is genetic
and around half is their environment.
With the mice, because we are in a controlled environment
where one day is very much like another,
and there are no particular stresses or social pressures or taboos,
these animals are able to make an entirely free choice,
largely driven by their genetics.
So that gene, is basically
that's the one that's saying that this isn't socially-driven,
it's not driven by peer-group pressure,
it is, basically, that's their make-up,
that's the way they were designed,
and that's what they're going to choose? That's right.
From my point of view as an alcoholic,
that's something that is great for me to hear,
that if there is a similar gene in adults, or in humans,
that this gene would say that it's not just my peer-group pressure.
It is the fact that I need to drink and I want to drink.
And it's that I choose, I actually seek drink rather than seeking water.
Scientists have discovered that the alco-mouse gene
is also present in humans.
It's one of the small handful of genes as yet identified,
that are thought to be associated
with an increased risk of alcohol dependency.
It's a small but important step towards an understanding
of the disease that blighted Tom's life for 15 years.
I came in here thinking I was just going to look at a mouse
that had been fed alcohol,
and this one mouse has given me a better understanding, in 15 minutes,
of my own illness
than 15 years of trying to search for answers.
To be told there is a possibility that there is a link
to a signal in my brain that was making me crave the alcohol more...
For me, it's...
I can't get it through how...
both upsetting that it's never been told to me before,
but also liberating that I've got answers
just from that mouse. That one mouse!
I'm all right, I'm fine.
Just got that off my chest. I'm sound.
Happy. Happy.
That's the thing. Happy.
Identifying genes is one thing.
Using that knowledge to make a medicine that works is another.
It takes around 15 years for any treatment
to make it from an initial idea,
through the trial stages and into the doctor's cabinet.
Gene therapy will be no exception.
I go running because it helps clear all the mucus from my chest.
As I jog along, I'm literally leaving like a trail of mucus behind me,
but if I didn't go running, that would all stay stuck in my lungs.
I just think it is so important that I do everything I possibly can
to keep my lungs in the best possible condition,
so that I will benefit if gene therapy does become a reality,
because I know and I understand that
once a lung damage progresses and gets worse,
it can't be corrected, and the only way I can benefit from gene therapy
is if my lungs are as healthy as possible.
That motivates me to go jogging every day
and to fight as much as I can to keep well.
So that, if gene therapy does one day become a reality,
I will benefit from it.
Sophie's hopes rest with the Cystic Fibrosis Gene Therapy Consortium.
This small, dedicated team of scientists
have been trying to work out how gene therapy might be used
to treat people living with cystic fibrosis today.
The gene therapy consists of man-made copies
of the healthy CFTR gene, suspended in a fatty liquid.
Taking part in the trial is Kevin, who also has cystic fibrosis.
He inhales the gene therapy via a nebuliser.
The aim of the trial is not to cure him, but to work out
the largest safe single dose that could be administered in the future.
Hi, Kevin. How are you? I'm all right. How are you doing?
How does it feel when you're nebulising the gene therapy?
I kind of feel like I'm breathing the future!
This is this crazy kind of chemical concoction
that's been made in a lab that you breathe in,
and it's really incredible what it does.
And it goes in and it changes everything inside your lungs.
Do you feel any different?
Right now? No. I don't expect to feel very different, really, at all.
What motivated you to take part in the trial?
Because it's, um, it's everything
that every science-fiction book I ever read as a kid has promised me.
It's like, it's what was dreamt of in '96 or whenever,
when the human genome project started. It's what was dreamt of.
And it's actually happening!
It's the fruition of all this genetics research.
It's actually giving us a product that can be used. And it's like...
It literally is like Star Trek gene-therapy stuff. It really is!
But there's a long way to go yet.
Lungs are particularly resistant to gene therapy.
They have a massive surface area that needs to be targeted,
and have also evolved to keep out unknown particles.
So thanks to Kevin and his colleagues and friends,
who are going to help us find the biggest safe single dose,
we're now in a position to move forward, probably around next July,
so July 2011,
into this world's biggest trial of repeated application.
We'll then be able to start dosing every month in July
and that will take us, overall, about a year and a half.
So we should be finishing around Christmas Eve 2012
and around that time we'll get a feeling whether this trial,
for the first time in the world,
has shown that patients can actually get better clinically.
That's never been done anywhere in the world.
And thinking of it for myself, is it realistic
for me to think that in my lifetime, I may benefit from gene therapy?
I think absolutely, it is realistic to think about it.
If this Wave 1, this first trial,
looks good at the end of December 2012,
I think we can then move it quite rapidly through into the NHS.
So in terms of timeline, do you know when it may become available?
Can you give a rough idea?
If everything goes fantastically at the end of 2012,
within two, three years, we might be able to put it into regular treatment.
But supposing it doesn't go fantastically,
then it will be much longer.
For me, it almost is like a race against time
and my hope is that gene therapy will become a reality
in the next few years, so I can benefit from it
before my condition gets any worse,
so that it will prevent my lungs from deteriorating any further
and enable me to live a long and happy life.
I know that there will come a point
when there's nothing, really, that anyone can do.
Once my lungs become so damaged, you can't reverse that.
It is quite scary when I think about the future.
I think about how a lot of people with CF end up in a wheelchair,
on oxygen 24 hours a day.
That's a really scary thought
and I just hope I never have to go through that,
because I'll benefit from gene therapy
before my lungs deteriorate that far.
Just knowing that these trials are taking place
and if they have positive results,
and within the next few years we see things progressing,
and in the near future
we can see gene therapy becoming a real possibility,
that's what gives me hope and helps motivate me
to try and keep as well as possible.
After a decade of intensive research,
a new order of medicine is entering the final stage of trials.
That of genetically targeted medicine... "personalised medicine".
For cancer patients,
targeted drugs hold the promise of being more effective,
and making the unwelcome side-effects
of traditional chemotherapy a thing of the past.
After the chemotherapy treatment, I just felt really, really queasy,
and that, on top of feeling horrible from the surgery and things,
was just... I just started to feel a bit sorry for myself.
My hair didn't start to fall out until after my second cycle.
In the end, after sort of a couple of weeks, I gave up
and got Graham to shave it all off for me,
which... He found that quite hard, I think.
I just remember being sat in the bath and just crying
and thinking, "This is just, it's just horrible."
I mean, Graham, he did, bless him,
he tried to make me feel a lot better cos he said,
"Actually, you've got quite a nice-shaped head".
And I did!
The Breakthrough Breast Cancer Research Centre in London
is developing a new drug that will treat Emma's type of cancer effectively,
but without inducing the side-effects that she experienced.
It's one of the most cutting edge trials
for the treatment of breast cancer today.
In charge is Professor Alan Ashworth.
Quite barbaric really, the treatment they give you.
It's literally poisoning you from top to toe.
Chemotherapy really just works by killing cells that are growing fast,
and that's why you get the other toxicities.
There's nothing clever about it at all.
Because some normal cells - such as hair, gut, and blood -
grow at the same rapid rate as the cancer cells
the chemotherapy is targeting,
these other cells are also poisoned.
But thanks to his knowledge of the genome, Alan thinks he has found
a weakness in some types of cancer that will be its Achilles heel.
Some tumour cells can't repair their DNA properly.
They actually don't care about repairing it,
they just carry on growing fast,
so what we've worked out a way of doing is trying to exploit that to treat cancer.
Alan's drug inhibits the ability of cells
to repair naturally-occurring defects in their DNA.
At a low concentration, healthy cells are strong enough to survive.
But Alan's breakthrough is that the same concentration
kills cancer cells that are bad at repairing their DNA.
It is an incredibly effective treatment,
and could mean the difference between life and death
for thousands of cancer patients.
So at this concentration here, all the mutant cells are killed,
but actually the normal cells are not really touched,
so potentially that translates into much more powerful treatments,
but much less side-effects as well,
because we're not really killing normal cells.
In fact, in my pocket here,
I have the drug that actually is being trialled now
in people with BRCA mutations, for the treatment of their cancer.
So you can have a look at it, it looks like a fairly bland substance,
but it is very powerful stuff. It's a little white powder.
As you can see on these cells.
Get the right cells and it'll kill them stone dead.
That's just fantastic.
This footage, specially shot in Alan's lab,
shows cancer cells replicating
and then dying as the drug takes effect.
Killing cancer cells while leaving so many healthy cells alive
is a significant breakthrough,
which may mark a turning point in our age-old battle with cancer.
It would not have been possible - at least not so quickly -
without knowledge of the genome.
We're in the 21st century, we've got the human genome sequence,
and we're still treating cancer with medieval treatments.
We cut it out with a big knife, or we burn it with radiation,
or we poison it with chemotherapy.
What we're trying to do is to use the genome information
to develop new ways of treating the cancer itself,
the genetic defects in the cancer, but not the normal cells.
Tom wants to know the results of the spit test he bought on the internet.
He has learnt that one mutated gene can make a mouse alcoholic.
He now wants to know what role his genes played
in contributing to his alcoholism.
Many of the genes Tom was tested for were found through a process
known as Genome Wide Association Studies.
In these studies, genetic data is taken
from people with a particular disease and from people without.
It's then compared and contrasted by teams of genetic statisticians.
They ushered in something of a gene gold-rush,
appearing to identify genes associated with diseases
as diverse as hypertension, obesity and depression.
For some, tests like the one Tom took
represent the progress that genomic science has made
over the past ten years,
and satisfy people's desire to know more about their genes.
Whether or not it will help Tom understand his alcoholism,
he's about to find out
with the help of Oxford University Professor Peter Donnelly,
an expert in genome statistics.
What the test shows is that you're in that middle class.
One of your chromosomes has got an A in the genetic code and one has a G.
And what the research suggests, although it's a bit tentative,
is that someone with your genetic type
has an increased risk - but by about 20%, so it's a fairly small effect -
a 20% increased risk, because of that genetic variant, of developing alcoholism.
So although it's tempting to say, "I've got the gene for alcoholism",
that's not going to be the case.
There won't be a single gene which determines whether people get alcoholism,
there will probably be many, many of them,
each one of which has a tiny effect.
And it's like...if you imagine driving in a car,
which is a slightly risky thing,
if you drive for six miles rather than five,
you're at slightly increased risk, but it's only a slight effect,
and if you stop after five miles,
that doesn't guarantee you won't have the accident.
I feel very deflated, to be quite honest with you,
because it appears they've just picked particular genes
and done small studies on people, and they've done reports,
and from what you're saying, we're not very far down the line
on finding any particular gene that's associated with alcoholism.
It just turns out we couldn't have picked this in advance,
that it's one of the harder nuts to crack, or puzzles to unlock,
in terms of the genetics.
But to use the analogy of a journey or a book,
it's like we're towards the end of chapter one of a great big book.
We don't know what's in the rest of it,
but we've made some progress and we're starting to understand.
Which is great for those in the field, but for people like yourself
who want to know what happens at the end of chapter 18,
we don't know that yet.
I thought it was great when we first did it,
I was really looking forward to the results.
I'm now looking at them and thinking, "I could have done without knowing."
It's good to know that there's a particular gene that I might have,
but it doesn't tell me anything significant to what I knew anyway,
the fact that I was an alcoholic.
It doesn't confirm or deny that at all.
You know, I'm an alcoholic, those genes don't tell me any different.
So it's a strange one.
The problem geneticists face in trying to understand alcoholism
is the same one they face in their bid to understand
other common diseases such as heart disease, diabetes, or dementia.
These illnesses, which many of us will get and many will die from,
are genetically very complex...
..borne of multiple genes subtly interacting with one another and their environment,
in different ways and to different degrees throughout our lives.
Ten years after the euphoria that accompanied the completion
of the human genome project, where do we stand?
Illnesses such as Tom's pose the biggest challenge to scientists.
Sequencing the genome is one thing, understanding it is another.
The complex interaction between multiple genes and their environment
means progress is steady but relatively slow.
However, the problem of finding the genes
and designing genetically-based treatments
is no longer insurmountable.
As for Tom, having run the hardest race on earth,
he is now training to row the Atlantic.
Sophie remains optimistic about the future.
Although new antibiotics are keeping her lungs clearer than before,
a gene therapy that will treat her is still elusive.
The challenge of getting the four healthy DNA letters
into her lungs persists.
Back home with her family, Emma, too, is optimistic.
In the age of the genome, it is our understanding of cancer above all
that is undergoing a transformation.
New ways of prescribing medicine and new treatments
are still a few years away,
but scientists are on track.
Emma has discovered that for her and her son Jamie,
the future is less foreboding.