It was 1997, when Maddie Juniper (pictured) was just six years old, that her
parents first noticed the changes.
Their formerly healthy, happy little girl had suddenly become constantly
hungry and thirsty and was also losing weight. Within weeks they had not
just a disease but a devastating diagnosis: type 1 diabetes.
It was, they were told, a disease that would be with her for life. She would
need to inject insulin every day and have a highly regulated diet. And no,
said the doctors, they had no real idea of the cause beyond the fact that it
was probably partly genetic.
“The doctors told us it was a disease with a genetic element,” said Sue
Sparkes, Maddie’s mother. “But there is no diabetes in our family and they
had no idea what genes were involved. Really they seemed to know very
little.”
Maddie’s diabetes was typical of a range of diseases that afflict modern
Britain on a vast scale. Type 1 and type 2 diabetes alone affect more than
3m people, while heart disease kills 110,000 a year and rheumatoid arthritis
afflicts about 500,000.
In 1997 such diseases were considered largely in isolation. All that they were
thought to have in common was their persistence and the misery they caused.
Some scientists suspected a genetic link but the apparently random way that
such diseases occurred within families made it hard to be sure. All they
could give patients were vague hints – just like those offered to Maddie’s
parents. It was, they all knew, not good enough.
“Back in the 1990s we had seen some real progress in uncovering genes for
particular diseases but the approach only worked for rare conditions like
cystic fibrosis and Huntington’s chorea,” said Peter Donnelly, professor of
statistics at Oxford University. “They were easy to spot because anyone who
had the gene always got the disease.
“We suspected there was a genetic component to many other conditions, too,
ranging from heart disease to schizophrenia, stroke and diabetes. What we
did not have was a way of finding out what those links were.”
Ten years later, however, Donnelly and his fellow researchers stand on the
threshold of a different world.
Last week they published research showing how it is now possible to analyse
one person’s genome and pick out the genetic variations behind a range of
common diseases.
In the study they selected six conditions: type 1 and type 2 diabetes, heart
disease, rheumatoid arthritis, manic depression and Crohn’s disease – where
the digestive tract becomes painfully inflamed.
Then they screened DNA from 14,000 patients with one of those conditions and
compared them with samples from 3,000 healthy controls.
Last week they triumphantly reported finding 24 genetic variants linked to one
or more of the targeted illnesses. Half of those gene variants have effects
that are new to science.
Such discoveries are unprecedented, but it is the technique they have helped
to pioneer that could have the greatest impact.
Donnelly believes that it could become the key that will unlock the genetic
secrets of many more conditions, including stroke, schizophrenia,
Alzheimer’s and cancer. How did science make such progress so fast? What
were the key breakthroughs and where will they lead?
In 1997, the year of Maddie’s diagnosis, nobody could have dreamt of such
rapid progress. For Dr Teri Manolio the key event of the late 1990s was the
setting up of the research programme that underpins all the recent advances
– the Human Genome Project (HGP).
“The HGP was the start of it all,” said Manolio, now director of the office of
population genomics at America’s national Human Genome Research Institute.
“It showed us that 99.7% of the DNA in the genome is identical, which is a
staggering finding. It means the variations between us lie in just 0.3% of
our DNA. That is what gives us our individuality and it is also where we can
find the causes of these diseases.”
Narrowing down the causes of disease to 0.3% of the human genome sounds
impressive – but analysing even this tiny fraction was a huge task. Genomes
are made up of four similar chemicals, called base pairs, which are repeated
billions of times.
The human genome, for example, has three billion base pairs – and the order
they occur in is crucial. A single tiny change, known as a single nucleotide
polymorphism or Snip, can raise the risk of disease. And there seemed to be
millions of them.
By the time the HGP was published in 2003, researchers knew that their next
task was to pin down the nature and location of all those changes. Thus was
born the next stage of the genome project, the so-called Snip Consortium.
“By 2005 the researchers had found 10m variations in the human genome and
catalogued them all,” said Manolio. “It was a fantastic achievement.”
This was still not the final stage. Analysing 10m gene variants would
overwhelm practical researchers such as Donnelly who wanted to use the new
understanding of the genome to seek out the causes of disease.
Between 2003 and 2005 researchers went through those 10m variants to pick out
the 500,000 most important ones, creating the so-called haplotype catalogue
or HapMap.
Meanwhile, in hospitals and clinics around Britain researchers were realising
the power of the new technologies and had begun to approach patients for
samples of their DNA. All were hoping to be the first to pinpoint the genes
that lay behind the diseases killing and afflicting millions of Britons.
It was the Wellcome Foundation, Britain’s leading private funder of medical
research, that first realised what was happening.
“We started to get a number of applications for funds for very similar
projects,” said Professor Mark Walport, director of the trust.
“The researchers wanted to use the [HapMap] data to scan the genomes of people
with particular diseases. The idea was to find what genes occurred more
commonly in them than in the rest of the population.” Walport decided it
would be foolish to fund a rash of separate projects and decided to bring
all the rival researchers together in one consortium.
It was a move that could have back-fired badly. University research groups are
fiercely competitive and generally hate to share their secrets. However,
once Walport had made it clear that working together was the only way he
would fund them, the opposition disappeared.
The Wellcome Trust Case Control Consortium was born from that agreement two
years ago and has since been at work with Donnelly at the helm. “We have had
to recognise that the ability to make progress depends on collaboration,”
said Miles Parkes, who leads one of several British groups studying Crohn’s
disease.
“The academics had been competitors but they have had to accept the new
approach and now they like it because it has accelerated progress. The
important thing is that we are moving towards understanding the disease and
hopefully finding better treatments.”
The British researchers were also spurred on by international competition that
has seen the same genome-scanning approach brought to bear on a wide range
of diseases.
Research papers published in America have picked out genes linked to cancers
of the prostate gland and breast, while others have found variants
associated with macular degeneration, a disease of the eyes that often leads
to blindness in the elderly. Even mental illness is showing itself
vulnerable to the genome scanning approach.
Nick Craddock, professor of psychiatry at Cardiff University, oversaw a
section of the Wellcome study focusing on the causes of manic depression,
also known as bipolar disorder. “We found a number of genes potentially
linked to this illness,” he said.
“One was very strong and there were several more that were nearly as
important. We think the same approach will show us the genes involved in
many other mental illnesses like schizophrenia and depression which affect
huge numbers of people.”
One thing that all the researchers involved in genome scanning empha-sise is
that turning their new knowledge into treatments will take years. But
ultimately they say that this research promises to open the way to an era of
“personalised” medicine in which doctors routinely analyse the DNA of
patients to find out which drugs will be the most effective for their genes,
rather than the existing approach of “one size fits all”.
For some the wait would be worth it, however long it took. This weekend Maddie
was celebrating her 16 birthday and revising for her GCSE exams – while also
trying to ensure that she kept her blood sugar levels under control.
“This disease hits children at random who have done nothing to deserve it. It
changes their lives for ever,” said Sparkes.
“The advances since Maddie was diagnosed have been tremendous already. If
finding those genes can point to a cure or more effective treatment, then it
will all be worthwhile.”
