Slow start, but gene knowledge comes good
Promises of bespoke medicines and magic bullets’’ for mankind’s biggest killers may be unfulfilled, but the true value of genetics is now being realised, reports Mark Henderson
IT WAS quite a vision of our genetic future: shortly before the first drafts of the human genome were unveiled in 2001, Francis Collins spelt out in bold terms what the project he had pioneered would ultimately mean for medicine. By 2010, scientists would understand how genes contribute to at least a dozen common illnesses such as diabetes and heart disease, the director of the US National Human Genome Research Institute said.
A new era of bespoke medicine lay ahead, in which drugs tailored to individuals’ genetic profiles would replace the traditional ‘‘ onesize-fits-all’’ approach. Insights from humanity’s genetic code were poised to transform health care.
Just a year ago, Collins’s timetable looked like fantasy. Science had had a version of the genome for five years, and parts of it for longer, yet had added surprisingly little to knowledge of the genetic roots of common diseases. The promised revolution had yet to begin.
It is now under way. The announcement in May that four common genes have been reliably linked to breast cancer is only the latest and most spectacular of a series of remarkable results that have led cautious scientists to speak openly of a tipping point in their understanding of how DNA affects our health.
Scores of genes that cause or influence disease are now known to science, but until recently it has been difficult to identify any that contribute to the greatest causes of ill-health — diabetes and heart disease, mental illness and most cancers.
The successes of the first phase of genome research were limited largely to genetic mutations that have devastating effects — but for very few people, such as those that cause Huntington’s disease and cystic fibrosis.
Four out of five women with mutated BRCA1 or BRCA2 genes will develop breast cancer. Only one woman in 500, however, carries these defects. Their discovery has transformed screening for a small minority, but it means nothing for more than 95 per cent of the 44,000 British women, and over 13,000 Australian women whose breast cancer is diagnosed each year.
Scientists have long known, from family and twin studies, that other genetic factors affect women’s risk, but hitherto it has been impossible to pinpoint what they are. The same has been true of other diseases.
All that is starting to change. After years of treading water, geneticists have started to publish a cascade of data about very common genetic variants that can subtly influence people’s risk of developing common diseases.
The new breast cancer genes, discovered by a team assembled by Cancer Research UK, have much less of an effect than the BRCA genes: the most damaging genetic profile raises the lifetime risk to about 17 per cent.
But they are much, much more common: one variant is carried by one in six women, and the rarest by one in 16.
That discovery followed the announcement in April of the first common gene that has been shown reliably to contribute to obesity. Similar studies have identified common genetic variants that predispose to heart disease and type 2 diabetes. In June a Wellcome Trust consortium published details of many more that are linked to seven major conditions, including high blood pressure, bipolar disorder and rheumatoid arthritis.
Where genetics was once capable of pinning down only rare mutations with a catastrophic impact, it is now tracing variants with smaller effects that are much more widespread. You might call it the democratisation of the genome.
‘‘ Democratisation is a good word for it,’’ said Mark Walport, director of the Wellcome Trust, the British biomedical charity that has funded much of the key research. ‘‘ What we are finding now is relevant to everyone, not just to those rare families who happen to be exceptionally unfortunate.’’
Professor Bruce Ponder of the University of Cambridge, whose team identified the new breast cancer genes, said: ‘‘ The genes we have seen so far are strong genes for spectacular stuff, but this is the real genetics that underlies variation in the population at large. These are the genes that affect how people react to their environments, and that influence, however slightly, their chances of developing common diseases.’’
This step change has been brought about by new technology and a change of approach. Traditional gene hunts have relied on a technique called linkage analysis, in which scientists study families in which several members have developed an inherited disorder. DNA samples from individuals with the disease are compared with samples from those who are unaffected. Around 100 subjects are usually enough, and no more than 300 DNA markers generally need to be scanned.
While this is efficient, it works only for genes with a large impact, raising risk by at least 200 per cent. Most genetic variants do not work like that, and to find them scientists have turned to a new method called whole genome association.
Such studies use unrelated subjects, and need to be much larger. The Wellcome Trust Case Control Consortium, which found the FTO gene and published more results in June, compared 2000 people with particular diseases with 3000 unaffected controls. As the subjects are not related, scientists must also look at hundreds of thousands of DNA markers to find any effects.
This approach can find common variants, which raise risks by as little as 10 to 20 per cent. The drawback is the vast amount of data that must be processed — it has become possible only with the advent of microarrays or ‘‘ gene chips’’ that can scan hundreds of thousands of genetic markers at once.
It is this that has enabled the spectacular recent advances. ‘‘ It’s been known in principle that whole genome association studies should be more powerful, but only in the last two years has it become affordable to do them with the large sample sizes we need,’’ said Peter Donnelly, of the University of Oxford, who chairs the Case Control Consortium.
‘‘ Since the genome was published, progress has been slower than people had hoped, but the pace has zoomed now. Each week and month, exciting new findings for important diseases are being published. That pace will continue. What we knew just a year ago is enormously different from what we know now.’’
This enhanced knowledge is changing the way scientists think about genes and disease. It is now recognised that there are very few conditions that are caused by single genes with big effects — the influence usually comes from dozens of genes, each of which has only a minor impact on its own.
‘‘ We are mostly finding that for any given disease there are zero, or at best one or two, genes with large effects,’’ said Mark McCarthy of the University of Oxford, who led the team that found FTO’s effect on obesity.
‘‘ Then there is a sprinkling of genes, perhaps five to 10, with modest effects of 10-20 per cent, and there may be many hundreds with even smaller effects.’’
For many conditions, indeed, these smaller effects may be all there are.
Robert Plomin of the Institute of Psychiatry in London, who specialises in behavioural disorders such as autism, doubts whether whole genome association will even find many moderate effects in his field.
This means that the genome will rarely provide medicine with ‘‘ magic bullets’’ that tackle disease by correcting faulty genes.
First, most of the variants that contribute to a high risk of breast cancer or diabetes are common, and are thus likely to have other important functions. We would use genetic engineering or gene therapy to alter them at our peril. Then there is the problem of numbers. So many different genes are playing a minor role that it is implausible to think we might correct them all.
The real value of this knowledge will thus be in understanding the basic biology of common diseases, so scientists can design better drugs to target the processes that our genes set in train. It should also allow the development of tests for gene combinations that create a significant risk.
That would then allow patients and their doctors to manipulate a factor that almost invariably interacts with genes to affect disease, and which is much easier to control: the environment. Women with a high breast cancer risk could be referred for more frequent screening. Those in danger of heart disease might change their diet and exercise patterns. In some cases, drugs will be appropriate, to change the biochemical environment in which genes operate in the body.
‘‘ What we are going to get out of this in the end is not genetic engineering, but environmental engineering,’’ Plomin said. ‘‘ A lot is going to be about changing behaviour, about education. It’s not always going to be: you’ve got this genetic problem and here’s a pill. Most genetic effects are going to be too small for that.’’ The Times