Life sciences: Advances in decoding aid diagnosis and treatment

It has taken a while but the era of genomics is dawning at last. The first draft of the human genome – the sequence of all 3bn biochemical “letters” of human genetic code – was completed in 2000, to a chorus of scientific hype about the benefits. Thereafter disillusion gradually set in, as genomic knowledge failed to make any perceptible difference to clinical practice, and commentators suggested it failed to live up to the initial enthusiasm.

Now, however, biomedical opinion is turning positive again. The ability to decode DNA and understand its function really is beginning to transform healthcare, providing new ways to diagnose and treat disease. The disappointment was due partly to overenthusiastic promotion of genomics in the 1990s. Scientists maynot have exaggerated the ultimate benefits but many certainly underestimated the time it would take to deliver them. “Genomics turned out to be much more complicated than we thought,” says Professor Tim Hubbard of the Wellcome Trust Sanger Institute near Cambridge. “But we have made enormous progress recently and I think it’s all coming together.”

The total number of human genes – defined as hereditary units giving the body instructions to make specific proteins, the workhorse molecules of biology – turned out to be far lower than most scientists had expected: only 20,000. But the regulatory DNA and “epigenetic” controls, which turn the genes on and off throughout life in response to different environmental conditions, show interleaved levels of complexity that scientists are just beginning to understand.

Professor Kay Davies, director of the Medical Research Council Functional Genomics Unit at the University of Oxford, gave Duchenne muscular dystrophy as an example of a relatively common genetic disease for which the prospects have been recently transformed. “Five years ago, I used to stand up in front of patient groups and tell parents that effective treatments might be on the horizon,” she says. “Today, I am talking of treatments that have almost reached the clinic. There is now real hope for the sufferers of this terrible [muscle wasting] disease.”

The dystrophin gene responsible – identified as long ago as 1986 – is so large and subject to such a wide range of defects that researchers have taken almost 30 years to understand the details well enough to come up with candidate therapies effective enough to test on patients. Two technological factors are enabling genomics to overcome the complexity barrier to understanding human biology. One is the computing power becoming available to analyse the torrents of DNA data, in the realm of gigabytes per human genome.

The other is the astonishing increase in the speed and fall in the price of instruments that read DNA sequences. The original Human Genome Project took several years and cost more than $1bn; today’s machines can sequence a human genome accurately within a day at a cost not far off $1,000. “I think we’re approaching a tipping point,” says George Church, professor of genetics at Harvard University. “Once we get below $1,000, we’ll be on the way to 1m genomes.” He estimates that worldwide about 25,000 people have already had their whole genome sequenced.

In the UK alone there are two separate projects to sequence 100,000 genomes each. One is taking place within the UK National Health Service (NHS), with an initial £100m government grant; a new state-owned company called Genomics England has been set up to deliver the project by 2017. The two initial focuses are cancer and rare diseases. Genomics England is working with the charity Cancer Research UK to sequence cancer patients and a sample of their tumour, and with the University of Cambridge to sequence patients with rare inherited diseases along with the DNA of their immediate family members.

The other initiative is the Personal Genome Project UK, which aims to find 100,000 volunteers to donate their genomes for research. Its distinctive feature is that, in contrast to Genomics England, which is making a big effort to protect the privacy of its patients’ DNA, the Personal Genome Project is based on “open consent”. Participants are given no guarantee of anonymity or confidentiality.

While the healthy volunteers in the Personal Genome Project will get back an expert analysis of their individual genome – with recommended medical actions highlighted – participation is primarily an act of scientific altruism. Researchers will be able to link participants’ DNA data with information about their health and lifestyle, to understand better the genetic causes of disease. NHS patients in the government’s 100k Genome Project will also be contributing to research, but they are more likely to benefit personally through the diagnostic power of genomics. John Bradley, who will run the Cambridge project on rare genetic diseases, says it “will bring enormous improvements to the care of patients.

“It will shorten the gap between the first signs of ill-health in a person and provide a conclusive diagnosis by using the power of modern DNA sequencing methods.” But cancer has been the most fruitful application so far of genomic medicine. By breaking down tumours with similar symptoms into genetic subgroups that have different outcomes and respond differently to treatment, it enables doctors to tailor therapy to the patient. While the study of breast cancer has led the way, melanoma, lung cancer and other tumours are following quickly behind.

At the same time, cancer illustrates the complexities brought to light by genomics. Sequencing of tumours within individual patients shows that, once the cancer starts to grow and spread, thousands of new genetic mutations arise – all are random but Darwinian evolution inevitably acts on them to select the ones best fitting to the cell’s niche in the patient’s body. The challenge is to identify the most important mutations driving the tumour’s development and find the best treatment for them.

Looking much further ahead, Sir John Chisholm, executive chairman of Genomics England, “can conceive of a day when every baby will have its DNA sequenced as part of its clinical record”. While nothing so far-reaching is on the NHS agenda, the US National Institutes of Health recently awarded $25m in grants to explore the potential of newborn baby genome sequencing.

VEL