Getting personal

The promise of cheap genome sequencing

“TWENTY years ago doctors had tight control over all medical information. We want that power to shift to individuals,” says Anne Wojcicki, a co-founder of 23andMe, a Californian genomics firm that counts Google as one of its investors. Her firm takes in saliva samples by mail, analyses a tiny bit of the genetic material they contain and posts information about the provider’s health and ancestry gleaned from them on a secure website.

She wants to extend the idea of patient empowerment to the age of genomics (the study of all genes in the genome and the interactions among them). Her customers are already forming online chat groups and blogs to share details of specific genetic mutations and exchange family and genomic histories.

Does the analysis done by her firm have enough predictive value for its subjects to take action? She points to the example of Sergey Brin, a co-founder of Google, who happens to be her husband. When an analysis by her company found that Mr Brin had an above-average risk of getting Parkinson’s disease, he began to take his exercise (which is thought to help prevent this disease) much more seriously.

The consumer-genomics firms that have sprung up in the past few years are all similarly upbeat about their prospects. David Agus of the University of Southern California (USC), an adviser to Navigenics, another such start-up, thinks that companies wanting to promote employee “wellness” will boost this trend. Among the investors in Navigenics is Kleiner Perkins, a venture-capital firm that was an early backer of Google, Amazon and AOL.

But consumer genomics is not just a Silicon Valley fad. YiGene, a Chinese start up, is jostling with several local rivals to provide genetic testing and counselling to Asian consumers. And it was Iceland’s deCODE that led the way by creating a massive database—made up of the country’s entire population—that it is now tapping to do genomic research. Kari Stefansson, its boss, thinks that in future genomic tests will be done on personal computers, and that all children will have their genomes fully sequenced at birth.

In the decade since the Human Genome Project reported preliminary results in 2000, the promised benefits of genome-inspired drugs and more individualised health care have failed to materialise. Could personalised medicine now be closer at hand?

Sniping at snips

Some academics remain deeply sceptical. Allan Balmain of the University of California, San Francisco questions the scientific basis for the claims made by such firms. David Altshuler of the Broad Institute, a genetics-research centre run jointly by Harvard and MIT, thinks the firms encourage people to read too much into their results. Such “fallacies”, he says, are causing a public backlash that could divert attention and resources from the worthier goal of genomics-inspired disease research.

One big concern is that the firms in question do not, in fact, sequence the entire genome for their analysis. That would be far too expensive, even though sequencing costs are falling fast. The firms analyse only a tiny part of a customer’s DNA. In particular, they look at certain parts of a chromosome known as single-nucleotide polymorphisms (SNPs, pronounced “snips”). They argue that variations in SNPs are correlated with the likelihood of developing a range of nasty diseases. The firms’ scientists insist they rely only on the best peer-reviewed scientific studies on the matter, and it is true that over the past two years a flood of well-designed studies, known as genome-wide association studies, has established correlations between a range of common SNP variants and diseases ranging from diabetes to various forms of cancer.

Craig Venter, a biotechnology pioneer, is usually a fan of brash upstarts. A decade ago he upstaged the boffins of the official Human Genome Project by privately sequencing his own genome faster and more cheaply. But he remains sceptical about analysing only the SNPs. He wants to see whole genomes sequenced because “we don’t yet know which parts of the genome are medically relevant.”

Others agree that sniffing around SNPs is an imperfect substitute for doing comprehensive scans of the full human genome. The gene-variant SNPs reported in those genome-wide studies are undoubtedly associated with diseases, but some believe their significance is greatly overstated. Even if firms uncover a handful of SNPs that suggest an increased risk of getting a disease, the customer may have a dozen other genes that lower the risk.

Some say that the common variants easily uncovered by today’s sequencing technologies are much less important than other, rarer variants. There is not enough knowledge to make sense of the torrent of genetic information being uncovered. The problem is that today’s tool of choice, the genome-wide association studies, which link genetic variants in a given population with known diseases, cannot easily find such needles in a haystack. But as the cost of sequencing drops, firms hope to be able to get much better at needle-spotting.

Yet another camp of sceptics rejects the whole idea that medicine will ever be truly personalised. It is unusual for a disease to be caused by only one or a few genetic defects. Most disorders, such as diabetes and heart disease, are linked to dozens or possibly hundreds of genes. And those genes affect only an individual’s susceptibility to a disease. Choices about exercise, diet, smoking and so on could have a bigger influence. So Dr Altshuler thinks it unlikely that scientists will ever be able to predict disease perfectly, never mind devise truly personal therapies.

Keep off my genome

Though he has the world’s most advanced gene-sequencing technology at his fingertips, Dr Altshuler refuses to get his own genome sequenced: “If someone gave it to me on a CD, I’d refuse to look at the disc. The information is meaningless.” Bill Gates agrees. He has not had his genome sequenced either, nor does he plan to, though after a moment’s reflection he adds, “unless I find out I have cancer.”

This last observation suggests that there is a future for the diagnostic use of whole-genome sequencing. But first the cost will have to come down with a bump, from perhaps $100,000 per scan today to below $1,000. That could happen in less than a decade. Until then, the biggest use of genomics is likely to be in drugs discovery.

Big pharmaceutical companies have watched their innovation pipelines dry up in recent years, but rapid advances in genomics now promise to change that. Cancer is at last beginning to reveal its secrets, thanks to a technology known as the biomarker, which is a genetic indicator different from an SNP. Biomarkers reveal such useful things as the effectiveness of potential new drugs in individuals or groups, as well as the likelihood of adverse reactions. A forthcoming report from the OECD argues that genetic biomarkers are emerging as one of the most effective means of improving the efficiency of drug discovery.

Researchers are now trying to find out to what extent the efficacy and safety of many new drugs is influenced by genetic factors. For example, during trials of an apparently unsuccessful drug for lung cancer made by AstraZeneca, a British drugs firm, USC’s Dr Agus discovered that the drug worked well in some of his patients of Asian descent. Similarly, some people of African origin seem to respond well to BiDil, a heart drug, whereas those of other ethnic stock do less well on it.

It is surprising, therefore, that the ailing drugs industry seems indifferent to genomics, except in cancer research. Dr Venter believes the reason is economic: “Genomics is totally changing the basis of medical research, but Big Pharma was better off when we knew less.”

Russ Altman of Stanford University agrees that the big drugs companies are dragging their feet on genomics, noting that the industry’s traditional blockbuster model with its huge potential market relies on standard remedies that work for everyone. That was a plausible strategy when scientists had few tools to determine the likely risks and benefits of new drugs, but given the advances in pharmacogenetics it is no longer sustainable.

Dr Altman’s team recently published a study in the New England Journal of Medicine on how to dose warfarin. This drug is widely used to prevent blood clots that could lead to strokes or heart attacks, but the correct dose can vary widely from patient to patient. Too high a dose can cause a patient to bleed dangerously, whereas too low a dose can lead to deadly clots. The study showed that dosing decisions that took account of variations in just two specific genes in addition to factors like age, weight and race produced far better outcomes than decisions based only on the latter traditional factors. Dr Altman thinks the Vioxx tragedy could have been avoided with proper genetic screening, but firms have little incentive to do this.

Now some drugs companies seem willing to plunge into targeted therapies. Sandra Peterson of Bayer, a German pharmaceutical giant, acknowledges that “old-fashioned blockbusters just aren’t going to happen any more.” She thinks the way to fix the drugs pipelines at big firms is to link pharmacogenetics with the information supplied by medical smart grids, moving towards a model of innovation that is informed, targeted and cheaper.

But Novartis’s Dr Vasella still rejects the notion of personalised medicine, pointing out that it would be economic folly for firms to develop a special pill for every patient. He accepts that linking individual genetics with specific therapies is the big challenge for his industry today, but he is still looking for a suitable business model.

Perhaps a better way of describing how genomics will change the drugs business model is mass customisation. The obvious parallel is clothing, which is rarely tailor-made but often personalised to reflect an individual’s needs and choices. Clayton Christensen of Harvard Business School offers a useful phrase to describe the point where pharmacogenetics and personalised medicine meet: “precision medicine”.

A new Moore’s law

Purists like Dr Venter sniff that the technology for reading SNPs is not good enough for serious applications like medicine, never mind how cheap it gets: only reliable full-genome scans will do. These are much more expensive because they must capture information about all 3 billion base pairs, the genetic “hitters” in the human genome. The gene chips used to study SNPs today can capture perhaps 1m.

“I spent ten years searching for just one gene,” says Dr Venter about his early career. “Today anyone can do it in 15 seconds.” The official Human Genome Project sequenced a single genome at the cost of about $4 billion. Dr Venter’s rival project did the same thing for $100m. The two competing teams agreed in 2003 that each of them had independently sequenced a human genome. Since then the industry has undergone a technological transformation. Sequencing equipment has been improving even faster than microprocessor performance, which doubles roughly every 18 months for the same outlay under a rule dubbed Moore’s law.

The sequencing technology works by figuring out the precise sequence of letters that make up the genetic code of life. The first generation of sequencing equipment was thorough but extremely slow and expensive. George Church of Harvard University, who worked on the original Human Genome Project and now advises several genomics firms, compares that cumbersome old technology to mainframe computing. Today’s second-generation technologies, he says, are already as disruptive as the original personal computers were to mainframes.

The newer sequencing machines borrow ideas from silicon-chip manufacturing. One consumer-genomics firm called Knome (pronounced “know-me”) uses nimble machines that deposit millions of tiny dots filled with DNA snippets on a flat surface, typically glass. The DNA in these dots can be “read” by molecular machines to signal the presence of different DNA variants. This process has brought down prices by a factor of ten every year since its introduction in 2005.

The next sequencing technologies promise to read whole genomes quickly and at a reasonable cost, and several rival firms are already racing to get them to market. When they do, it will have a profound impact on the economics of health care.

The X Prize Foundation, a charity, is now offering $10m to the first outfit to sequence 100 human genomes in ten days at a cost of $10,000 or less per genome. Many teams have signed up, but the most promising have their eyes on an even more lucrative prize: the multi-billion-dollar commercial market for affordable, accurate sequencing of whole genomes.

Illustration by Otto SteiningerOne such firm is Pacific Biosciences, based in Menlo Park, California. It makes novel use of fluorescent labels that allows it to read long stretches of DNA fragments, base by base, quickly and efficiently. Stephen Turner, the firm’s founder and chief technology officer, is confident that his firm will soon be able to sequence a complete human genome in under 15 minutes. He expects its first commercial product within two years.

Another, more tight-lipped, contender in the race for cheap full-genome sequencing is Oxford Nanopore. The British firm is developing a promising technology which involves passing genetic material through a tiny hole in a specially selected protein. This promises to read DNA directly, without a need for fluorescent labels. This would be a big breakthrough, but the firm will not yet say when it will be ready for commercial use or at what price.

Perhaps the most intriguing of the rivals is Complete Genomics. Its offices in Mountain View, California, are not far from the headquarters of Google, and are modest by comparison, but its business strategy is no less audacious than that of its big neighbour. The firm’s technical innovation involves packing lots of DNA into great numbers of tiny dense “nanoballs” which, in turn, are assembled in a highly efficient way into arrays that resemble microscope slides. The DNA sequence is worked out by using fluorescent tags, but does so in a way, developed by Dr Church’s laboratory at Harvard, that is much more accurate and quicker than the methods used up to now.

Service with a smile

This process is too complex for the average customer to handle, an apparent drawback that led to a brilliant commercial idea: rather than sell the equipment, Complete Genomics intends to sell a sequencing service. Clifford Reid, the chief executive, explains that his firm’s process can easily be adapted to huge volumes. By June he will be able to sequence a complete genome for under $5,000, and within a year his firm will have a commercial offering, he says.

If whole-genome sequencing can be done cheaply and accurately, it will be used much more widely in drug discovery and clinical practice. The consumer-genomics companies’ controversial promise of personalisation will at last be put to a proper test. In time the costs of sequencing will plunge towards $100 a genome. When it does, says Dr Altman, sequencing will become a commodity.

Dr Church even argues that genome sequencing “will in effect be available free” because companies will give away sequencing to sell other services, such as genetic interpretation—much as mobile operators “give away” handsets to get customers to sign up for lucrative service plans. And when this happens, he reckons, “it will be just like the internet: once all this information is floating around, a lot of creative people with PCs will nose around and develop applications.”

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