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Low-cost personal DNA readings are on the way
06 September 2007
NewScientist.com news service
Peter Aldhous, San Francisco

Enlarge Written in the genes?

"Genetics is about to get personal." So proclaims the website of 23andMe, a Californian company that is gearing up to offer people a guided tour of their own DNA. For the superstars of genetics, it has already got personal. Earlier this week, genomics pioneer Craig Venter revealed an almost complete sequence of his genome, while that of James Watson, co-discoverer of DNA's double-helix structure, has been available on the web since late June.

Given that Watson's genome took almost $1 million to read, most of us won't immediately be following in his and Venter's footsteps. It isn't necessary to read your entire genome, however, to browse many of the genetic variations that may influence your health. According to George Church, a geneticist at Harvard Medical School in Boston, the most pertinent information could be gleaned by sequencing the 1 per cent of the genome that codes for proteins. Thanks to the advances in sequencing technology, that might be done for as little as $1000 per person. "DNA chips", meanwhile, can scan your genome for common "spelling mistakes" for just a few hundred dollars. At that price, the era of personalised genomics is already dawning. "This is the year," claims Church.

To push the field forward, Church has launched the Personal Genome Project (PGP), in which he and nine other volunteers have signed up to have the protein-coding regions of their genome made available on the web, along with their medical records, photographs of facial features and the results of a questionnaire about their health and personal habits. Within a few months, he aims to start scaling up to 100,000 volunteers.

Church is also an adviser to both 23andMe - named for the number of chromosome pairs in the human genome - and Cambridge Genomics, two of the firms hoping to turn personalised genomics into big business. But is the world ready for their services? As well as raising questions about the protection of personal genetic data, there are concerns about how people will use information that, at this stage, even trained medical geneticists find extremely difficult to interpret.

"The really big thing is for medicine and biology to catch up," says Michael Egholm of 454 Life Sciences in Branford, Connecticut, which provided the technology used to read Watson's genome. "We're going to have routine genome sequencing long before physicians know how to make any sense of it."

Church's PGP is intended in part as a resource to help researchers investigate the biological consequences of individual DNA sequence variation. To facilitate this, the relevant genetic, medical and lifestyle information will be placed in a public database. Church does not intend to include the names of the 100,000 volunteers, but he will warn them that it may be possible for them to be identified from the information that they provide.

For this reason, the PGP is drawing up procedures for obtaining informed consent, detailing ways in which participants' personal information might, in theory, be misused. These range from discrimination in employment or insurance to more fanciful scenarios such as someone synthesising DNA that matches part of your genome, then planting it at a crime scene. The project will even have an entrance examination to ensure that people understand the potential risks of participating. Further raising the motivational bar, volunteers may be asked to pay up to 20 per cent of the cost of sequencing their DNA.

Even so, some observers have reservations about the motivations of those who may take part. "Putting your DNA out there for the whole world to see appeals to people who have a molecular exhibitionist streak," suggests Kathy Hudson, who heads the Genetics and Public Policy Center in Washington DC. She and other experts consulted by New Scientist nevertheless agree that the PGP should be a valuable project. "On balance, I applaud what George is doing," says Richard Gibbs, director of the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas.

Roadmap to health?

More controversial is the idea of companies providing paying customers with access to information about their own genomes. 23andMe - co-founded by Anne Wojcicki, wife of Google mogul Sergey Brin - is the best known. Based in Mountain View, California, the company plans to launch by the end of the year, and until then is keeping quiet about exactly what services it will provide. Informed sources expect it to concentrate initially on scanning customers' genomes for common genetic variants called SNPs - single-letter variations in our personal genetic code that are sometimes associated with disease. 23andMe's customers will also be able to share genetic information via web-based social networking - likely to appeal to people interested in using genetic data to help trace their family trees.

Navigenics, based just a short distance away in Redwood City, also intends to analyse customers' SNPs, but is more clearly focused on medical applications. "Your genes offer a roadmap to optimal health," claims its website, which includes a video explaining how customers can submit saliva samples and receive a read-out of their genome in return, with an explanation of what it means.

Massachusetts-based Cambridge Genomics, meanwhile, intends to move directly into DNA sequencing. Initially, customers can expect to pay around $40,000 for sequences of regions thought to be most relevant for health, rising to more than $1 million for a high-quality sequence of their entire genome. These costs will come down as sequencing technology continues to improve (see "Towards the $1000 genome"). Other companies are focusing on different aspects of "genome health", such as variations in our ability to repair DNA (see "Chromosome repairs").

Unlike Church's PGP, personalised genomics companies promise to keep prying eyes away from customers' genetic information - so one challenge lies in protecting the data from hackers. But the bigger concern, say geneticists, is how personal genomic information will be presented to customers, given our limited ability to interpret it at present (New Scientist, 19 August 2006, p 28).

Venter's genome, described in detail in PLoS Biology (DOI: 10.1371/journal.pbio.0050254), shows how far we have to go to fully understand the consequences of individual genetic variation. Researchers at the J. Craig Venter Institute in Rockville, Maryland, found 4.1 million differences between their boss's genome and the "reference" human sequence held by the US National Center for Biotechnology Information - around 30 per cent of which were new to science. Most of Venter's departures from the reference sequence were SNPs, but 22 per cent involved larger deletions, insertions, or other rearrangements of DNA.

The biological significance of most of these variants is unknown, and even looking at those that have been associated with definite traits (see Table) gives a confusing picture. For instance, SNPs in the gene LCT indicate that Venter should be able to tolerate the sugar lactose. In fact, he suffers from lactose intolerance, which is presumably due to the modifying effects of other genes, or to environmental influences.

Nevertheless, Venter is pleased with what he learned from his sequence. For instance, certain SNPs may put him at increased risk of cardiovascular disease and Alzheimer's. This, coupled with the knowledge that his father died of sudden heart failure, has led Venter to start taking a statin drug, which can help prevent both conditions.

Venter is in a privileged position when it comes to interpreting his personal genetics. "I could see that the information could have a very different impact on a less well-informed person," he says. Some people might panic on learning that they possess genetic variants that increase the risk of Alzheimer's disease, for example.

This is no reason to hold back the tide of personalised genomics, Venter argues. "I think people, if they want to know, have a right to know," he says. "But with that goes a responsibility to provide the most complete and accurate information."

That responsibility falls most heavily on the companies now preparing to enter the field. "We're caveating everything we say, and we're trying to turn it into English that everyone can understand," says Ari Kiirikki of Cambridge Genomics. Venter argues that experts in genomics must share the task of educating the public about what they can learn from poring over their own books of life. Gibbs agrees. "We don't want to develop a culture of giving people half-baked genetic information," he says.

From issue 2620 of New Scientist magazine, 06 September 2007, page 8-11

Towards the $1000 genome It worked for spaceflight, so why not for DNA sequencing? That's the logic behind the Archon X prize, a successor to the famous Ansari X prize, which was awarded to the first private team to develop a reusable space vehicle. Last year, the X Prize Foundation of Santa Monica, California, offered $10 million to the first team to sequence 100 human genomes in 10 days at a cost of less than $10,000 apiece. It shouldn't be too long before the prize is claimed. "We believe we're going to get to the $10,000 genome in about five years," says Michael Egholm of 454 Life Sciences in Branford, Connecticut, which has entered the contest. Beyond that, there is another $500,000 on offer from genomics pioneer Craig Venter for the first team to bring down the cost of sequencing a human genome to $1000. By then, geneticist George Church of Harvard Medical School in Boston predicts that many people will already have had at least the protein-coding regions of their genomes sequenced. Once it becomes cheap enough for us to afford to get our entire genomes read, he suggests, "everyone will get an upgrade".

Chromosome repairs It sounds like a ploy to separate the worried well from their money: for several hundred dollars, Australian company Reach100 will appraise the "health" of your genome and then prescribe vitamins and minerals to patch it up and hopefully keep you alive and kicking well into old age. Its first clinic opened in Adelaide in July and the second is set to open in Dubai in October. Clinics are also planned for Jakarta in Indonesia, and - once the analytical process has been automated to deal with expected demand - in the US. In principle, the science underpinning Reach100's approach makes sense. However, the whole field - dubbed nutrigenomics - remains controversial, and experts disagree over whether there is anywhere near enough evidence that the Reach100 approach helps prevent disease, and hence whether it can be offered as a service. Some even raise concerns about safety. Reach100 monitors wear and tear over a person's whole genome. It uses a blood test called the genome health analysis (GHA) to assess the extent of chromosomal breaks and losses in white blood cells. If you score badly, Reach100 doctors first eliminate genetic predispositions or exposure to toxins as the cause, and then measure blood levels of key micronutrients. If these turn out to be suboptimal you are prescribed vitamins and minerals, such as folate and zinc, sometimes at levels exceeding the recommended daily allowance (RDA). Two ideas underlie Reach100's approach. The first is that genome damage is the fundamental flaw underlying a wide variety of diseases, including neurodegenerative disorders and cancers, while an impaired ability to repair DNA is associated with diseases of accelerated ageing. The second is that the intake of micronutrients by many, especially older people, is below that required to keep their genome in peak condition. The situation is not helped by the fact that many RDAs are set to prevent deficiency diseases such as scurvy in young men, rather than to ensure adequate supplies in older people of cofactors such as folate, vitamin B12 and zinc, which are required by the enzymes that keep the genome in good repair. "The scientific basis [for Reach100's approach] is solid. Still, the benefits in terms of disease prevention have not yet been clearly demonstrated," says José Ordovas, director of the Nutrition and Genome Laboratory at Tufts University in Boston. Others point out, though, that many people already take vitamin and mineral supplements, and that doctors and dieticians are increasingly recommending them - often without monitoring blood levels of the micronutrients and their impact, as Reach100 claims to do. What's more, says Lynette Ferguson, director of Nutrigenomics New Zealand at the University of Auckland, there's a public demand for these types of services. "You can be too cautious, and leave the way clear for far less scrupulous operators," she says. The idea of clinics specialising in genome health is the brainchild of Michael Fenech of CSIRO, the Australian national research organisation, in Adelaide (Nutrition Research Reviews, vol 16, p 109). He is not on the Reach100 payroll, but is an adviser to the company, and his lab runs the GHA test. Fenech originally developed the test to monitor chromosomal damage by radiation and chemical carcinogens, for which it is routinely used worldwide. Over the past decade, several teams around the world, including Fenech's, have used the test, as well as other means to monitor genome damage, to show that even a slight reduction in key micronutrients such as folate causes significant chromosomal damage in cells in the lab. The findings are similar in animals, and the damage can be reduced by hiking up the micronutrients again. There's also emerging evidence that the GHA can predict cancer susceptibility. Last year, a team from the M. D. Anderson Cancer Center in Houston, Texas, found that the test is highly sensitive at spotting cigarette-induced DNA damage and concluded that it "may serve as a strong predictor of lung cancer risk" (Cancer Research, vol 66, p 6449). Earlier this year, a study of over 6000 healthy people in 10 countries found "preliminary evidence" that the GHA can predict the risk of cancers including stomach, colorectal and urogenital (Carcinogenesis, vol 28, p 625). Two clinical trials by Fenech's team have also shown that micronutrient supplements reduce genome damage in people or in lab. But what's missing, and it's a big omission, is a randomised controlled trial that directly tests whether a GHA and supplements can reduce disease risk or increase life expectancy, says epidemiologist Bruce Armstrong of the Sydney Cancer Centre in Australia. He also points out that you need to be sure that the vitamins and minerals don't turn out to be harmful. "We've had our fingers burnt before," he says, referring to studies that showed beta carotene, which was thought to prevent cancer, may increase the risk of lung cancer in smokers. Timing may also be an issue, says Ordovas. "You need to get customers while they are still young. If you have elevated DNA damage and you are in your 60s or 70s, you can't tell this person they are going to make it to 100." Rachel Nowak, Melbourne

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