Whole-genome breakthrough promises tonic for healthcare

Accurately sequencing an individual’s DNA for less than $1,000 is now possible

Commentators have long looked forward to the “thousand-dollar human genome” — the ability to sequence accurately all 3bn letters of an individual’s DNA for less than $1,000. In 2016 it seems likely to happen, 15 years after the completion of the first whole human genome in a decade-long $3bn research programme. The consequences for personalised healthcare could be profound.

Veritas Genetics, a Boston start-up company, announced in March the availability of whole genome sequencing together with interpretation and genetic counselling for $999 — the first time the price of a consumer genomics product has fallen below the thousand dollar barrier.

George Church, Harvard University genetics professor and co-founder of Veritas, predicts that whole genome sequencing will soon replace the partial DNA sequencing that, at present, dominates genetic testing.

“Now that the whole genome is this accessible, it will replace all genetic tests,” he says, “because it is all genetic tests and much, much more.”

The tests commercially available today read only a small fraction of the patient’s DNA. They may focus on specific genes known to be involved in a disease, on mutations scattered through the genome or on the “exome”, the part of the human genome containing active genes but not the DNA that controls their activity.

These partial DNA testing techniques are still considerably cheaper than whole genome sequencing. In September, for instance, Human Longevity, a San Diego company founded by genomics pioneer Craig Venter, announced a $250 exome sequencing service in collaboration with Discovery, the South African health insurer.

Veritas claims, however, that whole genome sequencing catches many clinically important DNA variants that lie outside genes. “The whole genome is the foundation of precision medicine and a lifetime resource to maximise quality of life and longevity,” says Mirza Cifric, the company’s chief executive.

While a host of companies such as Veritas and Human Longevity offer genomic services, backed by deep scientific and clinical knowledge about the relationship between genes and health, the instruments they use to read DNA come almost entirely from one source: Illumina. This Californian company’s machines are generating an estimated 90 per cent of the world’s DNA sequence data — thanks to technology acquired in 2007 when Illumina bought Solexa, a spinout from Cambridge university in the UK, for $650m.

Francis deSouza, Illumina’s president who will take over as chief executive in July from the long-serving Jay Flatley, points out that the DNA sequencing market is still in its infancy. “Until now it has been used largely for research,” he says. “The overarching story for the future will be the march of sequencing into the clinic.”

The first medical fields likely to be transformed by large-scale genomic diagnosis are prenatal screening for genetic defects in the embryo — and oncology. The concept of the “liquid biopsy”, diagnosing cancer from DNA that has leaked from the tumour into the bloodstream, is one of the hottest topics in oncology and Illumina has set up a subsidiary company, Grail, to exploit the market. Many others are in the field, too.

Although the cost of DNA sequencing per genome has fallen sharply, the machines are still big and expensive. This year Illumina launches its smallest and cheapest sequencer so far, the $49,500 MiniSeq, and it has promised a new machine called Firefly for late next year at a price below $30,000.

For a radically smaller, cheaper and more portable DNA reader, researchers can turn to the recently introduced MinIon from Oxford Nanopore, a start-up from Oxford university that focuses on a quite different technology: nanopore sequencing. MinIon is no larger than a mobile phone, fits into the USB port of a laptop computer and costs no more than $1,000 (though consumable reagents add to the running expenses).

The technology employs a microscopic hole within bacterial proteins — the nanopore — to act as a biosensor. A voltage is applied across the pore and, as DNA moves through it, the electric current changes in a way that distinguishes between the four biochemical “letters” of the genetic code: G, A, T and C. This direct electronic reading is quite different from the “sequencing by synthesis” technology developed by Illumina, which attaches fluorescent molecular tags to the DNA and uses a computerised camera to read the results.

MinIon has the advantage over its competitors of portability, which has enabled many scientists to use it in the field for identifying viruses and bacteria, plants and animals, from their genomes. It cannot come close to the larger Illumina machines for sequencing capacity.

Oxford Nanopore’s next offering, the desktop PromethIon being introduced this summer, is a more direct competitor for Illumina. Clive Brown, chief technologist at Oxford Nanopore, says the instrument will begin sequencing human genomes later this year.

A court case, however, is currently commanding Oxford Nanopore’s attention. In February Illumina sued the company in the US for allegedly infringing Illumina patents. Although it has no nanopore machines close to commercialisation, Illumina said it “has made substantial investments to obtain licenses and develop the nanopore sequencing technology invented by researchers at the University of Alabama and University of Washington.”

Oxford Nanopore, which has an extensive portfolio of nanopore patents from other universities, has issued a robust defence. It accuses Illumina of using the lawsuit “as yet another weapon in its long-running campaign to thwart Oxford Nanopore’s research and commercialisation efforts . . . with the ultimate intent of expanding its already overwhelming monopoly power into the nanopore space, which would be extremely detrimental to competition in the DNA sequencing market”.

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