Cheaper, Better, Faster, Stronger

Now that we’ve cracked the $1,000 genome, where will the DNA-sequencing revolution take us?

In January, the CEO of genome-sequencing company Illumina, Jay Flatley, made a stunning announcement at the J.P. Morgan Healthcare Conference in San Francisco. Introducing his firm’s new flagship DNA-sequencing instrument, Flatley declared that this machine would finally deliver the much-ballyhooed “$1,000 genome.”

Few observers were more astonished than I. In my book The $1,000 Genome, published in late 2010, I chronicled the plummeting cost of sequencing the 3 billion building blocks of DNA that make up the human genome. I imagined we would reach the $1,000 genome in a few years, but not quite so soon.

The “$1,000 genome” catchphrase was coined back in 2001, the same year that two teams published the first drafts of the human genome sequence, an event hailed by presidents and prime ministers as a historical landmark akin to the Apollo moon landing. But those first drafts had taken a decade and cost between $2 billion and $3 billion. Future progress in medicine would require a revolution in DNA sequencing akin to breakthroughs in the computer industry.

Fortunately, a few brilliant scientists were already devising exciting new methods to read the sequence of our genetic code. In 2007, the founder of 454 Life Sciences, Jonathan Rothberg, presented Nobel laureate James “Double Helix” Watson with his complete genome on a DVD. Even though Rothberg said “Project Jim” had cost $1 million, the effort marked the first time that an individual had been presented with his or her personal genome. Watson agreed to release his entire genome to the public, with the exception of a single gene on chromosome 19 called APOE, variants of which are associated with Alzheimer’s disease risk.

But 454’s days were numbered. After Illumina acquired a British outfit called Solexa in 2007, it steadily strengthened its grip on the sequencing market. This year already, half a dozen organizations have giddily forked over the $10 million for Illumina’s newest machines, capable of sequencing more than 150 human genomes in just three days.

Genome sequencing has been transforming clinical medicine since 2009, when Wisconsin geneticist Howard Jacob was asked by a colleague to sequence the genome of a very sick little boy, 4-year-old Nic Volker, who had a mystery autoimmune condition. The sequencing identified a critical mutation that ended Nic’s diagnostic odyssey and more than 100 fruitless surgeries, gave his doctors the rationale to conduct a bone marrow transplant, and probably saved his life. As Jacob’s team continues to sequence the genomes of patients with undiagnosed disorders, several health insurance companies have accepted the economic benefits of genome sequencing and are covering the costs.

Many other medical centers are following suit, including Baylor College of Medicine in Houston, where Christine Eng and colleagues have sequenced the genomes of more than 2,000 patients with suspected genetic disorders, reporting (in a 2013 article in the New England Journal of Medicine) a success rate of about 1 in 4.

The sequencing revolution is being felt in other areas, too: Noninvasive testing of fetal DNA in the mother’s blood can detect Down syndrome; preimplantation diagnosis can screen IVF embryos for more than 2,000 genetic disorders; and one company, GenePeeks, plans to transform screening at sperm banks by analyzing “virtual” progeny between client and donors. Tumor profiling — identifying mutations in individual tumors and matching the appropriate therapeutic — is taking off. And we haven’t even begun to discuss the impact on microbial sequencing, in areas from food safety to emerging diseases and the microbiome (the microbial ecosystem that lives inside our gut and on our skin and that appears to play a crucial role in human health).

As medical doctors prepare to accept the $1,000 genome, it is the “$1 million interpretation” that scares them — in other words, the challenges of interpreting the data (including expertise and IT systems), integrating genome data into electronic medical records, educating physicians lost in the language of DNA, and balancing the benefits of full disclosure versus a patient’s right to privacy.

Beyond the $1,000 Genome

The warm reception to Illumina’s $1,000 genome announcement is, in part, because Flatley’s calculation doesn’t just cover the cost of chemicals but also instrument depreciation (over four years), labor, and sample preparation. What it does not include, however, are electricity — which could be useful! — and the cost of storing all that data. Of course, if you can afford $10 million for a new sequencing setup, you must already have a fairly sophisticated data center.

For an individual interested in a full sequence, a good place to start is Illumina’s Understanding Your Genome conference. For $5,000, attendees receive their full personal genome presented on a new iPad. Meanwhile, a Belgian startup called Gentle offers personal exome sequencing for about $2,000, with the test ordered through a physician.

Can anyone dethrone Illumina? Not for a while, although one potential threat is British company Oxford Nanopore Technologies. This firm is commercializing the sequencing of DNA using bacterial proteins called nanopores, which are shaped like ring doughnuts. In February, researchers got their first glimpse of data generated by Oxford Nanopore: The sequence of a bacterial DNA molecule was deduced without expensive lasers or cameras, just by measuring the electrical current fluctuations as the DNA strand was threaded through the pore. What makes this especially remarkable is that Oxford’s instrument, the MinION, is slimmer than an iPhone and plugs directly into a laptop via a USB cord. I like to carry a prototype around in my jacket pocket just to impress people.

The nanopore system has a long way to go, but regardless of which company drives the market from here on, the future seems clear: DNA sequencing will become cheaper, faster, and more accurate in the coming years. In the words of Johns Hopkins medical geneticist David Valle, personalized medicine will someday be summed up as: “Sequence once, read often.”