One does not typically mention biosensors and DNA sequencing in the same breath. The former generally implies portable (possibly handheld) devices (for example, glucose meters) that accept chemical or biological substrates and display a measured quantity in a user-friendly way. DNA sequencing, by contrast, typically conjures images of large laboratory instruments that can run for days at a time and require highly trained human operators.

This perspective had a challenge in January 2012 during the World Economic Forum—an annual gathering of world-renowned political and corporate leaders in Davos, Switzerland. During one of the meetings, Jonathan Rothberg, chief executive officer of Ion Torrent (Guilford, Connecticut), demonstrated to the guests the company's latest DNA-sequencing machine, Ion Proton, described by some analysts as the world's first desktop semiconductor-based gene sequencer. (Life Technologies, a Carlsbad, California, biotechnology company, acquired Ion Torrent in 2010.) "It's the first machine that can do an entire human genome for less than 1000 dollars. It's the first machine than can read the genome in two hours," said Rothberg to global news agency AFP during an interview in Davos.

In the same month that Ion Torrent announced its leading-edge sequencer, Illumina Inc. of San Diego, California—Ion Torrent's biggest competitor—announced HiSeq 2500, a "genome-in-a-day" sequencer priced at $740 000, which is a significantly higher cost than the $149 000 cost of the Ion Proton sequencer. Some information sources suggest that currently, Illumina's cost for sequencing each genome is between $3000 and $5000, depending on the number of sequenced samples. Nevertheless, during an interview with Bloomberg in October 2011, the company's chief executive officer, Jay Flatley, provided a three- to four-year time frame for the company to reach the "$1000 genome" milestone. These new developments compare favorably with the prevailing weeklong lead time for sequencing a human genome. Illumina attracted media attention when on 25 January 2012, Roche, a Basel, Switzerland–based drug giant, made a hostile bid to acquire the company, which Illumina rejected. Notably, in 2007, Roche had purchased 454 Life Sciences, which was reportedly the first company to reduce drastically the cost of sequencing the human genome to about $500 000.

The $1000 Genome

The $1000 Genome catchphrase was first publicly recorded in December 2001 at a scientific retreat convened by the National Human Genome Research Institute following publication of the first draft of the Human Genome Project. At the time, the phrase aptly highlighted the chasm between the actual cost of the Human Genome Project (some $2.7 billion over a decade) and the $1000 cost benchmark for routine, affordable personal-genome sequencing. The recent claims by Ion Torrent represent the closest that the field has come toward the fulfillment of the decade-old scientific dream: sequencing an entire human genome at a cost of $1000 (or less). Currently, according to the Wall Street Journal, government and academic research centers are the principal buyers for sequencing machines. However, one expectation is that as the size of the machines shrinks and the sequencing price tag falls below the $1000 threshold, markets for genome sequencing will expand throughout the health-care system, where the machines can help doctors both prevent and treat illness. Roche's bid on Illumina is "a recognition that the high-value applications for sequencing technology are relatively near on the horizon," said Jorge Conde, cofounder of Knome, a genome-interpretation company based in Cambridge, Massachusetts, to Nature News.

Miniaturization of DNA Sequencers

The leading DNA-sequencing companies—Illumina, Ion Torrent, and 454 Life Sciences—rely on a similar sequencing approach: sequencing by synthesis. In short, starting with a single-stranded DNA template, the process builds a complementary DNA strand by incorporating one complementary nucleotide at a time (to the template strand) and registering the species (A, T, C, or G) of each added nucleotide. Whereas the other companies' methods use fluorescence-labeled nucleotides that are detectable on incorporation by means of expensive and bulky microscope systems, Ion Torrent determines incorporated nucleotides using a silicon chip that detects the released hydrogen ions during each incorporation step. This determination translates into noteworthy advantages for Ion Torrent systems: The systems are amenable to miniaturization, given that most of the action takes place on a chip (without the need for a microscope), and the chips themselves can ideally become miniaturized in future iterations. The theoretical outcome is a sequencing platform that is smaller and cheaper than competing platforms. The Ion Proton sequencer—Ion Torrent's latest sequencing platform—is comparable to a desktop photocopier in size. According to some analysts, subsequent iterations of the sequencing platform will become smaller and possibly approach the size of portable systems that researchers refer to as biosensors.

In spite of the potential miniaturization of the DNA-sequencing platforms, biological samples that contain DNA material to be sequenced may have to undergo special treatment (or sample preparation—the way that biological samples are treated before analysis). Sample-preparation activities—including extraction and PCR amplification of the DNA samples to be sequenced—may require the hands-on skills of a trained person (or, alternatively, an elaborate bulky platform that automates this process) and thus put DNA sequencers beyond the reach of ordinary (untrained) consumers. For long-term storage, DNA-sequencing reagents—including enzymes and nucleotides—require refrigeration to avoid spoilage. Such factors may prevent DNA-sequencing technology from leaving the confines of air-conditioned laboratories in the hands of highly trained individuals and may need to be addressed before DNA-sequencing biosensors can become widely useful in commercial biosensing applications.

The Delayed Promise of Genome Sequencing

Almost 12 years have elapsed since President Bill Clinton announced that the first draft of the human-genome sequence was complete in June 2000. At the time, this development was extremely exciting, because it projected a remarkable new approach to uncovering the genetic roots of common diseases like cancer and Alzheimer's and then generating the appropriate medical remedies. Looming on the same horizon was a huge potential market for genome-sequencing services and the requisite bioinformatics analysis systems for individuals to determine their genetic risk factors—such as genetic causes of ailments, susceptibility to diseases, and sensitivity to various medications. The sale of DNA-sequencing machines to research and medical facilities and possibly eventually to individuals also represented an enormous business opportunity. Accordingly, drug companies and business developers alike spent billions of dollars in positioning themselves to reap the benefits of the soon-to-be-revealed secrets of the human genetic code. But years of research and development have made it clearer that many disease-associated mutations in the human genome explain only a small fraction of the risk of contracting the associated disease. Instead, many common diseases are more likely to be caused by a variety of minor genetic variants that are statistically insignificant and hence more difficult to implicate in the cause of any particular disease. But as the cost of sequencing continues to fall from about $500 million for the first commercially sequenced human genome in 2003 to about $5000 at present with the possibility of a $1000 genome in the next one to four years, sequencing patients is likely to become a routine option. This routinization could increase our understanding of the correlation between variations in the human genome and disease susceptibility and in turn likely expand the sequencing market.

Today, DNA sequencing is enabling more and more discoveries. A recent study by scientists attached to St. Jude Children's Research Hospital—Washington University Pediatric Cancer Genome Project found that 78% of the children with a specific aggressive brain tumor had alterations in one of two protein-coding genes. The specific proteins play an important role in packaging DNA inside cells—a process that influences which genes turn on or off, repair of mutations, and the stability of DNA. "We are hopeful that identifying these mutations will lead us to new selective therapeutic targets, which are particularly important since this tumor cannot be treated surgically and still lacks effective therapies," said Suzanne Baker, one of the authors of the new study and coleader of the St. Jude Neurobiology and Brain Tumor Program, to Mark Johnson of Journal Sentinel. In January 2012, Bloomberg Businessweek reported a story involving a pair of twins, whose disease mystery found resolution (accurate diagnosis) through DNA sequencing after a decade of misdiagnosis and misdirected treatments. Then in February 2012, Nature News ran a story about Norway's efforts to become the first country to incorporate genome sequencing into its national health-care system. Following a three-year pilot phase that will involve sequencing tumors in search for cancer-related mutations and the associated treatments, the program plans to extend DNA-sequencing infrastructure to the 25 000 Norwegians who are diagnosed with cancer each year. These and other examples in various forums illustrate how the reduced cost of sequencing could routinize gene sequencing in clinical settings and in turn transform medical outcomes.

The devastating 2010 earthquake in Haiti may still be fresh in the memory of many pathologists, for DNA-sequencing-related reasons. The aftermath of the earthquake involved a major cholera outbreak, despite the fact that the island nation had not had a single case of the disease in half a century. DNA sequencing revealed that the cholera strain that precipitated the outbreak was nearly identical to strains circulating in South Asia. Eventually, using DNA sequencing, researchers traced that cholera outbreak back to UN peacekeepers from Nepal: Apparently, fecal matter from their camp infiltrated the local water sources and eventually caused approximately 520 000 cholera cases and about 7000 deaths. Knowing the origins of a pathogenic strain may help determine the most appropriate drugs to combat an outbreak on the basis of established medical countermeasures in the strain's area of origin. This example highlights the potential benefits of field-deployable DNA sequencers and their power to manage disease outbreaks.

Concluding Perspectives

Deciphering the genetic basis for diseases in general may continue to be an inveterate challenge. For example, a recent study of more than 5000 men treated for prostate cancer found that only 1.4% of them carried the defective gene that researchers believe increases the likelihood of developing the disease. Nevertheless, as the cost of gene sequencing drops to unprecedented levels, the rate of research toward understanding the relationship between variations in the human genome and disease susceptibility will likely increase. This increase in turn will likely accelerate the development of novel chemotherapies that aim at remedying the effects of the defective genes. Similar advances may further popularize DNA sequencing by allowing individuals to adapt their lifestyles (diet or exercise) to their personal genetic makeup in order to diminish the risk of illness.