Current sequencing technologies have made the $1,000 human genome a reality – a far cry from the $2.7 billion spent over 10 years to complete the Human Genome Project in 2000.
With money less of an issue, automated instruments can now routinely produce complete genomes. But cheap does not mean quick: getting genetic information remains a tedious task. Samples must be collected, prepared for analysis and sent to a specialised lab before being analysed by bioinformaticians – a process that can take anywhere from a week to a month.
The next generation of sequencers promise to accelerate genetic diagnosis, with the potential to truly transform medicine. In this vision, small third-generation devices will deliver results directly at the patient’s bed, effectively enabling the age of “P4 medicine”: personalized, predictive, preventive and participatory. This market is estimated to reach $20 billion a year, of which half would be spent genotyping cancer patients for personalised therapies.
The keys will be speed and portability. One much-discussed new device is MinION, a sequencer that looks like an external hard disk drive – considerably smaller than the usual fridge-sized sequencers. British start-up Oxford Nanopore Technologies has spent 10 years developing MinION, which directly records the A, T, G and C molecules that make up the genetic code as they travel through tiny holes (see Nanopore Sequencing).
Such nanopore detection offers exquisite sensitivity: MinION could be the first instrument to offer both portable and real-time sequencing. “I am optimistic about the technology. It could be on the market by mid-2015,” says Vladimir Benes, head of the genomics core facility and the European Molecular Biology Laboratory in Heidelberg, who has had early access to MinION. According to Benes, the long stretches that can be read by nanopore sequencing will simplify analysis of the data. Current second-generation techno‑ logies are based on shotgun sequencing, which produces small DNA fragments that have to be stitched back together by supercomputers. Since MinION should require less computer power and time, many experts expect it to allow genome sequencing on demand.
Portability will be the game changer. Entire genomes may make headlines, but they are not always necessary to obtain useful medical information. Small devices can also be used with a focus on signature genes and could be powerful field tools to detect traces of pathogens, such as viruses and bacteria, while identifying the mutations responsible for devastating cancers in individual patients. Because of its size, MinION has the potential of being really disruptive, but there are competitors.
Nanopore sequencing is also being pursued by other start-ups, like Rhode Island-based Nabsys. Meanwhile, multinational life science companies like Thermo Fisher and BioRad have acquired similar technologies to enter this competitive industry.
The market for sequencing instruments is currently shared among a handful of companies – Illumina, an American company, produced 90% of all worldwide DNA data in 2013. But the field is evolving quickly: less than six years after buying 454 Life Sciences (the U.S. biotech company that produced the first ever second-generation instrument), Switzerland’s Roche announced that it would kill the program by mid-2016 because it could not compete with Illumina. Instead, Roche spent $125 million in 2014 to acquire Genia, a California start-up that also develops nanopore sequencing.
Oxford Nanopore may be the hottest start-up in DNA sequencing, but there is no guarantee that it has a real advantage. Like its competitors, the British company refuses to discuss its technology. What is certain is that portable sequencers will soon make bedside genetic analysis a reality – and that this will shake medical diagnostics to the core.
Initially imagined by American biophysicist David Deamer in 1989, nanopore sequencing has been under development since 1995. The technology is based on a membrane containing tiny holes that can accommodate only one base DNA at a time. The value of a current flowing through an individual pore depends on whether it is blocked by an A, T, G or C. By monitoring the change in current as a string of DNA passes through the space, the sequence can be recorded. Two types of holes have been investigated: solid-state and protein-based.
Beyond the machine
It will take more than smaller and faster instruments to obtain bedside DNA diagnostics. “New devices alone will not make the revolution happen,” says Vladimir Benes of the European Molecular Biology Laboratory in Heidelberg. “The development of tools to analyse data cheaply will be crucial, too.” Establishing the link between diseases and sequencing data now still requires the extensive and costly work of a team of bioinformaticians.
“People focus way too much on the machine itself. What is important is the workflow,” says Thomas Theuringer of Qiagen, a German company specialized in instruments and consumables for life science research. “Clinical laboratories do not want to spend time on optimisation. They need good standardisation.” When analyzing DNA sequences, the quality of the bioinformatics tools and the reference DNA database are crucial, opening up a market as important as the gene sequencers themselves. There is also a lot of competition for data storage and analysis. Software companies, such as Swiss-based Sophia Genetics, are working on different solutions in close collaboration with sequencing companies and hospitals.