New opportunities in the genomic era

THE HUMAN GENOME

Ten years on from the publication of the draft human genome, Naturejobs takes a look at promising areas of job growth in bioinformatics, DNA sequencing and genomic medicine.

IN NOVEMBER 2010, more than 6,000 scientists and clinicians gathered at the Walter E. Washington Convention Center in Washington DC for the 60th annual meeting of the American Society of Human Genetics (ASHG). This was a record attendance, and of the wide variety of break-out sessions one topic drew a particularly large crowd. “The only room that was overflowing—and it had seating for 770—was one of the statistical genetics sessions that focused on databases,” explains ASHG executive vice president Joann Boughman. The session's popularity illustrates one of the key challenges—and opportunities—of the genomic era: what to do with the vast amount of data being generated by DNA sequencing. “When you start thinking about storing 3 billion base pairs of data from a million people, and then trying to figure out what that might mean, it becomes staggering,” says Boughman.

Genomics is big business. A recent report by investment bankers Cowen and Company estimates that the gene sequencing market will grow to $1.5 billion by 2015, up from $600 million in 2009. This growth is being fuelled by improvements in speed and cost, making these technologies accessible to more researchers: sequencing a human genome can now be done in a week, according to some estimates, and costs less than $40,000—and will certainly become quicker and cheaper.

In the ten years since the publication of the first draft of the human genome, genomics has established itself as a powerful tool in biomedical research. Many predict the next decade will bring several more developments, including a bioinformatics boom and long-awaited changes in how clinical medicine is practiced, especially oncology.

Burgeoning bioinformatics

We've crossed a threshold. Now the challenge is handling the amount of information that can be generated. Eric Green, director of the National Human Genome Research Institute

Genomic data are everywhere. The per-base cost of DNA sequencing is now around 100,000 times cheaper than it was a decade ago, and the current generation of sequencing machines can read around 250 billion bases each week. As the US National Human Genome Research Institute (NHGRI) points out in this issue of Nature (see Perspective in the Research section), sequencing DNA is no longer the bottleneck it once was in genomics. “We've crossed a threshold,” says NHGRI director Eric Green. “Now the challenge is handling the amount of information that can be generated.”

Tackling the challenges posed by the increasing volume of genomic data has helped bioinformatics to mature. “It's truly becoming recognized as a discipline in and of itself,” says Harold Garner, director of the Virginia Bioinformatics Institute (VBI) in the United States, which provides bioinformatics services and training as well as conducting research. Garner says that many bioinformaticians are moving from a support role to directly making observations and discoveries. But while demand for bioinformaticians is growing, supply is not keeping up. A recent Nature survey of around 1,100 life scientists found that scarcity of bioinformatic expertise is one of the main obstacles to making full use of sequencing data (see http://go.nature.com/ss9FI3). Fortunately there are indications that this is being addressed. Plans are in place to double the size of the VBI over the next ten years to 500 staff, and funding remains strong despite the uncertain economic outlook. In the United Kingdom, the European Molecular Biology Laboratory's European Bioinformatics Institute (EBI), located next to the Wellcome Trust Sanger Institute in Cambridge, is also helping to plug the skills gap by providing a wide range of bioinformatics training for researchers plus postgraduate degrees in bioinformatics. “In 2004 we ran 20 formal training courses, and in 2009 we ran well over 150,” says EBI director Janet Thornton. The courses are usually over-subscribed, and the EBI expects to run more in 2011.

As well as being in greater demand, the role of the bioinformatician is also becoming more diverse. “You have to be a bit of a jack-of-all-trades,” says Thornton. “You're dealing with huge amounts of data, and you also need to have a pretty good knowledge of the broader biology.” As more information is gleaned from the human genome, there will be a growing need for bioinformaticians who understand how the basic genetic data can help improve medical diagnosis and treatment. And away from the lab or clinic, there are opportunities for other bioinformaticians to publish original research by mining existing data. “[They] can take advantage of the tremendous amount of data amassing out there,” says Garner. “It's so vast that nobody is really going through and analysing it with complete thoroughness.”

The European Molecular Biology Laboratory's European Bioinformatics Institute is a leader in the bioinformatics revolution.

Sequencing: the next generation

When the current generation of state-of-the-art DNA sequencers first emerged in 2005, scientists and technicians accustomed to working with first-generation capillary sequencers had to change their approach to research. Targeting sections of the genome has been replaced with “let's just sequence the whole thing and figure out what's going on”, says Garner, adding that many technicians are now being asked to do much more data analysis. This is the case at the main gene sequencing facility at the Pasteur Institute in Paris, known as the Genopole. The facility had a next-generation lllumina sequencer installed in 2008 and upgraded in 2010, presenting new opportunities for the facility's two technicians. “They have a lot of interesting projects,” explains Genopole head Philippe Glaser. “They are both doing the sequencing, but they also contribute to the analysis.” Demand for the machine is high, and Glaser is looking at ways to increase capacity without taking on more technicians. “Some groups that are asking for a lot of sequences will construct the [DNA] libraries themselves,” Glaser explains. He estimates that freeing technicians from this preparatory step should double productivity at the Genopole.

Other labs have taken different approaches. The Centre for Genomic Regulation (CRG) in Barcelona, Spain, began using second-generation sequencers in mid-2008. “We have seen quite a dramatic increase in the use of these instruments,” says Heinz Himmelbauer, head of the sequencing unit at the CRG, who has overseen an increase in the number of technicians from two to five.

Moving from end-user to manufacturer, the sequencing industry itself is also providing new opportunities. Illumina, a leading manufacturer of high-speed sequencing technology, was founded in 1998 with just seven personnel. It now employs more than 2,000 people worldwide, and it is planning to hire a further 500 staff in 2011. Chief technology officer Mostafa Ronaghi says that while there will be new jobs in R&D, the majority of the company's expansion will be on the commercial side, such as in sales and marketing—and scientific skills are a major asset in these positions. “The majority of people in our sales department have a PhD and have done a postdoc,” explains Ronaghi. “These are technical sales, and they really need to understand the technology and the competitive landscape in order to address the needs of the customer.”

JANE ADES, NHGRI

Not all scientists have access to these advanced machines; some researchers still use capillary sequencers. As a low-cost, high-throughput alternative for these researchers, Illumina will be launching a compact sequencer, the MiSeq, later this year. The company says the MiSeq will be able to analyse data from purified DNA in as little as eight hours. Ronaghi adds that the company is planning to take this concept further, increasing the throughput to drive the cost-per-base down to a level where insurance companies would be willing to pay for full genome sequencing as part of treatment. “For wider use in the clinic we need to drop the cost below $1000 per genome,” he says.

The $1000 genome is a major target for both industry and academia. In September 2010 the NHGRI awarded more than $18 million in grants to ten teams of researchers to help spur the development of a third generation of higher speed, lower cost sequencing technologies. The largest grant will support research into single-molecule DNA sequencing using engineered nanopores. This approach, which removes the need for DNA amplification and labelling, is also being developed into a viable technology by Oxford University spin-out company Oxford Nanopore Technologies. The company's chief executive, Gordon Sanghera, says working on the next generation of sequencers requires a certain mindset. “You need people who are prepared to raise their head above their discipline parapet and get a broader view,” he says. The nature of the development pipeline also means that scientists and engineers must combine this creative thinking with a willingness to carry out less glamorous but equally important tasks. “There are moments of brilliance followed by lots and lots of bench science,” Sanghera explains.

These people are hard to find, and Oxford Nanopore works hard to attract top talent. It counts 19 nationalities among its 90 staff, and has a relatively flat management structure with merit-based remuneration to foster innovation. Sanghera says the effort is worth it: “When you get those people, you get this great confluence of ideas. They push that innovation to the next level.”

From bench to bedside

Many experts are predicting that the next decade will see a large-scale expansion of genomic medicine, with a range of associated career opportunities. “The medicine of the future will be data-rich and individualized,” says Hans Lehrach at the Max Planck Institute for Molecular Genetics. There is particular promise in oncology, where sequencing the genomes of both healthy and cancerous tissue could soon become routine practice. “This is not something that is going to happen a few decades from now,” says Lehrach. “It's what we're trying to do now.” Researchers are also looking beyond the genome itself to associated concepts such as the microbiome, which is a genetic catalogue of the microbial species that inhabit a defined environment such as the human body. “We have more microbial cells than human cells,” says Karen Nelson, director of the Rockville, Maryland campus of the J. Craig Venter Institute ( JCVI), one of four sequencing centres taking part in the Human Microbiome Project. These microbes, she continues, “contribute significantly to our health, disease and development”.

The fast pace of discovery poses several challenges that must be overcome before the potential of genomic medicine can be fully realized. “Clinicians and researchers need to have more of a dialogue,” says Nelson. Boughman agrees there is a knowledge gap, saying that although medical schools are doing a good job of teaching genetics and how it fits into the practice of medicine to the current trainees, there is a huge number of physicians who have been in practice for a long time who need to be brought up to date. This need to make primary care doctors aware of the latest research is leading to a growth in the number of geneticist educators, and there are also calls for an increase in the number of genetic counsellors for patients.

A bright future

NHGRI's Green is confident that scientists who combine experience in biology or medicine with another discipline such as informatics, computer science or mathematics have a bright future in genomics. He also sees a need for people who are “multilingual” in genomics and areas such as policy, political science, ethics or law. “The perfusion of genomics into so many areas of science, clinical medicine and society means that we need people who are trained in more than one area,” he says. But he calls for more research to ensure funding is used most effectively in today's challenging financial climate.

Those in the vanguard of genomics also emphasize the need for scientists interested in the field to develop a deeper appreciation of its potential for improving healthcare. Boughman says she is always surprised at the large number of molecular scientists or biochemists who had never met a patient with the disorder they were studying. “To really figure this out,” she says, “we are going to need to have all the pieces of the puzzle”.