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Next-Gen Sequencing Shows Promise for Public Health, but Faces Technical, Political, Social Hurdles

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By Monica Heger

This story was originally published Oct. 31.

International food-safety, epidemiological, pathogen-monitoring, and health agencies believe that next-generation sequencing will become the technology of choice for monitoring outbreaks and pathogens on a global scale within the next decade, according to a recent report.

In September, the Danish Technical University's National Food Institute hosted a meeting in Brussels that gathered experts to discuss the potential of the technology and the creation of a global database that would incorporate whole-genome sequence data of microorganisms to help identify and monitor pathogens rapidly.

According to a consensus report from the meeting, "it is likely that in five to 10 years all clinical microbiological laboratories will have a DNA sequencer in use on a daily basis and within that timeframe the costs for a complete bacterial genome sequence might be less than €100 [$138]."

The report notes, however, that "the future limiting factor will not be the cost of whole-genome sequencing, but how to assemble, process, and handle the large amount of data in a standardized way that will make the information useful, especially for diagnostics and surveillance." The authors also outline a number of political and social hurdles that must be resolved before the technology is widely adopted.

Boosted by the use of next-gen in identifying the Escherichia coli outbreak strain in Germany this summer, experts think that whole-genome sequencing of microbes and pathogens will be routinely used in a public health setting.

"There is no doubt that next-generation sequencing is going to play a major role in public health disease monitoring," Dag Harmsen, the head of research at the University of Münster and a participant at the meeting, told Clinical Sequencing News. Harmsen also led one of the first teams to sequence the E. coli strain on Life Technologies' Ion Torrent PGM (IS 6/7/2011).

Next-gen sequencing has created a "big opportunity" for "national and global public health to follow the development of disease in real time and space," added Jørgen Schlundt, the deputy director of the National Food Institute at the Technical University of Denmark and organizer of the September event.

It's "definitely the way forward," said Peter Gerner-Smidt, chief of the enteric diseases laboratory branch at the Centers for Disease Control and Prevention, who was also at the meeting.

There is need for a global system to share and use genomic data to address public health, not least because more than 25 percent of annual deaths worldwide are due to an infectious disease, and "current and new infectious disease challenges will continue to arise, given the trend toward globalization of travel and trade, coupled with demographic changes (urbanization, ageing) and increasing impact of the human population on natural environments," the authors wrote in the report.

The rapid development of genomic technologies, including next-gen sequencing, "holds great promise for improving the early detection, prevention, and control of current and emerging infectious diseases," they added.

Currently, outbreak strains are typed using capillary electrophoresis, said Harmsen, which is "not as information rich as next-gen," and also more time-consuming and cumbersome. By contrast, with next-gen sequencing, researchers can uncover "pathogenicity factors and antibiotic resistance."

He personally believes that next-gen sequencing could be implemented in the public health setting within the next couple of years, although the consensus report gave a more conservative estimate of five to 10 years.

The machines likely to be implemented would be the smaller benchtop systems — the PGM, Illumina's MiSeq, and 454's GS Junior — and possibly the Pacific Biosciences RS because it is fast and does not require amplification, Harmsen said.

The benchtop systems are ideal because they are quick and more affordable than full-size sequencers. In addition, for microbial sequencing, the throughput of an instrument like the HiSeq is not needed, he said.

Gerner-Smidt said the CDC is already starting to do some sequencing, and has platforms from 454, Illumina, Pacific Biosciences, and Ion Torrent. Ultimately though, "the ones we use in five years, the ones that will be implemented in diagnostics labs, will be very different from today's platforms," he said.

The goal, said Schlundt, is that a researcher could take an unknown microorganism, sequence it in a few hours, send the sequence to a database or a system of databases, and identify the pathogen within minutes.

"Basically, you're changing the way we've identified microorganisms since Pasteur," he said.

Technical Challenges

Despite the rapid improvements in sequencing technology, creating a global system to "aggregate, share, mine, and translate genomic data for microorganisms in real time" will have a number of challenges, the participants concluded.

First, such a system will be expensive. The group estimated that the cost of building a database that could host future sequencing data would be around $25 million. However, Schlundt said that is just the cost for building the database — not maintaining it. When all is said and done, costs could be upwards of $50 million to $100 million, he said.

Also, because next-gen sequencing is still a developing technology, there are no standards in terms of how to generate and analyze the data. "That's a huge issue," Schlundt said. International standardization bodies are not equipped to handle fast-moving technology like next-gen sequencing, he said. "They are more suited for something static."

While a database of whole-genome sequence data would not require "final sequencing" of all microorganisms, data quality will still be "crucial to avoiding typing errors," the group wrote. The GenBank model was cited as not containing adequately high quality data, which would lead to uncertain results.

In order to move into using whole-genome sequencing, the participants suggested using the human metagenomic research project as a model, and creating a database of current sequences with basic software tools for clinicians.

In addition, the field of virology already uses a sequence-based method for diagnosis and typing, but only on partial genome sequence data, not whole-genome. Meeting participants suggested that lessons could be learned from this experience about how to standardize data, for instance.

Harmsen added that the major technical hurdle would be improving the bioinformatics and analysis so that sequence data would be "easier for a physician or public health officer to understand."

A "plain language" report would have to be generated, he said, because raw base-pair data would not be meaningful for a clinician. Instead, a clinician would need a report of "one to two pages of text."

Political and Social Challenges

Despite these technical challenges, Schlundt said that the general thought at the meeting was that the technology is ready, but other factors must be addressed before next-gen sequencing is broadly adopted in the public health setting..

"The notion that this could be done was not discussed so much because everybody was simply agreeing that, 'Yes, of course you can [do this].' The technical capacity to do something like that will clearly be there soon," he said.

A greater challenge will be overcoming political and social hurdles, he said. For instance, there are lots of people involved in the "old ways" of typing micoorganisms, and "there will be some resistance because you have all these different specialists in different microorganisms."

"Someone who knows something about the mycobacterium that causes tuberculosis knows nothing about salmonella, knows nothing about noroviruses. … In the future, of course you still need these specialized specialists, but you don't need in every country a specialized lab for tuberculosis, a specialized lab for salmonella, and another one for campylobacter and one for hepatitis virus," Schlundt said.

In the future, a researcher could take any culture, sequence its DNA, and know what the microorganism is, he said.

Additionally, scientists, public health agencies, and governments may be averse to sharing sequence data. But, in order to establish a global database that can serve as an "early warning system," a sequence database would need to be open-access, the report authors concluded.

Exactly how much data, and what type of data, should be shared will also have to be worked out. Any policy will need to balance the need to share enough data to impact public health with privacy protection concerns.

Governance of such a system, policies for sharing data and materials, and political concerns were "seen to be the major obstacles," said Schlundt, and "where we need to put a lot of work if we want this to succeed."

Denmark has already started a proof-of-concept project to work out some of these issues. Researchers are working out how to develop a database and a system so that information and data can be exchanged quickly and between a number of stakeholders.

The time is right to begin working out the logistics, said Schlundt. While next-gen sequencing is still primarily a research tool and has not yet been adopted widely by public health agencies, the technology is moving quickly to the clinical side, and Schlundt said there is a window of opportunity to develop a global system that could have a great impact on public health.

"We need to start talking about how we want to do that now if we don't want to end up in a situation where we have many systems that don't work together," he said.

It is a "major opportunity for the world to take a step forward if we join forces."


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.

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