June 16, 2014
Forecasting Pandemics: oRACLE Chip Helps Scientists Quickly Predict
the Evolution of Viruses
Scientists in APL’s Research and Exploratory Development (RED) Mission Area have developed a device that will allow researchers to drastically reduce the time it takes to mimic the natural evolution of a virus in the lab. This tool—the droplet-based Rapid Acceleration of Laboratory Evolution (oRACLE) Chip—can potentially improve the nation’s ability to interdict emerging diseases, said RED’s Andrew Feldman. “But it can also be applied to addressing challenges of bacterial drug resistance, food safety, and biological weapons defense,” he added.
The work represents a major milestone in the Defense Advanced Research Projects Agency’s (DARPA) Prophecy program, under which a team led by APL and Harvard University is developing methods to predict how, and how fast, viruses might mutate.
The study of how viruses propagate is important for curing disease and preventing viral outbreaks. In nature, viruses compete with one another for dominance within the human body. The body’s immune system responds and begins to attack viruses when they’re detected, but there are rare variants—the most evolutionarily fit—in the viral population that can escape such evolutionary pressures and eventually dominate the population.
“We’ve got to have access to the most evolutionarily fit variants of a virus in order to truly understand what classes of viruses may emerge and when,” Feldman said.
Outrunning Mother Nature
Scientists can mimic this evolution by growing a virus in a test tube filled with a cell culture and then “passaging” it by transferring some into another test tube. But this is time-consuming and costly: using conventional high-throughput bioanalysis to study 50 million distinct evolution experiments would take about two years and more than $15 million. The “game-changing” oRACLE Chip can reduce that process to a few days, with material costs of $2.50.
Applying APL’s expertise in systems biology, optics, and biological assay development and Harvard’s prowess in microfluidics [a technology characterized by the engineered manipulation of fluids at the sub-millimeter scale], scientists applied droplet-based microfluidics to segregate and propagate a viral population as individual viral lineages, simultaneously performing millions of in vitro evolutionary bottlenecking experiments. The genomes of the evolving viral populations in each segregated lineage can be sequenced individually to determine mutations that enable viruses to evade evolutionary stresses, such as a drug or antibody.
“The oRACLE Chip allows us to quickly propagate millions of parallel passages of a virus over several generations in a short timescale—automating work that would have taken years to perform by hand into just hours,” Feldman said. “Evolving millions of independent viral lineages may allow the device to predict evolutionary mutations in advance of their occurrence.” Such experiments not only enable quantifying the risk that a particular antiviral drug will fail and when, but they produce the actual future escaping viruses, providing the targets for development of new drugs, and enabling a proactive approach to interdicting an emerging threat.
“If this tool can enable public health officials to prevent pandemic threats or understand the transition of new and deadly strains such as H7N9, this is going to have a great impact on human health,” Feldman said.
In May, the National Institutes of Health announced a grant to fund five Centers of Excellence for Influenza Research and Surveillance (CEIRS), including a $76 million center at the Johns Hopkins University, to develop innovative ways to identify and track influenza viruses worldwide. Scientists at the JHU CEIRS, partnering with Harvard, will be leveraging the oRACLE Chip to rapidly identify new influenza virus strains that may emerge as the next seasonal influenza or global pandemic that could threaten public health.
According to Andrew Pekosz, an associate professor in JHU’s Bloomberg School of Public Health and the codirector of the new center, developing seasonal flu vaccines can be a hit-or-miss proposition. Some vaccines don’t match the strain that emerges as the dominant virus in a given year, he said; and it takes too long to make a vaccine after identifying a new virus strain.
The Johns Hopkins CEIRS team hopes to improve the response to influenza epidemics and pandemics by isolating and characterizing new influenza virus strains faster and earlier in the flu season, thereby giving more time to generate vaccines and formulate public health intervention policies. The oRACLE Chip will be integral to that effort.
DARPA is also funding APL to continue to “stretch” the tool by applying it to the study of noroviruses (the source of cruise-ship illness), the human influenza virus, and the virus that causes dengue fever.
“We are looking at the application of the oRACLE Chip to address other microbial defense challenges, and other mission areas are finding applications for the technology,” Feldman said. For example, the system can count single bacteria in the drops with a drug and rapidly determine whether they are multiplying. “The technology can thus rapidly determine if a bacterium is drug-resistant, which is an important new tool for management of drug-resistant infections in the clinic, and Homeland Protection, where deliberate introduction of drug-resistance genes is a major concern for biological weapons defense.”
Media contact: Paulette Campbell, 240-228-6792, Paulette.Campbell@jhuapl.edu