DARPA Embraces the Biotech WorldLarry Maloney | February 03, 2015
When it comes to pushing the technology envelope, few organizations can match the impressive contributions of the Pentagon’s Defense Advanced Research Projects Agency (DARPA). Spawned a half century ago out of U.S. anxiety over former Soviet Union space program successes, DARPA research has spurred a litany of breakthroughs. Among the most prominent: the Internet, global positioning satellites, stealth materials, drones, reduced instruction set computing (RISC) and micro-electro-mechanical systems (MEMs).
While still focusing a hefty share of its $3 billion budget on defense-related technology, DARPA in 2014 launched a Biological Technologies Office (BTO) dedicated to exploring the intersection of biology and the physical sciences. Its projects target revolutionary technologies that may benefit civilians as much – and in some cases even more – than the military.
BTO’s founding director, Dr. Geoffrey Ling, knows well the value of biological and medical advances. A veteran of 27 years in the U.S. Army Medical Corps., he served as a neurointensive care physician in Afghanistan and Iraq. Dr. Ling, is also neurology professor at the Uniformed Services University of the Health Sciences. He describes key BTO programs in an interview with Engineering 360 contributing Editor Larry Maloney.
Maloney: What led DARPA to establish the Biological Technologies Office?
Ling: The office, announced by DARPA Director Arati Prabhakar last March (2014), speaks clearly to biology’s place in the world today. Biology has evolved from being primarily an observational science to a science that is both predictive and quantitative. More to the point, biology today has become a core science that can be developed into capabilities important for the nation’s defense. BTO seeks to harness the power of biological systems by applying the rigorous tools of engineering and related disciplines and to design next-generation technologies inspired by the life sciences.
Maloney: Turning to some of the 25 BTO programs described on the DARPA Web site, what activities fall within the Living Foundries initiative?
Ling: That program, which was started by Deputy BTO Director Alicia Jackson, focuses on leveraging synthetic biology, such as our ability to work with micro-organisms and DNA, to create products of value to America, such as pharmaceuticals, biofuels and new materials. Our interest is not just to create such products in a laboratory setting but to develop platforms that allow these products to be manufactured at scale. At the same time, we want to do a rigorous exploration of the governing tools of synthetic biology so that it becomes a much more predictable science.
We have already expanded Living Foundries under Dr. Justin Gallivan to include a new effort called Biological Robustness in Complex Settings (BRICS). To date, the work in synthetic biology has focused primarily on manipulating a micro-organism to make a substance, such as penicillin. However, these organisms tend to be fragile, requiring precise environmental controls to survive, and often lose their engineered advantages during the production process. As a result, the costs of producing pharmaceuticals can be expensive. Dr. Gallivan wants to develop methods to increase the biological robustness and stability of these engineered organisms, while maintaining or enhancing assurances of safety. But work in synthetic biology goes beyond looking at the behavior of organisms in the laboratory. For example, wouldn’t it be great if you could engineer a naturally occurring marine organism so it could help clean up oil spills?
Maloney: How would BTO’s Rapid Threat Assessment program help the medical community respond to sudden chemical and biological dangers, such as a deadly virus?
Ling: The problem today is that it can take decades to gain a cellular-level understanding of how new threat agents spread. It took 33 years for dedicated researchers to understand the mechanism of Cholera toxin. Dr. Barry Pallotta, manager of the Rapid Threat Assessment (RTA) program, aims to develop methods and technologies that can map the complete molecular mechanism of a threat agent within 30 days of its exposure to a human cell.
One tool in this approach is to use flash freezing to study cell cultures over a period of time, from the milliseconds immediately following exposure, to several days after when alterations in gene and protein expression might occur. You then do mass spectroscopy on these cultures to identify all the products present within the cell. In this way, you can reconstruct the mechanism of the threat agent and get a huge head start on developing therapies and strategies to defeat the threat.
Maloney: What are some other BTO programs that address world health concerns, such as the Ebola virus?
Ling: A good example is a program called Autonomous Diagnostics to Enable Prevention and Therapeutics (ADEPT), which relates well to Ebola, as well as other virus threats.
One of ADEPTs goal, managed by Col. Daniel Wattenberg, is to develop better ways to produce vaccines against threats. Current methods for creating vaccines can be time-consuming, expensive and often ineffective. Say we want to develop a vaccine for a new flu virus that has showed up in Thailand and will hit the U.S. in a year the process will start with isolating the virus from patient specimens in Thailand and then begin developing the vaccine for it, knowing that the virus is bound to mutate.
That whole process takes from nine months to a year. But there are several problems with this approach. A major one, as already noted, is that the virus is constantly mutating, which is one of the reasons why this year’s flu shot is only 23% effective. Col. Wattenberg wants to throw that whole model out.
Rather than focusing on the virus itself, his method focuses on analyzing the antibodies in blood samples of patients who have recovered successfully from a virus. Once you know the DNA and RNA of these antibodies, you can inject that DNA, and a person’s white blood cells will make the needed antibodies. The costs for this process at genetic labs would be pennies versus several dollars under conventional methods of vaccine manufacture. We looked at how much it would cost at scale to produce a flu vaccine by this new method. It turned out to be 40 cents per dose for a much more effective vaccine, versus $21 per dose under current methods. Commercialization of this new approach could be as little as a year away.
You mentioned the Ebola epidemic. The Adept program is currently working on a vaccine, based on analysis of the antibodies from U.S. physicians who survived the Ebola infection contracted during their work in West Africa.
Maloney: Moving from synthetic biology to engineered products, can you cite examples of new devices emerging from BTO research?
Ling: One is a dialysis-like device being developed to fight sepsis, which is an overwhelming infection of the blood stream. That condition not only threatens military personnel, such as those suffering combat injuries, but thousands of civilians as well.
We know that dialysis works in removing toxins from the blood when your kidneys fail, and we want to apply that same concept to removing the inflammatory mediators that accompany sepsis. The challenge here is to remove enough white blood cells to reduce the sepsis state, but preserve enough to enable the body to fight infection. The research team headed by Col. Matt Hepburn has built portable prototypes of such a device, which was originally conceived by Dr. Tim Broderick.
Maloney: How long will BTO pursue a research program if results are unclear?
Ling: DARPA’s guiding philosophy on projects is: High risk, high reward, plus a corollary: Fail fast, fail early. We don’t want to string out research that is not yielding positive results. As early as possible, we want to find out if the original scientific assumptions behind a project are valid, and if the research can lead to an actual product. In the case of the dialysis-like device for sepsis, we will likely know within the next 18 months if its workable and scalable.
Maloney: BTO’s Revolutionizing Prosthetics program has driven the development of some amazing electro-mechanical technologies. But how would you assess the progress in translating those successes into affordable prosthetics to serve patients, such as combat amputees?
Ling: We’re making significant progress, as was seen by last year’s FDA (Food and Drug Administration) approval of the DEKA Arm System, developed with funding from the Revolutionizing Prosthetics program. The battery-powered device is of similar size and weight to a natural limb and has six user-selectable grips. It also allows control of multiple joints using a variety of input devices, including wireless signals.
That arm is expensive, about $50,000, but as manufacturing is scaled up, prices will drop, perhaps by as much as a half. But you also must consider the value that a device such as this has in restoring an individual’s functional capabilities, as well as the value to society of having people return to the work force and make solid contributions. When that happens, the return on investment in this technology becomes extraordinary. Think about the value of this device to a 22-year-old combat amputee with another 50 or 60 years of life ahead.
Even so, you bring up a good point that my office must continue to address. That is, how can we expedite the transfer of technologies that we develop to the commercial marketplace? We are now working hard to build relationships with manufacturers who have the know-how both to turn DARPA-developed technologies into useful products and to create demand for those products in the marketplace. Otherwise, all we’re doing is science fair projects.
Maloney: DARPA is one of five federal agencies participating in the President’s $300-million BRAIN Initiative launched in 2013. What is BTO’s role in that effort?
Ling: BRAIN is an acronym for Brain Research through Advancing Innovative Neurotechnologies. That last word – neurotechnologies – is very important and it speaks to BTO’s work to develop tools and technologies that could lead to therapies for a wide range of conditions, such as Alzheimer’s and Parkinson’s diseases, depression and traumatic brain injury.
This country has a national treasure of phenomenal scientists and engineers working in the field of neuroscience and neurotechnology. They don’t lack work ethic or ideas; what they lack are better tools to do their work. DARPA’s commitment to develop these tools is $50 million annually over the next decade. BTO’s Dr. Justin Sanchez, a neuroscientist, is managing several brain research programs, including one dedicated to developing techniques for studying the brain at the mesoscale level, which typically involves analyzing how 1 to 10 million brain cells interact. This work is entirely different from studying the brain at the macroscale level, as in magnetic resonance imaging, or at the microscale level, where you study individual cells from a biopsy under a microscope.
Maloney: Looking ahead to the next five years, what are some of the emerging areas that BTO is exploring for possible new programs?
Ling: One area to keep your eye on is the relationship between fungi and the plant, animal and insect worlds. Research in this area can provide amazing insights that will have important impact on ecology and agriculture. We should also take a close look at the marine world, which can yield rich opportunities in new materials, new organisms, farming and much more.
In short, I am looking to bring such fields as marine biology, mycology and entomology into DARPA. These areas hold huge implications on issues ranging from global warming to scarce resources like clean water.
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