The Pentagon's research and development division, DARPA—the creative force behind the internet and GPS—retooled itself three years ago to create a new office dedicated to unraveling biology's engineering secrets. The new Biological Technologies Office (BTO) has a mission to "harness the power of biological systems" and design new defense technology. Over the past year, with a budget of about $296 million, it has been exploring challenges including memory improvement, human–machine symbiosis and speeding up disease detection and response.
DARPA, or the Defense Advanced Research Projects Agency, is hoping for some big returns. The director of its BTO, neuroprosthetic researcher Justin Sanchez, recently spoke with Scientific American about what to expect from his office in 2017, including work on neural implants to aid healthy people in their everyday lives and other advances that he says will "change the game" in medicine.
[An edited transcript of the interview follows.]
Before your office was created in April 2014, DARPA had already worked on some biological projects—including research on combatting antibiotic resistance and mental health interventions. What's changed with the creation of your office?
We had been doing biological work—at the interface of biology and engineering—for many years, but it was scattered throughout the offices. With our office there was a recognition that biological technologies were going to play such a crucial role in not only shaping where our country was going, but the threats coming to our country, and we needed a focused comprehensive effort going forward.
I'm particularly intrigued by BTO’s hope to develop programmable microbes to produce needed medications on the fly—an effort to sidestep concerns about stockpiling the right drugs or worrying about complex transport logistics. That sounds amazing. Where is that work now?
That's a program called "Living Foundries" — like a foundry where we would build something that's alive. Traditionally we use chemistry to make new compounds or new drugs. But recently we've realized that microbes like yeast and bacteria can also produce compounds, and we can program them to make those compounds by first understanding the chemical pathways they use. Take yeast. Yeast uses sugar for a variety of pathways to produce alcohols. If you reprogram those pathways, however, you could potentially have yeast build a variety of different compounds that they weren't initially designed to make and we would still use the same feedstocks — like sugar.
Our teams design the genetic codes that would be needed to reprogram the yeast. That is such a different idea about how to revolutionize the way we build compounds. That program set out to produce 1,000 new molecules throughout the duration of the program [which has three years left], and the teams are well on their way. I believe they have produced close to 100 new compounds already using these new pathways in yeast. It's about thinking about biology and marrying it with engineering tools, and then using those two components to design something.
So you are in the early days of building compounds to spec?
Yes. They are on milligram quantities of these new compounds, but ultimately, throughout the course of the program, they are scaling up to kilograms.
If we can design these entirely different foundries for building these compounds, we think it could revolutionize how we think about drug development and also nonmedical approaches, because this is a platform technology. Depending on what compound you are interested in — maybe some for medical uses or some that are for building a new material, like something more robust than the elements — there are lots of possibilities.
How will the new president-elect and Republican-dominated Congress affect your work?
We usually don't get in the middle of those kinds of things. The thing that I always like to emphasize is that our mission at DARPA remains the same no matter what the political climate is. Our mission is about breakthrough technologies for national security. It's our job and role to think well ahead of what others in the world are thinking about for science and technology. I think that mission transcends the vast political landscape that is out there. We have a very focused mission and we are trying to keep our country safe…, so we are sticking to that mission no matter what happens, not only in this election cycle but in future election cycles.
What project at BTO are you most excited about for 2017?
It's like your kids—you can't have just one favorite. I have multiple favorites. Let me share a few that will be really important to address in 2017. The first is an area we call "Outpacing Infectious Disease." Our current approach, whenever a new pathogen hits our shores, is that everybody scrambles. We want to get ahead of any pathogen that may hit our shores and be as ambitious as we can to take pandemics off the table. We have pioneered new work in DNA and RNA approaches to immunization. Specifically, we are thinking about nucleic acid approaches to immunization. The idea is that you can tell your cells that produce antibodies what the right code is for producing the antibodies that would be effective against a pathogen. So you would get a shot, but that shot would have a code in it to tell your cells how to respond to that pathogen—and what that would lead to is a near-instantaneous immunity against that pathogen and an ability to really fight against it.
If you contrast that against the traditional way we think about infectious disease, where it takes months — if not years — to not only identify the pathogen but go through a long manufacturing process to produce vaccines with big bioreactors and so on, [the current] process is far too slow for the kinds of threats that are ultimately coming to our country. That's why we took this radically different approach to develop this fundamental technology, to have DNA- and RNA-based approaches to fight infectious disease. I'm hoping we will have some big announcements about that in 2017.
What sort of announcements?
We are already getting some really good results in mouse models indicating that the nucleic acid approaches are working well. We're starting down the road of doing some safety work in humans. Those are the early research steps. We have every intention in the coming year of building new programs for this end-to-end platform. We look forward to making some announcements about how we are working in this space in 2017 that show that this isn't just an aspiration—this is something we're going after in BTO. If we are successful here, I think it will change the game about how we think about infectious disease.
In the past few years there has also been a lot of buzz around brain-controlled prosthetics and exoskeletons. How does DARPA's BTO fit into that space?
We are heavily vested in this area. We just had a small ceremony at Walter Reed — we delivered the first two commercially available "Luke" prosthetic arms, the world's most advanced prosthetic limbs. We work so hard [on research], but to see it going to the veterans — that's really great. While that's a step in brain-controlled prosthetics, we don't stop there.
I think in the future there are a wide variety of devices that can be controlled via neural activity, not just the assisted kind but also a kind able-bodied individuals could ultimately use in their everyday lives. Another thing we aspire to do in 2017 is think about neural technology in everyday life.
Really? What sort of applications are you thinking about for healthy, noninjured people to use in everyday applications?
I'm really intrigued by using neural technology to change how we interact with each other, how we communicate with each other and even maybe make decisions. I'm thinking about cognitive assistance. There are a whole host of ideas about how it could help a wide variety of people. The door is just opening up to even think about these kinds of concepts, and to think about technology today to go down that road.
DARPA has often operated without a lot of public exposure about its projects, at least until the work is completed. How do you see that model fitting in with the reality that a lot of the medical work your office does would potentially affect or benefit American civilians writ large?
At DARPA we love sharing [our] vision with the world, and we like working extremely hard and diligently below the radar to make sure we are delivering upon our promises—and when things are right, we share them with the world. One of the areas that we have been very out in the media about is our work on the Brain Initiative. That was an area where Pres. Obama set the challenge for our country. For the last couple years we have been working not only to prove out technology there [within the Brain Initiative], but also working with other federal agencies—NIH (National Institutes of Health) and NSF (National Science Foundation) to name a few—and to share our results internationally, so that other scientists and medical professionals could use the information that is coming out to accelerate ultimately what they are doing. The other area that we have been very out in the open about publicly is our infectious disease work. With every major milestone of testing a DNA or RNA approach we've made an announcement, and if one of the people we are funding gets additional funding from outside sources, we make an announcement.
Recently a DARPA-funded study, published in the journal Neuron, concluded that deep-brain stimulation failed to improve memory—and in fact actually worsened memory. But a previous study, a few years ago, found the opposite: that stimulation helpedmemory. So what does this mean for your office's work in this area?
Neurotechnology is a very big area in our office. We have made great strides on the medical side of things, showing direct neural interfaces [connections between the brain and a device like a neurostimulator, computer or prosthetic] can restore movement, sensation and health with neuropsychiatric disorders. What's interesting, with respect to the study that just came out, is that a large portion of people think you can locate an important area of the brain and stimulate away, and magically we get a response! That's not the case. When you map out what's going on in the brain, we've found that if you don't send the right codes into the brain you don't get a facilitation of memory—and you can even impair memory. The flip story is that if you do send the right codes in, you can get huge improvements in declarative memory. The program has also seen that side of the work turn out. So when I take a step back from seeing all of this and do an assessment of it, we have both sides of the coin. We understand the codes that impair memory and facilitate memory. I think it prompts deeper investigation for the next generation of brain exploration.
Just quickly, can you clarify what you mean by "code?"
The code is a couple of things. It is the precise firing of individual neurons. Let's say you have 100 neurons and they all fire at different times in different locations—it's interpreting all that turning-off and turning-on when trying to remember the word "Nancy" or "tree" — we can understand what those firing patterns mean and how they relate to the outside world. All those neural firing patterns collectively produce brain waves or rhythms, and we are studying the brain at that level, too. It's important to understand all those different facets of the brain because that's how it works. Without the ability to go in and make these measurements we would never have this understanding. That's why it's so important that an organization like DARPA can go forward and develop neurotechnology to do this. We have some teams on the program that are seeing huge improvements on memory performance in humans when you use the right kinds of codes.
Your office also has a "biochronicity" program that explores the role of time in biological functions and tries to manage the effects of time on human physiology.
We leave so much to chance because of our lack of understanding of biology. I think our understanding of biology is vastly growing. And our ability to interact with biology using engineering techniques will change the way we think about our body, brain and immune system—and the way we think about and interact with our food supply and things like that. I see such exciting times moving into the future. I think we are really hitting our stride now, and I think the kind of things and developments we will see in 2017 will really blow our minds.
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