BETR to BEST | Ep 86

Intro Voices
Coming to DARPA is like grabbing the nose cone of a rocket and holding on for dear life.

DARPA is a place where if you don't invent the internet, you only get a B.

A DARPA program manager quite literally invents tomorrow.

Coming to work every day and being humbled by that.

DARPA is not one person or one place. It's a collection of people that are excited about moving technology forward.

Stacey Wierzba
Hello and welcome to Voices from DARPA. My name is Stacy Wierzba, and I'll be your host for this episode. We sat down with Doctor Leonard Tender, or Lenny. Lenny joined DARPA in January 2023 as a program manager in the Biological Technologies Office. His research interests include developing new methods for user defined control of biological processes and supply chain resilience.

He earned a bachelor's degree from MIT, a doctoral degree from UNC, Chapel Hill, completed a post-doc fellowship at UC Berkeley and served as a visiting scientist in the Stanford University Department of Chemistry. He co-founded the International Society for Microbial Electrochemistry and Technology, and is a recipient of the Arthur S Fleming Award, which honors outstanding federal employees. But to hear him tell it, that's all fairly standard.

Lenny Tender
I did the normal routine - undergraduate, graduate school, postdoc, and then I was at the Naval Research Laboratory for 24 years right here in Washington, D.C. The Naval Research Laboratory is the Navy's in-house national laboratory, and I was a principal investigator and became a branch head. So I had been a DARPA Pi twice in my career, very, very early on and it actually launched my career.

And then later in my career around 2017, 2018 or so, there are a number of people who have gone from the Naval Research Laboratory to DARPA, and I had engaged with one of them and started having discussions and realized there's a lot of overlap, and I thought it'd be a really great challenge for me to take on.

My background, my formal training is in electrochemistry, which is studying the interaction of electrons and chemicals. But during the course of the 24 years I spent the Naval Research Laboratory, I started looking at how microorganisms are essentially little electrical machines and applying the tools of electrochemistry to study them. All living organisms fundamentally require a flux of electrons in and out.

And so for us, when we ingest food, we're essentially ingesting, say, glucose, which is the simplest case. And we take those carbon atoms and ultimately remove electrons from them. And that becomes the carbon dioxide that we exhale. And a lot of the processes that go on in our body are about moving those electrons around and stripping off the energy.

And microorganisms do the same thing. That became, for 20 years of my life, In fact, my first funded effort was a seedling effort from DARPA to take the very first steps of exploring that concept. And I could say that everything else that followed in my career for 24 years at the Naval Research Laboratory was based on that first set of experiments and sort of pioneer in understanding how microorganisms, how we can feed them electrons and pull electrons off of them using the tools of electrochemistry.

And so, towards the very end of my career, I started looking at organisms that are involved in infection, pathogenic organisms, in particular wound infection, and then understanding that when you have a wound infection, that means that you have a wound that's been colonized by organisms, and the organisms disrupt the normal healing process. And I wanted to really understand how those organisms can live in a wound.

So using the tools that we developed and working with some really great collaborators, in particular Professor Diane Newman from Caltech, who is an expert in these type of organisms, we figured out how the organisms are essentially breathing, how they're getting rid of their respired electrons. And we started wondering, well, would that have implications for wound infections? If we can start to sort of disrupt that process?

Stacey Wierzba
Disruption is an accomplishment DARPA prides itself on and constantly strives for. While disruption of the wound infection process might not seem immediately important to national security, it can be a matter of life or death.

Lenny Tender
Even in our last major conflict, so Operation Enduring Freedom, Operation Iraqi Freedom, even when we can get the injured warfighters off the battlefield into high level care within an hour, we are experiencing something like 27% of those people are experiencing debilitating wound infections. And so that's under really great conditions. Now we look at Ukraine, for example, and we're seeing 50% wound infections.

And of course in Ukraine, the difference is, is they're not able to get people out as quickly as possible. And then on top of that we're seeing high levels of multidrug resistant organisms. The whole antibiotic resistance. Right. So unfortunately war is a big driver of antibiotic resistance. And we're seeing right now in Ukraine is very high levels of antibiotic resistance.

And so right now the standard of care when a warfighter gets injured on the battlefield is you administer high dose antibiotics right away. There's two problems with that. The first is that, well, we're kind of running out of time on the antibiotics right. At some point, you know, a lot of them are just not going to be useful. Secondarily, there's a lot of good organisms that are actually, if not benign, actually beneficial to the wound healing process.

And if we're knocking everything out, that's not good. Right. And there's nuance in there and how you define infection because all wounds become contaminated with organisms. In fact, many wounds will become very contaminate, have a high load of microorganisms, but they'll continue on to heal well. And we don't want to mess with those wounds right. It's the ones that the wound healing begins to fail. Those are the only ones we want to go after.

Stacey Wierzba
The BioElectronics for Tissue Regeneration program, or BETR takes aim at these wounds with the intent to create what is essentially a smart bandage.

Lenny Tender
BETR was a program that I took over when I arrived at DARPA, and in fact, it was led by Paul Sheehan, who was the program manager that I knew from NRL who came to DARPA. And then he left shortly after I came and took over his program. And so that is a program that also is looking at wounds - not infected wounds.

Lenny Tender
But asking a fundamental question is, can we monitor a wound, the healing process in real time, and then interfere with or reprogram the natural healing process to either have the wound heal faster for a simple wound or for more complicated wound have it heal better. For the former., te simple wound, you can imagine, say, someone has had a pretty invasive surgery, right?

And you have a big, you know, incision on your chest. Well, imagine if you could apply a bandage. It's going to make it close off a lot faster. That would have tremendous payoffs in terms of just getting people out of the hospital a lot faster, recovering a lot faster For the latter, in terms of the more complicated wounds, for example, one of the wounds that soldiers, warfighters experience, is what we call volumetric muscle loss, wounds where you have a blast and essentially, I guess there's no other way to say it, a big part of a limb, say a leg ,is gone and you're lost a lot of muscle and nerves and blood vessels.

We have evolved naturally for those wounds to scar over. And scarring is sort of a way of sealing the wound to minimize infection. Imagine if you can reprogram that wound with a bandage or a dressing that is super smart so that it reprograms it not to scar, but to actually allow for functional tissue to regenerate and to replace the muscle.

And that's - and we actually have performers who have done both. And it's super, super exciting.

Stacey Wierzba
Now, that's not to say that you can go buy one of these bandages at your local pharmacy today.

Lenny Tender
Developing medical device technology is a very long process. And what we do at DARPA in really any activity is really de-risk a concept. And so when BETR started, the notion is can we understand a wound physiology at a high enough level and then actually have the tools that we can actually incorporate into the bandage to sort of reprogram the healing process.

And so we're talking about developing a whole new set of sensors that are monitoring. And the wounds a very complicated environment. You can have something like four different dozens of cell types that are all interacting, you know, in a coordinated, orchestrated process that's changing over time. And so we have to be able to monitor all that. And then can we know when we can intervene.

Right. And so for example, one team, built an incredible digital twin, really modeling the whole wound process, getting all the way down and understanding how all the signaling molecules and all those cells interact with each other and finding those sort of points that if there's like one signaling molecule at this one time point, if we can just adjust it at this level, this can have a profound impact.

Stacey Wierzba
A bandage sensing, analyzing and treating wounds without human intervention or additional computing sounds like something straight out of Star Trek, but it's being made possible today.

Lenny Tender
So a big component of this is it’s completely closed loop control. So you have your sensors, you have what you're sensing, you have different treatment regimes, methods of treating the infection that are embedded into the device that you can control the release of and regulate the administration of. And that's all going to be controlled through closed loop control on board a device, in addition to the technology development and commercialization and regulatory strategies and all that stuff, we're challenging the people to

also think ahead and say, well, imagine that., you know, you're wildly successful, but then you have to have all this follow-on funding and then you can get the clinical trials. The end product has to be something that is actually useful, right? And we want it to be useful on the battlefield because when a warfighter gets injured, the infection begins.

The process begins there. As soon as the skin is broken, the microbes start contaminating the wound. Right? It has to be practical, you know, in terms of being useful in a very, very forward environment. So it can't be extremely delicate. It can't rely upon a huge instrument in an analytical lab in a hospital somewhere, cold chain, you know, it could be a problem and then, you know, has to be manufactured at a reasonable cost.

We de-risk the concept, and we're actually at the point now where one of our performers is doing the first in-person clinical trials for not the whole bandage, but for the ability to monitor in real time how the wound is healing, and also to actually have the sensors all working, but actually use machine learning, training on the sensors, to say this is how the wound is progressing in time, which is a huge accomplishment.

There's a number of small companies that have been spun up and spun out as part of this effort. And DARPA's very big into that. Having companies being formed by the teams as their work is progressing to help with the commercial transition, because we're focused on delivering these technologies to the DoD, to the warfighters. But wound healing is a huge national problem.

The biggest type of wounds we deal with as a nation are diabetic foot ulcers costing hundreds of millions of dollars, if not billions of dollars to Medicaid and to the VA. And so it's a different type of wound, the diabetic foot ulcers are more chronic, but there's a lot of overlap in terms of what's going on. And so so we're driving the transition of this technology so that that market then it can eventually feed into the DoD.

Stacey Wierzba
DARPA's pretty much done with BETR now. Other groups are taking over. So Lenny figured it was time to revisit something put on the back burner when BETR first got started.

Lenny Tender
When that program was pitched, everyone recognize that wound infections were a big problem, but the previous program manager and the leadership of DARPA decided that just handling the wound by itself, the wound healing without infection was a hard enough problem. But overlying infection would be insanely difficult. Well, four and a half years later, we made tremendous progress on that ability to monitor and reprogram the healing process to a certain extent, which is very exciting.

And so now the time is ripe to build upon the lessons learned and add in the infection component.

Stacey Wierzba
This is where Lenny's new BioElectronics to Sense and Treat program, or BEST comes in.

Lenny Tender
You imagine a warfighter that's on the battlefield who is not severely wounded. I mean, if they were here in Arlington, Virginia, they'd go to the hospital. But when you're on a battlefield, they can get back up on their feet. If you can get that wound, you know, the bandage on and monitor for infection. That warfighter can return operations, but more likely and not given the unsanitary conditions.

And then also the stress that they're under and how compromised the immune system is going to be, they're going to be very susceptible to infection. But if we can stop that, then they can stay in operations. Right. And then we have a whole other cohort that are, for example, the ones with the bigger wounds are going to be flown out, just managing the wounds, if they're infected, requires orders of magnitude more caregiver attention, expense. It's traumatic for the warfighter. It can mean the difference between amputation and not amputation or where an amputation occurs. And so being able to just have technology that can automatically remove that concern of the infection would be very powerful. And so that's the goal of that program. So part of the capability is that it has to be adaptable for variability in people's immune response.

And so ideally the way this would work is you'd be looking for signatures of what microbes are there, but also on how the host is responding. There's a lot of overlap there. It could be, for example, that how the host is responding might tell you all you need to know. It could be which organisms are there, may tell you all you need to know, but people, their immune responses are very different.

Particularly people with diabetes, for example, but also warfighters. You know, you take a young, healthy person in their mid 20s here, you know, in Arlington, Virginia, and they get into an accident or something. Okay. But if they're on a battlefield and dehydrated and in shock and stress, if they're experiencing polytrauma, their immune system is going to completely be out of whack.

And so we need to be able to adjust for that. A lot of that is overlap with the BETR program. Part of the big accomplishments of the BETR program is being able to monitor the host immune response. And because the immune response, which is driving the healing process, being able to monitor that really gave us the mindset, the framework to say, well, we can do essentially the same thing for the infected wound.

Of course, it's not exactly the same, and in fact, it's going to be very different because of how the organisms affect the immune response. The actual programmatic timeline is three years, looking at two phases, a two year phase where we're looking at independently developing the monitoring capability and the treatment capability, but doing it in a manner so that in the third year they can be integrated together.

So they have to be coordinated. And then the third year is bringing together the closed loop control. It is a DARPA hard program in that there are pieces of technology out there that appears could do the job, but there is really not the complete package. And none of the pieces can do it as well as what we're going to need it to do separately.

And then thinking about tying it all together in the closed loop control is going to be a pretty awesome heavy lift. A lot of work goes into really all DARPA programs to make sure that you are tying it to a pressing problem. You know, we have in the building incredible people who are very connected within all their different branches of the military, and they're very enthusiastic and very effective at brokering relationships.

And so we have a lot of relationships that they broker. Working with our team is the Uniformed Services University, for example, and Walter Reed, for example, among others. Lawrence Livermore National Laboratory, they provide certain subject matter expertise. We have what are called SMEs that provide us a lot of expertise in terms of how we rigorously monitor and actively manage the program to optimize the opportunity for success in maximizing the output.

Stacey Wierzba
Speaking of maximizing output, there's another side of Lenny's program portfolio that seeks to do just that by finding value and utility in what's previously been seen as detritus.

Lenny Tender
There's other areas that I'm exploring that biology is a really good solution set. And so one of them is biomanufacturing, which is this notion of making useful materials out of available waste streams, feedstocks. We had a program that has just ended recently called ReSource, and was looking at whether or not it's feasible to take waste plastics and then convert them into useful materials, specifically foods, oils, lubricants, and to do it in austere and remote environments and do it with low energy input.

And it turns out that biology can play a very important role in that. Biology is really good at transforming one set of compounds into another set of compounds through microbial metabolism. And so we were actually very successful in that program.

Stacey Wierzba
Another of Lenny's programs in this area seeks to harness energy from the ocean. That's the BioLogical Undersea Energy program, or BLUE.

Lenny Tender
So BLUE is about determining whether or not an ocean deployed sensor can actually filter feed on dissolved organic matter in the ocean to generate electrical power. And so the background on this is a look at filter feeding animals in the ocean. Say take a dolphin for example. And the dolphin is eating fish - we're not going after fish, for sure - but a dolphin can eat about 30, 40kg of fish a day, and a dolphin can live about 40 years.

And the average output, if you average how much power they generate over 24 hours is about a kilowatt. So if anyone's an athlete out there, if you're like an avid bike rider and know how much wattage you can put out, peak wattage or wattage over ride? You know, a dolphin is putting out 1000W essentially 24/7, right?

And so all that fish that they're eating ultimately is the foundation of all that. It's just the dissolved organics that are in the ocean. There's a lot of biomass that's very small, below a millimeter in diameter. A lot of it is just runoff from rivers into coastal environments. You have phytoplankton blooms and etc. and it's a massive, massive, massive form of carbon that's involved in carbon cycling, biomass cycling, on the planet.

And so it's a fundamental question, is can we take oceanographic sensors, which the Department of Defense uses a lot of them, other agencies use a lot of them. Industry uses a lot of them. They're battery powered. Their batteries run out pretty quickly. And then the logistics of replacing the batteries or replacing whole devices is very daunting.

And so essentially they're very underused, right. If you can replicate that capability of converting that biomass into energy, which biology does, then that's like pretty cool because you can have your device being powered for very long periods of time, far longer than possible batteries. That opens up a whole range of possibilities. And so we have two teams that are now working on that.

They are different variations that are called bioreactors. It's about replicating what goes on in our GI tract or the GI tract of our oceanographic animal, like our dolphin, are really the the nucleus -that idea came from whales, which are amazing filter feeders. And, you know, converting that biomass into chemicals. And then you can use to then generate power.

In our case, we want to convert them into molecules, for example, that you can use a fuel cell to generate electrical power, but there's other pathways to do it. And so that's a program that's just starting. You know, we have a couple teams that started late last year and getting up and running pretty quickly. And it's a thrill to see that we're targeting ten watts, then 100W of power.

And so those seem to be very low amounts of power. But in terms of having an oceanographic sensor, they're actually pretty high. And that's average power over time. And so a lot of oceanographic devices that, you know, monitor weather and environment and stuff, those are battery power and they get deployed and then retrieved and then deploy and retrieve.

And if we can power something like that indefinitely. It'd be really pretty cool.

Stacey Wierzba
Not one to shy away from a challenge, Leonie continues to explore new avenues for biological technologies.

Lenny Tender
I'm thinking very hard about a future program in applied quantum biology, quantum mechanics. It turns out there are a number of physiological or biological processes that exhibit non-trivial quantum mechanical effects, which is really hard to do non-biologically, but biology seems to do it in noisy, messy environments and at room temperature. And so one of the things we're asking fundamentally is can you make a quantum computer that would operate at room temperature under noisy environments, which we can't do now, drawing from biology, that it seems to exhibit some of the necessary properties that that would require.

And so there's a case where biology may be a unique solution to an interesting problem.

Stacey Wierzba
Unique solutions to interesting problems is sort of what we're all about here at DARPA.

Lenny Tender
This is the most exhilarating experience I've ever had professionally. All programs start, you know, with a blank page. And, you know, the program manager is thinking about them and engaging with their team. And then the leadership of the office. And if you're successful to get it through and get it funded, then standing up there, especially when you have like a kickoff meeting where you're in front of the performer teams is so exciting when you have the performers there.

And it could be the professors and the industry people and the small company people and the students, the post-docs and the graduate students and undergraduates. And, you know, it could be, you know, 50 people there. And then you have the team also that as part of the government team who's helping us, the subject matter experts from, for example, from Walter Reed or from the Uniformed Services University.

It is such a rush. And then we typically have every six months, all the teams across the whole program will meet and present, have a review. And when you realize that they're all here working on a concept that you developed, that there's nothing really like that. And then on top of that, just the great support that we have.

I'm a bit of a ringleader, I'm a bit of a portfolio manager. I have a great team of technical experts. They're super smart and hard working that work under us to help us really rigorously, you know, put up ideas and then monitor them. And that whole dynamic interaction is really incredible. And so I would challenge anybody out there, especially if you're - because I'm biased, I'm in the Biological Technologies office - if you are at a point in your career where you're like, wait a minute, if I can really have an idea that if I can get the resources and the right people to do it, that could just really disrupt or blow up the whole field and have a huge impact. We talk about impact in terms of national security and that has many ways of doing that.

But if you're at some point in your career and you're thinking, well, if I can really push an area and have a big impact, I think I have an idea, you know, give us a try, drop me a line.

Stacey Wierzba
That's all for this episode of Voices from DARPA. For more information on any of the programs we discussed, or how you can get involved with the agency, check out the show notes or visit DARPA.mil. As always, thanks for listening.