A View from the CT Foxhole: Brad Ringeisen, Executive Director, Innovative Genomics Institute

Brad Ringeisen, Ph.D., is Executive Director of the Innovative Genomics Institute (IGI). Before his retirement from government service in July 2020, Dr. Ringeisen spent four years at the Defense Advanced Research Projects Agency (DARPA), most recently in the role of Director of the Biological Technologies Office where he managed a division working at the cutting edges of biology, physical sciences, and engineering. Dr. Ringeisen’s office overlapped with IGI on several occasions, on the Safe Genes program, which works to develop safe and more precise genome editing tools while preventing misuse of the technology, as well as IGI’s research into innovative solutions to mitigate acute radiation sickness.

Prior to his role at DARPA, Dr. Ringeisen served between 2002 and 2016 as the head of the Bioenergy and Biofabrication Section at the U.S. Naval Research Laboratory and spent two years developing point-of-care diagnostics for the Defense Threat Reduction Agency in the early 2010s.

In addition to his deep leadership experience, Dr. Ringeisen is a physical chemist with a Ph.D. from the University of Wisconsin-Madison and a pioneer in the field of live cell printing.

CTC: Over the course of your career, you’ve dedicated many years to the application of science to protect and advantage the U.S. warfighter, as well as serve the general public at the U.S. Naval Research Laboratory, at the Defense Threat Reduction Agency (DTRA), and at the Defense Advanced Research Projects Agency (DARPA) as well. What drew you to public service?

Ringeisen: I grew up in a university town; I grew up in Clemson, South Carolina. My father worked for a public school as the chair of the math department at Clemson University. I considered him a public servant as an employee of the state of South Carolina. And so, when I was finishing graduate school, I looked at non-traditional postdocs outside of the academic world. But I’ll be honest, I had just had my first child with my wife, and I needed a job. I needed a paycheck. So, it started as a job, and the DoD postdocs paid really well. It also gave me an opportunity to start my career on a strong footing. And it was exciting. I joined a lab that was putting pretty much every piece of biology in front of a laser. Who wouldn’t want to do that? It was a great opportunity to explore how to make thin films of biological materials and biosensors, and then we ultimately got into tissue engineering and bio printing. So, it was a really exciting opportunity.

From a broader perspective, the U.S. Naval Research Lab did great science, there’s great people there, it had a great mission, and you could basically wake up every day and ask yourself, “What can I do today for the military?” It gave you a mission every single day—help the warfighter, help the soldier—and I really enjoyed that mission. I did it for 15 years of my life, and I wouldn’t trade it for anything. Protecting against chemical/biological threats, helping understand traumatic brain injuries, helping soldiers heal better, creating clean energy options for the Navy—these are things that I did on a day-to-day basis. For me, biology and biotechnology for the Department of Defense, it was about helping people. It was about trying to help the environment. That’s what we did. And so, I could have done that in an academic lab, but for me, the Department of Defense gave me that umbrella to be able to help guide pursuits. You always had that mission that you were looking for.

CTC: You started at the U.S. Naval Research Lab just prior to 9/11. What impact did those attacks have on your view of the role of science in national security?

Ringeisen: Everything changed. The Naval Research Lab was founded as the first national lab. It was a fundamental, basic science laboratory. There’s a bust of Thomas Edison as you drive into the lab. And what he said was, ‘We need a lab for the Department of Defense and a national lab that gives you that level of expertise so you can avoid strategic surprise.’ Then 9/11 hits. I remember sitting in traffic for six hours trying to get home that day. I remember picking my kids up and driving my wife to West Virginia because the fighter jets were scrambled and flying around D.C. We were all scared. It was an impactful event for all of us.

And then the science changed. It became less about the fundamental basic science, and it became about what can you do right now in Iraq for chemical and biological threats, for Afghanistan for improvised explosive devices and all the brain and the spinal cord injuries. So, we started doing bio-printing for spinal cord repair. We started looking at blood-brain barriers to look at traumatic brain injury. The shift was pretty monumental. It’s one of those events, much like COVID-19, where it just changes the trajectory of science. And I don’t think the Naval Research Lab has ever really been the same since because people are constantly focusing on this very application-driven research now.

CTC: Can you talk specifically about the Biological Technologies Office (BTO) at DARPA, what it does, and how it developed during your time there?

Ringeisen: I’m really proud of what I did at the Biological Technologies Office. This was an office that was started in 2014. Prior to that, biology at DARPA was kind of hit-or-miss. It was supported by some office directors. It was supported by some program managers. There wasn’t a cohesive office to explore what biotechnology could do. [DARPA Director] Arati Prabhakar in 2014 founded the BTO, which I think was a phenomenal idea. The first director [of the BTO] was Dr. Geoff Ling. I still consider Geoff one of my mentors. He’s an amazing individual. He served as a military doctor in the Middle East. He has saved lives. Geoff is an amazing person. But when I joined the office in 2016, two years after, they had a scattering of new programs that they had started. It was kind of fits and starts. The number of program managers in the office was dwindling. So, when I came in, it was clear that we had to spend the money, create innovative new programs, and just hire. We needed to hire program managers. I was lucky enough to have a strong network of colleagues that I was able to reach out to and interview and tap to build up the portfolio of program managers that we had in that office. And boy, did they deliver. I am thankful to this day for a group of program managers that I hired. We went from maybe four or five program managers up to, by the time I left, 13 or 14 program managers—allowing us, in my opinion, to pretty much produce as much good science and as many new programs as any office in the agency. And we were one of the smallest budgets in the agency. I think during my tenure there, we pushed out 25 or 26 new programs totaling well over a billion dollars of research dollars. This was really innovative work.

We had four major program areas. We did pandemic prevention, we did warfighter health, we did warfighter performance, and we did something that we called operational biotechnology, which was basically the ability to use synthetic biology or the natural world to protect warfighters, to protect infrastructure, to do bio manufacturing for supply chain stability, and then, what could biology do to potentially provide for soldiers in field-forward situations.

Let me give you a couple flavors of things that we did. We looked at new ways of detecting and diagnosing disease. We invested in DNA and mRNA vaccines. We developed new CRISPR tools. We made foundational investments in things called engineering living materials. I just saw that Biomason went to Series C funding at $65 million;¹ we were some of the initial investors in that company. We discovered rapid ways to find antibodies to protect and treat warfighters exposed to emergent disease. And we did some pretty cool brain machine interfacing; robotic arms with tremendous degrees of freedom, being able to control those prosthetics with just your brain and thoughts alone; some pretty cool stuff. It was a playground of science. It was a sandbox of science across pretty much every possible area of biotechnology, and I found myself lucky to be able to lead it.

CTC: You’re currently the executive director of the Innovative Genomics Institute, founded by Nobel Laureate Jennifer Doudna to drive forward scientific research, advance public understanding of genome engineering, and guide the ethical use of these technologies.² Could you describe some of the cutting-edge research being done there and the broader work you do?

Ringeisen: Thank you for mentioning the ethical aspect of this work as well, because Jennifer Doudna, who is the founder of this organization, is I think the most inspirational and best scientist in the world. Jennifer founded this institute in part to not just innovate and push the science, but also to push it in an ethical way, an accessible way. We want to lower healthcare costs. We want to expand the accessibility of these technologies to farmers in the world that need them, to populations in the world that need them. It’s not just for those that can afford them. That’s at the core of what Jennifer and I want to do at the Innovative Genomics Institute.

Now, it’s a pretty amazing place as well. I know I just talked about DARPA, but one of the reasons I was attracted to the IGI is we don’t just work in human health. Yes, we do tremendous work in human health: We’re developing cures for sickle cell disease, for rare genetic diseases; we’re looking at ways to affect more complex and common diseases like cancer and neurodegenerative disease. But we’re also looking at feeding the world and creating food security and also trying to mitigate climate change and make agriculture more resilient to climate change. And so those are the areas that I’m tremendously excited about, tremendously passionate about, and when I interviewed for this job, Jennifer agreed that these were areas we also wanted to address. What other institute in the world uses a powerful tool like CRISPR and genome editing and looks at not just health, but also at feeding people, providing the nutrition that they need and doing it in a sustainable way. And that’s the IGI.

I count myself really lucky for being able to work with Jennifer and all the amazing professors and scientists that are there. We have people that are working on photosynthesis and trying to improve crop yields and carbon capture through photosynthesis. We’re currently performing the most extensive study of the rice microbiome, looking at carbon flow in that system, looking at methane and nitrous oxide emissions; we’re going to find some secrets and hopefully unlock approaches to reduce emissions from rice patties around the world.

And then we’re creating new editors and new ways to do editing, like epigenetic editing, ways that you don’t have to do double-strand breaks for editing. And we have a tremendous number of people that are innovating in ways to deliver editors to different cells, like plants and mammalian cells, as well as new ways to edit in general. There was a recent publication by Jill Banfield and Jennifer Doudna that showed they could edit communities of microorganisms.³ What are communities of microorganisms? That’s essentially the microbiome. How amazing would it be if you could unlock the potential of CRISPR to tune and tweak and manipulate the metabolism that’s going on in these complex environments, whether that’s a gut of a cow or the GI tract of a human or maybe on the skin or in soil? The potential there is pretty amazing. That’s the kind of innovation that the IGI works on.

CTC: As mentioned, you worked at DTRA, the U.S. Naval Research Laboratory, and the BTO at DARPA. Can you describe how the threat landscape has evolved over the last 10, even 20 years, particularly with respect to bioterrorism?

Ringeisen: Let’s start with the anthrax attacks in Washington, D.C. I moved to Washington, D.C., in 2000, 9/11 hits, and then shortly thereafter the anthrax attacks occurred. So that shaped and dramatically influenced the CBRN—chem, bio, rad, nuke—defense program in the United States within the Department of Defense. There was a shift to state-sponsored, big, impactful military-scale attacks involving things like aerosolized anthrax, just as an example. Could you weaponize smallpox? These scenarios were the focus from 2001 all the way through 2015. Most of the work and people were sort of tunnel-visioned on these very, what I would call, ‘traditional’ bio threats.

When I joined DTRA in 2012, there was a small group of people that were influenced by DARPA pretty significantly that came to DTRA and said, “Those are big threats and we have to think about those, but we really need to think about emergent disease, too. There are diseases emerging from animals that, with climate change, are going to just extend and happen more frequently. You’ve got populations colliding with these animal populations.” These were the things we were saying back in 2012, and we started to try to develop platforms—diagnostics platforms, bio surveillance platforms—to try to understand and better characterize emergent disease. It was not fully accepted by the CBRN community. If we flash forward another two years, you’ve got Ebola;^a people are starting to see this zoonotic transfer of disease. And all of a sudden, the Department of Defense is starting to pivot, and they’re starting to realize that emergent disease threats and spreading zoonotic disease may actually be a bigger threat than that more state-sponsored, big, militaristic kind of action. I’m pretty proud of the fact that in 2012, we were starting to think in that kind of way.

And then when I got to DARPA, we really started to push platforms that could rapidly respond to emergent disease. Because you don’t really ever know: Is it going to be Ebola? Is it going to be hantavirus? Is it going to be Lassa fever? Is it going to be coronavirus? Well, it turned out to be coronavirus, but you need rapid platforms to be able to pivot, and I think the Department of Defense started to do this. DARPA started to do this. And I credit the Department of Defense for seeding some of the technologies that were able to be put into play very, very quickly when COVID-19 hit. So, I’m actually pretty proud that they did pivot back in that 2016 to 2018 range, probably most likely because the 2014 Ebola outbreak, which started this attitude shift to help ‘stock the cupboards’ a little bit with some emerging technologies that helped us respond more rapidly when COVID-19 hit.

CTC: We’re two years into the global pandemic today and a year after the rollout of some highly effective vaccines for COVID-19. DARPA was an early buyer on mRNA vaccines, with a $25 million investment in Moderna in 2013.⁴ How consequential was that early investment to the development of the COVID-19 vaccines less than a decade later?

Ringeisen: Very consequential. I will mention Dan Wattendorf, a colonel in the Air Force who retired and became a program manager at DARPA. Dan had the foresight to invest in Moderna when not very many people were investing in this type of technology. There’s no money in infectious disease. The big biopharmaceutical companies were sitting on the sidelines for the most part; they were outsourcing vaccine production and vaccine manufacturing. And here you have Dan Wattendorf finding this tiny little company and saying, “I believe in your technology.” But I will also say that it’s not like Dan was clairvoyant and just pushed all of his money onto Moderna. That’s what DARPA does. They invest in portfolios of technology. Dan was looking at antibodies; he was looking at ways to filter viruses out of blood. He was looking at gene-encoded antibodies. He was looking at DNA vaccines. He had an entire portfolio of technologies for pandemic preparedness, and a few of them ended up panning out and playing a big role. And the two biggest ones were Moderna, which BTO funded to develop an mRNA vaccine for chikungunya.⁵ We saw safety data early on, so when COVID hit, we all thought, “Well, Moderna is going to be on this.” Because we had seen the phase one clinical trial data. So those investments were tremendously consequential.

The second company backed by DARPA that turned out to be important was this company called AbCellera.⁶ AbCellera was a company that had high throughput ways to screen B cells for antibody production, and you could basically have one cell per microwell and hundreds to thousands of wells per plate and then you could screen thousands and thousands of cells and antibodies to be able to pick out the most neutralizing antibody against SARS-CoV-2. Guess what? Eli Lilly picked up the best neutralizing antibody that AbCellera found, and it was manufactured under a label by Eli Lilly.^b So you never know when something is going to pay off, but that’s why DARPA is special: You can seed, and you’re given the freedom to make investments. And it’s not done in a vacuum. It’s not just Dan making those decisions. It’s Dan with his team of contract-support Ph.Ds. It’s the deputy director and the office director, and it’s the deputy of the agency and the director of the agency. And I can tell you from past experience that those decisions for the pandemic preparedness portfolio were made all the way at the level of the director of the agency. Arati [Prabhakar] was very active in the programs that Dan selected. Talk about a sandbox. The sandbox of DARPA enabled those investments to be had. So it’s a very special place, and you’ve got to preserve and protect it.

CTC: Do you think the pandemic has changed the government’s prioritization of science research and funding from perhaps a more ‘fits and starts’ approach before to a recognition today that a more sustained investment model is required?

Ringeisen: I’ll go back to the early days of DARPA; we were investing in rapid response platforms and bio surveillance. We wanted to try to predict and know what was going to be next, or rapid response platforms that could, if something did emerge, see if you could rapidly try and respond to it. That was a unique perspective. I think now you’re hearing people like Anthony Fauci and others echo some of those sentiments. We’re talking much more about pan-viral approaches, things that could be resilient against mutation. These are good ideas. If you could do pan-viral approaches and rapid response platforms, then you won’t be caught as unprepared as we were back in 2019 and 2020. So, I do think there’s been a shift, and I think it’s been a shift to the benefit. People realize now that you can make money in combating infectious disease, and that helps because that gets some of the private capital and equity off the bench as well. But I think the government realizes you need an entire pipeline. You’ve got to have the basic discovery work in a place like NIAID [National Institute of Allergy and Infectious Diseases], but you also need translational and innovative work at a place like DARPA. And then you also need to connect that to a place like BARDA [Biomedical Advanced Research and Development Authority] or JPEO-CBRND [Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense] to be able to hand off those technologies. So, my job at DARPA was that hand-off. The program managers would develop, but then I would communicate with JPEO. I would communicate with Jason Roos at the time, who was the deputy at the JPEO, to be able to find a landing spot, to be able to help fertilize that ground so that when something matured, there would be a home for it to be able to take off. So, it’s getting all the way from basic research to that translational work. And I think DARPA did a really great job of accomplishing that.

CTC: As you think about the past two years, what are the key lessons that you think should be learned from the pandemic in protecting the United States from biological threats moving forward?

Ringeisen: It’s those rapid response platforms. It’s a tragedy that we have not funded pan-viral approaches more than what we have. When I gathered our sort of ‘war room’ team very early—probably January, February of 2020. It was a solemn time, but I also told my program managers that this was a singular moment, a defining moment for DARPA BTO. We sat down for the entire day, and we white-boarded what the country really needed. We asked ourselves what we could do in the near-term (those were things like the antibody discovery platforms and the mRNA vaccines and the gene-encoded antibodies that we were developing), but then we also had half the white board on ‘if we just could dream the dream and we had a billion dollars, what would be the target?’ And that side of the white board was dominated by mutation-resilient technologies, pan-viral approaches for detection and treatment or prevention of disease. We didn’t get the billion dollars. So we did most of the work on the left side of the white board, which was the more near-term projects, with the Pentagon plus-up funding we did receive, and I never got the bigger payday to be able to pursue some of that longer-horizon work. Let’s hope that the people that are still in the government now are able to do that. But I think that really is where you need to go.

The last piece of that is bio surveillance. We need to be doing more testing. We need to be focused more on zoonotic disease, but you have to do it in a safe and responsible way. Dual-use research of concern is real, and you need boards of people to look at and vet this research before and after funding.

CTC: As somebody who was in an early ‘war room’ before the pandemic really took off, as somebody who had been tracking and thinking about biological threats, investing in mitigation measures and detection, are there aspects of where we are now two years later that are surprising to you, or are you not surprised by where we are now?

Ringeisen: That’s a hard question. If you look back on it, you can say, ‘We could have done a lot better in diagnostics. If we had identified early outbreaks and isolated earlier, we probably could have prevented a lot of deaths and a lot of early spread of the disease. If we’d had better distributed diagnostics like I was thinking about back in 2012 and 2013, perhaps that may have been managed better, but that didn’t happen.’ But when you look back on it honestly, with the spread that was going to go on in the world, we weren’t going to be able to become fully isolated. This was going to be something that was going to affect the entire world. The entire world was not prepared.

So, you can throw stones on the early days of what happened, about how we could have handled it better, and you absolutely probably could have prevented many deaths. If you could have pushed the timeline another three or six months, we would have been more prepared. Those antibody treatments, the vaccines, they would have been closer to being ready. And so, it was a tragedy. It was. But when you look at it from the perspective of now two years later, the disease was going to spread across the world regardless. This is going to become endemic. The best we can do is to try to mitigate and try to lessen the impact on the populations that are most dramatically affected. I think the mRNA vaccines are doing that. You’re seeing now testing becoming less of an issue as it becomes endemic. How often do we test for influenza? 10-20,000 people in United States die of influenza every year. Is COVID going to become like that? I think that’s the goal; as sad as it sounds, that’s the goal. We want it to become something like influenza, where you get a shot, you get a vaccine, it helps mitigate. The risk then is lessened as much as it can be for those that are most at risk. For me, it’s ‘how can we do better next time?’ Is it going to be COVID-25? Is it going to be Lassa fever? Is it going to be hantavirus? How can we do better for the next one?

CTC: Synthetic biology has increasingly come to the fore in national security conversations. For our readers, can you briefly describe what synthetic biology is and outline the benefits and risks associated with its use?

Ringeisen: Synthetic biology is basically a very natural step in a long history of understanding how we use and benefit from genetic information. It really started with the Human Genome Project; that was focused on sequencing and bringing down the cost of sequencing, sort of bringing sequencing to the masses. You have to be able to ‘read’ the genome before you can do anything like synthetic biology, which is more writing the genome. So, it started back 20-25 years ago with the genome sequencing revolution.

The next step from there was something called systems biology, where you wanted to try to more thoroughly understand the complexities that is life: the complexities that occur inside of cells, inside of plant cells, inside mammalian cells, how they fit and form tissues. That is a tremendously complex problem, and there was a field that emerged together with genome sequencing that was systems biology that used computational approaches to try to untangle essentially the mechanisms of life. And then systems biology slowly just merged and became synthetic biology when gene editing tools like zinc fingers and TALENs [transcription activator-like effector nucleases], and then ultimately CRISPR came on board. Now, all of a sudden, you can read, you can start to understand, and you can actually start to manipulate and modify the genome. Synthetic biology is essentially a catch-all term now that refers to being able to create with biology—almost like an engineering tool kit for biologists. An electrical engineer has their breadboard and they’re controlling it and use it as a testbed; biologists now have that same kit. Between the use of computers and the use of molecular tools and sequencing, you essentially have that tool kit.

There was a program at DARPA that we called Living Foundries⁷ that was basically one of the early starters of synthetic biology, and the core of that program was a design-build-test-learn cycle. That’s what it was: Let’s make biology like engineering, where we can do a design, build, test, and learn. That’s essentially synthetic biology.

CTC: And what are your views on the benefits and risks associated with the use of synthetic biology?

Ringeisen: First of all, there’s enormous benefit. We are talking about food security. We are talking about climate. We were talking about green manufacturing. We are talking about revolutionizing the way health care is performed. Just look at T-cell and Car T^c therapies and now CRISPR-based approaches, like being able to cure sickle cell disease in small populations of people right now. So, the potential is enormous. One of my friends and colleagues, Fyodor Urnov, was just quoted in an article about whether CRISPR is actually going to ‘live up to’ the expectations.⁸ Like ‘maybe this is actually going to happen. Maybe it’s actually going to live up to its expectations.’ And I think people are starting to realize that this might actually live up to its expectations and that there’s an enormous amount of potential. So, the list goes on and on in terms of the upside.

But we want to do this in an ethical way, in a way that is safe, that is in concert with regulators. That is the key. You need to bring in the FDA [U.S. Food and Drug Administration]. You need to bring in the USDA [U.S. Department of Agriculture]. You need to bring in the EPA [U.S. Environmental Protection Agency]. You would need to have focus groups for the populations of people that are going to be affected by the food that you make or the treatments that you innovate. This has to be done from the start, and that’s what the IGI does. The IGI has a public impact team led by Melinda Kliegman. She thinks about the ethical questions. She thinks about the regulatory pathways at the beginning. We have her embedded in the teams of scientists. I just met with her for 30 minutes before talking with you all to try to understand how we can do better at getting her speaking more frequently with IGI scientists so that when we make programmatic decisions about what scientific projects we’re going to do, that they are in line with the ethical and regulatory pathways that she sees as being viable. So, to me, there are risks. There will always be risks with new technology. There will be risks with the molecular tools that provide the ability to edit the genome. But if you do it openly, if you publish it openly, if you work with regulatory bodies, then the risk can be mitigated and minimized.

CTC: Your close colleague Jennifer Doudna’s groundbreaking development of the CRISPR-Cas9 system for genome engineering technology saw her and Emmanuelle Charpentier awarded the 2020 Nobel Prize in Chemistry and “forever changed the course of human and agricultural genomics research.”⁹ CRISPR-Cas9 gene-editing technology holds massive promise in transforming human health and curing diseases, yet huge scientific advances also generate unpredictable and unforeseen risks. In a June 2020 CTC Sentinel roundtable, Audrey Kurth Cronin noted that “with the ability to alter DNA through easily accessible tools like CRISPR/Cas9, individuals can change known bacterial or viral pathogens to make them more dangerous. Far more people have access to the means to do this, much more rapidly than ever before.”¹⁰ In your view, what is the benefit/risk matrix of CRISPR-Cas9 technology?

Ringeisen: That’s a great question. I’ll start again just by reiterating the potential. We cannot not use this technology to help society. We have to use this technology to help society. The benefits are just too many: We could save lives; we could mitigate or potentially reverse climate change. We have to use it. So, the question then is, how do we use it safely? How do we try to set up the guardrails to be able to use it safely? And again, I’ll go back to DARPA and Safe Genes.^d Helping put up some of those safety bumpers—some of those guardrails, the regulatory agencies, the BWC dual-use research of concern there—we have the guidelines to be able to help do this. You can go to those resources and say, ‘Is what I’m doing a dual-use research concern? Is what I’m doing going to produce ethical quagmires?’ We need to make sure that scientists are asking those questions. We need to make sure that the do-it-yourself scientist that might be in the garage is asking those questions. But the resources exist to do that. The regulatory agencies exist to be able to do that. The peer review process to publish manuscripts is there to be able to help buffer this as well. Program management offices in the government are there to help vet and think about these things.

So, I guess what I’m trying to say is having spent many, many years funding government research, the tools are there, the management structures are there, the review process is there in the funded research work. But it’s the unfunded, do-it-yourself-er—a grad student experimenting on the side, which all good grad students do—that we also need to think about. We need to help promote conversations and discussions that bring to light potential ethical, potential dual-use research of concern. These are conversations that have to be had. We have to have open forums to discuss these things. And as long as you’re going to have internal review boards to vet your science, to be able to get regulatory approval, to be able to do animal studies before you do human studies, to ensure safety, to have the characterization experiments in place to be able to ensure safety and minimize off-target effects, I think the tool kits are there to be able to do things safely. So yes, there are risks, but hopefully, those risks can be minimized by doing open science, by publishing, by holding these open forums to be able to discuss all of these issues.

CTC: You just stressed how important it is for do-it-yourself scientists to be asking the right questions about the safety of their research. In recent years, there has been tremendous growth in the DIY bio-community and biohackers. Do you see these communities as advantageous to pushing scientific boundaries (e.g., “Hewlett Packard Garage – Birthplace of Silicon Valley,”) or as a risk for unintentional development of biological pathogens? Or both?

Ringeisen: DIY is a good thing. There could be advances that stem from it. Crowd-sourcing is real. I’m a physical chemist. I’m a trained physical chemist. The experiments that I did in graduate school looked at surface dynamics, gas-liquid interfaces, and essentially, interfacial chemistry. I now lead a genomics institute at the cutting edge of genome engineering and CRISPR-Cas. So outside perspectives and looking at problems from different perspectives adds value to science. So, the last thing I want to do is to squash DIY scientists or people from asking questions that are not necessarily trained to be asking those questions. I think there’s true value in doing that. It’s just that they also need to be in the fold. They need to be in the mix of the conversation so that they understand the potential risks of something that they may be doing. And I think that’s a role of a place like IGI. I think it can help do that. We can have open forums, we can convene people from that community so that they can mix and interact with the Ph.D. scientists and the regulators, so that they can speak a little bit more knowledgeably about what some of those risks might be.

CTC: In CTC Sentinel, we examine the threat of terrorism across a range of different manifestations, including the misuse of technologies by nefarious groups or actors. How would you describe the risk of a non-state actor using synthetic biology and other advanced tools for malintent? How likely or unlikely is such a scenario?

Ringeisen: It’s a great question, and it’s probably the most frequently asked question that I received while I was at DARPA. Biology is complicated. Remember I was talking about systems biology? You look at a mechanistic map of what a living cell does on a day-to-day basis; it’s tremendously complex. When you then scale that to an entire organism or an entire population of organisms, it exponentially becomes more and more complex. So let me just emphasize that biology is complex.

Trying to determine genotype to phenotype is complicated. So, from A’s, G’s, C’s, and T’s^e to actual production of proteins and to actual realization of what life does, trying to make those connections is very, very difficult. Just going in and making one change in the genome, it’s very difficult to understand often what the phenotypic outcome of making that change is going to be. So, genotype to phenotype is difficult.¹¹ Delivery of these reagents to the specific cell or to the specific organism that you’re looking at is tremendously difficult. The IGI has entire teams looking at three or four different, very complex chemistries to try to get these reagents into the very specific cell types that you want to get them into. So, delivery is a tremendously, tremendously big challenge.

The efficiency of editing is tremendously difficult—again, entire teams of people looking at trying to go from one or two percent efficiency to five or 10 percent efficiency up to maybe 50 or 70 percent efficiency. So the picture I’m trying to paint here is that the biology is complicated, but then you also have delivery. You also have the efficiency of editing. You have the genotype to phenotype challenge to try to understand what you would even try to target. Consider the scenario where there is one individual with malintent—I think it’s just impractical to think that person is going to be able to make enormous strides in trying to do something very nefarious and very bad. That does not mean we can discount that threat, but we need to think about the threat and how to mitigate it and how to publicly start these conversations so that when a well-intending person in their garage starts doing things, they’re thinking about some of the risks associated with it—whether it’s a risk to themselves or a risk to their neighbors or a risk to others. So that’s the answer that I give. I still believe in that answer. Now that I’m at the IGI, I see the talent that it takes to be able to make significant inroads on these technologies and the use of these technologies, so I’m even more convinced that it is a challenge for a non-state actor to be able to try to make real inroads and do something nefarious.

CTC: One analyst has noted that “the merger of the biological data revolution with computing power,” especially machine and deep learning, has opened up the possibility of “ultra-targeted biological warfare” whereby “malicious actors could deploy a biological weapon over a broad geographic area but only affect targeted groups of people, or even individuals.”¹² In 2020, the United Nations Institute for Disarmament Research warned that “access to millions of human genomes—often with directly associated clinical data—means that bioinformaticists can begin to map infection susceptibilities in specific populations. This kind of information could also be used to develop ethnically targeted weapons.”¹³ A concern is that ultra-targeted biological weapons may be more palatable to rogue states and other actors because of the lower risk of ‘blowback.’ What thinking needs to be done about this future potential threat?

Ringeisen: Another great question, and it’s a question that’s circulated inside the Beltway quite frequently. Verbatim to what I just said, copy and paste here. So that’s said and done: All of those challenges would be equally as challenging for this scenario as well, number 1. Number 2, yes, computational advances, algorithmic advances, artificial intelligence, machine learning and ways to scan data in very rapid, very meaningful ways, of course that’s going to make it easier to identify potential similarities in somewhat more homogeneous populations. But I want to also emphasize that small variations in genomic information can lead to very significant differences in, again, expression of traits in populations. Even in a somewhat homogeneous population—maybe an ethnic population—there are still going to be genetic variations. And even if those genetic variations are small, it could affect the susceptibility of any of these types of approaches. So not only do you have all of the challenges that I just talked about, but you now also have to accept the challenges of biology and biology’s way of evolving and diversifying. Even in very similar populations—maybe they look similar from an outward perspective—but their genomic information still has significant variations, and so those that are similar, those components of the genome that might be ‘conserved,’ those might not be the targets that would allow you to do something nasty and nefarious.

The toolkits of AI and machine learning can provide an amazing aspect to be able to narrow in on targets for diseases and for ways to be able to help climate resilience of crops; that’s what those tools can be used for. And yes, they potentially could help aid in this type of nefarious work that you’re talking about. But I still think there are enormous challenge to really try to enact that.

CTC: You mentioned the Safe Genes program earlier. DARPA funded and instituted the Safe Genes Initiative during your time there, and its mission includes “protect[ing] warfighters and the homeland against intentional or accidental misuse of genome editing technologies.”¹⁴ What was that effort? Why was it important, and what other guardrail measures, that you can talk about, are in place?

Ringeisen: Absolutely. Again, I’ll have to give credit to Renee Wegrzyn, who was one of my colleagues at DARPA the whole time I was there. She left a few weeks after I left; she’s now at Ginkgo Bioworks. But Renee had the foresight. It was a great DARPA program. This was back in probably 2015, 2016 when she was starting to ideate this program. Again, that’s like three or four years after the discovery of CRISPR-Cas9. So, Wegrzyn realized that there was a gap in the development of safety measures for this technology, and perhaps we needed to do something to put up some guardrails. And there were three areas that Safe Genes was going to invest in. It was to try to make the technology safer. It was to try to create the capacity to block and stop and control gene-editing, and then potentially to even remediate or reverse it. Flash forward five-plus years later, what you see now is a diversification in technologies of gene editing. It’s not just CRISPR-Cas9. You’ve got base editing, you’ve got prime editing, you’ve got epigenetic editing.¹⁵ The propensity for off-target effects has gotten better so that you’re more precise and more accurate in your edits that you make. I credit Safe Genes for starting to think about those types of issues at a very, very early date. The forethought and vision of Renee was really exciting.

The other great part about Safe Genes was its transparency. We were the Department of Defense. And having that giant D in front of your name, as at DARPA, put a big target on our backs. So for Renee, to her credit, from the very beginning, transparency of this work was of the utmost importance. She went to the regulatory bodies, she held open forums, she gave interviews. She insisted that everybody publish their work in open and peer-reviewed journals. She worked with the EPA, USDA, and the FDA, and all of that was done in concert. And so, Renee set the mark. She said, ‘If you’re going to do work in this area, you should still be able to do this work for the Department of Defense, but you need to do it in an open and very transparent way.’

CTC: The Biological Weapons Convention entered into force in 1975, well before advances in biotechnology enabled rapid nucleotide synthesis, gene editing, genome sequencing, and so forth. From your perspective as a scientist and someone with extensive government experience, how could or should the BWC be updated to mitigate the risk associated with non-state actors and state actors developing or employing a biological weapon agent?

Ringeisen: It’s a great question. And honestly, the devil is going to be in the details here and in the interpretation of what’s going on. My personal opinion—this is just me speaking; I’m not a government employee anymore—I think that you want broad definitions and broad interpretations of things that are stated in the BWC. It should be a living, breathing, flexible document. There shouldn’t be a rigidity that says, ‘You can only consider these 10 biothreat organisms.’

All the things we talked about earlier in this interview—where we were talking about zoonotic disease, emergent disease, potentially nefarious actors doing things that they shouldn’t be doing with dual-use research of concern—I personally believe that BWC already covers all of those things, that if you take a broad interpretation, it’s basically there. So, for me, I think the framework is there and then it also has to be done in concert with regulatory agencies and boards for dual-use research of concern. We have these things set up. NIH has these things set up; the Department of Defense has these things set up. When I was at DARPA, we would go down to the Pentagon and talk with the lawyers about interpretations of the BWC prior to launching any program that might be crossing blurred lines there. And so, to me, all of those mechanisms, all those frameworks are already set up; it’s just a matter of ‘the devil in the details’ and referencing the right documents and having conversations about the interpretations. Now, if the regulatory bodies say, ‘Look, something’s emerged, some new technology has emerged that doesn’t quite fit into these’ or ‘We need to be more explicit to make sure that state actors and countries abide by these rules,’ then yes, that’s their job, and they need to do that. But for me, in my day-to-day jobs in the government, I felt the toolkit and the framework were there and the resources were there for me to be able to make the necessary decisions.

CTC: Given your background as a scientist and your lengthy government service, what do you think the next big threat is when it comes to the misuse of science? What keeps you up at night?

Ringeisen: I’m going to pivot on this question. I left DARPA in part because of climate change. I worked for the Department of Defense for 18 and a half years, 20 and a half years if you count the postdoc that I worked on at the Naval Research Lab as well. I thought about bio threats. I thought about chemical weapons. I thought about the effects of radiological weapons and radiological exposures. I thought about traumatic brain injury. I thought about blood coagulants and trying to stop hemorrhagic bleeding. I thought about these things and was passionate about them for 20 years. So, I could talk about the next bio threat, but I’d probably be wrong. One thing I know I’m not going to be wrong about is climate change, and I will insist to my grave that climate security is national security, that water security is national security, and that food security is national security. So, to me, the big elephant in the room that we all need to address to help stabilize the world is climate security, food security, and water security.

And to me, CRISPR and genome engineering and the ability to be able to modify plants, modify microbes, and modify human cells has the potential to dramatically affect these areas. And so, to me, there’s just so much that can be done. We are moving towards a carbon economy. Maybe it’s 20 years from now, maybe it’s 50 years from now, but if I was advising the president or if I was advising the Secretary of Defense, I would say the superpower of the future is going to be the superpower that can control carbon, that can use carbon, that can use greenhouse gases to provide what their country needs so that they’re not reliant on other countries. That, to me, is the best way to provide long-term security for our country. So, I’m trying to work to make crops resilient to climate, to absorb more carbon, to pump more carbon underground in root systems and soil carbon; I’m trying to work to have crops use less water so that we can use fresh water to drink and to minimize irrigation. I don’t want to go to war over water. I’m living out in Berkeley, California, now; we’re under threat of forest fire all the time. What can we do to try to help mitigate forest fires, to have forests store more carbon so that we can help neutralize the effects of climate change?

One of the reasons I left DARPA is because of the opportunity I now have to partner up with places like California-Berkeley, the University of California-Davis who we work closely with, the DOE [Department of Energy] laboratories like Lawrence Livermore and Lawrence Berkeley. The IGI is partnering with a tremendous number of smart scientists to try to create innovative biotechnology-drive solutions in these areas. CTC

Substantive Notes
[a] Editor’s Note: According to the World Health Organization (WHO), “the 2014–2016 outbreak in West Africa was the largest Ebola outbreak since the virus was first discovered in 1976.” According to the Centers for Disease Control and Prevention (CDC), “overall, eleven people were treated for Ebola in the United States during the 2014-2016 epidemic.” “Ebola virus disease,” WHO website; “2014-2016 Ebola Outbreak in West Africa,” CDC website.

[b] Editor’s Note: According to a company press release, “AbCellera initially mobilized its pandemic response platform against COVID-19 in March of 2020, resulting in the discovery of bamlanivimab, the first monoclonal antibody therapy for COVID-19 to reach human testing and to be authorized for emergency use by the U.S. Food and Drug Administration (FDA). Bamlanivimab alone and together with other antibodies has treated hundreds of thousands of patients, preventing COVID-19-related hospitalizations and death.” The press release also noted that “AbCellera’s pandemic response capabilities were developed over the past three years as part of the Defense Advanced Research Projects Agency (DARPA) Pandemic Prevention Platform (P3) program. The goal of the P3 program is to establish a robust technology platform for pandemic response capable of developing field-ready medical countermeasures within 60 days of isolation of an unknown viral pathogen.” “Lilly to Supply 614,000 Additional Doses of AbCellera-Discovered Bamlanivimab Together with Etesevimab to the U.S. Government for the Treatment or Post-Exposure Prevention of COVID-19,” AbCellera via Business Wire, November 2, 2021.

[c] Editor’s Note: “CAR T cell therapy is a type of immunotherapy used to fight cancer with altered immune cells. These specially altered white blood cells, called T cells, are modified to find and attack cancer cells in the body.” “CAR T Cell Therapy: Using Immune Cells to Fight Cancer,” Abramson Cancer Center, Penn Medicine.

[d] Editor’s Note: “DARPA launched the Safe Genes program in 2017 to establish a ‘safety by design’ strategy for guiding the development of an array of powerful, emergent genome editing technologies … to mitigate the risks and security concerns related to the accidental or intentional misuse of such technologies and, at the same time, enable the pursuit of novel genetic solutions that support public health and military force protection and readiness.” “Safe Genes Tool Kit Takes Shape,” Defense Advanced Research Projects Agency, October 15, 2019.

[e] Editor’s Note: There are “four types of bases found in a DNA molecule: adenine (A), cytosine (C), guanine (G), and thymine (T).” NIH website.

Citations
[1] Editor’s Note: “Biomason raises $65 million Series C round to scale biocement® technology,” biomason, February 28, 2022.

[2] “About Us: Advancing genome research for a better world,” Innovative Genomics Institute.

[3] Editor’s Note: Benjamin E. Rubin et al., “Species- and site-specific genome editing in complex bacterial communities,” Nature Microbiology 7:1 (2022).

[4] Editor’s Note: “DARPA Awards Moderna Therapeutics A Grant For Up To $25 Million to Develop Messenger RNA Therapeutics,” PR Newswire, October 2, 2013.

[5] Editor’s Note: See “Chikungunya Virus,” Centers for Disease Control and Prevention.

[6] Editor’s Note: See www.abcellera.com

[7] Editor’s Note: Anne Cheever, “Living Foundries,” Defense Advanced Research Projects Agency.

[8] Editor’s Note: Lisa Jarvis, “Crispr Might Actually Live Up to Its Immense Hype,” Bloomberg, March 1, 2022.

[9] “Jennifer Doudna,” Innovative Genomics Institute.

[10] Paul Cruickshank and Don Rassler, “A View from the CT Foxhole: A Virtual Roundtable on COVID-19 and Counterterrorism with Audrey Kurth Cronin, Lieutenant General (Ret) Michael Nagata, Magnus Ranstorp, Ali Soufan, and Juan Zarate,” CTC Sentinel 13:6 (2020).

[11] Editor’s Note: For further explanation of the genotype-phenotype distinction, see “Phenotype,” National Human Genome Research Institute and “The Genotype/Phenotype Distinction,” Stanford Encyclopedia of Philosophy, June 6, 2017. For more on the complexity of the relationship between genotype and phenotype, see “The Genotype-Phenotype Challenge,” in Robert Pool, Steven M. Moss, and Frances Sharples (rapporteurs), Next Steps for Functional Genomics (Washington, D.C.: National Academies Press, 2020), pp. 5-16.