Building Teams for High-Risk, High-Reward Research Projects with Jonathan Rivnay, PhD

[00:00:00] Erin Spain, MS: Welcome to Science in Translation, a podcast from NUCATS, Northwestern University Clinical and Translational Sciences Institute. I'm your host, Erin Spain. Building teams to take on well-funded high-risk, high-reward, biomedical and health research projects is something today's guest is very familiar with. In the past few years, Northwestern Engineering's Jonathan Rivnay became the co-principal investigator of two such projects. One, a Defense Advanced Research Projects Agency, DARPA, contract worth up to $33 million over four and a half years and another in Advanced Research Projects Agency for Health, ARPA- H, contract worth $45 million over five and a half years. Rivnay, a professor of biomedical engineering at Northwestern University's McCormick School of Engineering joins me to talk about these projects, his collaborations with NUCATS investigators, and the path to securing such funding. Welcome.

[00:01:10] Jonathan Rivnay, PhD: Thanks for having me, Erin.

[00:01:11] Erin Spain, MS: So you've been called a driving force in the future of the field of bioelectronic medicine. Tell me about your background and how you became interested in this emerging field.

[00:01:22] Jonathan Rivnay, PhD: My background is actually materials, and I only moved to bioelectronics during my postdoc, when I spent some time in Europe. I think the exciting aspect here is applying exciting new materials to bioelectronic systems that can really make a difference in terms of sensing, actuation, for diagnostics and therapeutics. And so that's really what's driven me in this direction.

[00:01:41] Erin Spain, MS: Yeah, was there a certain moment back in your career when this switch happened, when you thought, "Hmm, I would like to focus a little bit more on health and medicine and applying these to the human body?"

[00:01:53] Jonathan Rivnay, PhD: Some of the materials that I was working on in my early career are these active or functional polymer materials. Basically functional plastics that conduct electricity. And their early uses were in printable electronics and in applications for energy, like solar cells, for example. And what we realized is that because they are made of plastic, that they are these functional polymers, they're actually quite soft, and that provides an interesting opportunity for interfacing with biological systems. So that's really what got me into these applications.

[00:02:23] Erin Spain, MS: So here at Northwestern, there are several other people working in this space using implantables or devices to help with the health of humans. But there is this big gap out there that exists between traditional technology and biological systems. Tell me about the work that you're doing and how it aims to address that gap.

[00:02:44] Jonathan Rivnay, PhD: There's a few ways to address that gap. One is the one that I mentioned is the mechanics, making materials that are softer, that can communicate with biology using the same language of cells and tissues. So one of the big areas in my group is using these functional polymer materials that not only conduct electricity, but they allow for the motion and transport of ions. So in biology, a lot of communication occurs by biomolecular recognition or ionic transport. And so by developing active materials that can speak the language of biology, we think we can bridge that gap. Another way is actually trying to develop bio hybrid systems, where we bring either traditional or some of these organic bio electronic materials together with engineered biological systems, like cells or tissues that are developed in the lab and then interfaced with the body.

[00:03:32] Erin Spain, MS: to tackle these challenges, it requires a lot of people. It requires a lot of funding and that's something that you've been able to do really successfully is build these big teams. Tell me about the funding that you've been able to be a part of and the teams that you've been able to create.

[00:03:47] Jonathan Rivnay, PhD: To tackle such hard problems, I think you really need to take a step back and think about what expertise you need. And I think we're getting to the point where tackling hard problems at the interface of electronics and biology really requires people with backgrounds ranging from, not just, you know, clinicians and translational researchers, but also electrical engineers, material scientists, biomedical engineers, and then depending on application areas, various biologists. That's really important to keep in mind. It can't be done with a team of one or two. It has to be a big team. And so I've been fortunate to have gotten into those types of projects kind of early in my faculty career, and we've really leveraged that to tackle a number of different and kind of similar problems in a range of different application areas.

[00:04:31] Erin Spain, MS: Yeah, let's dig into that a little bit.

One of the first big projects that you were involved with was a DARPA funded project, the Defense Advanced Research Projects Agency. Now, this project was to develop a fully implantable device to control the body's sleep wake cycles. Tell me about this work.

[00:04:48] Jonathan Rivnay, PhD: Yeah, that's the first big project and one that I actually had an opportunity to lead. I actually got into these types of projects as part of a different, larger project also through DARPA that was aimed at targeting wound healing. And, that was the first time that I kind of met this crew of, I can call them friends now. I think that's one of the key things for building such big teams is finding people that you work very well with. Some of these collaborators from Carnegie Mellon, from Rice University, a few other places around the country, as well as here at Northwestern. I think one of the keys is remembering that on such a big project, you can take on a small but important role and keep in mind the larger goal of bringing together all the pieces. So in that project, my main role is developing sensors and actuators that would go directly on a wound bed, but you had people on this same project that were engineering mammalian cells, other folks that were investigating the biology of wound healing, others that do data science. So bringing everybody together to tackle this larger problem is something that really stuck with me and is one of the reasons that we got into the second DARPA project, which was on sleep and circadian rhythms.

[00:05:51] Erin Spain, MS: And these are not small projects. Tell me about the scale of these projects,you said you were leading the project, but there are many PIs involved.

[00:05:59] Jonathan Rivnay, PhD: So the DARPA project on sleep and circadian rhythms actually came about at the start of the pandemic. We're talking April 2020. I remember, working on this proposal with a number of the other PIs from the other institutions, from my closet with a couple of toddlers scratching at the door. But, I think it's very exciting to bring those projects together because everybody, even during a pandemic, is so motivated getting on these calls, thinking through ideas, and unlike many other projects that I've put in for funding, you're really talking about trying to tackle an idea that you may even have no preliminary data for, and you're just thinking, well, how do we solve this problem? What people are missing? What people do we need to bring into the team in order to tackle this challenging problem? And that's actually what happened. We were working on the proposal for the DARPA project, we realized we needed an expert in sleep and circadian biology, and, lo and behold, I realized that we actually have a Center for Sleep and Circadian Biology right here in Northwestern. So, sent a couple of cold emails and the team was formed, and we were able to kind of be off and running on this proposal.

[00:07:00] Erin Spain, MS: Tell me about some of those collaborators. Who are you working with?

[00:07:04] Jonathan Rivnay, PhD: So, we're working with Fred Turek and Martha Vitaturna in CSCB. And Phyllis Zee in Feinberg. And I found that I've actually learned a lot about sleep and circadian biology, you would expect, leading this project. But, we were able to essentially bring together the clinical and biological aspects with the engineering work, cell biology, bioelectronics, in order to kind of build a concept that we were able to pitch to DARPA.

[00:07:28] Erin Spain, MS: So you've already mentioned finding people that you like to work with, finding the people who have the expertise. And then how do you get all of these people, like you said, on a call together and have that creative energy going to start thinking about how to tackle this project? You did it during COVID, so it's possible to do virtually.

[00:07:46] Jonathan Rivnay, PhD: I almost want to say it was a little bit easier during COVID because everybody didn't have a schedule full of meetings. But, we're still able to do it now, as we're kind of ramping back up to full meeting load. And I think the key here is, because it's a bigger project, you're able to think outside of your own group's expertise. You're able to admit when maybe you can't do something, and you're able to lean on the expertise of others. That's actually one of the really fun aspects of team building.

[00:08:09] Erin Spain, MS: A lot of our folks at the medical school, of course, are using the NIH as a major funding resource. But as we mentioned, this is funded by the Defense Defense Advanced Research Projects Agency, and it's a large grant, $33 million. Tell me why this is such a good match for this type of large team-based science approach.

[00:08:30] Jonathan Rivnay, PhD: So agencies like DARPA and other newer agencies that are modeled after DARPA, such as ARPA-H, are really focused on high impact solutions to challenging problems. And doing it in a way that really can't be accomplished through traditional mechanisms like the NIH or a National Science Foundation, kind of typical grants. And that's one of the reasons is because they can move quick, they often have a more streamlined review process, and oftentimes they come with a bigger budget, which means that you can put together a larger team in order to tackle those big problems.

[00:09:03] Erin Spain, MS: I want to get into the specifics of this project a little bit. You're using living cells as a living pharmacy within implantable devices. This is so interesting. Can you explain this to me and how these cells are able to really become a living pharmacy and release therapeutic peptides?

[00:09:20] Jonathan Rivnay, PhD: This whole area of bio electronic devices is really fascinating. You're bringing together strengths from synthetic biology, things like mammalian cell engineering, which is not one of my core expertise areas. And that's the exciting part of being able to work with people who are experts there. But you're bringing together the synthetic biology with bio electronics, and you're doing it in a way that really requires co-design, right? You really need to develop the electronic system side by side, holding hands with the synthetic biology side. And one of the reasons this is exciting is because developments in mammalian synbio have really led to exciting new cell therapies. But one of the gaps there is that for many applications, you'd like to be able to regulate the dosing very precisely. Potentially the timing of when that therapeutic is released, and you can only really do that with the strengths of bioelectronics. It allows you to provide that aspect of control and also connect back to the clinician, the user, the patient, and whatever data is available out in the cloud or in the health records.

[00:10:22] Erin Spain, MS: You recently published a paper in Nature Communication highlighting a big advancement in this project that has to do with oxygen generation within the implant. Tell me about those findings and how it's able to really move this project forward.

[00:10:36] Jonathan Rivnay, PhD: So besides control, which again we need for the dosing and we need for the regulation, one of the challenges is that you can't actually load that many cells for a given volume without the cells dying. They need access to nutrients, they need oxygen. And one of the things that we found is that if we actually provide oxygen on site in the device, you're not only able to maintain the health and the productivity of those engineered cells, but you're able to have them in the device actually at higher loadings. And that means that you can have smaller devices because you can pack more cells into a specific device. And so the way this actually works is that we have a bioelectronic actuator. Basically a device that's a device within a device almost that does, electro catalytic water splitting. So what does that mean? We apply a voltage to this device, and it takes water that's just around the device and that cells are swimming in and it splits it into hydrogen and oxygen. And it turns out that the way that we designed this device, we can operate it safely, such that we're able to produce oxygen without all the nasty side products, like hydrogen peroxide or other chemicals that might lead to the cells losing viability, dying off..

[00:11:48] Erin Spain, MS: How innovative is this? Has there been anything like this in the literature before?

[00:11:52] Jonathan Rivnay, PhD: Yeah, there's a number of teams pursuing similar approaches, but one of the key outcomes of this work is that we're actually able to do it in complex environments, meaning with the cells that are implanted directly on top of the device, so that you don't get any of the side product formation that you would get from the salts that are around or other proteins and biomolecules that are floating around.

[00:12:13] Erin Spain, MS: What does this device look like right now? What is the prototype you're using and so we can all kind of see it in our mind?

[00:12:19] Jonathan Rivnay, PhD: So the envisioned device, depending on the application, we can envision it being relatively small. But the size of it really depends on the application, it depends on how potent the cells are, meaning how much of the therapy they're able to produce, and things like that. So right now, for the sleep project, this device is on kind of the centimeter scale, we're thinking about it being implanted underneath the skin. But for future iterations and for other applications, you can imagine it being implanted near a tumor, to affect the tumor microenvironment. You can imagine it being small enough so that it can be injectable under the skin.

[00:12:53] Erin Spain, MS: So this is the same device that you are going to be using on your ARPA -H project as well.

[00:12:58] Jonathan Rivnay, PhD: We're gonna be using similar concepts, So we're still gonna have living cell factories. They're still gonna be bioelectronic components to regulate the cells and to keep them alive and healthy. Now we're tackling a different problem and so this one is through ARPA-H. And for that application, we're targeting applications in ovarian cancer treatment.

[00:13:19] Erin Spain, MS: So this was just announced this fall. This 45 million dollar Advanced Research Projects Agency for Health, ARPA-H, to fast track the development of this first of a kind implant to sense and treat, you're saying, ovarian cancer. Tell me about this project and, again, the team that is in place to make this happen.

[00:13:38] Jonathan Rivnay, PhD: The core of the team is the same group of people that we've been working on with these other projects on sleep and on tissue regeneration. Now bringing in new folks to bring in additional innovations to tackle the translation and the cancer biology to treat ovarian cancer. This one in particular is led by collaborators at Rice University, and the idea here is to develop a biohybrid device that can be implanted into the intraperitoneal space to essentially affect the tumor environment of cancers like ovarian cancer.

[00:14:09] Erin Spain, MS: And these are cancers that are very difficult to treat. Explain to me what you've learned in this role about how difficult this can be for the toxic chemotherapy and the difficulty with surgery for cancers like ovarian cancer.

[00:14:24] Jonathan Rivnay, PhD: So one of the goals of this next iteration is that were able to make the treatment more personalized. So I talked to you about regulation, about being able to use the bioelectronics to control the delivery of certain therapies. Now you can imagine that certain therapeutic approaches might involve multiple therapies. So being able to have cells within the device that produce different biomolecules will be very important. The other aspect is that the particular dosage that you might want for certain therapies can be very variable. So being able to control the dose is obviously critical, but now having sensors on board that are able to quantify the toxicity, or quantify the efficacy of the therapy and adjust in real time is something that it hasn't been done, especially in cancer therapies.

[00:15:09] Erin Spain, MS: Tell me about how you bring physicians into a project like this. They would be the ones working with the patients and possibly even monitoring the device once it's able to work. Tell me about the role you see a physician playing.

[00:15:22] Jonathan Rivnay, PhD: I think one of the goals of putting any of these big teams together is keeping in mind that need to break out of this mode of designing a material or device and bringing it to a clinician and saying, here you go. We need to bring the translational and clinical professionals into the project from the very beginning. And that's a kind of a design challenge because they're the ones who know what the field looks like, what the current state of the art is, even specifics on how surgeries are done and the current clinical practice. And integrating that into the design and development process is really necessary for such a big team. And so that's why you bring them in early on, and you take their feedback and you have them involved in all the technical meetings, so that they can flag any issues that they see arising early on in the process, rather than when it's too late.

[00:16:07] Erin Spain, MS: So as you're moving these projects forward from the lab to the clinical setting, what are some of the challenges that you're already anticipating? And how do you plan on leaning on Northwestern Medicine and NUCATS investigators to solve some of these challenges?

[00:16:23] Jonathan Rivnay, PhD: Well, I think one of the aspects that's really exciting about this biohybrid implantable device approach is that it really is a platform. So it does need to be engineered for different applications, but you can imagine a number of different application areas where such an approach could be relevant. And I would say in any application where you need regulation, feedback and response, for example. You need high cell loadings. You can think of bioelectronics as a good partner for synthetic biology and cell engineering. And so, it really means that there's a number of application areas and a number of different areas of medicine that we can tap into to translate these technologies towards different ends.in terms of translating these technologies, there's still a long way to go. The end of the day, this is a combination product. It's both a biomedical device and it's a biologic. It's a cell therapy. So, navigating the regulatory landscape of a combination product like that, and all the other aspects that go into manufacturing, shipping, and implementing such a device.

[00:17:18] Erin Spain, MS: So a lot of challenges ahead, but something that you mentioned was this really is personalized precision medicine. And that's something that so many people listening they know is the future of medicine. Can you talk about how exciting it is to be a player in this field? An area that when you started off your career, this wasn't something that was on your radar. What's it like to be helping to push this field forward and to really play a part in precision medicine?

[00:17:45] Jonathan Rivnay, PhD: Well, I feel fortunate to have the opportunity to work on such projects and to even lead some of these projects. And I think it's a really exciting time. We're on the leading edge. We're really almost waiting for and pushing the boundaries on some of the aspects that will enable this technology. Things like wireless, power and communication, technologies to make the device sustainable and long lasting in a complex implantable environment. The leading edge of synthetic biology, right? Making cells that can be extremely potent so that maybe you don't need a large device. You can do this in an injectable format. All of these kind of advances are ones that we're, as a team, either pushing on or watching the field grow, such that it can enable this type of biohybrid device.

[00:18:29] Erin Spain, MS: I think one thing that's come through during our conversation today is the importance of team science and building a team that can pick up new projects and keep adding folks to the team to make it better and stronger. As we wrap up today, can you leave us with a few tips for people listening who are interested in maybe building a project like this or being part of a project? What advice would you like to give to them?

[00:18:52] Jonathan Rivnay, PhD: When you think of, as a researcher, your own area of expertise, I think oftentimes we set a boundary in terms of what we think we should be working on. I think that oftentimes leads to safe proposals, ones we can handle entirely on our own. But I think in reality, many of us have expertise outside of what we think we should be doing. And I think sometimes we need to step outside of that boundary. And that's where we, I think, are more comfortable relying on others' expertise to build these bigger teams and tackle larger problems.

[00:19:22] Erin Spain, MS: Good advice.

Well, thank you so much for being on the show and sharing some of your expertise and insight on these projects. We really appreciate your time today.

[00:19:30] Jonathan Rivnay, PhD: Thanks for having me. This has been fun.

[00:19:32] Erin Spain, MS: Subscribe to Science in Translation wherever you listen to your podcasts. To find out more about NUCATS, check out our website, nucats.northwestern.edu.