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Oby Ukadike: From the campus of Harvard Medical School, this is ThinkResearch, a podcast devoted to the stories behind clinical research. I'm Oby, your host.

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ThinkResearch is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center. And by NCATS, the National Center for Advancing Translational Sciences.

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At the beginning of almost every episode you hear of ThinkResearch, you hear me say, ThinkResearch is brought to you by Harvard Catalyst and NCATS, the National Center for Advancing Translational Sciences. Join us today as we sit down with Dr. Michael Kurilla, who is the Director of the Division of Clinical Innovation at NCATS.

In this capacity, he oversees the Clinical and Translational Science Awards Program, which supports innovative solutions to advance the efficiency, quality, and impact of translational science, with the ultimate goal of getting more treatments to more patients quickly. Dr. Kurilla received his MD and PhD in microbiology and immunology from Duke University. He was a postdoctoral research fellow at Harvard Medical School and completed a residency in pathology at Brigham and Women's Hospital. He received a Bachelor of Science in chemistry from the California Institute of Technology.

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Hi, Dr. Kurilla. Welcome to the show. Glad to have you here. Can you start by telling us a bit of your background and what led you to NIH and then NCATS?

Michael Kurilla: I started out, I guess, very traditional, thinking I was just going to be a ordinary research scientist. I was at the University of Virginia doing academic research after my residency in pathology. I was also doing clinical microbiology as part of my duties within the pathology department. And my focus on research at that point was viral immunology.

Interestingly enough, a colleague of mine that I always used to rely on for advice, he was a few years ahead of me. He called me out of the blue and said, I need somebody to head up an antimicrobial group here at a company, and would you be interested? And I said, sort of, but I can't really say that I know much about drug development.

And he said, well, that's the least of the concerns. He says, I need somebody who understands science and has a good understanding of clinical issues. And he said-- being a pathologist and running a basic research lab, he said, you have all of that. So that led me to industry.

And after a couple of different companies, buyouts, and transfers, and all that sort of thing, my wife told me that could I please get a job where we didn't have to move so often? And so--

Oby Ukadike: Fair enough.

Michael Kurilla: So I came to NIH and was in the National Institute of Allergy and Infectious Diseases. And then interestingly enough, it was shortly after 9/11 and biodefense was really kicking off.

NIAD was moving into the development of vaccines, drugs, and diagnostics for a lot of biodefense pathogens, and I headed up what was originally called the Office of Biodefense Research Affairs. We changed it to the Office of Biodefense, Research, Resources, and Translational Research, and was doing that, and involved in a wide array of activities.

We had bird flu back in 2005, which is back again now, causing problems. We had the H1N1. We had the Zika outbreak. We had Ebola in West Africa, on, and on, and on involved in many of those activities, and really produced some, I think, very good vaccines, therapeutics, and diagnostics that are in use today.

And then I got a call from a former colleague who had been at NIAD and asked me to take a look at a position over here in NCATS heading up the CTSA program, recognizing that as a program officer at NIH, you really have to understand the science, but at a certain level, you have some degree of being able to engage with senior scientific leadership and leadership within government, including Congress, and White House, and the attendant personnel there.

And as well as being able to engage with the media, as I'm doing now, and my years, almost 15 years doing biodefense, sort of prepared me for that. And in many ways, it's a slightly different focus, but in many ways it's very, very similar.

The fundamental aspect, I think, of what I do is really trying to effectively move all of the wonderful science that NIH funds and produces us across the world, basically, but to turn that science into effective health care solutions that work for patients, providers, health care systems, and provide overall general benefits, in terms of better health and well being to people.

Oby Ukadike: What is the CTSA program? And as a group, Harvard Catalyst is part of the CTSA program. Can you tell us, and the listeners, a little bit more about that? And what are the mission and goals of the program?

Michael Kurilla: So the CTSA program is actually-- it's actually older than NCATS itself as a center where the program is administered. And it really came out of a prior NIH director back in the early 2000s, Elias Zerhouni, who had that prescient notion that we have to slice and dice the biomedical enterprise. We have categorical institutes. We do it by disease. There's a National Cancer Institute. We do it by organ systems. There's the National Institute of Heart, Lung, and Blood.

And you have to do it in some way to divvy it up so you have effective management and oversight. But no matter how you do that, there isn't a right way. There isn't a single best way to do it.

But whatever way you do it, there will be certain elements of science, and particularly emerging science, that simply fall through the cracks. They don't fit neatly into the configuration that we're using. So Elias Zerhouni initiated the roadmap, which was trying to identify those elements of science that were being broadly utilized and implemented, but didn't necessarily have a specific home.

There was no institute or center that was taking ownership. And as a part of that, there was a component, which was referred to as reinventing the clinical enterprise. And this came about because of the recognition that clinical research, and particularly clinical research involving human subjects, is highly regulated and requires a huge amount of training and experience in order to be competitive for NIH awards.

And what was recognized was that there was a growing disconnect that the typical clinical researcher could not be trained sufficiently to be competitive for an NIH award in the time that tenure track usually evolves over, about a seven-year period. And we were losing people doing clinical research, simply because they couldn't get funded, therefore, they couldn't get tenure. Therefore, they went off and did something else.

Part of the raison d'etre for the CTSA was to create a comprehensive program that would address the clinical research, as opposed to a specific field within clinical research, but would generally think of clinical research itself as a topic. And that's where the whole notion of translational science. And so the CTSA is the Clinical and Translational Science Award program, came from that standpoint, recognizing that there has to be a support at the institutional level. Whereas we think of most NIH awards as going to an individual, an RO1 goes to a particular PI, a principal investigator.

But to have a system that would allow for the comprehensive training and development from very early stage, you could think of predocs, all the way through to postdocs, junior faculty, and that important middle category at the academic level, tenured, but not yet a full professor. Looking at making a system that would allow for the institution to develop a comprehensive training program that would be specifically targeted towards supporting clinical and translational science efforts, because we can do all the greatest science in the world. But if nobody can figure out something useful to do with those wonderful discoveries.

Congress gives us money to support health, the National Institutes of Health. They're not giving us money to publish papers. They know we have to do that. That's part of the job, and they fully expect that you're doing that. And they know that that has to happen.

But what they're really interested in seeing is tangible results, that they could say the money we gave to NIH has resulted in these treatments, these interventions, these reductions in certain diseases, this understanding that can provide advice, both to the patient and the health care provider, to better take care of existing diseases and treat and potentially-- my clinical colleagues are always reluctant to use this word-- but potentially "cure" a disease. We see very good examples of that in some prior efforts.

I think the other point I would raise is that there used to be a time, if you go back to the 1950s, and '60s, and '70s, there was a sort of golden age where it's a very cinematic version of the academic scientist is usually somebody by themselves in the subbasement of a building, generally after midnight, pouring stuff back and forth between test tubes and then says, Eureka! I've discovered a cure for something.

Then a pharmaceutical executive comes in and says, yes, we'll take it from there. And then a few years later, there's a treatment. And that's what I refer to as the cinematic version of how it works.

The pharmaceutical industry, that sector, as well as devices, and other types of things, they have evolved. They don't take things initially right after the discovery stage. It's very expensive. It's very complicated.

There's a very high failure and attrition rate. And so they like to see things move a little further down the pipeline to de-risk so that when they take something on, because they have to do much of the downstream, very expensive stuff. It's one thing if you've made a drug in the lab that you're making a few grams of the drug. But when you want to talk about a drug that's going to be used commercially that doctors are going to be able to prescribe, you're talking about being able to produce metric tons of a drug, and that's a very different scale. A lot of investment.

There's a lot of FDA, in terms of what you have to demonstrate, not just in terms of safety and efficacy that I think most academics are very familiar with, but the FDA is also concerned about quality of the manufacturing of that drug. And that's where it takes a lot of support and money to do that. And after you've produced the drug, then you have to put it in some form, what we refer to as fill finish.

It has to be in a capsule, a tablet, a liquid formulation, blister packs, injectables, all these sorts of things. And then you have to arrange for how you're going to store it, distribute it. That's where a lot of the expense and time and effort goes into. And that's where a lot of the pharmaceutical industry has to focus their efforts on.

And so it's incumbent on the academic community to now required to do more translational efforts that used to be something the pharmaceutical sector had exclusive control over, and really pioneered how that is done. It's been a learning experience, I think, for the academic community. But we've had some major successes. And I think it's just a skill set that's gradually being adopted and recognized. But it takes quite a bit of training to do.

Oby Ukadike: That is amazing. There's two questions that are coming up right now, and I may combine two of them, if you want to answer together, or if you want to parse them out. But one was the evolution of the CTSA program, which you started to talk about from its origins until now, and it's been over-- from what I looked at, I looked at a little bit of information before we got online, 18-plus years of thinking about the program work from when it began, to maybe when it became a formal award. What has that evolution looked like?

And the second question I have in mind is how does NCATS define clinical and translational research and science? I heard you talking about some of that and the different ways that people get to developing a drug and the pharmaceutical companies involvement. And even that nugget that you just gave about pharmaceutical companies used to do a little bit more work that is now done by someone who's a researcher, which I did not know, and find very interesting. What is the definition of CT research and science?

Michael Kurilla: So I think when we talk about clinical research, we're really talking about working with human beings. A lot of basic science doesn't even involve living organisms. It involves molecules, atoms.

It may involve tissue culture samples and those sorts of things. And then you move into animals, and clearly mice sort dominate the field. But ferrets, Guinea pigs, nonhuman primates, you name it. Almost every animal will play a role because of some unique niche. For example, a particular virus of some concern, but it hasn't caused any outbreaks.

Nipah virus. Cats turn out to be what you use as the animal model, because that one comes closest. Ferrets are used quite a bit in influenza, because mice don't get sniffly, runny noses and sneeze, but ferrets do.

So in terms of trying to mimic, the animal model is trying to mimic the human disease condition. But you can only go so far. There are some very key differences in the way disease processes work, and we learned this quite extensively when I was doing biodefense.

I can say with certainty that in all of the examples we used, it was never the mouse that best recapitulated human disease. For anthrax, we used rabbits, surprisingly enough. And nonhuman primates are used quite frequently. But eventually, you have to get to people, because that's where we want it to go.

There are unique differences in terms of how people metabolize drugs. There are unique toxicities that may be seen with humans that you don't see in mice. I always like to give the example that if penicillin were brought to the FDA today, if you look to see what penicillin does to Guinea pigs, the FDA probably would never allow it to go into people.

So we see some unique differences like this that emerge. And so we just can't assume that what we saw in the test tube, what we saw in the animal, is going to be recapitulated in what we see in people. We certainly need all those models, and we want to have as much information up front to know how we can approach it in studying people. But eventually, the clinical research, where the rubber meets the road, is really doing what we're doing in people.

The translational science is really that ability to take the fundamental scientific discoveries and reduce that to some practical, implementable intervention in some way, be that a drug, be that a diagnostic test, a vaccine. Be it a different way to approach patients.

We see this in terms of particular types of screening questionnaires, all of these sorts of things. And again, there's always emerging technology. And the emerging technology 10 years ago was genomics. And now the emerging technology is really artificial intelligence.

AI is really redefining, in many instances, the way we can do what we do. And so really trying to understand how we can best develop that, translate that from what we know scientifically into something that is implementable and practical, both for the patient and the provider to utilize, in terms of that health care delivery, is really the key feature of what translation is.

The translational science aspect of that, as in any sort of scientific field, is really understanding the fundamental underpinnings that define how that process takes place. For example, if you want to test a drug in people, you have to do some in vitro and in vivo toxicity studies to test the potential safety of that drug and look for potential toxicities.

That's a well-defined field. But again, as we move to more and more types of unique systems such as tissue chips, it's a new emerging field that pharmaceutical companies are very much interested in. The idea here is it's a sort of intermediate between the whole organism and tissue culture, where you can more faithfully replicate not just the cellular components of an organ, but more the organ itself.

So you can have a liver on a chip. You can have lungs on a chip. The lungs on a chip are sort of interesting, because in lung cells and tissue culture just behave like cells in tissue culture.

But tissue chip lungs actually breathe. There is air flow back and forth and the cells are being exposed to air pressure changes. And that actually influences the way they behave.

And so you're looking at them under more authentic conditions that sort of replicate what it looks like in vivo. The other advantage of tissue chips is that this is all aspirational, but you can actually derive a tissue chip from you that would actually test your ability to respond to a particular drug.

And the science as to how that is done, how people can do that on a reproducible basis is very important. And even more importantly is how the science can be done in such a way as to satisfy the FDA. The FDA never tells you how to do anything. You just take them things that you've done. And they basically do a thumbs up or thumbs down on it.

And they'll give you some advice and some suggestions on what you could do. But all the new technology comes with potential pluses and minuses. And the FDA is very much interested in exploring that. And so the science of how you approach, from a regulatory standpoint, demonstration of safety, efficacy, and quality is critical.

And that's what translational science is all about. It's understanding those fundamental principles so that when something new comes along, you already have a bookshelf with information. You already have a fund of knowledge that you can look at to see how this has behaved previously, and how we can compare it to what we've already seen before.

Translational science is really the general principles for how we take scientific discoveries and basic scientific information and translate that into implementable, viable, feasible health solutions for both the patient and the provider to be able to utilize.

Oby Ukadike: So how has the CTSA program changed and evolved over the last 18 plus years? Obviously, you've talked through some of it, but anything else you would highlight or a timeline you would walk us through?

Michael Kurilla: The CTSAs came about by replacing what had been a previously long standing and very successful NIH program called the GCRC, the General Clinical Research Centers. The funding for that was brought together and the GCRCs became the CTSAs.

That was run previously before the existence of NCATS. When this was established, that was through NCRR, the National Center for Research Resources. The entire time that the program was with NCRR was basically-- it was in a growth phase, because they took about a period of about five years to move from no CTSAs to the roughly 60.

That was the target number that they were going for. And it just happened that NCATS was established, basically, the year after NCRR finished the initial ramp up of the CTSA program. And so NCATS was established, the National Center for Advancing Translational science was established with the idea of really being a home within NIH that would focus-- its primary mission would be to focus on translational science.

It's in our name, National Center for Advancing Translational Sciences. We're also the only Institute or center at NIH that has a verb in its name, oddly enough. Even though I'm sure every other IC thinks they're advancing their field of science, ours specifically called it out. When NCATS took over, there was a conscious effort to rather than think as traditionally happens with a lot of NIH programs as a bunch of individual awards is to think about the CTSA really as being a program, being a consortium of academic institutions all focused around clinical and translational science.

Over the years, there's been a couple of activities that have been established for that. Training has always been a major component. Included within the CTSAs, our T's the traditional sort of NRSA-type awards, pre and post-doc. And then we have the junior faculty K awards, the K Scholars. These are young faculty.

To move in the direction of a real consortium, we created a couple of programs along the way. So one is referred to as the CCIAs, the Collaborative CTSA Innovation Awards. And the idea here is that multiple CCIAs come together around a specific project that no single institution is able to tackle on their own. So we've had a number of very successful CCIAs.

I'll just give one example. There's a wonderful program down in North Carolina. So there are three CTSAs in North Carolina. There's Wake Forest, UNC, and Duke. And they came together-- the three of those North Carolina institutions came together for a CCIA that they partnered with the State Department of Public Health, and they created a program called Early Check.

And the idea here is that newborns are tested for a wide variety of potentially genetic diseases. But historically, the diseases you test for are ones that you can actually directly intervene and do something about. So just as an example, phenylketonuria, if it's left untreated, will cause mental retardation. But it's relatively straightforward.

You put the child on a low phenylalanine diet for the first several years of their life and you avoid all of that consequence. But you have to know, as early as possible, so you do newborn screening. Another one is hypothyroidism will also lead to mental retardation, but you can treat the infant for that, if you know they have that.

So there's usually a large collection of these diseases that and it's usually done at a state level. The state does the testing and the state decides which ones they want to test for. This becomes a sort of chicken and egg, because how do you actually test for a potential intervention if you don't know who has the disease?

And if you need to treat them very early, you'd need to know from birth. So the early check created the opportunity for parents to opt in. No additional blood samples were needed. It was all done from that initial heel stick that was being done anyway.

But they specifically selected a few diseases for which they felt there were potential treatments coming down. They thought there would be treatments at some point. They could see what was being advanced. And so they initiated this. And it was quite successful.

And they do have one example of where one disease, spinal muscular atrophy, SMA, a treatment did become available. And they actually did pick up a child with SMA. And that child was able to get the treatment as early as possible.

Now the interesting thing about that is that early check has been so successful that there have been a number of foundations that have come in and said, you know, we think there's a lot more could do with this. And we're willing to put our support in.

And now they are actually supporting whole-genome sequencing of those samples and have identified a wide variety of genetic diseases. Again, quite rare. They started this last fall and they've already identified over 1,000 kids that have variable forms of subtle genetic disorders that are not as consequential as the child's going to die.

But slight modifications in diet and that sort of thing can actually really have an overall impact on the child's life. And I think the other aspect here is that we've been seeing a movement more and more that a lot of people are pushing for, that we should be thinking about doing genomic sequencing of all newborns because you will pick up all sorts of things.

And this is the kind of data that really supports that. There has been some interest from other states to see how North Carolina does this. Is it something we can consider taking on? So I think that's one successful CCIA award that is really changing the way we approach newborn screening in a very comprehensive and substantial and impactful manner.

The other thing that the CTSA program did was to think about some consortium-wide efforts. And so we've had a number of these. The Trial Innovation Network, which continues to be very successful in terms of focused on improving our efficiency and quality of clinical trials with a focus that, again, doesn't always get a lot of attention from the rest of NIH, but recognizing that in addition to the trial design and statistics, which they do quite a bit, and I think there's a lot of opportunities there, they also focus on aspects such as administrative and logistical aspects.

Just bringing multiple clinical trial sites online for multicenter trials can be a very, very burdensome process that takes an enormous amount of time. They've tried to streamline this as much as possible.

Another successful consortium effort we've had has been what we refer to as CD2H, or the Center for Data to Health. We want to think about being able to take advantage of all the digital information that we have embedded within electronic health records. But the way the system has evolved, EHRs from two different hospitals are not necessarily interoperable with one another, and they've focused on how to make that interoperable, rather than trying to-- this notion of getting everybody to do it one way is not likely to ever pan out.

What we said in academics in particular, the smaller the stakes, the more vicious people fight over them. And so that's the way EHRs have been. People are convinced that the way they do it, it has to be the right way.

And so CD2H really focused on, OK, we're not going to get people to change the way their EHRS are, but let's make something that we can actually allow two EHRs to talk to one another. That work that they did, what my head of informatics, Ken Gersing refers to as the general plumbing, which is not sexy, it's not exciting.

It's not the kind of thing that thrills study sections, but they focused on it. That resulted in our ability to actually stand up NC3, the National COVID Cohort Collaborative that is still to this day the largest aggregated database of COVID data that has been valuable and has produced hundreds of publications and continues to be used extensively.

And we're seeing interest across from NIH as how to replicate this, because people see the value of big data. The era of big data is upon us. And so this is an opportunity.

So the CTSAs have evolved from just single institutional awards, each doing their own thing. And we want them to do their own thing. I think one of the emphasis that I've really tried to stress is we're not trying to make everybody look the same. This is not a cookie cutter program.

Each institution has unique strengths because of all of their ancillary capabilities that they have embedded by the number of different professional schools. Some CTSAs have extensive engagement with their schools of engineering. Others have schools of public health, schools of nursing, schools, of dentistry, pharmacy, all of these sorts of things.

And they also have unique patient populations where they can do things that other CTSAs can't. We also see a size variation. Large CSAs behave very differently from CTSAs at small institutions.

In many instances, the smaller CTSAs, their institutions have said, we're just going to let you handle-- we're going to let you see that they handle all of our clinical research. You guys just take responsibility for that.

That doesn't happen at large institutions because they have so many other resources available to them. So we've seen some innovation, just in how institutions organize themselves. So I think the impact on the general research ecosystem is-- because of the presence of the CTSAs has been tremendously impactful.

Oby Ukadike: Thank you so much for joining us and talking us through the NCATS, the CTSA programs, and even sharing some of the different initiatives and groupings of CTSAs that are doing amazing work around the nation. It's really incredible to hear and to know that this work is happening now.

It's impactful now. It's very current. And so we really appreciate you being here.

Michael Kurilla: Thank you for having me. Always a pleasure.

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Oby Ukadike: Thank you for listening. If you enjoyed this episode, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community and beyond. We are always looking to connect and collaborate with the research community and would like to hear from you. Please feel free to email us at OnlineEducation.Catalyst.harvard.edu to inquire about being a guest on the podcast.

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