The Race to Uncover the Hidden Causes of Idiopathic Pulmonary Fibrosis

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Season four of The Fundamentals is here, and we're celebrating by doing a special two-episode release to launch the season!

On this episode of The Fundamentals, we talk to two clinician scientists determined to unlock the mysteries of idiopathic pulmonary fibrosis. Dr. Marc Peters-Golden and his mentee, Dr. Sean Fortier, discuss their research and the race to uncover the hidden causes of IPF to offer new hope to patients. 

Be sure to check out our second launch episode and our entire back catalog on The Fundamentals website, or on your favorite podcast player.

Transcript

Kelly Malcom:

Welcome to The Fundamentals, a podcast where we explore biomedical research here at Michigan Medicine. Research is fundamental to University of Michigan's mission to improve the world. On each episode, we'll meet the people behind the research, learn more about their fields and the fundamental questions they are trying to answer. I'm Kelly Malcom, a science writer and communication strategist for the University of Michigan Medical School. This season, we'll start by explaining a little bit of the history behind the questions our experts are asking and get a glimpse into the future of healthcare.

The term idiopathic has rather poignant roots in the Greek language, meaning one's own suffering. In modern medicine, a disease is described as idiopathic by process of elimination, essentially when a disease cannot be attributed to a known cause. Patients with idiopathic disease can feel alone, desperate for insights and help. One could argue that all diseases were at one time idiopathic. We can now name the causes of so many diseases and treat them, thanks to dedicated clinicians, researchers, and patients. From basic and discovery scientists who figure out how our body functions and what goes wrong, to researchers who come up with ways to treat diseases, to patients who advocate on behalf of everyone.

Uncovering the root cause of disease and developing therapies takes an enormous amount of dedication, investment, and time. One of the most common conditions to fall into this frustrating category is idiopathic pulmonary fibrosis or IPF, which is a form of lung scarring. On this episode of The Fundamentals, we talk to two clinician scientists determined to unlock the mysteries of this disease. Dr. Marc Peters-Golden, Professor Emeritus of Internal Medicine, who has spent more than 30 years studying lung disease. And his mentee, Dr. Sean Fortier, Assistant Professor of Internal Medicine, who has grabbed the baton in the race to uncover the hidden causes of IPF, to offer new hope to these patients. Welcome, Dr. Peters-Golden and Dr. Fortier. Thanks for being on the episode today.

Marc Peters-Golden:

Thank you.

Sean Fortier:

Thank you for inviting us.

Kelly Malcom:

Okay. So, this is a really important topic. I think we get a lot of inquiries about idiopathic pulmonary fibrosis or IPF from readers of our blog. But I definitely wanted to talk to you also about this condition and your work and doing research and getting us to where we are today. But why don't we take a step back and start with why did you both decide to study the lungs for a living and what really got you into it?

Marc Peters-Golden:

Maybe I'll start because I got into this before Sean was born, long before Sean was born. Well, I got into the lung because I was in college at the time of the first Earth Day, just to go back, and I got very interested in environmental problems. I majored in environmental studies, which was a major that I created. And I decided that I wanted not to go to grad school as I had been considering, but to go to med school because it was the health effects of environmental issues that really interested me the most. So, that was a really natural segue to the lung, because the lung is the internal organ that is constantly exposed to the air, and to all the pollutants, and microbes and toxins and so forth. So, that's how I got interested in the lung.

Sean Fortier:

Yeah. I have a little bit of a distinctive story from that. So, it was really hard to decide when in medical school what to focus on, even in residency. But I fell in love with critical care in the ICU, being able to get real time feedback and help people in need acutely. And it turns out that when the body's stressed, like in the ICU, the lungs are sometimes the first to go. And certainly, people are put on ventilatory support. And then the physiology of the lung was just very attractive. And it's a natural fellowship that combines pulmonary and critical care. And so, that's how I got into it. And then on fellowship, as the lung clinic and research took off, it just became very natural and fitting.

Kelly Malcom:

So, how did you ultimately come to study idiopathic pulmonary fibrosis? And I know you probably study other lung conditions than that, but what really brought you to that disease in particular?

Sean Fortier:

Well, joining Marc's lab, he was studying or is studying inflammation, so the immune system arm of lung conditions, as well as fibrosis. And so, I kind of had a choice, two major pillars of that. And for me, fibrosis was attractive because there's a massive need in patients. We don't have great treatments for this. The prognosis is poor. But from a biological perspective, it's also a very fascinating condition. There's a lot of parallels with cancer, in that you have to disable a number of fail-safe, cellularly speaking, that lead to fibrosis. And so, that was a problem I wanted to try and tackle.

Marc Peters-Golden:

As a clinician, I was seeing patients with pulmonary fibrosis from the very beginning, but doing research in it was something that I came to as a natural progression through the science that I was doing. I wasn't actually setting out to study pulmonary fibrosis. We were studying a particular gene that encodes for an enzyme. And we discovered by happenstance that this gene was defective in cells from patients with pulmonary fibrosis. And we didn't really know a lot about what this gene and this enzyme did in these lung cells and how it might relate to pulmonary fibrosis. So, that was 30 years ago, that we made that discovery. And that set me on this path that has been fascinating. We've learned a lot. And I've had the pleasure of having a lot of trainees and fellows, like Sean, to partner with me in exploring it.

Kelly Malcom:

So, I know 30 years is a long time, but we recently have had some breakthroughs for therapies for IPF, right? Can you tell us a little bit about those?

Sean Fortier:

The only medications approved to treat idiopathic pulmonary fibrosis and by extension, other conditions that lead to lung scarring, were about 10, 11 years ago now that a pair of drugs came out, pirfenidone and nintedanib. And then it was really a dry spell for the last decade, until October 2025, when there was a new drug approved, nerandomilast, which now has the brand name Jascayd. And then there's even another one on the horizon. And what's very interesting about both of them to Marc and I, well, of course, as clinicians, we want other options for our patients. But mechanistically, both of these medications, the latter one not yet being approved but promising, deal with a pathway that we study.

Kelly Malcom:

So, I think one of the things that I want to get across to people is how iterative science is. It takes a while. So, why does it take so long or over a decade to get to a new therapeutic?

Marc Peters-Golden:

Scientific progress is a process of building blocks, one building block after another. This pathway that Sean alluded to, this is the pathway that I got interested in 30 years ago and have been studying it all these years. And I'm not the only one studying this, certainly. Lots of researchers had been interested in this pathway, coming from the context that it was inhibitory of inflammatory processes. So, pharmaceutical companies that were trying to develop drugs to treat inflammatory conditions, such as asthma and COPD, were interested in this pathway. It's just that the focus had not really been on this pathway, as also inhibiting fibrosis. And that was the sort of angle that our work was really interested in.

And over the years, I think we just laid a lot of groundwork to understand better and better how this pathway was basically disrupted in fibrosis and then what the pathway did in fibrosis when it was present. And that led to the idea that we should be able to augment this pathway. It's a natural homeostatic pathway. We think of it as a break that is broken in fibrosis. And just again, the confluence of science, these new drugs basically in two different ways act to restore that break.

Sean Fortier:

Yeah. And just so we state it, it's the pathway is this second messenger cyclic or cyclic AMP, which is a chemical entity that is based off of actually the nucleotides that make up our DNA and RNA. And it's a very common second messenger in cells. It's not just in mammalian cells. It's also in microbes that use it. So, it's a very ancient evolutionarily conserved molecule. But as Marc said, the understanding of its role in fibrosis has been quite delayed. I would also say that things take a long time, because technology needs to catch up to ideas. And we now have the tools to assess the role of cyclic AMP. It's signaling within the cell and compartments within the cell, the timing of it in specific cell types. So, we're interested in fibroblasts those cells that lay down the matrix, the collagen and composed scar, but there's many different cells.

And in the last 10 years, we've now had the opportunity to specifically delete genes or augment pathways in specific cell types at specific times in animal models and in cells, using CRISPR or other methods. And so, that has been immensely powerful and opened our eyes to recontextualizing some of these pathways. But it always amazes me that something that has been known about for decades and decades, doesn't mean that there isn't more fruit to bear from its study in a different disease context.

Marc Peters-Golden:

The cyclic AMP pathway that we're talking about has already given rise to four Nobel Prizes.

Kelly Malcom:

Oh, wow.

Marc Peters-Golden:

Okay. These are investigators going back 40, 50 years, going back to how hormones work. And just understanding various aspects of this pathway, which as Sean said, is so fundamental, so primordial. Every cell in the body and in all organisms, plants included, use cyclic AMP as what we call a messenger. And it can do so many different things, but the focus just hadn't been on fibrosis, so that's been exciting.

Kelly Malcom:

So, you mentioned the technology had to catch up with the ideas. I know that there's a lot of hype around AI and maybe applying those tools to research or to science to maybe speed things up. Do you think that, or what's your opinion about using AI maybe to maybe advance some of these findings a little quicker?

Sean Fortier:

It's certainly an important tool. Finding our footing with how best to use it in different contexts, some indications are a little bit more obvious to me than others. So, one of the advents over the past decade or so has been omics. So, that is to say being able to take unbiasedly an entire sample of say cells and measure one entity. So, we are all familiar with the word genomics, where we understand what is being coded by the DNA. But now we have transcriptomics, so we can take all of the RNA, which is what is the code that comes from the DNA to make the protein that make the cell function. We can understand and quantify and measure all of those RNAs in the cell and in each cell from a sample and keep track of the cells throughout. So, that is immensely powerful. And you can imagine the terabytes and petabytes of data that come out of that, even from a single experiment sometimes, depending on how expansive it is.

The bioinformatics involved in that is massive, and so AI can be very helpful in those ways. I'm not a bioinformatician, but of course, that's an obvious application. On the other side of things, when you get to like the wet chemistry of a lab, where you're pipetting chemicals into cells and such, it's less obvious to me. But I, for one, use large language models to gather information, to interrogate the literature. Even to test out ideas and say, "I read about this in one area of science and in a disparate kind of field. I read about that. I think could there be a connection there?" And it's just a really useful tool to get at that.

Then you hear about these Nobel Prize winning algorithms like AlphaFold, where it used to be that you needed graduate students and four years of a PhD to solve a protein crystal structure, which is very important and useful. And that was done for decades. And now, 200 million or so have been solved. And thinking about drug discovery and AI in that is I'm sure immensely powerful. Personally, I'm using it more for research to confirm concepts right now, but I do anticipate more and more integrating it into my work.

Marc Peters-Golden:

We're not drug discoverers. That's not what we do. We're really more interested in understanding mechanisms and biological roles for different molecules, and how cells work, and how they talk to each other. But in the pharmaceutical industry, AI has been enormously important, because they can synthesize a molecule that has some attractive feature, but they're always wanting to optimize it. Can we make it better? Can we make it not only more efficacious, but can we make it so that it's efficacious and it lacks this negative side effect? So, in the old days, that required chemists to just make an endless array of similar molecules, every one of them, one at a time in a test tube.

AI can just look at the structure and understand from what's known, which atom in which location could be moved around a little bit to make things better. And it's just, again, not what we do, but I know that it has really sped up the drug discovery process. I think there are a lot of ways that AI and other technologies that basically allow us to more comprehensively, more efficiently utilize all the information that we need. It's a great thing, but as with any technology, it also can be abused. It also can be misused. Learning how to use it, use it to our advantage without it taking us down avenues we don't want to go down is always the issue.

Kelly Malcom:

Right. Okay. So, I know that when you are researching, often your answers also bring up more questions. So, are there things that you are still curious about that may have sprung from your work that you are still pondering?

Marc Peters-Golden:

That never ends. If that ended, science would end.

Kelly Malcom:

Right.

Marc Peters-Golden:

There's never an end to the questions. Any good research project is going to give you an answer that itself is going to lead to 10 more questions. That's just the nature of science, so that's not challenging. Every time you learn something, it always brings up new questions. Well, why did it work that way in this situation and not that situation or this cell and not that cell? Or how did it go wrong? Or how can we make it better? How can we fix it? So, there's just no end.

Sean Fortier:

I think the challenge is deciding among the questions that get raised, which should we pursue next? Because there's so many. And what's nice about being a physician scientist is always having in mind your patient. There's many worthwhile paths to pursue just for the sake of science and discovery. And I'm totally for that. But when we're thinking about, well, what could this translate to clinically, that helps narrow the field a little for us.

Marc Peters-Golden:

And as physician scientists, the questions that we might decide to focus on might very legitimately be different than the questions that our colleagues in basic science departments might decide to focus on.

Kelly Malcom:

So, how do those interact, the questions that come up from a basic scientist and on the clinical side? How do you meet?

Sean Fortier:

We definitely collaborate. And I think the perspective of someone that's PhD trained or has a master's or just had a different lab experience, or came to science with a different background is very valuable. They value our opinions it seems as well, whenever I work with them. There may be methodologic differences in the approach. There may be their background made to be different. They used to study cancer cells or have different techniques with how to approach. And so, it's hard to predict exactly what perspective they bring. I think the physician brings the obvious, "Well, we have a patient with a condition. They're likely going to need a treatment. There's a prognosis involved."

But I will say, because I think your question's also getting at what has your research found, what questions have been raised from there. And one of the main ones and a paradigm that Marc and I are championing, which we are not the only ones to do this. But it's not very common in the field, is to taking fibrosis patients present with established scar. And so much of the time or in the past, the studying or the paradigm has been let's take healthy cells and understand why they become fibrotic, and try and understand that process of healthy to diseased.

Although that's interesting and important, there has been a lot of work done. And disproportionately, there's been a paucity of work trying to understand how to get diseased to healthy or at least away from the pathogenic. So, in our case, we try and turn these pathogenic myofibroblasts, muscle-like fibroblasts that make scar back to a quiescent, more friendly homeostasis. And we want to know what that looks like, not just in the cellular standpoint. But why do some animals or individuals get lung injury and don't develop progressive scarring?

So, we're trying to understand what is normal about the healing process, the wound repair process, and how pathways, and changes in cell phenotype, and all the dynamics there differ and what could be missing in the states of fibrosis. And so, in a roundabout way to get to your question, what I'm so interested in is what does nature consider the important pathways to differentiate whether it's going to heal normally versus become scar. Because you can study many things in a dish, in a cell, and throw a wrench in all kinds of different pathways and say, "Oh, look, in the dish, these cells went away." But it's like a complex Rube Goldberg machine. You don't know if you touch this lever that it's going to affect many other things down the road, like a butterfly effect in a way.

And so, asking how it's done naturally, how it maybe evolved over time in different animals, to me gives more of a biologic plausibility. So, I'm wondering, what are the natural pathways that may be not working well in someone who already has fibrosis established, compared to someone who resolved that fibrosis, rather than can we prevent it? If we could, if there was a way to intervene with these patients to prevent it, that would be fantastic and ideal, but patients present to us with scar. And we are working. There's a whole field trying to work on how to predict this, but we don't have a biomarker for this condition. And so, that's why we focused more on this. So, I would love to know to uncover some of those pathways.

Marc Peters-Golden:

And we can talk more about that, but I want to go back to another aspect of your question. You asked about physician scientists interacting with basic scientists. And as Sean said, yes, we collaborate, interact frequently, but it's also worth just noting that we're physicians. But the research we do is not the kind of research that most physicians who do research do. Most physicians who do research do clinical research. They study groups of patients to try to understand clinical features or prognoses or they're testing various treatments. We're physician scientists. And the research we do is not clinical research, it's basic, it's what we call translational. We're trying to bridge that gap between the laboratory and the patient. So, I just wanted to make the point that just by virtue of being physicians who do the kind of basic research that we do, we are almost collaborating with the basic science part of ourselves.

So, yes, we do collaborate with other people who are basic scientists. But just by virtue of being a physician scientist who does basic and translational research, we are actually within ourselves. Our clinician self is talking to our scientific self. And for the sake of your audience, they might be interested to know that there aren't many people who do the kind of research we do, this physicians who do basic research. And we are a dying breed. And that's a whole topic for another podcast, but it's of grave concern.

Kelly Malcom:

Yeah. That actually relates to my next question, because I know one of the distinguishing features about University of Michigan and our academic medical center is that collaborative spirit and collaboration between the different fields. Do you feel like this is a unique place in that sense? Have you benefited from being so close to the basic scientists here, like on the same campus, that type of thing? What can you say about that?

Marc Peters-Golden:

I did my medical school, my residency, my fellowship elsewhere, and then came here for my first faculty position. And I had trained at other institutions that are considered topnotch. And one of the first things that struck me about Michigan when I first arrived all those years ago, is that it seemed like the people here were just as smart, just as knowledgeable, but their egos were smaller. It was a lot easier to talk to them. They were perfectly willing to talk to me as a new faculty member who was a nobody. They were welcoming. They were willing to help. And that collaborative spirit has remained a hallmark of Michigan in my experience here. And it's not that way everywhere. I've been here now for a long time. And part of what's kept me here has been that collaborative spirit.

Sean Fortier:

Yeah. And I've been at Michigan now for eight years. And I can only echo Marc's longer experience with it. But collaborating within the medical school, as well as the School of Biomedical Engineering has been great. I mean, I've had relationships with division chiefs and other departments in a collaborative effort. And again, it's a culture of collaboration and kindness. People really want to advance the work and that's the most important part.

Kelly Malcom:

So, because IPF has been so difficult to treat, there haven't been that many effective treatments, it doesn't have a great prognosis. I do know that the patients are very invested. What role do the patients play in research?

Sean Fortier:

So, you can get examples sometimes where patients will reach out to us about our manuscripts and about concepts there. And I think that's an attempt to better understand their disease and also look for hope. But sometimes, patients can empower themselves or family members can empower their loved ones with this disease by understanding it better. I think, culturally, we should endeavor to better understand and appreciate the scientific process and that it is slow. But we're marching forward very carefully, objectively, in good faith, to try and understand these complex processes in an effort to help people. And sometimes, patients give back. There's philanthropy. But spreading the word that these are difficult conditions and worthy of study is I think what patients can do.

Marc Peters-Golden:

We take our inspiration from patients, first of all. But also, many patients are willing to provide their blood, their cells, their tissue when they're having a biopsy or an operation. And we couldn't really do what we do without that. Sean and I were talking about this earlier today. People often are lacking trust in science and scientists. And that's a grave problem. But another aspect of it is that we're not taking care of patients every minute of every day. Some of us are doing a lot of teaching, a lot of educating, a lot of writing. Some of us are doing research, some of us are doing all of the above. But most times, patients aren't aware of what we do when we're not in clinic. And they know that we get paid by insurance companies and the government for the clinical care we provide them, but what they don't know is that we do these other things that are not necessarily as well or at all well-compensated or reimbursed or supported.

So, the teaching and the research, often it's a struggle to do those things. And so, I would like for patients to better understand that, that we take a lot of pride in our care that we provide to patients. And we want to be the best, but we want to be the best at research and at teaching as well. And they often don't know that we do these other things. Why would they? Why should they? But I'd like them to know. And I'd also like them to know that we could use their support in other ways, too.

Sean Fortier:

One of the ways to maybe bridge that trust, just thinking and reflecting on what you said, is with that knowledge, most people who have a good relationship with their doctor will trust what they say and that's kind of the idea. But if we're separating the science from the actual clinical care or the identities of those people, we're a social species. So, if you trust your doctor and you say, "You know what? I know you have my best interest in mind." And that's the same person who you trust that's going to say, "Well, I'm working on this research," whether it be at the basic science level or more translational clinical trials and such. And I collaborate with the very people who publish these or maybe I was part of that, then maybe the distrust that does permeate the culture can melt away a little bit. So, I think that would be helpful.

Kelly Malcom:

Yeah. And that's why I even wanted to start this podcast, was to make sure that people understood the people, the humans behind the science. We talk about the science all the time, but we don't get to hear why and what's motivating people like you to do the work. So, I think it's really important to hear directly from you. And you're right. The doctors that people do put their trust in are also looking for answers to help patients, ultimately. It's been really interesting and I'm so happy to talk to you both. Is there anything else you wanted to share with us or say before we sign off?

Marc Peters-Golden:

Thank you for doing this.

Sean Fortier:

Thank you very much.

Marc Peters-Golden:

It's super important.

Kelly Malcom:

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