A heartwarming Tale: How Basic Research into Cell Behavior Spurred an Advance in Transplant Surgery

Scientists, intensly focused on their own areas of research, don't usually stray out of their own lanes. So, Dr. Rohit Pappu, of Washington University in St. Louis, whose field is cellular and molecular biophysics and bioengineering, was surprised when asked to review a scientific publication about improving heart transplants. But when he began to read the article, he saw that a team of doctors at the Mayo Clinic, led by surgeon Paul Tang, had drawn on the basic research of his lab and others to save lives. Dr Pappu and Dr. Tang join us to tell this heartwarming tale about how studying little molecular communities within cells can lead to advances in medicine.  Veteran broadcast journalists Judy Muller and George Lewis are our guides for this podcast.

Transcript

Science Straight Up

Season 6, Episode 6

“A heartwarming Tale: How Basic Research into Cell Behavior Spurred an Advance in Transplant Surgery”

Dr. Rohit Pappu, Washington University, St. Louis

Also: Dr. Paul Tang, Mayo Clinic

Moderators: Judy Muller and George Lewis

(Theme, establish and fade under)

JUDY: From Telluride Science, this is a special edition of Science Straight Up.

GEORGE: And this time around…

DR. PAPPU: The body needs to know that this is not a bad thing. The heart needs to know that this is not a bad thing.

GEORGE: This is a heartwarming tale..pun intended…about how the success rate of heart transplants may soon be in for a big boost, thanks to some basic research into the fascinating way cells organize themselves in the body.

JUDY: Dr. Rohit Pappu is a professor of biomedical engineering at Washington University in St. Louis and a participant in this year’s workshops put on by Telluride Science.

GEORGE: His studies biomolecular condensates, something he calls little pop-up communities within cells that organize to get things done.

DR. PAPPU:  Essentially, the idea is that the right kind of molecules come together, they condense. They make up a community. That community is very selective for what types of chemistries can happen inside, but when they're no longer needed, boom they go away.

JUDY: He’s able to study these pop-up communities because of advances in imaging that can see things at the nanometer level. A billionth of a meter.  So, he’s immersed in his work when he gets a request from a medical journal, Nature Cardiovascular Research to review an article from the Mayo Clinic. The first thing he thought was why am I being asked to weigh in on cardiovascular stuff?  That’s far removed from the work I’m doing.

DR. PAPPU:  I honestly thought that this was a mistake. And then, you know, but then I quickly read the abstract, and the abstract just grabbed me.

GEORGE: He began to recognize some key words from HIS field and read on. 

JUDY: Those little pop-up communities within the cells sometimes detect stress, form themselves into stress granules and send out signals saying, essentially, “OK, game over, time to die now.” And why do they do that?

DR. PAPPU: Because, you know, the efficient suicide of a cell is actually very much part of a healthy response, right? And so, you know, if a cell gets to the point of no return, the best thing to do is to sort of cauterize it, so to speak.

(sound: heart monitor beeping)

JUDY: In a heart transplant operation, the heart cells undergo a whole lot of stress. Typically, the heart donor is brain dead but the body is being kept alive through artificial means. Then surgeons stop the heart… 

(sound: heart monitor flatline continuous tone)

…and remove it from the donor.

DR. PAPPU: You have about a four-to-five-hour window before, you know, you start the primary graft, which is, you know, essentially the transplantation procedure, and that there's a perfusion stage. I learned all this after I was asked (laughs) to review (laughter) It’s not like I knew any of this.

GEORGE: The heart is first put in a chilled container and transported to the place where the recipient patient is waiting for the life-saving transplant. Prior to being sewn into the patient’s chest, the heart is put in a perfusion chamber, where warmed blood fills it up.

DR. PAPPU: Effectively you ended up with sort of two problems, right? So the cold preservation and the perfusion chamber, basically creating for the organ, namely the heart, a stressful situation.

GEORGE: And as time passes, those pop-up communities can begin hitting the self-destruct button. That’s until the Mayo Clinic team found a way to stop them.

DR. PAPPU: The body needs to know this is not a bad thing; the heart needs to know this is not a bad thing. I didn’t and read this; I didn’t get much sleep.

GEORGE: He said it was heartwarming, both in the figurative and the literal sense.

DR. PAPPU: My heart was warmed. I It really, you know, and I realized that the surgeons know what they're doing. And I sort of moved on. What I did do was I shared this with as many of my colleagues around the world, you know, in who are in this business.

JUDY: Has this already changed what they're doing with these hearts when they are taken out of the donor, and because you have, like, four hour, five hour window. And before those little workshops were popping up and killing cells. How has that actually changed the practice? Yet?

DR. PAPPU: I believe so. But then again, you know, I'm not in the surgery room, so I would strongly urge you to contact, you know, Paul Tang at Mayo.

GEORGE: So we did contact Dr. Paul Tang at the Mayo Clinic in Rochester, Minnesota.

DR. TANG: I'm a cardiac surgeon, and I do transplant, heart transplants and and take care of patients with heart failure and end stage heart failure. And what I noticed was when, when you have a donor heart that comes in, if it works well, right from the get go, what's reperfusing The recipient? You know things, things are good.  Everybody loves it when, when it works from the get go, but unfortunately, for a portion of patients, it doesn't. And, and it's, it's, it's a tricky situation to be in.

JUDY: Picking up on the research of Dr. Pappu and others, the medical team at Mayo discovered that those little pop-up communities were, indeed, forming in heart cells and sending out self-destruct signals. If they could be stopped from forming, that could really boost the success rate of heart transplants.

DR. TANG:  So we're very interested in seeing how we can get these hearts to work more consistently. And we had read, you know, people's working, including Dr Pappu about biomolecular condensates. You know, how these how these molecules group together to supercharge signaling. What we find is we can break down some of These, not allow these condensates to occur, can actually improve hearts, and, you know, improve their function. 

GEORGE: The team at Mayo found a drug that does a pretty good job of stopping the condensates from forming.  Canrenone, used in Europe for a long time now but not yet approved by the FDA. That approval is now in the works.

DR. TANG: If you think about it, it's transplant, a very unusual situation. It's never, you know, in millions of years of evolution, if you're, if your organ is outside your body, you're probably getting, you know, you've been attacked by something, and that's the end. There's no chance for that organ to go into another body and get reperfused Like in a transplant situation. So there's no adaptation for it. So this is one of the ways that we try to understand what what nature, how nature reacts, and try and counteract some of those events, you know, letting the heart survive for longer outside the body and and get transplanted, and hopefully work well.

JUDY: The implications are huge. Today, only about half the hearts available for transplant get used.  But if medicine can get rid of that 4 to 5 hour window for successful outcomes, hospitals may be able to bank those unused hearts until a matching recipient shows up.

DR TANG:  So there, there are various processes in a cell that you can intervene on to prolong the survival. It's not just one magic bullet, it's multiple components, and you kind of hit each one, and they act either additively or synergistically to improve organ preservation. So it's an ongoing work and and I think we're just starting to understand how that works.

JUDY: We mentioned earlier that Dr. Pappu was participating in the science workshops put on by Telluride Science. The people in charge asked him to speak to the community about his basic research into molecular condensates. 

 These sessions are referred to as “town talks.” In his presentation, Dr Pappu said he and his team is trying to understand whether those pop-up communities—those condensates—might also play a role in diseases like dementia and ALS.  

DR PAPPU: In mutations that we inherit from our lineages that carry mutations that are sometimes associated with ALS one of the things you see is that stress granules don’t dissolve efficiently. And you accumulate this debris over time, creating a variety of problems. We tend to think of it primarily as a disease of the brain but lately some of us have come to think that this is a disease that is systemic but particularly a disease of the heart and so there is some crosstalk between the heart and the brain that we’ve got to start thinking about.  What we're doing is basically asking questions of, you know, how do normal stress granules form and how do they age? So physics actually matters in biology, how do ALS associated mutations cause these aberrant granules to persist. How do aberrant stress granules sort of start to dysfunction in specific ALS and, you know, frontotemporal dementias and in specific neurons. And the obvious question is what should you do? Should you just dissolve a stress granule or rescue a stress granule and in fact, interestingly enough, this particular question animates a lot of discussion, so it’s easy to say, “I will discover a drug.” But a drug to do what, exactly? So you need to first decide what to develop a drug to do before you start on drug discovery, right?

GEORGE: Remember, he was talking about how these little pop-up communities form and then spontaneously go away. But in diseases like ALS, they persist. Any mention of ALS brings to mind for some of us. Any mention of ALS brings to mind, for some of us, baseball legend Lou Gehrig and his poignant farewell at Yankee Stadium in 1939.

LOU GEHRIG: “Today, I consider myself the luckiest man on the face of the Earth.  I may have been given a bad break, but I’ve got an awful lot to live for.  Thank you.

GEORGE: From that moment on, ALS became widely known as Lou Gehrig’s disease. I asked Dr. Pappu about the apparent lack of progress in finding an ALS cure in the 86 years since Gehrig’s farewell. He quickly set me straight.

DR PAPPU: The question that you're asking is, you know, it's been 80 something years. Have we made any progress? I would actually say that when Lou Gehrig made his farewell speech, we knew nothing about a gene. We knew nothing about DNA and the double helical structure that came 30 years later. Then we realized, oh, wait a minute, you know, just knowing the structure of the DNA is not going to tell us anything, because, you know, we have loads of genes inside of the human cell. The brain always creates serious challenges, right? Because, and then some of us sort of live on the side where we're thinking that maybe by the time you start to see neurodegenerative signals, it's already too late. So if we now know that somebody carries a particular mutation, then there are diagnostics that maybe are more systemic, like including the heart, right? Because the same gene is there everywhere to get us to better understand what is actually going on before it's too late, right? And so some of the most promising sort of leads right now are, if you think about the diagnostics that are sort of getting earlier and earlier. There's a lot of remodeling that the brain can sort of do over time. So really, what you want to do is give the brain some help right over time. And so is that feasible? Seems so.

JUDY: In studying those pop-up communities, those condensates, Dr Pappu says a colleague, Lucia Strader, discovered that they’re constantly on the move.

DR PAPPU We worked together a couple of years ago, she said to me, I see these condensates moving, like what they move? How do they move? Right? I mean, they're not, you know, they didn't have a power bar. How are they running? Right? Well, it turns out that, you know, our cells have little highways. We call them actin cytoskeletons. They give the cell sort of integrity, right? And these condensates were basically using those as train tracks and using motors to actually move, but the movement. Think about it this way, if you drive your car over time, it breaks down. Keep driving, right? These suckers, they keep driving, they get stronger, right, because movement maintains their condensateness, right, which totally knocked my socks off. But it was one of those things. We were walking together in Zurich, and she said to me, you know, she shared this data. And I said, Oh, wait a minute, over in physics, there is something called motility induced phase separation, so the ability to condense whilst moving.

GEORGE: Motility Induced phase separation. It’s quite a mouthful, but heart surgeon Paul Tang says it’s a concept that aided his team in understanding the role of condensates inside the human heart.

DR TANG: Without people like Doctor Pappu and and whole condensate phase separation community, you know, we, we wouldn't understand, we wouldn't even know this process exists and and is, and it's very common, you know, us basic scientists do a lot of very exciting and cool stuff that maybe not everybody outside of their field understand. And at the same time, you know, doctors see patients and and we and we understand medical history, and we understand lab testing, and we try and search for things through the medical history and lab testing. Yeah, and and not necessarily understand a lot of the basic science advances that are going on. And I think you know the role of physician scientists is to serve as a bridge between those, those, those dichotomous, almost communities. And bring basic scientific advances into clinical applications at the same time, you know, identify clinical applications that basic scientists can can help or work on and and I think in that pipeline of individuals who are able to marry the two is really critical to to maintain. and it and it takes decades to if you think about a medical student, you know, let me talk about the cardiac surgery pipeline. So you go into medical school for four years, maybe you you either do an MD PhD, so that's eight years, and maybe not MD PhD, but you spend some time in the lab doing residency, that's two or three years. So so let's say that's eight you go to a general surgery program that's five years. So that's 13 years, and and then you go into cardiac surgery program that's eight that's that two to three years. So that that's 16 years and, or even the quicker programs already going as a six year from right from the get go at the graduate from medicine. So, so you're looking at 15,16, years before you you actually start your first job then and then, by the time you get to the point where you have a lab and you start being somewhat productive, eighteen, nineteen years have passed.

GEORGE (NEW NARRATION) Dr. Tang has walked that path, with a PhD from Yale in Cardiovascular immunology, as well as his MD from Duke University.

DR. TANG Thank you. You know that the role of besides all the discoveries we've made, in that paper, I wanted to highlight the importance of having, you know, young trainees going into clinician scientist or surgeon scientist training.

JUDY: And turning back to Dr. Pappu, he says he still believes the United States remains a beacon of scientific innovation, despite everything that’s going on right now.

DR. PAPPU There is a sort of an aspect of doing science in the US, which I hope will survive, that is unique to the US, which is that we live in truly multidisciplinary ecosystems, right? And so my lab itself is like a little micro economy of, you know, expertise that is of different stripes. You know, there are computer scientists, physicists, engineers, biochemists, cell biologists and me, right? I don't know how to define myself anymore. You know, we're not I cannot affix one label to our lab as you know, this is what we do. We kind of do a lot of everything. But whatever we do, you know, is spearheaded by domain experts, like, for example, I would not, you know, for example, dissect embryonic cells from the frog and image them, because I don't know how to do that. I'm a physicist, right? But once the data come into my hands, I know exactly how to think about it quantitatively. And the point I'm trying to make is that the unique aspect of science in the US, which people have tried to emulate in some parts of Europe or, you know, in Asia, but I will say it doesn't really work. Not to wax on eloquent about this. It's fundamentally what it means to be American, right? I mean, you're free to think and do the way you want to think and do things, right? And so that is that multidisciplinarity, where you know boundaries between disciplines don't limit your thinking, allow us to do all kinds of things. The thing that is uniquely American is that, you know, in good places like Wash U in particular, is that I have an idea, I have a thought, I have, you know, and then I can go right next door to my colleague in developmental biology or in a good, you know, neurology, or you know, cardiology, or, you know, chemistry, and say, I'm thinking about this problem a certain way. You know, have you seen something like this? And next thing you know, you're joining dots. And what happens from those conversations is whole new areas that you never thought about start to become in a part of your purview, right? And so I would never know how to read it have read, known how to read a nature cardiovascular research paper, if I was stuck in physics, doing general relativity, you know? 

JUDY: He couldn’t resist quoting that famous line from the movie “Field of Dreams.”

DR. PAPPU: If you build it, they will come right? So I think in science, that is absolutely true, right? I mean, if you, if you pursue the generation of knowledge with utmost rigor, and I, you know, this is the only thing about which I'll be spiritual, but some level of relentless devotion to the to the craft, I think people will find it. That's the beauty about the scientific ecosystem, right? I don't have to talk to a surgeon. I don't have to know a surgeon. They will find it in this case. But what is also happening is that I think we're seeing the prospect and the potential for accelerating a lot of this. Because what needs to happen at this incredibly opportune moment is, you know, for the community of common set centric scientists to be unleashed on a broader community. That means, you know, resources that sort of enable these multi and trans disciplinary conversations, because I won't necessarily know what biomedical problem, or, you know, what sort of plant science problem, or what ag problem, or, you know, a material science problem I could potentially be working on, but having those conversations, but also there being resources to enable the go between is enormously valuable. The US has historically been extremely good at doing this. So, and I'm not going to focus on this particular moment in time, because I think this is an aberration. I really do.

JUDY: Right at the end of World War Two, the eminent scientist Vannevar Bush wrote a blockbuster report called “Science, the Endless Frontier.” He argued for continuing government support of science, something that would guide Washington in the latter half of the 20th century as America turned into a scientific powerhouse. In it, he said that basic research is vital as it seeks to understand the world—in his words—  “Without thought of practical ends.” 

GEORGE: And so, Dr Pappu returns to the lab to take on the next big challenges, without thought of practical ends, but energized by the fact that his basic research helped a team of doctors at the Mayo Clinic and may eventually save a lot of lives. Truly a heartwarming tale.

DR. PAPPU: All the hard work we're all doing is now going to be impactful in real time.

(theme music)

GEORGE: We want to thank Dr Rohit Pappu and Dr Paul Tang for spending some of their valuable time with us. 

JUDY: And a big thank you to our sponsors, Alpine Bank and the Telluride Mountain Village Owners’ Association.  

GEORGE: Mark Kozak is Executive Director and CEO of Telluride Science, Cindy Fusting is Managing Director and CFO. Sara Friedberg is Lodging and Operations Manager and Annie Carlson is Director of Donor Relations.

JUDY: If YOU want to donate to the cause, go to Telluride Science-dot-ORG. That’s also where you can find our podcasts. And on your podcast apps like Spotify or Apple, look for “Science Straight up.” I’m Judy Muller.

GEORGE: And I’m George Lewis, inviting you to join us right here, next time, on “Science Straight Up.”

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