Learning from hibernating bears about preventing blood clots in humans

Transcript:

HELEN: Welcome to Talking About Blood. I’m Helen Osborne, host of this podcast series and a member of the advisory board for The Blood Project. I also produce and host my own podcast series about many aspects of health communication, and it’s called Health Literacy Out Loud. Today’s guest is Dr. Steffen Massberg, who’s professor of cardiology and director of the Department of Cardiology at Ludwig Maximilian University in Germany. In his full-time clinical practice, Steffen specializes in interventional cardiology. He also does research about the mechanisms of thrombosis.

Steffen’s goal in all this work is to find safer and more efficient approaches to patient care. Dr. Bill Aird is the hematologist who heads up The Blood Project. He introduced me to Steffen, saying that he thought podcast listeners would be especially interested in Steffen’s recent research that was published in the journal, Science. As Bill describes, this paper went from hibernating bears to mice, to pigs to humans, and an extraordinary discovery that fielded a potentially new target for preventing blood clots. Steffen, welcome to Talking About Blood.

STEFFEN: Thank you, Helen. Thank you. Looking forward to talk to you.

HELEN: This is quite the leap. From interventional cardiology, which is what you do all the time as you’re seeing and working with patients and clinical care, to cross-species studies and with colleagues worldwide. How did you make that leap between those two bodies of work?

STEFFEN: That’s actually how I came into cardiology. So I was already doing my doctoral thesis, very interested in blood platelets and their roles in different types of settings, and I wanted actually to continue research in that field. And I picked cardiology because I thought that in that discipline, platelets play an obvious role because they are involved in triggering myocardial infarction.

So I wanted to combine my clinical focus with the previously established research focus. That’s why I picked cardiology and I had the big luck that I was always able to recruit brilliant people into my clinical group that were also interested in doing basic research. And that allowed me to be able to continue clinical practice in interventional cardiology at the same time with research, basic research, but also clinical research.

HELEN: Thank you. So that kind of fills in the gap between the interest in blood and the interest in cardiology. They’re intimately linked. But then let’s go to the other part where this paper that Bill was so interested in, and I find fascinating about hibernating bears. I mean, that’s not your everyday practice, is hibernating bears. How in the world did that connection happen?

STEFFEN: So we are, as I said, already interested in the mechanisms of thrombosis and we wanted to understand why organisms or animals, in this case, the bears that are lying for almost six months in their tents do not develop thrombosis. This is surprising because we know on the other hand that humans that are immobilized, for example, hip fracture or for a long distance flight, they have a higher incidence of venous thrombosis or thrombus formation in the veins.

HELEN: Okay. I just want to ask you a question just as a non-physician, I have many roles here, but as a non-physician, but as someone who travels in planes a lot, I hear you really have to worry. You have to get up and walk around the aisles a little bit in a plane to prevent blood clots or exercise your legs. That’s the risk you’re talking about in there for humans?

STEFFEN: Yeah, the risk at long distance flies is very low in general. It’s a little bit higher in patients that have risk factors like adipositas or other risk factors that render them at a higher risk for venous thrombus formation. So then in this case, the immobilization during long distance flights can be the trigger that then in the end leads to venous thrombus formation. But it’s even more pronounced in patients that, for example, have a fracture, that they have a trauma that per se increases the risk of thrombus formation due to the trauma.

Trauma induces factors that can support trauma formation as such. And that in combination with the immobilization is known to be a risk factor of venous thrombus formation. And that’s why patients with fractures, many types of fractures are recommended to receive anticoagulant prophylaxis during the time of immobilization to prevent that, to reduce that risk.

And that’s why we thought that it would be interesting to see why bears that have a standard immobilization once a year for almost six months. It is not obvious why these should not develop thrombosis, and there’s no evidence that these bears have a higher incidence of thrombosis or have a thrombosis-related mortality during hibernation.

HELEN: Can I stop you just right there? I’m just curious about the bears. Okay.

STEFFEN: Yeah.

HELEN: So you’ve got the bears. I don’t know. I mean, here you are in Germany. I don’t know how many bears are hanging around in Germany. How did you think that’s what we want to be looking at is, this hibernating species and make the connection to your patients?

STEFFEN: Actually, that was more or less a coincidence that we met Ole Frobert, who is one of the colleagues that is working for the Swedish Bear Project, and they are managing all the research around hibernating bears. And we met them at a meeting and we discussed that it would be interesting to look at these bears. Because they are very standardized, we have a very well-developed structure of repeat measurements of blood samples of these bears. So it’s a very well-established research project already without us that we got into contact. And together, we came across the idea to better understand why these bears that do undergo hibernation, they don’t develop thrombosis.

And the overarching aim, of course, is why it could be a good tool to come across a mechanism that is a physiologic mechanism that has an antithrombotic action that protects bears from developing thrombosis during hibernation. And of course, we also wanted to go then if we expected to find a mechanism, if that would be the case, to look at other species too. So we also looked at pigs that have certain phases of hibernation, and then of course, went back to human patients.

HELEN: Okay. So our listeners for this podcast, Steffen, many of them are practicing hematologists who might’ve been doing this a long time and are brilliant in their fields and they just want to know more about the medical and scientific end of this. Our listeners also include those who are early in their careers, maybe they are in medical school, maybe they’re considering going into some of the sciences. And then there are people just like me, like bears and humans and blood clots, what’s the connection? So I’d like to start from the top. For those who are practicing hematologists and researchers worldwide, what did you learn that they would certainly want to know? What’d you learn from this study?

STEFFEN: So we looked at the bears first and we looked at the platelet compartment and found that… By omics approaches, and we found that platelets normally have a protein, which is a heat shock protein 47 that under physiological conditions without hibernation, is expressed in platelets, but it’s heavily down-regulated during hibernation. So it was the most prominently regulated protein when we compared awake bears compared to hibernating bears. And there was a strong downregulation during hibernation, and that caught, of course, our interest.

And then we developed this further. We looked at the effects of antagonists to the protein, and we found that, for example, in mice, the antagonists have an antithrombotic effect. And we also looked at patients and we found that long-term immobilization like in patients that are paralyzed, also, it’s associated with downregulation of this protein. So it appears to be a mechanism that is not only relevant in pigs or in bears, but also in humans.

HELEN: Oh, okay.

STEFFEN: And it appears to be a physiological adaption that is essential to act against thrombus formation. It takes some time until this mechanism becomes active. So once you have a fracture, the risk of thrombosis is increased because it takes several days until the protein becomes downregulated.

HELEN: And you keep using the term downregulation.

STEFFEN: Yeah, yeah. Please.

HELEN: Can you just explain for me and for others what you mean exactly by that term downregulation?

STEFFEN: That means that we find lower amounts of the protein at a certain condition. So in this case, we mean that by downregulation, there is less amount of the protein within a single platelet in hibernating bears compared to awake bears. And we now know that the downregulation, so the reduction in the production of the protein, takes place at the megakaryocyte levels. Megakaryocytes are the precursors that are responsible for the production of platelets. They reside in the bone marrow compartment.

And whenever there is immobilization for a longer period of time, like I’m talking about weeks or months, then megakaryocytes receive a signal that causes them to produce lower amounts of heat shock protein 47 in platelets. So the platelet numbers are more or less the same, but they contain lower amounts of HSP47, and the functional consequence of this lower amount is a lower platelet reactivity. So they are less reactive to activation. They are not as eager to become activated and to aggregate to form clots as they would be in case they have normal amounts of the protein.

HELEN: Was this finding a surprise?

STEFFEN: Yes, it was a surprise in various aspects. First of all, we did not expect so much that the protein that we identified would be involved so much in the physiological regulation of thrombus formation. On the other hand, we did not expect that it would be one protein that made such a difference. So we actually expected that there would be a group of different pathways that are regulated. And mostly, we expected that it would be common pathways, so that are already known to be involved in platelet regulation. But actually, that was not the case.

So the classical pathways that are responsible for controlling platelet function and for clot formation, they appear to be more or less unaffected by whether or not there was hibernation or immobilization in paralyzed patients. But instead, it appeared to be really a regulation on the level of this single individual body that has not been so much involved in platelet function so far. So it was a surprise. And then the other surprise, of course, was that this was not something that we found only in bears, which we started off, but also in pigs, in mice, and also in the end, in patients.

HELEN: Well, I want to hear… I want to go in two different directions with this one. One is what do you see that the outcome will be for patients having discovered this? And my other question is, is this a rare experience to be so surprised by scientific findings?

STEFFEN: Maybe I start with the last question first. I think this project was extraordinary from various aspects, because typically, as a researcher and also as somebody that is working in clinic, you do not get to do research on bears. And the people from my group that actually did the research, that was Manuela Thienel and Tobias Petzold and their PhD students that are on the paper, they were the ones that profited from the project because they got to travel to Sweden twice a year and to be involved in this really exciting Swedish Bear Project.

So it was a very extraordinary experience also because it was a very collaborative project with many groups, and particularly the Swedish and the Danish group. And on the other hand, of course, the finding was exciting also, not only from a mechanistic perspective, but also if you look at the potential applications. Because now we have protein that is regulated to prevent thrombosis, and that regulation is a physiological regulation because we find it in the physiological process of hibernation.

So it appears that during evolution, this process has been selected because it’s the best compromise between prevention of thrombosis and little side effects of bleeding complications. Because nowadays, if you want to prevent thrombus formation by our typical pharmacological approaches like antiplatelet drugs or anticoagulants, these typically have the… Or come at the price of increased bleeding complications.

So what we aimed or hoped to find was a mechanism, a target that could be used to prevent thrombosis, but as least as possible side effects, meaning a very low amount of bleeding complications. And since the bears use this mechanism, the regulation, an antagonist to the same protein could be a very promising tool to prevent clot formation, but at a very little expense of bleeding complication. That’s what we hope at, and that’s actually the direction we go for now.

HELEN: That’s what I was interested in, where you’re going. That’s referred to as translational research, isn’t it? When you go from-

STEFFEN: Yes.

HELEN: … the lab to-

STEFFEN: Exactly.

HELEN: So when you go from the lab to people, that’s my understanding of translational research.

STEFFEN: Yes, right. Exactly. Yeah, that’s what it is.

HELEN: Okay. So where do you see this going? What’s been happening? And I just want to mention a couple of things about your paper. We will have a link when it’s on Talking About Blood, but the title of the paper that was published in Science is “Immobility-associated thromboprotection is conserved across mammalian species from bears to human” and many, many authors. So that’s really exciting. I also want to tell you, I was looking for this, for the non-scientific paper, just a shorter version of it.

And it looks like people are just having a whole lot of fun with your research. One of the titles that was in Science Daily was, “Humans, and piglets, and bears, oh my! Preventing dangerous blood clots.” So you put a smile on a lot of people’s face in addition to doing amazing science. So where do you see this going as it translates into human medicine?

STEFFEN: So right now, we are working on developing two strategies to make use of the findings. And both of them actually are trying to modulate the protein function and the protein activity, or the protein expression. And in summary, in essence what we want to do is we want to develop novel antagonists to this pathway that is prothrombotic. And we hope that we will come up with a strategy to prevent clot formation at a lower expense of bleeding complications. And we are right now in the process of developing two antagonistic strategies.

HELEN: So exciting. So I think that you’ve done a wonderful summary of this to explain the scientific findings that you’ve come up with. And certainly, people in practice can go access your paper and learn more. I told you that another group of our listeners are people early in their careers, either early as researchers, early as scientists, early as medical people. What are the lessons learned? Aside from the physiology and the mechanisms of this, what advice or recommendations might you have?

And I’m thinking about the courage it might’ve taken for you to go talk to somebody about hibernating bears and together come up with this novel project. What would it be like for someone in their early careers to try something as offbeat, if I can use that term, like this? What would you like to say to them?

STEFFEN: I think two aspects. I think the way of looking at research and the topics, looking from a clinical perspective, the advantage maybe is that you always have a clinical question in the focus. So we had the aim to improve current strategies to treat clot formation or to prevent clot formation. So always have a focus that already has at some clinical implication. That is something personally I love about our research. It’s of course not the only approach, but it’s something that I personally really am excited about. And the other thing is, as we did in this project, this was a collaboration with basic research, Max Plank Institute, with pharmacy, with groups from Sweden, from Denmark and Munich and outside of Munich in Germany.

So it was very interdisciplinary and that actually was also one of the things that caught our excitement about this project. It’s not alone. Any single person in that would never have been able to do that. So it’s research that is interdisciplinary, is always something that allows you to reach another level because you learn a lot. You combine expertises, and that is something I would always try to incorporate into my research to have a focus that involves the expertise and requires the expertise of other disciplines.

HELEN: That’s fascinating there. And you took a risk too. You took a risk about something novel and untried.

STEFFEN: Going to the bears I think it’s not without risk, so that’s why I didn’t go, so I…

HELEN: Oh, you mean physically risk about those bears? Like maybe you’re going to a wake them up?

STEFFEN: Yeah, physically, yeah. Yeah, yeah.

HELEN: I hadn’t thought about that. I was thinking more in that intellectual risk there and career risk.

STEFFEN: Yeah, I know, I know.

HELEN: So you also put a smile on people’s face. What I also admire so much about your work and also my amazing opportunity hosting this podcast series is that I, as a lay person, can get something out of this too. So you’re talking about your interdisciplinary collaboration, you’re adding humor, you’re coming up with true value for helping us all be healthier and taking care of people, but you’re doing this at many levels that approach all of us, the curious lay person, the person who’s entering into the fields. I hope you’re inspiring them to take some risks and meet people perhaps, and other disciplines and your clinical work. Steffen, you are great. Thank you for being a guest on this podcast, of course. And sharing this. I hope that-

STEFFEN: Yeah, thank you for having me.

HELEN: It’s an honor. And one more bridge we crossed is you’re in Germany as we’re recording this and I’m in the US and our producer’s in the US and it’s all working out together. Thank you so much for being a guest on Talking About Blood.

STEFFEN: Thank you very much for inviting me. It was a great pleasure for me.

HELEN: As we just heard from Dr. Steffen Massberg, it’s important to consider clinical medicine, and scientific research, and human part, and animal part all together. We just can’t do this in our own silos. That’s what advances are all about, and that’s what The Blood Project is all about. To learn more about The Blood Project and explore its many resources for professionals and trainees and patients, go to thebloodproject.com. I invite you to also listen to my podcast series about health communication at healthliteracyoutloud.com. Please help spread the word about this podcast series and The Blood Project. Thank you for listening. Until next time, I’m Helen Osborne.

Dr. Massberg’s study of hibernating bears can be found here.