Revolutionizing Vascular Health with Dr. Nick Leeper

In this episode of Scrubcast, we sit down with Dr. Nick Leeper, Chief of Vascular Medicine at Stanford University, to explore his groundbreaking research in cardiovascular disease.

Dr. Leeper shares his lab's unique "hypothesis-free" methodology, where they analyze the entire genome to uncover genetic variants associated with heart disease. Additionally, Dr. Leeper highlights his collaborations with experts outside the School of Medicine to develop treatments straight out of science fiction.  Read Leeper’s Article in Nature Communications

Throughout the episode, Dr. Leeper emphasizes the importance of perseverance in research, drawing inspiration from Drs. Norm Shumway and Ron Dalman.

Rachel Baker: [00:00:00] Welcome to Scrubcast, where we take a closer look at the research happening at Stanford University's Department of Surgery. I'm your host, Rachel Baker. Today we're speaking with Dr. Nick Leeper. Welcome to the show.

Nick Leeper: Thanks, Rachel.

Rachel Baker: Thank you for joining us. Dr. Leeper. You are chief of Vascular Medicine here at Stanford and a professor in our division of vascular surgery.

But you are not a surgeon, so I'm just gonna ask the awkward question and get it out of the way. Why are you in the surgery department?

Nick Leeper: That's a great question. So I'm actually a board-certified cardiologist, but um, I actually am in love with blood vessels outside of the heart. So, I do a subspecialty of cardiology called vascular medicine, and you can kind of think of it as a hybrid between cardiology and vascular surgery.

And you know, when I came through my training years and years ago, I won't say how many years ago, my research was much more naturally [00:01:00] aligned with what was going on in the division of vascular surgery. So, I joined the Department of surgery to help, you know, build this bridge and this interface between internal medicine and surgery.

And we've had a lot of success trying to improve the care of patients with vascular disease and then, you know, through research, uh, related to their underlying conditions.

Rachel Baker: Fantastic. Well, we appreciate that you're in the Department of surgery, you did your residency in internal medicine. You completed two fellowships, one in cardiovascular and one in vascular medicine.

But what drew you to vascular in the first place? What was it about blood?

Nick Leeper: Well, I think about public health and, you know, what are the world's leading killers, and where can we have the largest uh, impact? Cardiovascular disease has long been the leading killer in the western world. It's overtaken infectious diseases as the leading killer worldwide and most cardiovascular disease like heart attack and stroke.[00:02:00]

Is driven by atherosclerosis, um, which is the buildup of plaque in the arteries. And so, when I was trying to decide what I wanted to do when I grew up, I, I thought I wanted to work on something that was important that could help a lot of people if we had success. And so that's why I chose to work on cardiovascular disease, uh, at a large scale and why I study this particular process in particular.

Rachel Baker: Awesome. Well, so one of the things your lab specializes in is genome wide association studies, or do we, do we pronounce this gee-waass [GWAS]? Yeah. Oh, excellent. Okay. So what does that mean?

Nick Leeper: You know, it's a, uh, it's a fancy term that really just applies to a case control study, but one that's applied across the entire genome.

And, and so, you know, what do I mean by that? Well, you know, if you think about our DNA, we have three billion base pairs in every cell, in every part of our body. Most of that DNA is pretty similar from person to [00:03:00] person, even species to species. The As, T's and C's and G's are, are pretty common across people. So it's actually a very small percentage of our DNA that makes us different, uh, tall versus short, black eyes versus brown eyes or diseased versus healthy.

And so the power of these genome wide approaches is we can get large. Populations of patients, both healthy controls and people with the disease of interest. And now the sequencing, uh, technology has gotten so affordable that we can very rapidly sequence all 3 billion base pairs.

Rachel Baker: Okay. I wanted to ask you about this.

Nick Leeper: Yeah, sure.

Rachel Baker: The original Human Genome Project, it took 13 years. To sequence a genome. How long does it take you?

Nick Leeper: Oh, I mean, it's, it's almost free. I mean, it was, uh, we send them out, uh, and they come back in a matter of days. We can do dozens of samples at a time. You're right. I mean, the, the Human Genome Project took, you know, like a [00:04:00] decade.

Billions of dollars. Yeah. Now it's, you know, less than a hundred dollars and, uh, comes right back.

Rachel Baker: Wow.

Nick Leeper: Yeah. And so, you know, the real power here is because people have made investments in doing this across large populations of patients. 500,000 people in the UK Biobank a million people in the million Veterans Project through the VA.

And so when you have these really large samples, you can start to make collections of people with or without a disease. Then you can find these genetic variants, which are more commonly found in people who have had a heart attack versus not. And that gives you the clue about what gene or pathway to go after.

And so this is really powerful. It's unbiased. It means that we're not chasing a hypothesis. We're saying, you know what, let's look across the entire genome and then let biology tell us where to look next.

Rachel Baker: Okay. That was my next question is, um, you, you say on your website that you're “hypothesis free,” so you're just throwing spaghetti at the wall and kind of seeing what [00:05:00] sticks? And then being like, oh, okay, I see an association here. Like, let's explore that.

Nick Leeper: Yeah, that's, that's exactly what we do. You know, we are, we are not really all that sophisticated to be honest, and in fact, it's kind of intentional. We do not wanna work on the things that we already know about, you know, we already know about.

LDL Cholesterol, we already know about high blood pressure. We already know about diabetes and I'm not saying that we don't have a lot of work left to do to, to further improve cholesterol management and diabetes management, but we know that even if you could fix all of the traditional risk factors that only about half of our, uh, risk for disease would be addressed.

So we are very much interested in the unknown. What is that other half that's in either inherited or through environmental exposures? You know, our behaviors, you know, what are these things doing that we can't yet address with current medicines? And so that's why we say we wanna intentionally look away from those and let the genome teach us what else we've been missing so [00:06:00] far.

And it's been really shocking because it's, it's things that we wouldn't have thought had any relevance to. Heart disease or stroke. You know, it's really things that we're learning from the field of oncology or immunology, uh, and it's really having to change the way we think about disease.

Rachel Baker: Super cool. So I want to dive into this paper that you authored in Nature Communications this past September.

I'll put a link for our listeners in the description. You've defined one of the terms that I think is important. atherosclerosis,

Nick Leeper: yeah,

Rachel Baker: buildup of plaques. We've talked about this on the podcast before, but then there's another term that you use in the paper and it's efferocytosis and that's the cleanup crew.

Nick Leeper: That's right.

Rachel Baker: Okay. Atherosclerosis happens when efferocytosis isn't working? There's an imbalance?

Nick Leeper: Yeah. Yeah. I mean, it, it's a pretty complicated process, but, but atherosclerosis is the process that builds up [00:07:00] in our arteries as we age. Uh, this is the plaque. It's composed of cholesterol and inflammatory cells and all kinds of other.

Gobbledygook that gets clogged up there over the years, by the way, this starts in our teenage years, uh, and takes decades to develop like a slow growing tumor. And there are a lot of reasons why atherosclerosis can progress. Uh, it's not one cause, but, but we believe that part of the problem is that our immune system.

Can't do its normal job and can't go after and get rid of this. We know that many cells in our body have the ability to identify this inflammatory stuff, these dying cells, these um, necrotic cells. And they should actually, I. Eat them and get rid of them, almost like, you know, Drano within the plaque.

Rachel Baker: Cool.

Nick Leeper: But again, because of genetics, uh, we know that certain people are born with defects in these mechanisms and then the immune system will kind of ignore this tissue and allow it to continue to accumulate over [00:08:00] time. So, we're very focused on trying to find ways to reactivate that and to get our immune system to.

Basically, take out the trash and remove all that built up plaque that we know leads to heart attacks and strokes.

Rachel Baker: So, you're saying no matter how many cheeseburgers I don't eat and how many miles on the elliptical I run, if my genetics are bad, I'm probably still gonna end up with some buildup in my arteries?

Nick Leeper: Yeah. I mean, if you picked your parents poorly and uh, didn't plan ahead, uh, you know, that's absolutely the case. I mean, for sure. We always start with, you know, education about lifestyle, diet, exercise in particular. I. You can only move the needle so far with those, and for a lot of patients, we need to be on aggressive cholesterol lowering medicines, and now we think we need to find ways to tackle these other aspects to get at what we call the residual risk that's not currently addressed.

Rachel Baker: Okay, so you were talking [00:09:00] about our immune system is supposed to go and eat the plaque and the bad, the necrotic cells and things. And so you identified a molecule that's called CD 47, and you call it the “don't eat me molecule.” Is it like, like my, my plaque is just like figured out a way to be like, “I'm staying here. Don't evict me. I'm a squatter.”

Nick Leeper: We think that's exactly what's happening, and it's really fascinating because this is the same type of process that cancers use as a way to escape the immune system. It's also a thing that invading bacteria use to try to escape, you know, removal by our inflammatory cells.

So we think that this gets turned on in a pathological way. And I kind of think of it as like a cloaking device, you know, so there's the plaque. The same way that there's an early cancer, and normally our immune system is smart enough to say, this is non-self, we should get rid of it. This is dangerous.

This is gonna cause trouble. Let's get [00:10:00] rid of it while we can. But it turns on these signals that basically make it invisible to our immune system. And they're actually called these funny terms, like, don't eat me signals. And so they basically, um, help these cells escape the immune surveillance that would normally be happening, and then they're allowed to continue to grow over time.

Rachel Baker: A side question, are you a Star Trek fan?

Nick Leeper: Uh, yeah, you know, Star Wars is more than Star Trek, but anything with aliens or explosions generally.

Rachel Baker: Well, you mentioned a cloaking device, so I'm like, are we calling the plaques, the Romulans here?

So, um, anyway, in an earlier study you cited it that you said systemic blockage of CD 47 resulted in anemia, and that's when you don't have enough iron in your blood. So obviously we can't just turn off CD 47 systemically. And so you've, you're trying to overcome, uh, that challenge?

Nick Leeper: Yeah, I mean, so, so a lot of what we've done since we've figured out that this [00:11:00] is the problem at baseline is we say, okay, well how do we, how do we reverse this?

How do we turn the immune system back on and make it start to engulf and get rid of all these cells that we don't want? And we can do that. It's not. Complicated. You just block the don't eat me signal. You take away the break and then all of a sudden the gas can go faster. But the problem is, is that the therapies we have in the first generation are a little bit too good.

Uh, they get, you know, I mean it's true. I mean, we can get rid of the cells we don't want in our plaque, but we also get some removal of healthy cells. And as you mentioned, the red blood cells are particularly susceptible for reasons we don't. Fully understand, but they will get gobbled up. And so while your plaque is melting away, or your cancer, if you're an oncologist, unfortunately the red cells get eaten up too.

And then you get anemia, which is a side effect that we really, you know, can't accept. Um mm-hmm. For, you know, thinking about applying this to lots of people with heart disease out there.

Rachel Baker: Got [00:12:00] it. I assume that it's anemia that's so bad that eating a little bit of red meat and some spinach is not gonna help me?

Nick Leeper: You know, in some cases we worry that we'd have to transfuse patients

Rachel Baker: oh, that's bad.

Nick Leeper: Yeah. It's probably worse than what we would want now. We have a lot of efforts trying to understand this biology better, to make a better mouse trap and find new ways to get the clearance where we want it.

But to leave the healthy tissue alone, one of the things we've done is we've partnered with, uh, our colleagues at the bioengineering school here, and we've been making, uh, what we call, uh, our Trojan horse nanoparticles. Where we can have basically a nanotherapy that will only go to the disease blood vessel.

And so now what we can do is we can deliver our very powerful therapy where we want it. We're not having it sent elsewhere. And so we've shown that this will lead to the benefit we want, but we don't get those side effects. We're not seeing the anemia, we're not seeing the clearance of other [00:13:00] healthy cells.

And so we think that this could be a way to have, uh, our cake and eat it too, and really have the benefit without the downside.

Rachel Baker: So are the nanoparticles, like the ones that we saw in Star Trek? You're like, yeah, I get an injection and all of a sudden there are all these little tiny bots flying, you know, flying through my bloodstream and being like, we're going to the heart.

And like, how do they know that? How do you program them to do that?

Nick Leeper: That, that's how I think about them. And we actually had an artist design a beautiful, uh, drawing that's, uh, exactly what, uh, along those lines, you know, we're still trying to understand why they are so specific for the inflamed cells. We don't really know why they're gobbled up there, but we love the fact that that's where they accumulate.

And so we can give very high concentrations of our therapies. We basically stick on the side of these nanoparticles without having them go elsewhere. And so it's exactly right. We give these intravenously, we've shown that they have potential in mouse models. We've shown they have potential in large animal models, and we're hoping that, you know, one day they'll be in humans as well.

Rachel Baker: [00:14:00] And so you partnered with someone from BioE to do this. Do you just like wander over there and be like, “hi. I've got a problem.” How, how does one do this? I've heard about how Stanford is like this slippery slope of collaboration. Like everyone just wants to collaborate with everybody else, but I don't, I don't know the first step. Maybe it's because I'm an introvert, but I, I would not know where to start.

Nick Leeper: Well, I mean, that's, you know, one of the real things that's magical about Stanford is that there are these traditional silos that we're used to really don't seem to apply. If you have a clever idea, you can go knock on the door of any of the Nobelists here or anybody that's, uh.

Department chair from a different vision or section. And my experience is they've always been open to clever ideas and the power of, you know, bringing a different viewpoint and bringing a different background and integrating our skills to tackle problems through a new rubric. You know, this is, uh, one of the things that make Stanford so special [00:15:00] and you know, I've never been told no so far, so it's a great thing about working here.

Rachel Baker: Amazing. Well, I absolutely wanna keep talking about this, but that sound means that it's time for our lightning round. On each episode of Scrubcast, we ask each of our guests the same three questions. And the first one is, who is a surgeon you admire and why? Do you, do you have surgeons that you admire?

Nick Leeper: I mean, I think the person that made the biggest impression on me was Norm Shumway. Uh, he was still, uh, practicing when I was a fellow here. And, uh, I've never seen somebody that made such pioneering advances that was so humble and so willing to invest in the next generation of trainees. Uh, he really wanted to pass on his legacy.

I just admire his perseverance. You know, inventing, you know, the concept of the heart transplant and implementing it in the United States for the first time, thinking through all the technical issues, the immunosuppression, figuring all that out and really, [00:16:00] really never giving up, uh, was very inspiring to me.

Rachel Baker: Absolutely. A hundred percent agree. Norm Shumway. Um, the second question we ask is, what is the best advice you have received in 10 words or fewer?

Nick Leeper: Uh, 10 words. Well, this probably comes from our last chief at vascular surgery. Ron Dalman, who you know, pretty early, taught me that. How does it go? Hard work beats talent when talent doesn't work hard.

Um, and you know, I like that because, you know, science is hard. It's hard to begin with just in general, but if you're tackling a big problem and you really wanna challenge paradigms, you're gonna get a lot of headwind. And you know, this concept of settled science is one that's really hard to surmount.

And I think that. You know, you have to be willing to not only do the hard work in the lab, but accept rejection, not feel bad for yourself. You know, understand that people are, are gonna initially resist the ideas and your grants and your papers, but, uh, sticking with [00:17:00] your beliefs and, uh, persevering, um, you know, this is where you see the enormous success from people like Shumway and the impact it can have.

So I think that, um, you know, just perseverance and, uh, having a never give up attitude was something I was glad that Ron taught me in my early days.

Rachel Baker: Love it. I'm gonna add that one to my wall. Well, in our last episode, we started asking our guests about their or music preferences. Is there such a thing as lab music? Is that a thing?

Nick Leeper: Oh, sure. Yeah. We, um, in my lab, uh, we like both kinds of music.

Rachel Baker: There are two different kinds. Only two?

Nick Leeper: Yeah, only two. Yeah.

Rachel Baker: What are the two different kinds of music?

Nick Leeper: Oh, you haven't seen Blues Brothers? I guess. Um,

Rachel Baker: no, I'm sorry. I'm okay. I'm showing my age.

Nick Leeper: Well, the classic is, uh, we like both kinds of music, country and western.

Rachel Baker: So, uh, a lot of Blake Shelton going on in [00:18:00] your lab.

Nick Leeper: Sure. We'll do it all. Yep. You know, our, our lab is really wonderful 'cause we have people from, you know, all over the world. So it really is a melting pot and we get to enjoy all the different, uh, cultures in our lab. And so we, we are always trying out new stuff.

Rachel Baker: Fabulous. Well, it has been a pleasure chatting to you. Before we go, one last question. What is next for Dr. Lieber?

Nick Leeper: Oh gosh. You know, we are now really moving beyond atherosclerosis alone and starting to look at the interface with cancer and cardiovascular disease. You know, we've known for a long time, there are many shared risk factors, but we, we think that there may be more than that, maybe.

Direct causal relationships. And so we think that if we can study this interface, we may be able to address both number one and two leading killers in the world. And we're really excited to, uh, embark in a bunch of new efforts that we're, uh, starting the lab at the moment.

Rachel Baker: Fantastic. Well, I look forward to seeing what you come up with.

Thank you so much for [00:19:00] joining us on Scrubcast.

Nick Leeper: Thanks Rachel.

Rachel Baker: And thank you to our listeners for tuning into this episode of Scrubcast. Until next time, stay sharp.

And that brings us to the end of another episode. If you like Scrub Cast, we hope you'll tell your friends and subscribe wherever you get your podcasts. Scrubcast is a production of Stanford University's Department of Surgery. Today's episode was produced by Rachel Baker. The music is by Midnight Rounds, and our chair is Dr. Mary Hawn.