#45: Poop Vs. Cancer

Quinn: Welcome to Important, Not Important. My name is Quinn Emmett.

Brian: And I'm Brian Colbert Kennedy.

Quinn: And this is Teddy.

Brian: Hey, Ted.

Quinn: Yep. Today's topic, it's the showdown everyone's been waiting for.

Brian: We've all been waiting for it, Quinn.

Quinn: I was going to say all season. We don't have fucking seasons.

Brian: All season long.

Quinn: We just keep going because this shit never stops. The showdown, the throw down, are you ready to rumble? Ladies and gentlemen, it's poop versus cancer. Pretty exciting.

Brian: It's a cage match, no holds barred.

Quinn: No holds barred. Our guest is Dr. Diwakar Davar. He is a professor of medicine at the University of Pittsburgh, and a medical oncologist and hematologist. He specializes in the management of advanced melanoma, and the development of early phase studies to test novel immuno therapeutic approaches to treat advanced cancers.

Brian: What Quinn said.

Quinn: Bang.

Brian: Boom. Yeah, he's doing some okay things.

Quinn: Yeah, right? Again, I feel very lucky, because we talked to a lot of folks who are just so above and beyond smart, but not just above and beyond smart, but applying themselves in this way where you want to go, what do I have to do to give you the tools to do your thing?

Brian: Right. Like, please just keep doing that. I will do anything to help you.

Quinn: Yeah, how do we divert air craft carrier money and resources to that thing, because it's just like what? I just always think these questions of, and knowing that science is incredibly difficult and no offense to any of these people, they will fail. And then they'll just pick up and try something else, because that's how science works. But also, what if he does it? What if it succeeds? That's just the mind blowing.

Brian: I mean, it will at some point. He or somebody on his team, or somebody who will be on that team in the future. Everything seems real crazy and then one day it happens.

Quinn: It's pretty awesome.

Brian: It was very cool to listen to this man talk, because it gets this enthusiasm in you going when you're thinking about what they're doing that, like holy shit, one day maybe there won't be cancer.

Quinn: Holy shit, indeed. Let's get talking to Dr. Davar.

Quinn: Our guest today is Dr. Diwakar Davar and together we're going to find out what your gut has to do with cancer treatments. Dr. Davar, welcome.

Diwakar Davar: Thank you for having me.

Brian: Yeah, thank you so much for being here. We're very excited to have you and to talk about this. Let's start just by letting us know who you are and what you do.

Diwakar Davar: Sure. I'm a medical oncologist. I primarily treat patients with melanoma. I do that at the University of Pittsburgh, which is unsurprisingly located in Pittsburgh.

Brian: You don't say.

Diwakar Davar: The scope of my practice involves treating patients with advanced cancer, and giving them a variety of different treatments. But I'm primarily centered around immunotherapy. Along with that, I also do some research. The scope of my research entails firstly, drug development. So, testing new molecules or new antibodies from drug companies in patients. A second aspect of what I do is evaluate third generation immune checkpoints. This is things that work even after the frontline drugs don't work, and the frontline drugs were stuff that people who just won a Nobel Prize helped develop.

Diwakar Davar: And the third thing that we do is we look at, which I think is the topic of this conversation, we look at the role of microbiome, specifically intestinal microbiome in mediating responses to immune therapy. We try and seeing whether by modulating that microbiome, whether we can actually effect responses even when traditional immunotherapies no longer work.

Quinn: Fascinating. I love it.

Brian: Yeah, it really is wild.

Quinn: I can't wait to get into that.

Brian: All right, Doctor, basically what we like to do with these podcasts is talk about something that we think is very important, that we think our listeners want to be engaged with, and want to help do something about. We're going to set up a little context, and figure out what specifically we can do to help you along, and help everybody who's trying to kill cancer, along with some specific action steps. If that sounds good?

Diwakar Davar: Sure.

Quinn: Awesome. Doctor, we usually start with one important, fun question. Instead of saying tell us your whole life story, we like to ask, Doctor, why are you vital to the survival of the species?

Diwakar Davar: Oh, that's a tough question. Depending on who you ask, some people might argue that I'm not that vital to the survival.

Quinn: Sure. But I want you to be bold. Be honest with us. Have some fun.

Diwakar Davar: I think our group, essentially it's a group, it's not just me as an individual, but our group, I think we're asking some very important questions. There are very few people asking these questions. What I think we're doing is, we're asking not only an important question that no one's asking, in a very important context, at a very important time. Because we now have for the very first time in the history of treating cancer, we have drugs that actually can take cancer that is advanced and put it into remission.

Diwakar Davar: It's kind of incredible for people to say that, and for other people not to be surprised. Even as recently as five, six years ago, there were no treatments that could put advanced cancer into remission. It wasn't until relatively recently that we've had successful immunotherapy. It's also important to qualify what one means by successful immunotherapy, because we've been trying to treat cancers with immunotherapy for as long as we've been treating cancers.

Diwakar Davar: And what we now have is successful immunotherapy, meaning there is a drug that's commercially available, multiple drugs made by several different companies now, but drugs that are commercially available, that you can get at any cancer center in the country. And it's not just in this country, it's in any other country as well, in which whether you're in Australia or in Alabama, you can get this drug, and this drug if you have a certain set of cancers, it works extraordinarily well and puts the cancer into remission.

Diwakar Davar: But, there's a tremendous financial cost to these drugs. There's also actually a side effect cost. Because even though the drugs kill cancer, we can sometimes produce very, very serious long term side effects. Overall speaking, they're good. That's part of the reason why this is the first Nobel Prize that has actually been awarded for a treatment that has actually directly improved the lives of patients. If you think about it, every other Nobel Prize in the history of medicine, every other Nobel Prize for medicine has been awarded for scientific advance. There's never been a Nobel Prize awarded for a scientific advance that has actually resulted in a treatment. That's something that we science geeks care about.

Brian: That's huge.

Diwakar Davar: The truth is ... Yeah, that's huge. These guys, Tasuku Honjo and Jim Allison, helped discover a drug, a pathway that resulted in a drug. And in the case of Jim Allison, he actually discovered the drug and Honjo helped develop the drug, that actually now cures cancer.

Quinn: That's incredible.

Diwakar Davar: So now, we are left with two things. In the people that the drugs work in, you've got side effects, you've got financial, toxicities, stuff like that. But more importantly, in the case of what we do, we are focused on why the drugs don't work. And what we've now discovered is that there are many reasons why these drugs don't work. But one reason appears to be the composition of the intestinal gut bacteria.

Quinn: Right. And that's what I want to dig into today. I feel like, migrating into our context here, Americans at the very least have been bombarded in the past 10 years with eat this yogurt, take this because it gives you probiotics, and now there's prebiotics, and this is how the gut works.

Quinn: At the same time, we're finding out that the gut is a very, very, very complicated and confusing place. That is to say, I feel like people thought, "Oh, we have our shit figured out a little bit." No pun intended. But what we're finding out now is how much we don't know about the gut, about the microbiome, and how different each of ours is from one another, how they're built, how they're affected by our genetics, by our environments, by antibiotics, by again, over marketed yogurt, and further, by cancer treatments and how they in turn affect cancer.

Quinn: It feels like we're at the tip of the iceberg with that stuff. But at the same time, like you said, it's interesting, because now we can start to really start to say, "Wait, maybe these things are affecting each other. Maybe this isn't just not working for some reason. Maybe we know enough about it to get started."

Quinn: I guess just to back up for folks, again, your gut isn't just your stomach. It's your mouth through your esophagus, your stomach, your intestines. And it's filled with trillions of microorganisms. More bacteria than you'd ever believe. I think they say it's like 13, 14 pounds of bacteria. And most it's good, and they help the nutrients, and they protect against pathogens, and they run your immune system. When they're out of whack, you get a whole load of issues.

Quinn: But the question for today is, how does cancer and cancer treatment relate to the gut? Of course, some microbes promote cell proliferation, which is great, or which is not great for cancer. Some protect against cancer, which is great. Cancer, of course, isn't one disease. So again, this whole thing is very complicated. And like you said, immunotherapy is working for some patients in an incredible way, and some not at all. And the question is, could those success rates, with improving them or where they are now, come down to the interaction with the gut?

Quinn: So, Doctor, if we could take a step back, I'd actually love to hear how you came into this specific perspective, this adventure. It sounds like it's more from the cancer side than the gut side. What was your path to start to take on this challenge?

Diwakar Davar: I guess it's important to acknowledge that in science, nobody ever, at least in biology, nobody actually wakes up one day and figures out that this is something that's important. It's always insights from what other people have done, and trying to expand on that in certain states.

Diwakar Davar: And so, in the context of these modern immunotherapies, I think people began to ask, as questioners do, we know that certain cancer treatments are affected by gut microbial composition. And the gut microbial composition exerts immune effects. There's systemic immunotherapy in the context of cancer, is not affected by the microbial composition of the gut microbial system.

Diwakar Davar: So, there were these two seminal papers that got published about two years ago now. Thinking of these two papers, the first paper was by Laurence Zitvogel. And Laurence Zitvogel in 2016, what they were doing is, they were collecting stool samples from patients who were receiving immune therapy. What they showed was that the effective immunotherapy in mice appeared to be affected by A, the use of antibiotics, and B, did not have any effect in mice that are grown in germ-free facilities. Meaning, when you grow a mouse in a germ-free facility, the mouse doesn't have a native colonization by bugs.

Quinn: Oh, right.

Diwakar Davar: And so, when mice were treated with antibiotics or grown in germ-free facilities, they did not respond to immune therapy.

Quinn: Not at all?

Diwakar Davar: Yeah. In the context of the model, not at all.

Quinn: Right. Fascinating.

Diwakar Davar: It's fairly easy to get mice to eat shit, so when you reconstituted the bacterial system by essentially oral gavage with particular bacteria, you could reconstitute the immune response. And it's a pretty elegant model. You have no response to the immune therapy in the control model. And then in the mouse that you actually try and treat with the immune therapy, you reconstitute the gut intestinal system by either, they did three different controls, but the major one is by oral gavage with a particular bacteria, response was reconstituted.

Diwakar Davar: That clearly suggested that there was a link between the intestinal microbial composition and the effect, at least, of this anticancer immunotherapy. In this context, CTLA-4 Blockade. And what was interesting was, when they took feces from patients who had durable, long term responses and gave it to mice, the fecal transplant from the humans actually reconstituted a response in the mouse.

Quinn: No way.

Diwakar Davar: That's kind of cool. Yeah.

Quinn: That's wild.

Diwakar Davar: Human shit cures mouse cancer. That's-

Quinn: That's wild. To make sure I'm getting this right, they took long time human patients who were responding to immunotherapy and gave it to those control mice that were raised in a clean environment. And they responded?

Diwakar Davar: And the mice had tumors that shrunk. Yeah.

Quinn: Wow. That's crazy. That's wild.

Diwakar Davar: That was one paper. That's-

Brian: That's one of the craziest things that's ever been said on our podcast.

Quinn: Yeah.

Diwakar Davar: The point is, the fecal transfer was additive with the immunotherapy. And then he did some very elegant work and isolated it down to the actual bacteria that he thinks is important and that is mediating this effect. And that-

Quinn: That was my next question. How much have we drilled down to discover what is the differentiator here?

Diwakar Davar: Firstly, that's very hard to do.

Quinn: Sure.

Diwakar Davar: There are many ways to try and think about how to do it. What he did was, he essentially looked at the bacterial species that appeared to change. His argument was that the species that is probably mediating the effect is the species that is probably changing the most from time zero to two weeks or one week. So that the species that is mediating the fact, must be the species that is increasing in abundance over time.

Diwakar Davar: What we know, at least as of 2016 when these papers came out and published and they got a lot of interesting hits, was that there appears to be differences in the growth kinetics of these mice, and that these growth kinetics can be eliminated by co-housing, and most likely is due to the effect of, at least at the time of the data, a particular bacteria, the [fitter 00:15:28] bacteria. And this administration of this bug along with, appears to control tumor in mice in the melanoma mouse model. And that this synergizes, it has an additive effect with immune therapy.

Diwakar Davar: And then [inaudible 00:15:41] data, suggesting that in a different immune therapy, of this case CTLA-4 immune therapy, a different bug appears to mediate the effect. But again, fecal transfer from human patients who were long term responders appears to result in cancer control in tumor bearing mice who are so treated.

Diwakar Davar: Is this true in human cancers? We now have three papers that have come out in the last 18 months. They've gotten a huge amount of press. These three papers look at primarily human data, in human cancer samples. That is in human patients who are treated with immune therapy. Intestinal microbial composition of respondents appears to be sufficiently different from non-respondents.

Diwakar Davar: What is interesting is that all three papers suggest that the bacteria in question is very different. Meaning that all three papers define very, very different bacteria as being associated as being responsible for the effect in responder patients.

Quinn: Right. That was my next question is if you could enlighten us a little bit on which cancers this is being tested on? Because obviously, I think everyone is aware of this at this point, cancer is not one disease. It is so many infinite number of different versions of it, and it's different for everybody. So yeah, I'm fascinated to hear about that. That differentiation must be frustrating, but at the same time very enlightening.

Diwakar Davar: Right. That brings us to an allied question, which is if this difference is real, and it's very important in science for us to say that in science we're very concerned with what we know. But we're also equally very, very reflective and contemplative of what we don't know.

Quinn: Sure.

Diwakar Davar: And the question is, if this is a real phenomenon, can this be modulated to actually affect treatment outcomes?

Quinn: Right. The end game.

Diwakar Davar: Right.

Quinn: So, what are the steps in between there? What are the steps there?

Diwakar Davar: That's a great question. There are many steps. And I'll say that the first thing is that the end game is not just one factor. The end game isn't just is the microbiome a valid target for therapeutic manipulation. I think that's the big 20,000 foot question. And the answer to that, I think is obviously, yes. Because many biopharmaceuticals are involved in trying to manipulate the microbiome to different ends. So clearly, the intestinal microbiome is a setting in which therapeutic intervention is certainly a possibility.

Diwakar Davar: The point being that this is a very, very important area that should be studied. Whether you believe it or not, it's something that should be studied in ongoing immunotherapy trials. That's one of the first things that I think this phenomena suggests. I think in response to that, major biopharmaceutical companies have started collecting, sampling the intestinal microbiome longitudinally in clinical trials that they are doing. And so, Bristol-Myers, Merck, and other major biopharmaceuticals are doing this. That tells you that, I think, not only academic investigators such as us in our group, but other investigators, even biopharmaceuticals have caught on to this idea that this is an important area that needs to be studied. That's, I think, one take home point.

Brian: I assume you're saying that because, are you guys feeling pushback while doing this research?

Diwakar Davar: No, no, no. We're not feeling pushback. If anything, it's an endorsement.

Brian: Okay.

Diwakar Davar: If you are doing this, and the biopharmaceuticals are like, "Well, whatever," then you're just working in isolation. But the fact that biopharmaceuticals are taking notice, and they are actually attempting to study this as well, suggests that everybody realizes that the data that's being collected is, at least at this time it may be very premature to make any major conclusions, but it certainly is a factor of interest. That's, I think, is the first important takeaway, that this is probably going to be an important sideline. All main actors, we don't know that, but it's going to be a very important factor that determines how drug development happens in the next couple of years, maybe even longer than that. At least in the context of immunotherapy, and it's a factor that people are studying. That's a very important fact.

Quinn: And it seems so valuable, I think. We try to do a good job with painting a comprehensive, objective viewpoint for folks, which is like immunotherapy has been incredibly successful in some ways. And in some ways, not effective at all. And in some ways, it has been dangerous for the patient. But it is very clear that there are reasons, whatever they are, and we're so far from totally defining them much less reach individual, that it works for some folks and it doesn't work for others. Or, works for some cancers and it doesn't work for others. So, it does seem like things like this, if you're getting indicators, it certainly seems worth pursuing. Like you said, it seems like the drug companies feel that way, too.

Diwakar Davar: Yeah. And the second thing that's interesting is that there are a couple of lead actors that are involved in trying to do interventional clinical trials in this space, in the context of cancer. There are at least several different companies, as well as academic investigators including our group, that are attempting to try and see whether modulating the intestinal microbiome can affect the outcome of cancer immunotherapy. I think that's the second wave of what's happening.

Diwakar Davar: These clinical trials obviously differ very significantly in the nature of the trial, the details of the trial, the details of the intervention, the patient populations, and so on and so forth. But what you're seeing is that a couple of different companies are getting involved in this space. They're trying to see whether, companies as well as academic investigators, are trying to see whether or not you can actually make, is there an intervention that you can do that actually changes the way cancer patients get treated.

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Brian: This if very exciting, and very overwhelming. There's just endless possibilities of where to go next. What are we looking at for the next year or five years? Or, is it not really known yet, because it is so early? I've got to ask, of course.

Diwakar Davar: I think the first thing that you're going to see, there's going to be a lot regarding the first part, which is I think a lot more groups are going to come out and start saying that we think that this particular bacteria is important, or that particular bacteria is important, or this particular bacteria is important. So, I think there's going to be a lot more noise. And in that noise, as that noise as being generated, there will be just as a result of noise, there's going to be a lot more interest on data harmonization.

Diwakar Davar: Because what tends to happen when you have noise is that somebody needs to step back and say, "Let's try and make sense of this." I think what we are trying to do, along with our collaborators, we have many collaborators, is we're trying to get a sense as to what the factors are that make a difference in mediating the signal to noise ratio.

Diwakar Davar: So, is it important to know what people are eating? We think so. Is it important to know how much exercise people are doing? We think so. Is it important to know what kind of medications people are taking? We think so. How do you try analyzing this data? Do you just draw a graph and try and plot these together? That's a little hard to do when you're dealing with things that are numbered in the trillions. And so, [crosstalk 00:24:51]

Quinn: No.

Diwakar Davar: Some kind of computational approach, typically involving things like neural networks and stuff like that, to try and make sense of how you get very, very diverse, disparate data points. And correlate things that may be very, very overly related, variables that are overly related, too tightly related, that traditional linear analysis is confounded by multicollinearity. And try and relate these diverse, disparate variables, such as cancer response, and receipt anomalously to immune therapy, and medication use, and microbial composition, using advanced computational techniques such as artificial neural network analysis.

Diwakar Davar: I think that's one of the first things that's probably going to start happening. There's going to be many, many data sets. A lot of noise. And then there's going to be some harmonization. And with harmonization, then we're going to get a better lens through which we can look at these data sets and make some sense as to the factors that are important. And some factors will win, some factors won't. And we don't know what factors will win. But let's try and collect as much of this as we can. I think that's one thing that's probably going to happen.

Quinn: Sure. Yeah. It's fascinating. It feels good to know it's in good hands painting those way points along the way, those measurement sticks. What do you feel like, quickly, are the biggest obstacles you guys have run into, or foresee running into over, again, let's limit it, the next 6 to 18 months?

Diwakar Davar: I think one of the factors is actually, and in many ways, these are things that other people have already answered. Where this research was done first, in the context of inflammatory bowel disease, in the setting of inflammatory bowel disease. I think of, again, the same thing. The people in the IBD world have been doing this for far longer time than we have in cancer. They started five, six years ago. And what they very quickly realized was you really needed large international groups.

Diwakar Davar: Essentially speaking, there's an American group, and then there's a European group. In the American group, everybody just pools their data. They try to analyze this. And then the experts in computation, the experts in microbiological, ecological analysis, the experts in immunology, and they try and figure out what's important, what's not important, and how to rationally design clinical trials. And then in Europe, there's the same thing, except in Europe.

Diwakar Davar: I think what we probably need in the next 6 to 18 months, and one of the barriers is, there probably needs to be groups that convene to say that this is what they're going to do, and these are the techniques that we are going to try and test, and these are the approaches that we're going to try and test, but let's try and test this in a fashion that is not overlapping. So that patients and resources aren't wasted, so that we aren't duplicating efforts that other people are already doing.

Diwakar Davar: Science is imperfect. It's not as straight and narrow as one might always imagine. There are lots of zig zags. But, trying to minimize the zig zags probably helps conserve resources, because the ultimate resources are patients' lives. And what we'd like to do is do this in as efficient a fashion as possible.

Quinn: Sure.

Diwakar Davar: But hopefully, something that we get done over the next 6 to 18 months is actually the formation of groups that help corral disparate investigators together and assign unique tasks, so that we can all work in a forward direction.

Quinn: Right. At least in the same direction. I guess that segues pretty well into, this is a little bit of a different conversation because obviously, we usually talk about things that can affect or are affecting everyone. Cancer is obviously affecting so many people. Everyone has a story, or knows someone, or is someone. Obviously, our listeners aren't all in line for immunotherapy, which is great. But, we do have a lot of patients and survivors, and some doctors and scientists, and Senators, and plenty of advocates listening. We'd like to say our listeners take action with their voice, their vote, and their dollar. What do you feel are the questions, or directives we should be asking of our representatives to fuel science like this, to help push your mission along?

Diwakar Davar: The first thing is, we have actually been very fortunate in that some of this research is actually being funded by the National Cancer Institute. When you read the news, it's very depressing. All the craziness that happens. But one thing that's very interesting, and this is, I think, true of Republicans and Democrats alike, is that one of the very few things that almost everybody seems to agree on is that funding research and funding the mission of science, and specifically the National Institutes of Health and the National Cancer Institute is something that has surprisingly, in these times, actually got very broad bipartisan support. And actually, the NCI budget has actually, currently it's $26.9 billion. That's $5.7 billion below the 2017 continuing resolution level. But it is a fairly significant amount.

Quinn: Sure. And you're right. I think that was interesting. I think Trump proposed cutting that greatly, and Congress said no way.

Brian: Yeah.

Diwakar Davar: Yeah. And that's actually very reassuring, because everybody complains about Congress, but Congress has actually done very well by the NCI. Because even though the NIH budget has been cut, the NCI's budget, that is the budget of the National Cancer Institute in the current fiscal year for 2019, has actually been increased by $79 million. That's $5.74 billion. And that's a $79 million increase over the fiscal year 2018. So, thanks to everybody, Republicans or Democrats or Independents, the NCI's budget is healthy. I think everybody should take stock in the fact that our elected representatives, regardless of stripe or party affiliation, appear to be cognizant of the mission of NCI.

Diwakar Davar: The second thing that I guess is useful is, this research, cancer research is very, very important. But this is also a very important area that for people to understand in that if you're a patient with cancer, you know somebody with cancer, you have a relative who is dealing with cancer, it's impossible to underscore how important it is that you are seeing a medical oncologist, or a surgical oncologist, or a radiation oncologist who is affiliated with a national cancer center, a comprehensive cancer center. Because, that's where a large bulk of this research happens.

Diwakar Davar: One of the things that you take away from all of this is that, sure, the investigators at the University of Pittsburgh may not necessarily agree with the investigators at the University of Chicago, may not necessarily agree with the investigators at the [inaudible 00:32:07] Cancer Center. But what's unique about all these three places is that they're all comprehensive cancer centers. And if you think the founding mission of the NCI, which was to designate these centers as being important areas for research to happen, one of the missions is to ensure that research happens at the level of the comprehensive cancer center.

Diwakar Davar: So, one of the reassuring features is that even in these times, in these struggling times, with so much disagreement between people, even in science, what's fascinating is that this research is happening as a result of NCI dollars. And people disagree on relative minute things, but the NCI's mission is being fulfilled because our clinical trials and this research is being supported by NCI dollars.

Diwakar Davar: So helping support that would be very useful. People sometimes give us charitable contributions. That's always welcome. People tell their elected legislators that, "These guys are helping us." And that's always getting a shout out on Twitter, on Facebook, or any other social media. That's helpful. Because ultimately, the science that gets funded is the science that helps people, but it's also the science that people hear about and know about.

Quinn: Sure.

Brian: Right.

Quinn: And I think that's a good note to folks. Again, like you said, Congress has been surprisingly and effectively supportive of science, even despite the pushback from the administration. That doesn't mean you don't need to call your representative, that means call your representative and thank them for doing what they're doing, and encourage them so they don't feel like they're left out in the cold with all the other shit going on. Thank them for their long term vision, and for focusing on what's good. And if you have a personal story, tell it. Whatever helps these people feel like they can do even more is important.

Brian: And personally, obviously knowing there's still so much to uncover, and we're very early on, do you have any guidance on what the rest of us should be doing to put ourselves and our gut, and our poop in the best place to succeed should something like this come our way?

Diwakar Davar: People often ask, "Is there a diet that I should be following?"

Quinn: Right.

Brian: Please tell me what to eat, Doctor, basically is what I'm asking.

Diwakar Davar: Yeah. "Should I not eat sugar? Should I not eat this?" And you know what's kind of crazy is that we are in the midst of doing a lot of deeply analyzing dietary histories and stuff to try and get a sense as to what's important, what's not important. But one of the early things that we've found out is that if you go back to the last 10 to 15 years of nutritional data, there are lots of data points that suggest that certain dietary elements are very important.

Diwakar Davar: When you break these down and you look at those in isolation, it appears that taking a high fiber appears to be important. Eating less red meat appears to be important. [inaudible 00:35:12] Omega 3, polyunsaturated fats and Omega 3 fatty acids appears to be important. Exercise appears to be important.

Diwakar Davar: But you know, lets stop there for a minute and think about that. Eating less red meat, eating polyunsaturated fatty acids and Omega 3s, and high fiber, not eating too much. That's kind of commonsensical. [crosstalk 00:35:37].

Brian: Normally.

Quinn: You would think so.

Diwakar Davar: Right. So what's interesting is that we are really rediscovering old truths at this point. I'm covering what I think is a scientific basis for things that were commonsensical all along. But we are identifying that there is a rational basis for doing things that most people all along knew to be true anyway. If we eat a 24 inch pie every day of the week, it's probably not a good thing. Whether it's because-

Brian: Okay. I'll stop doing that.

Diwakar Davar: It's bad for your gut microbiome, I don't know. But the point is, it's probably not helpful.

Quinn: Yeah, regardless, it's probably not helpful. You're right. It almost is like we're taking a step back to doing do this, do this and this. There's this great food and culture and health writer, Michael Pollan, and his famous quote is, I think it's really short, "Eat food. Not too much. Mostly plants."

Diwakar Davar: Mostly plants. Yeah.

Quinn: And look, you can ask all the questions you want about the microbiome and whether it's going to help you not get cancer or fight off cancer, but as well as everything else and all of our other issues, just eat real food that comes out of the ground, not too much of it, plants, and you'll be on the whole in a better place. And not to mention, an entirely different conversation, the environment will be in a much better place.

Brian: Wow. Hey, I have a really quick question. Did you ever figure out why those mice in Jackson were just right off the bat better at ...

Quinn: Yeah. What were they exposed to?

Diwakar Davar: No, no. They had different microbial species.

Brian: That's just ... huh.

Quinn: That's amazing.

Diwakar Davar: Yeah. That's why it's transmittable.

Quinn: Yeah. That's incredible.

Diwakar Davar: If you had to be a mouse-

Brian: And there's no reason for it, really? They just have a different species.

Diwakar Davar: Just better bugs. Yeah.

Brian: Better bugs.

Diwakar Davar: If we think about it, there are several populations on Earth where just by virtue of being born there, you tend to live longer. And it's very interesting. There's a socioeconomic reason for this. There's a demographic reason for this. But what's fascinating is that so much of what is considered socioeconomic is also biological. In that, what is the Mediterranean diet? The Mediterranean diet is a certain thing. But you don't have to live in the Mediterranean area to adopt a Mediterranean diet. It just so happens that the people who live there, kind of do, but you don't have to.

Diwakar Davar: And so what's interesting is that it suggests that a lot of these geographical differences, and ethno-demographic differences that we attribute to certain factors are actually mutable. They're not immutable.

Quinn: Yep. Sure.

Brian: Man, that's wild. Awesome. Doctor, thank you so much for being here and talking with us today. I know we've had you on for a bit. We'll wrap it up with just the last few questions. But, we really appreciate your time.

Quinn: Yeah, absolutely. This has been very enlightening for all of us. I think it's pretty awesome. So Doctor, sort of a lightning round here. Slightly off topic, slightly not. A little more meta. Doctor, when was the first time in your life when you realized you had the power of change, or the power to do something meaningful?

Diwakar Davar: Oh, the power of change was relatively early. I mean, I'm South Asian, so if you have Indian parents and you try and say no to something they want you to do, you just get hit. It's something unique. White people don't beat their kids. Indian parents do. So, I realized very early on that if I pissed my parents off things wouldn't go too well.

Diwakar Davar: So as far as change went, I am many things, but it's, again, primarily because I've always had this idea to try and make a difference in what we do and take care of patients. But it really comes from a fairly young age. My parents were fairly influential in getting me to choose this path.

Diwakar Davar: As for the second question, I think in science, you are a lot of who your mentor is. The mentorship issue in science is something that is very well known. But it's also at the same time, not necessarily as well recognized. We tend to ascribe a lot to individuals. But the truth is, it's never just one guy. It's always a group. And it's never just that guy. It's always what he learned from the people that we learn from.

Diwakar Davar: And in our case, this is maybe me talking, but the person who actually is driving a lot of this is actually the guy that I work with. He's a very influential human [inaudible 00:40:24]. He's been front and center in the development of novel immune therapies, and biological discoveries that have made huge differences in the treatment of cancer. If you're a cancer patient you may not necessarily know who he is, but if you're a cancer patient who's receiving a PD-1 immunotherapy, he's one, again, not the only one, but definitely one of the first to have shown this is an effective treatment for patients long before the clinical trials were actually done. It's thanks to him that we've got a lot of the work that we've done, done.

Diwakar Davar: You need people with tremendous ideas, and then you can translate those ideas into discoveries. But all of that stems from people that you work with in this collegial environment that one is in. Really, I think a lot of what we do is due to where we're at, and the environment that one is in. But also, the influence of one's mentors.

Quinn: I love that. Yeah.

Brian: That's an awesome answer.

Quinn: Mentorship. Nobody is too good-

Diwakar Davar: No man is an island. Right?

Quinn: Yeah. No human is too good for a good mentor in their life. It makes a huge difference. I'm lucky to have a few of those myself.

Brian: This field you work in seems like it could be overwhelming at times. When it is, Doctor, what do you do to-

Quinn: Specifically, how do you vent?

Diwakar Davar: I talk to my wife. She's a lawyer. She's very good at keeping it real. She actually used to be in politics. She worked on Ted Strickland's finance campaign. She worked on Ted Strickland's campaign as his finance director.

Quinn: Gotcha.

Diwakar Davar: She was in politics, then she was a lawyer, she is a lawyer. She helps keep it real. She helps especially when I get a little too serious.

Brian: Another great person to have. Not only a mentor, but the person you know every time when you need to talk you can go to that person and depend on them. How do you consume the news, Dr. Davar?

Diwakar Davar: Actually, we don't have a TV.

Brian: Nice. I like that.

Quinn: That's a great call.

Diwakar Davar: We don't have a TV at home, and we don't have a cable subscription. So I think we're limited to what we read and what we hear at work. Yeah, I primarily consume the news through my phone, because we don't have a TV.

Quinn: Love it.

Brian: Yeah, that's great.

Quinn: Brian's got his last question, favorite question.

Brian: Last question, favorite question. Doc, if you could Amazon Prime one book to Donald Trump, what book would that be?

Diwakar Davar: One of the books that I've found most interesting is actually several of the books by Atul Gawande and Siddhartha Mukherjee. They're physicians who write for a lay audience. I'd send him Atul Gawande's book. It's not the newest ones, the one that he wrote in 2014. It's called Being Mortal. It's a very interesting book that addresses hospice care.

Diwakar Davar: The reason it's important is because so much of what we think is important in science, we are so happy that the NCI is funding research in cancer and this and that. And that's very important. Cancer drugs sell. Companies make billions of dollars on stuff that sells. But these things ultimately help small groups of a select few groups of people.

Diwakar Davar: What Atul Gawande writes about in Being Mortal is that the one thing that is a certainty for every human is that human existence is by definition everybody is guaranteed death and taxes. What he talks about is that age related frailty, age related illness, cancer is something that in this country especially, that we've often overlooked. We spend so much money on advances in cancer care. And make no mistake, my research depends on that funding. But how much of what we do as we're doing it, do we ignore things that are very important? How much time is spent contemplating death? How much time is spent ensuring that people who are going to die, die well?

Quinn: We don't do a very good job of that in this country.

Diwakar Davar: We don't. We don't. It's tragic, because it happens in so many different levels. It happens because patients sometimes don't realize that, doctors sometimes don't realize when enough is enough. Patients aren't sometimes told that they have access to facilities such as hospice and hospice care. Sometimes, in certain parts of the country, because of issues to do with access to care, hospice facilities aren't available. Hospice doctors aren't necessarily as well remunerated as other doctors. And having this conversation isn't something that is necessarily as emphasized as it should be because of reimbursement models and stuff like that.

Diwakar Davar: So, the point is that as important as the work we do is, and we're trying to cure cancer and make sure that everybody dies of old age rather than cancer, we also need to realize that when these things don't work, we need to ensure that patients have the opportunity to die with dignity. It does involve access to some of these services, palliative care that in our culture of cure isn't necessarily sometimes as well emphasized, and often overlooked.

Brian: Yeah.

Quinn: I really love all his writing. That is a fantastic book. And definitely an alternative viewpoint that we need to start at least talking about more and instituting more. I've been trying to get Brian to read his other book, The Checklist Manifesto, for about two years now.

Diwakar Davar: Yeah. That's also a very good one.

Brian: I hear it's good. Yeah.

Quinn: It's a hell of a book. Well, Dr. Davar, we can't thank you enough for your time today. This has been super enlightening for all of us. And hopeful, and inspiring, and a little mind blowing. I know we have a very, very long way to go, but we appreciate having folks like you doing the work every day with such a well considered perspective.

Diwakar Davar: Oh, yeah. No problem. Thank you for having us.

Quinn: Yeah, of course. We will follow up with you at some point down the road to see how everything's going.

Diwakar Davar: Of course.

Quinn: Awesome. Sounds good. All right, Doctor, thank you so much. We'll talk to you soon.

Brian: Thank you.

Diwakar Davar: Take care. Bye.

Quinn: All right. Thanks.

Brian: You, too.

Quinn: Thanks to our incredible guest today, and thanks to all of you for tuning in. We hope this episode has made your commute, or awesome workout, or dish washing, or fucking dog walking late at night that much more pleasant. As a reminder, please subscribe to our free email newsletter at importantnotimportant.com. It is all the news most vital to our survival as a species.

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Quinn: Please.

Brian: And you can find the show notes from today right in your little podcast player, and at our website, importantnotimportant.com.

Quinn: Thanks to the very awesome Tim Blane for our jamming music. To all of you for listening. And finally, most importantly, to our moms for making us. Have a great day.

Brian: Thanks guys.