E96 JC Alverdy on Gut Microbiome and Solipsism

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Chad Ball  00:12

Welcome to the Cold Steel surgical podcast with your hosts Ameer Farooq and Chad Ball. We've had the absolute privilege of chatting with some amazing Canadian, as well as international, guests over the past year. While the topics have been broad in range, whether clinical, social or political. Our aims for the podcast continue to remain the same. We hope to inspire discussion, creativity, scholarly research, and career development in all Canadian surgeons. We hope you enjoy our second season as we continue to highlight some incredible guests, deliver detailed masterclass sessions on a myriad of clinical topics and introduce some fresh new features such as debate and companion formats. We hope you relish the podcast as much as we do.

Ameer Farooq  01:12

Dr. John C. Alverdy is a minimally invasive surgeon at the University of Chicago. He's an iconoclastic scientist whose research focuses on gut microbiome and its impact on surgical site infections. His lab, which is continuously NIH funded, has put out publications in Nature and many other high impact journals. Most importantly, however, Dr. Alverdy is willing to challenge commonly accepted ideas and assumptions like the basic tenant that we really know why anastomoses leak. He gave a fantastic talk this year at the American Society of Colon and Rectal Surgeons, and we'd highly encourage you all to listen to that as well. That was the Norman D. Nigro named lectureship. Now, Dr. Alverdy.  Dr. Alverdy, thank you so much for joining us on Cold Steel. Just to start with, could you tell us about where you grew up and where you did your training?

JC Alverdy  02:05

So I grew up in Chicago, Illinois, on the north-west side of the city. It was in the city proper. And it was a very nice neighborhood, middle class neighborhood. We had a three-bedroom, bath and a half house. My father is a son of an immigrant, and he was a dentist who went to Northwestern University, so undergrad and dental school. And, you know, on the block that I lived there was a doctor that lived to our left, a lawyer that lived to our right, down the hall was a bus driver, across the way was a plumber. There was a carpenter, it was a very interesting and mixed neighborhood. I grew up, I was born in 1953. Everybody just kind of played outside and didn't worry about anything. You know, you left the house when you were young, at eight o'clock in the morning in the summer and you didn't come home except for dinner. It was a great way to grow up. I went to a catholic grammar school, which was within walking distance of the neighborhood, and a catholic high school, and a catholic college, royal academy and Marquette University. Then I was a Spanish major in college, I wanted to go to foreign affairs school and that was not received well by my father, who was a great guy and loved me to death but he was a dentist and said, "you know, as a son of an immigrant, there are three things you can be, an engineer, a doctor or a dentist, otherwise you're going to starve, when the depression comes and the ceiling falls down." And so, that's kind of how I ended up, sort of last minute, going to medical school in Mexico, where I went for three years. Which turned out to be an interesting experience, especially with all the interest now in global medicine and understanding how, perhaps, 80%, 90% of the world receives health care. Then finished at Loyola University Medical School, where I spent the year. And then took up a residency at Michael Reese Hospital, which was the 1000 bed teaching hospital about three miles away from where I work now. It was a University of Chicago affiliated hospital. And there was a lot of cross-training between the programs here and the programs there. So that was my connection to the University of Chicago when Michael Reese started having financial trouble and the two institutions were going to merge. And as you can imagine what two large, powerful institutions, when they make the decision to merge, it's always complicated. There are egos that are bruised, and that sort of fell apart. I ended up coming to the University of Chicago, where I joined in 1993 as an assistant... as an associate professor, actually, I had already been at the other institution for five or six years and had been promoted. And I came to University of Chicago, not only because I partially trained here, but also because the University of Chicago is known and is still known as a research university. It's undoubtedly considered one of the premier research universities in the world. And its hospital at the time was not a sort of, full service, the go-to hospital. It was the place you go to when nobody else can solve your problem. And it's morphed now more into a full-service university teaching hospital, with outstanding service at all levels. Whether you're having your gallbladder removed, or a lung transplant. It's doesn't matter, we provide it at the highest level of service. But it was a place where, at every level of engagement that I had as a faculty member, at every level of engagement, the most appreciated and most rewarded element of your practice and career was the new knowledge that you created, that was supported in a way that really allowed me to be able to do the work that I do. Michael Reese was the same way. They were, sort of, sister institutions and Michael Reese, at the time, had the most number of NIH grants of any private hospital in the United States, at least when I trained there. So, it was very heavily involved in academic pursuits at their most fundamental molecular discovery level. So, I was used to that. And people always ask me, "how did you do it, how did you still operate and be, you know, considered a master surgeon and a competent surgeon and go-to surgeon and at the same time, have a lab?" and I said, "Well, you have to be in the right place." Because not every place allows faculty to do that. Where you can have one foot on one side of the bridge and another foot on the other, and actually be nurtured on both sides. Both the hospital presidents and the deans, and the chairs of surgery, the section chiefs, appreciated and made accommodations for you to do both. That's rare, it's not for everybody. But it's rare and if it's done right, you can be both an operating surgeon and have an enjoyable practice and enjoy the inner sanctum of the operating room, and you can also be fluent and conversant in molecular techniques. Now, I'm not sitting there, now, certainly had at one time, I'm not pipetting or killing mice, or running western blots myself, I have people that do that. But you have to be dedicated to do both, to actually end up being able to do both. So, I always say I had a non-traditional career. I mean, I'm not a trained scientist. I was a language major in college, with aspirations of something completely different than I am now. And yet, I think, one's own inner-directedness, and curiosity, and passion. I don't think those are enough, I think. It's almost obsession with a clinical problem that needs to be solved at a more molecular, fundamental level. You need to almost be obsessed with the problem because, you know, clinical medicine is so seductive, in a way. The patients pull you in, you're outstandingly trained, and you want to help them. And it's hard to let yourself be distracted by anything else. And certainly, you want to be a master surgeon, technically, and a master educator if you have a university hospital. So that's almost enough bandwidth right there to keep it going. So that's why I use the word obsession. I even have it in a slide. Like, you have to be obsessed with a problem to put in the time and energy that it takes to do both. Let's just say that.

Chad Ball  10:11

You know, that's such an amazing description. And there's so many things to unpack there. But I'd love to focus on just one and it's honestly unexpected, but I'm so glad you brought it up. In the last day or so here, I just was reviewing a peer reviewed manuscript submission for the journal, and it was interesting because it looked at academic productivity through a number of the metrics that you, of course, would know. You know, your h-index, your citation index, and all this sort of stuff. At the individual clinician slash academic surgeon level. And as you predict, things like having a master's degree or a PhD prior to entering med school or an MD PhD in med school, they were predictive of longer-term productivity. But there was a couple of very interesting things I'd love to ask you about. In particular, the range in terms of productivity was monstrous. When you look at the hyper-performers that were 2 or so standard deviations north of the mean. You know, it didn't really characterize the features of those people or the characteristics of them. But I'm curious what your thoughts are, having been so productive and world renowned for so long? And then the second part is, what are some of the core concepts or deliverables that really speak to your comment about being supported in the places you've been and where you are now, that have come your way? What would you recommend are things that are really to fight for or to ask for? Or for maybe a more junior person setting up a hybrid academic experience like yours?

JC Alverdy  11:55

Well, thanks. Those are very insightful questions. And they're different for everybody. Since I'm fascinated by bacteria, I always say, no two species of bacteria are alike. No two strains, no two individual isolates are alike. So, you know, we shouldn't racially profile bacteria, and we shouldn't do it to people, and we shouldn't do it to physicians, and we shouldn't do it to academic physicians, because we're all different. We're all motivated by different things. When you brought up the idea of these outliers, you know, what makes somebody, one person, so productive over the other? You know, it's a really difficult question to answer. I often use the... I gave a talk once, one of these evening talks I was asked to give. When you look at some of these amazing achievers, somebody like Miles Davis who still has an album that's the greatest jazz selling album of all time. And the guy is a childhood prodigy. He ends up at Juilliard at a time when not many African Americans could enter that school. And after about a year and a half, he goes to the dean, or a year, I don't know, and he says to the dean, "This is really wonderful. Thank you very much for the opportunity to work here." He says something like, "but there's nothing here you really can teach me." Imagine walking up to the dean of your medical school, or your chairman of your department of surgery and say, "you know, it's really wonderful working here at Harvard, Yale, whatever. But there's really nothing I can learn here"?

Chad Ball  13:43

Yeah, unbelievable. Yeah.

JC Alverdy  13:45

And then the guy figures out how to, you know, change the way jazz is being played and chord progressions, and creates modal jazz and all this other stuff around music theory, that people are just blown away. You know, the same thing could be said of somebody like Steve Jobs or others. It's, what is that inner directedness? And what is that obsession? I call it this, when I'm writing a grant, my family, they usually go, "dad's in a scientific trance, dad's in a trance, just stay away from him." What allows you to do that, right? One of the chairs here, the chair of medicine said to me once, he goes, "if you let people do what they love, they're usually very productive." Not everybody gets that opportunity, right? So, to answer the second part of your question about, how can I provide some pearls to junior people, I mean, think about that first job. You're just this young person out of your training, you feel good about yourself. Of course, who wouldn't want to be at this prestigious university hospital in Canada, or in the United States, or in London, or Australia, or New Zealand, where you have students and residents, and this that and the other. But that may not always jive with the job that they want to pay you to do and the job that's available at the time. Maybe it doesn't jive with where your family, your extended family, your parents and your grandparents, live. Or where your spouse or partner is willing to go. So, all this stuff just floats in there. And everybody kind of gets railroaded into being in a place where maybe they never thought they'd land up. And then the opportunities in that place, to my point, I was lucky, I grew up in Chicago. There's Rush, there's Northwestern, there's U of C, there's Loyola. Four great medical centers. My wife's family grew up in Chicago, she grew up in Chicago, all the extended family was here. I trained in a place that was three miles from the place I've been at for 30 years. Right? Geez Alverdy, you just had it made. Just being lucky enough to grow up in Chicago and somehow these positions opened up. That's true, there's no doubt that's true. But then the second part is, I've said this on other interviews, it's hard not to get seduced by the technical allure and the technical marvel or the technical fantasy, and the technical demands of surgery. How often, when you leave a case, do you go, "Oh, that was just amazing. I mean, not only was it technically beautiful and elegant, but I just saved that patient's life"? I mean, who gets to do that? And who doesn't want to keep doing that more? Maybe it was like when Miles Davis was playing, and I brought this up in this lecture, you got these other amazing jazz musicians. And if you've talked to any musicians, rock, jazz, they're playing off each other. It's like the band, right? One person plays something, and they hear it, the other person plays something and, you know, they may do a concert and play like they've never played a particular song the same way. And they're like, "oh, my god, that was amazing." Forget about how many people bought tickets and how much money they made. And the same thing happens with surgeons, right? You go into the operating room, and you've got some tumor wrapped around the diaphragm. You open it up and you've got some really amazing chief resident and a surgeon fellow, and I don't know who else you have in there. Great nurses, great circulating nurses, whatever it is that you need. Maybe new equipment, and it just goes perfectly. And you're like, "oh, that was just amazing." Who doesn't want to do that more? If you're in this rock band, or in this jazz... you want to go back to school? You want to start studying music theory and writing about it? Changing it? Or you want to just keep playing? And I think there's so many more people, there's so many people smarter than me, more talented with advanced degrees, that have trained, that were neuroscience majors at prestigious places and did postdocs and they're amazing. And I actually am thinking of one right now. Yet, they just want to be clinicians. I have one MD PhD who got his MD PhD from here and worked literally with a world-famous immunologist. And I said to him, "oh do you want to do any research? I mean, your [inaudible], amazing" and he goes, "No, I just got the PhD so they'd paid for my school, I was able to get it. I had no debt. You know, I moved to Chicago because my parents are here. This, that and the other." Like, wow, that's unbelievable that you want to do that. I wish I was, first of all, smart as you, to get into the MD PhD program here. Not to mention, get your school paid for. But all he wants to do is take care of patients and he's an amazing anesthesiologist, critical care specialist. On the other side of that is an MD PhD that I work with, probably who is one of the smartest people I know here. And he's hilarious. This guy is hilarious. He's MD PhD from Washington, went to Princeton undergrad. Wash U MD PhD. Then he never did a residency, but then he did a Rhodes Scholarship at Oxford, working under this brilliant neuroscientist. And I said, "Bobby, why didn't you ever do a residency?" He goes, "Oh, I always knew I wanted to be a neuroscientist, but I'm the son of immigrant parents. They're from India, and they said if you don't get an MD degree, we're gonna disown you." He says, "So I got the MD degree for my parents."

Ameer Farooq  20:25

You know, your analogy between surgery and Miles Davis, as a jazz musician, is just brilliant and it's just so on point. And I think it highlights, for our listeners and for us, just how hard your road potentially has been, dedicating the time to do something that is increasingly rare. This skill set as being a surgeon scientist is a very rare kind of breed now, in 2021. And so, I think it is worth just noting again, how hard that can be. And, as you say, what an obsession you must have had to do this. So, can you tell us a little bit about what started your obsession with the microbiome? And now it's sort of like a popular thing for everyone to talk about, microbiome, microbiome microbiome. But it certainly wasn't, I'm sure, when you started looking into it, certainly not in the surgical literature. So, what started your obsession with the microbiome and how it affects surgical site infections and anastomotic leaks and all the things we're going to talk about later on?

JC Alverdy  21:33

Sure. I've told this story before. Sorry to the listeners, if you've heard it before. When I was a resident, I was on the pediatric surgery service, and it was a combined service between the University of Chicago and Michael Reese Hospital. And there was this child who was about 10 or 11 years old, a couple years ago, a couple of years prior to his hospitalization, had leukemia. Was given chemotherapy. Did well, was disease free. And then he came in with an infection and he had had his Hickman line stolen from the chemotherapy. But had no evidence of disease, as far as we could tell. He had a fever and he looked sick. I cared for him because we had a pull of the Hickman line in and at some point, we ended up exploring this kid because, between all the king's horses and all the king's men, nobody could figure out what was wrong with this kid. But he was clearly infected. Infectious disease came by, he's on five antibiotics, the usual story for somebody like this. He wasn't neutropenic or anything. And I watched his mother rock him while he was on a ventilator, as he started to deteriorate. The tubing hooked and the mother's got the kid in her arms, rocking him with an endotracheal tube and tubing hooked to the ventilator. And I watched her rock him to his death. You know, once that face of a mother is seen, it can't be unseen. It's just... it's different for everybody, we all lose people that we love in life. But when a mother loses a child, I think it's a whole different thing. And so, I'm like, that infection had to come from somewhere. The kid had nothing on his skin. Everybody looking up and down. CAT scans. Everything we could do to try to figure out what the source of the infection was. And we didn't even know what infection he had, because blood cultures were negative. And he was in multiple organ failure, dying of infection. So, I had this idea that, the human, who we are, we're animals. We have nasal surfaces, lung surfaces, guts surfaces. This live being is not sterile. So that some pathogen somewhere, or group of pathogens, is driving this kid into organ failure and sepsis. And so, I wasn't the first to think of this, this idea of gut-derived sepsis. That somehow, microbes within the GI tract have assembled into a community that's gone from being commensal organisms, symbiotic organisms, to bad actors. And there were a lot of people studying bacterial translocation, a lot of immunity and I'm like, that can't be right. And so, I started studying it. And I think you brought this up in the sort of, teaser document that you sent me. You know, why was I studying gut immunity? You know, everything was framed and still is framed as a binary, right? It's the bugs against the immune system. And so, if you've given antibiotics, you've killed all the bugs, so it must be the immune system. But it can't be that simple. So that's why in the lecture that I gave, I don't know if you guys heard it, the Nigro lecture, I said... I quoted a very preeminent scientist at Hopkins, Arturo Casadevall. And he says, "Virulence or harmfulness is neither a property of the pathogen, nor is it a property of the host, but it is a property of their interaction." So, I like to frame this idea that if you have two partners, who are married or living together, and the arrangement, the relationship's not working out. Is it partner A or partner B? Or is it the chemistry between them? Unless somebody's a frank abuser or some sort of horrible person, it's usually they're both nice people, just the chemistry doesn't work. And I think we're going through that with this whole COVID thing. Everyone wants to say, "Oh, it's a new strain you got, that's why you died or something. No, it's IL-6. No, it must be a snip in TNF alpha in your immune system..." It's just, and Arturo and I have talked about this, it's too difficult to disentangle this molecular hairball. It's got to be some kind of a relationship that's peculiar to the person. What is their…I don't know, their nasal mucosal mucus biochemistry versus the surface biochemistry and the spike protein of the COVID, of the coronavirus. You know, they align perfectly. And I actually, unfortunately, had a close friend who died of COVID, he was a vascular surgeon. He just got it and three weeks later, he was dead. And there's no explanation. He was not on any meds, he was perfectly healthy. Jogged. And you want to say, "Well, he must have gotten a bad strain", or "he was of Italian descent", he was born in the United States. "Oh, no, it was because he was Italian!" That's not right. You know, millions of Italians got it and they were fine. But some died, yes. Okay, but you can't individualize it. You know, you can't explain it. We do that in surgery a lot. At M&M, right? We explain away things. But there's so much uncertainty in what we do. Which is why they say when you come up with a new idea, it takes a surgeon 15 years to make a change in his or her practice.

Chad Ball  28:06

Yeah, that's such a such a great point. I'm curious, just given your background and your life's, career's work, did you see the pandemic coming ahead of time? Did you have a sense that we would be in a global crisis like this, and it would go the way it's gone?

JC Alverdy  28:28

No, definitely not. In fact, nobody did. There's a paper somebody sent me from 2007 that examined coronaviruses in bats. And it said something to the effect of, this virus because it's airborne and is spread by respiratory, and they did some work with it and said it has a lethal component to it. They said something like, this virus has all the raw goods to cause a pandemic. But they didn't say it's gonna happen, they just said it has all the raw goods. But I like to think, and I listened to a podcast by Sam Harris. I can't remember this woman's name, but she was from the University of North Carolina and she's a sociologist, brilliant woman. And she said the coronavirus pandemic is nothing more than a dress rehearsal for what is to come.

Chad Ball  29:30

Yes, absolutely.

JC Alverdy  29:32

Yeah. And I like to think of these things, even the microbiome and even anastomotically, these are diseases of human progress. We've progressed along a path in which we eat highly processed, high fat, low fiber foods. We're all vaccinated, we take antibiotics. We take too many antibiotics. 70% of the antibiotics used in the United States are used in animals, in their feed. There's a climate problem, you know. When you look back, it always seems, "Yeah, you know, this was ready to happen. We're just too stupid to figure it out." But there are a lot of TED talks and podcasts now predicting the next pandemic to be, I hope they're wrong. Antibiotic resistance, emergence in surgical patients. So, Ameer and Chad, we operate on a patient, straightforward case. Let's say it's even a noncontaminated, not even colon, elective colon, or gallbladder or something. But let's say, a hip operation or knee operation, and patients are dying of multidrug resistant bacteria that are not from the wound, necessarily. It's not a wound infection. Maybe it's some sort of bug in your nose, or in a crypt deep in your cecum. Or, I don't know, in your gums. I have no idea. I hope they're wrong. But you know, it's scary.

Ameer Farooq  31:17

It's such a complex topic. And I really want to dive into some of the stuff that you talked about in your Norman D. Nigro lecture, because it just was absolutely fascinating. But I want to circle back to one of the things that you just talked about, you mentioned, which is this whole concept of M&M rounds. And how problematic, our leanings and our learnings from that institution can be fraught with danger. And one of the things that you said in your talk was that M&M rounds are where we go to learn from the ignorance of experts. There are 2 different errors that we make, this between comparison fallacy and solipsism. Could you just summarize for the audience, what did you mean by that? In terms of the M&M rounds and those 2 errors that you talked about in your lecture.

JC Alverdy  32:05

Yeah, thank you. So, the between-group comparison fallacy is really how we compare two groups, let's say in a randomized control trial or even a retrospective study. And if we have a p value difference between the two groups, and I'll just use this since we're interested in anastomic leak. Let's say you have two groups and there are different surgeons. And one surgeon has an anastomotic leak rate of 18% and the other has one of nine. And the p value is less than 0.05. You're like, you see, your surgeon makes a difference. I'm like, it's the surgeon? It's the surgeon. Look, the only thing different between these two groups is the surgeon, and there's a difference. Like, that's interesting. So, the surgeon that you'd go to with a 9% leak rate, who's better, right? Oh yeah, he's better, she's better, no question. Look at the data. So why did those 9% in his or her hands leak? Well, you know, there's biologic variability, blah, blah, blah. Okay. You have no explanation, right? No. Well, those were fat patients. I go, all the other ones were skinny? All the other ones were nonsmokers? Well, though, we didn't account for the within group differences. Ah. Now, the surgeon that had an 18% leak rate, now you're saying he or she's a bad surgeon? Yeah, that's right, higher than this guy over here, go to another hospital. I'm like, okay. So, that means 82% of the time, he or she got it right, correct. Yeah. Well, so was that luck? Or they're having a good day that day and a bad day, the other. No accounting for within group differences. Only between group differences and mean values. And you and I know, all of us, Chad, Ameer, all three of us know that those two groups were not perfectly equal. Right? If you could, anywhere, University of Toronto, University of Chicago, wherever, you could say, we have the lowest infection rate in the region for, I don't know, hip arthroplasty. The patients would be standing around the block waiting to get in line to see you. But nobody can do it because everybody has leaks, everybody has infections. These problems are rare, thank goodness. But the explanations on the accounting within the group that's treated, within the group, not between the group, is not, we don't get to that root cause. Which is why in that lecture, I use the idea of an airplane misadventure or an unexpected landing of an aeroplane, or God forbid a crash. The FAA, the NSTA, they get in there and they take that whole thing apart, they get the recorder, they get the black box, everything. And they don't just come up with an answer in M&M, next case. They take some three, four, five months with a jury and a board of experts, a consensus panel, and then they write up the draft of why they thought it happened. Do we ever do that for anastomotic leak or a wound infection?

Ameer Farooq  35:33

I mean, I remember this video or this tweet that you put out, where you said you showed two videos to this group of surgeons. And then in the first video, you said, "Okay, well, this anastomosis leaked. And tell me what went wrong in this technique in this video." So, the surgeon said, well, they did this wrong, and there was tension and blah, blah, blah. And in the second video, you said, "This one didn't leak, tell me what went right in this video." And they said, well, it's clearly much better, technically much superior. And then you said, "Well, actually, it was reversed." The second one leaked and the first one didn't. I don't think what you're getting at is like this nihilism that, we can't fix these problems or that it's out of our hands. But in fact, that maybe, and I think a big thrust of your talk at ASCRS was just this idea that we don't know what really causes anastomotic leaks, because we don't really examine them in that way. I do want to ask you to explain the second thing, which is on solipsism. And then in the talk, you really outline in a very beautiful way, the research, I think, going back to the 50s, that illustrated the idea that bacteria and the microbiome actually have a huge role to play in anastomotic leak. So we'd love to hear that series, because you presented that so beautifully.

JC Alverdy  36:58

Well, thank you so much. So, to this first idea of video imaging. I frame it this way, and I'll say this as briefly as I can, if you took all the grants that went to the NIH, that got accepted versus those that didn't, and then you took the people that didn't get their grant accepted. And you say, now I'm going to show you all the grants that got accepted. I can bet you, having been on, I am on study section, a lot of people would say, "Oh, my grant's just as good as that. I can't believe you accepted that." Or, "Why did you do that? That's wrong. Mine's better." Just like if you apply, at least to the United States, to Harvard, Yale or Princeton, and you don't get in. And then somebody handed you all the applications of the people that got into those schools. You'd be like, "Well, I'm as good as her or him or whatever. I can't believe they rejected me. My GPA was the same, my SATs, blah, blah, blah." It's too hard to be a judge of things that you think you're objective about. Okay? In fact, impossible. And Herb Zeh, who's the chair at U Texas Southwestern, he said the OR videos, what did he say? He gave a talk and said something like, we're not alone anymore in that operating room. It's no longer the inner sanctum. There's a company called Black Box, by the way, a company that will video everything in the operating room. Now, Chad and Ameer, you can imagine that if somebody videoed everything that you did in the operating room. I mean, let's say eight cameras are in there. And then you hand it, let's say the patient had a complication, and you handed that over to somebody, they find something that went wrong. Why did you let that work? "Did you see that? That student bumped his elbow, or her elbow, against the IV pole, that's what caused the staph infection." You're like... you know, you'd be looking at these people going, people break scrub all the time, people bump into IV poles all day long, 90% of my patients don't get an infection. You can't almost level the playing field unless you look at all the videos and that's why I did that. And boy, did I piss off the people when I did that video on the leak. You know, they were mad at me. Right? Because I showed how fickle we are in our judgments. And that's the word solipsism. I learned it from Ben Iseman. And he used that once at a lecture he gave when he was a visiting professor here. And he defined that as something like, the self is all-knowing based on the accumulated experience that one has, right? So that's why I said, it's where we learn from the ignorance of experts. I didn't mean that in a derogatory way. Ignorance means lack of knowledge, right? These are the experts. So, when the experts say, must have been ischemia. Must have been ischemia, what the hell do I know? I'm just a first-year resident, I don't know anything. But we don't dig in enough and we should. And so, I told this in the Nigro lecture, that I honestly got interested in anastomic leak, only because a resident came to me, and she wanted to go to colorectal surgery and study, and she needed me to do a project. She loved my line of research, which was to show how bacteria can become in vivo activated express virulence genes and virulence exoproducts that can cause damage to the epithelium. And she wanted to incorporate that into something have to do with colorectal. And I said, how about anastomotic leak? It was really that, that we started looking at the literature of. But here's the way I frame it. And this will make it really simple for everybody. For our listeners. You can't have a wound infection without bacteria. It's not possible. They have to be there, or you don't have a bacterial wound infection. No bacteria, no wound infection. But bacteria alone, the scientific lexicon is necessary and sufficient. Bacteria are necessary to cause a bacterial wound infection. But they are – alone – not sufficient to cause it. Because we know we spill bacteria in there all the time, and we don't get an infection. So, there's something else. Maybe it's a seroma, maybe it's a hematoma. Maybe it's this Trojan horse hypothesis where the wound is beat up a little bit, and the bacteria from the gums and the nose and the gut find their way. Who knows? But no bacteria, no bacteria wound infection. It's not possible. But we know that bacteria are required, but alone, not sufficient to cause a surgical site infection. Same with an anastomotic leak. Bacteria are required when we inactivate these collagenases bacteria, you don't get a leak. When, in 1955, Isidore Cohen got rid of the bacteria by putting a catheter directly in there, no anastomotic leak, even though the anastomoses were ischemic. But alone, because they're there all the time, alone, bacteria are not sufficient. So, bacteria are necessary, but alone, not sufficient. Which is why technique is important to a certain extent. You want to be gentle with the tissues, sure. You want them to have a good blood supply. You don't want them to be under tension, etc. But those aspects and certain things we can't control, you go in there and, let's say, you reach down and there's a bulky exophytic tumor at the peritoneal reflectics stuck to the lateral pelvic wall, and you're digging around there for two hours to get it out. Let's say, you get into some bleeding, now you've got other things going on. So, it's not that it's, alone, the bacteria, but now you've created the environmental cues. Maybe a little hypoxemia, a little blood loss, a little tissue trauma. And now you take these perfectly two pieces of intestine and, let's say, you're three to five centimeters above the anal verge, you've taken down the splenic flexure, you consummate your anastomosis, two donuts, looks beautiful, inject your ICG, everything's wonderful. You irrigate, you scope. Leak test is negative. You're like, "yes", but it's all that other stuff. On top of maybe having pathogenic bacteria there that you didn't know about. So, without the bacteria, no leak. But without those other cues, those bacteria are not going to be activated to cause the leak. So, these are things where people have said to the "it's not bacteria, we give antibiotics, can't be bacteria, it's got to be something else." And that's why industry, and they still are focused on, this is a problem that we can mechanically solve. It's got to be the stapler height, the compression. Or with the ICG, it's got to be blood flow. But I have to tell you, most hypotension and hypoxemia occurs postoperatively, not intraoperatively. I'd like to see an ICG study where they gave it two days post op and three days post op and looked at islands of ischemia that developed as a result of, I don't know, some of the collaterals clotting off or some of the hypotension or hypoxemia causing... you know, we did a study, we published it, where we actually scoped patients intra operatively, before they went home and two weeks later. And I got to tell you, post op day three. Those things, they look beautiful in the OR. Post op day three, man, that circumferential line, it looks puckered, it can be effeminate, there can be little islands of ischemia. But you know, the body seals it on the outside, it adapts, things get better. What am I supposed to say, Ameer, Chad? 95% of the time? What's the leak rate? Is the leak rate 5%? Yeah.

Chad Ball  45:40

Yeah, exactly. I'm glad you brought that paper up. You know, that's a very popular paper in Canada. And we refer to it often. It's an absolute beauty. I think, maybe extending that then, the question is, where do we go from here to quote unquote solve these issues? You're right, I think we all concur, it's not always mechanical, it's not always environmental. It's this really detailed and complex interaction. But what do you see in a perfect world, the next decade or so, in terms of lines of investigations and great hopes to try and improve our quality outcomes again?

JC Alverdy  46:28

That's a great question. And I do think it's going to be to address... again, remember the microbiome, it's not even bacteria now, we'll call it the microbiome, plays a key and contributory and causative role in anastomotic leak pathogenesis and surgical site infections. Beyond intraoperative contamination, in terms of SSIs, and beyond tension ischemia technique. Now, all those things are important. You want to keep the OR environment sterile. You want to change your gloves if you've had a messy operation. Yeah, all good, I'm not complaining about that. And technique, I teach good technique. Technique is very important. Do the best job you possibly can. But until we sort of tease out what is the natural history of good healing, which we're launching our grant on now, we need to know, serially, when we endoscope patients, why one patient's anastomosis looks beautiful over the course of the two weeks of healing. Just like their external wound, right? Some patients, you look and you're like, God you can hardly see your wound. Other patients, you got that inflammatory ridge, it looks a little red, they're complaining of pain. They do fine, but they just don't feel the same. What is the difference there? Is it all bacteria? Is it the bacterial host interaction? And how can we interdict in that process effectively without, and this was part of the Nigro lecture right, without just killing everything that threatens us. Because it's not an evolutionarily stable strategy. So, I think the answer is, and both of you know this, is we have to have a period of prehabilitation, dietary prehabilitation, where we really start saying to patients, look, this waking up every day of eating three eggs, five strips of bacon and white toast and butter and then a burger and fries for lunch. And mashed potatoes, meatloaf and gravy for dinner, it's got to stop at least for a week before I operate. That's number one. And then we have to know what we change when we shift that diet to this prehab diet. Which is, I don't know, I'm making this up because I don't know the answers. But the answers are knowable, I just don't know the answers. When I give you a kale smoothie and have you lost 10 pounds and get you in a little bit better shape. Quit smoking, all the... I got to know what I changed, first of all. Not just change it. And then, I got to know as you progress along the healing process, whether I've used too many antibiotics, I've used the right antibiotics, and whether I needed a bowel prep in that situation or purgative cleansed, or I didn't. And I need to see with my own eyes and track with some molecular data. And then, when you say five or 10 years from now, I can have a patient come in and just like you draw an albumin level, or just like you draw a transfer level or have them see anesthesia and they do an ASA class or whatever. I'm going to just say, let me have a little swab of your nose and your poop. And let me probe for some antimicrobial resistance genes or bad actors in there. See how many good bacteria you have, versus bad. And I'll get back to three or four days. Run a custom PCR and say, you know, you have colon cancer, you're not obstructed, I need about a week or 10 days to change your microbiome to a more favorable position. It's not gonna take me long, you know. And I'm going to tailor your antibiotics in a different way. That would be, to me, the Holy Grail. Which is to say, I'm going to manipulate your microbiome to your benefit. But I got to know what I'm doing. Right now, it's like, hey, how about a probiotic? Yeah, I heard these kale smoothies are good for you. It can't be just that, you know? So that, to me, is the future and it will reduce our use of antibiotics, which we need to do. Otherwise, this is a dress rehearsal for what's to come. Just like climate change and just like the antibiotic, postantibiotic era, antibiotic resistance crisis we're in, we got to be ahead of this. We have to look at it as a headwind and we have to get ahead of it.

Ameer Farooq  51:12

That's, I think, an inspiring vision for the future. And to me, it ties together so many different aspects of what different groups are trying to do to try to improve outcomes. And, I think, represents a shift in the way that we think about surgery in a much more complex way that we have, up until this point. I mean, I think it's very telling that a lot of this initial work was done in the 50s and really gone full cycle in terms of bowel prep and all these kinds of things. And we're only now kind of coming back to it. So, I'm so excited to see the work that you're going to continue to put out and hopefully others take up that mantle as well and keep going. And, somewhat facetiously, people on Twitter, after your lecture, were talking about feeding all their patients preoperatively broccoli. So maybe that's what we all need to do too. It's been an absolute pleasure, Dr. Alverdy, to have you on the show. And we can't thank you enough for taking out the time from your incredibly busy schedule. If you could go back in time and give yourself advice as maybe a senior resident or chief resident just about to graduate. What advice would you give yourself, knowing what you know, now?

JC Alverdy  52:30

That's a really great question. You're absolutely right. I think, for me, it was always about thinking of what I can't do versus what I'm capable of doing. Right? So, like, you know, as you know, as both of you know, you know, going into an academic department of surgery is intimidating. There are a lot of really smart people there. And when I use that word solipsism, there were a lot, at least when I was training, there were a lot of authoritative figures. A lot of autocratic, authoritative figures in surgery who were giants in surgery. If they said, I don't know, radiation for rectal cancer is a bunch of crap, don't do it. You went, radiation for... you didn't read anything. You just went to. Dr. so and so said radiation is bad, we're not doing it. It's because they had that kind of, they sat at an authoritative podium. And I'll give you this quick anecdote because, a student of mine, who is an MD PhD student here, he met Charles Huggins, who won the Nobel Prize for prostate cancer, developing both a PSA test as well as understanding that prostate cancer is hormonally driven. He was a urologist here at the University of Chicago. He won it in the 60s or something, brilliant guy. And he said to him, he goes up to him and he goes, "Dr. Huggins", he goes, "I just want to know one thing, how do you win a Nobel prize?" And Dr. Huggins looked at him and goes, "You see all the smart people around here, you know, the people that you respect, the people that you think are gods and goddesses that know more than you'll ever know. You gotta look at them right in the face and you have to say, what you're saying about whatever it is, I don't know, DNA, whatever. What you're studying and what you're saying is true, is wrong. And I'm going to spend my whole life proving it." Now, what kind of confidence does that take? I didn't have that. That I would say, if you said what we think, don't be intimidated by the world view of others. And don't think, ah I don't have a PhD, I don't have enough knowledge, I'm not really a trained scientist. I can't ask that question. Don't think that of yourself, because it limits you. And I remember the Ashton Kutcher movie, where he was Steve Jobs and the head of IBM looks at him and goes, after Apple failed, the head of IBM looks at Steve Jobs, he goes, "When are you going to get in your thick head that nobody ever is going to want a home computer." I mean, how did he prevail after the head of IBM tells him he's not only an idiot, but the thing he's trying to develop, nobody's going to ever want. Go read some Nobel Prize winners, read their speeches, and every one of them, their NIH grant, their papers got rejected, their NIH grant, their postdoctoral advisors told them, "You're an idiot, that'll never work." That is true of the woman that discovered telomerase. Elizabeth Blackburn. That is true of the CAST CRISPR thing. That is true. So many stories, they'll tell you, "Yeah, you know, my chief told me, don't do that. It's a big mistake." So that's the answer. That's how I'd answer that. You know, listen to your inner self, not what anybody else tells you. Be confident, it's hard.

Ameer Farooq  56:40

You've been listening to Cold Steel, the official podcast of the Canadian Journal of Surgery. If you've liked what you've been listening to, please leave us a review on iTunes. We'd love to hear your comments and feedback. So, feel free to email us at [email protected] or connect with us on Twitter @CanJSurg. Thanks again.