Profiles in surgical research: John Alverdy, MD, FACS

Editor’s note: The Bulletin is collaborating with the American College of Surgeons (ACS) Surgical Research Committee to present a series titled “Profiles in surgical research.” These interviews are published periodically and highlight prominent surgeon-scientist members of the ACS.

John Alverdy, MD, FACS, is a leading surgeon-scientist with a focus on the molecular basis of surgical infections and the gut microbiome. Dr. Alverdy is the Sarah and Harold Lincoln Thompson Professor of Surgery and executive vice-chair, department of surgery, University of Chicago, IL. His research has received continuous National Institutes of Health (NIH) funding since 1999, and he has mentored many postdoctoral fellows, surgical trainees, and colleagues. Dr. Alverdy has served in leadership positions at many national organizations. He was the 2016 president of the Surgical Infection Society. He presented the I.S. Ravdin Lecture in the Basic and Surgical Sciences at the ACS Clinical Congress 2017, and he received the American Surgical Association’s Flance-Karl Award in 2018 for his groundbreaking work in surgical infection pathogenesis and microbiome research.

Dr. Alverdy graduated from medical school at the Autonomous University of Guadalajara, Mexico, and spent one year at Loyola University Chicago Stritch School of Medicine, Maywood, IL, and then completed a surgical residency at Michael Reese Hospital, an affiliate of the University of Chicago at the time. He completed a surgical research fellowship at the University of California-San Francisco (UCSF) under the mentorship of George F. Sheldon, MD, FACS, ACS Past-President.

Dr. Alverdy was interviewed by Dr. Emamaullee in June.

How did you decide to go into a career in medicine?

My story is very nontraditional, and if I have had any success, it has been against all odds. If anyone looked at my background, they might think “this certainly is the road less traveled to end up as a tenured professor at University of Chicago with 20-plus years of NIH funding.” I was a Spanish major as an undergraduate with a minor in biology. My love of language and travel sent me on a path to foreign affairs schools with the intention of becoming a diplomat. I had little interest in becoming a physician except for the fact that my father, a dentist and son of an immigrant, insisted I go to medical school. I recall the day I spoke with my advisor, who felt that graduate school in biology would be my best bet to successfully compete for admission to an American medical school. Ironically, I had a strong distaste for biology, so being relatively fluent in Spanish, without applying to any American medical schools, I headed off to medical school in Guadalajara for three years.

My love of science grew as I began to take care of patients and recognized that many problems in medicine remained unsolved and their pathogenesis eluded explanation. I started seeing horrible infections inexplicably develop. At the time, very few surgeons were studying surgical infections at the molecular level. I completed a research sabbatical at UCSF, where I studied under immunologists and in a surgical lab that was interested in infection pathogenesis during parenteral nutrition. In the lab and during my early years as an independent investigator, I discovered that parenteral nutrition impairs local mucosal immunity in the gut. Yet I felt that this line of inquiry was not worth pursuing because it would just end up solving an immunologic puzzle, not a clinical problem.

What really changed the course of my work was realizing that a deeper molecular issue is at play in surgical infection. Yet prior to actually performing experiments, I spent many hours and days participating in conversations and drawing on napkins with world-class basic scientists at the University of Chicago. These experiences gave me the opportunity to think about problems in the most fundamental way. It was not so much the technical expertise that made the difference, as the method of thought.

Surgeons have the advantage of being outstanding experimentalists. Where we lose ground is translating our ideas into real, testable hypotheses and generating the molecular and mechanistic detail to prove their plausibility. Sometimes this situation occurs from a lack of opportunity, but mostly it is due to distraction. That distraction is the operating room (OR), where the seduction of instant gratification is often hard to resist. After all, who doesn’t like standing center stage in a theater as the lead actor?

Take me back to the future diplomat who ended up in medical school in Mexico.

I ended up there somewhat impulsively because I could live in a Spanish-speaking country and thought it might be an adventure. The admissions criteria were less stringent there, and it was a natural funnel for U.S. citizens to study abroad. Although not the issue then that it is now, I witnessed health care disparities firsthand in a way that was real, personal, and shocking. Seeing severely ill children being turned away from a public hospital was life-changing. One of my mentors said to me when I was a resident, “Guadalajara was your nutrition.” At the time, I did not know what he meant, but I think he was telling me that my experience there made me realize the grave impact that disease has on a human and on a community at large. For some reason, I felt compelled to understand, not just treat, serious surgical infections.

When I returned to the U.S. for my residency in a program affiliated with the University of Chicago, my professors and mentors recognized a hidden talent in me. My program director at Michael Reese, Charles L. Rice [MD, FACS], said, “You are too smart to just finish clinical surgery, so you are going to have to spend some time in the lab.” He gave me the choice of going to UCSF or Harvard [Boston, MA] and agreed to provide funding. This was in 1982, after my second year of residency. Back then, you just did what you were told. I went to UCSF, and George Sheldon, who ran the NIH research program there, mentored me and, at the end of my stay, wrote a letter to my program director stating, “This is the best surgical research fellow I’ve had in all my years here.” Honestly, I didn’t know how that could be, although I did a remarkable amount of work, collaborated with immunologists at UCSF, and made discoveries that were unexpected and exciting. Dr. Sheldon’s confidence, Dr. Rice’s mentorship, and the findings and publications I produced during that time made me think that I had an untapped talent for research.

When you learn about the proportion of surgeons who actually end up doing high-quality research and getting NIH funding, it can be disconcerting. Hearing your story will give people inspiration and hope that they can fight the uphill battle to try to do this, particularly in an environment that is so reimbursement-focused, resulting in decreased institutional support and increased clinical demands.

I often wonder if it is the institution’s demand for clinical productivity or the individual’s demand for clinical excellence that drives this problem. I have the utmost respect for surgeons who primarily function as master clinicians. That said, when we consider what it takes today for our citizens to become successful surgeons in an academic medical center that is charged with attracting complex patients in a competitive and mature marketplace, it is daunting.

This journey begins with four years of a near-flawless academic record at an undergraduate university, competitive selection at a U.S. medical school, and then seven years of general surgery to compete for a top fellowship. What we continue to ignore is that we have the longest, most rigorous and selective training process to become a specialty surgeon in the world. Among this group of cognitive elite, free markets demand an omnipresent service line, results that are transparent and cost-efficient, and patient satisfaction scores that remain within the top decile nationally. These demands are not being imposed by the department of surgery or the dean. It is the marketplace that demands clinical excellence on a grand scale, and the personal demand for excellence is simply a common trait of trainees. Our most intellectually gifted surgeons certainly are capable of competing for NIH funding. My personal experience is most of them simply do not want to do it, primarily because they feel they should not be doing it.

Today, a career in basic science investigation with sustained NIH funding is no longer a part-time job. It is not the same as being a high-volume surgeon in a high-volume institution. In a world with an ever-growing appetite for certainty, a career in basic research, especially for a surgeon, involves having an appetite for uncertainty. My opinion is that today’s mantra of mandating a culture of safety is spilling over into the career structure. A tenure track appointment to perform basic research with the expectation of sustained extramural funding, in my opinion, is no longer perceived as “safe.” Framing it simply as an issue of protected time, mentorship, and money also is incorrect. We need to dig deeper.

Typically, physicians receive their first R01 grant between the ages of 42 and 44. The chances of an MD getting that R01 refunded in the competing renewal cycle are less than 40 percent. As surgeons are increasingly trained to diagnose and treat with the growing demand for certainty, we are now asking our most qualified and intelligent graduates to embrace uncertainty and consider a career as a surgeon-scientist. One only has to think about the number of negative laparotomies presented at morbidity and mortality conferences 20 years ago and compare that percentage with today to understand that a fundamental change has occurred in our demand for clinical excellence. Today, all of medicine demands an unprecedented level of certainty, and that same ethos has spilled over into one’s career trajectory. Surgical science is not dead. It has never been more exciting. Unquestionably, one has to be well trained and properly resourced, but that is not enough. Millions of dollars are dedicated to incentivize faculty to do research, and most of the money spent results in abject failure. There is a dimension to a successful research career in surgery that cannot be precisely defined. Passion and curiosity do not describe what it takes to be a successful surgeon-scientist. It takes much more.

What are the key traits of a successful surgeon-scientist?

Biologist Edward O. Wilson said the key to great research is knowledge, obsession, and risk. Of course, one has to acquire enough knowledge and training and be smart enough to recognize the unmet needs and important questions in one’s field of interest. But obsession, not passion, is often what is needed to overcome the obvious risk associated with focusing on a research question that will require years of dedication and persistence in the face of constant grant and manuscript rejection. The minute that this course of action is perceived as jeopardizing other aspects of one’s professional life, the certainty principle is likely to kick in. Again, it’s easy to blame the chair, the dean, and the NIH. The demand for clinical excellence is inexorable. Just as we demand safe air travel, the expectation for high-volume, expert surgeons doing surgery in high-volume centers, and for structured curricula in training that leads to mastery of core competencies, unconsciously we are voicing our intolerance of uncertainty. No amount of protected time or training guarantees a successful career as a surgeon-scientist. But an obsessive drive to understand a complex problem, a rich research environment, and an imagination insensate to risk are all steps in the right direction. Physicist Richard Feynman said in science you must delude yourself, because if you consider your chances of finding something really important, you will be defeated from the outset.

Throughout our training, we strive for academic excellence, to be the top 1 percent. The leadership wants to build a research presence and be recognized as a top 25 NIH-funded department of surgery, but it is a foggy concept without a discrete process or framework for support. How can we reconcile this problem?

It does seem disingenuous on the one hand to aspire to greatness based on NIH rankings, especially if it is based on nonsurgeon PhDs holding much of the funding contracts. On the other hand, research infrastructure is expensive and if fewer surgeons in a department are willing to do it, outsourcing seems to make business sense. In my opinion, most major university medical centers are treasure troves of outstanding scientists who can be engaged to become key collaborators with surgical faculty. The operative word here is “engaged.” Surgeons are great experimentalists because of our rich clinical experience. But intellectually engaging a brilliant basic scientist to invest the time and activation energy to generate what would be considered exciting preliminary data that will withstand rigorous review and critique is another matter. Engaging such a collaborator is like dating; it is a courtship of intense intellectual engagement for the necessary chemistry to develop between you and a top scientist. This requires a deliberative process and time. One cannot simply pitch an idea or drop off samples and expect the other party to do the work. Often, departments will hire basic scientists to become independently functioning tissue engineers or immunologists without the need or expectation that they become engaged with faculty. Perhaps this is what you are referring to, which in my opinion is unsustainable.

When you accepted your first faculty position, were you given protected time, funding, and space?

My first job was with Gerald Moss [MD, FACS], chair of the Michael Reese Hospital. David Skinner [MD, FACS] appointed me as assistant professor when I graduated in 1986. Dr. Moss said, “I have a job for you. Your job is to seek truth.” I did not have any specified protected time. I functioned as a general surgeon and intensivist. I made research time a priority, but no one was tracking my time but me. Back then, you could roll out of bed and make your salary because we were collecting 80 cents on the dollar. Both my chairs told me that I had five to seven years to be known for something, and that my peers and elders needed to be able to say that this is John Alverdy’s original work. I worked really hard in the lab with little consciousness of how my time was being split. I knew I wanted to be both a competent and safe clinical surgeon and a successful scientist. I read a lot, had long conversations with brilliant scientists with whom I frequently scribbled on napkins, and realized that truly original science needs to be methodologically elegant with results that are unobvious. To succeed, you need to be inspired by great scientists and find a way to regularly engage with them. This perhaps is the hardest thing for a surgeon, because we tend to be impatient, distracted, and expect others to do the grunt work. At the same time, it is important to remain respected and competent in the OR. The key is not to be seduced by it. Therein lies the ruse.

What was your first significant breakthrough?

My first big discovery was to demonstrate, for the first time, that intestinal bacteria sense host stress, such as what occurs following injury, and then respond with enhanced virulence. At a time when everyone was studying how the host immune system responds to bacteria, I asked, “How do bacteria respond to the host?” My thinking was that pathogens are present in our patients all the time, so something about surgical injury must trigger them to express virulence. I showed that bacteria sense the physiologic stress of surgery by binding soluble compounds released by host tissues that transduce their quorum sensing resulting in virulence activation.

When I first pitched this idea, several immunologists said I should use mutant strains of bacteria and determine how loss of virulence pathways affects the immune response. I, however, decided to focus on the bacteria, reasoning that they were here first, and they must have evolved information processing systems to be able to sense the state of wellness or peril in the very host upon whom their survival depends. I had a couple of great conversations with scientists at the University of Chicago—James Shapiro [PhD, professor, department of biochemistry and molecular biology] and Robert Haselkorn [PhD, Fanny L. Pritzker Professor Emeritus, department of chemistry]—who advised me to make reporter strains so that I could track their en vivo virulence expression in mice exposed to surgical injury. They sent me to see Everett Greenberg [PhD, then professor of microbiology] at the University of Iowa [Iowa City]. Dr. Greenberg and I spent the entire afternoon in conversation. He immediately understood the importance of the work and put me on course to make, what was a big deal back then, GFP [also known as green fluorescent protein] reporter strains tagged to key virulence elements in Pseudomonas aeruginosa. This was in the 1990s. I also hired an amazing scientist, Olga Zaborina, PhD, who created reporter strains. It took the better part of a year to make it work, and the entire hypothesis was a gamble.

That must have been exciting. Did this support your first grant submission?

It was. We demonstrated that when Pseudomonas aeruginosa was present in the gut of a surgically injured animal, it activated its virulence circuitry and expressed toxins in contrast to strains placed in sham operated mice that remained deactivated. We then began to identify the soluble elements released into the gut that transduced the quorum sensing signaling system using reporter strains and in vitro conditions. Once the preliminary data were solid, my first R01 submission received a 0.8 percentile score with laudatory comments such as, “This is a complete departure from the way we think of infection and this PI [principal investigator] has created his own field of investigation.”

What was the secret? I just wanted to see things as they really are. I did not accept that serious infections were just a random encounter with a very bad pathogen. Patients are exposed to them all the time. One also has to be willing to intensely engage with inspirational scientists who force you to think with an annoying level of detail and rigor, especially to a surgeon. Finally, you must enjoy writing. You must see your grants as your magnum opus. To me, it’s all about imagination against the backdrop of scientific rigor. What’s the best way to train for this? Miguel de Cervantes and J.R.R. Tolkien, to start with. You get the idea.

I see people fail because they get pulled into laboratories that are highly resourced but somehow get orphaned into a line of reasoning that neither interests them nor aligns with their conceptual framework of the surgical problem. They feel unaligned, and the collaboration misfires. Being able to convince a laboratory to veer off course and commit resources and personnel to test your idea can be very tricky, if not impossible. As physicist Max Planck said, “Science advances one funeral at a time.” For a surgeon to be able to model the disease process she is most excited about, there is a fine line between abjuring the line of reasoning of an established scientist in the field and convincing them to test a novel hypothesis. Here is where creating chemistry between you and your collaborator comes in, mixed with knowledge, obsession, and risk.

How do we inspire future surgeon-scientists?

The operative word is “inspire.” In my 25 years at the University of Chicago, I must confess, our applicants and trainees are among the most brilliant and accomplished scholars I have ever seen. However, to enjoy a research experience such that one is willing to dedicate their life to it, one has to be willing to embrace more improvisational jazz than classical music. A foundation in classical music and music theory is important, but there is another dimension to improvisation that eludes explanation. Some people come into a lab and leave thinking, “I hate this! Nothing works, the blots don’t work, the antibodies suck.” Others find work-arounds and create their own music. Some of the greatest surgeons we are inspired by are those who are light on their feet, imperturbable, and great at improvisation. I guess what I am saying here is we have yet to figure out how to develop a core curriculum and incentive package that will produce the next Judah Folkman, Alfred Blalock, or William Halsted [all MD, FACS].

Do you believe that type of curiosity and abstract thinking is an inherent personality trait?

Do you have to be smart? Yes, you have to be smart. But how smart is enough, and how much do creativity and imagination play into a successful research career? Obviously, there is a magic blend somehow in there. Others have made analogies between science and music. The most masterfully trained classic musicians usually will never create an original composition. Taylor Swift never attended college or music school and can write innumerable songs with three simple block chords that play on forever. Try writing a hit song or try playing Rachmaninoff’s Prelude in C-sharp Minor—they are both really hard—and both are really different things. I guess the question is whether a sustained extramurally funded research surgeon can be “trained” or “incentivized,” or is it an emergent property?

It’s similar to the process of selecting surgical residents by board scores and the like. People want a cookbook recipe for the perfect surgical resident. In reality, each candidate is a little different.

I agree. Today, it seems that hard quantitative credentials overplay their hand in the selection process for residency. However, in a world that capitulates to the power of numbers, it is a hard trend to stop. My daughter is in medical school, as are many of my colleagues’ children. The emphasis on step one of the boards has shifted the focus from attending class to studying independently to hit the 90 percentile. I am certainly no expert on medical or surgical education; however, it may be time to consider what it is in academic surgery that we are trying to produce in the long run. Our business is the education and training of competent and responsible surgeons. However, discovery also is our business, and we cannot simply shift this core mission to nonsurgeon-scientists.

Have you had any big setbacks or challenging times along the way?

Most definitely, and this story is an example of the capriciousness of science and the critical need to improvise. For one entire year, we could not get our mice to develop sepsis following exposure to Pseudomonas when for over five years, mice would routinely die at a specified inoculum of the pathogen. We would inject huge doses of bacteria and all the mice looked perfectly fine. Of course, it was 2005, the year I needed to resubmit my NIH grant for competitive renewal. After months of troubleshooting, I stopped all experiments and visited several prominent infection-focused investigators in the Chicago area. One prominent investigator at Northwestern University told me she had the same problem with another lethal pathogen. After years of work and analysis, she found that the mice were being housed in a different room than the year before. It made all the difference. She decided she would figure it out with good science and after tens of thousands of dollars spent on sequencing mouse genes, she could not find the answer. So she put the mice back in the old room, and everything worked as expected. Because our focus was on gut bacteria, I imagined that something was changing the mouse’s microbiome and was programming the immune system in a unique way. Eventually, we got through it by studying how the microbiome is affected by environmental stress and how those changes affect the immune response to pathogens. This became the focus of my last competing renewal that received a very high score on first submission and was funded. I have learned that science is a process, not a result. It is frustrating and challenging and one has to be imperturbable because it’s too tempting to quit. It can be very frustrating to a surgical personality.

What can we do as a community to support surgeon-scientists in the next generation?

Leadership needs to support surgeons engaged in molecular-level science in a way that provides them freedom to explore and operate. The challenge is managing the opportunity costs when they are traveling and not providing reimbursable services. Leaders need to provide guidance, track progress, and help manage failures. Not every chair or section chief knows how to do this from personal experience or training. The operative word here is, again, “inspire.” Institutions, departments, chairs, and section chiefs need to inspire faculty to do molecular-level research. Their efforts need to be perceived as genuine and with the proper investment of time and money. We also need to recognize that not everyone can do research nor should they do research just for the sake of doing it. Although this discussion is beyond the scope of this interview, as a community, we need to gather and examine exactly what we are doing right and what we are doing wrong. Personally, I think the answers are right in front of us.

What has been the key to your success?

For reasons I do not fully understand, perhaps unencumbered of formal training as a scientist and thus not particularly wed to a canonical method of thinking, I was able to see things that others could not see. I have always been in awe of brilliant scientific thinkers such as Richard Dawkins, FRS, FRSL; E.O. Wilson, PhD; Fred Ausubel, PhD; and James Shapiro, PhD. Yet living up to the rigor that these scientists imposed on themselves to advance their theories is another matter.

My success could be summed up as having an imagination that allowed me to become a great experimentalist who could model surgical biology in a way that engaged the help of great scientists. I was lucky enough to have landed in, and survived in, a world-class research university surrounded by such scientists. But most importantly, I took the time and the risk to develop the intellectual chemistry required for one to test novel hypotheses and carry them out to their successful completion. This has to be done without the distraction of the OR but without ignoring it; otherwise, you will lose your biologic compass. Finally, you have to be in a department of surgery that rallies around you and is supportive of your role as both scientist and surgeon. In that regard, I have been both lucky and fortunate.