Now nearly 3½ years into my first faculty position, I am deeply grateful to have the opportunity to balance a clinical practice in complex hepatopancreatobiliary surgical oncology with an academic career in basic and translational pancreatic tumor immunology, a balancing act characterized by many joys but also occasional moments of abject despair and anguish. Nonetheless, I strive every day to unify these two worlds into a seamlessly integrated mission of discovery and healing. To this end, I am often asked by students, residents, and fellows—many of whom seek the same joy in their eventual careers—how to make it all come together. My response to them is that the magic happens when these two seemingly disparate worlds collide…
I then go on to explain that this takes equal doses of (1) discomfort with the status quo; (2) intentional investigation; and (3) remaining vulnerable to serendipity. The latter is particularly important, because the reluctance to acknowledge the importance of serendipity—i.e., the “ability to apply sagacity to chance observation”1—in the creative process may spell disaster for even the most intentional of planners. I often give the examples of seminal scientific discoveries that are shaped by insightful (and obviously serendipitous) clinical observations. In the early days of immunotherapy development, a group of scientists—disturbed by the long-standing clinical enigma of a 20% objective response to checkpoint blockade in unselected patients receiving immunotherapy—examined the immune microenvironments of tumors from a large cohort of resected colorectal cancers. They found that exactly 20% of tumors demonstrated dramatically higher levels of tumor-infiltrating CD8+ cytotoxic T lymphocytes and activated CD4+ T-helper type 1 cells–features we now refer to as a “hot” immune microenvironment. Amazingly, almost all of these tumors were characterized by microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) and expressed higher proportions of inhibitory immune checkpoint receptors such as PD-1, CTLA-4, and LAG3.2 These data ushered in the era of biomarker-driven immunotherapy trial development ultimately leading to the first-ever tissue-agonistic FDA approval of anti-PD-1 antibodies in MSI/MMR-deficient solid tumors, changing the scientific world forever.
The three key ingredients for scientific success enumerated above were no less important in the seminal discoveries by Barry Marshall and Robin Warren of Helicobacter pylori-induced gastritis and peptic ulcerogenesis. Their critical breakthrough echoed Alexander Fleming’s discovery of penicillin, wherein their frustration with the inability to grow these ulcerogenic organisms in vitro resulted in a culture condition three times longer than their intended plan—ultimately revealing H. pylori as the putative bacteria responsible for inflammatory injury to the gastric mucosa. A daring self-ingestion experiment…and the rest is history!
When I started my laboratory, I knew that in order to develop a competitive scientific footprint, I would have to find the sweet spot of achieving scientifically what most other surgeons might not be able to, and developing insights surgically that most scientists would not have access to. Therefore, a guiding principle in my laboratory is that the best science must be driven by the most insightful clinical observations. When investigated deeply, and sprinkled with scientific tenacity, serendipity, and good fortune, these scientific discoveries can be translated back to patients. While not remotely on the scale of the aforementioned MSI/H.pylori discoveries, we recently published a manuscript in eLife which underscores most of these guiding principles (https://bit.ly/3Czcsit).3 I had noticed quite early in my experience treating patients with localized pancreatic cancer with neoadjuvant chemotherapy±radiation, that patients who ultimately demonstrated favorable pathologic response upon surgical resection (i.e., tumor regression) had marked reduction in their circulating neutrophil-to-lymphocyte ratios (NLR) during neoadjuvant treatment. Investigating this further, we found a striking correlation between NLR attenuation during neoadjuvant therapy and improved pathologic response, and proceeded to model these observations in preclinical mouse models where we ultimately uncovered a neutrophil-fibroblast-tumor cell IL-1β/IL-6/STAT-3 signaling axis underlying chemoresistance and immune tolerance in the pancreatic tumor microenvironment. Excitingly, these and other allied observations have laid the foundation for clinical trials utilizing anti-IL-1β therapies in advanced pancreatic cancer patients (Precision Promise NCT NCT04229004).
What have the experiences of the AAS community been? I would love to learn more—please share examples in the comments section below or on social media tagging this article!
In my humble opinion, the incredible potential of surgical science will be realized by discoveries at the intersection of serendipity and clinical insight. To trainees and aspiring surgeon-scientists everywhere, search for those magical moments that make you scratch your head, wonder if this observation has ever been investigated before, question the status quo, and go to the bench (or laptop) to immerse yourself deeply in the search for answers. And always remember to allow yourself to remain susceptible to serendipity that might unlock avenues to a long and fruitful academic career in service of patients and science!
- Campbell WC. Serendipity in research involving laboratory animals. ILAR J 2005; 46:329–331.
- Llosa et al., The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints. Cancer Discov 2015; 5 (1): 43–51.
- De Castro Silva et al., Neutrophil-mediated fibroblast-tumor cell IL-6/STAT-3 signaling underlies the association between neutrophil-to-lymphocyte ratio dynamics and chemotherapy response in localized pancreatic cancer: a hybrid clinical-preclinical study. eLife 2022 Sep 15;11:e78921. doi: 10.7554/eLife.78921.