In a time of pandemic distractions and anxieties, it is easy to succumb to the tyranny of the immediate. Then an event happens to jolt the senses and trigger a flood of memories and broader reflection on those rare individuals who truly make a difference in advancing science and medicine and why they were successful. The death of Josh Fidler at 83 in Texas on May 8, 2020 was such a moment.
When superlatives are now too often diluted to describe the routine, the mundane, or the trivial, Josh stands as a true giant in cancer research for his pioneering insights into the metastatic process, the evolutionary dynamics of tumor–host interactions, and in revealing the daunting complexity of the tumor microenvironment as the principal challenge in the design of more effective treatments. The extravagant scale of tumor heterogeneity and the implications of clonal diversification in tumor progression for successful therapy demonstrated by his meticulous and painstaking research established much of the conceptual framework that has guided metastasis research, cancer drug discovery, and the design of new treatment strategies over the past half-century.
He published over 800 peer-reviewed papers and book chapters, co-founded the journal of Cancer Metastasis Reviews and served as President of the American Association for Cancer Research (1984–1985) and the International Society of Differentiation. Josh's status in cancer research is reflected in myriad prestigious honors, including among others, two NCI Outstanding Investigator Awards (1987, 1995); AACR's G.H.A. Clowes Memorial Award (1988); WHO Gold Medalist (1997); Bristol-Myers Squibb Award for Distinguished Cancer Research (1999); American Cancer Society Distinguished Service Awards (2004, 2013); Inaugural Fellow of the AACR Academy (2013), Fellowship of the American Association for the Advancement of Science (2007); and the American Society for Investigative Pathology Gold Headed Cane Award (2016). In his 36-year career at MD Anderson Cancer Center (1983–2019), the Institution honored him with the Ernst W. Bertner Memorial Award (1983), the Charles A. LeMaistre Outstanding Achievement Award (2004), the President's Award together with his wife Margaret L. Kripke (2007), and appointment as Professor Emeritus on his retirement in 2019.
An inventory of accomplishments and accolades attests to a productive professional career but often reveals little about the events and personal qualities that propelled such success and the networks of interdependencies, incentives, and impediments that shape the environment for research and the climate for acceptance of new ideas.
In the ever shifting cultural and ideological prejudices in debate about nature and nurture in shaping human performance and values, few would dispute that the lessons of survival in the face of existential threat(s) rank as potent architects and arbiters in both domains. Josh spent his childhood and adolescence in Jerusalem in the tumult of the formation of the State of Israel, the post-Holocaust waves of Jewish immigration, and armed military conflict, including the loss of his father in the 1948 War of Independence. Risk and resiliency were the omnipresent forces of adaptive endurance. I consider that these events were powerful influences on Josh's philosophy about life and career, his concern for family, friends and colleagues, and his deep commitment to reduce the toll of human suffering inflicted by metastatic disease.
He remained a keen observer of the geopolitics of the Middle East, took pride in his service in the IDF and the technological accomplishments and modernity of contemporary Israel. But as a first-generation immigrant to America (another bond we share), he was boundless in his praise and gratitude for the opportunities offered by U.S. education and the unmatched dynamism of the American research enterprise, achieving a Doctorate in Veterinary Medicine from the University of Oklahoma, followed by a PhD in pathology from the University of Pennsylvania under the mentorship of two icons of cancer biology, Peter Nowell and Irv Zeidman.
Although his entire research career was spent at leading institutions for human medicine, Josh considered his training in veterinary medicine, with its emphasis on comparative pathology and examination of commonalities in patterns of disease pathogenesis across species, to be an invaluable guide in shaping the intellectual eclecticism that was the hallmark of his approach to the study of metastatic disease.
The other legacy of his veterinary background was his shared passion with his wife Margaret for horses and the enjoyment of equestrian excursions at their Texas ranch. Sadly, it was an equestrian accident in Africa that inflicted a terrible orthopedic injury that eventually limited his riding activities later in life.
In the rich montage of experiences and accomplishments of Josh's career, two features stand preeminent in his approach to scientific challenges: never retreat from asking the research question that really matters, even when others may choose easier pathways to pad their resumes with nugatory publications; and never conform to the herd mentality of the moment if this deflects from pursuit of more difficult experimental questions. In honoring Josh with the MD Anderson Cancer Center's President's Award in 2007 the late John Mendelsohn captured these traits perfectly: “I consider Dr. Fidler as the chief gadfly at MD Anderson. He makes us think because he is a truly original thinker.”
The history of scientific enquiry shows that disruptive ideas do not have any easy gestation. Insights that create conceptual shifts that irreversibly alter the trajectory of a major field of research enquiry are met inevitably with initial denial and derision by the established order. Acceptance follows a predictable, and often protracted, three-stage evolution. First is the initial widespread and confident rejection of the new insights and their implications. As evidence accumulates, the second stage evolves into, “It's true but is it really relevant?” As broad consensus finally emerges, the mantra of the third stage becomes, “Of course it's true and relevant, but it's not new!” An inevitable fourth wave follows that confirms the aphorism that success has many parents as those uninvolved quickly lay claim to their own illusory contributions.
This concatenation in how ideas in science change is mirrored in the responses of the oncology community to the pioneering studies of Josh and Margaret Kripke on tumor heterogeneity at the NCI Frederick Cancer Center (1975–1983) and then at MD Anderson. Their seminal publications revealed that metastasis was a nonrandom event and that only a small fraction of clones within a malignant lesion was endowed with metastatic properties. Their sophisticated and technically demanding clonal analyses also revealed the sobering problem that continued geno-phenotypic changes in clones during tumor progression in response to the selection pressures imposed by the host immune system and/or therapy increased clonal “fitness” for metastatic spread and the emergence of drug resistance phenotypes.
These publications elicited the “clone wars” that pitted these new insights gained from the cell biology of metastasis against a vociferous and often vitriolic rearguard denial by some in the academic pathology community who sought refuge in Virchowian histopathologic criteria in which the ubiquity of abnormal cell morphology within malignant tumors was cited as surely indicative of the metastatic potential of all cells in a malignant lesion. As more studies validated the Fidler–Kripke observations on clonal heterogeneity in multiple human and experimental tumors, the initial stridency of denial quickly morphed into viewing clonal diversity as “obvious,” with predictable decline in the frequency of literature citations of these pioneering studies being seen as either passé or, one suspects, for many contemporary metastasis researchers papers never read.
The next phase in Josh's research innovation provided a biological explanation for the long recognized clinical observation that neoplasms arising in different organs and cell lineages metastasized preferentially to particular organs. This nonrandom process was not explicable by mere mechanical dissemination via the lymphatic or vascular systems. These patterns of selective metastatic spread were first described in 1889 by the English surgeon, Stephen Paget, who coined the term “seed and soil hypothesis” to explain these organotrophic patterns, likening the spread of cancer to airborne dispersal of plant seeds in which only those that land in the right “soil” will proliferate. Fidler's team, using the murine B16 melanoma, demonstrated the presence of clones in the primary tumor that would metastasize preferentially to particular organs. In my own collaboration with him in the 1980s, we demonstrated that membrane-bound vesicles released from clones with metastatic affinity for one organ could confer the same organ homing behavior on clones that would not ordinarily proliferate in this organ microenvironment. Without knowing it at the time we had stumbled on what has now become the vibrant research domain of exosome biology, in which exosomal transfer is now seen as a key intercellular communication pathway in metastasis, drug resistance, and in changing the properties of host cells to create a more receptive microenvironment to support the proliferation of arriving metastatic cells (“priming” of the metastatic niche).
Over several decades, the Fidler and Kripke research groups continued to highlight the complex interplay between tumor and host cell populations in metastatic risk and the crucial role of immune responses in the evolutionary dynamic of tumor progression (the three Es of cancer immunoediting: immune elimination, equilibrium, and escape), foreshadowing the role of future immunotherapies in cancer treatment.
The search for more effective therapies for metastatic disease was a logical extension of Josh's research on tumor heterogeneity. His creative intellect explored new approaches to targeted drug delivery using liposomal carriers for activation of tumoricidal macrophages. His research on host defense against metastatic spread revealed the protumorigenic effects of reactive astrocytes in both early and late stages of metastatic colonization of the brain and the disturbing role of astrocytic responses in promoting chemoresistance phenotypes in CNS metastases.
Transparency and sharing of data, research materials, and reagents should be a core tenet of scientific enquiry and collective research progress. The record reveals, however, that misplaced competitive instincts in the research community often detract from this ideal. Such obstructions were anathema to Josh. The Fidler laboratory was a generous supplier of numerous cell lines and metastatic clones to investigators around the world. Research publications using B16 melanoma clones sourced from his laboratory at MD Anderson are still among the most cited in the metastasis literature.
Josh's research philosophy in confronting the multidimensional complexities of metastatic disease might best be summarized as, “It's the biology, stupid!” He abhorred the reductionism of molecular biology. As he often remarked, the term “molecular biologist” is an oxymoron because too few know any biology and the narrowness of their education and training leaves them marooned in technology-centric silos that constrain their experimental horizons and their careers. These sentiments were voiced more in sadness than cynicism. Josh was quick to embrace the impressive analytical tools of leading edge molecular science in his research but was fierce in his demands that the data generated always be interpreted through the holistic lens of systems-based biology. In turn, the molecular biologists who were fortunate to join Josh's group benefited enormously from his role as educator and mentor in the need to look at the “big picture” and understand the dynamics of tumor–host interactions in the search for improved therapeutic interventions.
Systems-based approaches to the study of disease pathophysiology must, by definition, be transdisciplinary, integrate diverse specialized expertise, and analyze events across multiple spatial-temporal scales, ranging from real-time molecular signaling pathways to patient care. The breadth of Josh's scholarship, his quick assimilation of advances in analytic technologies, and changing paradigms in clinical care are reflected in the diversity of scientific and clinical skills, international backgrounds, and the network of collaborations that came to comprise the Fidler laboratory “alumni.” The term “family” might be more apt. Josh and Margaret created an environment of warmth, fun, support, and generosity that transcended the confines of the laboratory to create friendships and family ties sustained long after team members departed from MD Anderson, creating a legacy of a shared sense of being part of something special and a global diaspora of talent dedicated to Josh's goal of the conquest of metastasis.
No commentary on Josh Fidler would be complete without reference to his superb sense of humor. Time spent with Josh and Margaret, whether in the laboratory, at conferences around the world, or in their home was a roller coaster of intellectual passion punctuated by a constant stream of jokes from Josh. His endless comedic repertoire to fit every occasion ranged from the Talmudic to topical jokes worthy of any late-night TV show host. Humor was integral to his leadership. It uplifted, inspired, and was a key element in building the culture of egalitarian collegiality, shared purpose, and loyalty in his ever-expanding research group at MD Anderson.
Even with deserved accumulation of honors for his research, his penchant for self-deprecating humor provided a counterweight to remind everyone that the goal to improve treatment of metastatic disease was still unrealized. His modesty was matched by his distaste for conceit and the delusional arrogance sadly still too prevalent in academic research. The combination of his creative wit and pragmatism could be marshaled instantly to puncture pomposity and self-aggrandizement with stiletto accuracy.
I and the many in the cancer community who reached out to Margaret on the news of Josh's death to convey our condolences view it as a privilege to have worked with, learned from, and enjoyed the friendship of an individual of vision, boldness, demanding standards, buoyant optimism, untiring energy, humor, kindness, and generosity as both mentor and leader.
These perspectives on Josh can best be distilled in the context of a quote from the legendary UCLA basketball coach, John Wooden: “Be more concerned with your character than your reputation, because your character is what you really are, while your reputation is merely what others think you are.….the true test of a man's character is what he does when no one is watching.” Josh might not have been eligible to join the varsity basketball team, but he met Wooden's standard for how to live and membership of the “All-Star” team in cancer research.
Josh is survived by his wife and longtime collaborator, Dr. Margaret Kripke, who served as the founding chair of Immunology at MD Anderson and subsequently its executive vice president and chief academic officer. He is survived by his daughters Morli Josza of Palm Beach, FL, and Katherine Kripke Tsela of Washington, DC, his brother and sister-in-law Yaron and Talia Fidler, and grandchildren Eden, Evan, and Jake Josza.
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