Abstract
Cell biology is the study of the structure and function of the unit or units of living organisms. Enabled by current and evolving technologies, cell biologists today are embracing new scientific challenges that span many disciplines. The eclectic nature of cell biology is core to its future and remains its enduring legacy.
As an undergraduate student, my answer to the question “what is cell biology?” was fairly textbook. Cell biology is the study of the structure and function of the unit or units of living organisms. Intrinsic to the question of what is cell biology today is the more fun and engaging question: what are the open challenges for cell biologists, particularly regarding the emergence of fields such as microbiome studies. Here I outline one open challenge: deciphering the complex interactions between commensal microbiomes and host tissue.
While I was in college, I would have said the most exciting questions in cell biology focused on organelle biogenesis and that the ultimate challenge for cell biology was to assemble a nucleus, endoplasmic reticulum, or endolysosome in a test tube. The shine hasn’t faded from these questions for me, but graduate school provided me with a reality check into the complexity of such undertakings.
Yale’s Cell Biology and Immunobiology departments, and the faculty there that mentored me—Ira Mellman, Jorge Galan, Peter Cresswell, and Norma Andrews, whose expertise spans cell biology, immunology, and host–pathogen interactions—influenced the questions that fascinated me during graduate school and beyond. As a graduate student in the Mellman laboratory, I studied macropinocytosis and how dendritic cells developmentally regulate this form of endocytosis to control antigen uptake. Findings from Alan Hall’s laboratory that Rho GTPases regulate cell migration, morphogenesis, and polarity (Caron and Hall, 1998) and from Jorge Galan’s laboratory that Salmonella type III effectors regulate host Rho GTPases for invasion of the intestinal epithelium (Chen et al., 1996; Hardt et al., 1998; Fu and Galán, 1999) suggested that Salmonella might shed light on how dendritic cells control their own membrane ruffling and macropinocytosis. With Ira and Jorge’s mentorship and the use of Salmonella mutants and microinjection, we gained some insights into how dendritic cells use the Rho GTPase, Cdc42, to developmentally regulate endocytosis (Garrett et al., 2000).
These salmonella experiments were the start of my interest in transkingdom relationships. Bacteria have taught and continue to teach me about cell biology and immunology. For my postdoctoral work, I had the privilege to train with Laurie Glimcher, whose laboratory has made seminal discoveries in the molecular pathways that regulate CD4 T helper cell development and activation as well as the molecular pathogenesis of osteoporosis. I came to her laboratory to deepen my knowledge of immunology and mouse models. Her scientific fearlessness and incisive intellect nurtured my developing interests in the gut microbiota. I was fortunate to receive additional mentorship from two microbiota innovators and experts, Jeffrey I. Gordon and Andy Onderdonk, during my postdoc years. The fields that I studied as a graduate student and postdoc and the expertise of my mentors spanned cell biology, biochemistry, host–pathogen interaction, microbiome studies, cancer biology, and immunology. These exposures and broad training are reflected in the wide range of scientific questions that my laboratory tries to study. The questions that stoked my interest in cell biology (e.g., how organelles assemble and maintain their size and shape) are quite similar to the questions that sparked my interest in the gut microbiota: e.g., how does a gut microbiome assemble; what factors shape its size, composition, and organization; and how does it change in response to a perturbations like food, antibiotics, immunotherapy, infections, or aging of its host? The gut microbiota is in many respects a multicellular network and has even been referred to as a “forgotten organ.” Bacteria, archaea, and fungi are all cells, but is the study of the microbiota cell biology? For me this raises the question of when cell biology emerged as a discipline.
Susumu Ito, professor emeritus at Harvard Medical School, who has had a career in cell biology that has spanned more than six decades, told me that in the 1970s, departments of cell biology were born from departments of anatomy and physiology. Just as cell biology emerged from these fields, it is continuing to change with the times. More recently, systems biology departments have emerged and often are enriched with cell biologists. Synthetic biology appears to be the next wave that is sweeping up many cell biologists. These shifts in cell biology mirror the many complementary conceptualizations of the microbiota—a tunable, engineered circuit or network, a compartmentalized cell, and an organ (Fig. 1).