Cell Biology Redux

Abstract

I came to cell biology from genetics because I found myself interested in understanding how things worked, not just why they worked. Although genetics is the most logical of all branches of biology, in the end, genes are merely placeholders for the complex choreography played out by the proteins, lipids, carbohydrates, and nucleic acids constituting a cell. This is the purview of cell biology. I take an expansive view of cell biology, defining it as a field that embraces all others equally and adopts whatever technique or approach it takes to unravel a mechanism or concept. Cell biology also thrives on what is illogical. Indeed, cell biologists are attracted to questions that seem to violate first principles arguments, established mechanisms, statistics, or laws of thermodynamics. Indeed, striving to reveal the logic behind phenomena that violate conventional wisdom is how to best identify profound new concepts. Ira Mellman and his dog Sophie during a hike on Mt. Tamalpais. See also Mellman (2009) . My decision to become a cell biologist came at a time when modern cell biology (i.e., molecular cell biology) was just beginning. The field was emerging from its largely descriptive origins in cytology and pathology, realizing that there were functions to be solved behind the enticing images from two decades of electron microscopy. At that time, the mechanism underlying what had seemed to be the thermodynamically impossible translocation of proteins across membranes had just been revealed, using a combination of creatively demanding assays that reconstituted these complex events in vitro. It seemed clear that analogous approaches could reveal the conceptual and mechanistic framework for a wide variety of other complex integrated reactions that defined the organization of the cell. I became seduced by the problem of how intracellular vesicular traffic was coordinated to organize the secretion of proteins that had been translocated across the endoplasmic reticulum, and how secreted proteins could be recaptured, recycled, or degraded by endocytosis. It was mostly the latter problem, endocytosis, that led me to work with Zanvil Cohn and Ralph Steinman at Rockefeller University and then to form my own lab with Ari Helenius at Yale University School of Medicine. Ari and I found ourselves in the fortunate position of being able to play a significant role in the discovery, conceptual definition, and even naming of the “endosome.” This was but one of many fundamental cell biological concepts, today already taken for granted, that were emerging in the 1980s and 1990s. Fundamental insights seemingly occurred daily. Sitting in Ari's and my shared office, Peter Walter (visiting from UCSF) identified the small RNA component of signal recognition particle by having an accidental conversation with Elisabetta Ullu (whose lab was down the hall). Elsewhere, our efforts were complimented by the work of many others who showed how coat proteins select individual cargoes for forward or retrograde transport, how SNARE proteins worked to specify individual membrane fusion events, how macromolecular transport occurred across membranes other than the ER, and many more such breakthroughs. These concepts were so fundamental that they were easy to articulate and, as a result, garnered great attention in many different branches of biology. Cell biology was, for that period, probably the most exciting field around. So much so, I found myself increasingly committed even to the communication part, becoming involved with the Journal of Cell Biology, eventually serving as its Editor-in-Chief. It is invigorating to work in a field that is vibrant and appreciated as such by colleagues in other fields. Reviewing and editing are key to this process and to the health of our community. They also help you learn and even guide aspects of a field that are far beyond what you can do in your own laboratory. New concepts rightly drove exploration of biochemical mechanisms. Inexorably, we became so enamored of mechanisms that their exploration became less driven by concepts and more by a desire to understand individual events in ever greater detail. On the one hand, this is a great thing and an activity that can and should be vigorously pursued for cell biology's next 50 years. On the other hand, although some will undoubtedly disagree with me, this development steadily separated cell biology from the quest for new and generally applicable conceptual breakthroughs. Our collective success has changed cell biology, making it less visibly exciting to those outside its borders. In the coming decades, I would like to see the original vitality of exploration and conceptual discovery restored to cell biology. Happily, I believe this can be, and indeed is beginning to be, easily accomplished. The justification for this comes not from a desire to again be a driving influence on the progress of biological and biomedical science. Rather, biological and biomedical science will benefit immeasurably if the logic and criteria that have long characterized cell biology are applied to more complex systems-based problems. What does this mean? Cell biologists must learn how to embrace the challenge of applying principles learned at the single cell level to understanding the functional organization of complex systems. The nervous system has long been fair game in this regard, and indeed, the discovery of SNARE proteins was to a large extent enabled by studying synaptic vesicle function. In contrast, despite a common origin and a wealth of fundamental concepts waiting to be harvested, the immune system has generally been eschewed as a foreign problem by most cell biologists (Mellman, 2007 ). Over the past decade, I have moved my own laboratory's efforts in this direction, and have found it possible to capture many fundamental concepts in the area of antigen presentation by dendritic cells by applying the most rudimentary of cell biological principles, but doing so as a cell biologist and not an immunologist. I believe our field must look for how an understanding of basic cell function informs these larger fields and embrace these fields as the natural extension of our efforts. Increasingly, the need to apply cell biological reasoning is being understood by those coming from other fields, yet their work is often not as sophisticated as many of us would like. Rather than criticizing or ignoring these efforts, cell biologists must seek to integrate them. For the many young scientists today who are trying to frame their own interests and scientific obsessions, pursuing this integration to provide conceptual understanding at the cell biological level represents fertile ground in which to plant one's career. Finally, there is the small matter of human disease, both understanding its mechanisms and trying to do something about it. Rudolph Virchow, in the 19th century, already understood that all diseases were cellular in origin, which of course defines the opportunity for cell biology to grow in its reach scientifically as well as to become increasingly relevant to society by embracing the study of disease mechanisms and therapy. My recent move after 25 years in academia to Genentech is testing this hypothesis, and I can already report that “it works.” Understanding disease and designing realistic therapeutic strategies represents a daunting and exhilarating scientific challenge, one that I find a cell biologist can contribute to in unique ways. Although the rise of genomics has been widely attributed as revolutionizing the process of drug development, as I mentioned at the outset of this essay, “genes are merely placeholders for the complex choreography played out by the proteins, lipids, carbohydrates, and nucleic acids constituting a cell.” Their association with a given disease state, cancer in the case of my studies, is informative but does not lead to an understanding of what to do in the absence of integrated knowledge concerning their functions at the cellular level. Whether they know it or not, many of my colleagues here at Genentech have become superb, if self-taught, molecular cell biologists. I would urge cell biologists currently in training to consider the cell biology of complex systems, human disease, and drug discovery as ultimate career goals. Your science can be both interesting and useful, and you will be more easily able to communicate your excitement to other colleagues, friends, family, and the world at large.