Google maps of the cell: controlling intracellular traffic flow and direction

As a prologue to my presentation in the Symposium “Google Maps of the Cell: Controlling intracellular traffic flow and direction” at the 2019 ASCB|EMBO Meeting, I’d like to discuss my aspirations for the field of cell biology. In the book Consilience, E.O. Wilson reminds us of one of the most important aspirations in the sciences—the integration of knowledge across fields and scales: “The ongoing fragmentation of knowledge and resulting chaos…are not reflections of the real world, but artifacts of scholarship.” When knowledge can be linked across different fields of scholarship and consilience is achieved, a scientist can see past the phenomenology to achieve a deeper understanding of the underlying rules. And all of a sudden events that might appear very different—like an apple falling, or a sunset—can be singularly explained by the same underlying force, gravity.

The field of cell biology started with the use of electron microscopy and descriptions of subcellular structures that stained well with these methods, most notably membrane-bound organelles. These early descriptions created the framework for modern cell biology, and also some of the field’s blind spots and assumptions. For example, absent from these early descriptions, but very much important for the cell, are the dynamics (through time) of the subcellular organization and the organization of membrane-less organelles. Recent progress, made through the convergence of new imaging methods, modeling, and quantification of the biophysical properties of cells, has created opportunities for consilience, bringing to bear principles of biochemistry and biophysics to cell biology. One of those discoveries is the realization that fundamental physical properties, like those involved when liquids phase separate, can be used to in part explain cytosolic organization.

The concept that the cell is composed of sol-like liquids—a cytosol—is as old as the field of biochemistry, and proposals that phase separation could contribute to intracellular organization were made by biochemists decades ago. But what was lacking was integration of this knowledge and ideas into principles of cellular organization. The consilience of these ideas, facilitated by new tools and conceptual frameworks that bridged biochemistry, biophysics, and cell biology, enabled the emergence of concepts that reframed principles of cellular organization.

In my lab’s work, these new frameworks, and recent genetic and cell biological discoveries we made, led us to question assumptions about the organization of metabolism in neurons. Most of our understanding of metabolism comes from biochemical studies, and it is largely assumed that many of these processes, such as glycolysis, are distributed throughout the cell. Our examination of the localization of glycolytic proteins in Caenorhabditis elegans neurons revealed that glycolysis—a ten-step enzymatic process occurring in the cytosol—can dynamically compartmentalize through the formation of liquid-like condensates near synapses to sustain synaptic function. This raises a number of important questions, and an opportunity to integrate knowledge across scales: How are the biophysical properties of glycolytic proteins changing as they form condensates? How do these biophysical properties affect their biochemical activity? Is the compartmentalized biochemical activity affecting subcellular function, such as the function of the neuronal synapses where the condensates form? We know that synaptic function underpins the formation of memories: Are these condensates influencing neuronal function and emergent properties of the nervous system, like the formation of memories and behavior? If so, how are their biophysical and biochemical properties of glycolytic proteins in health and disease influencing memories and behavior?

In the biological sciences, the field of cell biology—the study of cellular organization—sits as a link between chemistry and physics (through molecular biology, biochemistry, and biophysics) and the organism (through development and physiology). The power of consilience and its potential impact for cell biology is perhaps best exemplified by looking at its history in a neighboring field, genetics. The linking of physics and chemistry to genetics resulted in the discovery of the DNA structure and its role in heredity, revealing underlying principles that govern disparate phenotypes and diversity in nature. As the cell biology field achieves its own consilience with biochemistry and biophysics, the new knowledge will likely illuminate underlying principles ruling emergent properties of tissues, organs, and organisms. Of particular interest to me, the cell biological principles of synaptic organization might illuminate emergent properties of the nervous system, such as memory and behavior. My lab’s aspiration and efforts are toward the facilitation of this consilience between cell biology and neuroscience. In that, and to close quoting E.O. Wilson: “The moral imperative of humanism is the endeavor alone, whether successful or not, provided the effort is honorable and failure memorable.…Let us see how high we can fly before the sun melts the wax in our wings.”