Quantitative biology on the rise

This volume marks the third special issue of Molecular Biology of the Cell devoted to quantitative cell biology (QCB). QCB is by no means different from the traditional discipline of cell biology, in the sense that we all are searching for general principles of proteins’ self-organization into molecular machines that make the cell function. On the surface, this task is not that different from the agenda of a condensed-matter physicist trying to predict properties of a crystal from forces between atoms, which, after centuries of precise measurements and mathematical calculations, resulted in an enviously complete and predictive body of knowledge. Our problem, however, is that the cell, like a crystal, is an emergent structure resulting from physicochemical interactions of molecular components, but it is infinitely more complex, as the number of component types is many orders of magnitude greater than in inorganic condensed matter, not to mention the greater variety of intermolecular interactions. Intuition and qualitative thinking have brought us a long way, as far as understanding the functioning of one protein at a time. But to understand how the cell as a whole is able to function, we have to continue to push toward cell biology becoming a fully quantitative science on a par with physics.

Issue editors, clockwise from top left: Jennifer Lippincott-Schwartz, Diane Lidke, Valerie Weaver, and Alexander Mogilner.

There are multiple stages to this process. We have to fully apply functional genomic, proteomic, and metabolomic approaches to complete inventories of the relevant molecules; determine molecular structures and identify molecular partners; develop and refine quantitative biochemistry and microscopy techniques to measure both rates of transport and reactions and localizations of the molecules in cells; test our understanding of key molecular machines by reconstituting them from purified components in vitro and in silico; and, ultimately, go back to the full complexity of the cell to perform physiological tests. Each research and review paper in this issue emphasizes aspects of this agenda.

Detailed quantitative data are the bread and butter of QCB. Not surprisingly, many articles in this issue are devoted to quantitative microscopy and image analysis, from single-molecule localization microscopy studies, to automated retrieval of intracellular superstructures from superresolution microscopy images, to new software to reliably correlate cell dynamics with spatially resolved protein concentrations. A few papers report results of applying such innovative techniques to elucidate three-dimensional nanometer-scale dynamic organization of protein and lipid assemblies and organelles on all subcellular scales, including receptor networks, kinetochores, chromosomes, nuclei, and plasma and intracellular membrane compartments. A number of studies are devoted to careful quantitative analysis of cell signaling pathways. Some cell biological subfields were recently given a boost by the rise of QCB, among them multicellular dynamics. Fittingly, a few articles, both experimental and theoretical, investigate how cell–cell adhesive and contractile interactions robustly organize growing tissues in health and disease. Cells are not just chemical entities, but also mechanical machines, and the currently booming area of cell mechanobiology has in fact arisen due to the QCB approaches, as highlighted in this issue by a study of a microscopic mechanosensing mechanism.

Iterative cycles of quantitative modeling and experimentation are the only way to understand the cell’s complexity. Hence, combining mathematical modeling with new methods in measurement and data analysis is a signature feature of the nascent QCB. This issue presents studies on the mechanisms of microtubule dynamic instability and mechanochemical mictotubule–motor interactions, illustrating how thoughtful modeling drives quantitative experiments and leading in turn to refined understanding of minute details of cytoskeletal machines, including the mitotic spindle. Last, but not least, throughout this issue one can appreciate insights from QCB approaches for understanding physiological responses of the cell in health and disease, including those of cancer cells, and of nervous and immune system cells.

Together, the reviews and studies in this issue demonstrate the growing strength of QCB. QCB’s popularity is reflected in the fact that quantitative experimental approaches and mathematical modeling are now parts of the latest editions of textbooks, one example being Molecular Biology of the Cell by Alberts et al. (2007). We are, however, facing enormous scientific challenges, including, but not limited to, embracing single-cell revolution and understanding what to do with overwhelming volumes of “omic” data. The more we embrace the quantitative character of cell dynamics, the closer we will be to predictive understanding of the cell. I and my fellow Issue Editors hope that you find the contents of this issue engaging and illuminating.