It's the Technology, Stupid

Abstract

Living organisms are incredibly complex. Almost every biological function arises from the combined action of multiple components whose interactions generate functions and properties that are not currently predictable from the attributes of the individual parts. Because they evolved, living systems solve design problems in idiosyncratic ways that can only be resolved by experiment. Unraveling this complexity, moving toward the prediction of phenotype from genotype, is the major challenge that life scientists, including cell biologists, will face over the next 50 years. As always in biological research, it will be new technologies that will determine what is achievable. But predicting new technologies is impossible, so here I describe currently foreseeable developments. Iain W. Mattaj Cellular parts lists, RNAs, proteins, protein modifications, lipids, will be increasingly complete, as will catalogs of the interactions that occur between these components. Single cells will continue to be amenable to a variety of genetic, biochemical, and imaging approaches that cannot be simply applied to complex organisms and intracellular processes coupled to cell–cell interactions provide the basis for the development, structure, and function of tissues, organs, and multicellular organisms. Therefore, the cell will undoubtedly remain at the center of biology in the next few decades, even though the nature of cell biology will change significantly. Cell biology will become more interdisciplinary. The boundaries with other biomedical disciplines have already blurred and physics, chemistry, mathematics, and computer science are also beginning to have a heavy influence. The recent and ongoing radical advances in imaging have turned molecular cell biology from a discipline dominated by reductionist experimental methods and descriptive morphology into a quantitative science geared at measuring, dissecting, and understanding molecular mechanisms in their in vivo context. This trend will continue. Imaging in four dimensions captures real-time data that reflects the physiological conditions and dynamics of the biological system under study. Fluorescence-based light microscopy techniques use reporter molecules to monitor the localization, and in an increasing number of cases the activity, of molecules inside cells. These methods will allow biochemical and biophysical parameters of cellular processes, such as signaling cascades or the assembly and disassembly of subcellular structures, to be quantitatively determined and thus provide the raw material for the type of modeling and simulation methods that, when applied together with experimental manipulation, will enable detailed understanding of the information flow that underlies cellular processes and functions. Thus, I foresee a broad, significant increase in our understanding of “how cells work.” The major current limitation is the small variety of available in vivo reporters and the small number that can be studied simultaneously. I confidently expect both of these limitations to yield to energetic attack over the next two decades. The recent advent of super-resolution microscopy and electron microscopic tomography are important steps in bridging the resolution gaps between cell and structural biology. These and other developments have led to a new approach, sometimes called cellular structural biology, that integrates across scales to move toward a detailed, structure-based understanding of cellular organization and function. In my view, the insight gained will change our way of thinking about cellular processes and how to manipulate them. In parallel, automated high-throughput and high-content microscopy have revolutionized the scale at which cell biology experiments can be done. Phenotypes of thousands of cells can now be screened in parallel, and image-processing software recognizes patterns and phenotypes more reliably than the human eye. Microfluidics will enhance single-cell study methods and the parallelization of biochemical assays. This will have a big impact in the years to come, for example, in systematically studying aspects of cellular phenotype based on interindividual or interspecies genetic variation. All of these developments suggest that cell biology will probably be substantially redefined in terms of its scope, scale, and toolbox and in the questions it addresses over the next 50 years. I encourage those entering the field to train as broadly as possible, studying chemistry, physics, or mathematics as well as biology. However, given that cells have already been under study for 400 years, we shouldn't be too surprised if there are still more questions than answers in 2060.