Brings cellular biology to life for students interested in medical science by explaining how mutations in genes can compromise virtually every cellular system and predispose to human disease. Knowledge of cell biology has led to new treatments for cancer, heart failure, cystic fibrosis, and many other diseases.
The history of science shows that the search for fundamental knowledge about nature unfolds steadily over centuries, always expanding the frontiers and never reaching what one would call an end point. Fields may get stuck in a rut and have to reinvent themselves from time to time with a paradigm shift [2], but so far no field of science familiar to me has run out of fundamental questions, all arising from previous work. Yet some serious scientists think that the spectacular progress in cellular and molecular biology since 1950 has already provided answers to most of the big questions in cell biology. The rest of us find that their predictions of the end of our discipline are way off the mark. How is this difference of opinion possible?
Cell Biology Thomas Pollard.pdf
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What's still missing in many areas of cell biology is an understanding of how molecules form the dynamical systems that bring the cell to life. Understanding dynamical processes is impossible from a list of their parts and their connections. Thus, many deep questions remain about the very essence of life, how life originated, and how cells and organisms have evolved.
The boxes show the steps and research methods that contribute to understanding molecular mechanisms in cell biology. Arrows show the progression of the work starting with the definition of a biological question, followed by collecting an inventory of the relevant molecules and then three large areas of research: structural studies, cellular observations and biochemical characterization. When simulations of the hypothesis fail to account for observations in cells (bottom box), the investigator must reexamine their assumptions about the participating molecules (upward center arrow) and the participating reactions (right box) and the numerical parameters used in the simulations. Simulations and observations converge as understanding improves.
The second step is to identify the parts list for each biological process. One must catalog the participating molecules and link each to a process. Genomics, genetics, clinical medicine, comparative biology, and biochemistry all contribute to finding the molecules. Completing this inventory has been and will continue to be a major quest for cell biologists, since one cannot understand mechanism without a good inventory.
Discovery of fundamental information about structure at all levels will continue to be the bedrock of cell biology. Typically a combination of structural methods contributes to answering most mechanistic questions. X-ray crystallography has matured to the point where it is accessible to the biology community, so every lab with an interesting molecule should aspire to obtain its atomic structure. Expert crystallographers remain essential to improve methods and determine challenging structures of large macromolecular complexes. NMR can determine structures of molecules of modest size and provides unique information about their dynamics. Supercomputers have expanded the reach of molecular dynamics simulations, which will grow in importance in cell biology. Most importantly for cell biology, electron tomography and super-resolution fluorescence microscopy are providing ever more detailed views of cellular architecture with better spatial and temporal resolution.
Testing mechanistic hypotheses requires information about the dynamics of the molecules in live cells and how systems of molecules adapt to change. Measurements in live cells are essential to learn how the crowded environment in a cell influences reaction rates compared to typical biochemical measurements in dilute solutions. Historically, measurements have been done on samples of many cells but it is now appreciated that more can be learned from studying one cell at a time. Even genetically identical cells can behave distinctly, and this variability may be a vital part of the biology.
Cell biologists have enough fundamental, mechanistic questions to maintain the strength of the field for decades more. Some scientists may view mechanistic studies in cell biology as only adding detail to an essentially completed picture. I urge them to appreciate that mechanistic work is the future of cell biology, especially its practical applications. This quest is no less fundamental than discovering the nature of dark matter and dark energy rather than simply knowing that they must exist.
Jennifer Lippincott-Swartz is Group Leader at the Howard Hughes Medical Institute Janelia Research Campus. Her lab uses live cell imaging approaches to analyze the spatio-temporal behaviour and dynamic interactions of molecules in cells with a special focus on neurobiology. Before Janelia, Lippincott-Swartz was a primary investigator and chief of the Section on Organelle Biology in the Cell Biology and Metabolism Branch. Her work there included a collaboration with physicists Eric Betzig and Harald Hess (now group leaders at Janelia), who proposed a new function for the photoactivatable protein. The scientists used the protein to generate photoactivatable fluorophores, or dyes, which enabled them to illuminate different sets of molecules sequentially, creating a microscope image far more detailed than previously possible. The method, called super-resolution microscopy, garnered Betzig the 2014 Nobel Prize in Chemistry. be457b7860
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