“This is the direction in which we have to go,” said De Camilli, who studies how brain cells package neurotransmitters, the chemicals that pass along neuronal signals. With these new data, they are beginning to answer scientific questions nearly as old as the limit that once held them back. Using custom-made fluorescence microscopes, some designed by Yale scientists, researchers at Yale are observing the live-cell dynamics of structures that they could previously see only in snapshots. In the last 20 years, however, scientists have found ways to overcome the diffraction limit and close that gap through what is called super-resolution light microscopy. Although each type of microscope had its uses, between them lay a large gap. In trying to learn the rules of cell biology’s game, scientists had at their disposal detailed still images from the electron microscope and views of the cell in action from the light microscope, with some of the most interesting players too small to see. That works out to a resolution of about 250 nanometers, around the size of the measles virus and about 400 times smaller than the width of a strand of human hair. Abbe, a contemporary of the microscope manufacturer Carl Zeiss.Ī light microscope, even with an excellent lens, cannot resolve structures smaller than about half the wavelength of the light used to illuminate them. Smaller structures-the vesicles carrying cellular messages and the protein scaffolding that gives cells their heft and shape-blur together because of what is called the diffraction limit, described in 1873 by Ernst K. To observe live cells, scientists use light microscopy, which includes the dissecting microscopes familiar from high school biology and extends to high-tech microscopes whose images brighten the pages of scientific journals.īut standard light microscopy too has a major limitation in resolution: scientists have known since the 19th century that it cannot resolve, or distinguish between, structures smaller than about the size of organelles. “There are a lot of biological problems that-if you could see them in living cells in action-we would be able to unravel.” If you are trying to learn the rules of the game, Toomre said, a snapshot doesn’t get you very far. Toomre, Ph.D., associate professor of cell biology, likes to compare an electron micrograph of a cell to a still photograph taken during a football game. The grayscale world pictured in such detail in electron micrographs, while powerful, is “a cellular cemetery,” in the words of Pietro De Camilli, M.D., FW ’79, the Eugene Higgins Professor of Cell Biology, professor of neurobiology, and director of the Yale Program in Cellular Neuroscience, Neurodegeneration and Repair.īecause electron microscopy’s vision is limited to dead cells, it provides just a snapshot of a cell’s inner workings. But although the electron microscope opened new avenues of research, it had a huge drawback as a tool for studying life: it can observe cells only after they are dead, treated with special fixatives, and sliced into thin sections or coated in a layer of metal. Palade, Ph.D., chair of Yale’s newly formed cell biology department, shared a Nobel Prize in physiology or medicine for using electron microscopy to elucidate the inner workings of cells-groundbreaking findings that some say ushered in the modern field of cell biology.
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