Cell Biology, Structural Biology
California Institute of Technology
Dr. Jensen is also a professor of biophysics and biology at the California Institute of Technology.
Structural Biology of Microbes and Viruses, and Ongoing Development of Electron Cryotomography
Caltech physicist Richard Feynman once said of electron microscopy: “It is very easy to answer many of these fundamental biological questions; you just look at the thing!” This is exactly what Grant Jensen is doing.
Jensen works at the forefront of a microscopy technique called electron cryotomography (ECT). ECT uses “plunge-freezing” to instantaneously immobilize living cells, preserving cellular structures in vitreous (glass-like) ice. The ice forms so quickly that water molecules don’t have a chance to rearrange to form damaging crystals. Using a state-of-the-art transmission electron cryo-microscope, the frozen cells are then tilted, one or two degrees at a time, and images recorded. The 2D images are then computationally reconstructed into a 3D picture of the cell and everything inside.
Jensen first saw the potential of ECT to answer fundamental biological questions as a postdoc at the Lawrence Berkeley National Lab. He quickly adopted the technique and, in 2002, started his own group at Caltech, where his research focuses on the ultrastructure of small cells, the structural biology of HIV, and ongoing technology development.
One of those technologies was necessitated by the productivity of his group. Realizing that the ever-increasing flood of tomographic data generated by his lab and others would be wasted without a way to curate it, he developed the Caltech Tomography Database. The database currently holds more than 25,000 tomographic datasets of more than 200 different biological samples imaged by his group. And, indeed, many answers to fundamental biological questions have come from looking at them.
Take, for example, the macromolecular machines that bacterial cells use to carry out their varied functions, from motility to warfare. In recent work, Jensen and his group solved the structure of the Myxococcus xanthus type IVa pilus (T4aP) motility machine. M. xanthus cells use this machinery to extend long fibers that attach to a surface (or to other M. xanthus cells in a predatory “wolf pack”) and subsequently retract, pulling the cell body forward. It’s a complicated machine, comprising many copies of a dozen or more unique proteins. The list of components was known, and in many cases, there were even atomic structures available, but the way they were all put together, and thus how the machine worked, remained a mystery. Using electron cryotomography and subtomogram averaging, Jensen and his group solved the overall structure of the machine inside intact cells. They then repeated the analysis with mutants either lacking components or containing tagged versions of the components to make them larger. This allowed them to pinpoint the location of each protein in the complex, and dock the existing structural knowledge into context, finally revealing how the T4aP works.
In other work, Jensen’s images revealed the structure and function of the bacterial type VI secretion system, a “poison-tipped spring-loaded molecular dagger” that cells use to kill neighboring competitors. They revealed the architectures of chemoreceptor arrays, flagellar motors, carboxysomes, storage granules, and the cell wall. Jensen’s approach, with its superior structural preservation, was able to reveal not only the existence of a bacterial cytoskeleton, but its variety. One particularly surprising insight came from their studies of sporulation; they observed that when Gram-negative bacteria sporulate, they interconvert inner and outer membranes, providing an intriguing hypothesis for the origin of the bacterial outer membrane.
Jensen has another passion: education. He and his group regularly make (and post to YouTube) movies and animations depicting the biological processes (like HIV maturation and bacterial motility) that they uncover. In addition, Jensen developed an online course, “Getting started in cryo-EM” (available on YouTube, iTunes U, and Coursera), to share his knowledge beyond the walls of any one classroom. The videos have already been viewed thousands of times on YouTube and Jensen says that nearly everywhere he travels, he meets young scientists who have watched the course. This focus on mentorship is also reflected in his track record in his own lab; six of his postdocs now run their own research groups around the world.