“Science surprises you all the time,” says Prof. Yosef Gruenbaum. “You start with a question, but you never know where you’ll end up.”
For the past 25 years, in his work at the Department of Genetics at the Hebrew University’s Alexander Silberman Institute of Life Sciences, Gruenbaum has studied a tiny structure — the nuclear lamina — that lies at the periphery of the nucleus of a cell. The lamina is a fibrous mesh network that makes up part of the nuclear envelope, which separates the nucleus from the rest of the cell. If the cell nucleus were a watermelon, the nuclear lamina would be located where the white inner rind meets the red pulp.
At first, the nuclear lamina was thought to be purely structural — just another part of the “dividing wall” between the nucleus and the rest of the cell. But over the past several decades — largely due to the work of Gruenbaum — the nuclear lamina has proven to be an important structure that performs functions of its own, such as regulating gene expression. As a measure of its importance, mutations in the nuclear lamina have been implicated in a broad range of diseases, from muscular dystrophy to progeria, a disorder that causes premature aging.
In a normally functioning cell, explains Gruenbaum, silent chromatin (strands of DNA and proteins with an extremely low level of gene expression) is located at the periphery of the nucleus, near the nuclear lamina. When it’s time to initiate the expression of a gene, silent chromatin travels towards the center of the nucleus and begins the process of gene expression. Recently Gruenbaum and his students introduced a mutation to the worm C. elegans that resulted in the removal of the nuclear lamina from the organism. They found that the silent chromatin traveled too prematurely to the center of the nucleus and the cell ended up dying.
In another recent study, conducted with colleagues at Switzerland’s Friedrich Miescher Institute and using the C. elegans model, they introduced a genetic mutation in the nuclear lamina that has been linked to Emery-Dreifuss muscular dystrophy in humans. In this case, they observed that the chromatins related to a specific muscle array remained at the periphery and did not travel to the center of the nucleus. In addition, the expression of the muscle array was severely reduced and the worms displayed defects in muscle tissue that resembled muscular dystrophy in humans. Thus, the nuclear lamina seems to play a crucial role in coordinating the precise timing for the “release” of chromatins from the nuclear periphery.
Gruenbaum, a Jerusalem native, did not begin his career as a biologist. After completing his undergraduate degree in chemistry and physics and his master’s in materials science, all at the Hebrew University, he worked in industry for several years before realizing that he wasn’t cut out for an industrial management position. He returned to the Hebrew University, where he completed his doctorate on DNA methylation at the Faculty of Medicine. Following a postdoc at the University of California, San Francisco, Gruenbaum joined the Hebrew University’s Department of Genetics.
In addition to his work on the nuclear lamina, Gruenbaum, who holds a secondary position as an adjunct professor at Northwestern University, has recently begun to work on a project to measure how cells sense and respond to high carbon dioxide levels. Together with his students, he has found that when C. elegans cells are exposed to chronically high carbon dioxide levels, they display problems with motility and muscle that are strikingly similar to those that occur in human pulmonary diseases.
Gruenbaum sees a clear guiding principle in all of his research: he wants to better understand how mutations cause different human diseases. He credits his students with playing a key role in his work. “At the University, I don’t feel like I’m getting old,” he says. “I work with young, bright students. I have to learn all the time. I’m constantly learning, constantly thinking.”
Prof. Gruenbaum’s research is funded by the Israel Science Foundation, the Legacy Foundation, the Israel Ministry of Health, the Binational Science Foundation and the Jacques Kluger Memorial Fund for Research into ALS.
By Anna Wexler, November 2011