Protein Reporters Go on Location


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Dr. Emmanuel Levy
Each cell in your body is an entire world: Hundreds of millions, or even billions, of protein molecules are crowded into its microscopic confines. Some have permanent “jobs” in particular locations in the cell while others move around. Some form parts of long-lasting structures while others are produced for particular tasks and degraded soon after. To get an overall picture of this world, we need to know the rules that underlie its “social structure.” For example: Are certain kinds of proteins more populous than others? Where do the various proteins “go to work”? Which other proteins do they meet up with – either casually or in longer-term partnerships?

Dr. Emmanuel Levy of the Structural Biology Department is working on clarifying the answers to these questions. To do so, he is using a technique he helped develop during his postdoctoral research in the lab of Prof. Stephen Michnick at the University of Montreal. Now, using this technique, Levy, together with Michnick, has observed the comings and goings of the proteins in some 4,000 strains of yeast cells. Their results paint a picture of the cell’s world in which “social networks” and chance meetings seem to play a much larger role than previously thought. The results of their study appeared recently in Cell Reports.

The new technique involves splitting a protein that is vital for the cell’s survival into two halves and attaching each half to another protein. One of those proteins is the reporter, the other the target. If the target protein approaches the reporter, the two halves of the split protein will reunite and the yeast strain will survive and grow. The more abundant the target protein is in the vicinity of the reporter, the healthier the growth of the yeast. The method is so good at measuring protein levels and their localization that the researchers obtained an accurate “census” of nearly all the proteins probed. This, says Levy, means that, for the first time, we can measure with great accuracy the protein concentration in a particular region of a living cell. Measuring local protein concentration is indeed hard-to-impossible to accomplish by other methods – for example, mass spectrometry, which involves killing the cell, or microscopy, which would be a very tedious undertaking on such a scale.

Reporters Illustration

“If we think of the campus of the Weizmann Institute as a cell and the people who work here as the proteins, the reporters we use can record how much time each individual spends in which building,” he says. Their findings show that proteins are highly varied in their habits. Indeed, the scientists were surprised at the wide range they measured: Unlike your average human workers, whose hours on the job don’t vary too much from one to the other, some proteins were thousands of times more industrious – that is, abundant – than others. “It’s as if some go to work for just a minute, while others spend a whole week straight in their workplace,” says Levy. The most abundant proteins were also likely to be seen outside of their regular workplace. Going back to the Weizmann Institute metaphor, a person who works in the cafeteria, if he is there for just a minute a week, will not make an impression. In contrast, someone who actually works in a chemistry lab but also spends a few hours a week in the cafeteria could create more personal ties with the serving staff. This has profound consequences for the incidence of protein interactions. An analysis of the data revealed that, in fact, the chances of any two proteins meeting were first and foremost a product of their numbers in the cell.

That, along with their other findings, raises some very basic questions about how the cell truly functions. Randomness – a basic principle of evolution – appears to be built into our cells’ constitution. Nature is an opportunistic tinkerer, Levy says, that is just as likely to repurpose a tool that’s at hand as to evolve a new one. So rather than working on the assumption that the world of the cell is a highly organized realm in which every protein has a place in the overall structure, this research implies that scientists might begin to view the world of the cell as a fuzzy, “social network” type of organization in which chance meetings around the cell may determine how it functions.

Setting up an Experimental Lab

Dr. Emmanuel Levy
Dr. Emmanuel Levy joined the Weizmann Institute in 2012, where he soon began setting up a robotic lab for proteome analysis. Here, hundreds of yeast colonies are grown on a single plate, and hundreds of plates can be incubated at once, their results photographed and analyzed by computer. He first started working experimentally with proteins in his postdoctoral research with Prof. Stephen Michnick at the University of Montreal; in his undergraduate and graduate studies in his native Paris, and then at Cambridge University, UK, Levy had focused on the theoretical side of proteins, studying their structure and their evolution.
Levy, whose previous experience in Israel had been a one-month vacation on a kibbutz, says he was persuaded to join the Institute after he had been invited to give a lecture to the department. “I chose to come here because it is the best place to do this type of science,” he says. He is married to Melanie, whom he met at Cambridge, and they are expecting their first child. Melanie is pursuing postdoctoral research in health law and bioethics. When he has spare time, Levy enjoys cooking and composing electronic music.   
Dr. Emmanuel Levy's research is supported by the  Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Louis and Fannie Tolz Collaborative Research Project; Anne-Marie Boucher, Canada; the Samuel and Helene Soref Foundation; and the estate of William Weingarten. Dr. Levy is the incumbent of the Recanati Career Development Chair of Cancer Research in Perpetuity.