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Cell Biology, With A Physicist’s Eye

Tuesday, December 2, 2014

Alex K. Shalek: IMES Core Faculty; Assistant Professor of Chemistry at MIT; Associate Member of the Ragon Institute of MGH, MIT and Harvard; Assistant in Immunology at MGH

Instead of doing physics research during graduate school, Alex Shalek’s graduate research advisor Hongkun Park, a chemist and a physicist, wanted him to figure out how the brain works. Not only was the idea grandiose, but also Park had no biology lab and no tools. All he could promise Shalek was that they would have fun.

Shalek, who joined the MIT faculty in July 2014 as a core member of the Institute for Medical Engineering and Science (IMES) and an assistant professor of Chemistry, spent his first five years of graduate study at Harvard University traveling from lab to lab to learn biological techniques and to fabricate new tools to perform them. “I was begging for help from anyone who would listen,” he says.

With the wide-eyed curiosity of an explorer of new lands, Shalek first looked for ways to improve on the patch clamp, a powerful but cumbersome tool for recording electrical signals in neurons. He built a bed of exquisitely small needles to lay cells on, enabling him to record from many at once without damaging the cells. Because these fine needles punctured the cells without killing them, he could also use them to deliver material into cells. “Coat the needles with a molecule and it acts like a molecular lollipop,” says Shalek. “We went crazy with the things we could do with this.”

Shalek used this system to begin to understand how adaptive immune cells called T cells learn their specialized functions. What puzzled Shalek was that genetically identical cells, when triggered the same way, did not behave the same way.

Biologists suggested reducing the complexity of the problem by zooming in on a small number of genes or looking at cell behavior on average. But Shalek, being a physicist, chose a different approach: “Let’s look at all of the cells individually and all of the genes in each cell and let’s hope we can figure out how to work with the massive data set to find patterns of behaviors.”

Shalek undertook this project as a post-doctoral fellow at Harvard working much of the time at The Broad Institute. He used single cell RNA-seq to take a snapshot of genome-wide mRNA expression levels, capturing a single cell’s activity at a given moment by revealing which proteins the cell wanted to manufacture. Ultimately, he needed snapshots of many cells to understand how they were responding to a trigger, so he helped develop a microfluidic device to capture 96 cells at a time. In all, he processed a time series of about 1800 cells.

He found that even in a pool of identical immune cells, a few rare cells act early to coordinate a response to bacteria entering the mix. “The quintessential behavior of the system relies upon signaling by rare cells,” he says.

Now in his own lab, Shalek is continuing to develop technologies that will allow him to delve even deeper into the underlying complexity of biology. He continues to work with immune cells but is also working with systems of vastly different cells, such as tumors, hoping to understand how cells of the same and different types work together at the systems-level in health and disease. “We need to look at thousands of cells at once to understand what is happening in highly heterogeneous systems such as tumors or the brain,” he says.

Shalek will also continue to engage the labs around him. “I do really interdisciplinary, collaborative science,” he says. “For me, IMES is a bridge between basic science, engineering and medicine. It brings together everything I need to be successful as a scientist and to work on questions in medicine that really matter.”