Collaborative Process

Alex Shalek wants to know how our immune cells collaborate—and might be manipulated—to keep us healthy and even save our lives.

“We like to think of cells as if they were people: How are they organized? Who talks to whom? And how do those lead to good or bad things on the whole?” says Shalek. “It’s as if we’re creating interrogation rooms for cells—building a toolbox to study how interactions between cells inform group dynamics.”

Shalek takes what he calls a “bottom-up” approach—using nanotechnology and molecular biology to see how single cells cooperate to create collective behaviors. In association with MIT Associate Professor of Chemical Engineering Chris Love, Shalek’s lab is developing new strategies using a microdevice with microscopic holding chambers to allow controllable pairing of cells.

“You put two cells together and you ask, ‘What’s different about the joint decisions they made compared to what I would’ve expected?’ We’re working on strategies to do this at increasing scale . . . . For example, what happens if you take 5 T-cells (from your adaptive immune system) and 5 dendritic cells (from your innate immune system)? Really it’s about trying to understand the basic dynamics of the cells’ ‘interpersonal’ relationships.”

The work—once considered “wholly impossible,” says Shalek—is now enabled by emerging genomics technologies and precision tools, many of which Shalek helped pioneer. In 2013, he partnered with the San Francisco-based life sciences company Fluidigm to pilot its C1 system for single-cell genomics, and, in 2014, co-developed the reverse-emulsion-based method called ‘Drop-Seq’ to scale and strengthen the approach. Most recently, the NIH’s High Risk, High-Reward Research Program (through which Shalek received a 2015 New Innovator Award), the Searle Scholars Program, and the Beckman Young Investigator Program are providing him with critical funding to innovate additional transformative technologies.

“We (want) to take the broadest view of cellular phenotype, to sequence all the RNA, to look for patterns across cells in the same way you might use demographics and psychographics to profile people,” says Shalek. “Even just few years ago it would’ve been difficult/impossible to profile the behavior of a single cell at the genomic scale—to look at everything it was thinking at a given moment—let alone do this for thousands of cells. But now we can ask really interesting fundamental questions of many cells with important clinical ramifications.”

Two areas of particular interest are HIV and cancer. Shalek, Associate Member of the Ragon Institute of MGH, MIT and Harvard, and the Broad Institute of MIT and Harvard, as well as Assistant in Immunology at MGH, explores the underpinnings of disease, cellular-level therapeutics, and potential prophylactics.

“Why are some patients naturally able to control the HIV virus to keep it at undetectable levels while others can’t?” he says. “We’re interested in what’s unique about these people’s immune systems. Do they have special cells that other people don’t have or is it that their immune systems just have better balance, better communication, or a better strategy for fighting things off?

“And we think similarly about cancer . . . . There have been some really cool discoveries using antibodies against PD-1 and CTLA-4 to reactivate the immune system so it goes crazy and fights tumors in a way that would be hard to imagine doing with any one drug. But tumor immunotherapy doesn’t work for all patients or all cancers. So, once again, I got interested in why not? Could we identify additional mechanisms that tumors use to suppress the immune system to help develop better combination therapies?”

Answering such questions could bring sweeping change.

“It’s sort of the ultimate version of personalized medicine. We’re trying to understand from these genome-wide profiling approaches who these cells are, how they’re changing under different conditions, and how we can mimic or prevent that for therapeutic gains.”

Shalek came to study the immune system by way of the brain. During his graduate work with Hongkun Park at Harvard University, the team developed a minimally invasive nanowire measuring bed. It proved so successful at invading neurons that Park’s colleague Aviv Regev, a core member of the Broad Institute, urged them to apply it to hard-to-fool immune cells. And it worked.

“The work my students and I do now is incredibly fast-paced,” says Shalek, who is the H.L.F. von Helmholtz Career Development Assistant Professor of Health Sciences and Technology (HST), Assistant Professor in Chemistry, Core Member of the Institute for Medical Engineering and Science (IMES), and an HST instructor. “Students bring me new data everyday. We’re always excited.”

Shalek is also excited about IMES.

“It’s an essential time for IMES. The problems are getting harder. The data is getting bigger. We’re trying to come together as a research community to collectively work on problems that would be crazy to imagine doing alone . . . . Bringing engineers and doctors together, integrating in their hospitals, really just trying to make the difference—bringing the best that MIT and Boston have offer to local and global clinical challenges.”