Solving the protein puzzle

“The most exciting part is when you fill in that first clue and the puzzle starts coming together.”

Meet Noah Dephoure, PhD

Human cells are a chatty bunch. Most of the time that’s a good thing, as messages can be relayed, for example, to start an immune response to unwelcome bacteria. Other times, however, inter-cell communications generate the wrong messages, creating pathological changes that can result in cancer and other diseases. Researchers understand many aspects of this communication process, but a complete grasp of such signaling remains an unfinished puzzle.

Fortunately, Noah Elias Dephoure, a biochemist who has dedicated his life to solving puzzles both in the lab and in his personal life, has his sights set on unraveling the mystery of how cell signaling can be harnessed to fight cancer. At his laboratory at Weill Cornell Medical College in New York City, he specializes in the study of protein kinases—enzymes that modify proteins to change their function or location.

“They can do so many different things and join together into big complexes,” marvels Dephoure, who when not playing with his young son on the weekend spends his Saturdays deftly navigating the notoriously difficult New York Times crossword, deciphering cryptic clues to reveal hidden meanings. “In that way, proteins are like words—you only have 26 letters, but think about how many different words you can make when you put various combinations together.”

“Proteins are like words—you only have 26 letters, but think about how many different words you can make when you put various combinations together.”

That time actually helps him in his day-to-day work, too. For Dephoure, whiling away an afternoon uncovering the secrets of a crossword puzzle or exploring his New York City neighborhood on his bicycle brings the same sense of joy and accomplishment as finding a long-sought answer in the lab. “I sometimes read through every clue and don’t immediately know the answers to any of them. The most exciting part is when you start tentatively penciling in a few answers and the whole thing starts to come together,” he reveals. “It is a similar feeling you have in the lab when something you have looked at for days, months, or even years begins to make sense.”

Dephoure first encountered protein kinases as a PhD student in the laboratory of Erin O’Shea at the University of California, San Francisco (UCSF). There he helped create a library of over 4,200 different yeast strains, culminating in a seminal paper he coauthored that has been cited by other researchers more than a thousand times.

That research helped cement his reputation as an innovator and marked a professional accomplishment but also, in a sense, a personal redemption. Just a few years earlier, Dephoure had dropped out of college and taken temporary office jobs to pay the bills. One of those gigs was as an office assistant to Nobel Prize winner David Baltimore, then at MIT. Daily exposure to Baltimore’s work inspired the young Dephoure to enroll in a summer immunology course, a decision that helped propel him toward UCSF and, later, Weill Cornell.

“It made me realize research was something I could understand and maybe even have some insights into,” he recalls fondly. “Lab work can be repetitive in nature, but I enjoyed even the mundane tasks because it meant keeping at it and figuring it out.”

“Lab work can be repetitive in nature, but I enjoyed even the mundane tasks because it meant keeping at it and figuring it out.”

That tenacity—whether in delving into the possibilities of protein kinases, working through the New York Times crossword puzzle, or pondering the science of baking as he putters around the kitchen—is a key part of what continues to drive Dephoure. Fortunately, over the years the tools that he uses in the lab have made that research a bit less complicated.

“In the past, if you wanted to figure out what proteins were present in your sample, you had to work really hard to make special tools just to identify one of them,” Dephoure says. “Now, you can break them all up, throw them in the mass spectrometer, and identify and quantify thousands of proteins at a time.”

Dephoure uses Thermo Scientific Tandem Mass Tag (TMT) reagents to identify and quantify proteins by mass spectrometry. “Thermo Fisher Scientific tools continue to enable improvements that have a serious impact on the quality and precision of the data we require. Where we once could examine 500 peptides at a time, now we can study tens of thousands” he says.

His goal is ultimately to understand signaling events that underlie basic cellular biology and human disease research. “We are still only scratching the surface of biological understanding. There are over 500 protein kinases encoded in the human genome, and we probably only know what about 100 of them do,” the biochemist muses. “Solving that puzzle could lead to breakthroughs in cancer therapies that attack the disease by stimulating the immune system.”

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