Story behind the story: Carla Mattos

Photo by Brooks Canaday.

There’s always a story behind the story. When I talk to researchers about new papers or grants, I ask way more ques­tions than I can pos­sibly cover in the body of a News@Northeastern article. One of my favorite ques­tions to ask is “how did you get inter­ested in this line of work?” It almost always brings with it a great anec­dote. Some­times it’s as simple as “my grad­uate advisor was working on this stuff and I fol­lowed suit,” which is by no means a boring response. I spent nearly a decade working in chem­istry labs because my under­grad­uate advisor inspired me so much. And I’m cer­tain I never would be writing this blog if it hadn’t been for those years. But some­times the responses are much more unexpected.

One such anec­dote sur­faced last month when I was talking with Carla Mattos about the a pro­tein called RAS that pro­motes cel­lular pro­lif­er­a­tion. She’s spent thou­sands of hours thinking about this pro­tein. In fact, she rewrote the book on it: she dis­cov­ered a novel reg­u­la­tory mech­a­nism for it when she alighted on some­thing called an allosteric binding site, or a part of the mol­e­cule that deter­mines its func­tional activity at another, remote part. I asked her how she became inter­ested in RAS and she chuckled.

Oh,” she sighed. “That…That was very, very much by chance!”

Ear­lier in our dis­cus­sion I asked her about some­thing I’d read on her web­site which she casu­ally dis­re­garded as having not much to do with the present study. But it turned out, her work in so-​​called mul­tiple sol­vent crystal struc­tures ini­ti­ated the entire foun­da­tion of her cur­rent lab.

Way back as a post doc I was studying pro­tein sur­faces using this method,” Mattos told me. She was using organic sol­vents as probes to detect hot-​​spots of activity on pro­teins. They would sub­merge bulky pro­tein crys­tals in var­ious organic sol­vents. Each dif­ferent sol­vent envi­ron­ment would create a unique struc­ture, which they would char­ac­terize. Then they’d super­im­pose all the struc­tures atop one another and look for areas of the pro­tein that had lots of dif­ferent organic sol­vents con­verging in the same place. “That cor­re­lates very well with affinity hot spots for protein-​​protein inter­ac­tions or protein-​​ligand interactions.”

When Mattos earned her first fac­ulty posi­tion back in 1999, the only pro­teins they’d ever per­formed this work on were extra­cel­lular. “They’re very sturdy, they have disul­fide bonds, and I thought back then prob­ably more amenable to be put in organic sol­vents and sur­viving.” When she got to North Car­olina State, she said, she wanted to look at a new kind of pro­tein with this method. She wanted an intra­cel­lular pro­tein that was small and stable enough to sur­vive the method.

She looked around in the lit­er­a­ture and landed on RAS. “Of course I didn’t know any­thing about sig­nalling trans­duc­tion path­ways back then, I barely knew what RAS did.” The first thing she did with the pro­tein was to deter­mine the sol­vent map. But the data turned up some strange things that she couldn’t explain. Instead of pub­lishing a random new struc­ture without any insights attached to it, Mattos and her team sat on the data and dug deeper into the story of RAS. “In between that data col­lec­tion and when it finally got pub­lished, we went off on this other track of under­standing how this pro­tein works and what we were seeing in the data sets.” The pub­li­ca­tion hap­pened over a decade later and it included an entire par­a­digm shift for RAS researchers.

Today, Mattos’ work is almost entirely focused on RAS. Her team still does per­form sol­vent map­ping, but usu­ally in the con­text of this par­tic­ular mol­e­cule and its inter­ac­tions with others.

I love sto­ries of sur­prise like this. It totally lays bare the intrigue of working as a sci­en­tist. It’s all about fol­lowing your nose, so to speak, asking ques­tions and seeing where they lead you. When one has the freedom to pursue those new leads, amazing things can happen.