The signal kept vanishing, but Kapil Ramachandran (@KVRamachandran5) kept searching for it. The then-graduate-student at Johns Hopkins was using tracing molecules called “radiolabels” to follow the life of proteins in a neuron. But in every trial, the radiolabel signal almost instantly disappeared. He was mystified. The radiolabels had to have gone somewhere.
He found the radiolabels in small peptides floating around outside the cell. It was as if something had chopped the radiolabeled proteins into pieces and pushed them out of the neuron. Fascinated, he tried to disrupt the phenomenon, hoping it would yield clues. The inhibitor that worked was one that—based on everything known at the time—seemed unlikely.
Ramachandran’s results showed that widely-studied molecular machines called proteasomes—nicknamed the “recycling centers” of the cell—were responsible. In most cells, proteasomes operate inside cells and break down proteins into amino acids that can be incorporated into new proteins. But these proteasomes appeared to be at the cell boundary and were releasing peptides to the world beyond, something that had never been seen before.
Today, Ramachandran studies these plasma-membrane-dwelling proteasomes as a Harvard Junior Fellow. Hosted by the Harvard Society of Fellows, Harvard Junior Fellowships are prestigious positions that allow early career scholars to conduct independent research, sometimes including establishing their own lab. Ramachandran has recruited undergraduate students from Northeastern University and will hire more undergraduates, technicians, and postdocs in the coming months.
Having his own lab space and support from MCB enabled Ramachandran to apply for and receive the NIH Director’s Early Independence Award, which provides five years of support to early career researchers who pursue “high risk, high reward” lines of inquiry.
“The idea is to take people who did interesting graduate work and transition them directly into an independent position,” Ramachandran explains. He adds that between NIH funding and the independence offered by his Junior Fellow position, he’s well situated to pursue challenging unexpected questions.
Ramachandran and the other Junior Fellows, who represent many disciplines, gather several times per week for meals and freewheeling discussions. For Ramachandran, the exposure to concepts from humanities and art is novel, because his science career began early.
As a high schooler in Austin, Texas, he became interested in how addiction worked and began cold-emailing professors at University of Texas at Austin, asking if they’d let him volunteer in their lab. A Drosophila geneticist named Nigel Atkinson took him up on the offer. Experiments quickly took over Ramachandran’s life, and scientific discovery became his passion.
When Ramachandran began his undergraduate education at Duke, he joined the lab of physiologist Geoffrey Pitt and studied a developmental disorder called Timothy Syndrome, which is caused by a mutation in a calcium channel.
“I’m really grateful to the people who taught me how to do science,” Ramachandran says. “While Nigel [Atkinson] gave me a lot of confidence and taught me scientific rigor, Geoff [Pitt] instilled a sense of discipline and organization and thoughtfulness.”
Afterward, he headed to Johns Hopkins for graduate school and joined Seth Margolis’ lab, where he discovered the neuronal membrane proteasomes.“I just stumbled onto this thing in rotation, and I could not stop working on it. It just got more and more and more interesting,” he says.
Ramachandran likens neuronal membrane proteasomes to paper shredders built into a wall. They’re a fast way of eliminating proteins, but the fragments made by neuronal membrane proteasomes may not be waste products. “The other way to think about it is that the signals–whatever this thing is spewing out into the world–are super-meaningful, and we have evidence of that,” he says.
Because neuronal membrane proteasomes were unknown until 2017, his lab has many unanswered questions to explore. “We’re working out the biochemical, genetic, and cell biological components of this entire system,” he says. “But also what are all these small fragments? And what is this degradation system doing? What is it signaling, and who is it signaling to?” Ramachandran believes that malfunctions in these neuronal proteasomes contribute to many neurological disorders, an area of active investigation in his lab.
He adds that he’s excited to be in MCB and encourages people to stop by his office to talk science. “We’re entering territory that requires a lot of thought,” he says. “Having more minds and more eyes on it is always better. That’s what I want, and that’s what I think this [MCB] community is really good at.”