BS/MS, Sciences, University of Calcutta, India
PhD, Molecular Biology, Albert Einstein College of Medicine
The scientific process is full of ups and downs, as developmental neuroscientist Kausik Si, PhD, can attest. Almost three years into his career as an independent scientist at Stowers, his lab lost all the fruit flies for their studies due to an incubator breakdown, setting their research back at least a year. Despite this disaster, Si’s team went on to conduct paradigm-shifting research on the stabilization of long-term memories in the brain.
Today, Si says he’s often asked about the story of his lab’s devastating loss. While the memory still stings, he hopes their rebound inspires budding investigators and established scientists alike. “It’s something that can happen to anybody, and then the question is, how do you survive it?” says Si, adding that it took a team effort and the generous support of the Institute to get his lab back on track. “It is possible to overcome something you didn’t plan for and is quite catastrophic.”
Born in a rural village in India, Si’s scientific learnings were fostered by his father, a high school physics and math teacher, and his college biochemistry professor. Si received his BS and MS degrees at the University of Calcutta. He moved to the United States for his doctorate and earned a PhD degree in molecular biology at Albert Einstein College of Medicine in 1999. After graduating, Si did his postdoctoral fellowship in the lab of Nobel Laureate Eric Kandel, MD, at Columbia University. Like his mentor, Si wanted to understand at the most basic level how memories are created in synapses, the junctions between neurons in the brain. He joined the Stowers Institute in 2005 and was appointed associate scientific director in 2019.
At Stowers, Si enjoys the freedom to perform research without boundaries. “For me, the most important thing is that I do the science that I want to do. Actually, that’s the reason I joined the Institute.” Sometimes that means being able to pursue ideas that may be controversial or take extra time to study, because they’ve never been explored before. “With a new idea, you have to develop new methods, new ways to probe that,” Si explains. “For example, a fruit fly brain is not a likely source to study protein structure because it is so small. Fruit flies are predominantly used for genetics. But we wanted to combine genetics, molecular biology, and classic biochemistry in a structure analysis of the brain, to get to the bottom of memory.”
The Si Lab investigates how a transient experience produces a persistent change in behavior and how, among the many experiences an animal encounters, only some produce persistent change in behavior.
In particular, the lab’s work focuses on a group of proteins, prion-like proteins, that has the propensity to aggregate or cluster together into an amyloid state. Historically, clustering of prions or prion-like proteins has been associated with harmful conditions. For example, amyloids in the brain are linked to Alzheimer’s and other neurodegenerative diseases in humans.
Si has found that some prions have a positive side and are essential for long-term memory. The way they aggregate is a feature, not a bug. When Si and his team launched their research, this was a controversial viewpoint, contradicting the long-held assumption that protein aggregates in the brain cause memory loss, resulting in cognitive decline. “We came in saying, ‘Look, in some cases when a protein aggregates, it does exactly the opposite, it helps the brain,’ ” Si says. “It took us literally fifteen years to figure out whether we were right.”
Si’s lab was the first to suggest that a CPEB, a protein with prion-like properties, may be at the center of a series of biochemical changes at the connection points between brain cells that form the basis for memory persistence. Working with the sea snail Aplysia, a popular model system to study learning and memory, Si and his colleagues later demonstrated that neuronal activity generates prion-like CPEB aggregates and, rather than poisoning a neuron like a harmful prion would, the transformed CPEB protein stabilizes connections between neurons. They also found that, like Aplysia CPEB, an activated fruit fly version called Orb2 undergoes prion-like changes to establish a persistent “memory trace.” In addition, the lab discovered that disrupting Orb2 impaired the formation of long-term memory in fruit flies.
In their 2020 report published in Science, Si and collaborators reported on the structure of Orb2, the first time an amyloid with a known biological function has ever been purified and described structurally from the brain. Surprisingly, the work showed Orb2 may be able to adopt the shape of an amyloid as part of its normal and necessary function. The finding raises two interesting possibilities that the Si Lab is pursuing further – that a similar amyloid also exists in humans, and that other proteins, known to have specific functions, are capable of achieving amyloid states to achieve alternate functions. To find the answers, Si’s lab is analyzing brain specimens from young, healthy patients who have undergone brain surgery, through a partnership with the Department of Neurosurgery at the University of Kansas Medical Center.
“So far we have worked on the snail, fruit fly, and mouse,” Si says. “All these organisms utilize amyloids to store memory. But it is possible that humans are different. And it is true that we have cell types and mental processes that are very distinct. And on top of that, we live much longer than any of these species. So that is the question. Does the human brain utilize amyloids in a completely different way? Or does it not employ such a mechanism to store memory? We’ll see where our research takes us.”It’s that sense of unpredictability, of not knowing what comes next, that energizes Si. “That’s what makes science exciting. That’s the reason you get up in the morning and go to work. I guess it’s also personality. Some people think about what can go wrong. I always think, okay, what could go right?”