“Lipids are like the pawns in a game of chess,” says Prof. Siddhesh Kamat from IISER Pune and winner of the 2024 Infosys Prize for Life Sciences. “They may look small, but you lose them, and the whole board shifts.”
Tall and broad-shouldered, with a smile that seems to arrive before his words, Siddhesh has an unhurried air about him. He was meant to be rushing off to the airport after our meeting, but you would not know it from the calm way he settled into the conversation.
His lab works at the intersection of chemistry and biology, trying to decode how lipids regulate cellular processes. Lipids are fats and fat-like molecules in the body, and they do much more than just store energy. Some lipids act like signals, helping cells talk to each other. One of the first challenges Siddhesh’s lab took up was lysophosphatidylserine, or lyso-PS for short, a unique signalling lipid linked to a rare neurodegenerative disorder called PHARC. This disease affects the nerves and senses, causing problems with movement, vision, and hearing.
Lyso-PS had long frustrated researchers because it is present only in trace amounts, changes rapidly depending on the cell’s environment, and cannot be tracked by the usual methods of biologists. “There were no antibodies, no chromophores, nothing,” he recalls. Antibodies are proteins that can lock onto a specific molecule and act like a marker while chromophores are chemicals that absorb light and make a molecule easier to detect – common tools that scientists use to understand functions of specific biomolecules, especially proteins.
The only way forward was to create a method from scratch. Siddhesh’s team turned to mass spectrometry, a technique that first turns molecules into charged particles, gently sprays them into the detector which then sorts and weighs them very precisely, like a filter that estimates weights. In biology, the technique is generally used to analyse proteins, which are long linear chains of varying lengths of 20 different amino acids.
On the contrary, lipids are non-linear molecules. That makes them more fragile when scientists try to extract them from the cells. If they are broken at this step, it is difficult to identify the lipid of interest among other cellular debris. Additionally, they are largely made up of varying lengths of only carbon and hydrogen unlike proteins. This is why antibodies or chromophores are almost impossible to develop in the first place for studying lipids. And, then each specific lipid is present in much smaller amounts in cells compared to proteins.
Siddhesh’s lab figured out a gentle organic extraction method to enrich cellular lyso-PS without breaking it, separate it from other cellular metabolites, and adjust the machine so that this rare molecule would give a clear signal. Bit by bit, they built a workflow that allowed lyso-PS to finally show up. This way, what was once invisible now became visible.
That breakthrough changed the direction of the lab. Once they had a reliable handle on lyso-PS, they realised the same strategies could be extended further. They began applying their methods to other molecules: first to lysophospholipids, which are lipids that act as messengers, then to phospholipids, the main building blocks of cell membranes. From there they moved to neutral lipids, the storage form of fat in cells, and then to familiar ones like cholesterol, which helps keep cell membranes stable, and triglycerides, which store energy in the body. Each step required new tweaks, but each step also expanded the range of what could be measured. Over the years, this grew into a full-fledged lipidomics platform, a system to measure and compare all the lipids in pretty much any biological sample, like making a catalog of its fats.
For the first time in India, researchers had access to a platform that could comprehensively map the near complete lipid landscape of a biological sample with depth and precision. “The science really opened up once we could measure these molecules properly,” Siddhesh says. “Suddenly, we were not just answering our own questions, but helping other labs ask new ones.” Today, his lab’s platform supports collaborations in neuroscience, cancer research, infectious biology, and metabolic disease. What began as a technical necessity has grown into a resource for an entire community of researchers.
What does it take to build a lab that achieves both scientific breakthroughs and national recognition?
“For me, it’s about picking the right people. I look for students who are like stem cells, as undifferentiated as possible, open, and ready to grow.” His tone is direct, but there is an ease in the way he talks about his team. He believes in direction, not dictation. “Let them make mistakes. Let them own their projects.”
He also maintains an open-door policy. “If someone knocks, I usually talk,” he says, smiling again. His students have freedom over their schedules, and he stays out of their personal lives unless invited in. “What I can do is create an atmosphere where they’re happy to come in every day and do the work.”
That openness extends to the unexpected directions research can take. “Most failed experiments are just mistakes,” he says. “But sometimes, something you didn’t anticipate shows up. And in today’s world of data-rich experiments, you might find those results are telling you something new, if you’re paying attention.”
His advice to aspiring researchers is simple. “Work hard. Nobody randomly gets lucky. They get lucky because they work hard. Accept that failure is a constant in research. Persevere. And most importantly, do what you like doing. Not what’s popular, not what your friend is doing. That’s the only way you’ll last.”
He also stresses the importance of choosing the right mentor. “It’s like a marriage,” he laughs. “You want to be sure the lab’s culture suits you, and only you can decide that.”
As the interview went on, time kept moving closer to his flight. Yet Siddhesh showed no signs of impatience, still seated with that same easy smile. Like his science, our conversation unfolded with focus and generosity, making room for the possibility that something valuable might emerge if you simply give it the time.
