Roop Mallik: From machines to molecular motors

Like everyone else, I grew up reading things such as, “Electrons move in orbits around the nucleus.” However, there was no way to see this happening. The fact that you could actually see motor-driven cargoes moving around blew my mind. The idea that I could build an instrument (an optical trap) to measure the forces from motors as they tug cargo along . . . that was the icing on the cake.

Motors spend their lives pulling against lipid membranes in the cell, yet we know remarkably little about what the membrane and the motor mean to each other. In this context, we are focusing on phagosome maturation. Micrometer-sized particles (e.g., bacteria and parasites) are ingested by immune cells and enclosed within a lipid membrane to make a phagosome. Phagosome maturation is intimately connected to the spatiotemporal location of the phagosome inside cells. Motors carry the phagosome around so that it can interact with other organelles to exchange lipids and proteins by kiss-and-run fusion. These interactions ensure a phagosome’s maturation and eventual fusion of its contents with lysosomes.

We recently showed that the dynein motor undergoes geometrical reorganization to cluster into cholesterol-rich lipid rafts on the membrane of a maturing phagosome (1). This reorganization propels the phagosome toward degradative lysosomes by allowing many dyneins to generate collective force together against a microtubule. This is exciting because many pathogens survive by “hijacking” lipid rafts (2). Indeed we showed that Leishmania actually uses a glycolipid called lipophosphoglycans to disrupt the clustering of dynein into lipid rafts, thereby blocking transport of phagosomes toward lysosomes (1). These investigations followed up on an earlier realization that dynein’s single-molecule architecture specially adapts it to work well in a team (3, 4, 5).

In the long run, I am also very interested to understand how motors control secretion of lipoproteins (VLDL) from the liver and if this is dependent on the feeding/fasting state of the animal (6). We are developing a hypothesis about how metabolic signals control motor-driven transport of lipid droplets and their consequent interactions with other organelles inside hepatocytes.

I always visualize a cellular process as a series of events happening at distinct time points and locations inside the cell. When building a hypothesis, the molecules are less important to me. I always worry more about geometry and causality. This is a pleasant hangover from my earlier life as a physicist. I wonder if traditional cell biologists think similarly. I have never asked them.

To value diversity: diversity of approaches to a problem, diversity in the people who make up a laboratory, how they think, how they react to a situation, etc. This is one reason I returned to India to set up my laboratory. There is a larger standard deviation associated with everything here. I like it.

My biggest accomplishment is a laboratory where my colleagues want to get to work every morning. They argue passionately about what they do, defend it with zeal, and are upset when things don’t work. I do not ask for anything more.

My mother, who carried on working very hard in spite of physical disability. She taught me not to complain. E.V. Sampathkumaran, from whom I learned the importance of building trust with my students. G. Krishnamoorthy, who guided me when I transitioned into biology. Steve Gross, from whom I learned to ask real biological questions and not just pretend to do biology as a physicist. My wife and colleague, Sreelaja, who was there to help when I didn’t know how a protein was different from DNA.

Judge when a project is not working, and stop it if you have to.

I often go hiking solo to remote mountains and fortresses. These abandoned places fascinate me because here I can imagine events, ways of living, and people who are long gone. I also love sports and play regularly (table tennis and badminton).

I always wanted to be a waiter in a restaurant because I imagined that I could gorge on the food at my lunch break. I also wanted to be a veterinary doctor, because I am very inspired by the writings of James Herriot.

I wrote a script and directed a few plays when I was in college. I cannot think of anything more difficult than that one.

To quote William McFee, “The world belongs to the enthusiast who keeps cool.”