Harvard University - Department of Molecular & Cellular Biology


by Cathryn Delude

July 8th, 2013

The MCB department is pleased to announce the tenure of Sharad Ramanathan, Associate professor of Molecular and Cellular Biology and of Applied Physics. Ramanathan embraces the physicist’s ideal that a complex system must have something “simple and pretty” inside, and his quest is to find that beautiful simplicity amid the messy circuitry of both single cells and animals.

“We want to know if we can read the mind of the cell or animal as it is getting information from the environment and making choices,” explains Ramanathan. “How many things do you have to measure? Everything? Or will measuring just a few things still enable you to read the mind of the organism to figure out what it is trying to do? If we knew what variables to measure within the complex system that control the circuitry, we could take control of the circuit and then understand how it works.”

This theme is echoed in an applied math graduate level class Ramanathan helped develop, offered by MCB and the School of Engineering and Applied Sciences. It is about a mathematical framework for making inferences based on incomplete information – the way we perceive 3D images in a 2D photograph, how we make sense of a conversation where the cell phone coverage is poor, or how we recognize a friend’s face even when it is partly obscured by a shadow.

Choosing One’s Fate
In one avenue of research, Ramanathan is looking for ways to infer what is happening in the underlying circuitry of stem cells. Stems cells are pluripotent and can choose among alternate fates: to remain a stem cell, or become one of several kinds of more differentiated progenitor cells. The cell’s decision may ultimately rest on conditions in the cell’s tissue environment, which trigger dynamic changes in a network of transcription signals for gene expression. What are the dynamics of that circuitry as the cell responds to changes in its environment and chooses its fate?

Using techniques from molecular biology and applied mathematics, Ramanathan’s lab is analyzing the temporal changes in the levels of different signaling proteins in the network as cells differentiate. They are finding factors that give the cell the ability to make decisions in the face of conflicting environmental signals.

A Wormy Virtual Reality
Ramanathan’s lab is adapting a similar approach to the nematode Caenorhabditis elegans. This tiny roundworm has only 302 neurons, and researchers have intricately mapped its nervous system and shown which neurons respond to certain conditions. Ramanathan wanted to take control of the relatively simple circuitry that regulates the worm’s response to the presence of food in the environment – turning “the system into a remote control video game and make the worm do what we wanted it to do.”

With post-doctoral researcher Askin Kocabas and graduate student Hannah Shen, he used optogenetics, a new technique of genetically engineering neurons to express proteins called opsins, which can be activated by brief, repetitive pulses of light. Optogenetics gives researchers precise temporal and spatial control over the activity of a selected type of neuron. The technique is widely used in many animals including mice.

To adapt optogenetics to a wiggling, 1mm-long worm, Ramanthan’s lab needed to develop methods to aim a laser beam at a single neuron and track its activity at the same time – made possible by labeling the targeted neuron with fluorescence. Led by Kocabas, the lab overcame this significant engineering obstacle by placing the worm on a moveable stage, and using arrays of micromirrors so the laser stayed focused on the desired neurons. The challenge was “to acquire an image of the animal, process that image, identify the neuron, track the animal, position your laser, and shoot the particular neuron – and do it all in 20 milliseconds, or about 50 times a second,” he told the Harvard Gazette about the study in the September 23, 2012 online issue of Nature.

Ramanathan and coworkers used this technique to trick the worm into believing that it sensed food, and in response the worm changed direction to locate the virtual food. Videos of this deception appeared in the paper’s supplementary materials to the Nature paper and the Gazette story. He hopes this experimental approach will demonstrate what needs to be measured in order to learn how to manipulate circuits and understand what activities they control.

The Road He Traveled Here
Ramanathan hails from India and received a Master’s of Science in Chemistry from the Indian Institute of Technology in Kanpur, India. He completed a doctorate in theoretical physics at Harvard University with Daniel Fisher and then pursued post-doctoral research at the Institute for Theoretical Physics, University of California, Santa Barbara. His researched focused on condensed matter theory and involved using field theory and renormalization group techniques to understand the dynamics of complex random systems.

Ramanathan joined Bell Laboratories in Murray Hill, New Jersey as a member of the technical team in theoretical physics. He had a small office and the freedom to work on whatever inspired him – sheer bliss. Other Bell scientists got him thinking about biological questions, but it was not very satisfying to think about biology in theoretical terms. “I needed to learn to experiment, so I talked with Alex Schier and began hanging out in his lab,” recalls Ramanathan, who soon after met with Andrew Murray. Intrigued, Ramanathan became a Bauer Fellow at Harvard, while still retaining his position at Bell labs. In 2008, he resigned from Bell Labs to become a junior faculty member in MCB and SEAS.

Strength in Ignorance
Learning to do biology was like starting graduate school all over again, but with a lot of mentors and advisors. “All your gods disappear when you change fields,” says Ramanathan. ”I couldn’t have made the switch without the spectacular amount of help from Alex and Andrew, and also Jeff Lichtman, Doug Melton, Catherine Dulac and Erin O’Shea. I harassed and bounced ideas off of them anytime I wanted to.”

“I think my biggest strength is my ignorance,” Ramanathan reflects on his switching fields. “You don’t know what the relevant questions are, and which questions are even answerable. You don’t know how difficult a question is, so you think it’s solvable.” The remote-control optogenetics worm experiment may be a case in point.

Ironically, at Bell Labs he was pushing pencils across papers and never dealt with technical/engineering equipment, so it was only after returning to Harvard to do biology that he learned to build specialized microscopes and cameras with the help of his 9 multi-skilled lab members. Now, they are building a camera and laser system that can track and manipulate the worm’s neurons at double time, 100 times per second.

What plans does he have for his lab now that he has tenure? “We’ll do whatever is fun” – and that’s sure to be challenging.

View Sharad Ramanathan's Faculty Profile