Breaking into the Cell

Combining mathematics, physics, engineering, and molecular bioscience, Madhav Mani aspires to create a new language that will shape the study of multicellular development for decades

A miraculous little movie dances across the screen of Madhav Mani’s laptop, looping hypnotically every 15 seconds. The silent drama plays out on a stage measured in microns — about the size of a typical bacterium — and depicts the movement of the morphogenetic furrow, or a wave of differentiation, that sweeps through a sheet of cells that will become the hexagonal units of the fruit fly’s eye.

Observing the scene, made possible by relatively recent advances in microscopy, even a secular viewer might be forgiven for interpreting the spectacle as the hand of God exerting a mysterious, transformative effect.

In the furrow’s wake are left cellular clusters. “These cells all get named and do different things: this one absorbs blue light, that one green, that one red,” says Mani, engineering sciences and applied mathematics. He is a basic science researcher who studies multicellular development and differentiation using the tools of physics and quantitative analysis. His work includes live-imaging and mathematical modeling to understand the emergence of an organism’s chemical and physical form in space and time. “We are one of the first labs ever able to make a movie like this.”

And there are more movies, like the one showing the development of C. elegans, a 1mm roundworm. “You’re not looking at an organ,” says Mani, pointing at the computer screen where an orb of green fluorescing proteins reveals cellular division. “This is the entire creature, from one cell to the full organism. You can see there’s a structure here. It doesn’t look like a soup of cells. There’s a program that’s being executed.”

His voice rises with the enthusiasm of a pioneer exploring terra incognita. A native of India who earned honors in math and theoretical physics at Cambridge before getting his doctorate in applied math and physics at Harvard, Mani speaks with a British accent that can settle back into an almost reverential murmur that expresses respect for what he calls “the phenomenon,” the collective cellular and tissue-level mechanisms that generate an organism’s complex cellular differentiation and morphology.

The winner of the prestigious 2016 Simons Foundation Investigator Award, and previously the Simons Postdoctoral Fellowship — just one of 30 awarded to exceptional young scientists nationwide — Mani is among a small community of basic researchers trying to “zoom away from the molecular view of living systems” that has defined the last half-century of foundational research in cell biology. Such work represents a successful model that he respects as the grounds for his own scholarship, but it’s a model that he says has been largely reductionist, focused on individual biological components. Instead, he concentrates on trying to understand the spatial-temporal patterns of development observed in living systems, the emergent and collective dynamics that are apparent during organismal development.

“I focus on geometry, forces, and signaling,” he says. “There’s a pattern that is being collectively sustained through cell-cell communication, alive in these tissues, that’s been unaddressed — even by those studying multicellular organisms.” In large part, Mani says, this is because scientists lack the very means to describe what is happening.

The Arrogance of Science

That is why his chief goal is to create a descriptive language, sufficiently generalizable so as to usher in an era of discovery in multicellular development. He knows it’s a grand challenge, not unlike the phenomenological language that allowed for the conception of Mendel’s laws of inheritance, Darwin’s theory of evolution, or thermodynamics. It’s very much a new field, says Mani, one that required him to write thousands upon thousands of lines of computer code as a postdoctoral student at the Kavli Institute of Theoretical Physics. There, he created the digital tool that allowed him to take images of living tissues as they are developing and to infer patterns of mechanical forces.

Mani’s passion impressed his mentor at Kavli, theoretical physicist Boris Shraiman. “Madhav amazed me by his fearless plunge into a new field as a postdoc,” he recalls. “He emerged with an exciting and ambitious interdisciplinary research program at the interface of biology with physics and math. His creativity and ‘can-do’ attitude, his contagious enthusiasm, and of course his breadth of scientific interests were a great asset for us.”

Today Mani comes across as an exuberant force willing to smash some crockery if it means cooking up a “beautiful idea” possessed of a stunning elegance. “Science is very arrogant,” Mani says, smiling and seeming a bit of the “annoyingly independent” child he recalls being, always ready to argue against tidy theories.

“I don’t just want to solve problems; I want to create problems and puzzles,” he says. “If I have to learn some detailed biochemistry to understand something, or some new aspect of physics, I’ll do it.”

That includes devouring the dictionary-sized Cell book on his desk. “I’ve never taken a biology course in my life,” admits Mani. He loves the phenomena that biologists work on, but the way that physicists and mathematicians explain them is what really attracts him. He harnesses the tools of the physical sciences to help understand living systems, an inherently interdisciplinary effort, though Mani bristles at the term.

“With this kind of science, interdisciplinary ain’t a choice,” he says. “The phenomenon requires it. You walk down the hall and across the bridge here in the Technology Institute to go from the applied math department into biology. That’s all it requires. It is as simple and as difficult as that.”

David Chopp, chair of the Engineering Sciences and Applied Mathematics Department, calls Mani’s work cutting edge. He says traditional qualitative experiments are receding in favor of “more carefully controlled and quantified experiments coupled to mathematics and statistics ... that can help explain biological phenomena and make testable predictions.” He believes that pioneering young faculty, like Madhav, are building “sturdy bridges between applied mathematics and the biological sciences community that will lead to even better fundamental understanding of biological processes.”

Mani says that it’s amazing how chemists, physicists, biologists, and mathematicians can observe the same phenomenon and yet each see something different. “This shows you how important your intellectual background is in shaping perception.”

His collaborations have flourished though. He works side by side with molecular biologists and, together, they create research synergies and experimental designs that include mathematical and physical intuitions right from the beginning, rather than stuck on later as an appendage. Combining these divergent disciplinary approaches helps unpack the complexity of the phenomena Mani studies.

“I’m not looking at a simple experiment where I’m observing a minimal living system. There is no minimal living system,” Mani says. “Our field is looking at complex, evolved organisms, downstream of 3 billion years of evolution. You’re diving in. That is a reason that many people don’t do what I do.”

By Matt GolosinskiFebruary 14, 2018