Splitting up is hard to do. Physics helps.

Biophysicist Sophie Dumont injects her quantitative training into cell biology to solve foundational mysteries.

In 1999, Sophie Dumont couldn’t stop reading about cells. It was problematic; she was a PhD candidate in theoretical physics at the University of Oxford, and had plenty of dense material to parse through for her thesis. But cell biology posed a series of tantalizing mysteries to Dumont, which she believed, as a trained physicist, she was in a unique position to solve. A year later, unable to shake her obsession with biology, she packed up her belongings, flew across the Atlantic Ocean, and began a PhD in biophysics at UC Berkeley.

The cellular process that captivated Dumont was surprisingly ordinary – it occurs hundreds of thousands of times a day in your body. It’s the mechanism by which one cell gives rise to two cells, called cell division. Multicellular organisms rely on cell division to replenish populations of cells that grow old and die over the course of a lifetime. But the details of how an individual cell splits in two were – and still are – somewhat fuzzy. Dumont wanted to understand the physical forces that cells were using to pull themselves apart.

M0016974 Figures showing cell division.
An illustration of cell division by E. and E. Noble Klein and Smith. The black squiggles are the DNA! Image courtesy of the Wellcome Trust.

The most important job a dividing cell must accomplish is a perfectly even allocation of DNA into each new ‘daughter’ cell. Without the correct genetic information, daughter cells quickly perish. It’s a formidable challenge: each cell packs two meters of DNA into a small membrane-bound structure called the nucleus. During cell division, this expanse of DNA is copied and packaged up into structures called chromosomes, the membrane around the nucleus breaks down, and the chromosomes are physically yanked to opposite ends of the cell, endowing each new daughter cell with an identical set of genetic information.

The molecular machinery that accomplishes this feat has captivated biologists for decades. When Dumont arrived in California, biologists believed that cells were using a process somewhat analogous to fly-fishing to move DNA around. It was known that as the cell divides, long protein cables are laid out along its length. One end of the cable to the side of the cell, and the other end attaches to the DNA swimming about in the middle. Researchers thought that these cables were then reeled in from each side of the dividing cell, dragging their DNA cargo along with them.

A video of cell division. The protein cables are stained green, and the DNA is stained red.

However, this model didn’t satisfy Dumont. It relied on there being only two locations at which most of the physical load was borne – one at each end of the cell. All well and good, except for an intriguing property of the protein cables: they are remarkably unstable, with bits falling off and others being restored all of the time. How does such an unstable cable provide the sustained force necessary for such an important process?

Dumont’s idea was that force might be distributed across the cables by way of many points of contact along the cables’ length. Instead of the motor reeling in a solo cable, a set of cables might be interconnected and thereby distribute the load over a larger area — more like a trawling net than a fishing line. That way, even though the cables individually  were unstable, their combined structural stability would allow the DNA to be pulled effectively to each end of the cell.

To test this hypothesis, Dumont needed a way of disrupting the organization of a molecular machine many times smaller than the width of a human hair. She settled on lasers. She reasoned that if she was able to use lasers to cut the cables as they were pulling their DNA cargo, she could distinguish between the two models by watching the recoil from the released tension. If there were only two points of load-bearing, the protein and DNA would snap backwards towards the opposite end of the cell. If the load was distributed over a wide area, cutting just one cable wouldn’t have much effect: the DNA would be held in place, and wouldn’t move far. Dumont and her research team (especially Mary Elting, now a professor at North Carolina State University) fired a strong laser beam at the protein cables in cells that were actively dividing, and took movies of the cables as they broke and their associated DNA.

When the laser beam blasted through the protein cable, the DNA stood still – stabilized in space even though the cable that was supposedly holding it had been cut. Vindication! Dumont has spent the rest of her time as a professor at the University of California, San Francisco characterizing exactly how strong these forces are, where along the length of the cable the bulk of the force rests, and which protein components connect to each other. She’s even sketched out a mathematical model that explains her data, injecting some of the professional bread and butter of theoretical physics into experimental biology.

Dumont’s findings add to the canon of cell biology, and allow researchers to better understand how cell division can go awry in disease. She is one of many physicists who have been inspired to apply a physics mindset to unsolved mysteries in the biosciences. The marriage of these fields allowed her to dissect a complex phenomenon in the cell and reframe it in mathematical terms, leading to her discovery. Interdisciplinary stories like this one are increasingly common, and highlight the importance of out-of-the-box thinking in pushing science forward.

Banner image courtesy of Jane Stout, research associate in the laboratory of Claire Walczak, Indiana University.

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