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Biology and physics rendezvous at the membrane

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Science  08 Dec 2017:
Vol. 358, Issue 6368, pp. 1265
DOI: 10.1126/science.aar2002

How cells absorb materials from their environment has, for decades, fascinated biologists and physicists alike. At the heart of this phenomenon is endocytosis, a mechanism that enables signaling among cells, synaptic transmission, intake of nutrients from the environment, and immune response, but also infection (1).

For any of these processes to take place, the cargo must pass through a lipid membrane, a largely impenetrable interface between the cell and its surroundings. What makes physicists interested in this biological question? It turns out that the behavior of biological membranes is deeply rooted in physics.

An important physical feature of biomembranes is that, although their surface is very large, their thickness spans only two molecules. This incredible separation of sizes allows membranes to keep many properties of a liquid, while at the same time behaving like tough elastic solids (2).

Biology and physics are no strangers to each other. A hundred years ago, D'Arcy Thompson used physical laws to explain many mechanisms of the living world, from setting the scaling that determines an animal's size to making analogies between cells and soaps in order to describe the growth of tissues, in his tremendously influential book, On Growth and Form (3).

Inspired by such quantitative thinking about life, I sought training in theory and experimental biophysics while passionately pursuing biological questions. I deeply wondered to what extent cells use basic physical principles to control crucial biological phenomena.

At the Curie Institute in Paris and at the University of Chicago, I teamed up with theorists, experimental physicists, and cell biologists to study protein trafficking into the cell. For years the canonical picture of endocytosis included a large number of players: clathrin, dynamin, and many other proteins, all intricately orchestrated to form complex structures that bend and cut the membrane (4). We noticed that some cargoes, including important signaling proteins and pathogens, completely bypass this pathway and require only a protein couple, BAR proteins, and molecular motors (5, 6). An added surprise was that this pathway took place very rapidly (5, 6). The mechanism we discovered hence demanded a much simpler explanation than endocytosis as we hitherto understood it.

As true physicists, our approach was a reductionist one. We built the minimal components that we believed cells require to absorb material via endocytosis, constructing microscopic lipid vesicles to represent cells. With laser tweezers, we manipulated their shape and mechanical properties, building thin-membrane nanotubes that mimic invaginations in the cell created by the cargo.

We first explored the mechanical role of BAR proteins, potent curvature generators in the cell (7). By combining physical modeling with experimental work, we found that BAR proteins make use of thermal fluctuations—the wavy motion of the membrane—to rapidly polymerize into exquisitely designed structures on the inner membrane surface (810). This architecture acts as scaffolding for the membrane, forcing it to bend into very thin tubules (11). The cargo on the outer side exploits these thin tubules to penetrate the cell.

Physics-based mechanism of membrane scission during nontraditional endocytosis

PHOTOS: (TOP TO BOTTOM) MIJO SIMUNOVIC; (12)

Remember, however, that the membrane is resilient, flexible, and fluid. How then can the tubule break to release the material into the cell's lumen? Quite accidentally, I found that tugging on a membrane tubule scaffolded by BAR proteins causes it to break (5).

It appears that a protein scaffold creates a barrier impeding the normal fluid flow of the components from the cell membrane into the tubule. Once we start to pull, the friction between the protein scaffold and the membrane underneath creates pores in the tubule, eventually completely disrupting it.

It is not difficult to understand such a mechanism. Consider pulling a cooked noodle out of a jar of honey (see the bottom photo). The noodle is elastic and will stretch for a short while; however, due to the viscosity of the honey and the friction between the two components, the noodle will eventually give in and break.

There are many motor proteins in the cell that can provide such a pulling force. Indeed, we found that a protein dynein tugs on scaffolded tubes filled with the incoming cargo, thus closing the loop on this biological phenomenon (12).

This membrane-cutting mechanism is simple, requires only a few components, and is quite intuitive (see the top photo). It has broad implications in cellular trafficking, potentially explaining many pathways that for years have remained elusive. This rendezvous of biology and physics exemplifies the symbiotic relationship between the two fields, creating so much more than the sum of its parts.

PHOTO: COURTESY OF MIJO SIMUNOVIC

FINALIST: CELL AND MOLECULAR BIOLOGY

Mijo Simunovic

A native of Europe, Mijo Simunovic sought higher education in the United States and in France, earning a Ph.D. in theoretical chemistry from the University of Chicago and a Ph.D. in experimental physics from the University of Paris. In his scientific work, he pursues complex biological problems that are fundamentally driven by physics. Currently, he is at The Rockefeller University where, as a junior fellow of the Simons Society, he uses stem cells to build experimental models of the human embryo, aimed at elucidating the earliest events in human development. Simunovic is passionate about teaching, having served as a teaching consultant at the University of Chicago and instructed undergraduate biophysics courses in Chicago and New York. www.sciencemag.org/content/358/6368/1265.3

References and Notes

  1. Acknowledgments: I am indebted to all our collaborators who inspired us to pursue this biological phenomenon and for making this research possible. Most important, I am thankful to my Ph.D. advisers, G. A. Voth at the University of Chicago and P. Bassereau at the Curie Institute, all the members of the Voth and Bassereau groups, and especially A. Callan-Jones and C. Prévost.

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