On a bookshelf in his office, MCB Professor of Molecular and Cellular Biology Philippe Cluzel keeps several beautifully bound leather tomes from his parents’ antiquarian bookstore in Paris’s Quartier Latin. One of these is a small, 19th century edition on phrenology. “When I was growing up, I was fascinated by the birth of new sciences. This book about a dubious science stood next to one on thermodynamics. I wondered what kind of argument makes something scientific when you are starting in a new direction.”
It’s a question he still contemplates in his lab in the Northwest Building, home of the emerging science of systems biology. It was Harvard’s commitment to this symbiosis of physical and biological sciences that attracted Cluzel here in 2008 with an appointment in the FAS Center for Systems Biology, the School of Engineering and Applied Sciences, and MCB.
Cluzel hopes this new scientific direction can explain the universal rules of nature. He himself focuses on signaling networks in bacterial chemotaxis, or locomotion. Signaling networks are ubiquitous in nature, including in cell division and – when cell division goes awry – in cancer. He hopes to discover their common design for relaying chemical signals among their various cellular components. It’s a long way from where he started when he entered science – or is it?
As a child, Cluzel liked to “fiddle” around and dream up things to build. For a while, he thought of becoming a chef. But his love of tinkering led him to pursue a bachelor’s and master’s degree in physics at the Paris VI University. For Ph.D. work starting in 1993, he attended the Institut Marie Curie in Paris, one of many universities in the Quartier Latin. There, he tackled big questions, like particle physics, that required big projects and big teams. But it was a collective tinkering; perhaps biology could offer more individualistic adventures. But there were so many talented biologists. What would they need a physicist for?
He discussed this question with another physicist-turning-biologist, Didier Chatenay, who became one of his dual Ph.D. advisors. “We thought biologists are very good with details, genes, and proteins,” Cluzel says. “But we physicists are good at ignoring details and looking at patterns, structural homologies, analogies, and the cohesive grammar of components that can apply to many organisms. If one system looks like another one, maybe they function in the same way and obey the same rules.” As outsiders to biology, physicists could offer a fresh look at old data and possibly fresh solutions to long-standing problems. So Cluzel tried to develop a new way to sequence DNA by measuring the force fields when unzipping the double-stranded helix.
“It didn’t work at all,” he notes wryly. “But it started a new field called micro-manipulation of individual molecules,” probing the interactions of proteins and nucleic acids at the single molecule level. This approach has detected variations in the behavior of single molecules that are masked at the population level, revealing that molecules have their own individuality. “They look identical but when you study them one by one, you see different rates of enzyme activity, for example.”
It is common to miss such variations by averaging the activity of many molecules, discarding outlier information as distractions. “But in physics, we find deviations informative because they show us how the system is designed. It’s a good perspective to bring to biology too,” not least because outliers can be important for species survival if they have evolved adaptive mutations.
He took this perspective to his post-doctoral research on bacterial chemotaxis at Princeton University in 1996. By studying bacteria in motion one by one, he discovered that bacteria also exhibit individual variability that reflects the design of their biological networks.
At Princeton, Cluzel joined the lab of Stanislas Leibler, who had assembled “the right mix” of physicists amid biologists, a rarity at that time. In work he continued in his own lab at the University of Chicago, Cluzel studied how biochemical signals direct the rotation of the flagella that propel the bacterium through its environment in search of nutrients and away from toxins. When this motor spins counterclockwise, the bacterium swims forward, and when it spins clockwise, it tumbles to change directions. “When life gets better, it tumbles less because it’s swimming in the right direction. When life gets worse, it tumbles more to find a better direction. It’s a random walk biased towards a better life.”
By sensing changes in the environment, the bacterium “decides” whether to swim or tumble. Given genetically identical bacteria in identical condition, it would seem they would all make the same decision. But au contraire, Cluzel discovered. To decipher the origin of this cellular variability, he adapted tools from physics to measure in real time the molecular interactions within single living cells. He compares it to determining why some seemingly identical watches run faster or slower by examining how their wheels and gears interact. He believes that understanding the variation in signal transduction in chemotaxis – why one outlier E. coli decides differently from its mates – will provide insights into why some cells in other biological systems make the wrong decision and can become malignant.
While at Chicago, Cluzel began looking at the relationship between the network design and its function. He noticed that some networks are more robust, more sensitive to molecular variability, and more prone to evolve. Also, natural networks, genetic networks, social networks, and computer networks all exhibit a similar architecture. They are all structured heterogeneously and scale-free, like an airline with a few centrally connected hubs and many other sparsely connected ports.
Why does nature – and the human mind – select these scale-free networks? By developing computer models that simulate chemotaxis in “virtual” E. coli, Cluzel’s group compared how the cells adapt to changing conditions in a scale-free network versus a random network designed so that all components are equally connected. The scale-free network conferred an evolutionary advantage, because the virtual bacteria could evolve to perform new tasks much more quickly and evenly.
Now at Harvard, Cluzel has the biologists in his “melting pot” lab testing hypotheses generated by this simulation of scale-free network design on living E. coli, and the physical and computer scientists are using the results to improve the simulation and to fine-tune the model of the signal transduction network.
“A systems biology lab is great for students who like fiddling, developing their own tools, building instruments, modeling, and testing. It takes an adventurous mind. It’s revisiting the science of the last century tinkerer,” Cluzel muses, and it’s what he was looking for as a youth.
A Literal Revolution
It’s too early to tell how the books about systems biology will be arranged on the shelves of future antiquarian bookstores, or if this work-in-progress will be considered a scientific revolution in the “radical departure” sense. But in the physical sense, systems biology is a revolution – a returning to the beginning point. “We’re revisiting systems worked out by biologists, such as bacterial chemotaxis, and looking at it from a new point of view. This helps us to see if we really understand it beyond the molecular description. Can we predict the behavior of individual cells or the trajectory of particles?”
This revolutionary spirit might be infectious. Cluzel finds other MCB members open and eager to engage with systems biology. “More colleagues are aware of the new tools, and I’m forging new relationship and new projects in many different directions. I’m also very happy to be in the same department with Howard C. Berg, who is a pioneer in bacterial chemotaxis,” and the Herchel Smith Professor of Physics and Professor of Molecular and Cellular Biology.
Besides this academic enthusiasm, Cluzel has other reasons to be happy at Harvard. Like the Quartier Latin, the Cambridge area has many universities, an innovative spirit, and good oysters. “It’s a good homolog, so it feels a bit like home.”