Bioengineering, Systems Biology
California Institute of Technology
Dr. Elowitz is also a professor of biology, bioengineering, and applied physics at the California Institute of Technology.
Dynamic Gene Circuits at the Single-Cell Level
Like the flickering green bacteria in one of his best known experiments, Michael Elowitz is a leading light in the field of synthetic biology.
In 2000, Elowitz broke open the fledgling science, which is concerned with understanding and building genetic circuits, by programming E. coli bacteria to blink like Christmas lights. The bacteria glow green after three genes in a looped sequence repress the next, one by one, and then spark a gene that turns on a fluorescent protein. After the circuit runs its course, the bacteria stop making the fluorescent protein and turn off until the cycle repeats.
"It's like a game of rock-paper-scissors," says Elowitz, who did the work with his adviser Stanislas Leibler. "You have three genes, and each one represses the next one." In the game, rock hammers scissors, scissors cut paper, and paper smothers rock. Except in this case, the final step also launches a flare.
Biologists told Elowitz the experiment wouldn't work—you can build and insert a new genetic circuit into living bacteria, but its behavior would be unpredictable. But it did work, and in 2000 the "Repressilator"—so called because it's a repressing oscillator—became one of the first human-made genetic circuits to operate inside an organism.
"I thought it had to work," says Elowitz. "But at the same time, the first time I saw it working, I was surprised. I was stunned, even."
Elowitz chose to develop an oscillator as his first genetic circuit for three reasons. First, as a trained physicist he knew that oscillators were workhorses in many physical systems. "A lot of things come down to simple harmonic oscillations," he says, such as a weight bobbing on a spring or swinging on a pendulum. Second, while a graduate student in Liebler's lab at Princeton University, he had become fascinated by biological oscillations, specifically, the natural clocks that dictate circadian rhythms. And finally, Elowitz says, "It seemed like a lot of fun to be able to program cells to flash on and off."
The urge to build genetic circuits surfaced early as Elowitz made the transition from physics to biology. As he read reams of genetics and molecular biology papers, Elowitz grew frustrated with the simple schematics that purported to describe how genes interact. "There was no sense of how well these diagrams could explain the complex behavior of the cell," he says. "It seemed pretty clear that if you really wanted to understand it, you had to start simple, and put together a minimal circuit from scratch."
Now Elowitz spends his time trying to dissect how key genetic circuits operate inside cells. "What do cells do?" he asks. "They control their own growth and development, they communicate with other cells, they differentiate, and they form structures. How they do each of these things is a fundamental question in biology. We're trying to understand them from the bottom up."
He's particularly interested in learning how cells make decisions about what type of cell to become. To delve into this phenomenon, he chose a model bacterium called Bacillus subtilis, which sometimes switches on a program that lets it gobble up DNA from its environment. This state, called competence, happens seemingly spontaneously. And in a dish of genetically identical B. subtilis, only 5–10 percent of the bacteria will flip into competence mode. "Why is it when you put these identical cells in the same environment, they do different things?" asks Elowitz. "It illustrates a basic phenomenon in biology. There's a lot of variability among cells that is not genetic."
Using methods he developed—such as a means to track and make movies of individual bacteria as they switch certain genes on and off—Elowitz, his postdoctoral fellow Gürol Süel, and his collaborator Jordi Garcia-Ojalvo discovered that competence is triggered by natural and random fluctuations inside individual cells. That is, sometimes one of the bacteria randomly makes a larger-than-normal amount of a specific protein. This excess protein then triggers the genetic competence program, causing the cell to become competent for a while and then switch back to its original state.
This research was built on discoveries that Elowitz, working with Peter Swain and other colleagues at the Rockefeller University, published in 2002. They showed that key properties of the cell, such as how actively it turns out different proteins, are intrinsically random. This principle overturns decades of dogma that said that genes—and networks of genes—operate in a completely predictable and fixed fashion.
This principle may apply not just in bacteria but also in complex multicellular organisms, like people, that grow and develop from a single cell. Elowitz is now asking how randomness is used, somewhat paradoxically, to more accurately control the shapes and patterns that make organisms work. To do that, he is trying to see whether methods like those he's used in bacteria can also work in the much larger and more complex animal cells. While these projects are just beginning, Elowitz is hopeful they will someday help us to better understand, and control, the behavior of both bacterial and animal cells.