Organisms from fruit flies to humans are governed by cycles of hunger, fatigue, and fertility. Aware that simple systems can illuminate complex ones, Michael Laub studies the circuits of genes and proteins that drive biological cycles on a very small scale—inside a single-celled microbe.
Laub's organism of choice is the bacterium Caulobacter crescentus, which lives in freshwater lakes and streams. C. crescentus is an ideal model organism for the study of cell cycles, says Laub. Unlike most other bacteria, it copies its circular chromosome only during a specific window of time during the cell cycle. That duplication must be carefully regulated by the numerous genes and proteins that control the organism's cell cycle, the series of events leading to the cell's division.
"An oscillation [or biological cycle] is never controlled by a single gene or protein," Laub explains. Progression through the cell cycle requires the coordination of DNA replication, chromosome segregation, and cell division. To ensure each process occurs at the right time and in the right order, "a circuitry of many genes and proteins underlies the ability of the cell to divide such that each daughter cell inherits a copy of the genome."
Laub has produced a model of the C. crescentus life cycle with key molecules he has identified, their connections to each other, and the feedback loops that regulate them. He has also shown that the circuit architecture, if not the proteins themselves, is similar to that found in the cells of complex organisms, including humans.
Laub first became interested in biological cycles—and research itself—during his junior year of college, while studying the slime mold Dictyostelium discoideum, an ideal model organism for studying multicellularity and development. "I learned I love the craft of working with my hands, seeing first-hand the results of experiments, and the dynamic aspect of biological systems," he says. Dictyostelium fascinated Laub because its development relies on the release, every seven minutes, of the key messenger molecule known as cyclic AMP, which transmits signals between cells.
Interested in the genes that control such cycles, Laub began working with C. crescentus as a graduate student at Stanford. With a homemade microarray—thousands of tiny daubs of DNA designed to be studied at once—he found hundreds of genes that ensure the bacterium divides only when nutrients are just right. "It hadn't been shown before that bacteria could increase and decrease expression of many genes specifically at the time they are needed," he notes.
As a research fellow at Harvard and later as an independent investigator at the Massachusetts Institute of Technology, Laub began to look at the circuits that determine when the genes are turned on or off during the cell cycle. "I wanted to know what pulls the puppet strings," he says. He found that messages from the outside world—such as changes in temperature or nutrient availability—are relayed to the proteins and DNA in the bacterium's cell division circuit by a series of distinct chemical reactions.
In the end, says Laub, even the smallest pieces of the puzzle reveal something about the cycles that govern life. The C. crescentus cell cycle, says Laub, "is a tractable model system for understanding the design principles of [biological cycles] found throughout biology."