2003 - Editor’s Note: Dr. Elowitz, along with fellow BWF Interfaces awardee, Dr. Eric Siggia, and two other researchers, published an article that made the cover of the August 16, 2002 issue of Science. The study, “Stochastic Gene Expression in a Single Cell,” revealed that stochasticity (“noise”) in the process of gene expression often leads two nearly identical genes to produce unequal amounts of protein. Noise fundamentally limits the accuracy of gene regulation.
Genetic researcher Dr. Michael Elowitz has designed his own biological clock, not the kind that has to do with reproduction, but a genetic clock he calls the “repressilator.” The clock, which is based on the bacterium Escherichia coli, works according to the oscillations of a series of three genes that are programmed to turn each other on and off. Each of these genes makes repressors that control the expression of the other two. The oscillation is analogous to genetic time-keeping systems found in organisms from Cyanobacteria to humans. Dr. Elowitz and his graduate advisor Dr. Stanislas Leibler published the results of their work on the repressilator in 2000. For the two researchers, it was an opportunity to design a genetic loop from scratch.
A 2002 BWF Career Awardee at the Scientific Interface, Dr. Elowitz is embarking on an exciting new approach to biological research that focuses not only on gene networks found in nature, but also on working from the ground up to build models of these genetic systems.
“It’s not a very good clock,” Dr. Elowitz admits, chuckling. But the primitive system, a first of its kind, has a lot to teach us. In cells, genes are decoded to make proteins in a process called expression. Expression is controlled by repressors, molecules that slow the decoding process by binding to DNA, thus halting the machinery that decodes our genes. Gene networks function because the genes themselves code the repressors—setting up interwoven and constantly reacting systems of expression.
But the erratic repressilator lacks those systems’ accuracy. That raised a fundamental question for Dr. Elowitz: To what extent is a cell’s erratic expression of certain genes due to inherent noise in the cell’s machinery?
Scientists studying a host of diseases, from cancer to anthrax, are constantly identifying the outside factors that lead to inconsistent gene expression. After designing his own genetic clock, however, Dr. Elowitz wanted to see how well the cell’s expression machinery operates when left to its own devices. “In a sense we were getting down to the ‘operational’ level—when the inherent randomness of molecular events affects cellular operations,” says Dr. Elowitz. “What we were trying to figure out, on a basic level, was how well cells are able to control themselves.”
Again, Dr. Elowitz designed his own genetic system, collaborating with three researchers at Rockefeller University—Dr. Peter Swain, Dr. Eric Siggia, and Dr. Arnold Levine—to tackle the problem. This time, the researchers put two virtually identical copies of a gene that makes colored protein onto a single DNA chromosome in an E. coli cell. By monitoring how the different genes, under identical conditions, would express their colored proteins at different rates, Dr. Elowitz was able to quantify just how inaccurate a cell can be at gene expression.
Dr. Elowitz’ s research, still at the basic level, has broad implications for genetics researchers, since he is furthering our understanding of how genes work together. But Dr. Elowitz also is laying the groundwork for an exciting new area of research: biological computing.
The nascent biocomputing movement links the rapidly growing computer and biotech industries. Biocomputing researchers aim to use designed genetic circuits as components in futuristic cell-based computers. Though still fanciful, biological computing components, based in living cells, could offer a stunning array of possibilities.
First, unlike our electronic devices, which can fail even if a single circuit blows, biocomputers could be flexible and adaptable, not crashing after a single error. Second, they could be cheap to make—genetically designed by scientists and then grown in giant batches. Third, they could be lightening fast and flexible, usable as controls for large-scale vats of bacteria to make chemicals or combined with silicon chips to make powerful biosensors.
The genetic networks in human cells already contain what bio-computing researchers consider genetic circuits that perform computations. Many genetic circuits, for instance, make decisions based on the concentrations of various chemicals in the cell’s environment. Dr. Elowitz’s clock is an important man-made circuit. Several years ago, a Boston University graduate student designed a genetic system that could store a 1 or 0 as information. Others, mimicking natural systems that do much the same thing in cells, have created microbial genetic switches that can stay on or off, depending on exterior stimuli. Researchers foresee such simple genetic circuits as building blocks in novel biological devices.
Beyond the exciting and still fictional possibilities, a number of tasks remain on the horizon for Dr. Elowitz, who says he enjoys drawing as a way to unwind after long hours in the laboratory.
He hopes to study whether certain kinds of gene networks in cells work with less noise—less inherent inconsistency—than others, and whether some cells have actually evolved to amplify noise as a way of creating a more diverse population. He then wants to choose several existing gene networks in the body and build synthetic models of the networks. BWF funding, says Dr. Elowitz, has allowed him to explore the unorthodox and yet unexplored field of modeling systems.
Dr. Elowitz says he feels a constant tug between his urge to search for universal principles, as in physics, and the necessity to characterize and understand particular biological systems. “The challenge is to become a good biologist,” says Dr. Elowitz, “without giving up the belief that simplifying principles exist in some form and can be discovered.”
In the meantime, this biologist is focusing on the basics. “Now we want to know how to make—and how cells make—a reliable circuit, and the clock is a good example,” Dr. Elowitz says.