"Synthetic Biology" Yields Bacteria That Take Pictures and Target Tumors

By Jeffrey Norris on June 30, 2006
In the 1966 movie Fantastic Voyage, a submarine crew of medical scientists and their vessel are miniaturized with top-secret technology. They travel the bloodstream of another, full-sized scientist in a quest to vanquish a blood clot in his brain. If you're willing to substitute radically modified bacteria for miniaturized humans - and scientific collegiality for secrecy - then science fiction is getting closer to reality. Researchers at UCSF and at several other leading universities nationwide are engineering bugs to do things they never could do before - including traveling the bloodstream to reach disease targets. No miniaturized submarine crews are at risk, and if a few million bacteria bite the dust, you can always raise more. Synthetic Biology Thinks Big
This emergent scientific field is known as synthetic biology. Goals range far beyond the single-gene manipulation usually associated with genetic engineering. The focus is on the development of cellular components - such as sensors and suites of genes - that can be swapped easily between organisms and assembled into unique "devices." These devices are engineered to perform useful and important tasks, typically within living microbes. "The approach is similar to the design of robotic systems - except that it is being applied at a microscopic scale in living systems," says UCSF's Chris Voigt, PhD, a leading synthetic biologist. For instance, bacteria have environmental sensors that react to stimuli, and integrated circuitry encoded in the genome that guides responses to stimuli. Voigt is creating sensors, linking them in circuits and inducing them to perform useful tasks in unique ways, often in response to variable cues from the surrounding microenvironment. Possible broad applications for synthetic biology include: * the discovery of new treatments for various diseases * new manufacturing processes * green materials * new ways to clean up the environment. ` So far, Voigt's UCSF School of Pharmacy research team has retooled bacteria to display photographic images and to target tumors. Not surprisingly, gut bacteria such as the harmless E. coli strains favored by Voigt and other researchers do not naturally produce photosensors. To create a synthetic "film," graduate student Anselm Levskaya and collaborators linked the input of a red-light-detecting sensor from a blue-green alga to E. coli components. The researchers inserted a gene for a protein that causes the bacteria to make a black pigment. They coupled pigment production to the light sensor, so that pigment would be made only in the dark. The group used stencils to pattern light exposure and produce bacterial photography. Images included a "Hello World" sign, the logo of the journal Nature - where the work was published last fall - and a whimsical "flying spaghetti monster." More important, the work demonstrated the sort of high-resolution spatial control over an engineered output that may be applicable in depositing lithographic materials. Targeting Tumors with Bacteria
Earlier this year, Voigt's group reported another milestone: engineering bacteria to invade tumors. Many types of bacteria preferentially associate with tumor tissue and may grow there at high density. In addition, a tumor often is a low-oxygen environment, compared with normal tissue. Voigt aimed to exploit these phenomena to engineer tumor-sensing bacteria that would enter tumor cells. Such bacteria could be used to get cancer drugs into the cells and kill them. This approach might eventually prove to be as good as, or better than, the use of other vehicles now being investigated for drug delivery, Voigt says. Voigt's group showed that either one of two sensors - one to detect low-oxygen conditions and one to detect cell density - could be linked with another bacterial module to trigger invasion of human cells by engineered E. coli. To sense high bacteria concentrations, postdoctoral fellow Chris Anderson, PhD, used lux, a "quorum-sensing" circuit from a marine bacterium, Vibrio fischeri. Thanks to this circuit, the bacterium is bioluminescent when present at high population density. Such high bacterial concentrations are supported by the nutrient-rich environment within the light-emitting organs of certain squids. Shortly after hatching, the squids selectively recruit the bacteria from surrounding ocean water. The bacteria do not emit light when swimming freely in the ocean at low bacterial concentrations. Anderson linked the lux circuit to a self-contained module, called inv, from another bacterium, Yersinia pseudotuberculosis. When activated, this module triggers production of a protein called invasin, which is sufficient to enable bacteria to invade mammalian cells. When present at high concentrations, E. coli outfitted with the lux circuit and the inv module linked together entered the cancer cells. The researchers also were able to link invasin production and tumor cell invasion to a different promoter of gene activation that is turned on only in response to low-oxygen conditions. "This strategy could be applied to processes other than invasion, such as the release of a therapeutic protein," Voigt says. "The combination of genetic modules encoding sensing, circuitry and actuator functions presents a general platform by which therapeutic functions can be programmed into bacteria."