Their latest achievement, detailed in a paper published in the January 21 issue of the journal Nature, is a crucial step in creating genetic sensors that might one day provide humans with advance information about temperature, poisons and other potential hazards in the environment by monitoring changes in the bacterium’s blinking rates.

“Programming living cells is one defining goal of the new field of synthetic biology,” said Jeff Hasty, associate professor of biology and bioengineering at UCSD who headed the research team with Lev Tsimring, associate director of UCSD’s BioCircuits Institute.

“Dr. Hasty and colleagues have used powerful genetic tools, backed by decades of detailed knowledge of bacterial processes, to create a system that delivers on the promise of synthetic biology — to engineer living organisms to meet pressing societal needs,” said James Anderson, who oversees computational biology grants at the NIH’s National Institute of General Medical Sciences. “The oscillating system they engineered sets the stage for the development of highly sensitive sensors that could have multiple applications in basic research, biotechnology and medicine.”

“Synchronization of clocks and oscillators in general has been a fascinating subject for physicists and applied mathematicians for centuries,” said Tsimring. “This began with the Dutch mathematician and astronomer Christiaan Huygens, who is credited with its serendipitous discovery in 1665 when he suspended a pair of nearly identical pendulum clocks (which he invented and patented some 8 years earlier) on the same wooden beam.”

“Synchronization plays a crucial role in physics and biology as a way of self-organization of highly regular behavior with less that perfect components. This phenomenon has a myriad of applications in modern technology, from communication networks to GPS. Our study demonstrates how inherently noisy gene oscillators can operate together with beautiful synchronicity and regularity once coupled together in a specific way.”

Over the past decade, researchers have gone from wiring genetic toggle switches and oscillators in living cells to building living circuits capable of pattern generation, noise shaping, edge detection and event counting. In their latest development, the UCSD researchers took advantage of a type of bacterial communication in which bacteria exchange small molecules.

“Many bacteria species are known to communicate by a mechanism known as quorum sensing, that is, relaying between them small molecules to trigger various behaviors,” said Hasty. “Other bacteria are known to disrupt this communication mechanism by degrading these relay molecules.”

Taking these communication elements from different organisms, Hasty and his team of researchers — who included UCSD bioengineering graduate students Tal Danino and Octavio Mondragon — designed and constructed a network in the genetic model bacterium E. coli with positive and negative feedback components to produce a colony of synchronized clocks.

Hasty said the architecture of the circuit is similar to his team’s previous genetic clock (see: here), but with the quorum sensing components allowing the phase information — that is, the oscillations between the bacterial cells — to be relayed.

The researchers constructed devices to precisely control the sizes of the bacterial colonies between two different scales: a micron, or a millionth of a meter, and a millimeter, or one-thousandth of a meter. At the micron scales, Hasty said the cells in the colonies oscillate synchronously from 50 to 90 minutes, a period that can be tuned externally. But at the longer, or millimeter scales, he noted, the time for diffusion of the signal becomes more important, allowing the researchers to actually observe the propagation of the signal through the colony.

“The use of quorum sensing is a promising approach to increase the sensitivity and robustness of the dynamic response to external signals,” said Hasty. “In nature, synchronization typically helps stabilize a desired behavior arising from a network of intrinsically noisy and unreliable elements. We think the synchronized genetic clock sets the stage for the use of microbes as a macroscopic biosensor with oscillatory output, or applications of using a synchronized periodic signal in drug delivery.”

The scientists received funding for their development from the National Institute of General Medical Sciences, which is part of the National Institutes of Health.

Disinfectants are the first line of defense against the spread of hospital-acquired infections and effective cleaning of surgical instruments is vital to beating them.

The German formula works against a wide range of germs, including some that survive ordinary disinfectants, such as Mycobacterium avium bacteria which can cause a tuberculosis-type illness and enteroviruses that may cause polio.

Drug-resistant bacteria, the so-called “superbugs,” are a growing problem in hospitals worldwide and poor hygiene among staff is often blamed for the spread of such infections. They kill about 25,000 people a year in Europe and about 19,000 in the United States.

In previous studies, the German team found a simple alkaline detergent that could eradicate prions — disease-causing proteins that are particularly hard to get rid of because they can become fixed onto surfaces through the use of some conventional disinfectants.

In their new study, Michael Beekes and Martin Mielke from the Institute’s hygiene department mixed the alkaline with varying amounts of alcohol and tested its ability to rid surgical instruments of bacteria, viruses and fungi and prions. They found that a mixture with 20 percent alcohol was best.

Beekes said he thought the new disinfectant could have a huge impact on hospital safety protocols.

“Standard formulations that eliminate prions are very corrosive,” he said in the study published in the Journal of General Virology.

“The solution we’ve come up with is not only safer and more material-friendly, but easy to prepare, cheap and highly effective against a wide variety of infectious agents.”

A Dutch study published last week found that the methicillin-resistant staphylococcus aureus (MRSA) superbug, which can cause blood poisoning, spreads not freely but in clusters, suggesting it is spread through healthcare systems by patients being repeatedly admitted to different hospitals.

For the last few years, Redinbo and his team has been working in close collaboration with Matthew C. Wolfgang, Ph.D., an assistant professor of microbiology and immunology and a member of the Cystic Fibrosis/Pulmonary Research and Treatment Center at UNC, trying to out how bacteria’s tiny legs or pili function. The researchers began to look at one of the many types of pili, called type IV pili. Type IV pili are basically long, dense fibers that bacteria assemble (extension) or disassemble (retraction) quite quickly.

“These pili act as grappling hooks — the bacteria extend the fibers out, the fibers attach or stick to a surface, and then retracted back into the bacteria, pulling it along,” said Wolfgang. “This crawling movement is called twitching motility, and without it Pseudomonas, a common cause of hospital-acquired pneumonia would never be able to move from the lung tissue into the bloodstream, where the infection becomes lethal.”

The researchers knew that inside the cell lie the tiny little motors — called ATPases — that drive the extension and retraction of the pili. One of these ATPases is the extension motor, which sticks the bacteria’s leg out. The other ATPase is the retraction motor, which pulls it back in. But what wasn’t clear was how the two motors were coordinated so that pushing and pulling didn’t occur at the same time. That is what Redinbo and Wolfgang set out to discover.

First, they resolved the crystal structure of the Pseudomonas PilY1 protein, which other research had shown was necessary for the creation of pili. They made large amounts of the protein, coaxed it out of solution so that it formed a crystal, and then put the crystal under intense x-ray beams through a process called x-ray diffraction that resulted in a series of spots. Based on the spots, the researchers calculated what the protein looked like. When they studied the structure, one particular site — the binding site of a calcium atom — looked like it could be important for the function of the protein. So the researchers began to tinker with the site, looking to see if the changes they made affected the protein’s behavior.

When they changed the protein so it could no longer bind calcium, the bacteria couldn’t make any legs. When they fooled the protein into thinking it was forever bound to calcium, the bacteria made legs but couldn’t retract them, essentially becoming paralyzed. The results suggested that the protein has to bind calcium to make legs, but it also has to be able to let go of the calcium to pull the legs back in.

“We found it pretty remarkable that the binding of a single atom to a protein that is outside the cell is sufficient to tell these motors that are inside the cell to either stop pushing or stop pulling,” said Redinbo. He says they are currently using a combination of genetics and biochemistry to out how this long-distance communication is possible.

The research was funded by the National Institutes of Health and the Howard Hughes Medical Institute. Study co-authors from UNC include graduate students Jillian Orans, Michael D. L. Johnson, Kimberly A. Coggan, Justin R. Sperlazza and Ryan W. Heiniger.