The ability to program living holds tremendous potential for energy, agriculture, water remediation and medicine, and synthetic biology is on the case.
Researchers have already designed a 'tool box' of small genetic components that act as intracellular switches, logic gates, counters and oscillators but wiring those components together to form larger circuits that can function as 'genetic programs' has been difficult, because of the small number of available wires.
Okay, no more metaphors, you get the idea. A new paper describes development of a rapid and tunable post-translational coupling for genetic circuits. The advance builds on development of biopixel (square trap) sensor arrays by the same group of scientists two years ago (Nature 481, 39-44 doi:10.1038/nature10722).
Independent genetic circuits are linked within single cells, illustrated under the magnifying glass, then coupled via quorum sensing at the colony level. Credit: Arthur Prindle, UC San Diego
The problem the researchers solved arises from the noisy cellular environment that tends to lead to highly variable circuit performance. The components of a cell are intermixed, crowded and constantly bumping into each other. This makes it difficult to reuse parts in different parts of a program, limiting the total number of available parts and wires. These difficulties hindered the creation of genetic programs that can read the cellular environment and react with the execution of a sequence of instructions.
The team’s breakthrough involves another metaphor - it is like a form of “frequency multiplexing” iny FM radio.
“This circuit lets us encode multiple independent environmental inputs into a single time series,” said Arthur Prindle, a bioengineering graduate student at U.C. San Diego and the first author of the study. “Multiple pieces of information are transferred using the same part. It works by using distinct frequencies to transmit different signals on a common channel.”
The key that enabled this breakthrough is the use of frequency, rather than amplitude, to convey information. “Combining two biological signals using amplitude is difficult because measurements of amplitude involve fluorescence and are usually relative. It’s not easy to separate out the contribution of each signal,” said Prindle. “When we use frequency, these relative measurements are made with respect to time, and can be readily extracted by measuring the time between peaks using any one of several analytical methods.”
Microfluidic device containing an array of biopixels (square traps) in which bacteria grow. Credit: Arthur Prindle, UC San Diego
While their application may be inspired by electronics, they caution in their paper against what they see as increasing “metaphorization” of engineering biology. We were guilty of that in the first two paragraphs of this article, but without metaphors synthetic biology can be arcane. Colloquially people understand engineering and circuits as concepts, even if they can't build them.
“We explicitly make the point that since biology is often too intertwined to engineer in the way we are accustomed in electronics, we must deal directly with bidirectional coupling and quantitatively understand its effects using computational models,” explained Prindle. “It’s important to find the right dose of inspiration from engineering concepts while making sure you aren’t being too reliant on your engineering metaphors.”
Enabling this breakthrough is the development of an intracellular wiring mechanism that enables rapid transmission of protein signals between the individual modules. The new wiring mechanism was inspired by a previous study in the lab on the bacterial stress response. It reduces the time lags that develop as a consequence of using proteins to activate or repress genes.
“The new coupling method is capable of reducing the signaling time delay between individual genetic circuits by more than an order of magnitude,” said Jeff Hasty, a professor of biology and bioengineering at UC San Diego who headed the team of researchers and co-directs the university’s BioCircuits Institute. “The state of the art has been about 20 to 40 minutes, but we can now do it in less than one minute.”
“What’s really exciting about this coupling method is the particular way we did it,” said Prindle. “Rather than trying to build from scratch, we made use of the enzyme machinery that the cell uses for rapid and precise signaling during times of stress. This is an appealing strategy because it lets us take advantage of the advanced machinery that nature has already evolved.”
Citation: Arthur Prindle, Jangir Selimkhanov, Howard Li, Ivan Razinkov, Lev S. Tsimring, Jeff Hasty, 'Rapid and tunable post-translational coupling of genetic circuits', Nature 508, 387–391 17 April 2014 doi:10.1038/nature13238
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