Synthetic Gene Circuits Process Analog and Digital Signals

Living cells can perform complex computations on the environmental signals they encounter, such as the analog signals found in human voices or vision and digital computations based on on/off processes such as a cell initiating its own death.

So far, synthetic biological systems have focused on either analog or digital processing. Motivated to expand possible applications, MIT engineers have created a way of processing both analog and digital computations in living cells. The resulting gene circuits could carry out complex computations.

Synthetic Biological Circuits

When an analog input is measured, such as a particular chemical relevant to a disease, the synthetic circuit turns on an output such as the drug to treat the disease if the level is within the correct range. Comparators are electronic devices that have two analog inputs; they then output a digital signal indicating the larger analog signal. Similar to the comparator, the analog input signals of the synthetic devices are converted into a digital output.

Analog signal: a continuous sine waves of varying length and amplitude.

According to lead researcher Timothy Lu, an associate professor of electrical engineering and computer science and of biological engineering at MIT, “Most of the work in synthetic biology has focused on the digital approach, because [digital systems] are much easier to program.”

Digital signal based on a binary system.

“Digital is basically a way of computing in which you get intelligence out of very simple parts because each part only does a very simple thing. But when you put them all together, you get something that is very smart,” said Lu. “However that requires you to be able to put many of these parts together, and the challenge in biology, at least currently, is that you can’t assemble billions of transistors like you can on a piece of silicon.”

Sending Mixed Signals

Lu and former microbiology PhD student Jacob Rubens were able to create the device based on multiple elements. A threshold module detects analog levels of a particular chemical by means of sensors. This threshold can control the recombination enzyme recombinase, which can switch a segment of DNA by inverting it.

In other words, it is converted into a digital output. When chemical concentrations reach a certain level, the threshold module expresses the recombinase gene, flipping the DNA segment, which also contains a gene regulatory element capable of altering the expression of the desired output.

“This is how we take an analog input, such as a concentration of a chemical, and convert it into a 0 or 1 signal,” said Lu. “And once that is done and you have a piece of DNA that can be flipped upside down, you can then put together any of those pieces of DNA to perform digital computing.”

The analog-to-digital converter circuit built by the team applies ternary logic, basing responses on levels of concentration of inputs, and produces two different outputs. Further advancements in the circuit could help detect glucose and provide the appropriate response based on concentration.

“If the glucose level was too high, you might want your cells to produce insulin,” said Lu. “If the glucose was too low, you might want them to make glucagon, and if it was in the middle, you wouldn’t want them to do anything.”

Applications for Gene Circuits

Detecting a variety of chemicals is possible by simply changing the type of sensor used. Areas of interest include providing appropriate drug responses for gut inflammation caused by bowel disease and engineering immune cells for cancer treatment based on various environmental inputs (oxygen and tumor lysis levels). Environmental applications include detecting concentrations of water pollutants.

“Developing these foundational tools and computational primitives is important as researchers try to build additional layers of sophistication for precisely controlling how cells interact with their environment,” said Ahmad Khalil, an assistant professor of biomedical engineering at Boston University who was not involved in the work.

The research team has developed a spinout company called Synlogic that focuses on using simpler versions of the circuit to engineer probiotic bacteria capable of treating gut diseases; clinical trials could begin within the next year.

For more stories about programmable biology, check out these two articles.