Precise and programmable biological circuits

15 hours ago

A team led by ETH professor Yaakov Benenson has developed several new components for biological circuits. These components are key building blocks for constructing precisely functioning and programmable bio-computers.

Bio-engineers are working on the development of biological computers with the aim of designing small circuits made from biological material that can be integrated into cells to change their functions. In the future, such developments could enable cancer cells to be reprogrammed, thereby preventing them from dividing at an uncontrollable rate. Stem cells could likewise be reprogrammed into differentiated organ cells.

The researchers have not progressed that far yet. Although they have spent the past 20 years developing individual components and prototypes of biological computers, bio-computers today still differ significantly from their counterparts made of silicon, and bio-engineers still face several major obstacles.

A silicon chip, for example, computes with ones and zeros current is either flowing or not and it can switch between these states in the blink of an eye. In contrast, biological signals are less clear: in addition to 'signal' and 'no signal', there is a plethora of intermediate states with 'a little bit of signal'. This is a particular disadvantage for bio-computer components that serve as sensors for specific biomolecules and transmit the relevant signal. Sometimes, they also send an output signal if no input signal is present, and the problem becomes worse when several such components are connected consecutively in a circuit.

A biosensor that does not 'leak'

ETH doctoral candidate Nicolas Lapique from the group led by Yaakov Benenson, Professor of Synthetic Biology in the Department of Biosystems Science and Engineering at ETH Zurich in Basel, has now developed a biological circuit that controls the activity of individual sensor components using internal "timer". This circuit prevents a sensor from being active when not required by the system; when required, it can be activated via a control signal. The researchers recently published their work in the scientific journal Nature Chemical Biology.

To understand the underlying technology, it is important to know that these biological sensors consist of synthetic genes that are read by enzymes and converted into RNA and proteins. In the controllable biosensor developed by Lapique, the gene responsible for the output signal is not active in its basic state, as it is installed in the wrong orientation in the circuit DNA. The gene is activated via a special enzyme, a recombinase, which extracts the gene from the circuit DNA and reinstalls it in the correct orientation, making it active. "The input signals can be transmitted much more accurately than before thanks to the precise control over timing in the circuit," says Benenson.

To date, the researchers have tested the function of their activation-ready sensor in cell culture of human kidney and cancer cells. Nevertheless, they are already looking ahead to further developing the sensor so that it can be used in a more complex bio-computer that detects and kills cancer cells. These bio-computers will be designed to detect typical cancer molecules. If cancer markers are found in a cell, the circuit could, for example, activate a cellular suicide programme. Healthy cells without cancer markers would remain unaffected by this process.

Versatile signal converter developed

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Precise and programmable biological circuits