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Scientists have taken a key step toward realizing the goal of building programmable bio-computers that could detect and kill cancer cells.

If cancer markers are found in a cell, the circuit could, for example, activate a cellular suicide program. Healthy cells without cancer markers would remain unaffected by this process.

Bio-computers 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 circuit upgrade

A team led by ETH Zurich 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.

The circuit controls the activity of individual sensor components using an 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.

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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 doctoral candidate Nicolas 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, professor of synthetic biology, who supervised Lapique’s work.

To date, the researchers have tested the function of their activation-ready sensor in cell culture of human kidney and cancer cells.

“In electronics, the different components that make up a circuit are always connected in the same way: with a wire through which the current either flows or not,” explains Benenson.

In biology, there are a variety of different signals—a host of different proteins or microRNA molecules. In order to combine biologic components in any desired sequence signal converters must be connected between them.

Signal converter

Laura Prochazka, also a doctoral candidate student under Benenson, has developed a versatile signal converter. She published her work recently in the magazine Nature Communications.

A special feature of the new component is that not only it converts one signal into another, but it can also be used to convert multiple input signals into multiple output signals in a straightforward manner.

This new biological platform will significantly increase the number of applications for biological circuits.

“The ability to combine biological components at will in a modular, plug-and-play fashion means that we now approach the stage when the concept of programming as we know it from software engineering can be applied to biological computers. Bio-engineers will literally be able to program in future,” says Benenson.

Source: ETH Zurich