Researchers from ETH Zurich have reprogrammed mammalian cells in such a way as to perform logical calculations like a pocket calculator. The cells owe this ability to one of the most complex gene networks that has ever been incorporated into a higher cell.

A team of researchers from ETH Zurich headed by Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich's Department of Biosystems Science and Engineering (D-BSSE) in Basel, has constructed a network of different genes that can perform calculations and, based on these, initiate specific metabolic steps. In principle, the scientists have developed circuit elements from biological components that are known as logic gates in computer technology and electrical engineering. The basis for the calculations performed is Boolean logic, which works with AND or XOR gates, for instance.

Calculator with modular structure

The researchers succeeded in combining these different gates with each other and interconnecting them to produce two important combinational circuits from digital electronics -- the half-adder and the half-subtractor. A half-adder adds up two binary numbers -- in other words, noughts and ones; a half-substractor de-ducts them from each other.

To programme the cell calculator, the ETH-Zurich researchers used two input signals that control the gene network. For test purposes, the biologists used the antibiotic erythromycin and the apple molecule phloretin. In the case of an AND gate, for instance, both inputs -- namely phloretin and erythromycin -- need to be present for the cell to calculate a one in the output. As a result of this one, the gene network triggers the formation of a fluorescent protein, which makes the cell glow. If one of the two input signals is lacking, the cell will not light up.

The first ″true″ programmable cell calculator

"By combining several logic gates, we have achieved an unprecedented level of complexity in a synthetic gene network in mammalian cells," stresses Professor Fussenegger. Moreover, it is remarkable that the bio-computer can process two different input and output signals in parallel. This sets the bio-calculator apart from digital electronics, which works exclusively with electrons. "By nature, a cell can process many different metabolic products in parallel," adds Professor Fussenegger.

The biological calculator has only been able to master basic binary arithmetic operations thus far and is therefore not a patch on a powerful PC. "However, it is wonderful that a mammalian cell can calculate like that," says Professor Fussenegger.

Scientists have already realised various circuit elements in yeasts and bacteria. The novelty, however, is that the biotechnologists managed to incorporate an entire system into a single cell, and a mammalian one at that.

Future applications conceivable

For Professor Fussenegger, it is conceivable that implanted cell calculators could monitor a patient's metabolism in the distant future and step in if necessary. "Intelligent" cell implants could be used in diabetes patients, for instance, by developing a circuit that recognises disease-related metabolic products and controls the release of therapeutically effective substances, such as insulin. However, the researchers are still a far cry from such an application.