Stanford leaps ahead on creating biological computers

A team of Stanford University bioengineers has created a biological transistor that allows engineers to compute inside living cells.

Published on March 28, in the magazine Science, the team details how it made a biological transistor from genetic material — DNA and RNA — in place of gears or electrons. The team calls its biological transistor the “transcriptor.”

The transcriptor allows engineers to compute inside living cells to record when cells have been exposed to certain external stimuli or environmental factors, or even to turn on and off cell reproduction as needed. It is the key component behind amplifying genetic logic, akin to the transistor and electronics, said Jerome Bonnet, a postdoctoral scholar in bioengineering and the paper’s lead author.

“Biological computers can be used to study and reprogram living systems, monitor environments and improve cellular therapeutics,” said Drew Endy, assistant professor of bioengineering and the paper’s senior author.

In electronics, a transistor controls the flow of electrons along a circuit. Similarly, in biologics, a transcriptor controls the flow of a specific protein — RNA polymerase — as it travels along a strand of DNA, the authors said. The researchers repurposed a group of natural proteins, called integrases, to attain digital control over the flow of RNA polymerase.

Using transcriptors, the team has created what are known in electrical engineering as logic gates, which can derive true-false answers to virtually any biochemical question that might be posed within a cell.

Transcriptor-based gates alone do not constitute a computer, but they are the third and final component of a biological computer that could operate within individual living cells, the scientists said. Despite their outward differences, all modern computers, from the early ENIAC to Apple, share three basic functions: storing, transmitting and performing logical operations on information.

Last year, Endy and his team made news in delivering the other two core components of a fully functional genetic computer. The first was a type of rewritable digital data storage within DNA. They also developed a mechanism for transmitting genetic information from cell to cell, a sort of biological Internet. It all adds up to creating a computer inside a living cell, they said.

The researchers refer to their transcriptor-based logic gates as “Boolean Integrase Logic,” or “BIL gates” for short. Digital logic is often referred to as “Boolean logic,” after George Boole, the mathematician who proposed the system in 1854. Today, Boolean logic typically takes the form of 1s and 0s within a computer. Answer true, gate open; answer false, gate closed. On. Off.

In a biological setting, the possibilities for logic are as limitless as in electronics, Bonnet said.

“You could test whether a given cell had been exposed to any number of external stimuli — the presence of glucose and caffeine, for instance,” he said.

Transcriptor-based logic gates would allow scientists to make that determination and to store the information so that they could easily identify cells that had been exposed and those that had not, he said.

Scientists could also tell the cell to start or stop reproducing if certain factors were present. By coupling transcriptor-based logic gates with the team’s biological Internet, it is possible to communicate genetic information from cell to cell to orchestrate the behavior of a group of cells, the researchers said.

The researchers used specific enzymes to create transcriptors and logic gates.

“We have been careful to select enzymes that function in bacteria, fungi, plants and animals, so that bio-computers can be engineered within a variety of organisms,” Bonnet said.

The biological transistor and its semiconducting cousin have a key similarity: signal amplification. With transcriptors, a very small change in the expression of an integrase can create a very large change in the expression of any two other genes, the researchers said. This is similar to electrical amplification, which was revolutionized by transistors.

Electrical signals traveling along wires get weaker the farther they travel, but by putting an amplifier every so often along the way, signals can be relayed across a great distance. The same would hold in biological systems as signals get transmitted among a group of cells, the researchers said.

“It is a concept similar to transistor radios. Relatively weak radio waves traveling through the air can get amplified into sound, ” said Pakpoom Subsoontorn, a Ph.D. candidate in bioengineering and co-author of the study who developed theoretical models to predict the behavior of transcriptor-based logic gates.

To bring the age of the biological computer to a much speedier reality, Endy and his team have contributed all of their transcriptor-based logic gates technology to the public domain so that others can harness and improve upon the tools.

“Most of biotechnology has not yet been imagined, let alone made true. By freely sharing important basic tools everyone can work better together,” Bonnet said.

The research was funded by the National Science Foundation and the Townshend Lamarre Foundation. Stanford’s Department of Bioengineering also supported the work.