Digital cells: computer circuits made of genes may soon program bacteria

Science News, April 26, 2003 by Erica Klarreich

Imagine a future in which a single drop of water holds a veritable army of living robots; in which people download software updates not for their computers, but for their bacteria; and in which specially programmed cells course through a person's arteries, monitoring blood sugar concentrations and keeping an eye out for cholesterol buildups. These scenarios still belong to the realm of science fiction--but implanting computer programs into living creatures may not be far away. In the past few years, scientists have taken the first steps towards creating a host of cellular robots that are programmed to carry out tasks such as detecting and cleaning up environmental pollutants, tracking down cancer cells in a body, and manufacturing antibiotics or molecularscale electronic components. These researchers have imported notions of electrical engineering--digital logic, memory, and oscillators--into the realm of biology. Their plan: to create cells with computer programs hardwired into the DNA.

"Eventually, the goal is to produce genetic `applets', little programs you could download into a cell simply by sticking DNA into it, the way you download Java applets from the Internet," says Timothy Gardner, a bioengineer at Boston University.

The goal is not to produce a Pentium in a test tube. Cellular computers will probably never rival silicon chips in speed and reliability. "We don't use cells because they're a good medium for computation but because they can actually do stuff for us," says Adam Arkin, a bioengineer at the University of California, Berkeley.

Scientists intend to harness the multitude of cellular activities, which go beyond the capacity of silicon devices. Living cells can survive on the flanks of undersea volcanoes and in acidic mine drainage. They operate amazingly efficient factories for producing antibiotics, enzymes, and other useful chemicals, and they generate numerous copies of themselves. Cells can detect minute changes around them, and perhaps most crucially, interact with their environment.

By cutting and pasting pieces of genetic material, and most recently using artificial evolution as a design tool, engineers are starting to program microbes to carry out behaviors that nature never dreamed of. "We're basically hacking DNA instead of software," says Ron Weiss of Princeton University.

CELLULAR LOGIC Digital circuits, the building blocks of modern computers, encode bits of information in zeros and ones and then manipulate them in exact, controlled ways. Cells, which are basically bags of organelles, proteins, and small molecules, might not at first glance seem promising for such computations.

However, as cells regulate their activities and respond to the environment, they use many of the same tricks that go into digital circuits, such as on-off switches and feedback loops. What's more, cells house one of the richest known information-processing systems. Their strands of DNA include detailed instructions on how and when to build each of thousands of proteins. A control center for each gene turns it on or off according to the cell's changing needs.

Just as electrical engineers wire together transistors--the basic on-off switches of silicon chips--into complicated circuits, researchers are now stringing together genes and control centers in novel combinations to build what they call genetic circuits, in which the output protein of one gene regulates the next gene.

Silicon circuits perform complex operations using a handful of simple components known as logic gates. Genetic-circuit engineers are now building the same devices inside cells. One such logic gate is the inverter, which outputs a 1 if the input is 0, and a 0 if the input is 1. Another is the AND gate, which takes two inputs, and outputs a 1 only if both inputs are 1s. Amazingly, as simple as these two gates sound, mathematicians can construct any logical operation by hooking up enough of them.

Between 1998 and 2001, Weiss took some of the first steps toward building cellular logic gates when he modeled and built a cellular inverter, an AND gate, and two other gates. In Weiss' inverter, the input bit and output bit are encoded in the concentrations of two proteins--for simplicity's sake, call them protein A and protein B. If the concentration of protein A is high, the input bit is a 1; if the concentration is low, the input bit is a 0. Similarly, the concentration of B corresponds to the output bit. Weiss constructed in Escherichia coli bacteria a loop of DNA containing two important pieces: the gene with the instructions for building protein B, and near that, a segment of DNA to which protein A binds.

To make protein B, a special molecule called messenger RNA assembles itself along the DNA, copying the gene's instructions and carrying them to the cell's protein-making factory. If the concentration of A is high, molecules of protein A will bind to the DNA loop and block the messenger RNA from attaching to the DNA. This prevents the cell from building protein B. If, on the other hand, the concentration of A is low, then protein B will be built in abundance. Thus, in Weiss' circuit, B is high when A is low, and vice versa. Weiss' other gates are constructed in similar, slightly more complicated ways.