May 2000

Biological Computing

Continued from page 2

By Simson L. Garfinkel

GeneTic Tock

As a graduate student at Princeton University, Rockefeller's Michael Elowitz constructed a genetic applet of his own-a clock.

In the world of digital computers, the clock is one of the most fundamental components. Clocks don't tell time-instead, they send out a train of pulses that are used to synchronize all the events taking place inside the machine. The first IBM PC had a clock that ticked 4.77 million times each second; today's top-of-the-line Pentium III computers have clocks that tick 800 million times a second. Elowitz's clock, by contrast, cycles once every 150 minutes or so.

The biological clock consists of four genes engineered into a bacterium. Three of them work together to turn the fourth, which encodes for a fluorescent protein, on and off-Elowitz calls this a "genetic circuit."

Although Elowitz's clock is a remarkable achievement, it doesn't keep great time-the span between tick and tock ranges anywhere from 120 minutes to 200 minutes. And with each clock running separately in each of many bacteria, coordination is a problem: Watch one bacterium under a microscope and you'll see regular intervals of glowing and dimness as the gene for the fluorescent protein is turned on and off, but put a mass of the bacteria together and they will all be out of sync.

lowitz hopes to learn from this tumult. "This was our first attempt," he says. "What we found is that the clock we built is very noisy-there is a lot of variability. A big question is what the origin of that noise is and how one could circumvent it. And how, in fact, real circuits that are produced by evolution are able to circumvent that noise."

While Elowitz works to improve his timing, B.U.'s Collins and Gardner are aiming to beat the corporate clock. They've filed for patents on the genetic flip-flop, and Collins is speaking with potential investors, working to form what would be the first biocomputing company. He hopes to have funding in place and the venture launched within a few months.

The prospective firm's early products might include a device that could detect food contamination or toxins used in chemical or biological warfare. This would be possible, Collins says, "if we could couple cells with chips and use them-external to the body-as sensing elements." By keeping the modified cells outside of the human body, the startup would skirt many Food and Drug Administration regulatory issues and possibly have a product on the market within a few years. But Collins' eventual goal is gene therapy-placing networks of genetic applets into a human host to treat such diseases as hemophilia or anemia.

Another possibility would be to use genetic switches to control biological reactors-which is where Knight's vision of a bridge to the chemical world comes in. "Larger chemical companies like DuPont are moving towards technologies where they can use cells as chemical factories to produce proteins," says Collins. "What you can do with these control circuits is to regulate the expression of different genes to produce your proteins of interest." Bacteria in a large bioreactor could be programmed to make different kinds of drugs, nutrients, vitamins-or even pesticides. Essentially, this would allow an entire factory to be retooled by throwing a single genetic switch.