circuits in which a series of genes are activated in a specific order.Such circuits, which mimic those found on computer chips, could be used to count the number of times a cell divides, or to study a sequence of developmental stages. They could also serve as biosensors that count exposures to different toxins.The team developed two types of cellular counters, both described in the May 29 issue of Science. Though the cellular circuits resemble computer circuits, the researchers are not trying to create tiny living computers."I don't think computational circuits in biology will ever match what we can do with a computer," said Timothy Lu, a graduate student in the Harvard-MIT Division of Health Sciences and Technology (HST) and one of two lead authors of the paper.Performing very elaborate computing inside cells would be extremely difficult because living cells are much harder to control than silicon chips. Instead, the researchers are focusing on designing small circuit components to accomplish specific tasks."Our goal is to build simple design tools that perform some aspect of cellular function," said Lu.Ari Friedland, a graduate student at Boston University, is also a lead author of the Science paper. Other authors are Xiao Wang, postdoctoral associate at BU; David Shi, BU undergraduate; George Church, faculty member at Harvard Medical School and HST; and James Collins, professor of biomedical engineering at BU.Learning to count To demonstrate their concept, the team built circuits that count up to three cellular events, but in theory, the counters could go much higher.The first counter, dubbed the RTC (Riboregulated Transcriptional Cascade) Counter, consists of a series of genes, each of which produces a protein that activates the next gene in the sequence.With the first stimulus for example, an influx of sugar into the cell the cell produces the first protein in the sequence, an RNA polymerase (an enzyme that controls transcription of another gene). During the second influx, the first RNA polymerase initiates production of the second protein, a different RNA polymerase.The number of steps in the sequence is, in theory, limited only by the number of distinct bacterial RNA polymerases. "Our goal is to use a library of these genes to create larger and larger cascades," said Lu.The counter's timescale is minutes or hours, making it suitable for keeping track of cell divisions. Such a counter would be potentially useful in studies of aging.The RTC Counter can be "reset" to start counting the same series over again, but it has no way to "remember" what it has counted. The team's second counter, called the DIC (DNA Invertase Cascade) Counter, can encode digital memory, storing a series of "bits" of information.The process relies on an enzyme known as invertase, which chops out a specific section of double-stranded DNA, flips it over and re-inserts it, altering the sequence in a predictable way.The DIC Counter consists of a series of DNA sequences. Each sequence includes a gene for a different invertase enzyme. When the first activation occurs, the first invertase gene is transcribed and assembled. It then binds the DNA and flips it over, ending its