5m Molecular Logic Circuits for Information Processing in Human Cells

Leonidas Bleris, FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138

Components of a living organism, from organs and tissues to single cells and subcellular compartments, exchange and process numerous molecular signals in order to coordinate their activity. When these components fail, they generate characteristic signals that often trigger self-repair processes but can also cause disease when left unchecked. In the not-so-distant future, engineered biomolecular circuits will process information in human cells monitoring in parallel multiple inputs, detecting minute changes, rapidly assessing a patient's condition, and responding in infinitesimal time. Such systems will be used for diagnosing, preventing, treating, and monitoring disease in ways that achieve optimal and highly specific individual health-care, redefining personalized medicine and opening the path to new technologies.

Today, scientists in the cross-sections of disciplines such as biology, chemistry, mathematics, and engineering strive to produce molecular circuits with novel and useful functionalities, in a strikingly similar manner to physicists and engineers that built the fundamental building blocks of computers and modern electronic devices during the 19th century. Similar to a transistor, the basic component of an electrical circuit, with the voltage indicating binary high and low output, in cells a gene can have a binary high and low state depending on the protein concentration. Towards this direction, there are several prototype "biodevices" that operate in cells, such as oscillators, toggle switches, and circuits implementing basic Boolean operations (i.e. AND, OR, NOT logic gates). These devices comprise of genetic and biochemical components such as RNA, DNA fragments, proteins, and inducer molecules.

We have constructed a de novo molecular information-processing gene network that operates in human kidney cells. This molecular circuit is based on RNA interference (RNAi), a mechanism for RNA-guided regulation of gene expression. We show that the RNAi pathway in human cells can form a molecular computing module capable of evaluating arbitrary Boolean expressions on endogenous cues. We experimentally demonstrate in human kidney cells the direct evaluation using exemplary expressions in standard forms with up to five logic variables.



Web Page: www.sysbio.harvard.edu/csb/benenson/bleris.html