Biological Computers: in Vivo Autonomous Doctors that Diagnose and Treat Disease
Summary Background: The promise of computers made from biological molecules lies in their potential to operate within the biochemical environment of a living organism and to interact with that environment through inputs and outputs with other biological molecules. For example, a biomolecular computer might act as an autonomous "doctor" within a cell. It could sense signals from the environment indicating disease, process them using its preprogrammed medical knowledge, and output a signal for the release of a therapeutic drug.
Invention: The creation of a biological computer composed of DNA, RNA, and/or protein that is able to diagnose in vivo the molecular symptoms of diseases and treat the disease by releasing a therapeutic molecule. The general circuit architecture of these Molecular Doctors include one or more sensor modules comprised of mediators that detect and respond to input cues. Examples of circuit mediators include siRNA, shRNA, miRNA, ribozymes, proteins, or RNA binding proteins.
In one example, a multi-component RNA- and/or protein-based biomolecular system is engineered to detect conditions related to abnormal expression of a number of arbitrary genes in mammalian cells, and to release an arbitrary biologically active protein upon detection. The system operates as a molecular automaton and can include one or more of: (1) molecular sensors that assess the levels of gene expression; (2) a molecular computation module that integrates the information related by the sensors and makes a diagnostic decision; and (3) a molecular actuator module that translates the output of the molecular computation into biological action.
Applications Applications: Molecular circuits and cells can be used in a variety of applications, for example in diagnostics and therapeutics.
Diagnostic Applications: A molecular circuits can be used to detect biomarkers associated with disorders such as cancer, metabolic disorders, infections, or immunological disorders (e.g., autoimmune diseases).
Therapeutics: An in vivo operational molecular circuit described can be used as a direct therapeutic modality or combination diagnostic/therapy. For example, the components of a molecular circuit can be delivered to a cancer cell, wherein the circuit comprises one or more sensors (mediators) capable of detecting, and responding to input cues such as, e.g., the expression of an oncogene and/or the lack of expression of a tumor suppressor protein
Differentiation Events: A molecular circuit can be introduced into a stem cell to produce one or more outputs indicative of different stages of differentiation, in response to one or more input cues indicative of differentiation state.
Pharmacokinetics: The molecular circuits herein can be used to monitor the pharmacokinetics of a small molecule compound or a therapeutic protein. For example, a circuit could be useful for determining (i) the permeability of a compound and/or (ii) the stability of a compound in a cell. The cell can also be introduced into an animal model to test for the half-life of clearance of a compound from the blood of the animal.
Publications: Rinaudo K, Bleris L, Maddamsetti R, Subramanian S, Weiss R, Benenson Y. A universal RNAi-based logic evaluator that operates in mammalian cells. 2007. Nature Biotechnology. 25(7):795-801.
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