Towards molecular computers that operate in a biological environment

Even though electronic computers are the only computer species we are accustomed to, the mathematical notion of a programmable computer has nothing to do with electronics. In fact, Alan Turing’s notional computer L.M. Turing, On computable numbers, with an application to the entcheidungsproblem, Proc. Lond. Math. Soc. 42 (1936) 230-265], which marked in 1936 the birth of modern computer science and still stands at its heart, has greater similarity to natural biomolecular machines such as the ribosome and polymerases than to electronic computers. This similarity led to the investigation of DNA-based computers C.H. Bennett, The thermodynamics of computation — Review, Int. J. Theoret. Phys. 21 (1982) 905-940; A.M. Adleman, Molecular computation of solutions to combinatorial problems, Science 266 (1994) 1021-1024]. Although parallelism, sequence specific hybridization and storage capacity, inherent to DNA and RNA molecules, can be exploited in molecular computers to solve complex mathematical problems Q. Ouyang, et al., DNA solution of the maximal clique problem, Science 278 (1997) 446-449; R.J. Lipton, DNA solution of hard computational problems, Science 268 (1995) 542-545; R.S. Braich, et al., Solution of a 20-variable 3-SAT problem on a DNA computer, Science 296 (2002) 499-502; Liu Q., et al., DNA computing on surfaces, Nature 403 (2000) 175-179; D. Faulhammer, et al., Molecular computation: RNA solutions to chess problems, Proc. Natl. Acad. Sci. USA 97 (2000) 1385-1389; C. Mao, et al., Logical computation using algorithmic self-assembly of DNA triple-crossover molecules, Nature 407 (2000) 493-496; A.J. Ruben, et al., The past, present and future of molecular computing, Nat. Rev. Mol. Cell. Biol. 1 (2000) 69-72], we believe that the more significant potential of molecular computers lies in their ability to interact directly with a biochemical environment such as the bloodstream and living cells. From this perspective, even simple molecular computations may have important consequences when performed in a proper context. We envision that molecular computers that operate in a biological environment can be the basis of “smart drugs”, which are potent drugs that activate only if certain environmental conditions hold. These conditions could include abnormalities in the molecular composition of the biological environment that are indicative of a particular disease. Here we review the research direction that set this vision and attempts to realize it.