Abstract: Despite more than 15 years of research, synthetic circuits in living cells have been largely limited to a handful of digital logic gates and have not scaled. We show that one important reason for this failure to scale is an overemphasis on digital abstractions rather than on recognizing the true noisy, analog, and probabilistic nature of biological circuits. We show that synthetic and natural DNA, RNA, and protein circuits in cells must use analog, collective analog, probabilistic, and hybrid analog-digital computational approaches to function; otherwise, even relatively simple computations in cells will exceed energy, molecular-count, and cellular-resource budgets.Analog circuits in electronics and molecular circuits in cell biology are also deeply connected: There are astounding similarities between the equations that describe noisy electronic flow in sub-threshold transistors and the equations that describe noisy molecular flow in chemical reactions, both of which obey the laws of exponential thermodynamics. Based on these similarities, it is possible to take a principled approach to design circuits in living cells. For example, we have engineered logarithmic analog computation in living cells with less than three transcription factors, almost two orders of magnitude more efficient than prior digital approaches to create a ‘bio-molecular slide rule’.  In addition, highly computationally intensive noisy DNA-protein and protein-protein networks can be rapidly simulated in mixed-signal supercomputing chips that naturally capture their noisiness, dynamics, and non-modular  interactions at lightning-fast speeds. Such an approach may enable large-scale design, analysis,   simulation, and measurement of cells to be more precise and robust than it is today.  To realize the promise of synthetic biology and systems biology for medicine, biotechnology, agriculture, and energy, we will need to go back to the future of computation and design and implement circuits via a collective analog approach like Nature does.

Bio: Rahul Sarpeshkar is a tenured professor at MIT where he heads a research group on Analog Circuits and Biological Systems. His group creates novel wet DNA-protein circuits in living cells and also advanced dry nanoelectronic circuits on silicon chips. His longstanding work on analog and biological computation and his most recent work have helped pioneer the field of analog synthetic biology. His work on a glucose fuel cell for medical implants was featured by Scientific American among 2012's 10 World Changing Ideas. He holds over 35 awarded patents and has authored more than 125 publications, including one that was featured on the cover of Nature. His recent book, Ultra Low Power Bioelectronics: Fundamentals, Biomedical Applications, and Bio-inspired Systems revealed the deep connections between analog transistor circuits and biochemical circuits. His group holds several first or best records in analog, bio-inspired, synthetic biology, medical device, ultra low power, and energy harvesting systems. His work has applications in implantable medical devices for the deaf, blind, and paralyzed and in biotechnology and medical applications that benefit from cellular engineering. He has received several awards including the NSF Career Award, the ONR Young Investigator Award, and the Packard Fellows Award. He received Bachelor’s degrees in Electrical Engineering and Physics at MIT and a PhD at CalTech. Before he joined MIT’s faculty, he was a member of the technical staff of Bell Labs’ division of biological computation.