The ability to program cells offers many opportunities to improve human health. Stem cells can be programmed to self-organize and differentiate to form tissues and organs. Viruses and bacteria can be used as novel antibiotics by developing “seek-and-destroy” programs. Similarly, the sensing and computing capabilities of bacteria can be used to convert them into drug delivery devices that are able to identify diseased cells and specific regions of the body in order to deliver targeted therapies. A relatively untouched area of therapeutic potential is the human microbiome; in other words, the bacteria that engage in symbiotic relationships with your body. Engineering colonizing bacteria offers a new route for the delivery of vaccines and therapeutics and the treatment of disease.
Circuits in cell biology and circuits in electronics may be viewed as being highly similar with biology using molecules, ions, proteins, and DNA rather than electrons and transistors. This project exploits the astoundingly detailed similarity between the equations of chemistry and the equations of subthreshold analog electronics to attempt to create large-scale nonlinear dynamical systems that mimic the sensing, actuation, and control systems of biological cells at ultra-fast time scales including their stochastic properties. This project has applications in both systems biology, which aims at an engineering understanding of molecular networks within the cell and in synthetic biology, where it can help solve several bottlenecks in its design, analysis, robustness, and scalability via rigorous analog circuit techniques. Work in this project involves the design and testing of molecular circuits in bacteria and yeast, the design and testing of analog microelectronic chips useful for ultra-fast simulations of molecular and cellular systems, and the creation of analog circuit models of molecular networks.
Our goal is to create a programming language for living cells that is similar to languages used to program computers and robots. This requires the development of a high-level language that allows a programmer to describe a desired function and computational methods that convert this language into a linear DNA sequence. The sequence is then built and inserted into an organism, which runs the program. Examples of programs built by the SBC include an edge detection program that gives bacteria to identify the light-dark interfaces in an image, a program that forms two-dimensional patters, and one that enables bacteria to count.
From wood to silk, we still obtain many materials from natural sources. In harvesting these materials, we rely on global abundances or the ability to be farmed. Enzyme-directed bio-mineralization can produce nanoparticles with unique structural and functional properties that are difficult to obtain by chemical routes. These have applications in a broad range of technologies, including electronics, photonics, MEMS, catalysis, and energy production and storage.
To build genetic programs, circuits need to be encoded in DNA. These so-called genetic circuits use biochemical interactions to implement functions that are analogous to electronic circuits, such as logic gates and oscillators. We are developing genetic circuits that encode new functions as well as methods to optimize their performance features. A significant challenge is the reliable connection of circuits to form programs. Computational methods based on biophysical principles are being developed to automatically tune circuits such that they can be connected to form layered programs.
Genetic programming is possible because of advances in the synthesis and construction of DNA. Companies dedicated to DNA synthesis are now able to chemically build sequences to order that are hundreds of thousands of bases long with every base specified. The center is developing methods to use microfluidics to synthesize DNA and proteins in parallel. In addition, methods to assemble genetic parts are valuable in creating many variations of pathways and programs. DNA assembly can also be coupled to liquid handling robots for rapid construction and prototyping.
Microbial chemical factories provide a renewable pathway to pharmaceuticals, specialty, and commodity chemicals. A large part of constructing a pathway to a desired chemical is assembling the correct enzymes that function together to convert a metabolite into a desired chemical. Aiding the process of discovery are the DNA sequence databases that now contain more than a hundred million genes from over two hundred thousand organisms. Bioinformatics and DNA synthesis enable the identification and access of these functions. In the future, it may be possible to specify a desired chemical structure and then computationally identify those enzymes that will collectively produce the target chemical.
A vision of the center is to be able to design and program complete genomes. Recently, work out of the Venter Institute demonstrated that it is possible to reconstruct a complete bacterial genome using chemical DNA synthesis, transplant it into a host chassis, and have the new genome “boot up.” The Church lab at Harvard has developed a method called MAGE to iteratively replace the genome of a cell with a synthetic version. Whole genome design requires the convergence of multiple technologies from synthetic biology, including reliable and characterized genetic parts, synthetic regulation and genetic circuits, computer aided design, and DNA synthesis.
Biological sensing and circuitry enables agricultural organisms to see and respond to their environment. “Smart” plants could be programmed to identify and respond to multiple threats, such as pathogens, toxins, desiccation, and nutrient availability. Microbes in the rhizome associate with plants and could be engineered to implement similar functions. Finally, the engineering of new chasses that use sunlight to fix carbon dioxide, such as cyanobacteria and algae, could yield low cost routes to renewable carbon-neutral chemicals and fuels as well as meeting global nutritional needs.
Natural genomes are shaped by evolution, a process of serendipity that produces complex and highly redundant genetic systems. Characterizing such a system often has the feel of peeling an onion, where there are endless layers of complex regulation. We are applying principles from synthetic biology to rebuild cellular functions from the bottom up. Natural regulation is systematically replaced with synthetic well-characterized genetic parts. This yields a “refactored” system whose genetics are fully specified. This process produces a platform for further engineering and to transfer functions between organisms. In the center, this is being applied to prokaryotic gene clusters that encode functions that include chemical synthesis, photosynthesis, and protein secretion.