Gene Design Goes Automatic

ILLUSTRATION BY THE PROJECT TWINS Y components that interact to produce one or human-designed combinations of genetic triggered totriggered make “protein A, interwhich then Under right the conditions, circuit the might be in response to agiven stimulus, such as atoxin. more proteins or RNA for molecules, example, BY ANNANOWOGRODZKI Medical inBoston, Massachusetts. School But David Riglar, asynthetic biologist at Harvard with proteinacts Bto give outcome C”, says modelled onmodelled electronic the ones, are of electronic circuits. circuits, Genetic our smartphone and laptop are made GOES AUTOMATIC Computer-aided design tools for genetic circuitry GENE DESIGN GENE DESIGN are starting to power synthetic biology. - or churning out protein. acertain Synthetic actions, such as enzyme activating aparticular out and bacteria yeastcially specific —to carry genetic circuits that can program cells —espe process by which researchers design complex tools are changing that. automate They the prone process. Computerized genetic-design at —alaborious, atime iterative and error- to design biological circuits manually, and one engineers,tools. by Genetic contrast, have had automated computer-aided design (CAD) circuits were different made invery ways. until or adecade ago, so two kinds these of © Electronics engineers design circuits using

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A l l r i g h t s r e s e r v e 13 DECEMBER 2018 | VOL 2018| NATURE 564| |291 DECEMBER 13 d . - she says: cells that can as sensors act and j5 to develop “living measurement systems”, group and genetic-design the tools uses Cello (NIST) inGaithersburg,ogy Maryland. Her National Institute of Standards and Technol Strychalski, amicrobial engineer at US the ered ‘synthetic to be biology’,” says Elizabeth inindustry,use and more. that include cells or antibodies, enzymes for in this way to produce biological drugs, sensors biologists have organisms single-celled used of genetic manipulations typically consid greatly expand accessibility the of kinds the “Design tools for genetic circuits should

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respond to their environment. “Those Escherichia coli. Now, they are jointly expand- sophisticated that they couldn’t be learned in a genetically engineered organisms then become ing the tool to work in yeast, he says. Densmore few days.” The hard part, Hessel says, is build- tools in their own right, allowing anyone new and Voigt are using Cello to design circuits ing and testing the resulting circuits. Peccoud ways to understand and control biology at the that produce a small signalling molecule in says he can teach even molecular biologists cellular scale.” response to the presence of two other mole- who have no computer-science background According to Douglas Densmore, who cules, and are working on circuits with mem- to use GenoCAD in just a few hours. heads the Cross-Disciplinary Integration of ory that function in different ways depending For those who need help, the greater Design Automation Research lab at Boston on the order in which they sense the targets, synthetic-biology community is probably the University, such tools represent a fundamen- says Densmore. best place to start. “Researchers in this field are tal shift in how genetic circuits are designed. Unlike Cello, other automated tools includ- generally accessible and helpful,” says Drew Previously, he explains, genetic-circuit design ing iBioSim, j5 and GenoCAD do not spit out Tack, a microbial engineer who works with Stry- was mostly a bespoke process. As a result, predictions for how well genetic circuits will chalski at NIST. “I would encourage someone designs were difficult to share, improve and perform or whether they’re correct. And they just starting to reach out for advice and take full scale up. “It is not realistic to build an industry all require the user to know and input informa- advantage of the considerable online resources” on artisanal approaches,” he says. Although tion about how the circuit will be structured. such as the GitHub code repository, he says. these “are great for early-stage research”, they One unfilled niche involves tools that are ultimately can’t be transferred to a large scale. A GENETIC GRAMMAR accessible for non-experts, but powerful and That’s where automation comes in. “Automa- GenoCAD, which is commercial but has an scalable enough to handle millions of base tion will begin the process of getting designs open-source version, provides rules that define pairs of DNA and many designs. Before it out of notebooks and into software,” he says. which functional parts of DNA sequences can shut down in August — along with Autodesk’s A growing collection of circuit-design go together, treating the sequences like pro- entire life-sciences team — Genetic Construc- tools suggests that the field agrees. Yet soft- gramming code. “DNA sequences have the tor did just that. The closure “was an internal ware development for synthetic biology is same linguistic complexity as programming strategic decision”, says Eli Groban, a compu- in flux. One tool, Genetic Constructor, was languages — there are rules that people need tational biologist who led project management abruptly terminated by its parent company, to respect,” explains Jean Peccoud, founder and strategy for the Autodesk life-sciences CAD software developer Autodesk Research and chief executive group When the company announced by in San Rafael, California, in August. But “Genetically of GenoFAB in San e-mail that Genetic Constructor was ending, researchers working in single-celled organ- engineered Francisco, which Groban says, it got replies from individual isms still have access to some open-source or organisms then developed the soft- research groups asking them to keep it going. freely available tools, including Cello, j5 and become tools ware as the founda- The tool’s user interface was designed to be another called iBioSim. They can use these in their own tion for a broader more accessible to the wider community of tools to weave circuits into whole genomes right.” set of genetic-design biologists than are tools aimed just at synthetic or to design thousands of variants to examine tools and services. biologists, he says. “The gaps that Genetic different combinations of genes, enzymes or “It’s a grammar. All those rules are formal Constructor wanted to fix still apply.” protein domains. representations of biological knowledge.” The use of genetic circuit-design tools is “CAD tools are absolutely required for the And from them, the software can translate a increasing among synthetic biologists, says design of biological systems,” says Andrew circuit design into the sequence for a physical Strychalski, albeit slowly. Groban says that Hessel, a genomic futurist and chief execu- piece of DNA, from which the circuit can be the problem is one of economics. “In the tive of Humane Genomic in San Francisco, built. (Cello is built on a similar set of rules: academic community, there’s this hesitation California. a language called Eugene, which Densmore to pay for software. No one really does that developed.) cost–benefit analysis” that it might be cheaper GENETIC CAD Created by the Joint BioEnergy Institute in to spend even tens of thousands of dollars on Densmore, who developed Cello, has a back- Emeryville, California, and licensed exclu- paid software than to get graduate students to ground in electronic design automation — and sively to TeselaGen in San Francisco, j5 allows spend significant amounts of time building it shows. Researchers can direct Cello to design researchers to design genetic circuits by drag- their own version, or designing circuits in the a genetic circuit that meets certain specifica- ging and dropping genetic control elements old-fashioned way. tions without having to tell the software any- onto a canvas. “You lay down a series of sym- Right now, “most biologists don’t work at thing about how to actually build it, just like bols that say, ‘I want a promoter here, I want a scale”, says Hessel, but that could be changing. with electronic-design tools. Users instruct ribosome binding site,’” says Densmore. Users He tells students that in their careers, they will the software — available both as source code can select multiple components that they operate on a vastly larger scale than their current and as a web application — using Verilog, the might want to test in a particular location, for lab work, managing liquid-handling robots and same computer language that electronics engi- instance to work out which combination pro- testing much bigger data sets of genetic variants. neers use to describe their silicon circuits. “You duces the most robust output. “Then you use Automated genetic-design tools might well be specify the function you want, not the way it rules to say, ‘Don’t put part A with part B, but required to make that happen. ■ is created,” Densmore explains. For instance, part C has to be after part D’, and then it enu- users could ask Cello to design a genetic circuit merates all the different combinations,” says Anna Nowogrodzki is a science writer based that produces a protein when it senses the pres- Densmore. Researchers at non-profit universi- in Boston, Massachusetts. ence of two particular antibodies. The software ties and institutes can use the software through would then work out which components must a free TeselaGen account; the firm also offers be put together to make that happen, and out- commercial accounts. CORRECTION put the nucleic-acid sequences required to No special skills are required to use auto- The Technology Feature ‘The clinical physically build it. Cello also predicts how well mated DNA-design tools, but because they code-breakers’ (Nature 562, 291–293; its circuits are likely to perform. do call for detailed specification of elements, 2018) gave the wrong affiliation for Jenny Densmore designed Cello in collaboration familiarity with computer programming helps. Taylor. She is co-director of the translational with the lab of synthetic biologist Christopher “I don’t think the learning curve is too steep genomic medicine programme at the Voigt at the Massachusetts Institute of Tech- right now, even in the more sophisticated Wellcome Trust Centre for Human Genetics. nology in Cambridge, for use in the bacterium tools,” says Hessel. “None of these tools are so