Circuit-makers target genetic bottlenecks

MIT researchers build a ‘toolbox’ for synthetic biology to help control novel genetic circuits in cells

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CAMBRIDGE, Mass.—For more than a decade, scientists havebeen at work to create genetic circuits that can perform a variety offunctions, including making new drug compounds, influencing the behavior ofcells and delivering medications, but have been limited as to the complexitywith which they can make these circuits. Timothy Lu, assistant professor ofelectrical engineering and computer science and a member of the ResearchLaboratory of Electronics at the Massachusetts Institute of Technology (MIT),along with various colleagues at other institutions, are on the road tochanging that by laying the groundwork for more complex circuits and creating a"toolbox" of synthetic biology components. 
The complex functions that people envision genetic circuitsperforming require controlling numerous genetic and cellular components, amongthem not only the genes in cells but the proteins that regulate them—a processthat typically involves transcription factors.
As Lu notes, most such research has been limited by thatfact that people have designed their synthetic circuits using transcriptionfactors found in bacteria; however, these don't always translate well tononbacterial cells, he says, and it can also be hard to scale them upward tomake more complex circuits.
Lu and his colleagues at Boston University (BU), Harvard MedicalSchool and Massachusetts General Hospital have stepped up to design a newtechnique to design transcription factors for nonbacterial cells, using yeastcells as their initial test case and coming up with an initial library of 19new transcription factors.
This is the start of a synthetic biology toolkit to makecomplex genetic circuits, Lu says, with the project slated to go on toward alarger, more challenging effort to keep making genetic components that can beassembled together to make ever-more-complex circuits that can do more and doit more precisely.
"There are a lot of new and cool circuits that have beendesigned to do some very interesting things, but many of them have been gettingtapped out in terms of complexity, with the most complex ones in the pastdecade having maybe six or seven components," Lu says. "There are not enoughreally well-characterized parts to built complex circuits, and then eachtranscription factor might have completely different underlying mechanisms ofaction or associated proteins. So, we wanted to do a more modular,scaffolding-style approach so that components could be similar, not cross-talknecessarily, and so on, and be able to put them into custom, higher-ordercircuits."
Having a toolbox of parts, essentially, will make it easierto build more complex circuits in conjunction with the more modular framework,theoretically limited primarily by the available selection of components andthe imagination of the researchers, he notes.
"There are many kinds of applications where this could helpin the life sciences; for example, trying to do drug screening and identifywhat particular pathways or genes your drugs turns on or off. Currently, youtag promoter genes of interest but one of the things you could do is buildhigher-order circuits with multiple pathways on the same circuit," Lu explains."You could have perhaps five or six different pathways and a single output togive you more high-info screening."
Farther out, Lu says, another area of interest for such complexcircuits might be for delivery of gene-based therapies, in which one coulddeliver a more complex circuit into the human body that might even be able toperform diagnostics in cells to provide more efficient and appropriatetreatment.
"We've shown that we can build a lot of these parts for thetoolkit and characterize them, and show that they work," he says. "Now we needto figure out if you can put them into much more complex circuits than everbefore. Also, can we really get a handle on how they work in silico and make predictive models for them?"
Lu predicts that he and his colleagues should have some goodresults within the next year, "and we hope the new stories we can put out willdemonstrate the power of using these parts as modular components in largercircuits."
Results of the work are described in the Aug. 3 issue of thejournal Cell. Other authors for thatarticle include Ahmad Khalil, assistant professor of biomedical engineering atBU; BU postdoc Caleb Bashor; Harvard grad student Cherie Ramirez; BU researchassistant Nora Pyenson; Keith Joung, associate chief of pathology for researchat Massachusetts General Hospital; and James Collins, BU professor ofbiomedical engineering.
Plans to even begin thinking about commercialization orseeking industry partners are pretty far out and it is too early to predictwhen that might happen, Lu acknowledges. The circuits they have built for yeastin their research are still relatively simple ones to show that the componentswork and the modular approach works, and next steps include building morecomplex circuits, such as massive 10- or 15-transcription factor circuits, withLu noting, "We want to see how far we can scale the type of circuits we can buildout of this framework."

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