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Circuit-makers target genetic bottlenecks
CAMBRIDGE, Mass.—For more than a decade, scientists have been at work to create genetic circuits that can perform a variety of functions, including making new drug compounds, influencing the behavior of cells and delivering medications, but have been limited as to the complexity with which they can make these circuits. Timothy Lu, assistant professor of electrical engineering and computer science and a member of the Research Laboratory of Electronics at the Massachusetts Institute of Technology (MIT), along with various colleagues at other institutions, are on the road to changing that by laying the groundwork for more complex circuits and creating a "toolbox" of synthetic biology components.
The complex functions that people envision genetic circuits performing require controlling numerous genetic and cellular components, among them not only the genes in cells but the proteins that regulate them—a process that typically involves transcription factors.
As Lu notes, most such research has been limited by that fact that people have designed their synthetic circuits using transcription factors found in bacteria; however, these don't always translate well to nonbacterial cells, he says, and it can also be hard to scale them upward to make more complex circuits.
Lu and his colleagues at Boston University (BU), Harvard Medical School and Massachusetts General Hospital have stepped up to design a new technique to design transcription factors for nonbacterial cells, using yeast cells as their initial test case and coming up with an initial library of 19 new transcription factors.
This is the start of a synthetic biology toolkit to make complex genetic circuits, Lu says, with the project slated to go on toward a larger, more challenging effort to keep making genetic components that can be assembled together to make ever- more-complex circuits that can do more and do it more precisely.
"There are a lot of new and cool circuits that have been designed to do some very interesting things, but many of them have been getting tapped out in terms of complexity, with the most complex ones in the past decade having maybe six or seven components," Lu says. "There are not enough really well-characterized parts to built complex circuits, and then each transcription factor might have completely different underlying mechanisms of action or associated proteins. So, we wanted to do a more modular, scaffolding-style approach so that components could be similar, not cross-talk necessarily, and so on, and be able to put them into custom, higher-order circuits."
Having a toolbox of parts, essentially, will make it easier to build more complex circuits in conjunction with the more modular framework, theoretically limited primarily by the available selection of components and the imagination of the researchers, he notes.
"There are many kinds of applications where this could help in the life sciences; for example, trying to do drug screening and identify what particular pathways or genes your drugs turns on or off. Currently, you tag promoter genes of interest but one of the things you could do is build higher-order circuits with multiple pathways on the same circuit," Lu explains. "You could have perhaps five or six different pathways and a single output to give you more high-info screening."
Farther out, Lu says, another area of interest for such complex circuits might be for delivery of gene-based therapies, in which one could deliver a more complex circuit into the human body that might even be able to perform diagnostics in cells to provide more efficient and appropriate treatment.
"We've shown that we can build a lot of these parts for the toolkit and characterize them, and show that they work," he says. "Now we need to figure out if you can put them into much more complex circuits than ever before. 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 good results within the next year, "and we hope the new stories we can put out will demonstrate the power of using these parts as modular components in larger circuits."
Results of the work are described in the Aug. 3 issue of the journal Cell. Other authors for that article include Ahmad Khalil, assistant professor of biomedical engineering at BU; BU postdoc Caleb Bashor; Harvard grad student Cherie Ramirez; BU research assistant Nora Pyenson; Keith Joung, associate chief of pathology for research at Massachusetts General Hospital; and James Collins, BU professor of biomedical engineering.
Plans to even begin thinking about commercialization or seeking industry partners are pretty far out and it is too early to predict when that might happen, Lu acknowledges. The circuits they have built for yeast in their research are still relatively simple ones to show that the components work and the modular approach works, and next steps include building more complex circuits, such as massive 10- or 15-transcription factor circuits, with Lu noting, "We want to see how far we can scale the type of circuits we can build out of this framework."