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Synthetic Biology—From Black Box to Toolbox
What would happen if you let a bunch of engineers run wild in a biology lab? Underneath the jury-rigged pipets, strewn papers, and linear algebra books, you might find a pack of synthetic biologists.
While synthetic biology is a diverse and complex field, one basic theme runs throughout: Synthetic biologists implement tools and ideas that make biological engineering more like other, more conventional forms of engineering.
Synthetic biology has attracted the attention of electrical engineers and programmers, whose minds recoil at the idea of components whose performance is variable and also difficult to swap into other systems. We are still far from the point when rational designs can go from drawing board to functional in a single fabrication and testing step.
Before the Experiment
A large portion of synthetic biology research is concerned with making tools. They apply complementary informatics, design, and genetic engineering approaches to the problem of genetic circuits.
The Act Ontology system being developed at UC-Berkeley changes the way we access and view gene functions, with a focus on interactions and circuits. It extends the usefulness of projects such as Gene Ontology (GO) to aggregate and distill the enormous volume of literature.
Also, databases such as the Parts Registry encourage cataloguing such data. Finding enough genetic parts there for a novel function, however, is still a long way away. Tools such as GenoCAD, ProMoT, and others allow user-friendly design of circuits, SynBioSS allows in silico chemical simulation of genetic circuits, and Clotho permits versatile data management.
The software projects are exciting because of what they would permit in the future; wet lab projects are exciting for what they allow now. Labs are working on not only the characterization of basic parts—promoters, repressors, activators, and so on—but also advanced components: bistable switches, scaffolds, and metabolic pathways.
Though this research may seem purely foundational, it is done with numerous industrial uses in mind—these are engineers we're talking about, after all. Protein scaffolding was demonstrated in optimizing the mevalonate pathway, which is three steps in the synthesis of artemisinin, an antimalarial drug.
Something closer to the clinic is the zinc-finger nuclease, an enzyme created by the fusion of zinc finger DNA-binding domains with an endonuclease's cleavage domain. The modularity of zinc fingers allows for predictable customization of the DNA that the nuclease recognizes and cuts, and there are kits for making the process easier.
Such nucleases form the basis for Sangamo's HIV treatment, SB-728-T. It consists of removing T cells and treating them with the nucleases to introduce a deletion in CCR5, creating the same sort of HIV resistance as seen in the patient who was cured through marrow transplants. Sangamo presented positive Phase I results last month and is working on a similar method to treat stem cells.
Zinc-finger nucleases (ZFN) have room for improvement, though; use of other modular DNA-binding proteins called TAL effectors suggests that TAL effector nucleases (TALEN) might be even easier to predict and engineer.
In any case, modular nucleases offer more precision in gene therapy than has previously been possible, reducing the risk of side effects (such as leukemia) and may lead to further applications and treatments. Gene therapy in situ is still considerably more difficult, so don't expect a ZFN or TALEN to repair BRCA genes—yet.
One project that showcases all the principles of synthetic biology is the tumor-killing bacterium. It requires modifications to the base genome, removing the immunogenic capsule and antigens from the bacterium; a sophisticated sensing, guidance, and activation logic system to direct the bacteria to tumors and activate them appropriately; and finally redundant safeguards to ensure the bacteria behave as predicted and dispose of the bacteria after their purpose is served. It is an engineering project at heart and demonstrates both design principles and new genetic parts.
Synthetic biology has the ability to enhance regulation and genetic failsafes. Every measure to prevent these activities makes for a more predictable (and safer) biological therapy. Eventually, it might be bacteria delivering gene repair packages, and the gene repairs might be as varied as treatments for phenylketonuria to cystic fibrosis. Considering all that's been done lately, a world where one can opt-out of genetic diseases doesn't seem so far away.
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