December 2011

Synthetic biology: edging toward the clinic

Cholera is rampant in the developing world, where affected populations often can’t afford the two vaccines currently available for more than $1.50 per dose, . March’s approach with engineered commensal bacteria would be relatively inexpensive: The bacteria could be laced into fermented foods, such as yogurt, and passed through communities as fermentation starters without incurring costs.

Cancer therapies also are being pursued. Current methods often cause unpleasant side effects in patients, because they take down healthy as well as cancerous cells. Ron Weiss’ group at MIT, in collaboration with the laboratory of Yaakov Benenson at ETH Zurich, described a system earlier this year that distinguished HeLa cells from normal ones in a mixed- cell culture with great specificity (5). The system used small interfering RNA to measure the expression of six microRNAs that marked cells as cancerous: Three of the microRNAs were typically overexpressed in HeLa cells, while the remaining ones were expressed at extremely low levels. When the magic combination of the six different expression levels of the microRNAs identified the cell as being HeLa, the artificial system triggered apoptosis in the cell. Weiss says the approach of using six different microRNA markers is much more sophisticated and specific than current therapies, which often rely on a single biomarker and are more prone to mistakes.

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The approach can be generalized for other types of cancer cell types and could accommodate other types of biomarkers, such as messenger RNAs and proteins, because “we look for the symptoms, not the underlying cause” of the cancer, says Weiss. Because each cell type has a unique combination of biomarkers, he says, it’s a matter of identifying those unique features of each cancer cell type for targeting purposes.

Technical difficulties
As with anything scientifically ambitious, the technical hurdles in synthetic biology are enormous at the early stages. To begin with, the experts say they need to expand the number of well-characterized molecular tools. “It would be so great to have a whole toolkit of well-characterized components sitting on the shelf that we could mix and match,” says Keasling. Meanwhile, Collins explains that the present-day tools of molecular biology “are relatively small and narrow, whether it’s Tet- or Lac-based systems or T7 phage.” He says there are numerous molecular parts that “are not sufficiently characterized or developed to be used as tools in synthetic biology.”

This is where the trove of molecular biology literature comes in, points out Pamela A. Silver of Harvard University. The old literature, she says, is “ripe with things that we can use as parts to build devices.” Silver gives the example of lambda phage, the subject of much research over the past 30 years. “The beauty of that work is that it was done in a lot of detail, and now we can turn around and apply it in a very quantitative and predictable way.”

The complexity of biology is challenging on two levels. First, interactions of synthetic components with endogenous players in different pathways within a given cell are inevitably a problem, says Keasling. Modern technologies that look at large ensembles of molecules, such as DNA arrays, proteomics and metabolomics, help us to understand how pathways are connected to one another. However, the introduction of a synthetic pathway may accidentally set off different pathways, he says, adding that, with the knowledge gained from these technologies, it’s often possible to re-engineer synthetic components to minimize interference.

Then there is the interaction of the engineered entity with the mammalian system. Fussenegger explains that researchers are just coming to grips with the complexities of human systems. “We still do not understand the dynamics of systems biology. We do not even understand the differences among humans in terms of genome,” he says. “If you want to implant something which interfaces with a very complex system, this is very difficult.” The complexity worries March: He says purported synthetic biology tools currently developed may get lost in the noise of complex systems.

This is why “synthetic biology is giving way to systems biology,” says Ellington. He explains that no matter how independent on paper a synthetic pathway appears to be from endogenous pathways in a cell on paper, it’s “going to interact with transcription, translation and signal transduction. Many of the ways in which it does interact are going to be unknown prior to implantation.”

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