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See Inside April 2005

In the Business of Synthetic Life

Synthetic biology might someday lead to artificial organisms. To James J. Collins, it already offers pharmaceutical promise, like turning a person's cells into custom drug factories
JAMES J. COLLINS: MAKING LIFE



TRACY POWELL
At first glance, the bacterial colonies that dot a petri dish in the Boston University laboratory of James J. Collins do not seem all that special. Each Escherichia coli bacterium has been genetically altered to manufacture a specific protein once the population density of the colony around it reaches a predefined level.

A skeptic might yawn. After all, genetic engineering isn't new. But these cells haven't just had a foreign gene spliced into them. Collins inserted a whole genetic network--he put in many genes that interact together as well as with the natural genetic machinery of the cell. In this case, he dropped in a quorum-sensing network from a Vibrio fischerii bacterium. If conventional genetic engineering is like changing the blade on a screwdriver, then Collins's approach is akin to altering the contents of the entire toolbox at once.

The 39-year-old Collins is a member of an emerging field called synthetic biology. Practitioners create novel ingredients for the recipe of life, including nucleic acids, amino acids and peptides. Some of them even hope to manufacture an artificial organism [see "Synthetic Life," by W. Wayt Gibbs; Scientific American, May 2004]. It is still considered a seed-stage discipline, where brilliant young scientists wow one another with proof-of-concept experiments and publish papers filled with pages of mathematical formulas. Collins, on the other hand, is the first to generate commercial technologies that are in the advanced stages of development. More than any other, he is proving that synthetic biology is ready for the marketplace, much more quickly than others expected it could be.

The most promising of those technologies is an RNA ribo-regulator, which Collins first described in 2004. It consists of a sequence of DNA that, with the help of a genetically engineered virus, integrates into a host bacterium's genome. The DNA then creates a loop of messenger RNA that binds to a site on the ribosome (the cell's protein factory), thereby blocking the production of a specified protein. The regulator can do the opposite, too: it can unblock the ribosome on command in order to start making that protein. Essentially the ribo-regulator enables scientists to dictate protein production, with close to 100 percent accuracy and efficiency.

Others quickly improved on the ribo-regulator. Richard Mulligan of Harvard Medical School designed one that can be activated when a specific molecule is added to mouse cells. If these technologies prove successful inside humans, a person's cells could be turned into pharmaceutical plants. Pills would be popped only to turn the micro factories on or off. Such a future is still years away, but the progress thus far amazes Collins. "I never would have dreamed that within a year this technology would already be working in mammals," he says. A company founded by Collins, called Cellicon Biotechnologies, is now negotiating with several firms for use in drug discovery.

The ribo-regulator is not the only technology with such tremendous commercial promise coming from Cellicon. The company has encoded the principles behind synthetic biology into software to help screen drug candidates for their effect on the whole cell, rather than just on one protein target. "Drug companies are great at creating an assay that proves a compound hits a specific target," Collins states. "Thus far they haven't been very good at predicting what it will do to all the other genes and proteins in a cell."

Collins's success in technology development lies in the fact that he straddles the line between engineering and science so effortlessly. "I'm not sure if the conventional definitions are very helpful anymore," he says. "In the end, I'm far more interested in seeing the fruit of my work help a human being. If I do some good science along the way, that's great, too." Others agree. "Collins's scientific work is all the more impressive because he's done it while doing real engineering," remarks George Church, a biologist at Harvard Medical School.

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