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BC's Holt Pushes Ahead With Synthetic Bio

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If anyone can build a microbe from scratch, it’s Rob Holt. A leader in the sequencing revolution — Holt was at Celera in the early days, and has authored several major sequencing initiatives — he is a first mover to rebuild a microbial genome. Holt now spends his days as head of sequencing at the BC Cancer Research Centre in Vancouver, leading efforts to create the first free-living microbe.

While other synthetic biology research has focused on creating novel components or building complex systems, Holt’s lab is attempting to synthesize a free-living cell from existing sequences of the bacteria H. influenzae.

One approach to create a self-replicating system, Holt says, is to combine the components of a cell and wait for them to come alive. “There are billions of components, different molecules,” he says of the difficulty in building a cell and then convincing it to self-replicate. “It’s conceivably very challenging and practically impossible at this point.”

To this end, Holt’s group is working on what he calls the top-down approach: taking existing microbial sequences and then activating a genome, such that “it propagates and actually expresses the organism that it encodes.”

His team has developed a model system in which the genome from the bacterium H. influenzae is fragmented and then reconstructed inside an E. coli host cell. Both are well characterized bacterial species, and since they’re related, Holt says, their genomes should be more compatible. Holt has found that there is sufficient cross-talk for genetic activation to occur, but his group is still working out the methods for joining such large molecules of DNA.

“We’ve decided that it is [feasible] because there is considerable recognition, for example, of the regulatory elements in H. influenzae by E. coli transcription factors,” Holt says. “It doesn’t do you any good just to stick a piece of DNA in a host cell, if the genes present aren’t going to be expressed.”

Holt hopes that constructing a free-living microbe will prove a way to learn about biology. Observing through trial and error the minimal number of parts needed to build a functional cell is made easier once one goes beyond theoretical sets, he says. “The only way you can actually determine what minimal set of genes might actually function in the real world is to build it.”

He adds that, in testing predictions, “synthetic biology doesn’t allow you to disregard any data that doesn’t fit with your theory, because if you do, you don’t have a successful reconstruction.”

Holt first became interested in synthetic biology in 1998 when he joined Celera during the height of the race to sequence the human genome. There, he was the principal investigator on several major projects, including sequencing the malaria mosquito genome and the rat genome. He headed to Canada in November 2002 to lead the high-throughput sequencing facility at the BC Cancer Center. While the facility is currently sequencing about 40 different projects, ranging from forestry genomics to infectious diseases and cancer, his other primary goal is finding genetic risk factors for psychiatric diseases such as schizophrenia.

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