Cenix BioScience announced last week the publication of its genome-wide RNAi screen for cell division genes in C. elegans, effectively ending the first chapter of the company's five-year history.
"It was, to our knowledge, the very first genome-scale screen to be attempted [using] RNAi," Chris Echeverri, Cenix CEO and CSO, told RNAi News this week. "Obviously, we haven't been the very first to publish a genome-scale screen, especially in C. elegans, but we focused not on being the first to publish. Rather, [we were] really trying to make sure we did it as right as could be.
"It's never going to be perfect," he said, "but the goal was to apply the same level of care and detailed analysis for a genome-wide screen as we would for a much smaller study."
The screen was funded in part by the Max Planck Society, and the resultant data — which includes about 40,000 time-lapse recordings, still micrographs, and text annotations from over 300,000 microinjection experiments — has been made freely available online by the Max Planck Institute for Molecular Cell Biology and Genetics at www.worm.mpi-cbg.de/phenobank2. It was also published in last week's Nature.
With the publication, Cenix has essentially ended its work in C. elegans, according to Echeverri. "Although [the screen] was our main project at the beginning, and a lot of development had to happen to build up the infrastructure to do this properly, … when RNAi became feasible in mammalian cells, we shifted our focus towards more advanced applications of" the gene-silencing technology, he explained. "Now, in fact, literally everything we do is in human cells or rodent cells."
The C. elegans work began with Cenix co-founder Pierre Gonczy while he was a postdoctoral fellow in the lab of Anthony Hyman at the European Molecular Biology Laboratory in Heidelberg, Germany. "Pierre was the first one in the group to have the idea of using RNAi as a genome-scale screening method," Echeverri said.
According to Echeverri, the idea sat until he arrived at Hyman's lab and was persuaded to start the project. "It took [Gonczy and Hyman] six or seven months to convince me of the wisdom of taking [the screen] on," he said. "In the end, I agreed to co-direct this with Pierre, and he and I … were able to get a group together within the lab and start this as a pilot project."
The initial interest, Echeverri said, was to identify all the genes involved in the first two rounds of mitotic cell division using time-lapse video microscopy, and in 1998 work began on "testing of the feasibility of doing genome-scale RNAi on one chromosome of C. elegans — chromosome 3, which corresponded to about 2,300 genes," he said. "We shot through most of that chromosome within two months, and we knew we had the basis for not only continuing the screen over the whole worm genome, but also exploring the feasibility of doing RNAi screening in other systems."
Additionally, "we realized that the time-lapse microscopy assay allowed us to pick up defects in a number of other processes [beyond cell division] that we could score," Echeverri said. "So it [began as] a screen focused on cell division, but it ended up giving information about a lot more than just that."
Ultimately the decision was made to continue the project through a biotech start-up, despite initial reservations by the researchers. "I have to admit I hesitated a lot — I was not convinced of the wisdom of" founding the start-up, Echeverri said. "But eventually I said, 'All right. Let's try it.'"
The result was Cenix, and after more than five years of work, the company has finally published its genome-wide screen.
"It's been bittersweet to finish the C. elegans chapter in Cenix," he added. "We don't have C. elegans projects going anymore and we don't offer it as a service anymore. The reality is that there just isn't enough demand for C. elegans projects and we have to focus on what works, and what works has worked for us — we had [our first] profitable year last year."