How a “sidetrack project” led to one of Mikko Taipale’s most influential papers

“In my experience, science happens in two ways,” says Mikko Taipale, professor of Molecular Genetics and PI at the Donnelly Centre. “The first is these projects where you have a plan, you execute it, and then you finish the project. Of course, you can never really predict how it goes, but you have an aim and, in the end, something comes out of it. The second type of project is more opportunistic.” 

Included in the soon-to-be-released list of Donnelly’s most impactful papers, the Taipale Lab published the Nature Methods paper “An efficient KRAB domain for CRISPRi applications in human cells” in 2020. It was a project that Taipale recalls as fitting firmly into his second category of exploratory, adaptable science research: a “sidetrack” stemming from another project, resulting in a path he and his PhD student Nader Alerasool followed until they reached a new discovery. 

Their paper established a technique to suppress gene expression in a human cell, improving the efficiency of the status quo of the time. When researchers use the gene-editing technology CRISPRi, the end goal is to change the observable properties of the organism, known as the phenotype, by silencing the function of a specific gene. The process is made possible by fusing an inactive version of the bacterial protein Cas9 to the group of transcriptional repression domains known as the Krüppel-associated box (KRAB). Where previous CRISPRi techniques resulted in incomplete silencing, Taipale and Alerasool systematically tested 57 different KRAB domains to find the best among them. 

“This project was never our intention from the beginning,” says Taipale. “We realized the reason why people use [the most commonly used KRAB domain] could be a historical accident—that it was just one of the first ones that was tested. When we started testing, there was a huge difference in the results—it was clear that we could write a story around it.” 

Out of the tested sites, the Taipale Lab established the exceptional repressing potency of the ZIM3 KRAB domain. Following the study, Taipale has shared the plasmids that the project generated with over a thousand different labs via the Addgene plasmid repository, resulting in leading labs adopting their findings as a new platform. 

“It's nice to make a small tool for the community,” says Taipale. “The aim is always to make better tools for people. If your hammer is not better than the previous hammer, it's worthless. But even small improvements can make a difference.” 

Taipale’s been working on everything from small improvements to ambitious aims since joining the Donnelly Centre in 2014. He’s built a life in Toronto, from shaping his dream lab at Donnelly, to getting his private pilot license and learning the city from a bird’s-eye-view. Throughout the years, the research focus of his lab has evolved in tandem with Taipale’s ever-changing interests. While he’s still interested in gene-silencing, his lab has moved into studying RNA regulation, host-pathogen interactions, protein design, and much more.

“Science is exciting, it's exhilarating—I can't see us focusing on one scientific question for the next twenty years. It may happen, but we're in the business of learning new things,” says Taipale. “I'm in the right environment at Donnelly—there's a lot of people with similar approaches, and I don't need to justify my focus or lack thereof. I can't think of many other places where we would have such a good fit in terms of mutual interests and opportunities.” 

Collaborating with labs in the Donnelly building and across the world, Taipale is looking forward to many more years of research; from both targeted projects and the “sidetrack” science that evolves into unexpected discoveries.