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CRISPR/Cas9 Takes Root in Core Facilities Worldwide

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NEW YORK (GenomeWeb) – In the spring of 2014, a genome editing working group at the University of Wisconsin, Madison held a campus-wide meeting about CRISPR.

Called GEEwisc, short for Genome Editing and Engineering at Wisconsin, the group was driven in large part by genetics Professor Xin Sun and the flyCRISPR team: Professors Kate O'Connor-Giles, Jill Wildonger, and Melissa Harrison, who in 2013 had become the first scientists to demonstrate CRISPR/Cas9 gene editing in Drosophila. It was the first in a series of public meetings for members to share their experiences working with CRISPR. The turnout suggested they might need more than just meetings to satisfy everyone's curiosity.

"That first meeting we had, the auditorium was just packed to the gills," Dustin Rubinstein, who at the time was a researcher in the O'Connor-Giles lab, told GenomeWeb. "The aisles were full, people were peeking through the doors." He estimated that several hundred scientists attended. "We realized GEEwisc was going to be an important group," Rubinstein said. It was after that meeting that the members, all early adopters of CRISPR/Cas9, committed to finding a way to help their neighbors hop on the CRISPR bandwagon.

"Once people find out you know stuff about CRISPR, everyone starts asking you questions all the time," Rubinstein said. "Everyone wants to ask you, 'How does it work? How can I use it, what's the easiest way, what am I supposed to do?'

"Rather than having a few professors getting bothered all the time, we thought we might as well have a genome editing facility. If everyone needs to do it, maybe everyone doesn't have to be an expert for it," he said.

Fast forward two years and Rubinstein is the director of UW-Madison's Translational Genomics Facility, which recently celebrated its first year of operation. Unlike its name, its aim is specific: to provide the university's research community with on-demand CRISPR expertise, a new node in a network of core facilities offering bioinformatics analysis, sequencing, stem cell line generation, and transgenic model organisms.

While having a standalone CRISPR core is uncommon, universities around the world are finding ways to offer their researchers access to CRISPR technology without having to become experts themselves. Harvard University alone has two CRISPR-savvy facilities — one for the medical school and one for the faculty of arts and sciences. Biomedical research powerhouses such as Johns Hopkins University, the Cleveland Clinic, Emory University, the University of California at San Diego, and the University of Pennsylvania, among others, all have core facilities offering CRISPR/Cas9, as do schools with expansive research programs like the University of Texas at Austin, and Cornell University. UW-Madison is somewhat unique in that it has not only basic biology and biomedical science, but also agricultural research programs. European institutions such as University College London, The Czech Centre for Phenogenomics, and the Universitat Autònoma de Barcelona have also joined the trend. Wherever they are, genome editing, transgenic animal, stem cell, genetic screening, and viral vector cores are bringing the benefits of the CRISPR revolution to their host institutions and beyond.

And the schools are often looking for corporate partners to help them. Sigma-Aldrich has launched an expansive partnership program with core facilities throughout the US and Europe.

For the Netherlands' University of Groningen, adding in CRISPR/Cas9 services to its long-awaited induced pluripotent stem cell core facility was an easy decision. The university's medical center had been talking about an iPSC core facility for years. "Then the plan came, and we thought maybe we can combine these technologies," said Daniel Warmerdam, one of the two senior postdocs who run the iPSC CRISPR Facility housed in Groningen's European Research Institute for Biological Ageing. "In some aspects they make each other stronger."

The iPSC CRISPR Facility will reach its full promise when it is able to create iPS cell lines from patient cells and use CRIPSR/Cas9 to edit genes associated with the diseases they bear.

"We're not quite there yet but we want to offer that," Warmerdam said. His facility opened just last month so it is beginning by offering gene knock-out and fluorescent protein tagging. It also has a collaboration with an epigenetics laboratory to use nuclease-null Cas9 (dCas9) fused to proteins that create or erase epigenetic modifications, and plans to offer CRISPR/Cas9 knock-out screens.

Each facility offers a different menu, but the full slate of CRISPR applications can be found if you look around. Karin Bornfeldt, director of the Viral Vector and Transgenic Mouse Core at the University of Washington's Diabetes Research Center, said her lab offers FokI-dCas9 fusion and Cas9 nickase methods of gene editing, in addition to plain old Cas9.

At UW-Madison, knock-out editing is by far the most popular request, Rubenstien said.  "About a third of the time, someone has a particular biological process they're interested in and they have a candidate gene they think is important, so they want to KO that gene and see what the phenotype is," he said. "That's classic and straightforward, really efficient."

Another popular service is for Rubinstein to knock-in a particular gene variant that has been identified through genome-wide association studies, answering the hypothetical question of, "If I make a single variant that is associated with a disease, do the rats [with that variant] get that disease as well?" he said. The remaining third is a mixed bag of CRISPR applications: conditional allele knockouts, CRISPR interference, and inserting transcription factor binding sites to boost expression of a particular gene.

"It's really [everything and] the kitchen sink," he said. "Overwhelmingly, by volume, it's genome editing but certainly were doing all that stuff."

Like Warmerdam's, Rubinstein's facility is small. He has one full-time employee and some help from undergraduates. But with a successful first year, the outfit is poised to expand, adding staff, new services and, for the first time, marketing.

"Everything has been word of mouth," Rubinstein said, but he has been busy enough without seeking new projects. "Early on there was a tremendous waiting list," he said. And it wasn't only UW-Madison researchers signing up for his services. Groups from around the country have enlisted his help, including some from the Midwest region such as Mayo Clinic, St. Jude Children's Research Hospital, and the University of Minnesota Twin Cities. He's even done some work for scientists at Oregon Health & Science University. Warmerdam said his facility works with labs at other institutions, as did Bornfeldt.

These outside parties won't receive the same favorable rates as those on campus. UW-Madison scientists are charged at cost of reagents, which is also the case at University Medical Center Groningen, while others pay Rubinstein a 53 percent premium. But for those with the money, it's a whole lot easier than learning to do CRISPR themselves. And Rubinstein can also plug into many of the other services available though UW-Madison's core facility network.

Rubinstein works closely with Kathy Krentz, who runs the school's Transgenic Animal Facility.

She'll often work with Rubinstein on projects from researchers in the medical school looking to create models of human disease. "We're meeting some people who have never worked with animals before. The way the CRISPR tech allows them to look at in vivo models, they're now saying 'I think I need to create a rat,'" she said. "They've gone from their model of choice, which may have been cell lines, and now we're able to capitulate [their disease of interest into animals."

She's been creating mouse and rat models for UW-Madison scientists for 25 years. From her vantage, the change has been dramatic. "It's night and day difference, a complete change of technology" she said. "We are able to edit the genome much faster and it's less labor intensive."

Ironically, it hasn't made her job any easier. "It creates more work for us," she said. "We are overwhelmed. We can't keep up with the phone calls and the emails — but that's a good thing."

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