Ross Wilson: A Voice for Meaningful CRISPR Innovation and Access to Therapeutic Genome Editing
Dr. Ross Wilson’s lab at the University of California, Berkeley and the Innovative Genomics Institute had a unique start: it was born out of an existing collaboration between UC Berkeley and Pfizer. In late 2015, as Ross was wrapping up his postdoc in Jennifer Doudna’s lab, a Pfizer grant needed a Project Manager. Ross took on the project, working with a small team to develop novel methods for gene editing.
The research stuck; he’s been running a lab whose work focuses on the delivery of CRISPR ever since, though now he’s independently funded. Broadly, Ross is interested in in vivo, cell-selective genome editing, or engineering genome editing enzymes (such as Cas9) to edit only certain cell types. His lab is focusing on delivering CRISPR to liver cells and immune cells via intravenous administration, both of which are implicated in a large set of genetic diseases.
From Fundamental Research to Direct Application
Ross’ scientific endeavors have been unified by his interest in the reactions between RNA and proteins, though the projects he’s focused on over the years have gradually shifted away from fundamental research, towards research with immediate medical impact. This shift is not all that surprising: Ross came from what he described as a “very medically oriented” family, and, almost by default, he thought he’d be a doctor. But during his undergraduate years as a pre-med student at Ohio State University, he was inspired by a chemistry professor to try research, and he ultimately recognized that medical school wasn’t for him. In part, he liked the idea of supporting himself, doing his own work.
University of California, Berkeley
Innovative Genomics Institute
Postdoc at UC Berkeley, Jennifer Doudna Lab
Ross became interested in biochemistry and structural biology, and he stayed at OSU in Mark Foster’s lab for his Ph.D. He spent part of his graduate career unraveling the structure of archeal RNase P, an enzyme with both protein and RNA subunits that is required for the maturation of tRNA, and another part modeling the structure and biochemical properties of a bacterial riboswitch involved in the regulation of gene expression. When it came time to pursue a postdoc, he was drawn to Jennifer Doudna’s lab. Ross didn’t join the lab to study CRISPR; it was 2010, before CRISPR was grabbing headlines, and at the time, “her lab was a world leader in research on RNA-protein complexes and structural biology.” Ross picked up a project on human RNA interference, a pathway containing an Argonaute that binds microRNAs — a targeted genetic enzyme, in many ways similar to Cas9.
By the time Ross took on the Pfizer project in 2015, doing research on CRISPR-Cas9 was, he said, “a pretty straightforward switch.” He was also excited to think about the impact of this work on human health and disease: CRISPR’s therapeutic potential was readily apparent, but there were a lot of challenging problems still to solve.
The Push and Pull Between Academia and Industry
During the first years of his lab, Ross spent time with one foot in academia and one foot in pharma. His collaborators at Pfizer were developing technologies to enable safe, effective, and targeted CRISPR therapeutics in hepatocytes, liver cells. They engineered a Cas9 that could be selectively recognized by a liver-specific receptor and internalized by liver-derived cells in vitro.
The exposure to the biotech and pharmaceutical industry was eye-opening for Ross. On the one hand, he gained a useful perspective on what it takes to bring a drug to the clinic. The rigor of both preclinical testing and quality control required a different type of problem solving than he had seen in academia. And, ultimately, he believes that this exposure will help him and his lab develop technologies that will be meaningful in the clinic.
On the other hand, Ross also saw some of industry’s limitations. In his opinion, it was and still is moving fast, too fast. “Right now, the whole CRISPR field is sprinting — even though I see it as more of a marathon — but established technologies are mismatched for in vivo, therapeutic use,” he explained. The successes, the promising gene edits, that have been demonstrated in vitro haven’t been easily translated in living organisms. (Ex vivo gene editing, or cell therapy, seems more immediately promising but has its own set of challenges.) Targeted delivery, what he and his collaborators were working on, remains another huge bottleneck: gene editing therapeutics can’t be effective or safe unless they are targeted to tissues implicated in a disease. The technique for receptor-mediated delivery that Ross and the Pfizer team developed was a step in the right direction, but this was only part of the battle: even when they could ensure that Cas9 was selectively internalized, it might not escape the cell’s endosome and then could not make any edits.
After a few years, having both feet back in academia made sense to Ross. “I think that the runway is too short in industry. The type of innovation we need [to develop in vivo genetic therapies] is going to take more than a year or two of intensive trying.” Ross doesn’t mean that developing successful CRISPR genetic therapies isn’t on the horizon, just that effectively treating or curing the majority of genetic diseases might require more time and more freedom to innovate than the field hopes. Ross felt that industry, in particular, had an “impatience around discovery.” It makes sense: companies that are the first to a technology can more easily license and use that technology in the clinic. Companies that can’t license a technology can’t use it.
Ross prefers to work without those constraints, but he still works with impact in mind. With CRISPR, “if you do it right, you only have to do it once per patient,” he says. Given this kind of drive, Ross has landed himself in a fortunate setting: the Innovative Genomics Institute (IGI), a collaboration between UC Berkeley and UCSF that’s focused on enabling its researchers to apply CRISPR-Cas9 to meaningful, real-world problems and to engage the community while they’re at it. It’s a nontraditional academic setting, one that suits Ross by channeling the best of both academia and industry. “The IGI seems like it is ideal for the delivery technologies were developing, to bring them into existence. The opportunity here is truly end-to-end. Going forward, I think it will be very important to have this kind of holistic approach.”
Increasing Access to Genome Editing Therapeutics
Much of Ross’ recent work has been motivated by a desire to improve access to genome editing therapies. It’s not enough to develop safe, effective therapeutics if the vast majority of the global population who would benefit from them can’t access them — because they’re too expensive for patients to buy or too expensive for companies to manufacture, because they’re extremely difficult to supply and administer, or all of the above. As new gene and cell therapies have hit the market at more than a million dollars a pop, this has become more imperative for Ross.
The issues of pricing and access are incredibly complex, and there are many parties involved. Ross thinks that the research community has a critical role to play; he implores others to look at their research through the lens of accessibility. “The approaches we have now are getting results, but we still need to develop new technologies that will help make them affordable and accessible,” he says. “For example, we’ve seen that using a viral vector can give you results in a mouse, but we know that it’s hard to scale up for humans.” It’s not just about whether a technology works in the lab, but whether it can be effectively developed and manufactured.
The complexity extends beyond manufacturing, into questions about how we test and deliver drugs. “The future for tissue-specific delivery is uncertain; it’s not clear how it’s going to be possible to suitably target CRISPR for widespread use,” Ross explains. “Early success for targeted therapies has been seen through ex vivo editing in hematopoietic cells and T cells — what’s known as cell therapy. Yet, these strategies are inaccessible because they require an entire team at a cutting-edge research hospital for each patient.”
Ross and his group are on a mission to develop one potential solution to this problem: a simple intravenous injection of a therapeutic enzyme, an in vivo therapy targeted to immune cells. If a genome editing therapeutic could be delivered efficiently into the bloodstream and safely into T cells, it would be much more cost effective than current gene and cell therapies. Ross hopes that this work — after more innovative problem solving and careful testing, of course — will translate to the clinic and to the market in a way that makes CRISPR medicine more accessible to patients worldwide. CRISPR-Cas has so much transformative potential, but Ross has to ask, will the technology really be as transformative as it promises if only few of many can unlock that potential?