Ahead of the Festival of Genomics in California this November, we’re posting some of the amazing conversations that we’ve had with the speakers. This interview with Jacob Corn, Managing Director and Scientific Director for Innovative Genomics Initiative first appeared in Issue 3 of Front Line Genomics magazine. Jacob will be presenting on “Harnessing the Revolution in Next-Generation Genome Editing for Fundamental Research and Real World Impact“.

Genome editing could give doctors the ability to cure the incurable. The potential is very appealing, despite the ethical issues that still need to be worked through. We’re at the beginning of an exciting journey, but there is still a long way to go.

Genome editing isn’t new. We’ve been doing it for years in various different systems. The concept of editing the human genome isn’t that new either. It’s a topic that has been subject of serious debate and fiction for years. So what’s changed? The concept of editing a human genome is no longer just a concept. It’s not in the realm of the possible yet, but is now very firmly in the realm of the plausible. And that’s what makes this such an exciting time. While the general media speculates, there is an incredible amount of activity behind the scenes to make sure that progress isn’t reckless. Through his work at the Innovative Genomics Initiative, Jacob Corn, is one of the key figures in making sure genome editing delivers on its bright promise

FLG: The CRISPR/Cas9 system has many advantages over zinc finger nucelases and TALENs based approaches to genome editing. It feels like genome editing is gathering the same kind of excitement as sequencing did when NGS began to offer practicality. These days, everything and anything is getting sequenced – how far away from a similar genome editing boom are we?

JC: Even though it feels like genome editing is everywhere, I think we’re still in the early stages of the boom. Labs all over the world are starting to use genome editing for their research, and many are having great success. But others are still trying to get started. In some cases this is the Paradox of Choice: since there are so many great reagents now for genome editing, some feel paralyzed about where to start. Hence, the IGI is offering a course this summer on Cas9-based editing for both human cells and model organisms. Other labs follow the biology to difficult systems where genome editing is less well explored, but I think these areas become more tractable with time and work. As more labs become comfortable with genome editing for basic research, we’ll see applications in the clinic and elsewhere rapidly follow. See a blog post I made recently for some speculation about where things might be going in the future.

FLG: Genome editing is starting to make its way across to the general public media. It’s always encouraging when a field captures the imagination, but it can take on a life of its own as misconceptions grow. How do you explain what genome editing actually is and why it’s practically beneficial to a lay audience?

JC: I find that lay audiences are already well acquainted with the general idea behind genome editing. Speculative fiction has been preparing us for this moment for decades. I’ve talked about the topic people from all walks of life; everyone gets it right away. You don’t need to know a thing about Cas9 or mechanisms of DNA break repair to understand. Most people very quickly get that genome editing means giving doctors the ability to repair genetic disorders that are currently an incurable luck of the draw for patients, and they see how much good that could do. But everyone also sees how much harm might come if we’re reckless and how much care should be taken. In the long term, the most concrete (and speculative) benefit is that our relationship with genetic diseases could fundamentally change. I’m not necessarily talking about germline editing, since one might have the same benefit with the ability to replace affected tissues with edited tissues. There is the opportunity for real and permanent cures for terrible diseases in which people currently just make do. That’s powerful stuff. But it’s a long road, and while some major technical roadblocks have been cleared, it’s still a long journey.

FLG: The need for public trust is something that can’t be ignored in today’s day and age. Is this a product of the new technologies that uncover and interact with what makes us individuals, such as NGS and CRIPSR, or are we just living in a media rich and information hungry age?

JC: I don’t think the need for public trust is anything new, and is just as important now as it has been for decades. Disruptive change is always nerve-racking: there were books about computersgone-rogue long before the internet age, and people were frightened of being unable to breathe at high speeds on the first major steam train line. As humans, we become used to the way things are, and it’s scary when things dramatically change in our lifetimes. But thanks to one of these disruptive technologies, the internet, media has become so democratised that there is a great opportunity to develop public trust. Anyone can meet and interact with researchers via things like Youtube, blogs, and video chats. At the IGI we’re dedicated to public outreach opportunities and have been busily making several videos to explain Cas9 technology.

We’re looking forward to continuing to engage with both scientists and the public about this new era of genome editing in the near future.

FLG: You have a great perspective on how various stakeholders interact around research. You had a spell at Genentech, and now you’re at the Innovative Genomics Initiative. With so much innovation coming out of the academic field, what do researchers need to do to give their work the best opportunity of translating into a viable healthcare application?

JC: I think this question is best addressed via an outlook, rather than a how-to list for turning your research into a drug, since fortune favors the prepared mind. The most important thing is learning to consider problems in multiple ways and at multiple scales of time and purpose. Academia is outstanding at breakthrough science that takes the long view: where are the blank spots in our understanding and how do we fill them in? Industry excels at the difficult job of understanding immediate needs in the real world and turning basic research into commodities that people come to depend upon. Both spheres are critically important, and both are hard, backbreaking work. I think much comes down to better communication between academia and industry. Not so long ago there was some frustration and even stigma associated with academia and industry working together. More recently, I think researchers on both sides very much want to learn from each other to have the best chance of making a positive difference in the world. And that’s the key – learning from each other. Let’s start with baby steps: next time you’re at a conference, whether you’re from academia or industry, find someone in the opposite camp and have lunch with them. Most times you’ll find all of the academics eating at one table and all of the industry folks at another table. Ask people at the table what they’ve been working on and why it’s hard. Really listen. Think about how your work might have some kind of impact on those difficulties, either in the next few years or the next few decades. For those interested in a few more words on this topic, I wrote a bit about better communication between academia and industry in a recent blog post.

FLG: In January, AstraZeneca announced their push into utilising CRISPR-Cas9. Part of this is collaboration with you guys at the Innovative Genomics Initiative. What kind of work will you be doing together?

JC: Our collaboration is aimed at using Cas9-based transcriptional regulators for basic research in many disease areas (oncology, cardiovascular, metabolic, respiratory, autoimmune and inflammatory diseases and regenerative medicine). We’re working together to identify and validate gene targets relative to several diseases and to understand how these factors go awry in disease. This collaboration is a two-way-street, with close communication and sharing of research data between AZ and IGI, with the goal of positively impacting drug discovery and development to hasten treatments to patients.

FLG: We talked at the top of the interview about the speed at which genome editing is developing. One of the things you’re passionate about at the Innovative Genomics Initiative, is thinking ahead to applications and really considering where this is all heading. What’s the short term and long term outlook for CRISPRCas9?

JC: I think this is best summarized in a blog post I recently made about short/medium/long term impacts of genome editing on human health:

Short: In the next few years I think we’ll see greater adoption of genome editing in many labs, both academic and industrial. This will mostly be what I call “RNAi v2.0″ — disruption of genes in a very fast and easy mode (either via CRISPRcutting or CRISPRinhibition). This will extend to both human cells and model organisms, but the scope accessible for reverse genetics will be greatly expanded. Now that more and more genomes are sequenced, we’ll finally have a way to figure out what biologies underly all of those great annotations in those organisms (reverse genetics) or screen for which genes are responsible for incredible phenotypes (forward genetics). How do salamanders regenerate limbs? How do some fungi turn insects into zombies? What are the roles of genes expressed during Plasmodium infection? Does ablating gene X slow tumor progression in this model system? Are all of these genes really necessary for epithelial differentiation in the gut? These kinds of questions will be broadly answerable in both academic and industrial research settings: fundamental discoveries that will accelerate and broaden our understanding of the world around us.

Medium: Within five years true gene editing (surgically replacing one sequence with a defined replacement) will have matured and be as easy in human cells and model organisms as plasmid mutation currently is bacteria. We’re already starting to see some hints of this on the horizon, so maybe this should even be in the “short” bin. But I think a lot of current work is focused on very low hanging fruit (important though it is), and there’s still no clear path towards quickly and robustly engineering silent or deleterious variants, for example mutants with a fitness disadvantage. So this one goes into “medium term”. Surgical introduction of mutation would be huge for any number of basic biologies, since it would enable one to readily ask reductionist and mechanistic questions in the context of a living cell or organism without confounding factors. On the translational front, in the medium term gene editing will totally change the way preclinical research is carried out. Custom-designed safety models (e.g. humanized rats), highly engineered cell lines to meld target and phenotypic screening, synthetic biology for enhanced drug production, and so on. People have been wanting to do these things for a long while and they might take a little longer to achieve in industry only because the focus will include robustness of the systems rather than purely speed, but they’re coming. More relevant to the general public, in the medium term we’ll start to see the widespread clinical emergence of ex vivo therapies that take advantage of gene editing, especially in the hematopoietic system. Clinical research and trials are already ongoing here (e.g. Sangamo’s work with ZFN knockout of CCR5 for HIV), but now I’m talking about FDA approval and widespread use of an edited product as a therapeutic. The trial data has so far been very impressive on many fronts, but time will tell and the finish line is always further away than you think. 

Long: Since the likelihood of anyone accurately predicting at this timescale is quite low, rather than make any specific predictions I’ll instead wax philosophic. Here we’re starting to talk about disruptive science fiction entering our lives in a real way. Things like in vivo editing in adult or postmitotic tissues. Sci-fi may actually be an apt comparison and offers a few positive examples of successful prognostication: Edward Bellamy predicted credit cards in 1888 and Arthur C. Clarke described communications satellites in 1945. And in a way, media of all kinds has been preparing us for genome editing for decades. I was recently asked how I explain what genome editing is and why it’s practically beneficial. But the thing is, I actually don’t need to do much explaining. I’ve talked about genome editing with taxi drivers, hair dressers, graphic designers, high school students, and Hollywood actresses. Everyone gets it right away. You don’t need to know a thing about Cas9 or mechanisms of DNA break repair to understand genome editing. Most people very quickly understand what genome editing is and they see how much good it could do. But everyone also sees how much harm might come if we’re reckless and how much care should be taken. So in the long term, our relationship with genetic diseases will fundamentally change. I’m not necessarily talking about germline editing, since one might have the same outcome with the ability to replace affected tissues with edited tissues. There is the opportunity for real and permanent cures for terrible diseases in which people currently just make do. That’s powerful stuff. But it’s a long road, and there’s a lot left to be done.

FLG: Innovative Genomics Initiative is going to play a major role in driving this. How did IGI form?

JC: The IGI was catalysed to bring together Bay Area expertise in genome editing and regulation by Jennifer Doudna (Berkeley) and Jonathan Weissman (UCSF), as well as Mike Botchan (Berkeley). After Jennifer’s work developing Cas9 as a programmable DNA nuclease and Jonathan’s work repurposing it as a programmable regulator of transcription, they recognized that this technology would quickly become bigger than any one lab could handle. Marsha Fenner was first recruited as the IGI Program Director and I was soon afterwards recruited to be the Scientific Director and Managing Director. Since then we’ve built stellar foundational labs at Berkeley and UCSF to push the boundaries of genome editing and regulation, as well as developed a wonderful group of IGI Affiliates throughout the Bay Area. More information on the foundational labs and the affiliates are available at https://innovativegenomics.org/about-igi/

FLG: You’ll have a very big role to play personally, as Managing Director and Scientific Director. What’s the focus of your research at the moment?

JC: We currently have three main thrusts. First is developing next-generation tools that push genome editing and regulation even further and enable exciting new discoveries. Second, we are using those new technologies for basic biological research, to better understand how complex cellular signalling networks are maintained. Ubiquitin-mediated signalling is one focus, but there are also on-going projects in areas such as transcriptional regulation and DNA damage. Third, we are committed to the short-term application of genome editing for impact in hematopoietic disease, both in discovering novel causative disease variants and working towards therapies to reverse disorders.

FLG: Research is just part of what you do, though. You also put in a considerable amount of work into building new models for collaboration between academia and industry, helping to promote entrepreneurship. How did that become an area of focus for you?

JC: When I began working as a group leader at Genentech, I was humbled by how little I knew about modern drug discovery and development. I had been a grad student and postdoc in top labs at major research and was taught well so had good handle on the biology, but research leadership is about much more than just science and there was still a steep learning curve. I’m very grateful to all of my Genentech colleagues who took time show me the ropes. Now I want to help expose graduate students and postdocs to different styles of research during their training, and if they’re interested to help them to help them understand the business side of their research. I think universities currently do an excellent job of training graduate students and postdocs how to think logically and critically about scientific problems, but we typically teach a very academic style of management. I’d like to not just teach people about academic or industry approaches, but broadly help them understand how various approaches are different and might be appropriate in various situations. How do you know when to move on from a project? How do you maintain a research group or a large multidisciplinary team? How do you obtain operational support for your ideas? These questions have wildly different answers if you’re in academia, an established company, or starting your own entrepreneurial adventure. I want to provide information and training that’s appropriate for career goals, as well as encourage more dynamic roles at the interface of academia, industry, and entrepreneurship. This will not only better prepare people for their own futures, but will lead to exciting new discoveries, technologies, and companies.

FLG: Are there any groups out there that you’re really excited about?

JC: One of the most exciting things about the genome editing revolution is that incredible work seems to pop up every week from the most unexpected places. This makes it very hard for me to single out any one group! Cas9’s extreme democratisation of genome editing for basic research is incredibly inclusive, and I love seeing the creative ways everyone is using it to answer their own biological questions.

FLG: Thank you for speaking with us. Is there anything else you want to mention?

JC: It’s my pleasure. The field of genome editing is moving incredibly quickly, and I’m excited about the IGI’s role in bringing about fundamental change in biological and biomedical research by enabling scientists to read and write in genomes with equal ease. Genome editing is already changing the research world and it’s just a matter of time before benefits are apparent in our day-to-day lives.

 Don’t forget! This interview with Jacob Corn, Managing Director and Scientific Director for Innovative Genomics Initiative first appeared in Issue 3 of Front Line Genomics magazine. Jacob will be presenting on “Harnessing the Revolution in Next-Generation Genome Editing for Fundamental Research and Real World Impact“. Register for the event here.




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