“The ultimate metric of success is that we change people’s lives”

It was already a few minutes past 10 a.m. in the morning. We were waiting for Charles Gubser to join us shortly, when Botond Roska received a message that he would be delayed for another few minutes as he was still on a call to nail down some details on an important transaction that had kept him busy for the last few weeks. The deal in question, which led to another 20-minute break in our interview later that morning, was a key achievement for the Institute of Molecular and Clinical Ophthalmology Basel (IOB). It revolved around the transfer of an optogenetic project to a new company, RhyGaze AG, that would continue the work to develop a novel treatment for a hereditary form of blindness. The closure of the agreement, which was only a few weeks away, not only reflected the fast-paced approach of the IOB, which had been founded some six years earlier. It also showed how it could leverage its research efforts to generate funds and translate some of its key research insights into breakthrough therapies. In a nutshell, the deal exemplifies the vision that inspired Novartis, the University of Basel, and the University Hospital Basel to join forces in 2017 to create the IOB. The hope was that by combining basic research with the work done at the Eye Clinic, the IOB would be able to develop new ophthalmologic treatments and overcome what was a dearth of new eye-care treatment options at the time. “I have high expectations for this new scientific center. Uniting our expertise in ophthalmologic research and clinical development and using new technologies such as gene therapy, I am sure the Institute of Molecular and Clinical Ophthalmology will change the practice of medicine and help patients around the world improve vision and quality of life,” former Novartis Chairman Joerg Reinhardt, who was among the key drivers to create the institute, said at the time. That the IOB would generate palpable results so fast was a positive surprise for all involved. At the beginning, the institute was no more than just an idea supported by a handful of people who had the courage to pave the way for a research and development center that could help ophthalmology out of its crisis mode. Much of the initial hope was resting on the work of Director Botond Roska, a former group leader at the Friedrich Miescher Institute in Basel, who had published several seminal papers that dived deep into retina research and looked at the opportunity to treat eye diseases with emerging gene technologies. While his research opened a new avenue to treat some severe eye conditions, several breakthrough developments were needed to help turn some of his basic research ideas into reality. One was the development of gene therapies per se, which hit an impasse around the millennium. Another one was the realization that eye disease research relied too heavily on animal models, which gave researchers the wrong clues. All of this changed several years back with the advent of more efficient gene technologies, the emergence of organoid research and the further advance of eye research. “Innovation in ophthalmology has been a great challenge, partly because our understanding of the eye on the molecular and cellular level has been slow to emerge,” said former Co-Director Charles Gubser. “One area that needed advancement was formulating an understanding of how the retina picks up information, computes it, and sends it to the brain. This is something where Botond and only a few other scientists have really delved in and been able to understand, and then manipulate how that system really works,” Gubser added. For Roska, besides the basic science insights, other key developments included the realization that animal eye models were not sufficient. “People started to recognize, both in industry and in basic science, that translation from mouse models to human is very difficult,” Roska said. “And most of the diseases, especially the common diseases, are not represented in a mouse, because a mouse is lacking the most important structure in our retina, the fovea or macula, which is important for vision.” As these strands converged, the time was ripe to create an institute such as the IOB that brings clinical and basic research together, said Roska. Also, he added, that with the inclusion of Charles Gubser, who joined from Novartis, where, among others, he had been working in the global drug development unit, the IOB gained the translational skills needed to work towards new therapies. Hence, for Gubser, while the basic research efforts at the IOB are important, the institute needs to stay focused on its research efforts to create outcomes that can benefit patients. “One aspect is to acknowledge that academic publishing is an important driver and metric of success at the IOB. But the real ultimate metric of success is that we change people’s lives. To do that, it takes a more intense focus on optimization and the creation of insights that can be translated into medicines,” he said. Mr. Roska, was the creation of the IOB a dream come true for you? The genesis of the IOB was based on a notable gap in ophthalmology. While the eye is uniquely accessible for treatments and diagnostics, there was a striking lack of therapeutic options compared to the wealth of anatomical and cellular knowledge we had. This disparity between knowledge and treatment effectiveness drove us to establish the IOB, aiming to harness this untapped potential to develop real solutions. For me personally, as I was already active in the field for more than two decades, it was a dream come true.

Some green can even be found in Klybeck, a former industrial site.

Mr. Gubser, which other factors were important? Advances on the molecular and cellular level made it possible to finally do predictive science and work on projects that can be potentially translated into therapies. On the other hand, what stands out with the IOB is the ability to work collaboratively between clinicians and molecular-level researchers. From a funding perspective, it was the right moment in time to invest in ophthalmology innovation through the IOB. And maybe what we’ll see from that is a real change in the way we approach the science of the eye, clinical practice in the eye, and then hopefully the therapeutic approaches. Did it take courage on the part of the founders? I believe that, from the point of view of the founders, which includes Novartis, the University of Basel, and the University Hospital Basel, it looked like all the advances in the ophthalmic space constituted a turning point, which prompted them to take the risk and create the institute. But it still took courage to do it since there was no guarantee that it would work. Mr. Roska, in terms of research you have made strong advances in rare disease areas. Where do you go from here? I think from the point of view of science, the initial focus on rare diseases made sense, since we had animal and human models of disease and we could work out gene-dependent and independent therapy approaches. But, of course, we also want to work in larger indications such as myopia – in fact there is no larger need than myopia. Going forward, the molecular mechanism and treatment for myopia will be a major theme for the IOB, and our goal is to approach it from different angles to slow myopia progression. What were some of the other lessons learned after the first six years of the IOB? I believe in the beginning we were very much determined to work on the basic science and make advances there. But we certainly had some challenges in how to translate our findings into potential medicines. With the engagement of Charles Gubser and scientists such as Bence György, the IOB was able to attract the translational skills needed and to start to develop an expertise in translation. Compared to the work of a basic scientist, who is led sometimes purely by his personal curiosity, and the work in the clinic, which is focused on care, the translational skill is something that we needed to develop. Mr. Gubser, can you talk a little bit about this translational mindset and the skills that are needed? In a nutshell, it boils down to understanding, on a quantitative level, how a potential therapy and its mechanism works. In the most advanced program we have, in the optogenetic approach to vision restoration, one of the central efforts has been to gain a clear understanding of the whole chain of events that makes up a therapy. Without that quantification, it’s very difficult to tell if what you’re doing is just a gimmick or luck, or something that has the potential to translate. What does this mean for basic science? Without excellent basic science, you cannot do good translation. So, if you don’t understand the system in depth, you won’t really be able to manipulate it reliably. And, having said this, much of that basic science depends on the premise that we work with the right models, not exclusively with animal models as in the past, but with human tissue as well as with organoids. Here, the IOB has also made massive progress. Furthermore, the collaboration with our colleagues from the clinic is and will be crucial going forward. Mr. Roska, do you agree with this observation? Very much so. First, the collaboration with the clinic really makes the IOB unique in the ophthalmology space. Also, in terms of quantitative skill, we are making inroads. To just give you one example: One of our group leaders is a professor of theoretical physics, who came to us for the very idea that our approach is so data-driven and that we want to generate a meticulous understanding of the processes we are researching. Is this also reflected in your Ph.D. program? Yes. A strong focus of our Ph.D. program is on this quantitative approach. For example, it’s obligatory for the students to take courses in programming and statistics and various other subjects that lend themselves to developing these specific skills. Mr. Gubser, with the focus on driving quantitative research with a strong bias on data-driven skills, how important is skill diversity at the IOB? I think the diversity of scientific backgrounds at the IOB is unusual. We have physicists, mathematicians, biologists, chemists, people who can build microscopes, people who can manipulate biological systems. This is very diverse. But it’s deliberately composed to support a range of different efforts, all focused on the eye. Also, the cultural diversity is high. We have colleagues from Kazakhstan, Portugal, the United States, and Brazil and many more. Their backgrounds and interests are extremely diverse, and this is generally a good thing, because people are brought together by what they really want to do, which is doing great science. Mr. Roska, given this diversity, could the IOB have its headquarters elsewhere? The genesis of the IOB is closely linked to Basel. Not many other places in the world had the know-how, the courage, and the financial means to create such an institute. But then, Switzerland has many other advantages too. It’s a very open place from a cultural point of view. It has a strong scientific community, and it has a funding system that allows researchers to work on top-notch science. All of this makes Switzerland and Basel a very strong place. Mr. Gubser, can you also talk about funding? Fundraising is always a challenge in the academic world. We have been very privileged to have strong support from our founders. That support was time-limited when we initially created the IOB. And I’m optimistic that we’ll be able to raise the next round of funding from the same founders, and possibly some other participants, to carry the IOB forward. But, of course, it will also depend on our work – but here I am optimistic given our success with the cone optogenetic project. With the transfer of your optogenetic assets you have found a way to not only translate scientific insights into a potential therapy, but also secure future funding. How do you plan to proceed from here? We’re open to different approaches. But fundraising for an asset that will go beyond the boundaries of the IOB, and potentially become a medicine, that too is challenging. And you know, it takes work, effort, and explanation. So, I think we will do some of that work. But we are open in terms of what the right model is. In the instance of our cone optogenetics efforts we have been able to secure venture funding. The next transactions might look different.