Building Bridges 2023 Spotlight Series: an interview with Eugene Yeo
Professor Eugene Yeo is the inaugural recipient of the Academia Europaea Sydney Brenner Medal. In our interview, he speaks on his personal connection with Sydney Brenner and continuing his legacy as a mentor.
About Eugene Yeo
Professor Eugene Yeo is a distinguished figure in the field of cellular and molecular medicine, renowned for his research journey at the intersection of biology, genomics, and therapeutics. Holding key positions at the University of California San Diego (UCSD) and now founding director of a new Center for RNA Technologies and Therapeutics at UCSD, as well as Chief Scientific Advisor at the new Sanford Laboratories for Innovative Medicines, he has dedicated his career to unravelling the mysteries of RNA processing in both development and disease. His pioneering work has extended to the application of CRISPR/Cas technology for in vivo RNA targeting and the advancement of techniques for large-scale protein-RNA interaction mapping.
Professor Yeo has authored more than 200 peer-reviewed publications, including book chapters and review articles, and serves on the editorial boards of several prestigious journals. His accolades include the Alfred P. Sloan Fellowship and the Early Career Award from the International RNA Society.
Read the interview
Gene, congratulations on being the inaugural recipient of the Academia Europaea Sydney Brenner Medal! What does this award mean to you?
“This award means a great deal to me. I knew Sydney personally for a large part of my professional training as a scientist, and he inspired me to start my career in science. He told me of all the careers to pursue, science is a fun one because you get to be passionate about it, and if you’re lucky, you can make an impact in ways that perhaps you don’t get the chance to in other careers. So, this means a lot to me – it’s really an honour in memory of Sydney. I’m happy to be able to carry on some small smidgen of his legacy as an amazing scientist and try to honour his passion for mentoring. I have a lot of mentees and over the years I’ve tried as hard as I can to be a great mentor like Sydney.”
How did your diverse academic background shape your research interests and career path?
“My double training in chemical engineering and economics really prepared me to be very quantitative in how I approach problem-solving. The unique thing about being a chemical engineer as an undergraduate student is that you do a fair bit of both computational modelling and statistics, but also experimental science such as organic and physical chemistry. So, there is an excellent balance between computational modelling and being able to test your hypotheses experimentally, and I really enjoyed that.
At the end of my undergraduate senior year (at University of Illinois Urbana-Champaign) I was curious about how chemical engineering could be applied to other areas. I wasn’t interested in going to work for a distillation plant, or building compounds – I wanted to understand more about how we can apply engineering technologies to biology. I had the opportunity to intern at Affymetrix, which was at that point a new company building microarrays that contain lawns of oligonucleotides that would enable the high throughput measurement of gene expression. Up to that point, studies of molecular biology would measure one or two transcripts of genes at the same time, but Affymetrix had the technology that could measure many different genes simultaneously, perhaps 7,000-10,000 genes at the same time. When I got involved in that internship, I was very excited about that kind of data, which to me forecasted where biology was heading – more quantitative data, more experiments in parallel, and thinking about things as a network and from a systems perspective.
After my internship, I had to go back to Singapore to serve in the military, but during the weekends and throughout the two years I was there I was fortunate to work at IMCB in Singapore. I worked with one of Sydney Brenner’s closest colleagues, Byrappa Venkatesh, in his lab, and there I learned the basics of molecular biology and cloning. It got me sufficiently excited that I decided that going to graduate school after my military service was the direction I wanted to take, and it was through lots of conversations with Sydney that I applied to MIT to study computational neuroscience. I was very influenced by Sydney, who insisted that the next century of mysteries is all about understanding how the brain works at all levels, and to me that sounded fascinating.
I started off in computational neuroscience at MIT and learned about machine learning – how algorithms learn from a lot of data, pattern recognition as a model for neuroscience, etc. I got very interested in trying to apply that to molecular biology, so I started working with Chris Burge who was at this point a junior investigator in biology at MIT. He was working in RNA splicing, so I got involved in applying computational and machine learning methods to try and understand the process of RNA splicing where introns are removed, and exons are spliced together to form mature messenger RNAs. I really enjoyed this combination of experimental science and computational modelling, particularly this tight cycle of iteration of learning from data and then predicting the next set of hypotheses to test and experiments that can be performed.
Once I’d completed my studies at MIT, I went to the Salk Institute in San Diego for my pro-doctoral fellowship. Again, I was quite influenced by Sydney, who advised that the Institute had amazing researchers looking at neural development and stem cell biology. I worked very closely with Rusty Gage on how RNA processing could impinge stem cell fate decisions, and after a few years I started my own lab at the University of California San Diego (in the Department of Cellular and Molecular Medicine), where I integrated all of my experiences. In my group we have engineers, we have cell and molecular biologists, we have computational scientists, and we focus on building stem cell-derived models of human diseases, and we also develop strategies to treat human diseases which are based on RNA-targeted therapeutics. I’ve continued my interests in RNA processing and splicing, and we evaluate how RNA binding proteins control RNA processing in different disease and developmental models.
So, it’s been quite the journey from an engineering and quantitative background to realising that biology was going to be truly quantitative, and experimentation would be large-scale in nature. I look for the most interesting problems that I can try to solve with my skillsets and my interest in both RNA and the brain.”
Could you provide an example of how your work in genomics has led to practical insights or potential applications in medical therapies?
“I’ve been very interested in developing technologies that enable a deep understanding of protein-RNA interaction maps and have developed resources; characterised antibodies, developed computational tools, and the framework to study protein-RNA interactions at a very high-throughput scale. My lab has provided these resources and opportunities to the scientific community, and already people have leveraged these to identify rules for regulating their specific RNA of interest or developing next-generation RNA-targeting drugs.
We’ve licensed some of our tools and technologies to one of our companies in San Diego, Eclipsebio Innovations. Eclipse provides these technologies to a wider audience than my individual lab could, and they work with 100-200 biotech and top pharma companies to enable and accelerate development in the RNA therapeutic space. These tools have a life of their own, they go on to catalyse research findings and innovate in many other areas, so that’s one area we’ve focused on – building the tools to enable RNA therapeutics.
The other area we focus on is developing methods that can be encoded in gene therapy vectors to modulate RNA to enable a therapeutic outcome. Very early on, we worked on ways to repurpose CRISPR proteins to bind RNA and destroy toxic RNA species. The field has accelerated quickly, and we’ve also leveraged technologies from other groups and deployed them to show that we can have therapeutic benefits in models like myotonic dystrophy, Huntington’s disease, in ALS, and other forms of neurodegeneration and now starting to look in oncology.
We’ve made contributions to RNA-targeted strategies that can be encapsulated with gene therapy vehicles and are moving towards other cargo for the therapeutic modulation of RNA in human cells. That has enabled us to launch companies to bring some of these pre-clinical ideas and assets to patients.”
As a co-founder of several biotech companies, how do you balance your academic work with your entrepreneurial successes?
“I’ve been very fortunate and grateful to have strong trainees who are interested in amplifying their basic research findings further after they have graduated, or finished their post-doctoral time in my group. I can serve as a lifelong mentor to them because together, we can try to build opportunities or companies to further some of these ideas, which often outlast the resources that our academic environment can provide. I don’t see it as tension between my time in an academic environment and my time in new company creation. I see my role as a mentor, and it’s a seamless trajectory of being a mentor to someone in my lab, in an academic environment, and then if they decide they want to stay involved we can build something new, or continue to develop a concept that we have started together. I just continue my role as a mentor to these individuals in a different setting – it’s the same role with different parameters.
It can be difficult with a busy home schedule. My wife and I have 3½-year-old twin girls at home, and my wife is also a faculty member at UCSD. We don’t have our parents or immediate family around us, my family lives in Singapore, and we’ve had to build our own support network in San Diego. It helps that my lab is a vibrant community of individuals that draws in excitement from our surrounding academic community, and also disseminates our technologies and our science to the community. I feel like we can leverage our colleagues and friends to balance our busy schedules, and that helps to provide the training and resources that we collectively enjoy for our research.”
What’s next for your work – what are your priorities and ambitions for your research?
“I’m very interested in trying to take our basic technologies and findings and continue to leverage these to get medicine to people. I can’t tell you how we’re doing that just yet – partly because we are still iterating, inventing, failing and then trying again. I’m interested in evaluating if RNA-binding proteins are going to be drug targets in the near future, for diseases from neurodegeneration to oncology to immunology. It’s incredibly exciting for me and for our ecosystem of entrepreneurs and scientists.
The other area we are very interested in is the question of ageing, and how RNA binding proteins and the process of RNA regulation change with age. There are significant differences already in some cell types as we age, where you have defects in RNA regulation. I think that helps us to understand age-related neurodegenerative diseases but also oncology. The biggest covariate for many of these different diseases is actually age, and so we are interested in trying to make inroads into understanding that through the lens of an RNA biologist.”
If you had to sum up your vision for the future of RNA genomics in a few sentences, what would it be?
“I think the future of RNA genomics will be continuing to evolve faster, stronger and cheaper technologies, and then deploying them to dissect disease mechanisms and accelerate the identification of new therapeutic modalities and mechanisms.
In the past, we would be happy in characterising differences in disease states, but I think we can leverage these to go deeper and faster in drug discovery. It’s a bit more of a translational angle, but it’s also a natural maturation of my research and my lab.”
About the Sydney Brenner Medal
The Academia Europaea Sydney Brenner Medal was established in 2022 to commemorate Sydney Brenner, one of the greatest scientists of the 20th century and one of the founding members of the Academy. The medal is an initiative of the Class C – Life Sciences and has been supported by inaugural donations from John Wong Eu-Li MAE (C5), Balázs Gulyás MAE (C3), Mr Philip Yeo (Singapore) and Dr Philip Goelet (US).
The SBM is given to honour the best in scholarship and personal achievements within a period of not more than 20 years after obtaining the PhD degree (with allowance for career breaks). The award is given to an individual scholar in the field of molecular biology and related disciplines, who receives a Bronze Medal of Sydney Brenner and a diploma, as well as delivering the Sydney Brenner Memorial Lecture.