Early manifestations of subcellular defects in neurodegenerative diseases

Neurodegenerative diseases like Alzheimer’s or ALS typically show their devastating effects late in life. What if the root causes of these cognitive diseases are slowly but steadily chipping away at brain cells much earlier on, possibly even in childhood or before we are born? Gene Yeo is leading a team investigating this possibility using human stem cells and brain organoids, tiny clusters of lab-grown brain tissue, that bear genetic mutations linked to certain forms of ALS or muscular dystrophy to study the earliest developmental changes caused by these mutations. Among other resources, they are planning to use stem cell lines gene-edited by researchers at the Allen Institute for Cell Science as the basis for their studies. In previous work, Yeo and his colleagues found that ALS-linked mutations trigger changes in one of the cell’s storage compartments, a structure known as stress granules. These alterations trigger cascading effects that change the location and composition of many proteins and other molecules in the cell. Capturing the earliest cellular changes linked to genetic forms of these degenerative diseases could point to new pathways for targeted therapies.  

Affiliated Investigators

Gene Yeo, Ph.D, MBA

University of California San Diego

Gene Yeo, Ph.D, MBA, is a Professor of Cellular and Molecular Medicine at the University of California San Diego (UCSD), a founding member of the Institute for Genomic Medicine and member of the UCSD Stem Cell Program and Moores Cancer Center. Dr. Yeo has a BSc in Chemical Engineering and a BA in Economics from the University of Illinois, Urbana-Champaign, a Ph.D. in Computational Neuroscience from Massachusetts Institute of Technology and an MBA from the UCSD Rady School of Management.  

Dr. Yeo is a computational and experimental scientist who has contributed to RNA biology and therapeutics. His primary research interest is in understanding the importance of RNA processing and the roles that RNA binding proteins (RBPs) play in development and disease. Since inception, Dr. Yeo’s lab has focused on uncovering molecular principles by which RBPs affect gene expression, how RBP-mediated post-transcriptional gene networks contribute to cellular homeostasis in stem cells and the brain, and how mutations in RBPs lead to human developmental and neurodegenerative disease. His lab pioneered computational algorithms and experimental methods in human disease-relevant systems to conduct systematic and large-scale studies. These multidisciplinary methods combine machine learning, biochemistry, molecular biology, genomics, chemistry and materials research. His lab develops methods that are systematic, robust and adoptable, such as enhanced CLIP for the purposes of large-scale mapping of protein-RNA interactions (Van Nostrand et al, Nature Methods, 2016). Gene’s lab is a major contributor of resources to study RBPs that enable hundreds of labs across many areas of bioscience, such as the world’s largest resource of RBP-specific antibodies that facilitated generation and interpretation of the most comprehensive maps of RBP-binding sites to date for hundreds of RBPs (Van Nostrand et al, Nature, 2020). They have also systematically uncovered RBPs that condense into RNA granules during stress and demonstrated strategies to leverage these for therapeutic use in neurodegeneration (Markmiller et al, Cell, 2018; Fang et al, Neuron, 2019; Wheeler et al, Nature Methods, 2020). His lab also demonstrated in vivo RNA targeting with CRISPR/Cas proteins (Nelles et al, Cell, 2016) with proof of concept in repeat expansion disorders (Batra et al, Cell, 2017; Batra et al, Nature Biomedical Engineering, 2020). Work from the Yeo lab has been highlighted in Nature Methods and Nature Reviews Genetics as “Method to Watch” and featured as a top story in Discover magazine in 2016. These efforts have led to clinical programs to develop medicines for RNA-related diseases. 

Dr. Yeo has authored more than 200 peer-reviewed publications including invited book chapters and review articles in the areas of neurodegeneration, RNA processing, computational biology and stem cell models; and served as Editor on two books on the biology of RNA binding proteins. Gene is on the Editorial Boards of the journals Cell Reports, Cell Research and eLife, and on the Advisory Board of Review commons. Gene joined UCSD as an Assistant Professor in 2008, was promoted with tenure to Associate Professor in 2014 and to Professor in 2016.  Gene was the first Crick-Jacobs Fellow at the Salk Institute (2005-2008) and is a recipient of the Alfred P Sloan Fellowship in recognition of his work in computational molecular biology (2011), Alpha Chi Sigma-Zeta Chapter Krug Lecturer (2016), Singapore National Research Foundation Visiting Investigatorship Award (2017), the inaugural Early Career Award from the International RNA Society (2017), the Blavatnik National Award Finalist (2018 & 2019), San Diego Xconomy Awardee for ‘Big Idea’ (2019) and 2019 recipient of the Highly Cited Researcher in Cross-Field category, recognizing the world’s most influential researchers of the past decade. Gene’s research has been funded by the National Institute of Health, National Science Foundation, California Institute for Regenerative Medicine, TargetALS, ALS Foundation, Department of Defense, Myotonic Dystrophy Association, Myotonic Dystrophy Foundation and Chan-Zuckerberg Initiative. Gene has also been funded and collaborates with biotech and pharmaceutical companies such as Takeda, Genentech and Roche.  

Gene is a co-founder of biotech companies which includes Locana, Eclipse Bioinnovations, Enzerna and Proteona. Gene played a critical role in the successful raising of $55M for Locana at series A (2019). Gene serves or had served on the scientific advisory boards of the Allen Institute of Immunology, Locana, Eclipse Bioinnovations, Proteona, Aquinnah, Cell Applications, Nugen (now Tecan), Sardona Therapeutics and Ribometrix. Gene is a senior advisor to Accelerator Life Sciences Partners. 

Gene is the founder of the SCREEN (San Diego Covid-19 Research Enterprise Network, 2020) and founding member of the SEARCH (San Diego Epidemiology and Research for Covid Health, 2020) alliances in San Diego. SCREEN has ~1000 scientist members in San Diego focusing on grassroots research coordination and community outreach. SEARCH is focused on epidemiology studies of the prevalence of the virus completing a 12000-person study of viral spread. Gene is on the Return to Work task force in Biocom. Gene is the faculty founder of DASL (Diversity and Science Lecture Series, 2020) providing a voice for scientists to discuss diversity, equity and inclusion challenges and celebrating their scientific achievements. Gene was a Sword of Honor recipient (the highest honor) in Officer Cadet School in 1999 and has served in the Singapore Navy as a Naval officer. Gene has completed 2 full Ironman-distance and multiple half-ironman-, olympic-, sprint-distance triathlons, full marathons and half-marathons, but now spends time rock climbing.