Dr. Gene Yeo is an associate professor in the department of Cellular and Molecular Medicine at UC San Diego. His laboratory focuses on stem cells, neurodegeneration and RNA, specifically examining different RNA binding proteins and their impact on RNA splicing. RNA binding proteins and RNA splicing are pivotal for gene expression control and protein levels. Before landing in California, Dr. Yeo did his PhD work at MIT in Computational Neuroscience, making him skilled in all those fascinating and intimidating computer algorithms that help analyze piles of scientific data. After receiving his PhD, Dr. Yeo decided that an MBA would be an excellent addition to his training and attended the Rady School of Management at UCSD. He has numerous awards including the Alfred P. Sloan Fellowship and the Crick-Jacobs Junior Fellowship.
Dr. Yeo gave an excellent talk that focused on two main topics: genetic mutations that result in RNA splicing changes and the emergence of the single cell transcriptome. Dr. Yeo discussed mutations in a specific RNA binding protein, which is found in patients that present similarly to Amyotrophic lateral sclerosis patients. Interestingly, while mutations in the protein caused only a few gene expression changes, they also caused hundreds of alternative splicing changes. These changes were not due to a simple loss of function in alternative splicing, but likely due to a gain of function, as they resulted in additional alternative splicing sites for the RNA. Dr. Yeo’s research expands on current ideas about how a mutation can affect not just gene expression level, but also the composition of the transcriptome. To better understand these transcriptional changes, the field of single cell transcriptomics has been utilized to illuminate the effects of a single mutation on an RNA message. Previously, transcriptome studies were done on a pooled population of cells. This can be problematic as these cells are all in different stages of their cell cycles, so what is being expressed in one cell may not be expressed in another. By focusing on a single cell’s transcriptome, one can see what changes are made without such variability in the expression background. These technologies will have a profound impact on how we view and study human disease.
Q: You talk about alternative splicing, how much do you think we still have to discover of the transcriptome and alternatively spliced versions?
GY: Many groups have now reported that over 90% of genes have different isoforms, which is an impressive number. I think we haven’t really exhausted finding all the alternative splice sites, we still have to look at different cells, and their stages of development. We also still have to look at the environmental effects. Alternative splicing is very complex and intriguing, we need to understand if all the information of alternative splicing is embedded in the DNA sequence or if the environment has an effect.
Q: Do you see the epigeneome and the transcriptome interacting with each other.
GY: Absolutely, there are long non-coding RNAs that are part of the transcriptome which interact with the epigenome. This interaction is still being teased apart, including where the factories are in the cell linking up gene expression and splicing.
Q: So back when I was in college they taught us about junk DNA, does that even exist anymore, or is all DNA useful?
GY: There are maybe some repetitive elements and introns which that might apply to, but even many of these elements have been found to be useful as structural components or for binding sites for proteins and epigenetic control. The introns seem to provide evolutionary advantages and lead to an increase in diversity.
Q: With that in mind is there a correlation between complexity of an organism and the amount of alternate splicing?
GY: People have done these studies and they have seen that in more complex organisms, more alternate splicing happens. This is a way creates more options from a limited amount of space and material of the genome.
Q: In your talk, you mention two proteins that are mutated in ALS/Lou Gehrig disease, TDP-43 and FUSTLS, were shown to have causative mutations in glycine rich regions. Could you speculate on why those mutations would contribute to the disease mechanism?
GY: From the work of others, it turns out that those regions may be involved in the aggregation or oligomerization of these proteins, and they make the proteins “stickier”. It creates a change in which the proteins “glue” to each other. It’s unfortunate and changes the way in which the cell behaves, ultimately contributing to the disease phenotypes.
Q: What would you say some of the advantages and disadvantages are for the single cell transcriptome analysis?
GY: I think some of the advantages are that you can really examine the relationships between every RNA and protein in that single cell. When you have a bulk or average measurement, that relationship can be lost due to background noise. One clear disadvantage is that it is very expensive and difficult to isolate and analyze data from a single cell. But all of this is being worked out. What is more intriguing is the question of whether in the future will we ever want to do bulk measurements if the cost for single cell measurements drops. I can’t see any reason to measure a bulk culture of cells if the effort and cost are the same as for a single cell. Eventually one would want to do single cell measurements in vivo, in an animal.
Q: It appears you have had several collaborations in both the Biotechnology Industry and the Academic realms; could you compare and contrast between the two?
GY: I think the nature of collaboration is generally similar, with each group sharing a common interest, but there is a difference in resources and goals. The resources available in industry are very different than those in academia. A company may have an expertise in medicinal chemistry and can make a compound very quickly, and this type of expertise can be more challenging to find in academia. The academic mindset can also be very different in what they are trying to accomplish in industry, in which they are very focused on a goal, and sometimes interesting tangential results do not get pursued if they are not part of that original goal. But that’s how fundamental discoveries are often made.
Q: I noticed you have worked in both Singapore and here at UCSD, could you compare and contrast some of the cultural differences in how research is conducted between these two locals?
GY: That’s a good question. The similarities are striking. We all want to do good science and make an impact, which is common in all countries. The differences come about with how the researchers interact with each other. It is not so much specific to the research, but more a function of the cultural differences between Americans and Asian groups. Some of the cultural differences need to be paid attention to in order to not misunderstand others. Americans tend to be very straightforward about what they say they want. In Asia, it is more about knowing where each person is coming from and their relationship to you sometimes outside of the research. I think once you are aware of the differences then it helps make collaborations easier, even resulting in friendships that are valued outside of the research relationship.
Q: So a bit of a genie in a bottle question, if you could have any technological advancement in your field, what would it be?
GY: For me it would be taking genome wide measurements within single cells in the organism without killing the cell. This would then allow us to have actual measurements of development and disease states in real time. We would probably need high resolution imaging as way to monitor individual cells. Nanotechnology could even play role in delivery for monitoring.
For more information on Dr. Yeo’s research, check out the Yeo Lab Website.