Some diseases are caused by a specific genetic mutation. Huntington’s disease, for example, is caused by mutations in a single gene important in nerve cells. Then there are complex diseases, where likely many genes, pathways and cell types may be involved—we just don’t understand yet how.
At La Jolla Institute for Immunology (LJI), Benjamin J. Schmiedel, Ph.D., is investigating how genetics are involved in increased disease risk. His research could lead to a better understanding of how to treat immune-mediated diseases such as inflammatory bowel disease (IBD), type 1 diabetes, asthma, Alzheimer’s, and more.
Schmiedel trained as a postdoctoral researcher in the laboratory of LJI Professor Pandurangan Vijayanand, M.D., Ph.D., where he investigated the role of genetics in immune cell function and helped to establish a database named the DICE (Database of Immune Cell Expression, Expression quantitative trait loci [eQTLs] and Epigenomics). DICE has proven highly valuable for understanding the role of common genetic variants in human disease on a genome-wide level.
Schmiedel was recently promoted to the position of LJI Research Assistant Professor, and he’s in the process of launching his own laboratory at the Institute. In this Q&A, he shares how his new laboratory will tackle several major challenges in immunology today.
Q: What inspired you to study genetics and the immune system?
A: I’ve always been detail-oriented and finding out the mechanism of how something works has always interested me. I was lucky to find this niche in science where I can work to better understand the effects of genetics and the immune system in health and disease. There’s so much that hasn’t been discovered yet.
We are analyzing the association of genetic variation and gene expression in immune cells. By linking our findings to statistical data on any human disease of interest, we are able to identify new genes and immune cell types that are likely involved in the risk of developing a disease. There is still a lot of ground to cover, and we only know very little right now. We are just at the beginning of understanding what is causing and driving disease.
How might research into immune cell genetics help patients?
We are building on insights from the DICE project. With DICE, we have made substantial progress in identifying genes and immune cell types that are relevant in immune-mediated diseases. Now we better understand how a gene is associated with, for example, IBD, diabetes, or asthma. Looking at the effects of genetic variation in immune cell types allows us to understand the underlying mechanisms of disease.
It has always somewhat saddened me to summarize and publish our findings in tables and lists, but not having the means to really investigate what a specific gene is doing in an immune cell and how this may relate to disease. Just by taking the second step, with experiments using human and animal model systems, we might find that some of our gene “hits” could actually be good drug targets—which may eventually help patients suffering from IDB, diabetes or asthma.
Will you now get to dig deeper into what these genes are doing?
Yes, I want to pursue this track of detailed investigation of specific candidate genes, using the knowledge that we gained from the DICE project. I want to move into a new direction and study the function and role in disease of some of the gene hits we have identified.
For example, my laboratory is now funded by an NIH grant to investigate a candidate gene in great detail and understand how it may affect the function of T cells in the context of inflammatory bowel disease.
What are you looking at right now when it comes to COVID-19?
I have a second NIH grant to gain understanding of the molecular mechanisms driving immune responses to infection with SARS-CoV-2. This project is building on research results from DICE that we obtained early in the COVID-19 pandemic. We were able to identify genes linked to COVID-19 severity, and found two genes of particular interest that likely play important roles in specific immune cell types during infection.
We will focus on identifying the relevant transcription factors driving expression of these genes and investigate which cellular pathways are affected, in order to understand what causes differences in symptoms and disease severity for COVID-19 patients.
What motivates you to stick with this research?
I have friends and family members suffering from immune-mediated diseases, and for some, COVID-19 was a big issue. I want to understand why some had severe cases of COVID-19 but others did not. It is very important to understand how genetic variation is contributing to disease development and severity, not just for COVID-19.
And if, by the end of my research career, I was able to help develop a new drug that is helping patients and reduces suffering from a disease, then all the effort was worth it.
How does LJI support your research?
It has been great to work at LJI, especially with LJI’s Flow Cytometry Core, which was helping us to isolate and purify all the immune cell types we have investigated so far. Moving forward, we will also have the Microscopy Core and LJI’s Department of Laboratory Animal Care (DLAC) supporting our work, in setting up model systems and readout methods. I’m excited for that!
