After a recent visit to ELRIGs Drug Discovery 2023, News-Medical Dr. Federico Dajas-Bailador, a leading expert in axon biology and drug discovery. In this interview, we discuss his groundbreaking work, its potential for the future of drug discovery, and its profound implications for the treatment of neurological disorders.
Can you provide an overview of your experience and background in research and drug discovery, including any specific areas or research interests?
My lab focuses primarily on neuroscience, but we approach problems from the perspective of axon biology. We are deeply interested in how neurons develop, undergo polarization, and establish/maintain connections. This understanding not only helps in the development of the nervous system but also sheds light on age-related degeneration associated with the loss of axon connections.
We use different cellular models, such as compartmentalized microfluidic neuronal cultures, to study how axons encounter different environments compared to cell bodies. In this context, our research focuses on RNA biology, particularly the role of non-coding RNAs or microRNAs in regulating local axon protein synthesis. This knowledge is especially valuable when exploring various diseases and conditions such as pain or neurodegeneration.
How important are events like drug discovery from the perspective of academia and why? What do you want to get out of being here at Drug Discovery 2023?
Events like ELRIG 2023 are incredibly insightful. Although I am aware of the academia-industry interface through collaborations, for example with Eli Lilly, attending such events on a larger scale opens up a new perspective. The goal is to bridge the gap between basic science academics and the broader investment field without losing focus on core processes. By joining, I hope to identify more opportunities for collaboration and application.
Your research has focused extensively on axon biology and small non-coding RNAs (sncRNAs). Can you explain why the study of sncRNAs in axons is significant and how it impacts our understanding of neuronal function? What effect does this have on drug discovery?
As an analogy, when axons are scaled as arms in the human body, you can think of the axon length relative to the neuron’s cell body as the equivalent distance from Nottingham to Paris. This significant length creates a logistical challenge for neurons. In order to express proteins at the axon terminal, which is away from the cell body, there is a requirement for translational regulation. In other words, there is a need for decentralized gene expression.
Here, small non-coding RNAs play a key role. Our work on microRNAs has shown their importance in spatio-temporal regulation of gene expression. This research aligns with current interests in RNA biology and offers potential avenues for drug discovery, especially given the advances in RNA technology post-Covid.
Image credit: whitehoune/Shutterstock.com
Collaborations have played an important role in your research career. Can you highlight some of the most influential collaborations and how they have contributed to your research in axon biology?
A significant collaboration with Versus Arthritis Pain Center in Nottingham, particularly with Vicky Chapman and Gareth Hathaway. Initially, my work was not focused on pain research, but joining the experts at this center led to half of my lab’s work being directed toward pain-related projects.
Another meaningful collaboration involved the study of motor neuron disease alongside the professor. Rob Layfield and Dr. Dan Scott. This collaboration allows us to advance our expertise in RNA and neuron development and apply it to conditions such as motor neuron disease.
In your work, you have explored the molecular mechanisms underlying neuronal sensitization in sensory neurons. How does this relate to your broader research on axon biology and what are the potential clinical implications?
At its core, pain involves sensory neurons that extend axons from their cell bodies to peripheral tissues and the spinal cord. Understanding these sensory terminals, especially their responses to various conditions such as inflammation, is important.
Our axon-RNA-centric approach allows us to identify RNA changes and exploit them to alter sensory states, providing a more accessible means for drug targeting.
Can you provide some insight into the potential applications and implications of your research for the broader fields of neuroscience, neurology, and drug discovery?
In a typical neuron, the cell body contains only 10–20% of the cytoplasm; The rest resides in axons and dendrites. Thus, understanding the neuron requires acknowledging the role of the axon. We advocate a research focus to consider this polarization and complex structure.
By highlighting the different transcriptomics between axons versus cell bodies and targeting their regulation, we can influence the function of whole neurons, potentially transforming treatment approaches.
As an associate professor and principal investigator, what advice do you have for aspiring researchers and students seeking careers in neuroscience or related fields?
Success in research requires passion. It is important to find a subject that truly interests you and dedicate yourself to it.
Although there may be long periods where efforts do not seem to yield desired or meaningful results, persistence is the key. When success comes, it is a deeply rewarding experience. Hold on to that feeling.
With emerging fields like AI and machine learning, how are these technologies being integrated into your research and drug discovery to accelerate the identification of potential drug candidates?
Although we have started the dialogue about integrating AI, it has not yet transformed our work. However, I see it as a significant tool, especially for managing and processing big data. AI can help bridge the skills gap in understanding both bioinformatics and biological terms, aiding in efficient data mining.
Can you discuss any ongoing or future research projects you are particularly excited about in the area of axon biology and sncRNA?
Of course. We are deeply exploring extracellular vesicles as a means of cell communication. Vesicles produced by these cells often carry microRNAs and other non-coding RNAs, presenting a unique way to understand how neurons modulate their environment, which is particularly interesting in neurological situations.
We are exploring extracellular vesicles as tools with which cells can communicate and shift gene expression patterns. And we’re looking at, for example, how early-life brain tumors like medulloblastoma can affect the development and activity of neurons, and how that can affect pain processing and neurological conditions later in life.
This was made possible by funding from the Medical Research Foundation, which supported a major collaboration between Gareth Hathaway, Beth Coyle, Vicky James, Anna Grabowska and my lab in Nottingham.
Finally, how do you envision the future of drug discovery and development related to your research on axon biology and sncRNAs?
Given the recent success of RNA-based therapies, I resisted a shift that RNA would gain more traction. Given the role that sncRNAs play in axons, our study aligns well with this trend. By understanding axonal RNA biology, we can pave the way for targeted therapies that could revolutionize how we approach various neurological conditions.
Where can readers find more information?
- Lucci, Cristiano, Mesquita-Ribeiro, Raquel, Rathbone, Alex and Dajas-Bailador, Federico, 2020. Spatiotemporal regulation of GSK3 beta levels by miRNA-26a regulates axon growth in cortical neurons. development. 147(3),
- Mesquita-Ribeiro, Raquel, Forte, Sebastian, Rathbone, Alex, Farias, Joaquina, Lucci, Cristiano, James Victoria, Sotelo-Silvera Jose, Duhagon Maria Ana, Dajas-Bailador Federico. 2021. Distinct small non-coding RNA landscapes in axons and extracellular vesicles of developing primary cortical neurons and the axoplasm of adult neurons. RNA Biology. 18, sup. 2.
- De Paulo, Andres, Eastman, Guillermo, Mesquita-Ribeiro, Raquel, Farias, Joaquina, McLean, Andrew, Kieslinger, Thomas, Colburn, Nancy, Munro, David, Sosa, Jose and Sotelo, Dajas-Bailador, Federico and Sotelo-Silvera. , Jose R., 2020. PDCD4 regulates axonal growth by translational repression of neurite outgrowth-related genes and is upregulated during the response to nerve injury. RNA. 26(11), 1637-+
- Loreto, Andrea, Hill, Ciaran S., Hewitt, Victoria L., Orsomando, Giuseppe, Angeletti, Carlo, Gilley, Jonathan, Lucci, Cristiano, Sanchez-Martinez, Alvaro, Whitworth, Alexander J., Conforti, Laura, Dajas- Bailador, Federico and Coleman, Michael P., 2020. Mitochondrial impairment activates the Wallerian pathway through NMNAT2 depletion leading to SARM1-dependent axon degeneration. Neurobiology of disease. 134.
About Dr. Federico Dajas-Bailador
Dr. Frederico Dajas-Bailador began his neuroscience research career as a graduate student at the IIBCE Institute Neurochemistry Department in Montevideo, Uruguay, before moving to the University of Bath (UK) to pursue a PhD in neuronal signaling in the lab of Prof. Sue Wannacott.
He then moved to the University of Manchester and followed a postdoc in the lab of Alan Whitmarsh and Nancy Papalopoulou focusing my research on the regulation of neuronal differentiation and polarization. Since moving to the University of Nottingham, he has established the Axon Biology Lab and integrated my research into several interdisciplinary groups at the University (Pain Center v Arthritis, Connective Neuromics and the newly created Nottingham Cluster-RNA).
The team investigates neuronal function and RNA biology at the cellular and molecular levels, focusing on the mechanisms that regulate axon development and function in health and disease.