Guillermo Parada Gonzalez Named 2022 Charles H. Best Fellow

The clues to how the mind works could be hiding in individual brain cells. And the postdoctoral researcher Guillermo Parada Gonzalez in on the hunt for them.

Parada Gonzalez is studying how alternative splicing, a process by which cells diversity their protein content, impacts brain development. To perform this work, last summer he joined the group of Ben Blencowe, a professor of molecular genetics in the Donnelly Centre and a world-leading researcher in the field.

Now Parada Gonzalez has been awarded the 2022 Charles H. Best Fellowship for his project which seeks to establish how alternative splicing contributes to the generation of different cell types in the brain and their ability to communicate with each other. The research could deepen our understanding of brain disorders, such as autism and schizophrenia, with implications for treatments.

“Winning this fellowship early in my postdoctoral training means a lot beyond the financial support it provides,” said Parada Gonzalez. “Knowing that my work is appreciated by others motivates me to keep pushing forward with my research."

The prestigious annual award recognizes an outstanding postdoctoral scientist in the Donnelly Centre whose foundational research holds potential for medical breakthroughs. Established in 2001 by The Charles H. Best Foundation, the fellowship celebrates the memory of Charles H. Best who co-discovered insulin as a life-saving drug with Dr. Frederick Banting at the University of Toronto in 1921.

During alternative splicing, the genes’ protein-coding segments, or exons, are variably stitched together into RNA messages, which serve as templates for building proteins. This allows for multiple protein isoforms to be encoded by the same gene, generating a greater molecular diversity within and across cells. One consequence of a bountiful molecular toolkit is that cells can specialize for various roles as they build complex tissues and organs.

Blencowe’s team previously showed that alternative splicing in the human body is most pronounced in the brain, and that this helps explain how it became the most complex organ on earth. They also discovered a highly conserved and dynamic network of neuronal splicing events involving very short exons, known as microexons.

Although microexons encode tiny portions of protein material, they influence how proteins interact with each other, which is a critical feature of all cellular processes. Errors in microexon splicing result in disrupted protein interactions, which can interfere with brain wiring and cognition. The team also reported microexon splicing errors in the brains of autistic individuals, further underscoring their link to brain disorders.

Research so far has mainly focused on taking bulk molecular measurements of the brain. But advances in single-cell technology, which allow researchers to measure RNA messages from individual cells within a tissue, have opened new possibilities for investigating how splicing affects biology on a much finer scale.

“With bulk methods, it’s like you’re putting a whole brain in the blender and taking average gene expression measurements,” said Parada Gonzalez.

“But the brain, and especially the cortex, which is important for higher order functions, is among the most heterogeneous tissues in the body. Therefore, understanding alternative splicing events at cell type resolution is particularly impotant for gaining a deeper understanding of how the brain works,” he said.

Parada Gonzalez is not new to the field. During his PhD, at the Wellcome Trust Sanger Institute in Cambridge, UK, he developed MicroExonator, a computational tool for the detection and quantification of microexon splicing in bulk and single-cell profiling experiments. He is now collaborating with other members of the Blencowe lab and Quaid Morris, computational biology expert and former investigator at the Donnelly Centre, who is now investigator at the Memorial Sloan Kettering Cancer Center, in New York City, to implement a machine learning approach to crack the genome code that governs microexon splicing.

For Parada Gonzalez, joining the Blencowe lab has been a dream come true.

“Ben is a world leader in the field, and I’ve been following his work since I was an undergraduate student in Chile,” he said.

“It’s a great privilege for me to be in his lab and I look forward to ongoing fruitful collaborations.”

Parada Gonzalez is using computational methods to analyze single-cell gene expression data from postmortem human cortices, collected by the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, as well as from the Allen Mouse Brain Atlas, which provide a comprehensive map of the brain at the molecular level. Through a recent Simons Foundation grant awarded to Blencowe’s team, Parada Gonzalez also plans to investigate splicing differences between postmortem brains from autistic and neurotypical individuals at single cell resolution.

The insights gained help could shed light on molecular bases behind autism and other neurological disorders, as well as inspire new molecular-based methods for an earlier diagnosis and possibly even treatment.

“History proves that understanding basic biology is key to the development of novel therapeutic approaches and advances in medicine in general,” Parada-Gonzales.

Follow us on LinkedIn and Twitter to keep up with Donnelly Centre news.