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What Gets Dr. Karun Singh's Neurons Firing?

Paige Collins

Paige Collins | Tuesday, January 24, 2017

We sat down with Dr. Karun Singh to learn more about how his lab is working on solving the mystery of neural disorders.

The human brain baffles us.

Of all the organs in our body, the brain is the one we know the least about.

All of the gaps in our knowledge about the brain are what drew Dr. Karun Singh to studying it in the first place. He wanted to understand how we function at the level of our neural circuitry – how our thought processes work, how our brain circuits form, and ultimately, how these are disrupted by disease.

He began his research career in developmental neuroscience, studying normal development of the human brain. It was through the course of this research that he became interested in the flip side of things: understanding what happens when development goes awry. He developed a curiosity about disorders in the brain, and Autism Spectrum Disorder (ASD) in particular.

ASD brings forth a whole new set of unknowns. We don’t know how it arises. We don’t know how to treat it. Defined as “a complex developmental brain disorder caused by a combination of genetic and environmental influences” that is “characterized, in varying degrees, by communication difficulties, social and behavioural challenges and repetitive behaviour,”1 ASD encompasses a range of disorders that manifest differently from person to person. This diversity, coupled with the fact that it’s a disorder in an organ we struggle to understand, makes unraveling the mystery of autism challenging. Research into autism is a lot like putting a mosaic together: each discovery is a tile that contributes to the larger picture, but it’s difficult to see what that larger picture is until all the tiles have been laid down.

Despite the challenges, researchers like Dr. Singh are working diligently on laying the tiles down. His lab is focused on using human stem cell-based models to pursue the genetic causes of autism as well as identifying and developing new therapeutics that address them.

“Basically, what we’re trying to do is discover the responsible genes; figure out what those genes do; find drugs that fix the overall downstream effects of the genetic mutations; and test those drugs in clinical trials,” explained Dr. Singh.

Since human neural cells are not readily available, the team relies on cellular programming technology to generate the cell types they need to create the human stem cell-based models. Dr. Singh’s lab takes more accessible cell types, like blood, and reprograms them into neural cells. The resulting neural cells are then used to create in vitro models of the neurological disorders of interest.

“We can study a patient’s specific disorder, in the exact brain cell that is dysfunctional, without ever touching their brain, it’s quite remarkable” said Dr. Singh.

These models also allow for patient-specific drug screening. Drug screening is like looking for a needle in a haystack; you have to screen thousands of drugs to (hopefully) find the one that is going to do what you need it to do in a patient. Dr. Singh can take the brain cells generated at the lab bench and apply them to the SCC-RI’s high-throughput drug discovery screening platform to test thousands of drugs and compounds on an individual’s own brain cells in order to figure out if anything is effective in their particular case of autism.

The practical benefit of being able to test on an individual’s own brain cells is, as Dr. Singh explains, “the level of certainty it brings to the safety and efficacy of a drug before bringing it to clinical trial.”

The value of this added layer of certainty can’t be overstated. The process of screening for drugs and bringing drugs to clinical testing requires an incredible amount of resources both financial and otherwise, so you really want to be sure you have strong candidates entering the translational pipeline.

Currently, there is no specific drug designated for the treatment of autism. Dr. Singh says now more than ever he feels a sense of urgency to address this serious deficiency and introduce new therapeutic options for people with autism, and for others living with neurological disorders.

“My interactions with patients and patient advocates, particularly through the Ontario Brain Institute’s autism program, have reinforced why we’re doing this. Hearing about the daily struggles of individuals with ASD, directly from the families themselves, has had a big impact on me – it’s information that doesn’t normally trickle down into the labs.”

Dr. Singh is looking to capitalize on this feeling and the growing momentum in the SCC-RI’s neural research program. This year, he plans to establish both a high-throughput phenotyping platform to quickly study how autism genes impair brain function and a drug discovery pipeline in collaboration with the Bhatia lab, who have paved the way in our Institute with the success of their cancer drug screening efforts.

“It’s a very exciting time right now. There’s no other institute in Canada with a neural program like ours; not only are we studying human neurological disorders using human neural cells, which is rare in and of itself, but we’re putting forth a truly cohesive effort. The synergy we’re developing in the Institute is going to allow us to be more effective. The work we’re doing is only possible if you have the tools, resources and knowledge that we have access to.”

Despite all of the unknowns, and the inherent challenges of neural research, Dr. Singh is sure that there is no other work he would rather be doing.