Modelling diseases of the brain through stem cells

Hello SGC members and to the millions of scientific readers across the globe,

My name is Thomas Durcan, and I am an assistant professor at the Montreal Neurological Institute (MNI) and McGill University, where I also lead the SGC tissue platform in Montreal. You can call me the stem cell guy, as everything I and my team does is centered on human stem cells, developing disease models for understanding and treating diseases of the brain. So who am I, well let me introduce myself. I hail from Dublin, Ireland where I was born and raised. I wanted to clone dinosaurs from the moment I saw Jurassic park, so I did everything in my power to become a scientist. During my time at University College Dublin, I looked at the DNA of plants, although no breakthroughs emerged in my quest for dinosaurs. With a degree in hand, I headed across to North America, first to the USA and the University of Notre Dame, and then onto colder climes in Canada, settling in Montreal, Quebec. It is here in Montreal, where I have learned to survive winter, to sample the finest bagels, to develop a passion for wine and where I got the opportunity to understand the cellular and molecular causes of Parkinson’s disease working in the lab of Dr. Edward Fon.

However, all my studies were with regular old Hela or HEK293T cells, cells that are clearly not neuronal. When studying a disease of the brain, it would make sense to actually study a human neuron, but these aren’t readily accessible. I can’t go up to someone and ask them for their neurons as what you are born with is kind of what you need. So for years, our field was stuck, we had some advances, but it was always in a Hela-type cell, or animal model, which often lacked many of the features of the human disease itself. Then the breakthrough came, in 2006 with the Yamanaka factors. A set of four transcription factors that when introduced into skin cells from a mouse or human, brought them back to the beginning. It reprogrammed the cell, and made it pluripotent, coining the term induced pluripotent stem cell or iPSC. By reprogramming the skin cell, it removed all epigenetics and created a stem cell, that was capable of generating any tissue or cell type within the human body. All it needed, was the correct set of factors to do so.

SInce this seminal publication, the field has grown exponentially and I started working on stem cells in 2014, leading to the creation of the iPSC platform at the MNI, under the direction of Dr. Edward Fon, and myself as group leader, and in partnership with the iPSC platform at the Universite of Laval, under the leadership of Jack Puymerat.

When we began, we were three people, and fast forward to 2019, our group is now over 30 full time staff and students, and growing every month, with the iPSC platform starting its transition this year into the Early Drug Discovery Unit (Neuro-EDDU- further details to follow). With iPSCs at the core of our mission we are now engaged in many early drug discovery projects with researchers, biotech and large pharma, generating neurons for studying Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS) and neurodevelopmental biology. Not only are we generating neurons on 2D dishes, but we have been growing minibrains by the thousands, with these 3D neuronal organoids mimicking the human brain more closely then anything seen with 2D cultures. At the same time, we have been fortunate that CRISPR genome editing has emerged, providing us the tools to edit a gene at the base pair level. This technology is at the core of our involvement with the ALS-RAP project, in which we are making a panel of over 30 KO cells against ALS-associated genes, using these cells to validate antibodies. With all these tools now set up within the group, new big data approaches are being explored by members of my team, both for image based and MultiOmics based analysis of neurons and other disease-relevant cells generated from patient iPSCs.

This is just a snap-shot into the type of things we are doing, and we are now a step closer to making dinosaur stem cells, fulfilling a life long dream of mine, while also advancing new therapies into the clinic that we hope will one day treat these devastating disorders. Yet, we can’t do this alone, which is why for my blog I will be starting to make available all our SOPs as part of the open science mission of the MNI and TOSI. All our tips and tricks will be posted on a regular basis, from how to grow an iPSC all the way to to how to make a minibrain will be added to the blog over the coming months, to show everyone how to work with iPSCs. In parallel, as one of the three leads on the ALS-RAP project, I will be posting updates on our antibody validation efforts and progress on this project, keeping people up to date on antibodies we are testing, and pointing to ones you should consider working with.

I look forward to opening the doors to our group, and hopefully over the coming months you will enjoy hearing about the work being done in Montreal, and at the MNI on stem cells and antibody validation. Next time, I will start by introducing our SOPs for working with iPSCs, starting with how to thaw a frozen vial of iPSCs. To talk or to lean more  feel free to reach me through linkedin.

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