CMMT Newsletter September 2020

Changing the World: It Pays to Dream

In 1983, Dr. Michael Hayden arrived at the University of British Columbia (UBC) with a big idea, some might even say a dream. A physician-scientist with a focus on genetic diseases, particularly Huntington’s Disease and lipoprotein disorders, Dr. Hayden sought to establish a research centre that embraced an approach to science that was collaborative, open and interdisciplinary and committed to translation of science into products and services that would positively impact patients’ lives.

Genetics was in its infancy at the time, an emerging area of research that was set to revolutionize medicine. Recognizing this, Dr. Hayden persuaded Merck, the largest pharmaceutical company in the world at that time, to get involved. This was to be a first and telling success for the

CMMT, with Merck providing the biggest extramural donation they had ever made to any centre anywhere in the world. “They committed $15 million in the mid 1990s, on the understanding that they wouldn’t pay for the infrastructure,” Dr. Hayden said. “It was a lot of money then and it’s a lot today.” Impressively, the partnership continued with Merck re-committing another $15 million for another five years at the end of the initial five-year period. “So, Merck provided 10 years of funding and a total of $30 million” Dr. Hayden said.

The challenge was to build the infrastructure. “I recognized that it would be good to have the centre on the BC Children’s Hospital site where many of the diseases we were focussed on impacted the children and families accessing the hospital,” Dr. Hayden said. Importantly, there was also space to build. “BCCH supported this idea and Elisabeth Riley, the president of BCCH at the time, came with me to meet with the provincial government to help raise the money. Aubrey Tingle, who was then Assistant Dean of Research in the Faculty of Medicine at UBC, and Vice President of Research and Education at the Children’s & Women’s Health Centre of BC, was also very involved.

Once the funding was secured, the design process for the Centre began, with the understanding that the founding principles be reflected in the architecture of the building. “Everyone had meetings with the architects – the students, postdocs, assistants– in an effort to provide a framework that would foster collaboration and open us to other forms of creativity,” Dr. Hayden said. Among the building features that resulted from this process are art alcoves. They have been used to host art events, one of which involved Grace McCarthy, the then Deputy Premier of BC, opening an art exhibit of First Nations work. “The physical structure was very important to compliment the research, to support and strengthen community,” Dr. Hayden said.

While the CMMT was under construction, the hiring began. “The Merck funding was used to hire numerous people who have since gone on to do profound things,” Dr. Hayden said. The list includes Dr. Philip Hieter, who was working on yeast models at Johns Hopkins University and subsequently went on to become the head of the Michael Smith Laboratories and Frank Jirik, who went to Calgary and established a core centre for mouse studies, Beth Simpson, known for her work in mouse models, came from the Jackson Laboratory. Wyeth Wasserman, who was working on transcription and gene regulation, came from the Karolinska Institute in Sweden. He is now Vice President, Research, at BCCH. Francis Ouellette, an expert in bioinformatics, also joined the team as did Elizabeth Conibear, who was working in a variety of model organisms. “It was wonderful,” Dr. Hayden said. “These people were funded entirely by Merck for the first five years, after which people began to get grants and other support.

Building on this very strong foundation, Michael Kobor, a medical geneticist whose research focuses on the epigenetic regulation of gene expression and genome function, joined the CMMT from UC Berkeley in 2005. In 2009, Stefan Taubert joined the CMMT from UCSF. He works primarily with nematode worm C. elegans and the mouse, to study fundamental concepts of biology and their relevance to human health and disease.

The CMMT has also attracted hundreds of students. “We have graduated hundreds of graduate and postdoc students, all committed to the principles of new approaches and also open to industry,” Dr. Hayden said. Today, there are approximately 200 students at CMMT.

Notably, the Centre was very committed to the community from the outset. “We started family rounds and the mini medical school at Children’s Hospital where we ran courses introducing high school students in the community to science and genetics,” Dr. Hayden said. “We brought the Gairdner International Symposium to the CMMT at the BCCHRI site.” Co-mentoring among the students was also initiated from the get-go. “We had students who worked together who could go from one lab to another and we shared equipment and resources,” Dr. Hayden said.

Additionally, the CMMT was established as the home for numerous national networks. The Canadian Genetic Disease Network is one example, which has not only spun off several companies representing Canada in the international genetics space but has also led in the discovery of more than 35 disease causing genes.

“We built a national network of core facilities so it was not necessary to re-build the infrastructure in individual locations but rather it would be made available anywhere in the country for priority projects.” Dr. Hayden said. Dr. Daniel Goldowitz also joined the CMMT and led a successful application to be one of the federally funded NCEs, NeuroDevNet [recently rebranded as Kids Brain Health (KBHN) Network], a national network committed to fostering improved development in children.

In fact, the list of achievements stemming from the CMMT is not only lengthy but significant, including advances on lipoprotein lipase deficiency that eventually led to the first approved gene therapy in the world, Glybera. “Journals have been founded here, such as the Journal of Huntington’s Disease which was initiated by Blair Leavitt, one of my postdocs who became a faculty member,” Dr. Hayden said.

In keeping with the mantra of translational research, bench to bedside companies such as Xenon Pharmaceuticals have also spun out from the CMMT. “People from my lab and other labs here have gone on to work at Xenon and other local companies such as StemCell technologies and Abcellera where they were able to continue their work and focus on translation,” Dr. Hayden said. Founded in the late 1990s, Xenon Pharma has raised hundreds of millions of dollars and is now publicly traded. Those commitments have led to significant economic activity, wellbeing and hope. “Xenon is developing new approaches to treat intractable epilepsy and world leading in that space with global partners and acclaim from around the world. Dr. Simon Pimstone, one of our past students, is the CEO,” Dr. Hayden said.

After serving as the CMMT’s first director for 15 years, Dr. Hayden was also recruited to a pharmaceutical company to lead research. He has now come back, heading up his own lab with a focus on neurodegenerative diseases and novel approaches to gene therapy. “It’s been an amazing journey,” he said. “I’m also delighted to have Bruce Verchere as the new director, to help take the CMMT to an even higher level.”

Today, the CMMT is a world model for translational research. Holding to its founding principles of being interdisciplinary, open, collaborative, patient-centered and proactive within the community, the Centre will continue to focus on fostering the development of the next generation of scientists in BC and in Canada.
“There is a belief that we can change the world from the CMMT,” Dr. Hayden said. “In other words, we’re looking to be the best by world and global standards and be able to bring hope and light where there has been so much darkness for some children and families.”

Managing the Unknown

Dawn Ng is a powerhouse. Focused, resourceful and efficient, she is the face of Human Resources at the CMMT in addition to being Executive Assistant to CMMT’s founder, Dr. Michael R. Hayden. While she’s used to giving 200 percent, like so many people right now, she finds herself in new territory working from home during a global pandemic.

“Human Resources is something different every day,” she said. “For me, the biggest challenge has been the lack of boundaries. My office is 10 seconds away. I’m working off the dining table and my second bedroom, and there is no break. I find I’m replying to an ever-growing list of emails after hours. I need to be mindful of that, but it’s challenging,” she said.
As to when she can get back into her office full time, well, that’s anybody’s guess right now. Currently, each lab at the CMMT is running at reduced capacity, per the Phase 2 guidelines established by PHSA. “The CMMT is adhering to BCCHRI’s guidelines, as we’re located on the Oak Street campus, and this falls under PHSA,” Dawn explains. The Phase 2 guidelines don’t increase the number of people allowed on campus. It’s not known when they will be back to Phase 4 full capacity. “We have to remain flexible. I can only pop into the office every so often,” she said.

Dawn notes that COVID-19 is proving a challenge for all CMMT employees, particularly those people working from home who have small children. “One of the great things about CMMT/UBC is that we’re flexible, we strive for that family-life balance for our employees, we accommodate as much as we can for our staff without compromising the work.” Each lab maintains contact with its people through Zoom and other platforms. “UBC has released a lot of mental health guidelines and online drop-in sessions are also available,” Dawn said.

On the upside, Dawn has found that COVID-19 has forced her take to stock of what she needs in life. “I used to eat out every weekend and now I don’t need to,” she said. And she’s walking to do her daily errands rather than driving because she lives centrally.

“COVID-19 has helped me put things into perspective and appreciate what I had before.” And, like all of us, she is wondering what the new normal will look like. “Right now is a time for self-reflection and self-improvement. I’ve taken the opportunity to pursue the UBC Certificate in Project Management. This has been something I’ve been meaning to do in recent years and I thought, why waste a good crisis? It was a struggle not to be able to go to the gym in the earlier days of the pandemic, I have had to improvise my home workouts since the gym was closed. Being physically active is so important for my mental health and it was a great stress relief. It is important to look at the positive side of everything. COVID-19 has provided a reason for me to work on self-development, self-awareness, self-reflection. It gives us an opportunity to learn how to speak to other people, and be mindful of what others are going through.”

Refining Clustering Technology

Single-cell RNA sequencing (scRNA-seq) has made the investigation of the cellular composition of complex tissues possible, with unprecedented resolution. Deciphering cell type composition is one of the most important applications of scRNA-seq. Clustering technology, while fundamental to this process, can lack precision. In his work at the Mostafavi lab, Elijah Willie is researching ways in which to refine clustering technology and thereby increase its precision.
“Clustering is a technique that attempts to cluster similar objects together, “Elijah says. This is not always easy because sometimes clustering methods will uncover groups where they may not exist. “My research is trying to develop a clustering method for single cell data. I’m interested in trying to determine if natural clusters exist in data and, if so, how do we accurately identify them.”

So far, his research has led to the development of two methods: one which seeks evidence for cluster structure inherent to a dataset and another which is a clustering method that seeks to find this structure. The results from both simulated studies and real data are promising.

Elijah started at CMMT in September of 2018. He remembers being influenced by a lecture given by Dr. Sara Mostafavi while he was working in the epidemiology lab at Simon Fraser University as a research assistant. He sent Dr. Mostafavi an email to see if she was taking students into her lab, and the rest is history. He enjoys the environment with the lab and finds it very friendly and supportive. “We’re one of the only computation labs within CMMT, along with Wyeth Wasserman’s lab,” he explains. “We’re a very small group. It’s a good environment, everyone knows each other and they are all working on interesting things and sharing.” He also enjoys the fact that Dr. Mostafavi’s lab shares space with the Wasserman lab. “We’re only 9 -10 people, approximately. I know some people in the Wasserman lab, it’s nice to share their environment as well.”

While Elijah admits that COVID-19 has impacted the social aspect of the lab, it has not impacted his ability to work. “One of the advantages of having a computation lab is that you can work remotely,” he said. “I can work from home on my computer.” When he does have spare time, Elijah enjoys playing soccer, reading philosophy, and popular science books, and spending time with family and friends.

Nearly at the end of his graduate studies, Elijah is seeking employment within the research side of industry. “I still want to be involved in research but I also want to pursue my Ph.D. within the next 5 years,” he adds. He’s found that the process of doing a master’s degree has enabled him to grow not only as a researcher but also as a person. “I have learned to ask the right types of questions and how to make ideas come to life. Pursuing a master’s has not only deepened my understanding and interest in the biological sciences, but it has also enabled me to acquire skills that would benefit me for the rest of my life.”

A Series of Fortunate Opportunies

Fifteen years ago, an eager young researcher attended the BCCHR’s Summer Student Research Program and loved it so much she stayed. Since then, most of her time has been spent working in the Kobor Lab at the CMMT where she had the opportunity to build an exciting research program and mentor undergraduate and graduate students. Now it’s time for a move, as this year Dr. Maria Aristizabal became an Assistant Professor in the Biology Department at Queen’s University in Kingston, Ontario.
“I’ve been a part of CMMT for a long time and have benefited tremendously from this amazing opportunity,” Maria said. “CMMT is a close-knit network of researches, with a beautiful sense of community. When I started, our seminar series was very well attended so you could get a lot of feedback, this was so important.” She also notes that being able to attend seminars that spanned a wide variety of topics led her expand her research in ways she hadn’t previously considered. “It was very valuable,” she said.

Dr. Aristizabal’s area of research involves studying transcription and epigenetic changes that occur in response to challenge, the goal being to understand how these mechanisms contribute to adaptation and shape future responses. As part of Dr. Michael Kobor’s lab, Maria uses budding yeast and the fruit fly system which she pairs with high-throughput and targeted genetic, molecular and biochemical techniques to find answers.

Her research trajectory began when she was accepted into a unique biotechnology program offered jointly by the UBC and the British Columbia Institute of Technology, in 2004. “I was so fortunate to be accepted into the program, as they only took 22 students,” Maria said. “It was fantastic, you got an incredible amount of hands on research experience, which I loved.” It was through connections in that program that she was introduced to the work being done in the Kobor lab. “My friend Grace Leung had spent the previous summer in the Kobor lab and what she did sounded exactly like what I wanted to do. So, I messaged Dr. Kobor to see if I could get a position and I did.” She went on to do her PhD at the Kobor lab and then a joint postdoctoral fellowship with Dr. Marla Sokolowski at the University of Toronto, a pioneer in the study of gene by environment interactions and behavioral genetics.

“I don’t think I would be where I am now without the wonderful opportunities I was given and the environments I trained in,” Maria said. “I think if you have a really wonderful environment to work in it makes you love what you do even more.”

Dr. Aristizabal started her position at Queens University on July 1st, but you may still see her around as pandemic-related delays have pushed her move date to October. Her hope is that research like hers may one day explain why diseases seem to affect some individuals more than others. “I hope that we can begin to understand why people are differentially susceptible to disease,” she said. Answering this question has never been more relevant. “In the current pandemic, we are seeing huge differences in disease severity between males and females as well as between children, adults and older adults. We need to understand how sex and age affect biology if we want to understand health,” she said. Perhaps that’s the next opportunity.

Awards

Neel Mehta (Hayden Lab), 2020 Research Trainee Award, Michael Smith Foundation for Health Research, “Redevelopment and Optimization of an Adeno-Associated Virus Gene Therapy Product for the Treatment of Lipoprotein Lipase Deficiency”.

Publications

A Novel Mouse Model for Pyridoxine-Dependent Epilepsy Due to Antiquitin Deficiency

A team of international researchers lead by Dr. Hilal Al Shekaili and UBC CMMT Professor Blair R. Leavitt have developed a novel mouse model for a rare genetic disorder that is already helping clinicians to better understand the disease and develop new treatments. 

The disease, pyridoxine-dependent epilepsy (PDE), affects approximately 1 in 60,000 people and is associated with seizures, developmental delay and brain abnormalities. People living with PDE are unable to properly break down specific nutrients in their diet, leading to a toxic buildup of byproducts that interfere with brain development and alter the brain’s ability to function properly. 

The seizures in PDE can be controlled in most children with anti-seizure medications, large daily doses of pyridoxine (a type of vitamin B6 found in food), and a strict diet. Unfortunately, this therapy is not effective for all patients, and can be very difficult for patients and families to adhere to and does not prevent the development of brain abnormalities. Severe neurological problems such as developmental delay and learning disorders persist in many of these children despite the best treatments currently available.

This new mouse model provides hope for a brighter future for kids with PDE, and with the support of a recently awarded operating grant from the CIHR, is already enabling the team of researchers at the CMMT to better understand how this disease disrupts brain function and impairs normal brain development. In addition, this new disease model is providing an exciting research tool for developing more precise and effective therapies for this devastating childhood brain disease.

Link to publication: https://academic.oup.com/hmg/advance-article-abstract/doi/10.1093/hmg/ddaa202/5910909?redirectedFrom=fulltext


CRISPR/Cas9-mediated gene editing can prevent vision loss in mice

“The findings of this study represent crucial steps toward a future cure for aniridia in children” said Zeinab Mohanna and UBC CMMT Professor Dr. Elizabeth (Beth) Simpson.

A recent study presents important steps toward a future treatment for aniridia-related vision problems and blindness in kids. Aniridia, a rare genetic eye disorder caused by mutations in the PAX6 gene, results in the complete or partial absence of the iris (the coloured part of the eye) and varied levels of vision loss or impairment. 
  Most children with aniridia have low vision starting at birth and may develop blindness and other eye-related problems — such as cataracts and glaucoma — in their teens or adulthood. Individuals with aniridia typically experience light sensitivity and rapid, involuntary eye movements called nystagmus. Some may also experience non-eye-related problems like reduced sense of smell and neurodevelopmental conditions.

“There are currently no long-term vision-saving therapies or cures for aniridia, meaning that new treatment strategies are needed,” said principal investigator Dr. Elizabeth M. Simpson.  

The researchers, whose results were published in Molecular Therapy—Methods & Clinical Development, worked with a mouse model which has a patient-specific mutation identical to a PAX6 aniridia-causing mutation in humans. 

Link to publication:
https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(20)30032-2

Events

2020 Gairdner Symposium
Date: Monday, October 26, 2:00– 4:30pm PST
Location: Zoom
Hosted by Dr. Michael Hayden, Centre for Molecular Medicine and Therapeutics, University of British Columbia
 
This free inspiring public live lecture will feature:
1. Dr. Guy Rouleau
Recipient of the Canada Gairdner Wightman Award 2020
“For identifying and elucidating the genetic architecture of neurological and psychiatric diseases, including ALS, autism and schizophrenia, and his leadership in the field of Open Science”
Director of the Montreal Neurological Institute-Hospital (The Neuro); Professor & Chair of the Department of Neurology and Neurosurgery, McGill University; Director of the Department of Neuroscience, McGill University Health Centre
 
2. Dr. Roel Nusse
Recipient of the Canada Gairdner International Award 2020
“For pioneering work on the Wnt signaling pathway and its importance in development, cancer and stem cells”
Professor & Chair, Department of Developmental Biology; Member, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine. Virginia and Daniel K. Ludwig Professor of Cancer Research. Investigator, Howard Hughes Medical Institute
 
For questions or more information please contact Jessica at jshum@cmmt.ubc.ca

Thank You

Dr Stefan Taubert has assumed the role of Graduate Advisor of the Graduate Studies Program in the Department of Medical Genetics as of August 1, 2020. 

We extend our most heartfelt thanks to Dr Matt Lorincz, Department of Medical Genetics, for his significant contributions over the past years as Graduate Advisor! Dr Lorincz ran the Program from 2014-2020.

Did You Know?

  • Thursday, October 1, 2020 is Mid-Autumn Festival, also known as Moon Festival or Mooncake Festival. On this day, it is believed that the moon is at its brightest and fullest size, coinciding with harvest time in the middle of Autumn.
  • Fall Back – remember to set your clocks back 1 hour on Sunday, November 1, 2020.
  • Movember takes place during the month of November to raise awareness of men’s health issues, such as prostate cancer, testicular cancer, and men’s suicide.
Our next newsletter will be published December 2020 month-end.
Submit storyline suggestions to media@cmmt.ubc.ca by December 1st, 2020.
Submit awards, events, publications, kudos, etc. to media@cmmt.ubc.ca up to until December 19th, 2020.
Copyright © 2020 Centre for Molecular Medicine and Therapeutics, All rights reserved.

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