CBR Magazine: April 2024

HOTWIRE THE CURE turning cold tumors hot

APRIL 2024

RESEARCH THAT makes you smile

MODIFYING MATERIAL SURFACES FOR BIOMEDICAL APPLICATIONS

ABOUT CBR The CBR aims to improve the health and well-being of patients through innovative research in blood and blood-related processes.

GOALS CBR Research & Clinical Goals • Improve the quality and safety of • • Patient-driven. Innovative. Community.

Over the past year, donor support has helped us develop novel approaches to battle severe bleeding in rural areas, delineate the mechanisms of inflammatory diseases, and increase the quality of blood products used in transfusions — only a few examples among many pioneering discoveries. With your continued support, the CBR will further transform innovative ideas into life-enhancing solutions.

blood product collection, storage and delivery Create new knowledge to better treat bleeding and clotting disorders Develop novel approaches to modulate the immune system to treat inflammation and infections and promote wound repair

The CBR needs you to help fund our programs, which range from $50 to $100,000. We invite you to explore opportunities at the CBR where your partnership with us will result in positive impacts on education, training and meaningful research. Examples of initiatives that need your support include: Opportunity

Cost

Reward leadership in students and staff with the Neil Mackenzie Mentorship Award

$50

Expose trainees to diverse career opportunities with the CBR Career Night

$1,000

Jumpstart a postdoctoral fellow’s career with the Postdoctoral Transition Award

$5,000

Support a clinical fellow in Translational Research Studies

$75,000

Make a CBR Symposium possible

$25,000$100,000

Explore further: www.cbr.ubc.ca/support-us Edward M. Conway, MD, PhD Director, Centre for Blood Research Tel: 604.822.4252 | Email: ed.conway@ubc.ca

E D U C AT I O N CBR Education Commitment • Support student research through competitive undergraduate, graduate, and postgraduate awards • Offer a range of stimulating educational symposia, workshops, and seminars • Provide cutting-edge career development opportunities for our trainees

in this issue PUBLISHED BY Knowledge Translation Committee DESIGNER Kaitlyn Chuong/Sarah Bowers CONTRIBUTING EDITORS Ahmed Kabil* Alexandra Witt* Andy An Charlotte Gilmore Clara Xia Colton Strong Dr. Emily Park* Erik Lamoureux Iryna Liubchak John Perrier Julliet Zama Kaitlyn Chuong Loulou Cai Marie Johns Marie-Soleil Smith* Michael Hughes* Mya Bal Natalia Nayyar Rhonda Thygesen Sarah Bowers* Stephanie Besoiu

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The CBR magazine is published by the Centre for Blood Research, with many articles written and edited by the CBR Knowledge Translation (KT) Committee, a group of undergraduates, graduate students, postdoctoral fellows, research associates, and technicians who are interested in science writing, blogging, and mixed media communications. It is distributed free of charge to CBR and UBC alumni, friends, and the scientific community. Opinions expressed in the magazine do not necessarily reflect the views of the centre or the university.

Address correspondence to: The Centre for Blood Research 4th Floor, Life Sciences Centre 2350 Health Sciences Mall Vancouver, BC, Canada V6T 1Z3 The KT Committee publishes at CBR News (cbr.ubc.ca) and covers a wide range of topics, from recent research highlights and opinion pieces on science and academia, to event coverage and CBR initiatives. If you are interested in participating in the KT Committee, email Kaitlyn at: kaitlyn. chuong@ubc.ca or talk to one of the members! All undergraduates, graduate students, PDFs, RAs, and technicians are welcome to join.

CONTACT kaitlyn.chuong@ubc.ca

Knowledge Translation Committee

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How Superbugs Get Their Superpowers

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Pain Amplified: Revealing the High Levels of Chronic Pain Among Women Living with HIV

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Modifying Material Surfaces for Biomedical Applications

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The Clinical Implications of the Connection between COVID-19 and Sepsis

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Hotwire the Cure: Turning Cold Tumors Hot

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Research That Makes You Want to Smile: Novel Role for Granzyme B in Periodontal Inflammation

* indicates Editorial Board member COVER ART “Sun(flower) of my heart”, Eliana Al-Haddad BLOG cbr.ubc.ca FACEBOOK @cbrubc TWITTER @CBR_UBC INSTAGRAM @cbr_ubc LINKEDIN UBC Centre for Blood Research

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The Discovery of New Sentinels on the Immune Watchtower for Cancer

24 CD248 Promotes Insulin Resistance

by Binding to the Insulin Receptor and Dampening Its Insulin-Induced Autophosphorylation

AWARDS

EVENTS 14

Earl W. Davie Symposium 2023: Seventeen Years of Connecting Through Science Sharing

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CBR Events, Socials & Activites

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Rolling Towards Wellness: CBR Members Lace Up for Skating!

PEOPLE 10

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CBR Spotlights Female Leaders for #WomeninScience 2024 Celebrating Women & Girls in Science: Marie Johns Reflects on Her Journey in STEM

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SLAS Grant Advances Translation Technology for CAR-T Cell Research – Samuel Berryman

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CBR Alumni: Rhonda Thygesen Graduate Profile

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BIOCAPS Spotlight: Marija Vuckovic

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2022-23 CBR Travel Award Recipients

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CBR Travel Awards: Attending CROI 2023

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CBR Kudos & Laurels

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Two CBR Researchers Awarded The CFI Innovation Fund

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Breakthrough in Blood Clot Breakdown Treatment

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Department of Medical Genetics Teaching Award - Dr. Wilfred Jefferies

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CBR Alumni: Get in Touch!

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Canadian Blood Services Announce New Dana Devine Award

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CBR Cover Art Contest

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Special Thanks

SPECIAL FEATURE

Science beyond academia 3

How superbugs get their superpowers THIS ARTICLE WAS ORIGINALLY POSTED ON THE UBC FACULTY OF MEDICINE WEBSITE

A

recent study led by UBC researchers is shedding light on how one of the world’s most notorious superbugs, Staphylococcus aureus (S. aureus), develops resistance to antibiotics.

The findings, published in Nature, provide critical insights that will help drive the development of more effective therapeutics to combat the growing global threat of drug-resistant bacterial infections.

“The rise of antibiotic-resistant bacteria has rendered many life-saving drugs ineffective, jeopardizing our ability to combat infectious disease,” says the study’s senior author Dr. Natalie Strynadka, a distinguished professor of biochemistry and molecular biology at UBC, and Tier 1 Canada Research Chair in structureguided antibiotic discovery. “Having a clearer understanding of how resistance develops is absolutely critical for facilitating a new cocktail of therapies that preserve the effectiveness of existing antibiotics.”

S. aureus is a bacterium commonly found on the skin of healthy individuals. However, it can cause potentially life-threatening infections when it enters the body through a wound or other means.

Of particular concern is the ability of S. aureus to adapt and develop resistance to beta-lactam antibiotics, like penicillin, that are one of the most commonly prescribed drugs to treat infections globally. New strains including methicillin-resistant S. aureus, or MRSA, have caused significant outbreaks in healthcare and community settings globally, leading the World Health Organization to include S. aureus on their list of priority pathogens that pose the greatest threat to human health. A microscopic master switch For the study, the research team used cryoelectron microscopy (cryo-EM) to determine the molecular structure of a key protein, BlaR1, that exists in the cell membrane of S. aureus and is known to play a key role in resistance to betalactam antibiotics.

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Cryo-EM is a powerful imaging technique that uses a beam of electrons to map the three-dimensional structure of biological macromolecules. Until now, the structure of BlaR1 and the mechanisms by which it enables antibiotic resistance has eluded scientists worldwide. The UBC team overcame previous barriers by using novel techniques to purify and isolate the protein, work led by PhD student Andrew Alexander and research technologist Marija Vuckovic.

“This is the first study to present the fulllength structure of this important protein,” said Dr. Liam Worrall, Research Associate, who led the data processing and structure analysis in the study with assistance from PhD student Jinhong Hu. “With cryo-EM, we’re able to visualize how S. aureus detects and reacts to the presence of beta-lactam antibiotics, providing atomic level understanding of the first critical steps of cellular events that take place to enable antibiotic resistance.”

The three-dimensional structure of BlaR1 was determined using the open access High Resolution Macromolecular Cryo-Electron Microscopy facility in the Life Sciences Institute at UBC. The study’s findings reveal that the BlaR1 protein changes shape when it comes into contact with beta-lactam antibiotics. This sends signals across the cell membrane, triggering a series of steps that instruct the bacteria to produce enzymes and proteins that give it antibiotic-fighting superpowers.

“ The question now becomes, how

can we cut the circuit and turn off that resistance in one fell swoop by targeting BlaR1.

DR. NATALIE STRYNADKA

For Dr. Strynadka, it’s an important breakthrough that will allow scientists to fight back against anti-microbial resistance.

“BlaR1 is like a master switch controlling broad-spectrum beta-lactam antibiotic resistance mechanisms in S. aureus.

The question now becomes, how can we cut the circuit and turn off that resistance in one fell swoop by targeting BlaR1,” said Dr. Strynadka.

The researchers are now turning their attention to identifying ways of intervening in this cellular pathway, which could take the form of small molecule drugs or vaccines. The potential of such drugs could extend beyond S. aureus, as similar signaling systems have been identified in other high-priority pathogens such as Clostridium difficile and Mycobacterium tuberculosis.

With more than a million people a year estimated to die from antibiotic-resistant infections, and a dwindling number of new antibiotics being discovered, it’s urgent work.

Members of the High Resolution Macromolecular Cryo-Electron Microscopy lab at UBC. From left to right: Dr. Natalie Strynadka, Marija Vuckovic, Dr. Liam Worrall, Dr. Claire Atkinson, Joeseph Felt.

“We have fewer and fewer tools at our disposal to fight these superbugs, threatening over a century of medical progress,” said Dr. Strynadka. “This study opens up new avenues for understanding and targeting antibiotic resistance in a range of priority pathogens, ensuring the preservation of the beta-lactam antibiotics for combating infectious diseases.”

Alexander, J.A.N., Worrall, L.J., Hu, J. et al. Structural basis of broad-spectrum beta-lactam resistance in Staphylococcus aureus. Nature 613, 375–382 (2023).

2022-23 CBR Travel Award Recipients!

Over the years, with the support of Travel Awards provided by the CBR, numerous Postdoctoral Fellows, Research Associates and graduate trainees have had the opportunity to attend scientific conferences and further their professional development.

This past year, CBR was pleased to support 9 award recipients, who attended and presented at conferences and workshops around the globe. Following their conference attendance, recipients shared their experiences through short reflection blogs on the CBR website, which delve into their educational experiences and key takeaways.

Congratulations to the 2022-2023 Travel Award recipients!

Ahmed Kabil, McNagny Lab

Loulou Cai, Cote Lab

Calem Kenward, Strynadka Lab

Melina Messing, McNagny Lab

Colton Strong, Kastrup Lab

Nicolas Pereyra, Devine Lab

Felix Hong, Kim Lab

Steven Jiang, Kim Lab

Haifeng Ji, Kizhakkedathu Lab

Learn more about CBR Travel Awards and how you can apply: https://cbr.ubc.ca/research-and-training/grad-pdf-training/

The 2022-2023 Travel Award recipients. From left to right, top to bottom: Ahmed Kabil, Calem Kenward, Colton Strong, Felix Hong, Haifeng Ji, Loulou Cai, Melina Messing, Nicolas Pereyra, Steven Jiang.

AWARDS

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Pain Amplified: Revealing the High Levels of Chronic Pain Among Women Living with HIV

BY LOULOU CAI, PHD CANDIDATE, COTE LAB

I

t is widely known that on average, women have longer lifespans than men. However, this is not the case for women living with HIV (WLWH) in Canada, who have shorter lifespans than men living with HIV. One important piece of the puzzle that may help to explain this phenomenon relates to chronic pain.

Chronic pain, especially among WLWH, can significantly impact medication adherence, retention in care, mobility, mental/emotional well-being, and quality of life. The etiology of pain in people living with HIV is poorly understood, but likely multifactorial, partly related to side effects from early HIV drugs1. Several reviews have described the prevalence and risk factors in pain for people living with HIV2-5. However, there are few studies that focus on women specifically, even though data suggest that women in the general population are more likely to experience chronic pain as compared to men. A recent publication by members of the Côté Lab, “Global Prevalence of Chronic Pain in Women with HIV: A Systematic Review and Meta-analysis”, explores articles published in the last 40 years that investigated pain in WLWH. Overall, 35 studies were included in the meta-analysis, which spanned 22 countries and included 19,966 participants. The most commonly reported type of pain was peripheral neuropathy (n=22), followed by widespread or other types of chronic pain, including fibromyalgia and

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headache. The pooled prevalence of chronic pain across all 35 studies was 31.2%, with the lowest reported at 4.0% and the highest at 84.1%. There was considerable heterogeneity, highlighting methodological and demographic differences within the analyzed studies.

Three of the studies compared the prevalence of chronic pain between WLWH and HIV-negative controls, where WLWH had significantly higher levels of pain compared to controls.

The global prevalence of pain found in this study (31.2%) is similar to the prevalence of chronic pain among HIV-negative persons in middle- and low-income countries (33%), but higher than the prevalence in the United States (20.4%). This article also highlights major gaps in the literature, including for example, studies of pain that is more specific to women, such as those with breast, pelvic, vaginal, and/or menstrual pain. In addition, only one article discussed pain severity, which is a critical component of understanding the pain experience and its effect on the quality of life. Overall, the results suggest that chronic pain is highly prevalent among WLWH and warrants regular assessment at healthcare visits.

Lastly, they echo the recommendations of the Global Task Force for Chronic Pain in People With HIV, which include the need for further research on effective methods of pain management, as well as the etiology of chronic pain.

In summary, to reiterate the authors’ final thoughts, “We therefore wish to emphasize the importance of sharing research results about chronic pain with women with HIV to validate their experiences, increase opportunities for meaningful dialogue, identify knowledge gaps, and encourage colearning between clinical, academic, and community partners.”

Povshedna, T., Swann, S.A., Levy, S.L.A. et al. Global Prevalence of Chronic Pain in Women with HIV: A Systematic Review and Meta-analysis. Open Forum Infectious Disease 10, Online (2023).

Images from CATIE, Canada’s source for HIV and hepatitis C information, and the British Columbia CARMA-CHIWOS Collaboration (BCC3) Study team.

CBR Travel Awards: Attending CROI 2023

BY LOULOU CAI, PHD CANDIDATE, COTE LAB

The Conference on Retroviruses and Opportunistic Infections is one of the most extensive scientific conferences on HIV/AIDS, as well as currently prominent viruses such as SARS-CoV-2 and M-pox virus in 2023. The conference is interdisciplinary, featuring the best basic, translational, clinical, and epidemiological research in HIV/AIDS. While it is a North American conference, over half of its attendees are international. This year, I had the opportunity to present a poster describing some of the findings from our lab regarding potential toxicities in a specific class of antiretroviral medication on immune cells.

This was my first international conference experience, and it proved to be extremely valuable. Prior to the official opening of the conference, there was a New Investigator Workshop designed specifically for new researchers. The talks in this workshop provided an understanding of fundamental aspects of HIV virology, relevant immunology, as well as an overview of the history and potential trajectories of HIV research. Topics included the power of community engagement and advances in HIV treatment, prevention, and cure. Additionally, CROI offered activities for new researchers, providing opportunities to interact in small groups with luminaries in the field. I was able to advance my knowledge on specific topics of interest to our lab, such as the side effects of antiretrovirals in women and children, sex differences in immune aging in the context of HIV, and the effects of other chronic/ latent viruses on markers of aging. Thanks to the support from the CBR, I had the chance to engage in ground-breaking oral research talks and poster sessions that expanded my knowledge across numerous subjects.

The poster I presented described the effects of a specific antiretroviral class on mitochondrial health, as well as markers of immune activation in peripheral blood mononuclear cells. This antiretroviral class, known as integrase strand transfer inhibitors (INSTIs), plays a crucial role in preventing HIV integration into the genome. It is now one of the most widely used HIV medications around the world. However, despite their efficacy, tolerability, and low pill burden, less is known about their mitochondrial toxicities compared to older antiretrovirals. The INSTI dolutegravir has been associated with weight gain in adults, which may indicate changes in cellular metabolism governed by mitochondria.

During my presentation, I was approached by a few industry representatives who showed interest and concern regarding the results.

(Hint: dolutegravir may have mitochondrial toxicities. Check out my poster below to learn more!)

I would like to express my gratitude to the CBR for supporting my attendance at CROI 2023 in Seattle. The academic benefits and knowledge I gained from this event are invaluable to my research career.

CROI logo

CBR Travel Award recipient Loulou Cai presenting their poster titled “Several HIV Integrase Inhibitors Affect Immune Cell Mitochondria, Proliferation and Apoptosis ex vivo at the Conference on Retroviruses and Opportunistic Infections.

Learn more about CBR Travel Awards and how you can apply: https://cbr.ubc.ca/research-and-training/grad-pdf-training/cbr-travel-awards/

AWARDS

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Modifying Material Surfaces for Biomedical Applications Featuring: Hydrophilic Polymer-Guided Polycatecholamine Assembly and Surface Deposition

BY ERIK LAMOUREUX, PHD CANDIDATE, MA LAB

In this piece, Erik Lamoureux introduces the unique challenges associated with biomaterial surface modifications in a biomedical setting, and a recent publication on studies by the Kizhakkedathu group at the UBC Centre for Blood Research (CBR) that could help address these challenges.

The modification of surfaces to produce innovative materials has allowed for the development of cutting-edge technologies ranging from automobile parts to electronics, and even biomaterials with applications in medicine.

In the setting of organ transplant and surgery, there is a need for sutures and biomedical devices made of materials that function under wet conditions and on soft tissues, that are resistant to bacterial infection, and are biocompatible to avoid unwanted host immune responses.

Although recent research has led to innovations such as self-dissolving (biodegradable) stitching materials, there remains a need for affordable and safe alternatives. Existing biomaterials do not provide adequate protection from risks such as implant-associated infection, where antibiotic-resistant biofilms may grow on the device, necessitating their removal. Additionally, foreign blood-contacting materials can trigger clot formation around the implanted device and/or in the circulation, resulting in serious and even fatal vascular events.

In a recent publication in ACS Applied Materials & Interfaces, the Kizhakkedathu group from the CBR studied the properties of (poly)catecholamines (e.g., polydopamine, PDA, and polynorepinephrine, PNE) with functional molecules that bind to the coatings. Using a one-step dipping process, nanoaggregates clump together to form nanoparticles large enough to form solids in solution and ultimately a crosslinked hydrophilic surface coating with anti-biofilm properties (Figure 2). Importantly, this codeposition method has improved versatility and scalability compared to conventional (twostep dipping) processes. The Kizhakkedathu group investigated co-deposition of (poly) catecholamines (e.g., PDA and PNE) and six different hydrophilic polymers noted for their anti-biofilm characteristics. The authors first evaluated the stabilization of the nanoaggregates and found that if interactions between PDA and its co-deposited polymer were too strong in solution, no nanoparticles were produced and the surface covering was not sufficient to prevent biofilm growth (e.g., PDA-PVP in Figure 2). When interactions

The development of coatings to modify surface properties for improved biocompatibility and hemocompatibility is a promising and important way for researchers to address these challenges.

To inform their studies, scientists turned to sea mussels because these animals secrete a complex protein mixture that allows them to adhere to nearly all types of materials under dry and wet conditions (Figure 1). In fact, the chemical composition of an adhesive mussel protein informed the development of polydopamine (PDA) universal coatings which, along with other catecholamine-based coatings, are now used to modify material surfaces for biomedical applications.

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Figure 1. Stylized image of mussel adhering to a wet surface. The external byssal threads have remarkable chemical and material properties for attaching to all sorts of wet surfaces. These properties that are equally desirable for materials designed for clinical applications in the human body, and as such, this example from nature has informed the design of novel biomaterials. Created with GPT-4’s DALL-E.

between the PDA and polymer were less strong, the crosslinked surface coating more effectively prevented biofilm growth (e.g., see PDA-PDMA in Figure 2). Coatings formed by the polymers were hydrophilic (water-loving), as indicated by water being spread out on the surface instead of “beading” as you would see on a water-proof raincoat. Desirable coatings not only need to be water-loving to integrate with the wet conditions of the body but also must not accumulate bacteria and other unwanted organisms. The researchers also evaluated the coatings’ anti-adhesive and anti-fouling properties, including low surface charge.20 Overall, the PDA-PDMA coating performed the best in resisting biofilm formation for two types of bacteria (Figure 2). Incredibly, codeposition of PDA with PDMA afforded a 43-fold reduction in biofilm formation, as compared with a 6.7-fold reduction when the PDA coating was modified with PDMA postdeposition (the conventional two-step dipping process). Due to its versatility, simplicity, and scalability, dopamine-assisted co-deposition is a remarkable tool for developing novel biomaterials.

Overall, this work by the Kizhakkedathu group underlines the enormous value of co-depositing catecholamines with various polymers to improve the quality of antifouling biofilminhibiting coatings. The findings, which continue to rapidly evolve, is of major interest in the development of materials with enhanced biocompatibility, hemocompatibility, and resistance against bacterial infection.

Erik would like to thank Michael W. Kulka, formerly with the Kizhakkedathu group, for his helpful feedback on an early version of this article.

Y. Mei, K. Yu, H. Yazdani-Ahmadabadi, D. Lange and J. N. Kizhakkedathu, ACS Appl. Mater. Interfaces, 2022, 14, 39577–39590.

Figure 2. Graphical abstract of the Kizhakkedathu group’s work. Catecholamines (e.g., PDA) and hydrophilic polymers were co-deposited to produce anti-adhesive coatings on various substrates.1 The polymers investigated included: Poly(dimethylacrylamide) (PDMA), Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), poly(ethylene oxide) (PEO), hyperbranched polyglycerol (hPG), Polyvinylpyrrolidone (PVP), and Poly(2-ethyl-2-oxazoline) (PEOx), where Polypropylene (PP) served as a control material. The bottom row shows fluorescent microscopy images where the green labels indicate bacterial growth, indicating poorer quality anti-biofilm properties.

Two CBR researchers awarded The CFI Innovation Fund Two Centre for Blood Research (CBR) researchers are UBC leads for ten projects who have been awarded The CFI Innovation Fund in the latest round of funding. The CBR Scientists are: Dr. Leonard Foster

Dr. Natalie Strynadka

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

Project - Transformative and disruptive systems immunology

Project - TRaC: Therapies for Rare Cancers

UBC Faculty of Medicine-affiliated research projects have been awarded more than $18 million in federal funding from the Canada Foundation for Innovation (CFI) Innovation Fund, Natural Sciences and Engineering Research Council of Canada (NSERC) Alliance Grants 2022, and Social Sciences and Research Council (SSHRC) Insight Development Grants.

This story was adapted from the Faculty of Medicine website, with minor changes.

Congratulations, Dr. Foster and Dr. Strynadka, and to the rest of The Faculty of Medicine-led projects and UBC researchers!

AWARDS

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L-R: Dr. Agnes Lee, Dr. Hayley Merkeley, Dr. Hélène Côté, Dr. Karen Cheung, Dr. Kelly Brown, Dr. Natalie Strynadka

CBR Spotlights Female Leaders for #WomenInScience 2024

BY KAITLYN CHUONG, COMMUNICATIONS & PROGRAMS COORDINATOR & ALEXANDRA WITT, PHD CANDIDATE, PRYZDIAL LAB

February 11 is recognized by the United Nations (UN) as the International Day of Women and Girls in Science, which aims to spotlight the contributions of women in science, technology, and innovation. This day is a reminder that women and girls play a critical role in STEM communities and an opportunity to promote full and equal access to science around the world.

This year, we had the pleasure of chatting with several leaders in the CBR community to learn more about their research, share their stories, and celebrate all that they do. The CBR is proud to have dedicated, passionate, and driven female leaders that students, trainees, and staff can learn from.

What is the focus of your work?

Dr. Agnes Lee: Treatment of cancer-associated thrombosis has been the main focus of my research for the past 20 years. I am a clinical trialist and a hematologist. As a result of my work, I’ve also been involved in developing clinical practice guidelines and participating in data monitoring committees for clinical trials.

Dr. Hayley Merkeley: My research is focused on the clinical care of patients with red blood cell disorders like sickle cell anemia and thalassemia, including the efficacy of new treatments and improvement of existing care.

Dr. Hélène Côté: I have two main research topics: 1) Understanding why people living with HIV, and more particularly women living with HIV, experience aging-associated diseases many years earlier than men living with HIV or women who are HIV-negative. 2) Understanding the effects of in utero exposure to HIV medications, and why children born to mothers with HIV have more neurodevelopmental and neuropsychiatric diseases.

Dr. Karen Cheung: Our research group uses nano- and microfabrication techniques to develop technologies for life sciences and medicine. We take advantage of phenomena at the microscale that allow us to control the microenvironment around microtissues, and create representative models of organs on chips. Our group has ongoing projects in tissue engineering, silicon photonic biosensors, inkjet dispensing of single cells for sequencing and proteomics, implantable microelectrode neural interfaces, and development of microfluidic organs-on-chip.

Dr. Kelly Brown: Research in my laboratory is done in partnership with clinicians, patients, and advocates towards a common goal of providing the best evidence-based care for children with vasculitis and other rheumatic diseases. My team uses a bedside-to-bench approach to discover and validate quantifiable biomarkers that can aid with diagnosis and treatment decisions for affected children. Our initiative on childhood-onset vasculitis was supported by a multi-year CIHR grant that enabled the largest collection of data and samples from (> 400) children with vasculitis - which is remarkable given that there are only 1-2 new diagnosed cases per year in BC! Dr. Natalie Strynadka: Our lab uses an array of molecular biology, biochemical, and biophysical techniques such as x-ray crystallography and cryo-electron microscopy to determine atomic structures of membrane protein complexes that represent logical targets for structureguided anti-microbial and vaccine discovery. We use this atomic information as precise blueprints to design new therapeutics to combat drug resistant infections.

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What brought you to science?

“I love doing research and pursuing new knowledge. Ever since I was young I have wanted to make new discoveries. I also love applying this new knowledge to solve problems; this combination has brought me to biomedical engineering.” - Dr. Cheung

Did you have any female mentors that inspired you throughout your career?

“I think I naturally gravitate towards the arts, but what I love about medicine is translating science into patient experiences. Especially in meaningful ways such as reducing the amount of pain they experience or helping them grow their families. My undergraduate background is in Hispanic studies and psychology, and I want to highlight that there are many paths to becoming a doctor, which enriches our profession.” - Dr. Merkeley

“Structural biology has a long history of amazing, trailblazing women in the field. This includes Nobel Prize laureate Dorothy Hodgkin, the first to characterize insulin and penicillin amongst other important works. My PhD supervisor trained with her at Oxford, and I was fortunate enough to meet and speak with her as a graduate student on several occasions. These interactions had a lasting impact not only on my love of atomic level science and process, but the faith that one can nurture both a family (Professor Hodgkin had 3 children) and a scientific career as a woman.” - Dr. Strynadka

“Growing up, I spent large parts of each summer roaming and helping out on my grandparent’s wheat farm in rural Alberta.

That freedom to explore and the wisdom of my grandmother (an unofficial but truly impressive botanist, conservationist and artist…) laid an early foundation for loving nature and the scientific underpinnings therein.” - Dr. Strynadka

What’s your biggest accomplishment?

Did you face any challenges as a woman in STEM? What motivated you to continue your work?

“Balancing the priorities of work and home is always a challenge.

Reality is that the ‘balance’ is not a static space, where we stand squarely on our feet; but rather it is a scale that tips 360 degrees constantly and we do our best to not fall off! Some days I might not be the best mother and other days I might fall short of being the best doctor or the best researcher, but I try my best and remind myself that, sometimes, I did do a fantastic job! My biggest motivation is my kids – how can I make the world a better place for them?” - Dr. Lee “By the time I reached school age, I was already aware of, perplexed about, annoyed by, and wholly uninterested in society’s expectations of who I, as a girl, was - and was not - supposed to be. Being true to myself in the face of deep-rooted societal gender stereotypes has been a challenge, but one that is lessened by the inspiration that comes from others (my students, colleagues, community) that are taking steps to educate themselves about EDI, understand the experiences of others, and enact positive change towards a more equitable workplace and society.” - Dr. Brown

“Unfortunately not. There were very few women in the Biochemistry department back then. I think however because of that, I make a point of supporting young women in science and find pleasure in supervising the new generation of scientists.” - Dr. Côté

“I first began thinking about patient-partnered research when I was tasked with the analysis of patient samples as an undergraduate thesis student. I’ve been thinking about and teaching myself to be a translational researcher ever since. It has been especially meaningful and rewarding to become the first PhD scientist hired to the UBC (clinical) Division of Pediatric Rheumatology and Scientific Lead of one of only a couple of labs in Canada where researchers can get specialized training in patient-oriented research on childhood-onset rheumatic diseases.” - Dr. Brown “The CLOT trial, published in NEJM in 2003, demonstrated superiority of low molecular weight heparin (LMWH) over warfarin for treatment of cancer-associated thrombosis. This helped to change clinical practice worldwide and established LMWH as the first line therapy for this indication. To-date, LMWH remains one of the drugs of choice in treating patients with cancer and thrombosis.”

- Dr. Lee “Establishing two large cohorts of people living with HIV. One of women (cis and trans) and girls, and the other, pregnant women and their infants. And now, doing community-based research, and employing community research associates (women living with HIV who have been trained in research).” - Dr. Côté

What advice would you give to early career woman scientists?

“Sometimes it’s hard to look around and know that women tend to have lower self-confidence and feel less self-efficacy about our abilities in science and engineering. It’s natural to internally expend mental energy dealing with microaggressions. Finding a way to speak up and intervene, unprompted, when we observe these situations happening to others, can help mitigate these negative experiences on our colleagues, and help sustain more women in STEM.” - Dr. Cheung “Trust your instincts and training and be confident. Our male colleagues often feel inadequacy the same way we do but have been conditioned by society to present more confidently. At the same time, it is always important to remain humble and learn from our colleagues and patients. The more experience you gain, the more comfortable you will be learning to strike this balance.” - Dr. Merkeley Thank you to Drs. Brown, Cheung, Côté, Lee, Merkeley and Strynadka for sharing their stories with us! We are proud to have you as part of our CBR community, and can’t wait to see all that you will continue to accomplish in the future.

PEOPLE

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The Clinical Implications of the Connection between COVID-19 and Sepsis

BY ANDY AN, MD/PHD CANDIDATE, HANCOCK LAB

It has been four years since the start of the COVID-19 pandemic, with over 700 million infections and 7 million deaths. These numbers continue to rise as this disease significantly impacts our healthcare system and society, warranting continued extensive research. Two recent studies by the Hancock Lab1,2, published in Frontiers in Immunology, focus on severe COVID-19 and another infectious disease called sepsis, revealing surprising parallels in their pathophysiology and offering potential new treatments for both diseases. The authors investigated 42 patients admitted to the intensive care unit (ICU) at St. Michael’s Hospital in Toronto for respiratory complications, either from severe COVID-19 or pulmonary sepsis, and followed up a week later.

Whole blood was drawn at both timepoints, allowing for longitudinal study of gene expression.

Displayed is a protein-protein interaction network of dysregulated persistent genes found in COVID-19 and sepsis patients who died in the ICU [2]. Circled are the top 15 hub genes, which are genes and their protein products with multiple interactions with other dysregulated genes/ proteins during severe disease. Hub genes are attractive pharmacological targets for drugs as their protein products may be key in driving underlying pathology, and the authors found several repurposed drugs that may target these hubs to treat both diseases [2].

Protein-protein interaction network of dysregulated persistent genes found in COVID-19 and sepsis patients who died in the ICU. Circled are the top 15 hub genes, which are genes and their protein products with multiple interactions with other dysregulated genes/proteins during severe disease. [2]

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Displayed is a protein-protein interaction network of dysregulated persistent genes found in COVID-19 and sepsis patients who died in the ICU [2]. Circled are the top 15 hub genes, which are genes and their protein products with multiple interactions with other dysregulated genes/ proteins during severe disease. Hub genes are attractive pharmacological targets for drugs as their protein products may be key in driving underlying pathology, and the authors found several repurposed drugs that may target these hubs to treat both diseases [2].

The first study1, “Severe COVID-19 and non-COVID-19 severe sepsis converge transcriptionally after a week in the intensive care unit, indicating common disease mechanisms” explores how the gene expression profile of COVID-19, a novel disease caused by a novel virus, is surprisingly similar to sepsis, a disease that has been studied since the time of Hippocrates. Sepsis is a severe condition that occurs when the body’s response to infection goes into overdrive and causes organ damage, and is estimated to be involved in 1 of 5 global deaths. At ICU admission, COVID-19 patients and sepsis patients had similar clinical presentation; however, they had over 1,000 genes that were differentially expressed between them. Many antiviral genes were expressed higher in COVID-19 patients, which was expected considering the viral etiology of COVID-19. Surprisingly, when these two groups of patients were compared one week later, the number of differentially expressed genes dropped dramatically to only 9 genes, suggesting a convergence in gene expression indicative of an ultimate shared pathophysiology. Furthermore, throughout the hospitalization, both groups had similar immune dysfunction, with dysregulation of immune pathways such as interleukin-1 and interleukin-6 signaling, complement pathways, and neutrophil degranulation.

The authors concluded that due to these gene expression similarities, severe COVID-19 was essentially a form of viral sepsis, with a distinct initial antiviral response on top of shared immune dysfunction. This finding has two important clinical implications. First, the early peak and waning of the antiviral response likely explains why antiviral therapies for COVID-19 (e.g., remdesivir, Paxlovid, and monoclonal antibodies against viral proteins) are most effective early in disease, when the major driver of disease is the virus itself. Once this antiviral response passes, especially in later, more severe forms of this disease, the focus should shift to targeted immunomodulatory therapies to treat underlying immune dysfunction. Second, considering that COVID-19 is a form of viral sepsis, this further supports the application of decades of sepsis research into biomarkers and clinical care

to COVID-19. Likewise, the vast amount of research into new immunomodulatory therapies developed for COVID-19 may be repurposed and tested in sepsis patients. This reciprocity would be extremely beneficial as sepsis currently lacks specific treatments beyond antibiotics and supportive care.

What immunomodulatory therapies would be appropriate for both COVID-19 and sepsis? To answer this question, further investigations regarding the shared immune dysfunction was necessary. This was done in the second study2, “Persistence is Key: Unresolved Immune Dysfunction is Lethal in Both COVID-19 and non-COVID-19 Sepsis”, which focuses on the mechanisms driving mortality in both groups. Interestingly, patients who eventually died in the ICU had almost a 4-fold higher number of “persistent genes” compared to survivors.

Persistent genes were genes that remained dysregulated throughout the ICU stay, and many of these genes played a key role in several immune pathways, highlighting persistent immune dysfunction. This was centred around both adaptive immunosuppression (e.g., dysfunctional T cell signaling) and innate immune overactivation (e.g., IL-1 signaling). To find potential therapeutics to target these pathways, the authors

turned to bioinformatic methods such as drug-gene set enrichment and network analysis to find already approved drugs that could be repurposed to inhibit some of these persistently dysregulated genes. Drug-gene set enrichment focused on identifying drugs that could turn off specific groups of genes, while network analysis identified “hub” genes that interact with multiple other dysregulated genes and could be pharmaceutically targeted to inhibit whole processes. Overall, several repurposed drugs were identified that could be investigated further in in vitro, in vivo, and clinical studies.

The results from both studies highlight the importance of understanding the immune dysregulation seen in COVID-19, which could guide clinical management and opens doors to novel treatment strategies for both COVID-19 and for sepsis.

As we continue to grapple with more iterations of SARSCoV-2, these insights are vital for managing COVID-19 and ultimately preparing for future pandemics.

An AY, Baghela A, Zhang P, Falsafi R, Lee AH, Trahtemberg U, Baker AJ, dos Santos CC, Hancock REW. Persistence is key: unresolved immune dysfunction is lethal in both COVID-19 and non-COVID-19 sepsis. Frontiers in Immunology 2023; 14:1254873.

Department of Medical Genetics Teaching Award - Dr. Wilfred Jefferies a collaborative environment without creating an internally competitive environment.

What makes him a great teacher?

Dr. Jefferies was nominated by Dr. Cheryl Pfeifer, a Research Associate in his lab. We asked Cheryl to share more details on why she nominated Dr. Jefferies and what makes him an exceptional teacher!

How long have you known and worked with him?

I have known Dr. Jefferies as a departmental colleague since 1992, and worked with him in his lab since the middle of 1999, first as a postdoctoral fellow and later as a research associate.

Why did you nominate him for the award?

Over the years, I have seen Dr. Jefferies supervise and mentor numerous undergraduates, graduate students and postdoctoral fellows. I have admired the respect and freedom he gives to the trainees, and the way he encourages them to seek out and discover science, to ask questions, and to work with others in the lab. Within the lab, he has always sought to create

Dr. Jefferies is a great teacher because he is truly excited about science, which overflows into his teaching. He has the ability to see the big picture through all the details, and through this, helps the students learn what is important. He fosters creative thinking and encourages looking at a problem/idea from many different angles. Dr. Jefferies teaches in more of a coaching style where he provides main points and resources and then encourages the students to initiate their own discovery journey.

While this can initially be a source of frustration to students accustomed to a more direct style, most have embraced this freedom and have come to a greater understanding and realization of the science than they would have otherwise.

“

The award was very well-deserved. Dr. Jefferies is a great mentor, teacher and researcher because he’s a fantastic out-of-the-box thinker and problem solver. Conversations with him are very stimulating and can lead to me taking research directions that I hadn’t considered before. I also appreciate that he is a good listener and seems to take away as much from these conversations as I do.

DR. GIORGIA CASPANI, POSTDOCTORAL FELLOW, JEFFERIES LAB

AWARDS

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Earl W. Davie Symposium 2023: Seventeen years of connecting through science sharing

BY IRYNA LIUBCHAK, CHEUNG LAB & JULLIET ZAMA, COTE LAB

O

n November 16th, 2023, the Centre for Blood Research (CBR) held their 17th annual Earl W. Davie Symposium, a research event that brings together scientists, medical doctors, healthcare professionals, and trainees in the field of blood research and beyond. The symposium was held at UBC Robson Square, on the traditional territory of the Musqueam, Squamish, and Tsleil-Waututh people.

How the Day Kicked Off The full-day program featured expert talks on hemostasis, thrombosis, and bleeding disorders. Impressive presentations from students and more than 30 trainee research posters were also highlighted throughout the day.

Following the opening remarks from CBR Director Dr. Ed Conway, the symposium began with a talk from Dr. Jeffrey Zwicker, Chief of Hematology Service at Memorial Sloan Kettering Cancer Center in New York City. Dr. Zwicker has dedicated his research to predicting thrombosis in cancer patients and reported an association between the low levels of CD200R1 expression in neoplasmatic cells and the high risk of thrombosis. This was followed by a series of presentations on the topic of bleeding disorders.

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Keynote Speakers Every year, the CBR invites two keynote speakers to the symposium. These speakers typically come from outside Vancouver to share their research.

This year, the CBR brought Dr. Alisa S. Wolberg from the University of North Carolina, Chapel Hill and Dr. Paul F. Bray from the University of Utah.

platelet genes that contribute to stroke pathogenesis and risk. He discovered that platelet aggregation had no effect of race but PAR4 did show some reactivity after genetic analysis. This led to his conclusion that higher incidence and worse outcomes of strokes were in blacks. His group also focuses on platelet, bleeding, and thrombosis disorders.

The first keynote speaker of the symposium was Dr. Wolberg, who presented a talk on the role of fibrinogen and factor XIII in venous thrombosis. Dr. Wolberg’s lab discovered that factor XIII mediates red blood cell (RBC) presence in the blood clot by increasing the stiffness of individual fibrin fibers in the clot and thus creating a fibrin net that retains RBCs. Currently, they are working on evaluating the potential of synthetic tridegin variants – a highly specific factor XIII inhibitors – to release RBC from the blood clot and thus, reduce the blood flow occlusion by the clot.

Dr. Bray was our second keynote speaker of the day. He presented on the topic of “Racial Disparities and Stroke Pharmacogenetics: The PlateletNeutrophil affair”. In one of his papers titled platelet PAR4 reactivity by rs773902 genotype involving white and black individuals, his goal was to identify

Keynote speakers, Dr. Alisa Wolberg (top) and Dr. Paul Bray (bottom) with Dr. Edward Conway.

Audience members listening to speakers at the 17th Annual Earl W. Davie Symposium.

Science Sharing & Experiences While a majority of presentations were centered around scientific contributions, we were also fortunate to hear speakers share their personal experiences with blood disorders. These stories are vital to researchers; listening to personal experiences helps us understand their struggles and lead us to develop services that can truly be shaped for them.

One such speaker was Rick Waines, a member of the Canadian hemophilia blood society, who shared his journey with hemophilia A. Hemophilia A is an inherited bleeding disorder in which the blood does not clot properly due to a deficiency in factor VIII. This can lead to severe bleeding in the joints, muscles, and vital organs, resulting in significant morbidity and mortality. Rick discussed the different treatments he has used over the years and shared his various challenges, including acquiring HCV and HIV through contaminated blood products. He also offered insights into why he declined an opportunity to take part in a clinical trial for gene therapy.

Thankfully, due to advocacy through the hemophilia society, Rick now has access to a once weekly sub-cutaneous monoclonal antibody injection, which was further discussed later in the day

by Dr. Angelina Marinkovic, to treat his hemophilia that has greatly reduced his treatment burden.

The symposium was a great opportunity to observe how science moves from the benchtop to bedside. A great example of this was the lecture by Dr. Michael Holinstat from the University of Michigan.

Anti-platelet therapy used for decreasing

the risk of thrombosis often comes with an increased risk of bleeding, thus there is a need to find new drug targets within the cascade of platelet function regulation. Dr. Holinstat’s group and collaborators identified 12-lipoxygenase (12-LOX), an enzyme primarily expressed in platelets that facilitates their activation, as a potential candidate. After four years of screening more than 553,000 different compounds for a highly selective inhibitor of the 12-LOX, they found one with promise.ML355 demonstrated an ability to inhibit thrombosis in laboratory mice without significant side effects on hemostasis. Currently, ML355 is in the phase II clinical trials for the treatment of heparin-induced thrombocytopenia and thrombosis (HITT).

Naiman-Vickars Professorship Highlight One of the symposium highlights was the Naiman-Vickars Professorship awardee Dr. Elisabeth Battinelli, an expert in platelet biology from Harvard University.

Dr. Battinelli and her team explored the role of platelets in cancer and malignancy.

Their research revealed that platelets, when incubated with tumor cells, release CCL5 and subsequently activate the IL-8 pathway in breast cancer cells through the upregulation of the CCR5 receptor.

Further experiments were conducted using aspirin as an anti-platelet agent, which successfully reduced CCL5 release and prevented IL-8 production in tumor cells. Additionally, Dr. Battinelli’s team showed that platelets can upregulate PDL1, a transmembrane protein that can be highly expressed on tumour cells, which can prevent T-cell attack. Of note, when they incubated tumour cells with platelets that were pre-treated with aspirin, there was no upregulation of PD-L1. Despite their findings, the use of aspirin in the context of cancer is under debate given the recent evidence that aspirin is associated with a higher mortality rate from cancer.

presenters from out of town who came to share their research! The Best Poster Presentation went to Stephanie Besoiu, a PhD Student in the Jefferies Lab, for her poster on Novel MHC Class l Antigen Cross Priming Ability of Type 2 Innate Lymphoid cells. To end the day, we had the pleasure of listening to five outstanding trainees from Canadian and US institutions who presented their oral talks. After the formal program, a reception was held where everyone got to connect and network with attendees and speakers.

The Centre for Blood Research would like to thank their event sponsors, without whom the 17th Annual Earl W. Davie Symposium would not have been possible: the Naiman-Vickars Endowment Fund, Bayer, the Canadian Blood Services, novo nordisk, GRIFOLS, CSL Behring, ALEXION, Recordati Rare Diseases, Pfizer and Stago.

Joyce Teodoro presenting her poster.

Grace Kuo presenting her poster.

Incredible Poster Presentations This year, we had a record-high 34 posters presented by trainees, postdoctoral fellows, clinical fellows, and research associates. Many of these posters came from members within the CBR, but there were several poster

Kaitlyn Chuong presenting Stephanie Besoiu with the Best Poster Presentation award.

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Hotwire the Cure: Turning Cold Tumors Hot

BY MYA BAL, NATALIA NAYYAR & CHARLOTTE GILMORE, UNDERGRADUATE STUDENTS, MCNAGNY LAB

Ovarian cancer is a silent killer. With subtle symptoms, it is often detected at an advanced stage. Current gold-standard treatments have major side-effects that diminish patient quality of life. Sadly, despite treatment with surgery and aggressive chemotherapy, the cancer is highly likely to return. More effective and less toxic treatments are urgently needed.

Research by Dr. Julyanne Brassard, recently published in Frontiers in Oncology,[1] highlights a promising new therapeutic target for ovarian cancer. Her study was conducted in the research labs of Prof. Kelly McNagny and Prof. Calvin Roskelley, in collaboration with the BC Cancer Agency (Deeley) and MAPCore. Dr. Brassard found that a tumor-specific form of podocalyxin (PODXL) (the PODO447 epitope) is expressed on a subset of tumor cells in 60% of patients with high-grade serous ovarian cancer (HGSOC). HGSOC is the most prevalent and lethal type of ovarian cancer. Importantly, in HGSOC, the PODO447 epitope is highly expressed in tumors with a ‘cold’ immune profile. Cold tumors lack immune cells that could help eliminate tumor cells. Conversely, ‘hot’ tumors have T and B cells and other inflammatory cells, supplied by the body’s own immune system, to help fight the cancer. Thus, even when treated with chemotherapy, cold tumors are typically associated with the most dismal prognoses. Finding ways to convert ‘cold’ tumors into ‘hot’ tumors would predictably make current treatments more effective. (Figure 1).

While normally expressed in some healthy tissue (including

Left to right: Mya Bal, Natalia Nayyar, Charlotte Gilmore.

blood vessels), PODXL expression on tumor cells is universally linked to poor prognosis because it promotes tumor spread (metastasis). Spread of tumor cells from the site of origin to other organs is most often the cause of death in cancer. Discovery of the PODO447 epitope in HGSOC, particularly in ‘cold’ tumor types, makes it a promising target for treatment since it permits the development of therapies that target hard-to-treat tumors while avoiding healthy tissue. Dr. Brassard’s insights suggest that tumor cells expressing the PODO447 epitope have engaged mechanisms to evade the immune system. She is currently working with collaborators on mapping out the underlying mechanisms of immune evasion in PODO447High HGSOC tumors.

When asked why she thinks cold HGSOC tumors express high levels of the PODO447 epitope, Dr. Brassard said: “When a protein like podocalyxin is expressed on normal cells, there are important processing steps (called glycosylation) that add chains of sugars to ‘decorate’ the mature protein. These glycosylations are important for normal protein function. But, during transformation of normal cells to tumor cells, protein glycosylation is altered. Some of these alterations may provide tumor cells with a survival advantage, help them spread, or help them hide from the immune system. The PODO447 epitope seems to arise from altered glycosylation in tumor cells and it is probably generated by mechanisms linked to the immune evasion characteristics of tumors. This is something I will test in my future research.”

In related research, the McNagny & Roskelley teams generated a monoclonal antibody (PODO447 mAb) to target tumor-expressed PODXL. When coupled to a potent toxin (ie, an antibody-drug conjugate (ADC)), PODO447-ADC effectively kills human ovarian and pancreatic tumor cells in preclinical mouse models. Brassard is working to optimize the PODO447-ADC prototype and bring this promising new therapy to the clinic.

Figure 1.The tumor-specific PODO447 epitope is a new therapeutic target for ovarian cancer treatment. (A) The PODO447 epitope is a new biomarker of ‘cold’ tumors in ovarian cancer. (B) A PODO447 antibody drug conjugate (ADC) may help eliminate tumor cells in chemoresistant and recurrent ovarian cancer by turning ‘cold’ tumors ‘hot’. Figure made with BioRender.com and is a modified version of Fig 6 from Brassard et al.

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Brassard, J., Hughes, M.R., Dean, P., et al. A tumor-restricted glycoform of podocalyxin is a highly sensitive marker of immunologically cold high-grade serous ovarian cancer. Frontiers in Oncology 13, (2023).

Celebrating women & girls in science: Marie Johns reflects on her journey in STEM address the urgent need for effective therapies.

By clarifying the role of different factors in AD, I hope my work can lead to a paradigm shift in the way we perceive and treat this devastating disease, offering hope to millions of patients and families affected by AD and related dementias.

Marie Johns, PhD Candidate, Jefferies Lab

What did your journey into science graduate studies, and your research field specifically, look like?

Shortly after I started my undergraduate studies in biology and behavioural neuroscience, my grandpa was diagnosed with Lewy Body Dementia, and like many relatives of dementia patients, I felt powerless to help him. I was already fascinated with genetics and neuroscience at the time, so I challenged myself to learn everything I could to help him and my family. I remember explaining to him the concept of ‘long-term potentiation’ in the context of memory retention, and encouraging him to practice recalling memories he wanted to remember, like family members’ faces and important events. When he passed away, I decided I wanted to make a bigger difference for patients and families like my own. This desire, coupled with a fascination in neuroscience and genetics, is what drew me to the Jefferies lab for my PhD studies.

What is the current focus of your research, and what impact do you hope it will have?

My thesis research centers around the neurovascular theory of Alzheimer’s Disease (AD), a progressive brain disorder with no known cure. While traditionally linked to protein plaque buildup, my lab’s pioneering work has suggested that blood vessel dysfunction in the brain can also play a significant role in AD progression. Using advanced transcriptomics, I hope to better understand AD’s molecular characteristics and the role of blood vessels specifically to

What have been your greatest successes and achievements to celebrate?

I’m fortunate to have recently celebrated several key successes. In the lab, I’m particularly proud and thankful to have received the Omer H. Patrick II Memorial Prize in Alzheimer’s Disease research. As well, I recently won ‘Best of British Columbia’ at the Cascadia 5.0 BC Regenerative Medicine Conference, which affirmed for me the impact and importance of pursuing my research.

Outside the lab, my election to co-President for the Medical Genetics Graduate Student Association and the Interdisciplinary Graduate Student Network has allowed me to become a leader in my graduate student community, where I love organizing academic and social events where graduate students can connect.

Finally, it has been incredibly rewarding raising PADS Russell, a service dog-in-training, for a local non-profit. Training him to grow from a rambunctious puppy to a patient, calm, and well-mannered dog has been an incredible challenge, but also a lesson in perseverance.

These experiences, both in and outside the lab, have not only marked significant achievements in my academic career, but have also contributed to my personal growth, underscoring for me the importance of taking a well-rounded approach in academia.

What has been the biggest challenge you have faced in your scientific research journey?

As a student navigating my PhD journey with an invisible disability, I have been presented a unique set of challenges. One of the most significant I would say is the scarcity of role models in the academic sphere who have

publicly shared their invisible disability. This is likely attributed to the stigmas that still exist, which often discourage individuals from openly discussing their experiences.

While I have been fortunate to receive a considerable amount of understanding and support from my peers and mentors, I have also encountered judgment and discrimination along the way. Despite these experiences being difficult, they have taught me the invaluable skills of self-advocacy and resilience. Assertively communicating my needs and rights has been empowering, and I have seen changes in academia towards supporting more inclusive and supportive environments.

What advice would you give to young girls and women starting out in STEM? Get yourself out there! You’d be surprised the experience you can gain when you apply yourself to every opportunity you come across. Something will land, which will lead to the next opportunity, and the next. For me, my research experience started with a faculty member taking a chance on me for a directed study course in a molecular biology lab. Once I gained that initial lab experience, I got my first summer research assistant position, which led to an internship at STEMCELL Technologies, followed by a summer research program in Germany!

I did, however, face rejection along the way to these experiences. If there’s anything I’ve learned from this, it’s that persevering in the face of a challenge will lead to success, and that everyone faces obstacles along the way. It’s important, then, to remember to have a short-term memory for setbacks, and a longer-term memory for your successes as you carve your own path.

This story is re-published from the Michael Smith Laboratories (MSL) website.

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Research That Makes You Want to Smile: Novel Role for Granzyme B in Periodontal Inflammation

BY JOHN PERRIER, MASTERS STUDENT, PRYZDIAL LAB

Have you ever wondered how our immune system is intertwined with our oral health? More specifically, how proteins secreted by cytotoxic T-cells and natural killer cells can affect the progression of advanced gum disease, also known as periodontitis?

Researchers in the Kim lab at the Centre for Blood Research have discovered a new role for serine protease Granzyme B (GzmB) in signaling within the connective tissue cells of our periodontium, such as fibroblasts.1The periodontium refers to the tissues which surround and support the tooth. It has previously been established that gingival fibroblasts contribute to periodontitis by secreting matrix metalloproteinases (MMP) in response to biofilm buildup.2 Because GzmB degrades extracellular matrix proteins, activates pro-inflammatory cytokines, and interacts with a receptor present on gingival fibroblasts, protease-activated receptor-1 (PAR-1), this study hoped to uncover a role for GzmB in the degradation of periodontium connective tissue.

To assess whether GzmB can contribute to MMP-1 release, the team made use of in vitro and in vivo assays, as well as gingival crevicular fluid (GCF) samples collected from a cohort of over 100 individuals. Looking at healthy individuals, people with gingivitis, and people with periodontitis, the researchers used a GzmB-specific enzyme-linked immunosorbent assay (ELISAs) to establish that the concentration of GzmB is elevated when damage to the periodontium has occurred. GCF samples showed that those with periodontitis or gingivitis had nearly 5 times the concentration of GzmB present, relative to healthy samples.

Using cultured human gingival fibroblasts, the way that GzmB can trigger MMP-1 release from gingival fibroblasts was revealed. MMP1-specific ELISAs of GzmB treated cells showed a significant increase in MMP-1 release over a 24h period, and even more interestingly showed a 2-3fold higher MMP activity. Building on previous reports showing a link between pro-inflammatory stimuli and Erk1/2 phosphorylation6, the authors of this study went further, showing that MMP-1 upregulation by GzmB is dependent on Erk1/2 MAPK signaling. This was confirmed through immunoblot analysis of gingival fibroblast lysates, showing an increase of phosphorylated Erk1/2 following addition of GzmB. But how does GzmB initiate this signaling pathway? That would be through the aforementioned receptor, PAR-1. GzmB

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can proteolytically activate this transmembrane receptor, which in turn leads to the downstream activation of Erk1/2 MAPK. An antibody which inhibits PAR-1 function, ATAP-2, was used to dissect the role of PAR1 signaling in GzmBmediated MMP-1 release. ATAP-2 blocking of PAR-1 greatly reduced MMP-1 secretion in gingival fibroblasts treated with GzmB. This study establishes a novel signaling pathway, implicating GzmB in the pathogenesis of periodontal disease for the first time. Using human clinical samples, the Kim lab showed that the local concentration of GzmB is higher in those impacted by both gingivitis and periodontitis. This finding is put into context as the authors define the Erk1/2- and PAR1-dependant signaling pathway for GzmB which results in MMP-1 release from gingival fibroblasts. The current study highlights the potential for GzmB to be used as a therapeutic target to mitigate tissue damage caused by periodontitis.

Ben-Eltriki M, Ahmadi AR, Nakao Y, et al. Granzyme B promotes matrix metalloproteinase-1 (MMP-1) release from gingival fibroblasts in a PAR1- and Erk1/2-dependent manner: A novel role in periodontal inflammation. Journal of Periodontal Research. 2023;n/a(n/a).

Theilade E, Wright WH, Jensen SB, Löe H. Experimental gingivitis in man. Journal of Periodontal Research. 1966;1(1):1-13.

Cover of the Journal of Periodontal Research, 2023.

CBR Events, Socials & Activities December 2023 | LSC

January 2024 | LSC

March 2024 | LSC

CBR Winter Wonderland

New Year Potluck

The Great CBR Bake Off

Rolling Towards Wellness: CBR Laces Up for Skating!

On Thursday, February 22nd, we saw 23 CBR members from various labs at the UBC Thunderbird Arena for a fun afternoon of public drop-in skating and socializing.

The CBR Skate & Snack was organized by the Health & Wellness Committee, driven to building an inclusive, supportive and connected community at the CBR. This event was designed to bring members out of the lab and to help them de-stress, relax and have fun!

CBR members got to enjoy ice time for an hour.

Afterwards, we went to the LSC 4th Floor Pod to enjoy some hot chocolate, snacks and conversation! It was a great afternoon full of smiles, exercise and interaction.

Thank you to the Health & Wellness Committee for organizing this activity. There will be lots of other great events to look forward to this year!

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SLAS Grant Advances Translation Technology for CAR-T Cell Research – Samuel Berryman In less than a year after receiving his SLAS Graduate Education Fellowship Grant, Samuel Berryman moved from grant winner to Innovation AveNEW exhibitor. His academic research rapidly expanded into a start-up company with a marketable product – all with the support of SLAS and its network of life sciences leaders.

“The first pass through any life sciences experiment is always about learning – don’t be afraid to be messy, make mistakes or break things. It’s the second pass that’s about refining and reproducing,” says Samuel Berryman, a Ph.D. candidate in the Department of Mechanical Engineering from the University of British Columbia (UBC, Vancouver, BC, Canada), and recipient of the 2023 SLAS Graduate Education Fellowship Grant.

Berryman is a rapid-fire solution finder as he works to overcome the limitations associated with the analysis of chimeric antigen receptor T (CAR-T) cell therapies. He even wrote in his application for the SLAS grant, “I am best suited for research because I cannot just work on a small portion of a project. I need to take it apart and learn how every aspect of it fits together.” Berryman laughs and affirms that this is still the case one year into his two-year grant.

In the process of advancing his research objectives outlined in the grant proposal, Berryman invented a platform to evaluate CAR-T cells at the single-cell level, developed a process to manufacture the technology, started a business – ImageCyte – and applied to be on Innovation AveNEW at SLAS2024.

“We’re expanding the work in a number of different ways, but starting a company was the really big surprise from the last year!” says Berryman. “Our technology has many applications beyond what we originally envisioned. I’ve been working on new projects that potential customers would like to see, ranging from single-cell drug screening to spheroid generation and completing quick proof-of-concept demonstrations.”

Sharing this vision is Berryman’s advisor, Hongshen Ma, Ph.D., a UBC professor who is also his partner in the new business venture. “We have all these fantastic AI tools that have been used to analyze images to identify people and objects. Now we can use this approach to assess the properties of therapeutic cells,” Ma explains.

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Samuel Berryman

“Currently, it’s difficult to take pictures of cells and associate them with their type or function,” Ma continues. “While this information is likely available in cell images, we need a good way to associate the images with outcomes of assays. The device that Sam has built will be good for this – we can put single cells into these chambers, take high-quality images, and then assay each cell to associate the cell image with its function and behavior.” Ma adds that the resulting data can be compiled, shared and built upon by other scientists.

Berryman’s device features an array of millions of nano-well chambers that have been photolithographically fabricated inside standard glass-bottom micro-well plates. Researchers deposit single cells into individual chambers to observe cell characteristics ranging from cell phenotypes to dynamic behaviors.

In his research, Berryman is placing individual CAR-T cells and target cancer cells in the nano-wells to perform a killing assay to identify functionally superior CAR-T cells. He will acquire high-quality images of these cells to use AI approaches to identify cell morphologies indicative of highly functional CAR-T cells. This work will provide an improved assay to perform quality control of CAR-T cell function.

With A Little Help from Friends “The SLAS Graduate Education Fellowship Grant is a great opportunity, because it gives you the platform to present your research first and foremost. It also opens the door to taking part in the SLAS community,” says Berryman. “Whether the applicant is looking for a postdoc, a job in industry or – as in my case – a commercial partner, there are so many opportunities to connect with people at SLAS.” Samuel presenting at SLAS2024.

Eyes Wide Open Berryman, whose academic pursuits switched from mechanical to biomedical engineering during his graduate studies, appreciates the constant opportunity to continue learning in life sciences. “You don’t just learn one thing and then do it over and over again. You have to constantly be learning and adapting. With everything you do, there is the opportunity for it to have a lasting impact in medicine, which is deeply rewarding,” he comments.

He compares this to the manufacturing process associated with his newly minted nano-well device. “It’s one thing to make a device that you use a couple of times in an academic lab, however, when you want to make devices that could be used by external users, there’s another threshold to meet in terms of quality control,” comments Berryman.

At the start of his grant, Berryman met with manufacturing companies to discuss mass producing the device by licensing the intellectual property, but it quickly became apparent that the best option was to develop a process to manufacture the device himself.

The opportunity on SLAS Innovation AveNEW offered Berryman a chance to showcase the device and present its usefulness to a broader audience of life sciences researchers.

“Taking part in Innovation AveNEW at SLAS2024 and giving an SLAS Ignite presentation was an incredible experience for us, especially being a company at such an early stage,” Berryman comments.

“While we had the opportunity to build brand awareness with potential customers, we found that it was even more important to make initial contact with many of the exhibiting companies. Following the conference, we are going to be translating those conversations into new manufacturing opportunities, development projects and potential distribution agreements. This was all made possible by the sponsorship we received through the Innovation AveNEW platform. We highly recommend other life sciences startup companies take advantage of the opportunity. It is an accelerant that will drive your company towards success.”

This story was originally posted on The Society for Laboratory Automation and Screening (SLAS) website.

Berryman describes himself as fortunate that SLAS is sponsoring the journey of his technology from research to commercialization and adds that the encouragement from Ma also has been invaluable.

“He’s been extremely supportive along the way, and as we commercialize this device together, we’re shifting from me working for him to working together as a team. It’s an interesting transition,” Berryman says, adding that he continues to look for ways to pay forward the support he’s received.

“You learn a lot from the people you mentor and teach.

Mentoring is a great opportunity to help solidify your own knowledge,” he comments. For the past five years, Berryman has been a teaching assistant for the mechatronic product design course at UBC. “I helped run the labs and developed some of the course design. I loved doing this. Among the 40 or so people that you teach, you develop a few different approaches to help others understand the subject matter.

This gives you an opportunity to learn the material more thoroughly.”

A try- and try-again approach is one Berryman recommends to others as they pursue science. “There are so many positive learning outcomes that develop from making small mistakes and escaping from the lab for a break,” comments the newlywed Berryman, who enjoys spending hours out of the lab with his wife, Rachael, and the couple’s dog, Dante – and occasionally hitting the links for a few holes of golf.

“Science is not easy,” he says. “The advice I give is, don’t restrict your research or your ambition to familiar territory – that’s not how you learn. Instead, seek excellent mentors to guide you through this unknown territory and make your decisions based on the potential to expand your knowledge base. Even if you fail along the way, you gain wisdom to use toward whatever comes next.”

Samuel playing golf.

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The Discovery of New Sentinels on the Immune Watchtower for Cancer

BY STEPHANIE BESOIU & CLARA XIA, PHD STUDENTS, JEFFERIES LAB

Approximately 2 in 5 Canadians will be diagnosed with cancer in their lifetime, and yet we still have a limited understanding of cancer immunity, greatly impacting treatment efficacy (1). One underexplored area is the research into which immune cells help prime and carry out anti-tumour immune responses.

acquire heightened T-cell recruitment and type-1 signatures (C0 and C1) during tumour development (see Figure 1). Other smaller subpopulations showed signatures for antigenpresentation (C6), KLRG1+ inflammatory (C2), IL25R+ memory (C7), and Th1-related (C4) functions, the latter of which may play an important role in effective anti-tumour responses. Interestingly, these clusters changed under different conditions, shifting towards beneficial pro-inflammatory immunity during both tumour development and external IL-33 activation. The identification of these previously unrecognized ILC2 subsets challenges traditional views and underscores the importance of ILC2s in immune surveillance.

In the latest study by the Jefferies lab, we delve into the intricate world of type-2 innate lymphoid cells (ILC2), specifically exploring their plasticity during tumour expansion (2). ILC2s are a recently discovered type of immune cell, conventionally involved in maintaining tissue homeostasis and responding to various environmental challenges such as parasite infection and allergic disease (3,4). The general involvement of ILC2s in the immune response to various tumours has been studied, however their This paper advances our understanding of the specific functions in different tumour types remain role of ILC2s in the context of tumour growth. controversial. Some evidence implicates ILC2s in We discovered and characterized several new the promotion of tumour development, while our ILC2 subpopulations, providing valuable insights lab’s earlier research established that ILC2s play a into the specific mechanism and functions of crucial role in supporting anti-tumour Th1 responses ILC2s in the tumour microenvironment. By by promoting interactions between the innate deciphering the crosstalk between ILC2 and and adaptive components of the immune system. neighbouring immune cells and tumour cells, Additionally, mounting evidence points to a novel we aim to further elucidate the broader impact function for ILC2 in activating cytolytic T lymphocytes, of ILC2 diversity on the overall anti-tumour which aids in the reduction of tumour growth and immune responses and pave the way for metastasis (5,6). To explain these contradictory innovative and effective therapeutic strategies in findings, we proposed that there may be multiple cancer treatment. undescribed subpopulations of ILC2s. To address this, we used single-cell RNA sequencing on lung-derived ILC2s from tumour-bearing mice, and with or without Xia CW, Saranchova I, Finkel PL, et al. A diversity of novel type-2 innate lymphoid cell subpopulations revealed during tumour expansion. Commun external ILC2 activation by the cytokine IL-33. With Biol. 2024 Jan 3;7(1):1–15. the single-cell RNA sequencing approach, we were able to analyze individual cells within a population, obtaining much greater detail on the genetic and transcriptional heterogeneity that can be masked in bulk RNA sequencing methods. Additionally, single-cell sequencing enabled the identification and characterization of rare cell types that might be present in low abundance within a sample.

The results of the study revealed a surprising diversity of novel ILC2 subpopulations. These subpopulations exhibited distinct genotypes which infer different functional characteristics, suggesting specialized roles in the tumour microenvironment. For example, we found populations marked for different phases of cell development: proliferation, transition, terminal, and memory. The main portion of the ILC2s retained conventional type-2 identity while being able to

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Figure 1: Graph-based clustering of ILC2s based on their transcriptional profiles, identifying eight subpopulations of ILC2s.

Some specific populations may have a potential role in antitumor immune responses. Each dot represents a single cell.

CBR alumni: Rhonda Thygesen - Graduate Profile Which lab and what degree were you pursuing at UBC and CBR? What was your research about?

I was in Dr. Leonard Foster’s lab in the department of Biochemistry and Molecular Biology pursuing my MSc. My research was on honey bee health in highbush blueberry crops in the lower mainland. I used proteomics to investigate biomarkers associated with pesticide and pathogen stress in blueberries.

What inspired you to pursue your program?

Rhonda Thygesen

It was my college professors who inspired me to pursue graduate school because I want to pursue a career in undergraduate teaching and mentoring. I also had great mentors through summer work who introduced me to honey bee research and the field of applied science. At the time I wanted to explore a molecular approach to pollinator health and work with a top Canadian researcher, and that’s what brought me to UBC and Leonard’s lab.

What is one piece of advice you would give a new grad student?

My advice would be to take full advantage of the opportunities around you. I got to try so many new experiences during my masters including guest lecturing, writing sci comm articles, attending conferences, and more. There is also so much to do outside of your studies. Make sure your work and life are balanced and do the things you love. For me this meant starting to cycle, learning to climb, improving my skiing, more backpacking than I ever had time to do, and kayaking and trail running becoming key parts of my life. I was encouraged by my supervisor to pursue new opportunities in and out of academia and it truly helped me flourish.

Most memorable part of your graduate student experience?

This is a tough one, I’ve been fortunate to have many great experiences throughout grad school! I will talk about two experiences. I always enjoy the lab trips that Leonard coordinates every summer. I got to go to two trips - one to Mt Assiniboine just outside of Banff, Alberta where we stayed for a week in cabins and hiked or fished by the lake and mountains during the days. We also paddled by sea kayak the Deer Group islands outside of Bamfield, BC and spent the week paddling, relaxing, cooking, and enjoying each other’s company on a white sandy beach. Lastly, in September 2023 myself, Leonard, and one of my closest colleagues from the lab travelled to Santiago, Chile for the Apimondia 2024 conference. We spent 10 days in Santiago while attending the conference and also took time after the conference to head to Cajon del Maipo in the Southeastern Andes, where we stayed for a few days hiking the surrounding mountains and staying in an off-grid cabin overlooking a valley of the Andes. I am grateful for all the experiences and fun times I have had with my colleagues who have now become my friends.

What is your favourite non-academic activity?

I love to adventure outdoors and throughout my masters spent a lot of time finding ways to do that. I am a big backcountry skier and currently am working at a remote backcountry lodge in the Selkirk mountains. I am also a certified kayak guide with the SKAGBC in the summertime. I also trail run, backpack, bike, and climb. If I am not busy doing something outside, I am likely reading or knitting.

Rhonda pictured in front of the mountains

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CD248 Promotes Insulin Resistance by Binding to the Insulin Receptor and Dampening Its Insulin-Induced Autophosphorylation THIS STORY IS REPUBLISHED FROM THE SCIENCE OF VANCOUVER WEBSITE. Science in Vancouver profiled a recent publication in EBioMedicine from the laboratory of Dr. Edward Conway (pictured) at the UBC Centre for Blood Research. Dr. Conway is a Professor of Medicine, Director of the Centre for Blood Research (CBR), and a Scientist at the Life Sciences Institute at UBC.

Can you provide a brief overview of your lab’s current research focus?

The goal of my lab is to delineate molecular mechanisms underlying vascular and inflammatory disorders with a view to developing novel diagnostic and therapeutic approaches.

Our current focus is on characterizing the structure and function of a cell-surface expressed protein, CD248, which promotes inflammation, coagulation, cell proliferation and fibrosis. By using molecular/cell biology techniques and genetically modified mice, in conjunction with human studies, we are aiming to gain new insights into how this protein impacts the risk of developing venous and arterial thrombosis, atherosclerosis, cancer and type 2 diabetes.

What is the significance of the findings in this publication?

Type 2 diabetes (T2D) is a common, chronic inflammatory disorder that is associated with a high risk of vascular disease, stroke, heart disease, kidney failure, retinopathy and cancer. Critical in the development of T2D is the resistance of key organs, such as adipose, liver and muscle, to the activities of insulin. Insulin normally exerts its glucose and lipid metabolic effects by binding to the cell surface-expressed insulin receptor which is thus autophosphorylated, triggering a cascade of intracellular events that maintain metabolic homeostasis. The mechanisms of insulin resistance in T2D are incompletely understood, but have almost entirely been attributed to alterations in insulin-induced signaling pathways inside the cell. These pathways have been challenging to pharmacologically target, which explains why there are currently no drugs that specifically reverse insulin resistance. More accessible therapeutic targets would predictably be of huge value.

We previously showed that CD248 is highly expressed by white adipocytes, with levels that are positively correlated to obesity and insulin resistance in humans. The potential therapeutic relevance was highlighted by our finding that deletion of the CD248 gene in adipocytes and other cells reverses insulin resistance and T2D. Led by PDF Dr.

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Dr. Ed Conway speaking at a CBR symposium.

Patricia Benedet and with the help of many collaborators, we have now extended these observations by delineating the mechanisms by which CD248 promotes insulin resistance, thereby uncovering a novel potential therapeutic strategy.

Using gold-standard insulin clamps in diet-induced insulin-resistant mice, we first showed that a lack of CD248 improves glucose metabolism by enhancing insulin sensitivity in the liver and in white adipose tissue.

The effects of CD248 on insulin-triggered intracellular signaling were then characterized in cell and explant tissues from mice and humans. This led to our finding that CD248 promotes insulin resistance by blocking insulin from binding to the insulin receptor, preventing the latter’s autophosphorylation. Notably, CD248 achieves this via the direct interaction of its extracellular domain with the extracellular domain of the insulin receptor.

The implication of our work is that reversal of the insulinresistant state may be achieved by reducing CD248 expression and/or by blocking the interaction of CD248 with the insulin receptor. That this CD248-insulin receptor interaction occurs on the cell surface provides a uniquely accessible potential therapeutic target to restore insulin sensitivity and to improve metabolic health.

What are the next steps for this research?

We are currently working with colleagues at the CBR and UBC, at the University of Alberta, in the USA and in Sweden to 1. resolve the structures of CD248, the insulin receptor and insulin to identify key sites involved in their interactions,

and 2. to screen for, identify, and ultimately clinically assess compounds that reverse the CD248-insulin receptor interaction and improve insulin signaling and insulin sensitivity.

In addition to the potential of developing a direct therapy to reverse the glucometabolic disturbances of T2D, we are also exploring approaches to reduce the heightened CD248-dependent T2D/obesity-associated risk of cancer, renal dysfunction and vascular disease/ thrombosis.

Insulin receptors (left) and glucose uptake (right). Laser scanning confocal microscopy images provided by Dr. Patricia de Oliveira Benedet, Post Doctoral Fellow, Conway Lab.

This research was funded by: The Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.

Benedet, P.O., Safikhan, N.S., Pereira, M.J., et al. CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation. EBioMedicine (2024).

Members of the Conway Lab.

CBR KUDOS & LAURELS awards, achievements & accolades Dr. Wilfred Jeffries

Dr. Wilfred Jefferies receives 2023 NSERC Discovery Grant The NSERC is investing more than $514 million over five years through the Discovery Research Program. This funding will offer recipients the stability and freedom to pursue promising research avenues as they emerge to build the foundation for innovation and economic growth.

Dr. Hugh Kim

Dr. Hugh Kim – Reach Recipient Dr. Hugh Kim is one of sixteen UBC project recipients that have received new funding from Michael Smith Health Research BC through the 2023 Convening & Collaborating (C2) and Reach programs. This funding will go towards supporting the 2024 World Thrombosis Day event.

Dr. Chris Overall

Dr. Christopher Overall among UBC’s 2023 Distinguished University Scholars Dr. Chris Overall has been honoured as a Distinguished University Scholar at UBC for 2023. Dr. Overall is the first faculty member from Dentistry to receive this distinction! Dr. Overall will receive research operating funds from the Office of the Provost and VicePresident Academic and stipend support.

Read about more awards and accolades at: www.cbr.ubc.ca/category/news/awards/

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Breakthrough in blood clot breakdown treatment The following is a partial transcript of a conversation between podcast host, Chris Smith and CBR scientist, Dr. Christian Kastrup. The Naked Scientists website hosts award-winning science podcasts and science radio shows.

CS: Because in the circulation there’s a sort of dynamic equilibrium, a seesaw in operation where the body’s trying to clot, but at the same time trying to break down a clot.

And so you’ve got the things in balance in the healthy situation. So in someone who has a bleeding disorder like haemophilia, is the seesaw tipped too far one way and you are saying, well, can we try and balance it back up again?

Dr. Christian Kastrup

Chris Smith (CS): Bleeding disorders are very common: some of them affect as many as one person in every one hundred. And in the case of conditions like haemophilia, where blood fails to clot efficiently, which can lead to painful sustained bleeds into joints, internal organs and even the brain, the emphasis on treating the problem has focused hitherto on replacing the clotting chemical factor that’s missing from the blood in affected people.

This often necessitates daily injections. But as Christian Kastrup, at the University of British Columbia has shown this week, we might be able to think about treating this in a different way: rather than making blood clot better, perhaps we can reduce the ability of the blood to break down blood clots, a process driven by an enzyme called plasmin. This is actually activated as soon as a blood clot starts to form. The purpose of this apparently counterintuitive measures is to prevent the clotting system going out of control and blocking blood vessels. So he’s developed a way, using mRNA a bit like the Covid vaccine technology, to temporarily turn down the production of the precursor chemical used to make plasmin in the liver.

The result is a rebalancing of the clotting process…

Dr. Christian Kastrup: During bleeding, what happens in a normal situation, our blood will react and it’ll set off a process where proteins accumulate, then that’s called a blood clot. But the problem is for some people, they don’t have the right proteins in their blood. They might be missing a protein, and so they’re not able to form a really good blood clot. And so that can lead to excessive bleeding. And so what we wanted to do in this study was to come up with a way to control the proteins in the blood to help make that blood clot stronger and help prevent it from getting degraded by the enzymes that would normally degrade blood clots in blood.

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Dr. Kastrup: Yeah, that’s exactly right. Someone with a bleeding disorder, and there’s many different types that can include haemophilia or von Wands disease or many other types of bleeding disorders. It’s hard to form a blood clot in the wound. And sometimes in those cases, the blood clot is not very strong. And so that that balance that you’re referring to, the balance can come into play and the blood clot can be degraded before it’s able to do its job and stop the bleeding. And so what we’re trying to do in this study is to create an agent that can help remove those enzymes that degrade blood clots. And so by doing that, any blood clot that the person’s bleeding disorders will form, even though normally it’d be unstable, we can make it more stable.

CS: It’s effectively then taking some weight off one side of the seesaw. So it does tip the balance back a bit more.

Dr. Kastrup: Yep, that’s exactly right. So we tip the balance away from having too much degradation of the blood clot back to where it’s in balance and the person would be able to form a stable blood clot.

CS: So what is the element or the chemical that you’ve gone for to try to balance things up a bit more?

Dr. Kastrup: The chemical we’ve gone after is an enzyme called plasmin. Plasma’s role in the body is to degrade the clot. And in the clot there’s another protein called fibrin.

And so what plasmin does is it comes in and cleaves fibrin and helps dissolve the blood clot. We wanted to come up with a way to remove some of that plasmin to rebalance the system. Plasma in the enzyme actually comes from this protein plasminogen and plasminogen is circulating in our bodies all the time. But where the blood clots form, that’s where plasminogen leads to plasmin. And so we targeted plasminogen and we target it where it’s made in the liver from messenger RNA. So develop an agent that would degrade that mRNA, which then removes plasminogen from the blood and then prevents the formation of plasmin and prevents excessive degradation of the blood clot.

CS: How long does the effect last for? So if you take an individual or an animal that’s got a bleeding problem, how long can you control it with this technology?

Dr. Kastrup: The advantage of this technology is that it has a really long acting time. So when we do one injection targeting plasminogen, it actually decreases the amount of plasminogen for several weeks.

CS: And how effective is it if you do this in the animal equivalent of haemophilia? For example, can you do what you set out to achieve, which is to rebalance the clotting system so that you don’t have bleeding problems anymore?

Dr. Kastrup: It’s very effective. If plasminogen is normally at a hundred percent, we can take it down to a 5 - 10%. And in animal models of bleeding disorders, it’s really effective at

decreasing the amount of blood loss. And so with animals that have haemophilia A, they would normally bleed a lot more than normal animals. But with this therapy, the amount of time that they’re bleeding for and the amount of blood loss they lose is much less when they’re on the agent.

CS: Is there not danger if you de-power the body’s ability to bust its own clots that there’s a chance you could end up clogging up blood vessels when you don’t want to and you increase the risk of things like a coronary thrombus, a heart attack in other words, or a stroke?

Dr. Kastrup: It’s a really good question for that. We looked really closely at people that actually have deficiencies in plasminogen. It’s a rare condition, but it does occur, and it was really surprising. These patients, they don’t have a risk of thrombosis. They don’t have a risk of getting blood clots. And so what that tells us is if you have just a little bit of plasminogen in your blood, it’s enough to degrade clots when we have a big clot in your blood vessel that shouldn’t be there.

Strilchuk, A.W., Batty, P., Hur, W.S., et al. Lipid nanoparticles and siRNA targeting plasminogen provide long-acting inhibition of fibrinolysis in murine and canine models of hemophilia A. Science Translational Medicine. Accepted and In Press (2024).

You can listen to the full podcast here: https://www.thenakedscientists.com/ articles/interviews/breakthrough-blood-clot-breakdown-treatment Image taken from The Naked Scientists Podcast website.

CBR alumni: Get in touch!

Regardless of when you graduated, we hope that you will keep in touch and stay engaged with us!

Are you a CBR alum who wants to share your experiences, connect with the CBR, have your profile featured, or update your contact information?

Contact the CBR Communications and Programs Coordinator: Kaitlyn Chuong (kaitlyn.chuong@ubc.ca) Visit our alumni page: www.cbr.ubc.ca/alumni

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Canadian Blood Services Announce New Dana Devine Award

BY KAITLYN CHUONG, COMMUNICATIONS & PROGRAMS COORDINATOR

”

Dana Devine was my mother bear. I was a graduate student in a new country cut off from my family due to various circumstances. She is an incredible, supportive, loving human being, an amazing scientist with accomplishments that many dream of and a mentor to many. Her wishes were genuinely to see her students and staff succeed in whatever they chose to do.

That support always came with a smile and a helping hand.

JIHAN MARJAN, PHD

“

Dr. Dana Devine

Canadian Blood Services (CBS) is proud to announce a new award in honour of Dr. Dana Devine to support early career scientists in a field related to transfusion science and medicine, blood banking and blood biotherapies. The award is delivered in partnership with the Canadian Society for Transfusion Medicine (CSTM) and will be announced at the CSTM Annual Conference, where the recipient will deliver a lecture and receive an award in the value of $750.00.

The CBS Dana Devine Award program recognizes promising scientists in a field related to transfusion science and medicine, blood banking and blood biotherapies. The program provides an opportunity for their research to be recognized by the transfusion community and is intended to support their career progression in academia in support of the blood system. More details about the award including the nomination process and application form can be found here.

Dr. Devine is one of the CBR’s founding members and is an integral part of the Centre. She helped write the $15 million Canadian Foundation for Innovation (CFI) grant application that led to the CBR’s creation, along with other founding members Drs. Ross MacGillivray, Grant Mauk, Don Brooks, and Charles Haynes. In addition to her long-time work with the CBR, Dr. Devine held many other reputable positions, including her roles as a professor in UBC’s Department of Pathology & Laboratory Medicine, the chief scientist at Canadian Blood Services, the president-elect of the American Association of Blood Banks (AABB), and the Editor-in-Chief of the blood transfusion journal Vox Sanguinis.

Throughout Dr. Devine’s career, she made countless memories and a strong impact in the lives of many colleagues and students. Several individuals who had the pleasure of working with Dr. Devine shared their experiences with us.

I am so fortunate to have had the opportunity to train under Dr. Dana Devine, a leader in transfusion medicine and a scientist that has shaped the current blood banking system in Canada. Her vast knowledge, wisdom and mentorship has enhanced my overall experience as a trainee in her lab. One of the many special things about Dana was her commitment to her people. Despite the several senior roles she held at various national and international organizations, Dana was always available to her trainees, leaving her door open and welcoming impromptu meetings with excitement and ready to give helpful feedback.

COLTON STRONG, PHD CANDIDATE

”

I feel incredibly fortunate to have been mentored by Dana – a brilliant scientist, a star in transfusion medicine, and an amazing human being. Working closely with Dana for over 30 years, I witnessed her love for encouraging trainees to excel and grow – I can’t imagine a more perfect award in her name than this one. One of my favorite memories of working in her lab? When I was a graduate student, we would set up a small station at the back of the lab and Dana would trim my hair when it got too long, LOL! KATHERINE SERRANO, PREVIOUS RESEARCH ASSOCIATE

“

Dana was my PhD supervisor, and I was privileged to have her as a Board Member on my most recent company. There is no better role model for empathetic mentorship, unwavering dedication, and fearless leadership. Dana is an intellectual powerhouse who inspired generations of trainees and is the standard against which many young scientists have modeled their careers. I am honored to have gotten to train directly under her, and proud of Canadian Blood Services and the Canadian Society for Transfusion Medicine for recognizing Dana’s achievements with an early career discovery scientist award. Congratulations Dana! This is very well deserved.

JONATHAN THON, PHD

Thank you and congratulations to Dr. Devine on her career in transfusion medicine and for the significant impacts she’s made on the field and to the CBR community!

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CBR Spring Magazine - Cover Art Contest (Winner)

Sun(flower) of my heart Eliana Al-Haddad, Administrative Assistant, Jefferies Lab

Description: This is a watercolour painting I created to convey a fusion of the organic and natural world, symbolizing life, growth, and vitality stemming from within.

Cover Art Contest Submissions

Luminous Adiposity During Glucose Uptake

That Sneaky Virus

Dr. Patricia de Oliveira Benedet, Postdoctoral Fellow, Conway Lab

Dr. Georgina Butler, Research Associate, Overall Lab

Nervous Nature

Mouse VSMC Stained for Alpha SMA

Is that Boba or Champange?

Dr. Nasrin Zohreh, Research Associate, Cheung & Kizhakkedathu Lab

Nooshin Safikhan, Research Assistant, Conway Lab

Dr. Marine Theret, Postdoctoral Fellow, Rossi Lab

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BIOCAPS Spotlight: Marija Vuckovic Marija is a laboratory manager at the Strynadka lab in the department of Biochemistry & Molecular Biology at the University of British Columbia. She completed her B.Sc. and M.Sc. in Biochemistry at the University of Belgrade, Serbia and moved to Canada in 2002. In 2003, she joined Natalie Strynadka’s Lab as a Research Assistant and have since worked on numerous projects and publications. She possesses extensive experience in conducting protein over-expression across a broad range of bacterial cells (BSL1- E. coli; L. lactis, and BSL2-Salmonella Typhimurium; SAUSA300; EHEC; EPEC), as well as in yeast, insect, mammalian cell, and cell-free expression systems.

Employing a blend of molecular biology and structural biology techniques—including X-ray crystallography and cryo-electron microscopy (cryo-EM)—she has played an instrumental role in determining the structures of various type 3 secretion and bacterial cell-wall membrane spanning protein complexes.

Marija Vuckovic

Tell us about your current research focus and project.

Alongside numerous other members of the Strynadka Lab, I have dedicated many years, even to this day, to depicting the structure and function of the type 3 secretion system, essential for the virulence of many disease-causing Gram-negative bacteria including Salmonella typhimurium, Shigella dysenteriae, Enteropathogenic Escherichia coli (EPEC) and Pseudomonas aeruginosa. T3SS is a syringe shaped nanomachine composed of more than 20 proteins, that allows the specific and direct transport of bacterial virulence effectors across three membrane bilayers, delivering them from the cytoplasm to human host cells.

My additional research focus revolves around broad-spectrum B-lactam antibiotic resistance in Staphylococcus aureus, a prominent cause of infections globally. In clinical strains, resistance is primarily regulated by BlaR1, a two-component signaling receptor responsible for sensing B-lactams. It operates by directly cleaving the repressor BlaI, thereby inducing the expression of B-lactamase and the B-lactam-resistant transpeptidase PBP2a. The structure of S. aureus BlaR1 has been unclear since the gene’s initial identification over 30 years ago. Our lab has recently published the first high resolution cryoEM data that reveals the structure and advances our understanding of BlaR1-mediated antibiotic resistance. This work provides insights into the mechanism of BlaR1 signal transduction, potentially facilitating the development of therapeutics to treat drug resistant MRSA infections.

What first motivated you to pursue your career?

What got me into biochemistry was the excitement of learning about life’s inner workings. I wanted to dig deep into cells and molecules to find ways to help people. The idea that my work could potentially make a difference in addressing significant health challenges is incredibly fulfilling and motivates me every day.

What do you like most about your job?

What I like most about my job is that no two days in the lab are the same, each bringing the possibility of doing something new. One day I might be conducting an exciting experiment to uncover a small piece of the antibiotic resistance puzzle, another day I might be optimizing PCR to ensure successful cloning, or on yet another day I might be troubleshooting a broken piece of equipment or receiving training on a brand-new one.

Another highlight of my job is working with passionate young students who possess the same drive and dedication towards research as me. I do my best to assist and train them throughout their journey in the lab by addressing their many inquisitive questions. Despite the difference in age and having many duties to juggle, I still somehow manage to keep up with them.

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What is your favourite place to visit?

Despite having traveled to various places, Costa Rica holds a special place in my heart. The friendly and welcoming locals, along with the incredible and diverse wildlife, create a truly amazing atmosphere that enhances every experience. Its rich biodiversity, encompassing lush rainforests, stunning coastlines, and numerous volcanoes, is definitely a sight to behold.

Learning Spanish and immersing myself in this blend of human warmth and diverse animal life has made each of my visits to Costa Rica truly unforgettable.

Marija is literally the heartbeat of our laboratory. Over the past two decades, every group member has been elevated by the amazing expertise, energy and kindness she brings to her role as wet lab manager.

”

DR. NATALIE STRYNADKA, CBR PRINCIPAL INVESTIGATOR

What advice would you give to a trainee just starting out?

I love cloning, and despite conducting various research and experiments, cloning has always been my niche. You can’t be the best at everything, so stay open-minded and allow yourself the freedom to explore until you discover that specific area or topic where you feel most comfortable and excel in it.

This story is republished from the Department of Biochemistry & Molecular Biology website: https://biochem.ubc.ca/biocaps-spotlight-marija-vuckovic/.

Photo of the Strynadka Lab taken from their website.

We would like to thank the Naiman-Vickars Endowment Fund, Canadian Blood Services & The Faculty of Medicine for their continuous support, without whom the Norman Bethune Symposium and many CBR Programs would not have been possible:

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Centre for Blood Research 4th Floor, 2350 Health Sciences Mall Vancouver, BC Canada V6T 1Z3 www.cbr.ubc.ca