CMMT Newsletter March 2023

The Space in Between

Seth Parker, an Assistant Professor in the department of Biochemistry and Molecular Biology at UBC, arrived at CMMT to set up his own lab in 2020, on the heels of Covid 19. Fresh from New York, where he was a postdoctoral fellow at New York University School of Medicine, Dr. Parker studies the metabolism and transport of specific metabolites in cancer.

Now an investigator in the UBC Faculty of Medicine, Dr. Parker and his lab are working to identify and characterize specific transporter proteins that are required by cells to fulfill their metabolic needs. Within this objective, they are investigating the “space in between” that are the mechanisms that drive selective transporter expression in disease, how transporters function in specific physiological contexts, and how they may target the unique metabolic demands of cancer for possible therapeutic development.

Ironically, Dr. Parker admits that it was originally outer space, rather than the smallest of inner spaces that first drew him to science. “As a child I liked space and I still do,” he said. “I wanted to be an aeronautical engineer, which led me down the engineering path, which was my focus for my undergrad and PhD.” Somewhere along the line he changed to chemical engineering, noting that he was likely influenced by his mother who was studying to be a nurse while he was still in high school.

It was during a summer research program offered at the University of Colorado Anschutz Hospital in Aurora, Colorado, that Dr. Parker became interested in cancer research. He was connected with a biochemistry faculty working on ubiquitination in cancer. “I really liked it and continued working there for the next three years,” he said. One thing led to another and he found his way to Dr. Christian Metallo’s lab which was doing research into cancer metabolism. “It my first foray into mass spectrometry and cancer metabolism research and that’s what I’ve been involved with since then.” He completed his PhD in bioengineering, and under Dr. Metallo he engineered new methods to study cancer metabolism. Dr. Parker then went on to do his post-doctoral degree under Alec Kimmelman at NYU School of Medicine.

While there, Dr. Parker published a paper in Cancer Discovery, that revealed a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC), a disease with a 5-year survival rate of approximately 10%. Together with Dr. Alec Kimmelman, they’ve shown that the amino acid transporter SLC38A2 is pivotal in PDAC tumor growth and may be a viable therapeutic target not only in PDAC but also, potentially, in other types of cancer.

“During my postdoctoral fellowship I was influenced by a paper published by my postdoc advisor before I started in his lab,” Dr. Parker said. He had found that non-cancerous cell types in pancreatic tumours exchanged nutrients to PDAC cells to help them thrive. “That changed my perspective and I began thinking about the tumour microenvironment and how other cell types share nutrients,” he said. He found that the one nutrient that was exchanged between different cell types and the tumours was the amino acid alanine, which became the focus of his postdoctoral work, and ultimately, the paper published in Cancer Discovery. “We found transporter protein SLC38A2 had very strong effects on tumour cells and how they metabolised alanine,” he said. “So our focus changed from characterizing the exchange mechanisms to investigating SLC38A2 as a therapeutic target.”

As a result of their work, Dr. Parker and Dr. Kimmelman received a drug discovery award from the Mark Foundation, the purpose of which is to identify first-in-class small molecule inhibitors that target SLC38A2.

Most recently, Dr. Parker received a CIHR Project Grant to delve deeper into metabolism and amino acid transport in PDAC. “This is helping us study why these tumour cells are so dependent on alanine, and what population of patients would benefit from an inhibitor,” he said. “We’re trying to figure out what makes these cells so vulnerable to this target. There could be some similarities to other tumour types as well. So the grant is for basic science to try and understand alanine metabolism in these cells and develop a model system to apply our findings further.”

While things are running smoothly now, moving countries and setting up a brand-new lab during a pandemic was not without its challenges. “I accepted the position in January 2020 right before the pandemic,” Dr. Parker said. Many bureaucratic processes halted once the pandemic began, so getting into Canada from New York took some time. “My wife and I sent all our belongings to Canada before we had work permits. We were living out of suitcases,” he said. But the timing worked out in the end. “It actually worked out perfectly with respect to quarantines and getting an apartment.”

When Dr. Parker is not in the lab, he enjoys rock climbing and has found some good local sites and also enjoys climbing in a gym setting. “I find climbing more social than doing a sport on your own. It was kind of hard to find people to go with initially, but in winter you can’t go outside but you can still rock climb indoors.” So that leaves time for him to brew his wine and beer. A great winter pastime, and a little light engineering.

A Novel Opportunity

The evolution of personalized genomic medicine is potentially transformational, opening many new fields of research. One area of particular interest to Paola Arguello Pascualli is the genetic data used to measure health outcomes. A PhD student in medical genetics, co-supervised by Dr. Jessica Dennis and Dr. Mike Kobor, Paola’s work involves investigating associations between ancestrally informed polygenic scores and health outcomes in diverse populations, with extensions to other health-relevant biomarkers, such as epigenetic clocks. Born and raised in Mexico, Paola brings a unique perspective to her studies, that of the Latin population which, it turns out, is under-represented in most of the data used in biomedical sciences. She realizes that this situation presents a novel opportunity for research and one in which she is personally invested.

“The more I learned in the classroom, the more I realized that much of the knowledge we have today comes from male populations and those of European ancestry,” Paola said. “Even when I spoke with a friend in medical school in Mexico she told me they use old standards of practice for diagnoses based on data that may not be translatable to Latin populations.” For example, when she began her PhD, Paola came across a condition known as ethnic leukopenia, which refers to low levels of white blood cells. “The threshold is set in European-descent populations, so it doesn’t mean those lower levels are clinically relevant, they are just lower than the reference,” she said. “This is a medical condition that doesn’t say anything about your health, just your ethnicity. I didn’t know this until I started my PhD. I felt that if I did research using data from people with European ancestry I would be contributing to the biases. I knew I had to do better.”
 
Because epigenetic epidemiology is a relatively new field, Paola is starting pretty much at ground zero.  “I had to go back to genetics to see what people are doing to understand the inherent human variation across different ancestries and how that could affect our estimations, she said. “We often don’t think about genetic ancestry and ethnicity when we do research, but it is very important in medical research. When we include that information as part of the picture it can help us to understand the effect of our environment on our genes and how variation works.”
 
It was Paola’s inherent curiosity that led her to a career in science and this particular area of research. “I’m a very curious person,” she said. “I always like to ask questions. Science gave me a way to keep asking questions and showed me how much fun finding the answers can be. I learned it was okay to ask questions and if there’s data, I can find an answer.”
 
Having completed a degree in Genomic Sciences at the National Autonomous University of Mexico, Paola found the medical genetics program at UBC, and Dr. Michael Kobor’s lab. “He is looking at how the environment gets under our skin,” she said. She has now been at the CMMT for three years, through the Covid 19 pandemic, which has proved insightful. “I received the Friedman Award for Scholars in Health, through UBC, and it allowed me to do two internships, one in the USA and other in Mexico, which I just completed,” she said.  During her internship in Mexico she focused on the specifics of genetic admixture in Latin populations. The internship in California focused on the epidemiology of health disparities and underrepresented populations.
 
The internships were planned and funded pre-Covid. “During Covid I had to change my travel plans but I was able to travel to Mexico once I had received my first Covid 19 vaccine,” she said. “Being in different places during the pandemic made me aware of the differences between our health care systems and helped me realize that Latin communities are underserved in many areas of research.  It gave me context for why I want to do what I do.”
 
Paola hopes to go back to Mexico to continue her work in the future. “There is the Mexican Institute for Medical Genetics, where the focus is Latin populations. The research is not as supported as it is here which puts us at a disadvantage” she said. “I hope to go back to Mexico one day and contribute to the knowledge that will serve my community.”
 
When Paola is not traveling or working, she loves to go for long walks with her dog Luna. “My dog is my pastime.” Paola has ADHD and she is very open about it. “I hope that sharing with people helps to remove some of the stigma attached to ADHD and other mental health conditions,” she said. “We can achieve all the same things as our neurotypical peers, we just need different support to get there.” Her dog is an emotional support animal and Paola is training her to be her psychiatric service dog. “I am learning how to train her so we are always teaching each other.”

Teaching by Example

Abisola Kehinde is modern day scientist with a clear sense of purpose. Currently a PhD Student at Seth Parker’s lab at BC Children’s Hospital Research Institute and UBC, she is interested in how nutrients and their transporters can be used to mitigate or treat metabolic diseases. Originally, she wanted to go to medical school, but as fate would have it, biochemistry became the way forward.

Born and raised in Lagos, Nigeria, Abisola says it was the influence of her science teacher that led her to pursue a career in science. “I naturally enjoyed biology in high school. Our teacher was amazing, he would take us through science in a very exciting way,” she said. “However, as students, we weren’t aware of how science can change the world. All myself and my peers knew was that if you are very good at science you can study medicine. I wasn’t exposed to other avenues of study, and solving other problems in science,” she said. As it turned out, the queue to get into medical school was prohibitive. “Not everyone makes it in,” she said. “I was given biochemistry and that’s when I realized how interesting it is.”

Having completed her Bachelor of Science at Lagos State University where she studied plant biology, Abisola travelled to UBC, Kelowna campus in 2019 to do her Masters degree. She worked on developing by-products from breadfruit, which proved to be a bit of a watershed experience. “In Nigeria we have a limited number of research labs so I was never really exposed to some cutting edge techniques,” she said. “During my masters I had to develop methods and apply cutting edge techniques to solve research problems, and I was fascinated by this.”
 
Not surprisingly, when she moved to Vancouver in 2021 to pursue her PhD, Abisola became interested in Seth Parker’s research looking at nutrient biochemistry and their transporters as they relate to cancer cells. “When I read about Seth and his mind-blowing research in cancer, I realized I also want to study cancer cells and work towards the development of effective treatments for different types of cancer. It was very exciting to consider being able to contribute to cancer research,” she said. She approached Seth and was accepted into the PhD program to study metabolic disease. Her current research is aimed at tracking the metabolism of nutrients such as amino acids in cancer cells and tumors with a view to possible development of a therapeutic strategy to inhibit those nutrients in such a way that only affects the cancer cells. That’s cutting edge.
 
In her free time, Abisola likes to share her knowledge and enthusiasm with other female science students. Abisola has volunteered for UBC’s Let’s Talk Science and is currently the vice president of a Muslim students’ club. “I like to volunteer, and I like to inspire women to do science,” she said. “I interact with a lot of woman and undergrads,” she said. “There are students that don’t know about Masters degrees and PhDs and they don’t know how to navigate graduate school. I like to talk to them and motivate them to do graduate school. I like volunteering for equity, diversity and inclusion EDI groups and encourage them to enjoy whatever they’re doing in their undergrad programs.”
 
As for the future, Abisola’s goal is to become a professor in her field and teach. What better way to start than teaching by example.

In Pursuit of Treatment for a Neurodevelopmental Disorder

Pyridoxine (or vitamin B6)-dependent epilepsy (PDE) is a rare epileptic and neurodevelopmental disease. Children affected with this disease suffer drug-resistant epileptic seizures and neurodevelopmental disabilities, along with brain morphological abnormalities in some cases. The first reported case of PDE goes back to 1954 when an infant with intractable convulsions was, accidentally, found to respond to treatment with pyridoxine. The term “pyridoxine-dependent” was hence used to describe this phenotype. It wasn’t until more than half a century later when scientists were able to decipher the genetic defect underlying this disease and its relation to pyridoxine. It was found that PDE is caused by mutations in a gene known as antiquitin or ALDH7A1. The gene codes for an enzyme that catalyzes an intermediate step in the lysine catabolism pathway in brain. Dysfunction of this enzyme leads to buildup of specific lysine metabolites in tissues and biofluids which have been utilized as diagnostic biomarkers for PDE. One of the accumulating metabolites spontaneously condenses with the biologically active form of vitamin B6 (pyridoxal 5’-phopshate), leading to depletion of this important cofactor for neurotransmitter synthesis. 

As more PDE cases are published, it has become evident to scientists that pyridoxine treatment does not prevent accumulation of the presumably neurotoxic lysine metabolites and, consequently, the majority of patients still suffer neurodevelopmental deficits despite seizure control with pyridoxine. Progress in understanding disease biology and devising more effective treatments have been hampered by the lack of appropriate animal models. Working towards filling this gap during my PhD research in the Leavitt Lab, I have generated and characterized the first mouse model for this disease. The model recapitulated the biochemical and clinical seizure phenotypes seen in human patients.  In addition, it showed remarkable amenability to dietary manipulations where the severity of the phenotype can be fine-tuned by the amount of lysine in the diet.

During my postdoc fellowship my focus has been to carry out more in-depth characterization of the disease pathophysiology and to devise effective therapies for this treatable inborn error of metabolism. Because of its success, the model has received multiple research grants that collectively are worth over $1M. We currently have four therapeutic study trials in mouse models that target pathogenic metabolites. These trials encompass a diverse set of strategies including upstream enzyme inhibition, lysine uptake inhibition using amino acid supplementation, enzyme substitution therapy and pharmacological inhibition of the lysine pathway using a drug that was discovered by high-throughput screening in patient cells. Recent data collected from the amino acid supplementation trial showed promising results in which the pathogenic metabolites were significantly reduced in the brains of treated mice by up to 75% compared to untreated mice.  

My short and sweet journey in the CMMT has culminated successfully in getting an assistant professor position at the top university in my home country (Oman). I will be soon moving to the new university to start a new chapter of my academic career and life. Inspired by my enriching experience at the CMMT and Leavitt Lab, I am planning to establish my own research lab there while continuing to collaborate on the ongoing PDE research here.

Publications

Roussakis AA, Gennaro M, Gordon M, Reilmann R, Borowsky B, Rynkowski G, Lao-Kaim N, Papoutsou Z, Savola J, Hayden MR, Owen D, Kalk N, Lingford-Hughes A, Gunn R, Searle G, Tabrizi S, Piccini P. A PET-CT study on neuroinflammation in Huntington’s patients participating in a randomised trial with laquinimod. Brain Communications. In press.

Cutts A, Chowdhury S, Ratkay L, Eyers M, Young C, Namdari R, Cadieux J, Chahal N, Grimwood M, Zhang Z, Lin S, Tietjen I, Xie Z, Robinette L, Sojo L, Waldbrook M, Hayden MR, Mansour T, Pimstone S, Goldberg Y, Webb M, Cohen C. Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1 (DMT1): Preclinical Efficacy Against Iron Overload and Safety Evaluation. J Pharmacol Exp Ther. In press.

Mackay JP, Smith-Dijak AI, Koch ET, Zhang P, Fung E, Nassrallah WB, Buren C, Schmidt M, Hayden MR, Raymond LA. Axonal ER Ca2+ Release Selectively Enhances Activity-Independent Glutamate Release in a Huntington Disease Model. J Neurosci. 2023 Mar 21:JN-RM-1593-22. PMID: 36944490

Darpo B, Geva M, Ferber G, Goldberg YP, Cruz-Herranz A, Mehra M, Kovacs R, Hayden MR. Pridopidine does not significantly prolong the QTc interval at the clinically relevant therapeutic dose. Neurol Ther. 2023 Feb 22. doi: 10.1007/s40120-023-00449-w. Online ahead of print. PMID: 36811812

Joachimiak P, Ciesiolka A, Kozlowska E, Switonski PM, Figura G, Surdyka M, Kalinowska-Poska Z, Figiel M, Caron NS, Hayden MR, Fiszer A. Precise allele-specific quantitation of ATXN3 and HTT transcripts in polyQ disease models. BMC Biol. 2023 Feb 1;21(1):17. PMID: 36726088

Lemarié F, Sanders SS, Nguyen Y, Martin D, Hayden MR. Full-length huntingtin is palmitoylated at multiple sites and post-translationally myristoylated following caspase-cleavage. Front Physiol. 2023 Jan 13;14:1086112. doi: 10.3389/fphys.2023.1086112. eCollection 2023. PMID: 36711022

Engelbrecht H.R., Merrill S. M., Gladish N., MacIsaac J. L., Lin D. T. S., Ecker S., Chrysohoou C.A., Pes G.M., Kobor M.S., and Rehkopf D.H. (2022). Sex Differences in Epigenetic Age in Mediterranean High Longevity Regions. Front Aging. 3:1007098. 

Hernandez Cordero A.I., Yang C.X., Li X., Yang J., Shaipanich T., MacIsaac J.L., Lin D.T.S., Kobor M.S., Horvath S., Man S.F.P., Sin D.D., and Leung J.M. (2022) The Blood DNA Methylation Clock GrimAge Is a Robust Surrogate for Airway Epithelia Aging. Biomedicines. 10:3094. 

Hernandez Cordero A.I., Li X., Yang C.X., Yang J., MacIsaac J.L., Dever K., Kobor M.S., Milne S., van Eeden S.F., Shaipanich T., Lam S., Leung J.M., Sin D.D. (2023) Systemic and Airway Epigenetic Disruptions Are Associated with Health Status in COPD. Biomedicines. 11:134. 

McGreevy K.M., Radak Z., Torma F., Jokai M., Lu A.T., Belsky D.W., Binder A., Marioni R.E., Ferrucci L., Pośpiech E., Branicki W., Ossowski A., Sitek A., Spólnicka M., Raffield L.M., Reiner A.P., Cox S., Kobor M.S., Corcoran D.L., & Horvath, S. (2023). DNAmFitAge: biological age indicator incorporating physical fitness. Aging. 15: 10. Online ahead of print. 

Fu M.P., Merrill S.M., Sharma M., Gibson W.T., Turvey S.E., & Kobor M.S. (2023) Rare diseases of epigenetic origin: Challenges and opportunities. Frontiers in genetics. 14: 1113086.  

Feil D., Abrishamcar S., Christensen G. M., Vanker A., Koen N., Kilanowski A., Hoffman N., Wedderburn C. J., Donald K.A., Kobor M.S., Zar H.J., Stein D.J., & Hüls A. (2023) DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort. Clin Epigenetics. 15: 31. 

Chen J., Gatev E., Everson T., Conneely K.N., Koen N., Epstein M.P., Kobor M.S., Zar H.J., Stein D.J., & Hüls A. (2023) Pruning and thresholding approach for methylation risk scores in multi-ancestry populations. Epigenetics. 18: 2187172.

Biasibetti-Brendler H., and Kobor M.S. (2023) Epigenetics. In Eisenstat D., Yager J., Oberlander T., Goldowitz D. (Eds). Neurodevelopmental Pediatrics: Genetic and Environmental Influences. 123-145. Book Chapter.

Awards & Congrats

• Michael Kobor
  2^nd place in the 2022 IHDCYH Talks Video Competition, “The role of the exposome in health throughout the life course”, CIHR

• Wyeth Wasserman
  UBC Killam Research Fellowships

• Stefan Taubert
  CIHR Project Grant, “Genetic mapping of a stress response and pro-longevity network in C. elegans and human cancer cells”

• Wyeth Wasserman & Mahmoud Pouladi
  CIHR Operating Grant – PA: Genetics (Bridge Funding: Research Priorities), “Deep Learning-Based Design of Synthetic Promoters for Oligodendroglia-Specific Expression”

• Wyeth Wasserman & Bruce Verchere
  CIHR-JDRF Type 1 Diabetes and Precision Medicine Team Grant, “Precise Treatment for Pediatric Diabetes: Providing the right care, for the right patient, at the right time, over time”

• Theresa Williams
  CMMT TG Facility Lead has won a travel award from CALAS Pacific Chapter to travel to the Annual Symposium in May

• Pardis Kazemian
  BCCHRI BB&D Theme Trainee Boost award

• Jessica Dawson
  BCCHRI BB&D Theme Trainee Boost award

• Paula Littlejohn
  Triangle AMPLIFY award, Research fellow 2023-2025

Fun Facts

• The Titanic sank on April 15, 1912. 
• May is the only month that does not begin or end on the same day of the week as any other month in any year. 

• June 27, 1859 – The song “Happy Birthday to You” was first sung. 
• The king of hearts is the only king without a moustache. 

• Elephants are the only mammals that can’t jump. 

Our next newsletter will be released July 2023. Submit storyline suggestions to media@cmmt.ubc.ca by July 15, 2023. Submit awards, events, publications, kudos, etc. to media@cmmt.ubc.ca by July 15, 2023.

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