Dr. Peter Roy, principal investigator of the Roy Lab and professor at the University of Toronto, describes his projects using the worm (Caenorhabditis elegans), the development of a drug discovery platform, and recent transition to yeast (Saccharomyces cerevisiae) in the search of small molecules that combat pathogen-borne diseases.

Alisha Imtiaz, Katie Bui, and Samiksha Babbar

In the last decade alone, human populations have increased by one billion individuals, with the United Nations predicting a rise to 10 billion by 2080^1,2. This trend raises concerns about food scarcity, water stress, and the spread of pathogen-borne illnesses that threaten human, plant, and animal health worldwide. Currently a failure rate of over 96% has been observed in drug development, with 90% of drugs failing during clinical development³. Finding novel targets in pathogens affecting humans, agriculture, or animals in a timely manner has therefore become more crucial in recent years. To address this need, researchers have been screening large numbers of small molecules for a desired effect, making it a popular approach for novel drug discovery. Hence, tools that can increase the speed of screening are especially valuable, as they enable efficient and economically feasible drug discovery⁴.

Increasing population sizes demand increased resources and subsequently cause a rise in global disease burden. This risk is further amplified by the existence of parasitic nematodes, microscopic roundworms affecting more than one third of the human population through their effects on crops and domestic animals⁵. This highlights the growing need for nematicides, drugs that can kill or control nematode populations. One such story of this drug discovery hunt originated in 1993 with the soil-dwelling, non-parasitic nematode, Caenorhabditis elegans, also referred to by scientists as “the worm.” Dr. Peter Roy, a PhD student at the time, used the worm as a model organism to study neural axon guidance and migration, and soon found a life-long interest in leveraging its potential. More than twenty years later, Dr. Roy now works as a professor in the Molecular Genetics department at the University of Toronto and leads an independent lab in the Donnelly Centre for Cellular and Biomolecular Research. “I have worked with the worm for over 33 years,” says Dr. Roy. “It being an animal, having exceptional genetic power is what I was passionate about when I started with it and is exceptionally useful still.” His research group has seen multiple discoveries and publications emerge from this one-millimeter worm and has been able to secure substantial research funding focused on small-molecule discovery.

Figure 1 | Dr. Peter Roy, PhD. Professor at the University of Toronto, Dept of Molecular Genetics, Dept of Pharmacology and Toxicology, Donnelly Centre Member, Canada Research Chair in Chemical Genetics. Picture provided by Dr. Peter Roy.

Novel Nematicide Discovery using C. Elegans

Recently, Roy posed a provocative question in his first invited review: “Why would anyone want to screen drugs against the model nematode Caenorhabditis elegans?”⁴ In the era of drug discovery using advanced approaches in gene editing and complex model systems, we can often still rely on the worm’s unique biological abilities as a subject of small-molecule research in labs. Some of these include: a life cycle of three days, the lack of need for a host, and asexual reproduction. According to Roy’s review, the most common subject areas that use C. elegans for drug discovery are aging and longevity, neurobiology, and antimicrobials. For drug screening, these features are important because they enable analysis across all life stages with minimal cost and time investment. High-throughput screens can test thousands of molecules at once, and therefore many of the benefits in the simplicity and cost efficiency of C. elegans make it a suitable tool⁴.

Figure 2 | Picture of a strain of Caenorhabditis elegans where the nervous system glows red, highlighting its unique neurobiology. Picture from Peter Roy, Ashwin Seetharamin and Rachel Bagg.

The use of C. elegans as both a model organism and a screening platform has launched the Roy lab’s key nematicide projects. Dr. Roy’s work with the worm focuses on screening small molecules in a high throughput or large scale fashion, with the focus of finding nematicides that may be toxic to the worm’s normal functionality. This work on small molecule screens was a natural shift from Roy’s early developmental work on the worm. As he describes it, “The projects and main interests of the lab are a bit like a raft on the river. We often just follow the river, we do not invent a new river.” These projects were built from his own research, as well as the ideas of his colleagues and other researchers using the worm. The lab has added to this “river” of ideas for almost a decade, producing novel papers on potential compounds and their molecular mechanisms.

One such project led to the identification of three novel molecules belonging to the class of imidazothiazoles, double-ringed compounds that have previously been used in a range of pharmaceutical contexts for their anti-cancer and anti-inflammatory effects^1,6. Roy’s team discovered that these candidate nematicides require metabolic activation by nematodes to become toxic, and that this is the key mechanism  of nematode death. The identification of imidazothiazoles that can function as nematicides can benefit parasite control in crop production¹. There is also potential utility in the health of humans, livestock, and domestic animals^1,6.

A Surprising Twist with Cytochrome P450 and Yeast

Studying the mechanism of action for imidazothiazoles became an interesting development for the lab. Andrew Burns, a post-doctoral fellow in the lab, discovered that this compound was actually made toxic to the worm, or “bioactivated,” by cytochrome P450 (CYP450)¹. CYP450s are a family of proteins found across all kingdoms of life, including humans, and are involved in the metabolism of both foreign and endogenous compounds⁷. Generally, they detoxify their substrates, but sometimes they can also heighten the biological activity of a relatively inert compound, making it toxic. This was an interesting notion for the Roy lab and further motivated another student to express the nematode-specific cytochrome P450 in yeast (Saccharomyces cerevisiae) to test whether incubating with imidazothiazoles would similarly lead to bioactivation. The results were positive, and indicated that the yeast expressing P450 enzymes from a specific organism can model how that organism metabolizes a given compound.

Yeast are also relatively inexpensive to cultivate, making them especially well-suited for high-throughput assays. This benefit marks a transition from working primarily with the worm to incorporating yeast into the lab’s screening strategy and raises an important question: can this approach be generalized to other organisms, and does it have real-world utility?

It turns out the answer is yes. Brittany Cooke, a PhD student in the lab, expressed a mosquito P450 in yeast and screened molecules with hopes of finding those selectively bioactivated by this mosquito-specific P450. The global burden of mosquito-borne diseases has been rising in recent years, with an estimated 390 million people worldwide affected by dengue virus alone⁸. Despite this rise, standard vector-control protocols are facing threats as mosquitoes evolve resistance to widely used insecticides. CYP450s have been implicated in this increasing resistance because they metabolize insecticides at a faster rate⁹. Roy states that by “exploiting the fact that resistant mosquitoes upregulate P450s, making them hypersensitive to new compounds,” they can identify those that become lethal specifically in resistant mosquitoes and leverage their own mechanism of resistance against them.

With this project, the lab aims to discover novel insecticides effective in managing mosquitoes carrying malaria, Zika virus, dengue and other diseases. Implementing these experiments with  yeast has contributed to the development of a novel, massively paralleled drug and pesticide screening technology called PEXIL^TM (Figure 3). This outstanding project contributed to Dr. Roy receiving the inaugural Derrick Rossi Innovation Award, recognizing the potential of this idea. “Nothing comes out of thin air,” Roy states when speaking about the development of his ideas and this is clearly apparent as the lab continues to build on previous findings.

Figure 3 | P450-driven toxification is assessed in the PEXIL^TM assay using a mixed population of yeast strains, each engineered to express a different P450 from an organism and identifiable by a DNA barcode. When these yeast are incubated with small-molecule libraries, differences in yeast fitness indicate P450-dependent toxification. Adapted on BioRender from¹⁰.

Working with Different Model Organisms

            Making the decision to work with multiple organisms is challenging, but can certainly pay off. Roy echoes this sentiment as he says, “The key to any model organism is to recognize its strengths and figure out ways to circumvent its weaknesses.” Every model organism has its specific protocols, strengths, and weaknesses that require the right resources, time, and effort from team members.

Despite working with the worm for over 30 years, Roy recognizes that no model system, even the worm, is perfect. Deciding which model organism to focus on depends on the biological relevance, scientific question, cost, time, and scalability. “We are reaching the last few publications with C. elegans, and understanding the power of this organism [yeast] was powerful enough to move away from the worm.” Yeast provides a simple, scalable platform to determine whether a compound is activated by a specific P450 before progressing to more complex organisms. Working with yeast for a drug-discovery assay like this highlights its strengths as a model system since high-throughput screening may not be possible with complex organisms such as insects.

Science is a Team Sport

Dr. Roy does not shy away from leveraging collaboration in his search for new small molecules, as reflected by his many papers with groups within the department and abroad. One of his main motivations, he explains, is that “the technologies and tools we use allow you to make connections in genes and biologies for which you may not be an expert in, or for which your model system may not be best suited. It’s really a marriage of convenience and quite a fun process.” His approach to research has always been to motivate connections with others; whether with a mentor, a colleague, or a trainee, he sees the complexities of genetics as problems best tackled through a collaborative approach.

When asked about the crucial transition from working with the worm to working with yeast, Roy credited the collegial atmosphere within the Molecular Genetics department in the Donnelly Center. He emphasized the invaluable support of researchers including Charles Boone, Brenda Andrews, and Leah Cowen in helping the Roy lab get accustomed to working with yeast. Their expertise in yeast facilitated his lab’s efforts to adapt and refine PEXIL^TM as a technology.

For students and scientists making their way into the field, Dr. Roy emphasizes that the key ingredients for scientific discovery in genetics are time, effort, and guidance. Projects in his lab are not discovered by luck but are the culmination of deep thought and experimentation from every member of the team. In both clinical and research settings, he compares genetics to solving a puzzle: finding those key pieces that fit can be frustrating at times, but they reveal a rewarding process that fulfills aspects of the bigger picture.

             Dr. Roy’s demonstrated approach to using model organisms, understanding their trade-offs, and transition into yeast  exemplifies  a highly optimized approach for small-molecule screening. These discoveries translate into applications that address overpopulation, risks to human health, and food scarcity, which Roy remains passionate about contributing to. From a conversation with Roy, it is clear that his interests in genetics are always through a utilitarian approach, with a personal goal of ensuring his research helps address real-world problems. Together, his discoveries underscore how genetics, collaboration, and innovative use of model systems can help protect human health and address emerging threats. Roy emphasizes this  same philosophy as he states, “I am motivated to give back to the world in some real way. It’s not to say that one approach to research is better than the other; we are all trying to impact the world.”

References

1.     Burns, A. R. et al. Selective control of parasitic nematodes using bioactivated nematicides. Nature 618, 102–109 (2023).

2.     Tilman, D., Balzer, C., Hill, J. & Befort, B. L. Global food demand and the sustainable intensification of agriculture. Proc. Natl. Acad. Sci. 108, 20260–20264 (2011).

3.     Hingorani, A. D. et al. Improving the odds of drug development success through human genomics: modelling study. Sci. Rep. 9, 18911 (2019).

4.     Roy, P. J. Drug screens using the nematode Caenorhabditis elegans. GENETICS 231, iyaf141 (2025).

5.     Hunter, M. C., Smith, R. G., Schipanski, M. E., Atwood, L. W. & Mortensen, D. A. Agriculture in 2050: Recalibrating Targets for Sustainable Intensification. BioScience 67, 386–391 (2017).

6.     Ali, I., Lone, M. N. & Aboul-Enein, H. Y. Imidazoles as potential anticancer agents. Med. Chem. Commun. 8, 1742–1773 (2017).

7.     Hossam Abdelmonem, B. et al. Decoding the Role of CYP450 Enzymes in Metabolism and Disease: A Comprehensive Review. Biomedicines 12, 1467 (2024).

8.     Damian, D. Mosquito‐Borne Viruses of Clinical Significance. Health Sci. Rep. 9, e71814 (2026).

9.     Chandor-Proust, A. et al. The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling. Biochem. J. 455, 75–85 (2013).

10.Krinsky, M. High Throughput Assay for Cytochrome P450 Drug and Agrochemical Toxification Share: (2019).

As new technologies reveal increasingly complex cancer genomes, clinical laboratory scientist Dr. Peter Sabatini explains the challenges of turning genomic discoveries into clinical diagnostic tools.

Raina Cui, Samran Prasla, and Samy Danial

Cancer genomics has transformed how we understand, diagnose, and treat cancer. Advances in sequencing technologies and genomic analysis now allow researchers and clinicians to detect genetic alterations with unprecedented precision¹. However, generating genomic data is only part of the challenge. Translating these discoveries into routine clinical care requires not only accurate interpretation of complex findings but also alignment with healthcare systems, particularly regulatory approval processes and reimbursement frameworks. In many cases, these systems struggle to keep pace with the speed of scientific progress. During our conversation with Dr. Peter Sabatini, a clinical laboratory scientist at BC Cancer and former scientist at the University Health Network (UHN), this disconnect emerged as a recurring theme. “Sometimes the technology is advancing more than policy,” he noted.

Dr. Sabatini’s career reflects the evolving nature of genomic medicine. After completing his PhD in cardiovascular science at the University of Toronto, he worked in industry at Luminex Molecular Diagnostics, where he developed molecular diagnostic tests that required regulatory approval from agencies such as the FDA and Health Canada before being implemented in clinical laboratories. He later transitioned into clinical training in molecular genetics and cytogenetics at The Hospital for Sick Children. Today, as a Fellow of the Canadian College of Medical Geneticists, his work focuses on implementing emerging genomic technologies in cancer diagnostics.

 Dr. Peter Sabatini, Clinical Laboratory Scientist at BC Cancer and Clinical Associate Professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia, and Fellow of the Canadian College of Medical Geneticists in Molecular Genetics. Photo provided by Dr. Sabatini.

In high-volume clinical genomics laboratories, innovative tools like optical genome mapping (OGM) are improving the accuracy of tumour characterization. OGM, in particular, has attracted attention for its high-resolution detection of chromosomal abnormalities. It works by stretching very long DNA molecules across tiny channels and labeling specific sequence patterns with fluorescent markers (Fig. 1A). By comparing these patterns to a reference genome, researchers can identify structural variants (SVs), which are large genomic changes greater than 50 base pairs, such as duplications, deletions, or inversions² (Fig. 1B). According to Dr. Sabatini, the motivation to implement OGM was largely driven by the limitations of traditional cytogenetic approaches, like karyotyping, which can miss smaller or complex SVs (Table 1). “The data was clear that the clinical utility was better,” he explained, describing why the technology was introduced into the clinical workflow.

In addition, by combining molecular analysis with the visualization of large structural genomic changes, OGM provides a single, high-resolution platform capable of detecting SVs and copy number variations, effectively consolidating what previously required separate tests such as karyotyping, FISH, and microarrays³. For example, modern diagnostic laboratories are typically divided into molecular and cytogenetic units. Molecular diagnostic laboratories focus on detecting small-scale genomic changes, while cytogenetic laboratories are better suited for visualizing large-scale genomic changes. OGM integrates these capabilities into a single platform, unifying disciplines that have historically operated separately, allowing laboratories to simplify existing cytogenetic and molecular assays into one unified assay, ultimately reducing operational burden and simplifying clinical report generation. This higher-resolution detection is particularly valuable in cancers such as leukemias, where identifying cryptic or complex SVs directly informs diagnosis, prognosis, and therapeutic decision-making⁴.

Figure 1 | Optimal genome mapping (OGM) workflow and interpretation. (A) Schematic of the procedure of OGM. The OGM method relies on isolation of high molecular weight DNA using an extraction protocol designed to minimize shearing forces. The DNA is fluorescently labelled using fluorophores that bind to CTTAAG hexamer motifs that occur at a frequency of 14-17 every 100kb⁵. The labelled DNA is linearized and run through silicon microfluidic chips where the fluorescent banding pattern is imaged. The banding pattern of each DNA fragment is unique; this property is used to align the DNA fragments to a reference sequence based on matching banding patterns, producing consensus maps. The consensus map is then compared in silico to the expected banding pattern of a reference genome. DNA containing SVs will display different banding patterns compared to the reference sequence at the location of the variation^3,5. (B) Examples of structural variants identified by OGM. Yellow and orange color represents the reference sequence. Blue represents the test sample. The black lines indicate the location and pattern of the CTTAAG motifs. Figure taken from⁵.

Table 1 | Base Pair Resolution differences between Karyotyping, Fluorescent In Situ Hybridization (FISH), Chromosomal Microarray Analysis (CMA), Optical Genome Mapping (OGM). Table from⁶.

While high-resolution methods reveal more variants, this increased sensitivity introduces new challenges for clinical interpretation. Many of these variants are classified as variants of uncertain significance (VUSs), meaning their implications for patient care remain unclear. For example, Chen et al.⁷ reported that 41% of individuals undergoing multi-gene panel testing had at least one VUS⁷. As Dr. Sabatini explains, “Because it’s high resolution, we are seeing so many more things… How do we know what’s real and not? Should we report them?” Translating these findings into actionable clinical insights requires bridging the gap between technical detection and practical application. “A scientist has one context, but a clinician showing the report to a patient is completely different. Taking all that nerdy science and making it sort of applicable is where we’re trying to make it happen,” he adds. By combining technical capability with hands-on experience, laboratories are gradually learning how to interpret complex genomic data and integrate it into patient care.

More recently, Dr. Sabatini has focused on developing RNA-based approaches to improve the diagnosis and classification of diffuse large B-cell lymphoma (DLBCL), one of the most genetically diverse types of lymphoma. In collaboration with UHN and BC Cancer, he helped validate LexA120, an RNA expression panel that classifies tumours based on gene expression patterns rather than individual genomic rearrangements. By assessing which genes are turned on or off, RNA-based classifiers capture the tumour’s molecular signature, providing insight into its underlying biology and prognosis. This approach can distinguish patients with poorer versus more favorable outcomes, offering a more comprehensive picture of tumour behavior⁸. In current clinical practice, patients are often stratified into risk categories using fluorescence in situ hybridization (FISH), a technique that detects specific DNA sequences and chromosomal rearrangements. However, FISH testing can be technically challenging and time-consuming, and it focuses only on a few selected genomic markers⁹. In contrast, RNA-based classifiers such as LexA120 provide broader information about tumour biology, are faster, more cost-effective, and easier to interpret⁶.

Despite these advantages, implementing new RNA-based diagnostics in the clinic often encounters policy-related barriers. Even when they appear clinically superior to traditional FISH testing, current drug approvals and reimbursement frameworks remain tied to FISH-based diagnostic tests. As a result, laboratories may struggle to adopt newer technologies, even when they offer clear clinical benefits. “So it’s like sometimes the technology is advancing more than policy, which is too bad. They really should be together,” Dr. Sabatini explained, highlighting the challenge of aligning innovation with healthcare regulations. To overcome these barriers, early and ongoing multidisciplinary collaboration is essential. “All of the disciplines need to be at the table from the outset,” he emphasized, noting that involving clinicians, laboratory scientists, and policymakers from the beginning helps ensure new genomic technologies can be implemented effectively, ultimately improving patient care.

Another growing challenge in clinical genomics is scale. As testing volumes continue to rise, laboratories must process an increasing number of samples while simultaneously implementing new technologies. This growing caseload can take time away from case review and report sign-out. Unlike traditional biochemistry labs, where results follow well-established guidelines, genomic testing remains highly personalized and labor-intensive, particularly because many variants still lack clear frameworks for interpretation. While this individualized approach is essential for accurate and ethical reporting, it becomes increasingly difficult to sustain as demand grows. To address this, Dr. Sabatini emphasizes the need for more efficient and scalable workflows. Looking ahead, he envisions a future where genomic testing is consolidated into a small number of comprehensive assays. Long-read sequencing, in particular, is a promising step in this direction, as it reads longer stretches of DNA, allowing it to capture both single-nucleotide variants and complex structural changes within a single workflow¹⁰. “Maybe instead of having 100 different tests in the lab, we’ll have two,” he said. Such consolidation could reduce operational burden, shorten turnaround times, and provide clinicians with more integrated and actionable insights. Ultimately, modern tools such as optical genome mapping, RNA-based classifiers, and long-read sequencing each offer unique advantages for detecting SVs, gene expression patterns, and complex genomic changes. Together, these technologies provide a more complete picture of the cancer genome and can simplify the workflow.

A recurring theme in Dr. Sabatini’s work is that the impact of cancer genomics depends not just on technological innovation, but on how complex data are interpreted, validated, and translated into patient care. Achieving this requires interdisciplinary teams of clinicians, laboratory scientists, bioinformaticians, and policymakers, yet these groups often operate in isolation. “The lab gets a little bit left behind,” he noted. Bridging this gap demands earlier and sustained collaboration, along with alignment between scientific advances and healthcare policy. “We need to break down those silos so we can all work together,” Dr. Sabatini emphasizes, highlighting the importance of interdisciplinary teamwork in translating genomic insights into clinically actionable decisions. Ultimately, it is this balance between innovation and implementation that will shape the future of precision oncology.

Despite the technical and operational challenges, Dr. Sabatini finds the most rewarding moments in individual patient cases, where genomic data can directly impact clinical decision-making. In one memorable instance, his team used whole-genome sequencing, a method that reads the entire DNA sequence of a patient’s genome, to investigate a structural variant that another laboratory had labeled as a VUS. By examining the broader genomic context, they were able to uncover the underlying mechanism behind the variant, which ultimately changed how it was interpreted and reported. “I like finding those moments where you can really see the mechanism behind the structural change,” he said. “That’s when I get that ‘aha’ moment.” These moments highlight the investigative nature of clinical genomics, where scientists often need to piece together complex genomic information to better understand disease. They also underscore the real-world impact of this work: moving beyond uncertainty to provide clearer answers that can inform diagnosis, guide treatment decisions, and ultimately improve patient care.

Dr. Sabatini remains optimistic about the future of cancer genomics, despite ongoing challenges in translating complex genomic findings into routine clinical practice. He notes that this gap is gradually narrowing as newer generations of trainees gain greater exposure to genomics and become more comfortable working with genomic data. As Dr. Peter Sabatini reflects, “Progress is made sometimes one retirement at a time,” highlighting a generational shift toward stronger genomic literacy and more collaborative, interdisciplinary practice. For students and early-career scientists entering the field, he emphasizes the importance of curiosity and adaptability: “Every day is a new thing,” he said, “so it’s exciting.”

References

1.         Mardis, E. R. The Impact of Next-Generation Sequencing on Cancer Genomics: From Discovery to Clinic. Cold Spring Harb. Perspect. Med. 9, a036269 (2019).

2.         Dremsek, P. et al. Optical Genome Mapping in Routine Human Genetic Diagnostics—Its Advantages and Limitations. Genes 12, 1958 (2021).

3.         Levy, B., Burnside, R. D. & Akkari, Y. Optical Genome Mapping: A New Tool for Cytogenomic Analysis. Genes 16, 924 (2025).

4.         Loghavi, S. et al. Optical genome mapping improves the accuracy of classification, risk stratification, and personalized treatment strategies for patients with acute myeloid leukemia. Am. J. Hematol. 99, 1959–1968 (2024).

5.         Optical genome mapping: A ‘tool’ with significant potential from Discovery to Diagnostics. College of American Pathologists Available at: https://www.cap.org/member-resources/articles/optical-genome-mapping-a-tool-with-significant-potential-from-discovery-to-diagnostics.

6.         Signiosbio-Admin. Next generation cytogenomics: Optical genome mapping (OGM) for detection of chromosome structure variations. Signiosbio powered by medgenome (2024). Available at: https://www.signiosbio.com/blog/next-generation-cytogenomics-optical-genome-mapping-ogm-for-detection-of-chromosome-structure-variations/.

7.         Chen, E. et al. Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing. JAMA Netw. Open 6, e2339571 (2023).

8.         Sabatini, P. J. B. et al. Validation of a Modular Gene Expression Assay for Risk Stratification and Subtyping Lymphomas. J. Mol. Diagn. 28, 1–7 (2026).

9.         Chrzanowska, N. M., Kowalewski, J. & Lewandowska, M. A. Use of Fluorescence In Situ Hybridization (FISH) in Diagnosis and Tailored Therapies in Solid Tumors. Molecules 25, 1864 (2020).

10. Marx, V. Method of the year: long-read sequencing. Nat. Methods 20, 6–11 (2023).

Dr. Hernan Gonorazky at the Hospital for Sick Children reflects on the past and future of gene therapies, uncovering a flawed system not initially designed for the continuous treatment of patients with previously “non-treatable” disorders.

Alina Elahie, Matt Hudson, and Emily Wang

Have you ever wondered how rare a “rare disease” truly is? What if they are much more common than you would have imagined? One such rare disease is spinal muscular atrophy (SMA), a neuromuscular disorder characterized by α motor neuron degeneration in the spinal cord¹. It is one of the most common pediatric autosomal recessive genetic disorders with a carrier frequency of 1 in 50 and a disease frequency of 1 in 5,000 to 10,000 live births¹. SMA is caused by homozygous deletion, or two abnormal copies, of the survival motor neuron 1 (SMN1) gene, which leads to deficient survival motor neuron (SMN) protein¹. Such a deficiency results in breathing or respiratory difficulties, feeding difficulties, muscle wasting, and muscle weakness from an early age¹. To date, five types of SMA have been identified – types 0 to IV – all of which differ in clinical presentation, severity, and prevalence¹.

In addition to problems with SMN1, SMA severity is often influenced by the copy number of the SMN2 gene, which is paralogous or highly similar to SMN1, but functions at a much lower capacity and therefore cannot completely rescue the SMA phenotype¹. Individuals with fewer SMN2 copies typically have more severe forms of SMA (types 0–II), whereas individuals with more SMN2 copies are less impacted by disease (types III–IV)¹. Aside from the natural compensatory mechanisms provided by SMN2, researchers from around the world have made notable therapeutic advances in recent years¹. Gene therapy approaches such as replacing the defective SMN1 or enhancing the compensatory SMN2, in addition to improved standard of care, have altered the natural disease trajectory of SMA^1,2. Individuals with more severe forms of SMA now have extended life expectancy and slower disease progression¹.

Dr. Hernan Gonorazky is a leading SMA researcher in Canada who specializes in gene therapies (Figure 1). He is the director of the Neuromuscular and Movement Disorders Program at the Hospital for Sick Children (SickKids) and is an assistant professor at the University of Toronto Faculty of Medicine^3,4. His research utilizes a variety of clinical and research methodologies with the aim of characterizing childhood neuromuscular disorders and discovering possible genetic therapies³.

Figure 1 | Dr. Hernan Gonorazky, MD, CSCN Diplomate (EMG). Dr. Hernan Gonorazky is the Program Director of the Neuromuscular and Movement Disorders Fellowships at the Hospital for Sick Children, a Staff Physician in the Division of Neurology at the Hospital for Sick Children, and an Assistant Professor at the University of Toronto Faculty of Medicine. Image from ³.

During medical school training in Argentina, Dr. Gonorazky became interested in neuromuscular disorders while working with patients affected by myasthenia gravis, an autoimmune neuromuscular condition⁵. His interest in neurology was strengthened by his family background, as his father was a neurologist and his mother worked in genetics. Such influences naturally led him towards combining both fields. Dr. Gonorazky developed a particular interest in muscle disorders or myopathies, many of which have strong genetic underpinnings. He was interested in exploring fundamental questions such as why certain muscles are more affected than others despite having identical genetic profiles. Following the completion of his residency in adult neurology, Dr. Gonorazky pursued a fellowship in neuromuscular disorders and has made significant contributions to research in pediatric neuromuscular disorders ever since. He poses a vital question: What happens to patients after gene therapy?

SMA Treatments – What’s On The Table?

As SMA is a degenerative and progressive disorder, timely management and immediate administration of available therapies are of the utmost importance. Gene therapies as a concept and treatment option may be scary to patients and families, especially when they are dealing with the emotional turmoil associated with an SMA diagnosis. According to Dr. Gonorazky, in order to give children newly diagnosed with severe types of SMA the best chance of success, he needs to quickly gain the trust of families along with the rest of the medical team and explain the importance of early treatment.

Children with severe neuromuscular disorders like SMA only received palliative treatments for their symptoms until gene therapies to replace defective genes with functional ones were made available (Figure 2). In fact, Dr. Gonorazky and his team recently treated two infants with SMA (one term and one preterm) using a Health Canada–approved gene therapy via infusion named Zolgensma, aiming to protect as many motor neurons as they could as early as possible^6,7. Both patients showed better muscle control at 4 months of age than would be expected otherwise, considering their genetic diagnosis, highlighting the feasibility and success of early gene therapy. When asked about how the treatment landscape for neuromuscular disorders has changed over time, Dr. Gonorazky noted that he has seen a dramatic shift in what would be defined as treatable vs. non-treatable, particularly in SMA cases where gene therapies are available. “In the population that we actually follow”, said Dr. Gonorazky, “we have already transitioned quite a few to adult care. I used to see patients with SMA passing away, and now I see them walking.”

Figure 2 | Gene therapy offers new hope to patients born with spinal muscular atrophy. Dr. Hernan Gonorazky examines David Tenaglia Valdez during a 9-month check-up. Image from ⁷.

You’ve Graduated from Pediatric Care – Now What?

According to Dr. Gonorazky, one of the biggest challenges faced by patients with neuromuscular disorders is what happens outside of the hospitals. While pediatric care can be highly supportive, transition into adulthood often exposes a harsh reality of fragmented systems and difficulties accessing care. As he explained, clinicians can sometimes “baby powder” their patients too much, shielding them from the difficulties they will eventually face in the healthcare system. Once patients transition to adult care, many suddenly find themselves fighting for access to medical resources. A qualitative study of the experiences of patients with SMA who aged out of pediatric care at SickKids and moved to adult care at Sunnybrook Health Science Centre reported that a “disjointed” care transition period and physically inaccessible adult healthcare settings were noted by patients⁸. Moreover, the authors suggested the need for more multidisciplinary care teams in the adult system, as there is in the pediatric system⁸.

“[Transition of care] is an Ontario problem”, Dr. Gonorazky noted, pointing to the broader systemic gaps in supporting adults with complex health conditions. Preparing pediatric patients for the transition is crucial, but this also raises a difficult question: How can healthcare providers help if the necessary support systems simply do not exist? “The question isn’t whether that is an issue,” he said, “but where are the resources to do that?” Reflecting on his own background, Dr. Gonorazky added, “I come from a country [Argentina] that actually does not have resources”, a perspective that continues to shape how he views issues surrounding access to care.

The Future of Gene Therapies in Clinical Trials

At SickKids, Dr. Gonorazky is involved in multiple sponsored clinical trials focused on neuromuscular disorders. Despite the significant amounts of time and effort contributed and the fact that clinicians often do not receive any additional compensation, he sees these clinical trials as essential. “So why do I do it?” he asked. “Because it is important for the families.” Clinical trials offer patients access to therapies that otherwise may not be available locally, and spare families from long-distance travel to other cities or even other countries like the United States. Fortunately, recent trends show that clinical trials are moving toward the promise of precision child health, particularly through gene therapies.

For Dr. Gonorazky, the future of genetic medicine lies in thinking beyond diagnosis. Researchers must question how to design effective therapies, how to continue to care for patients who have undergone gene therapies, and even start to think about what the “ideal” gene would look like in gene therapies. He compares different alleles or versions of genes to different cars that one might purchase, “There are cars out there that are like Ferraris, or you can have a really [junky] car – which version do you think will be better? We need to start thinking that way.” This raises an interesting ethical question in human gene therapy⁹: When designing constructs for gene therapy, should we aim to reinvent the wheel and give these patients a supercharged gene? Or should we use a wildtype copy of the gene that we know works in the healthy population? However, it is notable that clinicians like Dr. Gonorazky are starting to think about such ethical questions in this new era of therapeutic gene editing.

When it comes to designing new gene therapies, Dr. Gonorazky envisions a platform-based approach as the best way to bring these treatments to patients. In essence, he says that this would involve approving the different components of gene therapies – the vectors or packaging that are used to deliver genes to target cells, the gene constructs, and the promoters chosen to specify where these new constructs should be expressed – to speed up the process of creating gene therapies using a “mix-and-match” method. He stated, “AAV8 or AAV9 [two common viral vectors used in gene therapy], we use them clinically. Do I need to test these again or not? What about the promoters? If it has been used before, do we need to test it again? The question is how we are going to deal with these pipelines to get [these treatments] fast enough and cheaper.”

In conclusion, Dr. Gonorazky’s experiences have led him to reflect on how care can be improved for pediatric patients with neuromuscular disorders, both in terms of treatment and transition of care. Scientific advances have been hitting their intended targets, but do we have the systems in place to adapt to such rapid discoveries and accommodate quality patient care in the long term? According to Dr. Gonorazky, he is more concerned with the policy rather than the science – “the therapies are going to keep coming, but how they are going to be managed, studied, and approved – that will be interesting.”

References

1. Mercuri, E., Pera, M. C., Scoto, M., Finkel, R. & Muntoni, F. Spinal muscular atrophy — insights and challenges in the treatment era. Nature Reviews Neurology 16, 706–715 (2020).

2. Finkel, R., Bertini, E., Muntoni, F. & Mercuri, E. 209th ENMC International Workshop: Outcome measures and clinical trial readiness in spinal muscular atrophy 7–9 November 2014, Heemskerk, the Netherlands. Neuromuscular Disorders 25, 593–602 (2015).

3. Hernan Gonorazky: Sickkids directory. SickKids Available at: https://www.sickkids.ca/en/staff/g/hernan-gonorazky/. (Accessed: 8th March 2026)

4. Hernan Gonorazky. Hernan Gonorazky | Department of Paediatrics Available at: https://paeds.utoronto.ca/faculty/hernan-gonorazky. (Accessed: 8th March 2026)

5. Gilhus, N. E., Tzartos, S., Evoli, A., Palace, J., Burns, T. M. & Verschuuren, J. J. G. M. Myasthenia gravis. Nature Reviews Disease Primers 5, 30 (2019).

6. Nigro, E. et al. Case report: A case of spinal muscular atrophy in a preterm infant: Risks and benefits of treatment. Frontiers in Neurology 14, (2023).

7. Ogilvie, M. He was born with a deadly mutation. Delivered five weeks early to start gene therapy at SickKids, his progress is offering new hope. Toronto Star (2026). Available at: https://www.thestar.com/news/gta/gene-therapy-at-sickkids/article_60e20d45-367c-4fed-a79d-6e730cb39a77.html. (Accessed: 8th March 2026)

8. Munn, J. et al. Understanding the experiences of adults with spinal muscular atrophy & their transition to an adult program: A mixed methods study. Journal of Neuromuscular Diseases (2025).

9. Joseph, A. M., Karas, M., Ramadan, Y., Joubran, E. & Jacobs, R. J. Ethical perspectives of therapeutic human genome editing from multiple and diverse viewpoints: A scoping review. Cureus 14, e31927 (2022).

Dr. Christine Armour, MS MD FRCPC CCMG is a leading clinical expert in prenatal genetics determined to improve prenatal care for pregnant individuals and their babies. She provides expert insight into the importance of prenatal screening and provincial policies ensuring equitable access and care.

Sarah Hammond, Isabella Harmic, and Yixin He

Dr. Christine Armour, MS MD FRCPC CCMG, Clinical Geneticist at the Children’s Hospital of Eastern Ontario (CHEO), co-Medical Director (Genetics) of Prenatal Screening Ontario (PSO), Investigator at CHEO Research Institute, and Associate Professor of Pediatrics at the University of Ottawa¹. Image from ¹.

Pregnancy can be a time of excitement and anticipation but it may also bring uncertainty. All pregnant individuals wish for a healthy baby, but creating another human being is an intricate biological process, and outcomes can vary during conception, pregnancy or birth. Early miscarriage is relatively common, with 25% of clinically recognized pregnancies resulting in miscarriage, and approximately 60% of early pregnancy losses are a result of a chromosome difference in the fetus². To reduce uncertainty and obtain more information about their pregnancy, individuals may choose to pursue prenatal screening. Prenatal screening can help the pregnant individual and their healthcare provider better understand the health of their pregnancy and baby, identify which tests and treatments would be informative, make important decisions about pregnancy options, and plan for a safe delivery³. This is why Prenatal Screening Ontario (PSO) plays such an essential role in pregnancy, supporting informed decision making and personalized care. At the forefront of the prenatal screening field is Dr. Christine Armour, a Clinical Geneticist at the Children’s Hospital of Eastern Ontario (CHEO) and co-Medical Director (Genetics) of PSO. Dr. Armour has been passionate about improving prenatal screening for patients throughout her whole career and created a lasting impact in this field.

To understand Dr. Armour’s work, it’s important to clarify that in the field of prenatal testing, some techniques are diagnostic, while others are used for screening. Diagnostic tests include methods such as amniocentesis and chorionic villus sampling (CVS). These techniques directly sample fetal DNA to produce a definitive genetic diagnosis, but are invasive and associated with a risk of miscarriage in up to 1% of pregnant individuals⁴. Due to this risk, prenatal screening is typically offered before a diagnostic test, allowing those with a low probability of having a child with a chromosome difference to avoid unnecessary risks to the pregnancy. Prenatal screening broadly encompasses several methods, such as ultrasounds, maternal serum screening tests, and non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cffDNA). These tests are all non-invasive and thus pose no risk of pregnancy loss, but can only estimate the probability of chromosome differences in the fetus⁵. The respective information obtained balanced against the risks is important to understand for individuals considering diagnostic prenatal testing.

In Ontario, publicly funded NIPT has been available to pregnancies at greater chance of aneuploidy since 2014 and represents the most accurate prenatal screening method available for chromosome differences⁶. As the placenta naturally sheds DNA, it becomes available to access via a blood sample taken from the pregnant individual, albeit at low concentrations (Figure 1). However, not only can cffDNA be conflated with naturally occurring maternal cell-free DNA, which is also found in the blood at higher concentrations, it is also possible that the placenta’s DNA is not the exact same as the fetus’. Dr. Armour notes, “Cell-free DNA doesn’t come directly from the fetus. It comes from the placenta. So, the best way to think of it is that it’s like a placenta biopsy.” This is one reason why this technique is not diagnostic, and limited to reporting the likelihood of whether the fetus has a chromosome difference⁷.

Figure 1. Diagram of Cell-Free Fetal DNA in the Bloodstream. Diagram by Rather⁷ displays how short DNA fragments are shed from placental cells into the bloodstream, where they can be accessed with a non-invasive blood draw. DNA shedding occurs due to natural cellular processes, such as cell death, so naturally, maternal cell-free DNA is also found in the blood. Figure taken from ⁷.

The full potential of prenatal screening is yet to be realized. Currently, prenatal screening allows for the identification of the most common chromosome differences: trisomies 21, 18 and 13, and optionally, sex chromosome differences. Dr. Armour notes that Ontario is currently developing new screening initiatives, including a Rhesus D (RhD) blood type screen expected to launch in 2026, which predicts the fetal RhD blood type through cffDNA screening in maternal blood⁸. When an RhD-negative pregnant individual carries an RhD-positive baby, they may be exposed to fetal blood during pregnancy and produce antibodies that could potentially pose a risk of hemolytic disease of the fetus/newborn in a future pregnancy. Traditionally, all RhD-negative pregnant individuals without antibodies receive RhD Immune Globulin (RhIG) treatment regardless of the fetal blood type⁸. This new genetic screening technology, however, would reserve this treatment for pregnancies where the fetus is predicted to be RhD-positive.

Outside of the prenatal screening methods that PSO oversees, there are other emerging technologies in the field that may improve the patient experience. In the current clinical pathway, a positive maternal carrier screen for an autosomal recessive condition, such as cystic fibrosis, would often trigger an offer of a separate round of paternal carrier testing. This process can take up to 6 weeks to produce results, prolonging anxiety for families. By contrast, the newly developed single-gene NIPT (sgNIPT) requires only a maternal blood sample to screen for certain autosomal recessive conditions in the fetus, eliminating the need for a paternal sample altogether⁹. Results would take only 9-16 days, offering a faster and more patient-centred experience⁹.

While there may be many genetic conditions that patients wish to screen for early in a pregnancy, there are some limitations to what is possible. In Ontario, there are many steps that must take place when determining whether a screen should be implemented across the province. When the provincial health authorities are considering funding a prenatal screen, there is a very detailed process they follow to ensure the clinical benefit and accessibility of the screen. A test may be nominated for implementation with a Health Technology Assessment. Dr. Armour speaks about the process required to implement a screen provincially: “We have to make a proposal to the province, a business case, for why a screen should be rolled out. There is a lot of background work that gets put into how screens are added, justified, and how the proposal is built… it can sometimes take years to make it into our current system.”

PSO is housed within Better Outcomes Registry and Network (BORN) Ontario, the province’s maternal, newborn and child registry which collects all health outcomes and information related to maternal-child health in the province. This includes in vitro fertilization (IVF) data, maternal care information, prenatal screening data, birth setting and delivery characteristics, and newborn screening outcomes, providing a wealth of robust data. Dr. Armour emphasizes the impact of BORN: “It is quite powerful in Ontario, because many places do not have those outcomes, so we will get all prenatal screening data and cytogenetic data, and we are able to look at outcomes and performance of these tests,” she comments, “in many other places around the world, they can’t do that. The cytogenetics labs don’t necessarily talk to the screening labs, so they won’t have all outcomes.” The implementation of PSO allowed for standardized oversight and review of screening performance across the province. PSO also acts as a reliable resource for prenatal screening education, providing support for clinicians and pregnant individuals⁵. As such, Dr. Armour’s involvement with BORN and PSO was a natural choice, given her deep commitment to population health and her position as co-Medical Director enables her to further improve maternal, prenatal and reproductive care.

            In a previous podcast interview, the host compared Dr. Armour to a “choir master”, since she collaborates with policymakers and researchers across disciplines¹⁰. Most notably, she consistently values the patient perspective. She acknowledges that patients will naturally hold different views on prenatal screening, and it is the clinician’s role to ensure the patient has all the necessary information to come to an informed decision. Dr. Armour emphasizes that all screening is voluntary and strongly believes in the power of education: “Knowledge translation is equally important.” It is because of this belief that PSO developed the “My Screening Pathway” tool. The site is designed for anyone who is pregnant or thinking about pregnancy, helping them understand their options for prenatal screening. Users can take a quiz to get a personalized pathway and timeline of their prenatal screening options (Figure 2)³.

Figure 2. Example Output of My Screening Pathway Tool. The My Screening Pathway³ quiz takes information from the pregnant individual, or one considering pregnancy as is demonstrated here. The resulting output provides a timeline of prenatal screening options available to them and clinical resources. This output fosters discussion between the patient and their healthcare provider. Figure from ³.

Undergoing prenatal screening is not the end of the journey – patients also need to understand how to interpret their results. As a reminder, screening is not the same as diagnostic testing, as it only provides a probability of the fetus having a certain condition. An important statistic is the positive predictive value, which is the probability that a positive screen result correctly indicates that a specific condition is present. When screening for rare disorders, a positive result may come with a relatively low positive predictive value, meaning it does not equate to a confirmed diagnosis. This is why, among chromosomal aneuploidies, trisomy 21 (more commonly known as Down syndrome) has the highest prevalence and therefore tends to have the highest positive predictive value. Thus, while a high-risk result can understandably cause concern, it is important to remember that it is not a diagnosis. Dr. Armour highlights that with the information provided by non-invasive screening, “[pregnant individuals] can have the chance to decide if they want to do invasive testing to confirm whether their pregnancy has [a genetic] condition or not.” For those who want a definitive answer, diagnostic testing remains as an available option.

Dr. Armour and her team are dedicated to empowering pregnant individuals to have meaningful conversations with their healthcare providers about receiving the care that is right for them and their pregnancy. Ultimately, prenatal screening isn’t just about generating a risk score, the goal is to provide families with meaningful information. The work of clinicians and programs like PSO ensures pregnant individuals have access to the knowledge they need in order to move forward in their pregnancy journey with more confidence.

References

1. Christine Armour. CHEO Research Institute https://www.cheoresearch.ca/research/find-a-researcher/christine-armour/.

2. Shorter, J. M., Atrio, J. M. & Schreiber, C. A. Management of early pregnancy loss, with a focus on patient centered care. Semin. Perinatol. 43, 84–94 (2019).

3. PSO. My Screening Pathway. https://myscreeningpathway.ca/about.

4. Alliance, G. & Screening Services, T. N. Y.-M.-A. C. for G. and N. PRENATAL SCREENING AND TESTING. in Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals (Genetic Alliance, 2009).

5. About Us. Prenatal Screening Ontario https://www.prenatalscreeningontario.ca/about-us/.

6. Women’s Experiences of Publicly Funded Non-Invasive Prenatal Testing in Ontario, Canada – Meredith Vanstone, Karima Yacoub, Mita Giacomini, Danielle Hulan, Sarah McDonald, 2015. https://journals.sagepub.com/doi/10.1177/1049732315589745.

7. Rather, R. A. Fetal Origin Circulating Cell-Free Nucleic Acids in Maternal Circulation and Their Clinical Importance. in Non-invasive Prenatal Screening (NIPS) in Clinical Practice (eds Rather, R. A. & Saha, S. C.) 17–35 (Springer Nature, Singapore, 2024). doi:10.1007/978-981-97-6402-0_2.

8. Practice Bulletin No. 181: Prevention of Rh D Alloimmunization. Obstet. Gynecol. 130, e57 (2017).

9. Wynn, J., Hoskovec, J., Carter, R. D., Ross, M. J. & Perni, S. C. Performance of single-gene noninvasive prenatal testing for autosomal recessive conditions in a general population setting. Prenat. Diagn. 43, 1344–1354 (2023). 10.CIHICanada. Can AI Help Identify Babies at Risk of Autism? (2025).

Dr. Anita Villani, Co-Director of the SickKids Cancer Sequencing (KiCS) program, discusses pioneering the integration and clinical utility of genomic sequencing into paediatric oncology, emphasizing its success hinges on prioritizing patients before breakthroughs.

Tessa Pelino, Parneet Kaur and Michael Lit

Paediatric oncology is often celebrated for its high survival rates compared to adult cases, yet the story differs for children with rare, metastatic, or relapsed cancers whose outcomes remain stubbornly poor. In these unfortunate cases, conventional treatments such as chemotherapy, surgery and radiation are ineffective and leave families with limited options. 

To address this issue, paediatric oncologist Dr. Anita Villani joined efforts to launch the SickKids Cancer Sequencing (KiCS) program within the Hospital for Sick Children (SickKids) in Toronto, ON, which she now co-directs with Drs. David Malkin and Adam Shlien. A precision oncology program that determines how comprehensive genomic sequencing can meaningfully guide paediatric care. In her words, “The real push [for KiCS] was the clinical need to say we have done as much as we can with our standard approaches… [these approaches] were not moving the needle for many different types of paediatric cancers.” This metaphorical needle describes the stagnation in survival rates of children with high-risk, relapsed or metastatic tumours. 

Additionally, the initiation and progression of paediatric cancer is not nearly as researched as adult cases. Children are not simply “little adults”, they have distinct tumour characteristics that require specialized research to interpret effectively. This is where KiCS comes in, generating a detailed genomic profile, or “fingerprint”, of every child’s tumour to accurately diagnose the cancer type, understand what contributes to its development and how we can target its biggest vulnerabilities. As Dr. Villani put it, “If we could increase our knowledge of the drivers of these tumours … paired with [current] drug development and targeted agents, would that give us more [and better] options for treatment?” 

Dr. Anita Villani, Staff Oncologist and Co-Director of KiCS at SickKids, Molecular Tumour Board Lead and Associate Professor in the Department of Paediatrics at the University of Toronto. Photo provided by Dr. Villani.

Beyond KiCS’s maturation, Dr. Villani shares her candid perspective on the program’s overall impact. She highlights the hope it offers families navigating complex cancer diagnoses while acknowledging the humility required to recognize KiCS’ own clinical limitations, and the next steps in progressing paediatric precision medicine.

Early Career and KiCS Initiation

Dr. Villani’s journey to oncology was shaped by a deep interest in genetics and molecular biology tracing back to her undergraduate degree in Biology at York University, where “[she] had always been interested in genetics, genomics, and molecular biology.” This curiosity carried her through medical training at the University of Ottawa, her general pediatrics training and a subsequent paediatric hematology and oncology fellowship at SickKids. Dr. Villani found that genomics was not well embedded in general medical training at the time, so she decided to pursue a Master’s degree in Genetics and Genome Biology at the University of Toronto. This intentional training allowed her to serve as a translator, a “Bridge between the two worlds” of researchers and clinicians, progressing cancer research grounded in patient care.

Her perspective was instrumental when KiCS launched in 2016 to test the clinical utility of genetic analysis. Walking down memory lane, she shares that over the past decade, KiCS has evolved from a small team of six to a rigorous multidisciplinary research engine that has supported nearly 1000 patients. Dr. Villani reflects, “It was a privilege for me to grow up with the KiCS program”. Growth, she emphasizes, is made possible with their collaborative model built on clinicians, scientists, and families bringing cutting-edge genomic tools to the children who need them most. 

A Sneak Peek Inside KiCS’ Workflow

Once enrolled in KiCS, the first step is dual sequencing of both the tumour tissue and normal cells to distinguish tumour-specific alterations from inherited germline variants.¹ Their workflow begins by processing these samples through next-generation whole genome sequencing (WGS), currently for research purposes, complemented by clinically validated cancer-associated gene panels and/or transcriptomic analysis for clinical insights (Figure 1).

Figure 1 | Illustration of KiCS Patient Sample Workflow. Upon patient enrollment, samples from both somatic tumour and normal germline cells undergo next-generation sequencing for a comprehensive analysis of cancer-specific variants. Sequencing includes whole genome sequencing, primarily used in the research arm, and two clinically-validated tests: a targeted cancer-associated gene panel and transcriptomic analysis. The targeted panel covers 864 genes, identifying single-nucleotide variants, small insertions and deletions, and copy number changes. Transcriptome analysis allows for the identification of any present gene fusions or translocations, as well as relative levels of gene expression. Individualized reports are reviewed by an expert molecular tumour board for diagnostic, prognostic, and treatment management purposes. Figure adapted from.^1,2

KiCS has made many major milestones in genetic discovery over the past decade (Figure 2). Kickstarting with the first 300 children they enrolled, where 44% had relapsed cancer, and 58% had already undergone chemotherapy or radiation with no success.³ These early participants represented “Several groups of patients whose outcomes were fairly poor,” as Dr. Villani noted, where molecular insights were especially valuable. Once variant annotation was complete, patient profiles were reviewed by a multidisciplinary molecular tumour board composed of geneticists, oncologists, pathologists, genome analysts, scientists, genetic counsellors, bioinformaticians and others, to evaluate possible impacts on patient management.³ Each variant was interpreted for relevance to the tumour’s biology, and clinically-actionable variants were flagged for targeted therapies, clinical trial eligibility, and refined diagnostic and prognostic insights. In the end, potential therapeutic targets were successfully found in 54% of those 300 participants, offering treatment pathways that may have otherwise remained unrecognized.³ 

This work showcased that relapsed cancers carried a higher mutational burden than previously recognized.^3,4,5 Further, by comparing the genetic landscape at diagnosis versus relapse of these patients, researchers identified new driver mutations not initially present.³ Highlighting the dynamic nature of cancer even within a single patient, supporting the clinical necessity of repeat genomic profiling for new tumours. Additionally, the team unexpectedly found elevated defects in cancer predisposition genes that are commonly implicated in adult cancers, such as DNA mismatch repair or homologous recombination genes like BRCA (typically associated with breast cancer) – a finding that is still being actively investigated by many groups internationally.³ All in all, showcasing how KiCS is increasing our understanding of paediatric cancer genetics. 

Figure 2 | Timeline of Key Milestones in the SickKids Cancer Sequencing (KiCS) program. This illustrative timeline depicts major victories in the KiCS program at SickKids from 2016 to 2025. Figure generated with Canva on March 16th, 2026, information sourced from^3,6 

More Data, More Questions: Navigating Genomic Uncertainty 

Although KiCS is undeniably benefiting patient outcomes, a humbling reality is that identifying a tumour-associated variant and knowing how to match it with a therapeutic is not always straightforward. As Dr. Villani explained, “This excess of data [can be a hurdle itself], picking out what’s important to know … but not clear how to use. That is a big reality of this entire endeavour.” She emphasizes that “The technology moved more quickly than our ability to know what to do with the information.”

Children with relapsed or metastatic cancers feel this gap intensely.After multiple rounds of treatment, their tumours have evolved under those selective pressures, leading them to acquire resistance and often more aggressive phenotypes.⁷ Moreover, paediatric cancers arise from distinct developmental pathways that have far fewer validated targeted therapies than adult cancers. While sequencing may identify a mutation, understanding what that means to the cancer’s characteristics and which treatments are most effective is not always possible.^7,8  In Dr. Villani’s words, in most cases, it is unfortunately unlikely that “Adding a single drug, even based on a molecular profile, is going to be a game changer for these tumours, especially in a multiply relapsed setting when we also appreciate how complicated cancer genomes are.” But, providing potential additional options can be very meaningful, as can the insights about prognosis and heritable cancer predisposition.

For Dr. Villani, this is where humility is essential, not only for KiCS, but for all areas of precision medicine. Their goal is not to identify more variants; it is to understand which variant’s identity can meaningfully guide patient care. For families struggling with a sick child, this uncertainty in genomics can be beyond difficult to process. Many parents hope that comprehensive sequencing will give them clear answers about treatments or the progression of their child’s disease but results rarely fall into those neat categories. Oftentimes, a genomic finding may refine a diagnosis or prognosis but point toward therapeutic targets that are not clinically validated. Others may uncover variants of uncertain significance (VUS), where there is not enough evidence to know whether the change affects disease. All in all, obtaining genetic information does not always translate to clear direction.

Dr. Villani describes her approaches to these conversations, “It starts with setting expectations. We hope we’re going to find something useful. Whether it will change care … it might not, and that’s okay. Most families appreciate the effort to understand as best we can.” She emphasized that navigating these results with transparency and care is what gives families the comfort in knowing their clinicians have pursued every possible avenue in their child’s best interest.

How KiCS is Changing the Game

Despite these complexities, Dr. Villani remains optimistic about the future of paediatric precision oncology. With nearly 1000 patients now enrolled, she doesn’t see KiCS as a finished product but as a “development engine” where emerging technologies can be tested, refined, and responsibly integrated into clinical care. As she put it, “Our vision is to continue pushing [genomic research] into clinical care where we can continue to improve the way we do things for patients.”

A central part of that vision involves rethinking the program’s foundation. KiCS was originally built on targeted cancer gene panels, but Dr. Villani sees WGS as the natural progression, “A genome backbone is probably the best thing we should be aiming for as opposed to our panel-based sequencing that we know can miss certain types of variants.” She argues a genome backbone will provide a complete view of tumour biology onto which RNA analysis and targeted panels can be layered to further identify structural variants, copy number changes, gene fusions, and inherited predisposition syndromes where necessary.³ 

Transcriptomic analysis of RNA expression adds another dimension to KiCS’ genomic approach.³ While WGS can reveal previously unknown mutations in a cancer-associated gene (or non-coding region) at the DNA level, transcriptomic analysis looks at the regulation and expression of that region to complete the full picture of genetic impact. This gives clinicians a direct way to monitor cancer cells’ behaviour in real time, especially useful to assess how well or poorly a cancer responds to treatment. Within KiCS, this technique has already helped reclassify diagnoses that standard pathology could not, offering accurate and timely guidance for treatment decisions.³

Future Directions 

One of the most active areas in oncology today is circulating tumour DNA (ctDNA), a liquid biopsy biomarker consisting of tumour DNA fragments released by cancer cells into the body fluids such as blood or cerebrospinal fluid.⁹ Unlike traditional biopsies that are invasive and difficult to repeat in children, liquid biopsies pose a less invasive method to monitor disease over time.⁹ Early studies suggest ctDNA can detect relapse earlier than imaging and serve as a prognostic marker for treatment response.⁹  

Dr. Villani shares that although ctDNA shows real potential, it is not yet ready for routine clinical use in children. KiCS has been preparing for the future by biobanking liquid biopsy samples of past and current patients whilst developing the technology to detect ctDNA reliably. As evidence grows, programs like KiCS will be well-positioned to integrate these tools promptly and safely. As she put it, “We’re still growing in paediatric oncology to know exactly how to use it [ctDNA]. When the paediatric oncology community feels we’re ready, we’ll be confident in our ability to run that sequencing, interpret it, and apply it clinically.” 

Over its lifetime, KiCS has evolved from an exploratory research initiative into a vital clinical engine for paediatric oncology within SickKids. By bridging bench science to bedside care, it continues to guide the development of next-generation genomic tools for oncology. The hope is that more programs like KiCS will foster a future where molecular insights translate into clear diagnoses, precise treatments, and, most significantly, improved outcomes for the children and families at the heart of this work.

References

1. Cohen-Gogo, S. et al. Precision oncology for children: A primer for paediatricians. Paediatr. Child Health 28, 278 (2023).

2. SickKids. SickKids study demonstrates how comprehensive genetic sequencing informs a new standard of cancer care. Available at: https://www.sickkids.ca/en/news/archive/2023/sickkids-study-demonstrates-how-comprehensive-genetic-sequencing-informs-a-new-standard-of-cancer-care/ (2023).

3. Villani, A. et al. The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations. Nat. Cancer 4, 203 (2022).

4. Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 2018 555:7696 555, 321–327 (2018).

5. Ma, X. et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 2018 555:7696 555, 371–376 (2018).

6. SickKids Garron Family Cancer Centre. 2019–2020 Annual Report. Available at: https://www.sickkids.ca/contentassets/5b9e1ab9c8834d59bf2ea49b883dc6ab/sickkids-gfcc-2019-2020-annual-report.pdf (2020).

7. Worst, B. C. et al. Next-generation personalised medicine for high-risk paediatric cancer patients – The INFORM pilot study. Eur. J. Cancer 65, 91–101 (2016).

8. Mody, R. J. et al. Integrative clinical sequencing in the management of children and young adults with refractory or relapsed cancer. JAMA 314, 913 (2015).

9. Wan, J. C. M. et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nature Reviews Cancer 2017 17:4 17, 223–238 (2017).

Dr. Philippe Bedard discusses the evolution of the OCTANE project, sharing how genomic tumor profiling has opened new personalized treatment opportunities for patients while building one of Ontario’s most valuable research resources for understanding cancer.

Tali Laszlo, Lauren Pearo and Melissa Elgie

Dr. Philippe Bedard, MD, FRCPC, is a Clinician Investigator and Staff Medical Oncologist at the Princess Margaret Cancer Centre and Professor in the Department of Medicine at the University of Toronto. He serves as Clinical Director of the Cancer Genomics Program and Co-Director of the Phase I Drug Development Program at Princess Margaret. Dr. Bedard is also a member of the steering committee for the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Project and the Co-Principal Investigator of the OCTANE project at Princess Margaret. Image taken from The Princess Margaret Cancer Foundation Instagram page¹.

At the intersection of clinical care and genomic research, Dr. Philippe Bedard has spent much of his career transforming how cancer patients are matched to emerging therapies. As a medical oncologist and clinical researcher at the Princess Margaret Cancer Centre in Toronto, Canada, Dr. Bedard works on early-phase drug development. Over the last decade, his work has helped build the infrastructure that supports precision oncology in Ontario.

Early Days of Precision Oncology

When Dr. Bedard began working at Princess Margaret more than 15 years ago, cancer genomics was still emerging as a clinical tool. Targeted therapies, which are drugs designed to attack cancer cells with specific genetic changes, were in their infancy. “It was at the beginning stages of targeted therapy in cancer treatment”, he recalled. “There was a growing need to try and identify patients who might have specific mutations in their cancers and match them to clinical trials with new drugs.” That need ultimately laid the groundwork for a series of initiatives that culminated in the Ontario-wide Cancer TArgeted Nucleic acid Evaluation (OCTANE) study in 2016.

Before OCTANE existed, Dr. Bedard and his colleagues launched an institutional initiative known as IMPACT (Integrated Molecular Profiling in Advanced Cancers Trial). IMPACT was designed to bring genomic testing into routine cancer research at Princess Margaret. At the time, sequencing technologies were far more limited than they are today. The program relied on hotspot mutation testing of tumor DNA using a platform called Sequenom, which could detect common genomic variants across a defined set of genes². Over time, the program transitioned to whole-genome and transcriptome sequencing, enabling researchers to examine a wider range of cancer-related genes simultaneously.

The IMPACT project quickly proved valuable for both clinicians and patients. The demand for genomic testing grew rapidly, and the program helped establish sequencing as a part of the clinical workflow at Princess Margaret. But the initiative also revealed a larger opportunity. Researchers across Ontario wanted access to the same technologies and data infrastructure. To address this need, Dr. Bedard and collaborators began designing a new province-wide effort to connect multiple cancer centres.

Building the OCTANE Project

That effort eventually became the OCTANE study, a collaborative research program designed to integrate genomic testing and clinical data across multiple institutions. The study analyses previously collected clinical data and tumor samples to identify biomarkers: specific molecular features of a patient’s cancer that can help predict which treatments will be most beneficial to a patient or how the cancer might progress. This information can help guide the use of targeted therapies and match individuals to clinical trials. With support from the Ontario Institute for Cancer Research, OCTANE launched with seven cancer centres across Ontario. Its goal was to create a shared platform for tumor sequencing, sample storage, and a searchable genomic database while building a province-wide registry of targeted gene testing results for cancer researchers³.This would allow them to access data and samples from patients who have consented to further research. Thanks to the OCTANE project, patient treatment strategies have undergone a dramatic shift away from a “one-size-fits-all” mentality to precision medicine⁴.

In OCTANE 1.0, researchers focused on patients with advanced solid tumors. Tumor samples were sequenced using panel-based Next Generation Sequencing (NGS), initially targeting about 50 genes and later expanded to larger panels capable of detecting copy-number variants (CNVs). Results were returned to the patient’s oncologist, and further research samples were also collected (Fig. 1). Tumor tissue, blood samples, and clinical data were collected and stored, creating one of Ontario’s largest oncology biorepositories. This system allows researchers to explore genomic and clinical data. “If they’re interested in looking at a cohort of patients with a specific condition [or] mutation in their cancer, they could easily pull that out,” Dr. Bedard explained.

Fig 1. OCTANE 1 study process.  (A) Patients at Ontario hospitals are identified and consent to participate, allowing access to archived formalin-fixed paraffin-embedded (FFPE) tumor tissue and the collection of a blood sample for germline DNA. tumor samples undergo pathology review and hematoxylin and eosin (H+E) imaging. (B) De-identified clinical information is transferred from participating hospitals to licensed clinical laboratories. (C) tumor DNA is extracted, and panel-based genomic testing is performed, with results returned to clinicians and uploaded to a shared research portal. (D) tumor DNA/RNA, germline DNA, and plasma are stored in the Ontario Institute for Cancer Research (OICR) Tissue Portal, where selected cases undergo additional translational genomic analyses for test development, comprehensive profiling, and discovery research. Figure taken from³.

Building on the success of OCTANE 1.0, the team later launched OCTANE 2.0, an expanded phase of the study that focuses on specific patient groups and collects longitudinal patient data to understand why cancer relapses and stops responding to treatment. OCTANE 2.0 collects blood samples, CT/MRI imaging at multiple time points, and tumor tissue if the cancer returns or progresses. A major goal of this phase is to detect molecular residual disease (MRD), which refers to the small amount of cancer cells that remain in the body after surgery to remove the main tumor. In this phase of the study, circulating tumor DNA (ctDNA) is analysed alongside imaging features such as tumor shape, size, and texture. Using this information, researchers aim to build computer models that predict which treatments are most suitable and identify patients at high risk of relapse (Fig. 2)⁵. The impact of OCTANE 1.0 and 2.0 is clearly quantified, with 6,253 patients enrolled in the study as of December 2025 and 4,754 patients whose tumor samples have undergone NGS testing. In addition, 18% of patients with clinically actionable mutations received targeted therapy through OCTANE’s initiatives, showcasing the program’s success⁶.

Fig 2. ctDNA extraction and uses in cancer diagnosis, treatment, and relapse detection. When tumor cells undergo apoptosis or necrosis, small fragments of tumor-derived DNA are released into the bloodstream. These fragments, known as circulating tumor DNA (ctDNA), can be isolated from a patient’s blood and analysed through genomic sequencing. Identified genetic variants can then be used in a range of clinical contexts, such as in OCTANE 2.0, to help guide treatment decisions and enable more personalized approaches to cancer care. Figure taken from⁷.

When Genomics Meets the Clinic: Highlights and Challenges

As one of the Principal Investigators of the OCTANE project⁶ and a medical oncologist, Dr. Bedard has the privilege of directly treating patients and translating the findings of OCTANE to patients for their clinical care. For Dr. Bedard, a meaningful aspect of his involvement in OCTANE lies in witnessing the more immediate benefits provided to his patients. “I can think of several patients who have had this type of testing and were successfully matched to a treatment, often through a clinical trial that wouldn’t otherwise have been an option. In some cases, those drugs are now approved and are being used to treat a much wider population of patients.” An example of such a clinical trial available to OCTANE patients is the Canadian Cancer Trials Group CAPTUR study². The aim of the study is to test the response of these cancers to currently available targeted therapeutics². Dr. Bedard emphasizes that genomic characterization of cancer can be “transformational” for those with the disease. OCTANE’s testing initiatives provide significant support to ground-breaking milestones in the field of targeted cancer therapeutics.

However, highly impactful projects come with significant challenges. Pursuing a project involving multiple stakeholders naturally introduces several moving parts. Different laboratories perform different types of genomics tests and have varying capacities, and these variables need to be considered when working toward a common goal. This challenge is addressed by the project’s centralized leadership at one institution, allowing principal investigators to set standards for the other groups involved. In the initial stages of OCTANE recruitment, small pilot studies were conducted with a few patients to “test run” the processes in place and ensure smooth translation to a larger network of clinicians and patients. As a new approach to genomics-guided therapeutics, Dr. Bedard explains that many oncologists are unfamiliar with these tests and how they are applied to patient care. Naturally, as the clinical research community pursues projects like OCTANE, individuals will become familiarized with similar approaches. The larger community’s growing understanding is great news for researchers, given that studies like OCTANE are unlikely to be phased out anytime soon.

Gaining the support of the larger research community is just one piece of the puzzle. Questions about how these strategies will be implemented into Canada’s healthcare system are those that investigators like Dr. Bedard must grapple with. As a publicly-funded system, there are certain standards that all therapeutic approaches must meet to be covered by Canada’s universal health insurance – something Dr. Bedard finds particularly difficult about the OCTANE initiative. “More than 10 years into doing this type of research, I still find it difficult that we can’t offer this kind of testing routinely to all patients, largely because it isn’t reimbursed within our health‑care system”, Dr. Bedard explained. These difficulties suggest that the current state of Canada’s healthcare system is not set up to effectively translate research discoveries into patient care. Dr. Bedard’s description of the reality of the healthcare scene in Canada suggests this could be a hurdle that researchers and clinicians continue to contend with in the push to revolutionize cancer patient care.

The Future of OCTANE

For Dr. Bedard, the infrastructure and collaborative network built through OCTANE are just as valuable as the data it has generated. While OCTANE has already generated a large repository of genomic and clinical data, the biorepositories and patient cohorts established through the study may enable entirely new lines of research in the coming years. At the heart of this long-term value is patients’ willingness to contribute their data and biological samples for research. Through OCTANE, many patients have consented to the use of anonymized information and leftover clinical samples in future studies, creating a resource that researchers can revisit as scientific tools and questions evolve.

As cancer genomics continues to evolve, so too will the OCTANE project. This will depend on Dr. Bedard and his colleagues’ ability to adapt to new technologies and address a broader scope of research questions. One of the most promising directions for OCTANE is to improve how clinical data is collected and analysed. Despite advances in genomic sequencing, Dr. Bedard notes that a major bottleneck in research remains the way clinical information is recorded. “Much of the clinical data that we collect is very manual,” he said. “And in 2026, it doesn’t really make a lot of sense because most of our medical information is buried in text-based notes and different electronic medical record systems.” This fragmented system makes it difficult for researchers to efficiently analyse treatment histories, outcomes, and other clinical variables alongside genomic data. To address this challenge, Dr. Bedard and his colleagues are interested in leveraging artificial intelligence, particularly large language models, to extract information from electronic medical records. Automating parts of the data collection process could significantly reduce the time researchers spend manually reviewing patient charts, allowing datasets to be updated more efficiently and enabling larger studies in the future. The clinical datasets generated through OCTANE may also provide a valuable foundation for developing and validating these AI-driven approaches.

Yet, Dr. Bedard emphasizes that technological innovation alone cannot transform cancer care. As genomic testing becomes more common, ensuring that clinicians understand and can act on these results is equally important. In oncology, this often takes place through multidisciplinary “tumor boards”, which entail regular meetings where oncologists, pathologists, geneticists, and other specialists review complex patient cases together. These discussions help clinicians interpret genomic findings and determine whether they may open new treatment options for patients. Improving genomic literacy among clinicians is essential for integrating precision medicine into routine care. Collaborative forums allow experts from multiple disciplines to share knowledge and ensure that genomic discoveries translate into meaningful treatment decisions.

Lessons in Cancer Research

Reflecting on his own career, Dr. Bedard also offered advice for students and early-career researchers entering the field. While breakthroughs in genomics often capture attention, the reality of research is frequently slower and more complex than expected. “There are always unanticipated problems that come up that you have to troubleshoot.” Large collaborative studies like OCTANE involve many moving parts, and unexpected challenges are inevitable. One lesson Dr. Bedard has learned from running these projects is the importance of breaking complex workflows into manageable steps before scaling up. “In these types of studies, we always started out with recruiting a single patient or a couple of patients in a week,” he explained. “Then we’d meet as a team, go over what worked and what didn’t, and try to understand where the hiccups were.” By identifying potential bottlenecks early and refining processes before expanding recruitment across larger networks, research teams can build stronger systems that support long-term, large-scale collaboration. As genomic technologies continue to advance and new analytical tools emerge, the future of projects like OCTANE will likely depend on this combination of innovation, collaboration, and persistence; qualities that Dr. Bedard believes are essential for translating genomic discoveries into better outcomes for patients.

References

1. The Princess Margaret Cancer Foundation. Dr. Philippe Bedard: Cancer Hero Spotlight. Instagram. https://www.instagram.com/p/DNDwPKgs5QL/ (2025).
2. Bedard, P. L. et al. Princess Margaret cancer centre (Pmcc) integrated molecular profiling in advanced cancers trial (Impact) using genotyping and targeted next-generation sequencing (Ngs). Journal of Clinical Oncology 31, 11002–11002 (2013).
3. Malone, E. R. et al. OCTANE (Ontario-wide Cancer Targeted Nucleic Acid Evaluation): a platform for intraprovincial, national, and international clinical data-sharing. Current Oncology 26, e618 (2019).
4. Malone, E. R., Oliva, M., Sabatini, P. J. B., Stockley, T. L. & Siu, L. L. Molecular profiling for precision cancer therapies. Genome Med 12, 8 (2020).
5. Ontario-wide Cancer Targeted Nucleic Acid Evaluation 2.0. Ontario Institute for Cancer Research https://oicr.on.ca/ontario-wide-cancer-targeted-nucleic-acid-evaluation-2-0/
6. OCTANE | UHN. https://octane.uhnresearch.ca/index.html#teams.
7. Sakaeda, S. & Naito, Y. Circulating tumor DNA in oncology. Processes 9, 2198 (2021).