2021 Ramsay Grant Study Summaries

“Symptoms, Mechanisms and Sex: Exploring Sex Differences in ME/CFS through Integrated Computational Analyses”

 Dr. Sara Ballouz, PhD, (Principal Investigator), is the senior research officer at the Garvan-Weizmann Centre for Cellular Genomics in New South Wales, Australia. One of her main scientific interests includes studying genome variation, genetic architecture of complex diseases and the influence of different genotypes on gene and protein function. 

Dr. Anna Liza Kretzschmar, PhD, is a postdoctoral fellow and research officer at the Garvan-Weizmann Centre for Cellular Genomics. Her work includes large dataset exploration through bioinformatics, such as developing molecular characterization approaches and monitoring systems of fish poisoning. 

The team will build a network analysis tool to parse and homogenize survey-driven data to allow for comparability of phenotype information from patients with ME/CFS and with Long Covid in multiple registries.

These tools have the possibility of producing a better understanding of disease subsets, improve informatics approaches, and develop machine learning/algorithms for characterizing the disease. Both will also complete single-cell immune transcriptomic data in a sex-specific manner for ME/CFS patients, which could produce insight into how ME/CFS differs between males and females (an understudied question). 

Study Summary 

We plan to tackle how ME/CFS and sex differences manifest through an exploration of gene expression and cellular heterogeneity of the immune system in ME/CFS. We hope to find celltypes, genes and gene interactions associated with ME/CFS symptoms to eventually lead to better diagnoses and treatments. 

Alongside this, we will address the problems in diagnosis and classification of ME/CFS through a computational analysis of phenotypic, survey and biomarker data. Both aims involve the use of biobanked samples and data: the first requires blood samples to profile the immune systems of ME/CFS sufferers and the second survey responses and quantitative traits to data mine and highlight features to aid in classification and diagnosis of disease.   

It is anticipated that this research will provide characteristics of ME/CFS at the symptomatic, molecular and cellular levels. The ultimate goal is to use this knowledge for molecularly characterizing the blood of ME/CFS individuals and their symptoms to identify and diagnose patients, leading to improved clinical treatments. 

“Physiological and Cognitive Function in Patients with PASC or ME before and after Inspiratory Muscle Training” 

Heather Edgell, PhD, (Principal Investigator), is an associate professor in the Kinesiology and Health Sciences Department at York University where she founded the Women’s Cardiovascular Health Lab, an autonomic and cardiorespiratory testing lab.

Lauren Sergio, PhD, (Principal Investigator) is a professor in the Kinesiology and Health Sciences Department at York University working on projects related to the neural control of movement.

Angela Cheung, MD, (Principal Investigator), is a senior scientist and staff general internist at the University Health Network whose research interests include integrative medicine, functional outcomes, quality of life and health services research.  

The team will provide people with ME/CFS, people with Long Covid and a comparator group of healthy controls with an eight-week period of inspiratory muscle training (IMT) to strengthen the muscles used to breathe.

They hypothesize that a reduction of hyperventilation (which has been observed in both conditions) will increase plasma levels of carbon dioxide and improve brain blood flow, brain function and cognition. The investigators will measure a number of cardiovascular and pulmonary markers of health at baseline and following the IMT intervention. 

Study Summary 

After the severe acute respiratory syndrome (SARS-CoV) pandemic of 2003, 27% of survivors in Hong Kong had developed ME/CFS, commonly known as chronic fatigue syndrome. It was found that SARS survivors had persistent functional disability one year after discharge from the ICU due to impaired muscle function. 

Subsequently in 2011, another group of researchers investigated a sub-set of SARS survivors who developed musculoskeletal pain, weakness, fatigability and shortness of breath and found sleep abnormalities similar to ME patients. 

These changes are already frequently observed in survivors of the current COVID-19 pandemic, which is an infection of the SARS-CoV-2 virus. These patients have anecdotally been known as “longhaulers,” yet as of February 2021, they are now known as having “Post Acute Sequelae of SARS-CoV-2” or PASC.

Recently, it was noted that in a cohort of 234 Covid-19 survivors, ~30% experienced persistent symptoms including fatigue (most common) and cognitive dysfunction in the form of “brain fog.” Some patients still experienced these symptoms 9 months after infection. In Canada and the United States, there have been over 30 million cases of Covid-19, and if previous observations hold true (i.e. 30% of survivors develop ME) over 9 million people in Canada and the United States alone could already be developing ME from their SARS-CoV-2 infection.

In these populations, exercise has been shown to be a beneficial treatment avenue. Due to fatigue, however, it is very difficult to perform and to maintain adherence to a program. Therefore, we are suggesting that inspiratory muscle training (IMT) can be implemented as it is easily accessible commercially and it is relatively easy to conduct, even in a supine posture.

Patients with current Covid-19 infection or PASC are known to experience hyperventilation and IMT training has been shown to reduce hyperventilation in chronic conditions such as heart failure. This reduction of hyperventilation will increase arterial levels of carbon dioxide back to normal levels which will increase brain blood flow and increase brain function and cognition.

We hypothesize that PASC patients will have developed ME symptoms and will display vascular and pulmonary dysfunction. We further hypothesize that eight weeks of IMT will improve both vascular and pulmonary function in PASC and ME. 

In patients with PASC or ME and a group of healthy controls, we will measure autonomic symptoms, ME symptoms, vascular function, cardiovascular response to upright tilt, pulmonary function, cognitive function and the breathing and brain blood flow responses to low oxygen and low carbon dioxide. These measurements will be conducted before and after an eight-week IMT training protocol to observe improvements. 

“Microbial Aryl Hydrocarbon Receptor Agonists in ME/CFS” 

Dr. David Esteban, PhD, (Principal Investigator), is an associate professor of biology at Vassar College. He has a broad background in microbiology and uses both wet-lab experiments and bioinformatics to address research questions related to the host-microbe interaction. 

Dr. Esteban will investigate the production of molecules by microbes in the gut that activate a specific receptor (called aryl hydrocarbon or AhR). AhR dysregulation is implicated not only in gastrointestinal disease, such as inflammatory bowel disease, but also in multiple sclerosis, rheumatoid arthritis, psoriasis and viral infections.

The hypothesis, if proven, could unite a number of different observations that have been made in ME/CFS: dysbiosis of the gut microbiome, “leaky gut,” abnormal tryptophan metabolites and neuroinflammation.

 Study Summary 

The gut microbiome is a complex and dynamic community of microorganisms that reside in the gastrointestinal tract. Not simply passive residents, gut microbes impact systems in the human body including gastrointestinal function, inflammation and neurological processes. Alterations in the gut microbiome, termed dysbiosis, is often associated with disease and can be both a contributor to and a consequence of disease. Several studies have described dysbiosis in people with ME/CFS.  

Metabolism of the amino acid tryptophan by microbes in the gut yields products (called agonists) that activate the aryl hydrocarbon receptor (AhR). AhR is a regulator of inflammation and homeostasis, and is expressed in cells of the gut, immune system, and other tissues.

In studies of gastrointestinal diseases, microbial production of AhR agonists from tryptophan reduces disease severity and improves gut barrier function. However, because the microbiome affects, and is affected by, organ systems beyond the gut itself (including the immune system, the nervous system, and the endocrine system) microbially derived AhR agonists may have systemic effects. 

AhR dysregulation is implicated not only in gastrointestinal disease such as inflammatory bowel disease, but also in multiple sclerosis, rheumatoid arthritis, psoriasis and viral infections. This underscores the need to understand processes taking place in the gut as part of a complex multisystem disease. The specific role of AhR and microbially derived agonists in ME/CFS, however, has not been investigated. Together, dysbiosis and the high prevalence of gastrointestinal symptoms in ME/CFS, and its function in modulating other neurological and autoimmune diseases, point to AhR as a possible regulator of disease in ME/CFS.   

The purpose of this study is to investigate the production of, and response to, microbially derived AhR agonists in ME/CFS. We propose that the microbiomes of people with ME/CFS produce less or different AhR agonists, contributing to pathological inflammation and disrupted gastrointestinal homeostasis.

Experiments will be conducted to measure AhR activating function and the induction of genes important in gut barrier homeostasis and inflammation by gut microbial communities from people with ME/CFS.  We will also identify AhR agonists and characterize the gut microbial community.  

The underlying mechanisms of pathogenesis in ME/CFS remain unidentified, leaving a crucial gap that makes treatment a significant challenge. Tryptophan metabolites regulate several autoimmune and inflammatory diseases, but as yet, no experimental work on ME/CFS has been done to specifically investigate the role of AhR or its microbially derived agonists. Importantly, AhR is a druggable target so uncovering a role for AhR in ME/CFS can also reveal a target for treatment.  

“Blood-Brain Barrier Imaging as a Biomarker for ME/CFS”  

Alon Friedman, PhD, (Principal Investigator) is founder and CEO of Emagix, an AI software, as well as a professor of neuroscience. Dr. Friedman’s research focus is on how the interaction between components of the neurovascular network (e.g. nerve cells, glia and vasculature) underlies abnormal brain functions. 

Javeria Hashmi, PhD, is an assistant professor and a Canada Research Chair Tier II (Pain) nominee who has trained in brain imaging and pain research. Her lab’s main focus is on chronic pain mechanisms and therapy. 

The team will complete a study to assess blood-brain barrier (BBB) integrity in the brains of people with ME/CFS and of controls. A “leaky” BBB often correlates with neuroinflammation, which researchers believe could contribute to symptoms of ME/CFS. However, it has not previously been possible to assess leaky blood vessels in meaningful detail. This proposal would use a recently improved magnetic resonance imaging (MRI) technology to assess leakage of the BBB, along with other measures of brain structure and function. 

 Study Summary

This research aims to address the challenge of reliable and objective clinical diagnosis of ME/CFS. The wide range of symptoms associated with the disorder and the lack of uniform diagnostic criteria result in frequent misdiagnoses and improper treatment. On average, individuals with ME/CFS receive their diagnosis five years after symptoms appear.

 To target this challenge, we aim to establish an objective and reliable method for diagnosing ME/CFS using MRI. We have developed a novel MRI approach that maps the integrity of small blood vessels in the brain and identifies brain regions with leaky vasculature. Importantly, leaky blood vessels have been suggested to play a role in ME/CFS symptoms since they allow leakage of substances from the blood to the brain. Such leakage causes inflammation in brain tissue (neuroinflammation) which is suggested to be a key feature of ME/CFS.  

We propose to conduct the first study investigating the health of brain vasculature in ME/CFS patients and to test whether the newly developed MRI approach can allow the diagnosis of ME/CFS. 

In this one-year proof-of-concept study we will scan 20 patients with ME/CFS and 20 healthy individuals (similar in age and sex). The occurrence and extent of leaky blood vessels will be compared between the two groups. We will next characterize which brain networks are affected by leaky blood vessels, and whether this pathology is associated with other brain abnormalities detectable using additional cutting-edge MRI techniques.   

We expect to find greater occurrence of leaky blood vessels in the brains of patients with ME/CFS compared to controls and to identify specific brain networks that are more likely to be affected than others. We further anticipate that brain networks with leaky blood vessels will be associated with abnormalities in their structure, function, and volume.  

The results of this research will provide the preliminary evidence necessary for conducting a larger study that would allow the diagnostic validation of the approach in a large number of patients with ME/CFS. Moreover, the insights from this work may set the stage for the development of new ME/CFS treatments that target the health of the brain’s blood vessels and neuroinflammation.  

“Application of Machine Learning and Text Analytics in a Cohort of People with ME/CFS and People with Long Covid to Capture Disease Severity, Potential Associations and Sequential Patterns of Events” 

Efthymios Kalafatis, MSc, (Principal Investigator) is a data scientist with 21 years of experience in data analysis, including the application of artificial intelligence and machine learning methods in the healthcare, banking, social media and other sectors. 

Kathleen Mudie, MSc, is a research senior manager at the Solve ME/CFS Initiative with epidemiological experience in ME/CFS as well as other chronic conditions, such as chronic kidney disease, hypertension and diabetes.

Kalafatis will lead the project, which will capitalize on the power that health tracking has to help us better identify meaningful patterns in chronic illness research by applying powerful machine learning and analysis methods to better understand symptoms, identify potential associations with treatments and life events and examine models of temporal patterns.   

Study Summary 

We propose using cutting-edge machine learning and text analytics methods in data collected from participants of the You + ME Registry that will enable fast and cost-effective research into ME/CFS, Long Covid and other diseases. 

Our goal is to combine questionnaire data and data from the mobile symptom tracking app in order to identify across all participants patterns with symptoms, treatments, life events and activities. We will also look at how these patterns can change over time at the individual level. Findings of this study have the potential to highlight areas of research necessary for furthering our understanding of these diseases, both in research and in clinical practice.

“Discovery of Pathological Autoantibodies in ME/CFS and Post-Acute Sequelae of SARS-CoV-2 Infection” 

Aaron Ring, PhD, (Principal Investigator) is an associate professor of immunobiology at Yale University. His laboratory focuses on understanding and manipulating the activity of immune receptors using precision pharmacology and on applying methods in which desired traits are created through repeated rounds of genetic changes to create new pharmacological tools and therapeutics for the immune system. 

Dr. Ring will examine autoantibody reactivities of ME/CFS patients using a technique called Rapid Extracellular Autoantibody Profiling (REAP). This study will build on previous work of autoantibodies in ME/CFS by using a technology and approach that will give this disease mechanism a much more in-depth investigation. Dr. Ring will also compare the ME/CFS data to a previously studied Long Covid cohort. A more rigorous investigation of a potential autoimmune component of ME/CFS could open the door to biomarkers and a host of therapies (for example, B-cell depleting drugs). 

 Study Summary 

 ME/CFS is a debilitating, multisystemic condition of uncertain etiology. However, evidence of immune system dysfunction, including the presence of autoantibodies, is well-established in ME/CFS patients. While some patients benefit from B cell – or antibody-depleting therapies, the role and significance of autoantibodies in ME/CFS pathophysiology is not well understood. 

In this grant, we propose to use Rapid Extracellular Antigen Profiling (REAP) to comprehensively assess the autoantibody reactivities of ME/CFS patients against 4,200 extracellular human proteins and 50 pathogen antigens expressed in a yeast display library. 

Then we will assess the biological functionality of these autoantibodies using ex vivo assays. With statistical modeling, we will ask whether specific ME/CFS reactivities correlate with clinical parameters or symptoms and whether autoantibodies can be used as a framework to subset patients within this heterogeneous diagnosis.

Overall, this work represents the first comprehensive and unbiased survey of autoantibody reactivities in ME/CFS. We believe our findings will generate novel insights into the role of humoral autoimmunity in ME/CFS pathophysiology. 

“ME/CFS and Long Covid: Are They the Same Condition?” 

Jennifer Stone, PhD, (Principal Investigator) is a newly-minted PhD recipient with a thesis in evidence synthesis methodology at Australian National University.

Brett Lidbury, PhD is an associate professor at the National Centre for Epidemiology and Public Health at Australian National University and an established ME/CFS researcher.

Alice Richardson, PhD, is an associate professor and director of the Statistical Consulting Unit at Australian National University. 

The team will use advanced analytic methods to compare individuals with ME/CFS against Long Covid controls and healthy controls on important demographic and clinical characteristics. 

Study Summary 

ME/CFS is a complex and highly individualized condition characterized by persistent fatigue and other symptoms that are exacerbated by exertion. Previously recognized as a psychogenic illness, individuals with ME/CFS have suffered a lingering negative stigma in addition to inadequate funding for research and inconsistent case definitions guiding clinical practice, resulting in suboptimal diagnosis and treatment. 

The emergence of ME/CFS symptoms following Covid-19 infection (Long Covid) has been documented, providing support for ME/CFS as a post viral illness. The Solve ME/CFS Initiative presents a unique opportunity to increase our understanding of ME/CFS as a post viral infection following the Covid-19 pandemic and provide insight into working case definitions through the identification of ME/CFS and Long Covid subgroups and treatments.

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