Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Centers

The Columbia ME/CFS Collaborative Research Center

The Center for Solutions for ME/CFS (CfS for ME/CFS) is an interdisciplinary, inter-institutional center comprising clinicians, clinical investigators, and basic scientists who work together to understand the pathogenesis of ME/CFS and develop evidence-based strategies for interventions that prevent and mitigate disease. The CfS for ME/CFS is designed to rapidly adapt to the insights and opportunities that are continuously emerging in the field of ME/CFS research.

Center Director, W. Ian Lipkin, MD

The Columbia ME/CFS Collaborative Research Center was led by W. Ian Lipkin, MD. Dr. Lipkin is the Director of the Center for Solutions for ME/CFS and the Director for the Center of Infection and Immunity with the Mailman School of Public Health at Columbia University. Dr. Lipkin is internationally recognized for his contributions to global public health through the innovative methods he developed for diagnosis, surveillance, and discovery in the field of infectious diseases. He led the team that refuted a role for XMRV as the cause of ME/CFS.

Network Funded Projects

Study 1

Microbiology of ME/CFS

Summary of Findings: This study consisted of a large survey of blood, saliva, and feces for bacteria, viruses, and fungi potentially implicated in the pathogenesis of ME/CFS. Samples were collected at discrete geographic locations at up to four timepoints and analyzed using high throughput sequencing methods and polymerase chain reaction. The most substantive finding was a reduced amount of Faecalibacterium prausnitzii and Eubacterium rectale in ME/CFS–two of the most abundant, health-promoting, butyrate-producers in the human gut, and of an attendant decrease in levels of fecal short-chain fatty acids. Butyrate is implicated in maintenance of the integrity of the colonic mucosa and in immunoregulation. Linkage of these findings to symptom severity provides support for clinical trials that explore the utility of dietary, probiotic, and prebiotic interventions to boost colonic butyrate production in ME/CFS. Additional Activities:

A pilot study of the fecal microbiome in ME/CFS that revealed dysbiosis and laid the foundation for a larger study.
An unbiased plasma proteome analysis demonstrating the antigen drive that substantiates efforts in serology.
Analyses of viral nucleic acid in blood, feces, and saliva of patients with ME/CFS. No consistent group-specific differences other than a lower prevalence of anelloviruses in cases compared to healthy controls were found. These findings suggest that future studies on viral infections in ME/CFS should focus on adaptive immune responses rather than surveillance for viral gene products.

Study 2

Molecular Signatures for ME/CFS Sub-Types

Summary: This study consisted of metabolomic, proteomic, and transcriptomic analyses of samples from the same subjects assessed in the Microbiology of ME/CFS study. The study identified metabolomic disturbances that may provide key insights about cellular abnormalities and new methods for statistical analysis. Proteomic and transcriptomic findings reveal evidence of endoplasmic reticulum (ER) stress after exercise. This is important because the ER serves many roles in the cell including calcium storage, protein synthesis, and lipid metabolism Additional Activities:

A pilot study of the plasma metabolome in ME/CFS that provided a predictive biomarker model of ME/CFS and laid the foundation for a larger investigation.
The first report of peroxisomal dysfunction in ME/CFS. Peroxisomes are oxidative organelles engaged in synthesis of plasmalogens and other ether phospholipids critical to CNS structure and function.
Demonstrated Bayesian statistics can enable insights that cannot be obtained using classical univariate analyses that follow a frequentist approach, using p-values to reject a null-hypothesis.
The first report of cytokine expression from T cells in post exertional malaise following exercise and ex vivo stimulation with immunostimulatory agents. The results support a model of ME/CFS pathogenesis wherein hypersensitivity to microbial stimuli results in immunological activation that is more pronounced in females than in males.

Study 3

Clinical Correlates and Diagnostics in ME/CFS

Summary: This study consisted of blood samples before and after exercise tolerance testing, validation of a test for autonomic dysfunction, and analysis of questionnaires collected over a period of several years. Additional Activities:

Validated simple orthostatic challenge test (in office setting) produced worsened symptoms, altered hemodynamic responses, and cognitive abnormalities in people with post-acute sequelae of SARS-CoV-2 infection (PASC)/Long COVID and ME/CFS.
Identified 102 people with ME/CFS and 522 others with severe fatigue not due to ME/CFS. Risk factor analyses indicated qualitatively different mechanisms for the pathogenesis of ME/CFS and the common complaints of severe fatigue associated with a higher age and BMI, hormone therapy, increased alcohol intake, and decreased caffeine intake.
An early review of similarities and distinctions between ME/CFS and PASC/Long COVID that posed specific research questions.
Update on state of knowledge regarding epidemiology, pathogenesis and management of ME/CFS and PASC/Long COVID.

The Cornell ME/CFS Collaborative Research Center

The Cornell Center for Enervating NeuroImmune Disease conducts and promotes interdisciplinary research to identify the causes, biomarkers, and pathophysiology of ME/CFS with the goal of developing diagnostic and treatment methods. The Center draws expertise from Cornell's flagship campus and medical college, a local research institute, Ithaca College, and medical practices, utilizing their collective scientific and clinical expertise in advanced neuroimaging techniques, proteomics, metabolism, molecular biology, and genetics.

Center Director, Maureen Hanson, PhD

Photo by Dave Burbank

The Cornell ME/CFS Collaborative Research Center was led by three Principal Investigators, Maureen Hanson, PhD., Andrew Grimson, PhD, and Dikoma Shungu, PhD. Dr. Hanson, a Liberty Hyde Bailey Professor at Cornell University in Ithaca, NY, directs Cornell's Center for Enervating NeuroImmune Disease. Dr. Grimson is a Professor in the Department of Molecular Biology & Genetics at Cornell University. Dr. Shungu is Professor of Physics in Radiology at Weill Cornell Medicine in Manhattan, NY.

Clinical Core:

The Clinical Core of the Cornell ME/CFS Center at Ithaca College cooperated with the John Chia Clinic in Torrance, CA, and Weill Cornell Medicine to recruit 82 healthy sedentary individuals and 91 individuals with ME/CFS to participate in cardiopulmonary exercise tests (CPET). Blood and urine samples collected before and after each CPET have been analyzed by a variety of methods in the three Projects.

Integrative Data Analysis Core:

The Core was led by Jennifer Grenier at Cornell University and Arindam RoyChoudhury at Weill Cornell Medicine. The Core assisted the three Network-Funded Projects in analysis of data and interfaced with the Data Management and Coordinating Center to provide information for the mapMECFS database.

Network Funded Projects

Study 1

Oxidative Stress and Neuroinflammation: Co-conspirators in ME/CFS Pathophysiology: Lead, Dr. Dikoma Shungu

Summary: The main objective of this research project was to use advanced magnetic resonance (MR) and PET neuroimaging techniques before and after symptom provocation with physical exercise to test a pathophysiological model of ME/CFS in which oxidative stress, neuroinflammation, and, possibly, mitochondrial dysfunction are key interacting mechanisms in the etiopathogenesis of the disorder. As briefly summarized below, neuroimaging data collected at Weill Cornell Medicine from 31 individuals with ME/CFS and 21 healthy individuals supported the presence of CNS oxidative stress in ME/CFS, but found no central effects of physical exercise on neurochemistry. Cortical Glutathione as a Marker of CNS Oxidative Stress in ME CFS: Statistical analyses comparing levels of occipital and striatal glutathione (GSH) measured with MR spectroscopy (MRS) between and within ME/CFS patients and healthy volunteers (HC) at baseline and 24h following CPET were conducted. The results are below. Occipital GSH:

Between-Groups Comparisons: Consistent with our published results, occipital GSH was lower in ME/CFS compared to HC in the occipital brain region both at baseline (PRE: P=0.016) and at 24h following CPET (POST: P=0.007), the GSH deficit in ME/CFS relative to HC remained. The finding is consistent with the presence of oxidative stress in in the occipital cortex of the ME/CFS.
Within-Group Comparisons (PRE-POST CPET): Levels of occipital GSH within the ME/CFS/em> patients or the HC group did not differ significantly between baseline and 24h post-CPET, a surprising and currently unexplained observation.

Striatal Glutathione:

Between-Groups Comparisons: We found no significant striatal GSH deficit in ME/CFS compared to HC, either PRE (P=0.46) or at 24h POST CPET, indicating similar levels of oxidative stress.
Within-Group Comparisons: Levels of striatal GSH within the ME/CFS patients or the HC group did not differ significantly between PRE and 24h POST-CPET

Study 2

Probing the Pathophysiology of ME/CFS through Proteomics and Metabolomics: Lead, Dr. Maureen Hanson

Summary: Blood and urine samples from subjects who performed two-day Cardiopulmonary Exercise Tests (CPETS) were analyzed by plasma metabolomics, plasma and extracellular vesicle (EV) proteomics, serology, flux analysis, and flow cytometry to uncover markers and mechanisms of post-exertional malaise in ME/CFS. We confirmed that ME/CFS cases and healthy controls and males and females differ in their physiological and molecular responses to exercise. Controls were able to reproduce their first CPET (CPET-1) measures, but ME/CFS subjects exhibited declines in their peak work effort, exercise time, peak oxygen consumption, heart rate, and O2pulse during the second CPET (CPET-2). Measures at the ventilatory/anaerobic or gas exchange threshold (VAT) in CPET-2 were also different in cases vs. controls. ME/CFS cases exhibited a worsened impairment status in CPET-2 vs CPET-1. Abnormal CPET responses were observed even when cases were matched with controls for aerobic capacity, indicating that aerobic fitness level has little impact on the factors that contribute to exertion intolerance in ME/CFS. ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. Metabolites in plasma of ME/CFS cases and controls differed in response to CPETs, especially with regard to energy-related pathways and ones involving glutamate metabolism, which is important for proper function of many organs in the body, including the brain. The urine metabolome of ME/CFS patients during recovery from exercise exhibited few changes from baseline, while significant changes were induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients. The protein content of extracellular vesicles, which are released from many types of cells, were found to differ in ME/CFS cases and controls. Among the affected proteins are ones involved in immune signaling and blood coagulation. T cells were found to exhibit abnormal metabolism in ME/CFS patients that could impair their activity.

Study 3

Deciphering Gene Dysregulation Across the Immune System in ME/CFS with Single-Cell Transcriptomics: Lead, Dr. Andrew Grimson

Summary: Lymphocytes isolated from 30 ME/CFS and 30 control subjects before a maximal CPET and 24 hours later were subjected to single-cell RNAseq analysis with the 10x Genomics platform to provide definitive data on gene regulatory changes in leukocytes from ME/CFS patients. We observed that prior to exercise ME/CFS patients exhibited dysregulation of gene expression in classical monocytes. The pathways that were aberrant were suggestive of inappropriate differentiation and migration to tissue. Using a machine learning approach, it was possible to identify monocytes with a "diseased" pattern of gene expression as well as others with more normal gene expression. The fraction of disease vs. normal cells differed between patients correlated with metrics of disease severity, with a greater level of symptoms in those with higher levels of "diseased" monocytes. Platelets were the most dysregulated cell type when comparisons were made between the transcriptome at baseline and 24 hours after the exercise challenge. We discovered patterns indicative of improper platelet activation in patients. Most cell types did not differ greatly in gene expression changes between pre- and post-exercise.

The Jackson Laboratory ME/CFS Collaborative Research Center

The Jackson Laboratory (JAX) is an independent, nonprofit biomedical research institution whose mission is to discover precise genomic solutions for human disease. The JAX CRC brought together experts in computational biology, statistics, chemistry, immunology, metabolomics, and microbiology to test an emerging hypothesis about the interplay between a patient's immune system, metabolism, and microbiome in the onset and progression of ME/CFS.

Center Director, Derya Unutmaz, MD

The Jackson Laboratory ME/CFS Collaborative Research Center was led by Derya Unutmaz, MD. Dr. Unutmaz is a Professor and Principal Investigator at The Jackson Laboratory for Genomic Medicine. His research team investigates the biology of the human immune system and the relevance of human T cell subsets to normal immune response, diseases, and aging. His expertise in immunology, microbiology, and pathology has led to advances in the understanding of how T cells contribute to immune suppression during infection and other chronic diseases.

Clinical Core:

Bateman Horne Center

The Bateman Horne Center Clinical Core was co-led by Lucinda Bateman, MD and Suzanne Vernon, PhD. The goal of the Center is to improve access to informed health care for individuals with ME/CFS, Long COVID, and fibromyalgia by translating their clinical expertise into medical education and research initiatives.

Network Funded Projects

Study 1

Immune Profiling

Summary: This study used multi-color flow cytometry to identify frequencies and functional subsets of immune cells within peripheral blood mononuclear cells (PBMC). The team established updated antibody panels of up to 20 color, and 6 different panels, generating more than 300 immune cell/function data points per patient.

Study 2

Metabolism Study

Summary: For this study JAX performed a targeted analysis of metabolites in blood samples. Selection of up to 1000 metabolites was performed in multiple time points through Metabolon. JAX has accumulated approximately 500 thousand data points. Additional metabolomics are available on Long COVID patients. This study linked metabolism to immune and microbiome disturbances. Machine learning approaches were used to associate metabolomics and microbiome data sets.

Study 3

Microbiome Study

Summary: This study consisted of metagenomic sequencing of stool samples for microbiome analysis. Thousands of bacteria strains were screen and potential aryl hydrocarbon receptor (AHR) pathway metabolites were identified via culturomics. The Jax team utilized AI-based topological analysis to integrate data from immune systems, metabolism, and the microbiome. They identified disturbances in various immune compartments that correlate with metabolic pathways, which are further linked to alterations in the microbiome. This comprehensive analysis aims to pinpoint precise actionable targets for therapeutic intervention in ME/CFS. Additionally, it will facilitate the grouping of patients into specific categories, enhancing the precision of medical treatments.

Funding was provided through grants U54-AI-138370, U54-NS-105539, U54-NS-105541, and U24-NS-105535 supported by: