Updated: Oct 11, 2018
By Howard Searle
Have you ever wondered what research is being done here in BC into the mystery of Myalgic Encephalomyelitis?
I had this very thought, so I contacted Dr. David Patrick, Professor at the School of Population and Public Health, University of British Columbia, and Shoshana Parker, Clinical Research Coordinator.
Both Dr. Patrick and Shoshana were extremely helpful and informative. In fact, so much so, that I am including some of my interview with Dr. Patrick, along with a summary of three of their main studies.
Part 1: Interview with Dr. Patrick
I asked Dr. Patrick (who, rumour has it, also plays guitar around town with his blues band) what motivates him to undertake medical research.
Dr P: The first, in public health and medical practice, is the people. When you can see a large burden of illness in individual people and see its impact on a population, you naturally want to know if you can do anything that might change things. The second, is a love of the scientific process. It's not for everyone, but it works better than anything else humans have invented to get reliable answers. If you ask a good question and have the means to at least try to answer it, you need to get down to doing the research.
H: How do you decide on which medical question to investigate? Dr. P: In the case of ME/CFS, it was the very high unaddressed burden of illness together with the opportunity posed by new technologies that allow us to look at the complexity of the condition in new ways.
H: Is medical research "top secret" to prevent the theft of ideas that could lead to lucrative patents? Dr. P: Increasingly, this is the wrong way to go. Many funders and institutions are developing policies to make sure that key information is accessible for others to analyze. H: Funding for one study comes from the US National Institutes of Health, and for another, from ME Research UK. Does this cover all your costs for those studies? Do you receive research funding from British Columbian or Canadian sources also? Dr. P: Our largest and first grant came from the BC Center for Disease Control (BCCDC) Foundation for Population and Public Health and is an expression of the interest of the BC government in finding answers in this area.
H: How do you keep abreast of new ME/CFS research findings around the world when the total collective knowledge of humans is now doubling every (? nine) years? Dr. P: We do regular searches on PubMed and the referencing software, Mendeley - also identifies articles for me to review.
H: My understanding of the medication Rituximab is that it is a monoclonal antibody that attaches to B-cells of the immune system and triggers their death. Is ME/CFS believed to be a disease in which there are too many B cells, overactive B cells or dysfunctional B cells? Dr. P: One theory is that something B cells are doing matters. This could be antibody production or cell to cell signaling. This fall, the Norwegian phase 3 RCT with Rituximab will conclude. Only then can we determine whether there is strong, objective evidence for such an effect. H: I have read about tragic consequences of patients being given Rituximab which then re-activated a virus (such as Hepatitis B, or JC Virus leading to fatal Progressive Multifocal Leukoencephalopathy) that had previously been neutralized and held in check by B cells. What is the mechanism of action of Rituximab that is being used on ME/CFS patients and do the gains for the patient outweigh the risks of this medication? Dr. P: Rituximab is indeed, an immunosuppressive medication. It works by bringing down the population of B cells. This actually does not eliminate all antibody production because much of it comes from mature plasma cells that are not affected. I think we should be very cautious about using these medications and need very good evidence of efficacy and risk from clinical trials. I should note that our colleagues in rheumatology use the drug quite a bit and that the kind of complications you mention remain fairly rare.
Part 2: UBC Studies
Here is a summary of what I found out about their work.
Study: Discovery in Chronic Fatigue Syndrome, Chronic Lyme Disease And Systemic Lupus Erythematosus, 2011 - 2017
The ME research effort at UBC began with the Complex Chronic Disease Study, funded by the BCCDC Foundation for Population and Public Health.
The CCD study was our first effort to marshal the powers of new discovery technologies in the search for possible causes for ME/CFS. Since we were looking very broadly using three broad-reaching discovery technologies, we actually considered it a hypothesis-generating study. In other words, we wanted to see if these new tools would give us new observations that might open up fresh lines of inquiry.
- Dr. David Patrick
This study compared ME/CFS patients with healthy controls, as well as with two groups of patients: patients with Systemic Lupus Erythematosus (a disease whose symptoms overlap those of ME/CFS); and patients with chronic “Alternately Diagnosed Lyme Disease”.
These 4 patient groups were compared in terms of their reported levels of disability. In so doing, the utility of the Functional Capacity Scale (FCS), developed by Dr. Alison Bested, was compared to the Karnofsky Performance Scale to determine which provided higher delineation of patient symptoms. As it turns out, the FCS had a fairly useful dynamic range, better able to correlate health and debility than did the Karnofsky for their ME/CFS patients.
Method 1: blood samples were processed to look for previously unrecognized or unique microorganisms (such as Borrelia which causes Lyme Disease) that could characterize each group. None were found.
Method 2: RNA sequencing was conducted on blood samples to examine differences in the expression of genes that may be present between the groups. Again, none were found, but the researchers did find that the gene expression signature typically seen in Lyme Disease was NOT present in the group with Aalternately diagnosed@ Lyme Disease, a finding which may prove useful in understanding that condition better.
Method 3: peptide-array based immunosignature assays were done on antibodies in blood samples to look for identifiable patterns that could possibly serve as a tool for positively diagnosing the presence of ME/CFS in a patient. Also, the assays were examined to see if they divide known ME/CFS patients into different subsets.
To help you understand this part of the study, let me first give you some basics about antibodies. Antibodies, also referred to as immunoglobulins, are glycoproteins naturally produced in response to invading foreign particles (called antigens) such as viruses and microorganisms. Antibodies are Y-shaped protein structures that play a critical role in the immune system’s defense against infection and disease. Various types of antigens are recognized by antibodies: (1) proteins such as receptors on cancer cells; (2) sugars on bacterial and viral cell surfaces; (3) hormones; (4) chemicals; (5) nucleic acid structures of DNA or RNA.
Because antibodies are long-lived and multiply as needed, at any given time you have a large collection of different antibodies circulating in your blood. These circulating antibodies represent a history of the infections or antigens that you have been exposed to over the course of your lifetime. A higher number of particular antibodies will be indicative of an active or a more recent infection.
New medical technology allows us to take a snapshot of a person=s antibody repertoire, called an immunosignature, by taking a blood serum sample (which contains your antibodies) and adding a drop onto a standardized peptide array chip (which are now mass-produced using techniques from the semi-conductor industry). The antibodies will bind with the proteins on the plate in a pattern that can analyzed and processed to produce your unique immunosignature, which can sometimes be further analyzed to deduce one or more illnesses that are current or recent.
You may have heard that ME/CFS often appears in people following some sort of viral infection. Which virus or viruses are the culprits? The use of immunosignature studies may soon provide an answer to this question.
Keeping this background in mind, the UBC study was conducted with the hope of deducing a sound hypothesis about the cause of ME/CFS, which at present remains unknown; and secondly, to create, with other investigators, a library of information on ME/CFS host factors as a resource for further research.
This methodology produced some interesting results. Firstly, the UBC researchers seem to have found a unique subset of ME/CFS patient with similar antibody immunosignatures. Secondly, their preliminary analysis indicated that there may be a pattern of antibody signature that is unique to ME/CFS patients in a Norwegian study who responded favourably to treatment with Rituximab (a monoclonal antibody medication that suppresses the action of immune system B-cells). These two findings must now be reproduced in new studies in order to be scientifically validated.
Several articles have been written on this study, we’ve posted a couple here:
Study: Exploring Host Gene Expression During Post-Exertional Symptom Flare in ME/CFS
This UBC study examines the possible causes and the physical processes responsible for post-exertional malaise in ME/CFS patients, which is one of the hallmark symptoms of the disease. This study is funded by a grant from the US National Institutes of Health (NIH).
People with ME/CFS suffer profound fatigue that is made worse by physical or mental activity and generally report other symptoms such as problems with sleep, thinking and body pain. Over half a million Canadians experience symptoms congruent with this syndrome and many suffer high levels of disability and are completely bedridden.
The overall aim of this study is to examine the cause and physical processes involved in ME/CFS by combining new methods of genetic studies and a unique experimental design.
The UBC researchers are taking a fresh look at why people with ME/CFS feel profoundly tired following exercise. They took blood samples before each of two standardized exercise tests, and samples 48 hours after and 7 days after the first exercise test. Newly available gene sequencing methods were used to make comparisons in how gene expression differs between the ME/CFS patient and control groups. The exercise testing is designed to provoke a measurable response and also permits unbiased classification of patients according to their exercise response. The gene sequencing allows a much deeper examination of which genes may be activated and expressed after exercise and during the recovery period. By looking for differences in exercise response and gene expression in those with ME/CFS and in healthy people before and after an exercise challenge, the researchers hope to identify specific patterns or responses that might explain the crash and prolonged fatigue symptoms, help with diagnosis, and point to pathways for therapy.
Study: Can an Immunosignature Assay identify patients with ME/CFS who will benefit from B Cell Depletion with Rituximab?
A third study underway teams up the UBC researchers with the Norwegian group that is conducting the Phase 3 randomized control trial of Rituximab to treat ME/CFS patients. The UBC research group has the goal of being able to use the immunosignature they identified in the first study to clearly predict which patients will respond to the treatment.
Only the lead investigators know which patients are getting the real drug, and which are getting a placebo (which makes it a “blinded” study). The Norwegian study will not be unblinded until 2018, at which time we will find out if the UBC researchers accurately predicted those who improve with the treatment and not the placebo and thus if their hypothesis represents sound science. Let’s keep our fingers crossed and hope that this method works. If we could use an immunosignature to accurately predict which ME/CFS patients would benefit from Rituximab, this would be a big step forward in the treatment of this disease.