Reprinted with the kind permission of the Microbe Discovery Project.
Columbia University – Center for Infection and Immunity has seriously upped the ante on the initial microbe discovery project in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Their impressive, rigorous new study could point the way to diagnostic tests, and even treatments – but first they need the funds to complete the work.
ME/CFS is an urgent challenge in clinical medicine and public health. There is no diagnostic test or specific treatment for ME/CFS, and in the United States alone there are a minimum of 836,000 afflicted individuals. Social and other costs for patients and their families are phenomenal, with medical care costing $24 billion – just in the US. While the US domestic cost is high, ME/CFS is very much a global problem.
The current project at the CII at Columbia University in New York is called ‘Microbial Discovery and Immunity in ME/CFS’. It builds on the foundation they established during the National Institutes of Health’s (NIH) multicenter study of XMRV/pMLV viruses in ME/CFS, led by Dr. Lipkin.
Since that first study – the team has published very significant research showing the immune system of patients who have recently developed ME/CFS look markedly different from those who have been ill for much longer. That immune signature work was partially supported by the Chronic Fatigue Initiative, who have also funded CII studies into pathogen discovery, metabolomics, proteomics, epigenetic analysis and immune profiling. There has been a wealth of investigation in process at CII – not to mention their other collaborative work in progress.
The CII has pioneered many relevant research techniques, has a stellar track record in research as well as unique expertise. The laboratory team has extensive experience in infectious disease epidemiology, microbe discovery and de-discovery, as well as in the development of sensitive blood tests and animal models needed to test for causal relationships and investigate disease causing mechanisms. Pathogens are not the only string in CII’s bow, their work also encompasses the immune system and neuro-immune areas.
It is hard to exaggerate how much rigor and expertise CII brings to the field of science in ME/CFS. They carefully investigate and go where the leads take them. With all this early investigative work under their belt – this new monster study is suggestive that the CII has good leads they are following. The Microbe Discovery Project team is ecstatic to bring you more details!
Comprehensive deep diving
The study intends to test the hypothesis that ME/CFS cases and controls have different bacterial, fungal or viral microflora in the oropharynx (mouth and throat regions), lower gastrointestinal tract (gut) and blood in a massive, well-powered study. By rigorously characterizing cases and controls and using state-of-the-art methods for identifying microbes, even currently-unknown ones, the CII will also study patients and controls for evidence of differences in immune system function and metabolic function.
This will be the first ME/CFS study to look at the microbiome over time. They are collecting stool and saliva at four different times over the course of a year, allowing the researchers to see if the changes in microbiome and immune system are related to changes in symptoms over time. Blood is also collected at the first and last time points.
All ME/CFS cases have been carefully diagnosed and meet both Fukuda criteria and the stricter Canadian criteria. The study will have 125 ME/CFS patients and 125 healthy matched controls.
Patients come from five expert centers for ME/CFS research and treatment across the United States. These include Dr. Lucinda Bateman, Bateman Horne Center, Salt Lake City; Dr. Nancy Klimas, Institute for Neuro Immune Medicine, Nova Southeastern University, Miami; Dr. Susan Levine, Private Practice, New York; Dr. Jose Montoya, Infectious Disease Clinic, Stanford and Dr. Daniel Peterson, Sierra Internal Medicine, Incline Village. The team has now recruited all the patients and controls they need, and enrollment is closed.
The CII only have the funding to rigorously collect, organize and store samples. They have NO funding to test and analyze the samples – which will generate a colossal amount of data from a large and carefully diagnosed, representative group of patients. If they get the funding they intend to do any or all of the following testing and analysis.
First off, the CII plans to investigate the human microbiome as it relates to ME/CFS, to determine how bacteria, fungi, viruses – and the immune response to them – contribute to the disease.
They will use high-tech methods to identify and quantify all the different bacteria (bacteriome), fungi (mycobiome) and viruses (virome) in each person’s gut and mouth/throat microbiome, effectively creating a map of each person’s microbiome. This alone is a huge undertaking in order to identify potential triggers of immune response and or metabolic problems.
The team then intends to apply a series of even more new technologies to test the blood for proteins, metabolites and immune markers to tease out what’s going wrong in people with ME/CFS.
VirCapSeq-VERT, is the Virome-Capture-Sequencing platform for Vertebrate viruses. This is powerful new technology invented by CII and hailed by Scientific American as one of the “world changing ideas” of 2015. It is a system to broadly screen for all viral infections in vertebrates including humans. This test has much greater sensitivity than the current standard molecular techniques, and increases viral matches from 100 to 10,000-fold compared with conventional high-throughput tests.
This testing identifies any virus that has ever been found to be in a person – 1.7 million agents are reported to be tapped through this testing. This work would clearly increase the yield of viruses detected in people with ME/CFS.
Proteomics, is the large-scale study of proteins in the blood, which gives researchers a protein ‘signature ’. By looking at all the proteins in the blood, rather than just focusing on a few, researchers get a much fuller picture of what’s going on, or wrong, in the body.
The aim is to identify biomarkers in blood that can be used for diagnosis, to predict illness progression and track responses to interventions. Biomarkers may also help identify targets for new therapies.
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Metabolomics, in a similar way to proteomics, is the study of ‘metabolites’, all the small chemicals in any tissue or the blood such as amino acids or hormones that result from metabolic processes in cells. This yields clues about what’s gone wrong in the body. Increasingly researchers are turning to the new field of metabolomics to understand disease. Ron Davis recently reported fascinating preliminary metabolomics findings in ME/CFS that suggest something is going seriously wrong with how patients produce energy from food.
As with proteomics, metabolomics may be used to identify potential ‘biomarkers’ that can be used for diagnosis and therapeutic targets. For instance, if the work identifies specific problems in energy metabolism, researchers can aim to tackle these problems with drugs, or even with supplements.
To identify biomarkers for diagnosis, prognosis, as well as potential therapeutic targets, and to determine the history of exposure to infectious agents that may trigger onset or exacerbation of ME/CFS.
The team will look to see if particular versions of genes are associated with subgroups that may predict course of illness or response to different treatments.
Epigenetics is the main system that turns some genes on and some genes off long-term, without affecting the DNA sequence itself. This study will look for epigenetic signatures that may be associated with ME/CFS and that may correlate with infectious or other triggers.
Homing in on ME/CFS
This study represents a comprehensive, robust investigation of the priority areas of research for ME/CFS that Dr. Lipkin recently identified in his letter to the NIH. This work now includes complex data mining and more. This can only be described as a tour de force that will home in on molecular detail – dive deeper, solidify findings and parse out subgroups. This is just the type of study that will help lead to diagnostic tools and possible treatment therapies.
There is some important key study strengths that are worth noting:
- The study is a good size, big enough to robustly detect even modest differences between patients and controls, and to tease out subgroups.
- Each of the four samples taken from every patient is limited to a three-month seasonal time frame to take into account natural, seasonal variations in bacterial, fungal, viral communities and immune system function.
- Patients come from strategic geographic distribution of sites across the United States.
- They will also collect data throughout the study on any new diagnoses or medications.
- A large effort has been undertaken to recruit a diverse population of patients and controls so that they will be more representative of the whole patient population. This means that any conclusions should apply to most patients, rather than being specific to a particular type of patient recruited for a particular study.
- Clinics will also indicate whether or not patients have cognitive problems (eg. memory or concentration) to help see if this identifies a clear subgroup.
Dr. Lipkin also explained in the letter to the NIH that their aim is to develop a Clinical Trials Unit to:
“rigorously examine interventions, including probiotic/nutritional, biological (e.g., immune regulators; anti-cytokine antibodies), medication and potentially, microbiome-related (e.g., fecal microbiome transplantation, other) approaches.”
As the team already has close links with five expert clinics, the trials unit is well placed to recruit patients to get trials moving as fast as possible. This study would be part of the building block foundation for the establishment of a center of excellence in ME/CFS research, that will hopefully ultimately have a global component.
There are no two ways about it – this study needs funding. More than a quarter of samples and questionnaires have already been collected and this analyses needs to get moving. They could be testing and analyzing these right now if the funds were available. The cost is often a lot more for analysis than collection, especially with this type of testing. The CII team is actively seeking funds to complete the work.
Our patient-led Microbe Discovery Project with all the support from the ME/CFS global community has helped to raise over $1.5 million in funds for CII research – our community made that happen. These funds along with an NIH NINDS grant and heavy subsidization by CII, enabling this collection.
CII needs at least $5 Million to test and analyze the samples. But, we can do more!
So far, the NIH has only given the researchers enough to partly cover recruiting patients and collecting samples, but the study is stranded without the funds for the all-important tests and analysis. We sincerely hope the NIH will decide to help make up some of the shortfall, but can we afford to wait? See our previous blog.
Too many people are too sick. Too many people have no support, help or treatments. There is a huge and urgent need for high quality research, and the CII team really needs our community’s help – so that they can help patients. We are still in a position of needing to bail-out mainstream research.
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