Thanks to Simon and MEAction for allowing Health Rising to post Simon’s exposition of the truly remarkable chronic fatigue syndrome (ME/CFS) study about to take place at the NIH. This blog first appeared on MEAction. Most images and captions were added by me – Cort)
Blink and you’d missed it. In just six minutes and six slides, Dr Avindra Nath unveiled one of the most in-depth, comprehensive and innovative ME/CFS studies ever proposed: it’s the first fruit of Director Dr Francis Collins’s ‘new start’ for ME/CFS at the US National Institutes of Health (NIH). There wasn’t a lot of detail, but even from the preliminary information that’s available it’s clear that we’re looking at a very impressive project.
Since it was first announced, concerns about the study—including the selection criteria, the choice of control groups and the views of some of the researchers on the team—have dominated discussion in the ME/CFS community. During questions after his presentation, Nath said he was keen to have input from patients, citing his admiration for the role the patients’ group ACT UP played in research during the early AIDS epidemic. Carol Head, CEO of the Solve ME/CFS Initiative, has had encouraging discussions with Dr Vicky Whittemore of the NIH about patients’ concerns. She’ll discuss further with the NIH on March 8th, and I hope the NIH will engage with those criticisms then.
But looking closely at what we know so far about what the NIH is planning, it’s clear that it’s applying some extraordinary science to the problem of ME/CFS, science that could make a huge difference—despite the potential pitfalls.
The NIH is devoting some of the remarkable firepower available at its Intramural Center to probe deeply into the disease. When the study is done, researchers will probably know more about the 40 patients included than any other individuals in the history of ME/CFS, with the possible exception of the severely ill patients being studied by the End ME/CFS Project.
The NIH will train some of its clinical research center’s firepower on ME/CFS
Dr Nath, who is Chief of the Section of Infections of the Nervous System at the NIH’s National Institute of Neurological Diseases and Stroke, will lead the study: and he believes the immune system is where the action is.
He commented that many studies find interesting — but mostly inconsistent — immune abnormalities in patients, and that ME/CFS often begins with an infection. He said the promising results from pilot treatment studies with rituximab (which targets antibody-producing B cells) also pointed to a key role in the immune system, at least for some patients.
“Our hypothesis is that post-infectious ME/CFS is triggered by a viral illness that results in immune-mediated brain dysfunction”. Dr. Nath
The NIH is taking a very thorough approach to investigating immune (and other) problems. Although it’s relatively small, with 40 patients and 60 controls, the study is extraordinarily comprehensive, with two more studies due to build on its results, culminating, it’s planned, in trials of immunomodulatory agents.
- The study will take an astonishingly in-depth look at the immune system, both via the blood and spinal fluid. On the basis of the initial findings, the NIH will decide where to target even more sophisticated tests.
- The researchers will use a wide range of measures: thinking tests, metabolic tests that even measure how much energy patients burn as they sleep, autonomic function tests, and self-reported fatigue alongside activity measurement.
- Best of all, the study will look at how most of these measures are changed by exercise, focusing on the core feature of ME/CFS.
- And they will use two types of technology to probe what happens in the brain when patients are hit by exercise.
- The most ambitious part of the study will use cutting-edge technology to try to reproduce in the laboratory the clinical or biological abnormalities seen in patients. It could dramatically speed up understanding of the illness and the development of treatments.
The hope is that this intensive approach will crack open the illness so researchers can see more clearly what’s inside – providing clues that could help reveal the mechanism of the illness, and lead to treatments.
Details of the Study
Please note that most of this article is based on Dr Nath’s brief talk and slides at the CDC Grand Rounds in February 2016, and because details were quite sparse I’ve included a little information from the prematurely published (and then withdrawn) study protocol. I haven’t had the chance to fact-check my report with the NIH and so any errors are mine.
Patients and Controls
The NIH will recruit 40 ME/CFS patients, who will be thoroughly assessed and diagnosed according to the Canadian Consensus Criteria (generally thought to be the most rigorous case definition for diagnosis), as well as meeting the 1994 Fukuda/CDC criteria. Patients must also have a documented infectious onset at the start of their illness, such as glandular fever — because this study is pursuing the hypothesis that an initial infectious illness triggers long-term problems in the brain.
By focusing only on those with an infectious onset the NIH believe they will get a cleaner, more consistent group, making it easier to detect real, relevant differences among the inevitable random variation between patients. Patients also need to have been ill for between six months and five years and to have post-exertional malaise — the cardinal symptom of ME/CFS.
Those with a confirmed diagnosis then come back for a week as in-patients for an incredibly detailed evaluation.
Along with 20 healthy controls will be 20 post-Lyme disease patients who no longer have fatigue and 20 patients with functional movement disorder. These are patients with movement problems that are considered to be psychologically caused—one of the concerns that the ME/CFS community has about the study.
That’s a total of 100 people, making this a relatively small study and increasing the chance of false positives. However, the next phase of the study will be a validation of findings from this initial phase, which increases the likelihood of robust findings emerging.
Nath outlined four goals of the study.
1. Detailed Assessment of Patients (Phenotyping)
Phenotyping aims to describe patients in as much detail as possible. Beyond the assessments needed for diagnosis itself, researchers will check patients for neurological problems (including a brain scan) and will test basic autonomic body functions such as sweating and breathing, blood pressure, heart rate and tolerance of being upright. Experts in infectious diseases will assess patients. And researchers will also test memory and thinking performance, and monitor fatigue and activity levels — and test exercise capacity. Not a bad start.
2. Understanding the Biology Behind Patients’ Problems with Exercise
Researchers will home in on the central feature of this illness — how exertion wreaks havoc — by looking under the hood both before and, critically, after exercise.
They will focus on the brain using functional MRI scans, which show which brain circuits are in action (the provisional protocol said patients would be doing thinking and exercise tasks during these brain scans). This should help reveal what’s happening in the brain when patients are exhausted.
For the first time in ME/CFS, researchers will also be using a remarkable technique called transcranial magnetic stimulation to probe brain function. It uses magnets placed around the head to generate tiny electrical pulses in specific places in the brain, and researchers can check if the body responds to, say, activation of the brain’s movement centre, in the way it should. The technique has been used to diagnose conditions such as multiple sclerosis and Alzheimer’s disease.
Not only will the researchers measure patients’ energy use during exercise, they will also measure how much energy patients use as they sleep and rest before and after exercise, using a sealed metabolic chamber. This is another first in ME/CFS research.
The thinking and memory tests, and body function (autonomic) tests done before exercise will be repeated after to see what changes.
An possible downside of using exercise testing – which could prove so valuable – is that it might only attract patients who don’t have a strong reaction to exercise, which might bias results. Though the fact patients are in hospital for a week eases the strain, and patients might be willing to suffer a lot from exercise if the believe the study is important.
3. Identifying Immune System and Microbiome Abnormalities
This is where the researchers will zoom in on cellular and molecular problems.
The NIH will cover the basics by measuring cytokines, which essentially show the immune system talking to itself and to the rest of the body, and by identifying the number and type of different immune cells (such as antibody-producing B cells and natural killer cells).
These have been studied quite a bit in ME/CFS, as in last year’s finding from Columbia University that cytokine levels are elevated in patients who’d been ill for under three years, compared with those who’d been ill for longer. But the NIH will be going beyond previous work by doing this for spinal fluid as well as blood in the same patients. This will give an indication of what’s happening in the brain, and in addition, they’ll look for autoantibodies that could attack the brain.
The researchers will also look for any viruses that might be present, with a particularly in-depth approach for Herpes viruses.
But there’s a lot more.
Researchers will be sequencing T-cell receptors, which are a part of the immune system and are similar to antibodies in that they show which targets the immune system has already learned to identify as a threat. Each person has at least 100,000 of these receptors, and this will be one of the first ME/CFS studies to look at them. This may provide clues as to what might be driving problems in the immune system.
The researchers will also be looking at all the proteins in blood and spinal fluid: Dr Nath said they can detect at least 1,500 different proteins — proteins that will give clues about how cells are functioning, which types of cell are most active and how they are interacting with one another.
On top of that, the team will spy on what cells are doing using metabolomics. As cells do their work, they leave fingerprints behind in the form of specific chemicals, and these can provide a snapshot of how the cell is functioning at that moment. If unusual patterns are found in these chemical fingerprints, that could provide a clue about what’s making patients sick.
This in-depth approach to the immune system might sound familiar — Professor Ron Davis is using similar approaches to the immune system, including sequencing T cell receptors, as part of the Open Medicine Foundation’s Severely Ill study (as well as probing the immune system in other sophisticated ways that don’t feature in the NIH study).
Extraordinarily, Nath said the detailed immune profiling is just an initial screen to spot where the real problems are likely to be, so that the researchers can home in on them with the most appropriate tests. He said that this two-step approach was needed “because there are innumerable amounts of very time-consuming, tedious assays for each cell type that you could potentially do, or interactions between cell types”.
Note that point about interactions between different cell types. Nath said he’d consulted with NIH systems-biology and immune-cell expert Dr Ronald Germain, who specialises not just in how each type of immune cell works (or goes wrong) but also in how they interact.
Perhaps the problem in ME/CFS will be in how different immune cell types interact rather than in a single cell type. And the phenomenally complex immune system is all about how the many different immune cells come together to produce a co-ordinated response.
And if all that isn’t enough, the study will look at both the gut and oral microbiomes, both before and after exercise.
4. Reproducing ME/CFS in living systems in the laboratory
Up to this point, the NIH plan is largely to pursue existing research angles, often pushing them further and bringing together many, many approaches in a single intensive study. But they are also cutting loose and trying to recreate the illness in the laboratory, using tissue from patients.
Growing ME/CFS Neurones in the Lab
A challenge in studying a disease like ME/CFS that affects the brain is that you can’t snip neurones out of the brains of living patients to find out what’s wrong with them (at least not without doing grievous harm!). The NIH is planning to use some amazing new technology to get around this problem: they’ll take blood stem-cells from patients and use adult stem-cell technology to turn those cells into neurones — neurones that are still essentially patients’ cells.
From patient blood stem cells to neurones. Image from Dr Nath’s recent presentation.
Researchers will check the functioning of these neurones, including their mitochondria and the neurones’ ability to generate and respond to electrical signals. Next, researchers will see if spinal fluid or blood plasma will trigger functional problems in these neurones: maybe it’s something in these fluids that’s causing the problem in ME/CFS.
Creating ‘Humanised Mice’ Using Patient Cells
NIH researchers will create ‘humanised mice’ that essentially have immune systems seeded by patients’ cells. They will then test if spinal fluid or antibodies from patients will lead to fatigue or other ME/CFS-like symptoms in the mice.
Dr Nath pointed out that if these experimental systems are able to reproduce the clinical or biological abnormalities seen in these patients, it would be a huge step towards understanding the biology of the disease. And it could help develop new treatments faster.
A Promising Start From the NIH
In a remarkably short period of time the NIH have planned a small but incredibly comprehensive study. It not only zeroes in on the key problem of the effect of exertion, but also looks deeply at both the immune system and the brain — two areas that many researchers believe play a major role in the illness. And the NIH will try to develop disease models in the lab that could revolutionize how researchers study ME/CFS.
Nath explained that this study is just the first phase. Phase Two will follow patients longer-term and aims to validate the findings of Phase One, particularly for biomarkers. Nath said that If they manage to identify causes of the illness or symptoms, Phase Three will be an initial treatment study of immunomodulatory drugs.
My guess is that this first phase will cost at least a million dollars (a hundred people will be in-patients for a week of extensive testing) and maybe a great deal more.
An enormous amount of thought and imagination has gone into designing this intensive study, and it seems to me that Dr Nath is taking this disease extremely seriously. The study plan isn’t perfect, but it isn’t final yet, either. And it could prove to be the beginning of a new era for ME/CFS at the NIH — one that finally delivers for patients.
I’d asked Dr Vicky Whittemore is she had any corrections to the content and got this reply:
The only correction I have at this time is that it has been decided that they will not include individuals with functional movement disorders in this study