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Interview: Ian Lipkin's million dollar apeal for microbiome study
Friday 14 February 2014
Interview: Ian Lipkin’s Million Dollar Appeal for Microbiome Study
Simon McGrath recently secured an interview with the world famous Dr Ian Lipkin – a scientist who continues to believe that ME/CFS has a physical cause – to discover more about his plans for a major study of the gut microbiome and to find out why he’s asking the patient community for its support…
Dr W. Ian Lipkin has demonstrated a clear commitment to ME/CFS research. First came his study looking at Borna virus in the 1990’s, and then the landmark study that ruled out XMRV as a cause, and most recently we have heard about the huge pathogen and immune study – a vast collaboration with many key clinicians and researchers, including Dr Dan Peterson and Professor Jose Montoya.
That research had already found clear signs of immune activation in patients and, when I spoke to him, Lipkin was clearly excited about the very latest results to emerge from the study – I wish I could reveal more, but a paper has just been submitted and details are embargoed until publication.
Lipkin believes that immune activation may be responsible for driving the symptoms associated with ME/CFS. And that the immune activation and could itself be triggered by bugs, not in the blood, but found in the vast ecosystem of bacteria, viruses and fungi, that constitute the gut microbiome.
However, he doesn’t have the funds to pursue this research and so he’s appealing to the patient community for the one million dollars he needs to get the work done. The payoff? A better understanding of the illness and the possibility of new treatments.
The smoking gun
The immune activation he’s found could explain fatigue – it’s almost a universal symptom of infections like flu, and is actually a consequence of immune activation rather than caused by pathogens themselves.
The same could be true of other ME/CFS symptoms including disturbed sleep and brain dysfunction which again are typical symptoms of immune activation.
Lipkin is eager to build on this work. He believes the immune activation is a smoking gun and now wants to track down who or what pulled the trigger.
“I am more keen than ever … to see if we can identify the trigger”
There are several credible places to look for the culprits triggering the activation. One is white blood cells: some viruses could be hiding out in cells and so wouldn’t have been found by the initial search in the blood plasma – and Lipkin already has a white blood cell study lined up.
However, his attention is particularly focused on the microbiome, the large ecosystem of bugs that live on our skin and within our ‘inner tube‘ that leads from mouth to bottom.
There are at least one trillion bugs in the gut microbiome – and there are more immune cells in the gut than anywhere else: it’s a great place to hunt for bugs that might be triggering immune activation.
Microbiome problems are increasingly being linked to serious illness. The most striking example is the superbug Clostridium Difficile (C. diff), which has become a major problem in hospitals. C. diff lives in most of our guts harmlessly at low levels, but it can take over (particularly if ‘good’ bacteria are killed off) – causing diarrhoea and even death. Happily, doctors have discovered that severe C. diff cases can be treated relatively easily by restoring the microbiome; unhappily, this involves a faecal transplant.
The potential to treat disease by restoring the microbiome is one reason this area of research is attracting so much attention. This recent article explains more about the microbiome, how it might link to ME/CFS and looks at other research being performed.
“If the answer were simple, it would be done by now”
Irritable Bowel Disease is another example – here inflammation is believed to result from changes in the microbiome. Lipkin’s team have just been studying women in sub-saharan Africa and found that certain bacteria in the vaginal microbiome increase the risk of HIV infection. Lipkin thinks the gut microbiome could be playing a similarly important role in ME/CFS:
“By analogy with animals and human situations, we see that different populations of fungi, bacteria and viruses in the colon can have an impact on the immune system and give rise to cytokine activation which could cause the symptom complexes we see in ME/CFS”
in other words:
changes in microbiome > immune activation > symptoms of ME/CFS
I asked Lipkin if this meant particular bugs causing inflammation and he said that is certainly possible. But, he added, another route to illness is that an overgrowth of ‘’bad’’ bacteria could form a film, preventing ‘’good’’ bacteria from interacting positively with the immune system (see this article for more) – an indirect way of causing immune dysfunction.
The exact role that microorganisms in the gut play in health and in the development of disease is complex and still being determined. There are many plausible hypotheses, says Lipkin, and only research can show which (if any) are right.
If the microbiome is the cause, is it treatable?
If the microbiome is the cause (or a cause, or even a contributor) of ME/CFS, it might be relatively easy to treat, perhaps with probiotics, restriction diets, drugs, or even faecal transplants.
Cause or effect?
Of course, the first step in this process is demonstrating a strong link between the microbiome and ME/CFS. If one is found then the next step is to look for evidence it plays a causal role: i.e. do microbiome changescause immune dysfunction, as opposed to being a consequence of or simply associated with immune dysfunction?
Lipkin says one option is to use an animal model: the idea would be to introduce the microbes suspected of triggering ME/CFS into the gut microbiome of animals, to see if this leads to similar symptoms and immune activation as seen in humans. Something that has been used to study Metabolic syndrome.
If there is evidence of a causal role, Lipkin says they would look to establish clinical trials of treatments that could include probiotics, antibiotics followed by prebiotics, restriction diets and possibly even faecal transplants. He believes that there would not be a single microbiome cause of the illness, but different types – potentially fungal, bacterial and viral problems causing three separate types of immune dysfunction.
Lipkin calls these different types ‘endophenotypes’ and it could lead to personalised medicine, where the particular treatment depends on the specific form of the illness. There will be endophenotypes beyond those in the gut, such as genetics endophenotypes, and it is highly unlikely that the microbiome would account for all forms of ME/CFS – but this approach could tackle a very substantial proportion of cases.
The study breakdown
Lipkin’s proposed study will look at all three trees of life: bacteria, fungi and viruses in the microbiome of 100 patients and 100 controls recruited for a previous NIH study. It will cost a cool million dollars:
1. Sample collection: $150,000
Collection of faecal (and blood) samples from patients, including checking the initial ME/CFS diagnosis remains valid and shipping chilled samples back to the labs at Columbia.
2. Faecal Microbiome sequencing and Analysis: $317,000
- Separate, purify and perform high-throughput sequencing of viruses, fungi and bacteria
Comparison of patient and control microbiomes: bacteria, fungi and viruses that differ in prevalence between CFS subjects and controls will be considered candidates for contributing to either health or disease.
3. Development of highly-accurate real-time PCR assays to confirm findings and levels of microbes: $328,000
This will quantify how much there is of each bug of interest (the main high throughput sequencing approach gives an indication of quantity but is less accurate than real-time PCR).
It’s possible, that the most important thing isn’t the presence or absence of a microbe, but the amount of it – as with C.Difficile. These assays will also be used to check that key microbes haven’t been missed in any patient or controls who were negative for them in initial sequencing, as PCR assays are far more sensitive than high-throughput sequencing.
4. Cytokine analysis: $86,000
The study will again measure cytokines in blood and undertake data analysis to see if there is an association between cytokine profiles and immune profiles. It would then provide strong evidence of an important relationship between the microbiome and immune dysfunction – the hypothesis driving this study. Sophisticated analysis will be required on the vast amount of data generated by microbiome and cytokine profiling; happily, Lipkin’s Center for Infection and Immunity have a team of biostatisticians dedicated to such work.
5. Development of antibody tests for important bugs identified by the microbiome work: $249,000
It could be a few individual species or particular groups of microbes, but antibody tests will be developed by Lipkin’s lab to allow much easier testing to see if the same problems in this sample are found in the wider patient population.
As well as guiding treatments, the PCR assays and antibody tests developed here could both provide a diagnostic test for ME/CFS.
Scientist in a hurry for answers
Dr Lipkin is a scientist in a hurry for answers. That’s true both in his work trying to stop a new pandemic in its tracks, and in his work on ME/CFS.
He wants to follow up as many promising leads as possible, as soon as possible – rather than waiting for the results of a single study before planning a new one if the first draws a blank.
That’s why he set up a huge study looking for specific pathogens such as EBV, but also used deep sequencing alongside that to search for any other pathogen, known or unknown.
He’s looked in blood plasma for pathogens but is also about to look for them in white blood cells too.
He set the study up to look at immune markers including cytokines as well as for pathogens – and the significant findings of immune activation show the value of backing more than one horse.
On top of all this, Lipkin has invested in a gene expression study using samples from the same study, with results expected shortly that could throw up new leads in epigenetics and genomics.
Dr Lipkin has committed a huge amount of his 60-strong institution’s time to pursuing numerous studies, all aiming to uncover what’s really going on in ME/CFS
Too much, too soon?
However, it may be that the NIH is not in such a hurry as it has declined to fund the study at this time.
But then the NIH has only ever committed relatively small amounts of funding to ME/CFS – around $5 million a year, compared with around $115 million annually for MS and $284 million for Asthma.
Its funding record firmly suggests the NIH’s priorities lie elsewhere.
So, as Lipkin says, “we are stuck”. It’s possible that the NIH will fund this work in the future, and possible they won’t.
The question is, do we want to wait?
“We are already well behind where we should be”
Dr Lipkin has now appealed to patients to fund his latest study that aims to hunt in the gut microbiome for the ‘trigger’ of the immune activation his study found in ME/CFS. And he needs a cool million dollars to pay for the study outlined above.
Actually, the study comes to a bit over a million dollars (see above) - $1.13 million, to which another $140,000 of costs for maintaining the high-tech equipment used and general lab costs making $1.27 million in total. However, the initial target has been set at $1 million.
In his CDC telecast to patients last September, Lipkin explained the microbiome project was being held up by this lack of funds, and urged patients to contact their representatives in Congress.
He also appealed directly to patients who could afford to do so, to invest in research:
“It may not be appropriate to pass the hat, but that is exactly what I am doing”
How long will it take for the results? “Within a year”, said Lipkin
The man is in a hurry, and the study is all set up and ready to go – once funding is available.
“As long as I can do it, I will do it. I‘m eager to start, I‘m optimistic it will bear fruit, it‘s not just an academic exercise, it could lead to treatment”
When I mentioned to Dr Mady Hornig, the Principal Investigator on this study, that I was interviewing Dr Lipkin she added: “Terrific – we need the resources to get this done”.
Crowdsourcing: Together we can make it happen
I do think we are very lucky to have Dr Lipkin on our case and believe that we should back his new study, which will be performed at his Center for Infection and Immunity, Columbia University – the world’s largest and most advanced academic center in microbe discovery, identification and diagnosis.
“Why don‘t we crowdsource this, we are all losing valuable time in our lives?”
ME/CFS patient, Vanessa Li, responded to Lipkin’s call last year, by contacting his office and suggesting crowdsourcing in a similar way to MEandYou, which through the efforts of Dr Maria Gjerpe had raised an astonishing $0.5 million towards the Norwegian Rituximab trial in 90 days.
Lipkin was a physician in San Francisco at the start of the AIDS epidemic and commented how, when the government was reluctant to pay, much of the important early work was funded by private donors so he’s very open to this possibility. He continued to seek funds for his work from institutions, but as that hasn’t worked he is now asking patients if they can make the study happen – and has given this interview to launch the million dollar appeal.
Donate to the ME/CFS microbiome study
I have just donated and hope many other patients will do too. Just click on the button below and follow the instructions. The option is to donate to CFS research, but in the next page you can add ‘special instructions’ such as ‘for the microbiome study’.
We need only for every US patient to donate $1. Or one in ten patients to donate $10.
“The CDC says there are more than one million ME/CFS patients today in the US alone. There is no reason why, if every patient were made aware of Dr. Lipkin’s appeal and donated $1, that we should fail to raise the $1 million. An esteemed researcher doing high-caliber work is taking a serious interest in finding out the cause of our desperately under-researched illness. Now is the time to act!”
The above, with comments, originally appeared here.
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