Lipkin finds biomarkers not bugs

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The CDC PCOCA telephone broadcast on 10 September 2013, featured a lengthy presentation from Dr Ian Lipkin who revealed some stunning initial results from the study that is primarily hunting for pathogens in ME/CFS. Simon McGrath and Russell Fleming (Firestormm) review this exciting and possibly game-changing news...


Dr Ian Lipkin
Lead Researcher
Chronic Fatigue Initiative (CFI)
Pathogen Discovery and Pathogenesis Study

Read the full Lipkin Transcript: Here.

Dr Ian Lipkin has been a human whirlwind in ME/CFS research since he became involved a few years back, and he's just surprised us all by announcing the first results from the world's largest ever biomedical ME/CFS study in a public broadcast!

He started off by lowering expectations: their results thus far do not implicate a single infectious agent and they have not discovered the cause of CFS. But he then wowed the hundreds listening to the conference call by revealing they had found strong evidence for immune overstimulation, both in blood plasma and in cerebro spinal fluid; and that they were now hard at work trying to identify what could be causing these abnormalities.

The big pathogen hunt draws a blank thus far

This study is looking exhaustively for any pathogen: viral, bacterial, fungal or parasitic, to see if a chronic infection could explain ME/CFS. Many of the results are in, but so far there is no clear sign of viruses at least. It is every bit a collaborative effort, with patients provided by long-established physicians including Dr Dan Peterson and Professor Jose Montoya.

The Key Players

Lipkin began by thanking the clinicians who had provided the all-important samples. Effectively it was a roll call of America's top ME/CFS physicians:

Professors Jose Montoya, Anthony Komaroff and Nancy Klimas; and Drs Dan Peterson, Lucinda Bateman, Sue Levine and Donna Felsenstein.

The study itself was run by Dr Mady Hornig (CFI Principal Investigator) at the Centre for Infection and Immunity at Mailman School of Public Health; where Lipkin is also based.

He went on to acknowledged the very necessary support of the Chronic Fatigue Initiative, the Evans Foundation and an anonymous donor supporting Montoya's work.​

First the researchers looked at blood plasma for 285 CFS patients and 201 controls from Jose Montoya at Stanford (these are serious numbers). They searched for genetic evidence of infection using a panel that was able to detect 20 specific bacteria, viruses or parasites; including Epstein-Barr virus, Human Herpes Virus 6, enteroviruses, Influenza A and Borrelia bacteria.

Next they used high throughput sequencing, a method that was pioneered by Lipkin and colleagues that was used to discover over 500 viruses – so they felt fairly confident that if a virus was present, then they would have found it.

But they effectively drew a blank using both methods - only 1.4% of CFS patients were found to have HHV6 infection, but so did 1% of controls.

Other findings...

Lipkin said they also found Anelloviruses in 75% of those studied in plasma samples, but it was not specific for Chronic Fatigue Syndrome (we don't currently have separate figures for patients and controls). Anellovirus is believed to cause widespread chronic infection in the human population, but has not yet been associated to any specific disease. "I really don’t know at this point what this finding means" said Lipkin.

They also found retroviruses in 85% of the sample pools. However, Lipkin expressed caution:

"It is very difficult at this point to know whether or not this is clinically significant. And given the previous experience with retroviruses in Chronic Fatigue, I am going to be very clear in telling you – although I am reporting this at present – in Professor Montoya’s samples neither he nor we have concluded that there is a relationship to disease ...if I were to place bets and speculate, I would say that this is not going to pan out."

Window on the brain: Cerebrospinal fluid samples

Both Lipkin and Hornig were clearly excited to have had access to the 60 cerebrospinal fluid samples from Peterson, and kindly donated by his ME/CFS patients. Cerebrospinal fluid bathes our brain and spinal cord so it gives access to what goes on in the brain, a prime site of interest to researchers, but hard to access; so these spinal tap samples are precious.

However, using the same molecular techniques to track down pathogens as they had applied to Jose Montoya's samples, Lipkin's team again drew a blank.

At the Invest in ME conference in May, Hornig said they had tentative findings that there might just be a novel pathogen or pathogen candidate in these samples - but it was too early to say for sure. In reply to a question yesterday, Lipkin said there is no more to report:

"we do not yet have a novel pathogen nor do we have a pathogen candidate in which I would have any confidence. So at this point we have no plans to publish anything."
Nonetheless, he also said they hadn't finished all the DNA sequencing work on these samples, so this is not yet a dead end.

Immune stimulation and biomarkers

Up to this point we'd heard a lot of very impressive negative findings, based on large, well-defined samples of patients and controls, and using powerful research techniques. But what we most wanted to hear about was positive leads - and Ian Lipkin duly obliged:


Plasma is the clear fluid left when blood is separated

They took plasma from the CFI cohort of 200 very well-defined ME/CFS cases and 200 controls collected by clinicians (See 'Key Players' above). Then they searched for cytokines and chemokines, which are regulators and controllers of the immune system.

The big finding was a decrease in levels of Interleukin's IL-17, IL-2, IL-8 and in TNF-alpha - all of which have a role in pro-inflammatory responses. Lipkin believes these significant differences are worth follow-up in larger cohorts to better understand what they mean.

Professor Jonathan Edwards (who is an adviser to the planned UK Rituximab trial) commented on this forum yesterday, that it was a surprise to see TNF-alpha levels decrease, and suggested it could mean that 'inflammation' is too crude a concept for the process.

Lipkin and colleagues also found upregulation in Leptin, a hormone that plays a key role in regulating energy uptake and use, and Serpin, a protein family with multiple roles. More obscure cytokines, and and their cousins chemokines, were also affected but Lipkin didn't give any further detail.

Two new patient types revealed

Ian Lipkin said they found something very surprising in their data: there appear to be substantial differences in profiles between those people who have had the disease for 3 years or less and those who have had the disease for more than 3 years. And that this is important because, "it could have implications for therapy as well as for diagnosis".

In the ‘early group’, who have been ill for less than 3 years, there seem to be a number of markers suggestive of some sort of allergy aspect. For example there are often increased numbers of eosinophils in blood, with more differences in cytokines. But while this is tentative, he was more confident in the finding the IL-17 was elevated in these 'early' patients, compared with reduced levels in patients ill for over three years.

Lipkin said that he thought this 3-year division could be very important and that it hadn't been something they were looking for; but would be looked at in any future work they did.

Cerebrospinal fluid: different differences

Lipkin's team also found differences in cerebrospinal fluid biomarkers between patients and controls. I'm not sure from what he said if there were significant differences between the 'early' group and patients who had been ill for more than three years. However, they did find that patients had elevated levels of the TH-2 type cytokines IL-10 and IL-13 and elevated levels of four TH-1 cytokine: IL-1 beta, TNF-alpha, IL-5, and IL-17. Lipkin said this is compatible with a profile of some particular types of response that may provide insights into immunological dysregulation in Chronic Fatigue Syndrome.

So, overall they found clear differences between patients and controls in both plasma and spinal fluid. Many immune differences have been detected before, but findings are not very consistent and none had used such a large and robustly-defined patient cohort (meeting Fukuda and Canadian criteria), or with such carefully matched controls.

HEALTH WARNING

Dr Ian Lipkin again was very clear that he did NOT recommend anyone act on these provisional findings: he doesn't want anyone to get a spinal tap, or measure the cytokine levels and hope to modulate them with drugs based on this research: it's too early for that.​

The lost years...
Back in 1999 Ian Lipkin published his first paper on CFS, which ruled out a connection between the illness and Borna Disease Virus (one of the many viruses he's discovered). But crucially they found evidence of polyclonal B-cell reactivity. He commented that back then:

"there was a very strong sentiment in some portions of the scientific and clinical communities – not always and not everywhere – but in some portions of the community, that this was a psychological illness. What I said was that based on our findings we had very strong evidence that people with Chronic Fatigue Syndrome were truly ill with a physical illness and they deserved a "Deep Dive" to find out why they were ill."
He noted that was a long time ago and dryly added "I am pleased to see that people are now paying much more attention to this disorder and what we can do about it".
What next?

"I still believe the primary cause is likely to be an infectious agent."
Having found clear signs of cytokine abnormalities, Lipkin wants to find out what is causing these changes; he currently thinks that an ongoing stimulus is causing immune system activation which might be resulting in the symptoms we associate with the disease. And interestingly, he still believes that infection lies at the root of it all - despite not yet finding any infections.

The team - working closely with the clinicians he's already mentioned - plan even more extensive work on a cohort of 200 CFI patients and controls. They will further test for viruses and crucially they will also look for bacteria and fungi by sequencing ribosomal RNA (which should detect unknown bacteria and fungi, as well as known ones).

Previous infection detection

The group has looked for current pathogens in the blood and spinal fluid samples they have - and has so far drawn a blank, though there is more work underway. However, what if the trigger for ME/CFS is an earlier infection that has since been cleared: the 'hit and run' scenario Hornig has described? Lipkin says they are looking for "shadows" of previous infections by searching for antibodies against specific infections, rather than the infections themselves (the body will continue to produce low levels of specific antibodies years after an infection has been cleared (the basis of much immunity)).

They will use a technique called LIPS to look for antibodies against particular known infection. In addition, as in their viral sequencing work, they will use an 'unbiased' system (using peptide arrays) that should detect all potential viruses - or rather antibodies against them. They don't currently have an 'unbiased' system that works on bacteria or fungi.

Fecal future?

What excites Ian Lipkin most is the gut microbiome, the community of micro-organisms that live in our gut - which might seem odd given his focus so far on pathogens and the immune system. However, it turns out that the microbiome can have a profound influence on the immune system and may be important in many diseases. Hornig and Lipkin have already developed techniques to study the microbiome, and have shown it could be a factor in autism and even in the severity of colon cancer.

It turns out the best way to find out what lives in the microbiome is to measure what comes out of the gut: fecal matter, or 'poop' to you and me. Their ME/CFS microbiome project has started, but Lipkin felt there wasn't enough material in the first attempt at gathering samples, so things have been delayed as they switch to a new technique (the 'special' collection cups).

The Big Ask: "we can't do this without you"

Microbiome research is very expensive (analysis, not sample collection), and they currently only have the funds to do 10% of what's needed. In fact, throughout the call, Lipkin was stressing the need for more funds, because good research costs and ME/CFS is woefully underfunded: there just isn't enough money to do the work needed. The current science budget cuts (Sequestration) in the US makes the climate even harder.

"It is probably inappropriate for me to be passing the hat, but that’s precisely what I am doing."

He urged patients to contact their representatives in Congress, demanding more funding for ME/CFS research - pointing out that in the early days of HIV, there was little funding until patients demanded it. He also said that if patients were able to afford it, they should invest in research themselves.

Conclusion

ME/CFS research is coming of age. Ian Lipkin has reported these early - and soon-to-be published results - from a huge study, using 285 of Jose Montoya's patients, the 200 patients from the Chronic Fatigue Initiative, plus the 60 'gold-dust' spinal fluid samples from Dan Peterson's patients. Using state-of-the-art techniques, they have largely ruled out a role for a specific pathogen - though that work is incomplete. And they have strong evidence of ongoing immune stimulation in ME/CFS patients, with abnormalities found in both the blood and spinal fluid. The next stage involves deeper searching for bacteria and fungi, looking for 'shadows' of previous infections and investigating the gut microbiome. These are exciting times!

Thanks to the CDC for organizing the presentation and to Firestormm for providing a transcript of this talk, and above all to Dr Ian Lipkin for taking time out to talk to patients.

If you would like to donate to Ian Lipkin's research, click here. In the comments box, put "for M.E/C.F.S Study" to make sure it goes to the right place.


Simon McGrath tweets on ME/CFS research:



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Comments

Many viruses like the nervous system, so its possible that those markers found in csf are from viruses. Meningittis is one that comes to find and a recent study i read somewhere and dont have a link, maybe someone can help out, but with some type of new testing ebv was found to be a major cause of viral meningittis where the older testing methods couldnt detect which infection was the issue. chickenpox/shingles loves the nervous system.

All comes down to which types of tests are the best for which viruses.

I still cant get past many of us not having chronic viral infections when most of us have low nk function, who's job it is to kill viruses. if its herpes virus or some other virus, if they cant find them then they probably haven't looked in the right places or don't have the right tests.

A quick search of other auto immune illnesses too show viral infections play apart in some of them. There is even some with MS who have improved on valtrex. Maybe when all this is sorted they will possibly find viral infections implicated in other illnesses that they dont have the final answer in like many auto immune illnesses.

That's my opinion anyway.

A few good points here: NK cells however play a more major role in innate immunity - the job of clearing up viruses is generally down to the adaptive immune system with T-cells and B-cells + the antibodies the B-cells produce.

To me it seems a little strange that despite these results people still hold strongly onto the viral causation. I understand the argument of tissue-specific viruses but I would expect some clues to still be present in these samples. There has to come a point where we come to accept that viruses aren't the major cause of pathology in ME and I think we're fast approaching that - certainly it is worth testing these things to the fullest of our abilities but if the evidence isn't there you have to move on to other hypotheses. I think there is little argument that they are the most common triggering factor, likely due to the immune response they initiate, but if results searching for them keep turning up a blank we need to explore other areas and I think autoimmunity is both the most associated with the viral ideas and also probably the most exciting area at the minute.
 
The failure to replicate virus results is not a recent phenomena, it is a consistent one over 20 years. Viruses seem to be key triggers for onset of symptoms, but evidence for chronic infection has remained elusive for a long time, and there are many other good hypotheses out there...
 
A few good points here: NK cells however play a more major role in innate immunity - the job of clearing up viruses is generally down to the adaptive immune system with T-cells and B-cells + the antibodies the B-cells produce.

To me it seems a little strange that despite these results people still hold strongly onto the viral causation. I understand the argument of tissue-specific viruses but I would expect some clues to still be present in these samples. There has to come a point where we come to accept that viruses aren't the major cause of pathology in ME and I think we're fast approaching that - certainly it is worth testing these things to the fullest of our abilities but if the evidence isn't there you have to move on to other hypotheses. I think there is little argument that they are the most common triggering factor, likely due to the immune response they initiate, but if results searching for them keep turning up a blank we need to explore other areas and I think autoimmunity is both the most associated with the viral ideas and also probably the most exciting area at the minute.
The reason I think viruses may still be involved (not necessarily causal, but involved) is because Dr Chia found enterovirus in about 2/3 of my stomach biopsy cells. Unless the sample was contaminated I just can't see how this cannot be significant. I hope to hear from Dr Chia on these issue - ie lack of enteroviral RNA in the plasma and CSF.

I do agree, however, it is puzzling there is no RNA of these viruses in the blood if they are involved.
 
The reason I think viruses may still be involved (not necessarily causal, but involved) is because Dr Chia found enterovirus in about 2/3 of my stomach biopsy cells. Unless the sample was contaminated I just can't see how this cannot be significant. I hope to hear from Dr Chia on these issue - ie lack of enteroviral RNA in the plasma and CSF.

I do agree, however, it is puzzling there is no RNA of these viruses in the blood if they are involved.
I admit to knowing very little about enteroviruses. I do know that it's possible these widespread infections are not always the cause of disease. I would though like to hear from Dr Chia with regard to Lipkin's work here. Maybe once it's published he will be willing to review? I am sure many doctors involved in ME work will be reviewing the data and hopefully talking to their patients - even if only to reassure.
 
Definitely should be sub typing. I think many hold onto the virus theory as there is a group of cfsers who improve on antivirals. Myself dont believe it is the cause but treating them can help alot. Nk cells are there for a reason and work with other t cells and b cells. No reason why this dysfunction can reduce e the immune systems ability to contrl viral infections.
The autoimmune theory so far hasn't had alot of success at all that has been posted by people here?

Some recent studies show not only nk but cd8 t cells have low function. I believe its these abnormalities that allow one to get a variety of infections or maybe hit and run. I dont know what they would call this, an immune deficiency or dysfunction.
 
The failure to replicate virus results is not a recent phenomena, it is a consistent one over 20 years. Viruses seem to be key triggers for onset of symptoms, but evidence for chronic infection has remained elusive for a long time, and there are many other good hypotheses out there...
Proper accurate testing as well as well defined cfs study participants could account for there inability to find viruses. Doesn't seem to be a problem for lerner Peterson klimas, as well as being able to treat and improve many of them.
 
I admit to knowing very little about enteroviruses. I do know that it's possible these widespread infections are not always the cause of disease. I would though like to hear from Dr Chia with regard to Lipkin's work here. Maybe once it's published he will be willing to review? I am sure many doctors involved in ME work will be reviewing the data and hopefully talking to their patients - even if only to reassure.
I dont think lipkins current work has alot to offer. All it seems to be doing is giving us more questions then answers. We will have to wait until its finished.
Montoya is doing a separate pathogen study?? Do we know when this will be finished??
 
I refuse to believe the immunesystem attacks self for no reason. I always have and likely always will.

It's an incredibly complex topic and one I plan to explore more in a possible article in the future. Suffice it to say that there is generally a trigger in autoimmune diseases which moves it from a silent (ie non symptomatic) state into a seemingly active and debilitating state. These triggers can include non-self things such as viruses or bacterial infections - but the immune response then appears to be self perpetuating.
 
Serpins are a superfamily of proteins, and their function is critically reliant on proper folding. We already know we have increased protein misfolding (KDM finding?) and that we have a mechanism for decreased folding: glutathione deficiency. So are septins, while abundant in quantity, really abundant functionally or deficient? I don't know.

http://www.ncbi.nlm.nih.gov/pubmed/21781239

Here is a recent review on serpins:

http://genomebiology.com/2006/7/5/216

Serpins are involved in regulating proteases, but also as transport molecules, involving both corticosteroids and thyroid hormone. Its worth noting that one of these, corticosteroid binding hormone, may be involved in producing CFS-like symptoms.

Have a gander at this table: http://genomebiology.com/2006/7/5/216/table/T1

In order to make sense of Lipkin's finding we need to know which serpins are involved. Until then the range of possible impact is very open to wild speculation.
 
The reason I think viruses may still be involved (not necessarily causal, but involved) is because Dr Chia found enterovirus in about 2/3 of my stomach biopsy cells. Unless the sample was contaminated I just can't see how this cannot be significant. I hope to hear from Dr Chia on these issue - ie lack of enteroviral RNA in the plasma and CSF.

I do agree, however, it is puzzling there is no RNA of these viruses in the blood if they are involved.
If the biospy included staining of cells to be viewed under a microscope, the possibility of contamination is unlikely. If its just an assay to detect presence of the cells, then contamination is possible. I don't recall exactly, but haven't both been done and the biopsies found to be positive?
 
I refuse to believe the immunesystem attacks self for no reason. I always have and likely always will.
One theory of autoimmune is due to how the antibody immune system works. The B cells randomly reshuffle some of their DNA to make antibodies ... which have random targets. Any that match native proteins near where this occurs should be eliminated. A few years back there was a paper showing that proteins that are only expressed far from where the B cells are adapting may not lead to elimination of these B cells.

When the immune cells are activated by something its due to a protein or protein complex match. If there is sufficient activation then the activated cells multiply - clonal expansion. This is when we develop resistance to pathogens - we have sufficient antibodies to fight them. This is what Rituximab targets - it kills B cells. This is what Lipkin found in the earlier paper. Our immune systems are reacting to something.

B cells might also create autoantibodies in numbers due to cross-reactivity. The cells are responding to something else, but the antibodies have sufficient affinity to self-proteins that they get weakly attacked.
 
(neuro)toxines -produced by microflora- can trigger the immunesystem. I think this is the next step to investigate.
 
One theory of autoimmune is due to how the antibody immune system works. The B cells randomly reshuffle some of their DNA to make antibodies ... which have random targets. Any that match native proteins near where this occurs should be eliminated. A few years back there was a paper showing that proteins that are only expressed far from where the B cells are adapting may not lead to elimination of these B cells.

When the immune cells are activated by something its due to a protein or protein complex match. If there is sufficient activation then the activated cells multiply - clonal expansion. This is when we develop resistance to pathogens - we have sufficient antibodies to fight them. This is what Rituximab targets - it kills B cells. This is what Lipkin found in the earlier paper. Our immune systems are reacting to something.

B cells might also create autoantibodies in numbers due to cross-reactivity. The cells are responding to something else, but the antibodies have sufficient affinity to self-proteins that they get weakly attacked.

Yep - I think it is also worth mentioning that a small degree of autoimmunity with regards to the production of autoantibodies is a good thing. The argument that autoimmunity needs an external stimulus is a little silly when you consider the benefits that autoimmunity has with regard to detecting and successfully fighting cancerous cells. If autoimmunity was a bad things then it would likely no longer exist in the human (and other organisms) population as the genes and traits responsible for it would have not been selected for during evolution.
Autoimmunity only becomes a bad thing when the immune response gets stuck in cycles over-expressing randomly created autoantibodies and the response that ensues therein.
 
http://www.jimmunol.org/content/174/6/3137.full

Leptin in Immunology
Abstract

Leptin is an adipokine which conveys information on energy availability. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of leptin in the pathophysiology of immune responses
This is an old paper, so take what it says too seriously. I am citing it to introduce a point. In obesity research high leptin from fat cells is thought to not make it to the brain at a high enough rate, and so does not send proper signals to the hypothalamus.

Leptin sends a signal to the brain that there is plenty of energy available, crank up the metabolic rate. What if there isn't, if the leptin is derived some other way? If you have low energy capacity.with high leptin, what happens? What happens if the signal is distorted, as found in obesity, and the hypothalamus is not getting the message that there is too much energy?

Its also worth noting that women make more leptin than men. Is this related to why more women get ME than men?
 
One theory of autoimmune is due to how the antibody immune system works. The B cells randomly reshuffle some of their DNA to make antibodies ... which have random targets. Any that match native proteins near where this occurs should be eliminated. A few years back there was a paper showing that proteins that are only expressed far from where the B cells are adapting may not lead to elimination of these B cells.

When the immune cells are activated by something its due to a protein or protein complex match. If there is sufficient activation then the activated cells multiply - clonal expansion. This is when we develop resistance to pathogens - we have sufficient antibodies to fight them. This is what Rituximab targets - it kills B cells. This is what Lipkin found in the earlier paper. Our immune systems are reacting to something.

B cells might also create autoantibodies in numbers due to cross-reactivity. The cells are responding to something else, but the antibodies have sufficient affinity to self-proteins that they get weakly attacked.

Yep - I think it is also worth mentioning that a small degree of autoimmunity with regards to the production of autoantibodies is a good thing. The argument that autoimmunity needs an external stimulus is a little silly when you consider the benefits that autoimmunity has with regard to detecting and successfully fighting cancerous cells. If autoimmunity was a bad things then it would likely no longer exist in the human (and other organisms) population as the genes and traits responsible for it would have not been selected for during evolution.
Autoimmunity only becomes a bad thing when the immune response gets stuck in cycles over-expressing randomly created autoantibodies and the response that ensues therein.
I quite like the theory of the immune system as a cognitive network that arises out of the Santiago theory of cognition.

No need to discriminate between self and non-self or to consider autoimmunity as necessarily a problem except in the (relatively) rare case of a massive infection.

In this theory the role of the immune network is not to seek out and kill but to regulate both
self and non-self within the parameters necessary to maintain the organism's physiological integrity. Therefore a certain level of foreign organisms is tolerated and regulated. Otherwise how could we tolerate our own beneficial bacteria and how would symbiosis (eg mitochondria) have evolved.

http://combusem.com/CAPRA4.HTM

Quite possibly bollocks though ;)
 
Marco Maturana's theory is complicated and requires careful reading and analysis. I met Humberto Maturana, the founder of much of modern systems biology, as I went to one of his two day seminars. Systems that survive are ones that maintain balance, but that does not mean its seeking balance. Its just mechanisms that tend to maintain balance. Systems that adapt or evolve to maintain balance better have an evolutionary advantage.

Systems view always have to take details into account, and environment, and mechanism and ... Its one reason why so many try to avoid them. Its not easy taking a systems view, nor even easy to know where to put the boundaries for the system analysis.

What it does imply is that the current state of the system is also a reflection of how it has changed during its history. In other words, its something dynamic. The immune system is definitely dynamic. I would like to see more work on treating the immune system as a dynamic system over time, but alas that is not where the science is going. The research is usually heavily reductionistic, which is what makes it more amenable to scientific enquiry.
 
Marco Maturana's theory is complicated and requires careful reading and analysis. I met Humberto Maturana, the founder of much of modern systems biology, as I went to one of his two day seminars. Systems that survive are ones that maintain balance, but that does not mean its seeking balance. Its just mechanisms that tend to maintain balance. Systems that adapt or evolve to maintain balance better have an evolutionary advantage.

Systems view always have to take details into account, and environment, and mechanism and ... Its one reason why so many try to avoid them. Its not easy taking a systems view, nor even easy to know where to put the boundaries for the system analysis.

What it does imply is that the current state of the system is also a reflection of how it has changed during its history. In other words, its something dynamic. The immune system is definitely dynamic. I would like to see more work on treating the immune system as a dynamic system over time, but alas that is not where the science is going. The research is usually heavily reductionistic, which is what makes it more amenable to scientific enquiry.
Hi Alex

Must have been an interesting seminar.

I feel there's a lot in the theory but as you know its getting on a bit now - I don't know if mainstream medicine has embraced any of it - plus while these theories have been highly influential (and influenced by) cybernetics and chaos theory - Varela and Maturana may have over-extended the theory into areas where they've less expertise.

I do like the idea though that autoimmunity may involve a failure of connectivity in the immune network (Broderick I believe suggested something with regard to immune findings in ME/CFS).

There's also the possibility that complex systems (as the immune system must be) may be prone to rapid flips to another stable (but dysregulated) state.

All intellectually satisfying but unlikely to be of any practical help in the near future.
 
I think the issue with sequencing blood and CSF is that some of these agents don't really inhabit either. For example, Lyme testing via PCR in blood and in CSF is specific, but has very low yield. Its mainly a tissue based infection. Some other pathogens might be the opposite. Its really hard to make hard conclusions as to what extent a pathogen is involved unless you know where it primarily lives and those tissues are sampled. So its important that they also look for the antibodies as well.
It does seem like some pathogens favour tissue but many, including Borrelia, are often enough found in the blood. If any had been missed in the patient exclusion phase then with as many subjects as this (260?) and with the best techniques available being used, you'd have thought if present then at least some cases would have been picked up, but instead we have zero. Borrelia as a cause therefore looks pretty unlikely now, though some other bacteria being responsible is yet to be ruled out as i understand it. It'll be interesting to see if they find anything, or not.