All posts tagged hanson

ME/CFS Seahorse Energy Production Study Shows Surprises

Dr. Maureen Hanson leads one of the three NIH funded ME/CFS research centers, but her ME/CFS research doesn’t stop there.  Using samples from Dr. Daniel Peterson provided by the Simmaron Research Foundation, she’s also been assessing the metabolism of one of the most important cells in our immune systems: our T-cells.

T-cells affect a large part of our adaptive immune response that clears out infections. They do this by regulating our immune response (CD-4 or Helper T-cells) and/or by killing off pathogens that have infected other cells (CD-8 or cytotoxic T-cells).

Hanson and Mandarano and Seahorse machine

Maureen Hanson, Alexandra Mandarano and the Seahorse machine

Prior to getting activated, T-cells are primarily on sentry duty.  Once activated by dendritic cells presenting little bits of pathogens to them things change dramatically, however. The T-cells rev up their cellular engines to order to start pumping out cytokines or clones en masse in order to stop the infection. Both parts of energy production – glycolysis and oxidative phosphorylation –  have to jump into action.

In short, assessing the energy production of activated T-cells is a perfect way to determine if their energy metabolism has been affected in ME/CFS – and that’s just what Maureen Hanson’s group did.

Alexandra Mandarano, a graduate student in Hanson’s lab, took T-cells from 53 healthy controls and 45 pretty long duration (avg. a@ 12.7 years) ME/CFS patients and healthy controls and tricked them into going into high alert with antibodies plus IL-2. Then, using the Seahorse Flux Analyzer, she examined how well the two parts of their cellular energy production system did in both unactivated and activated T-cells:  glycolysis – the anaerobic part which takes place outside the mitochondria, and oxidative phosphorylation – the aerobic part which takes place inside the mitochondria (and produces far more ATP) .

Dr. Hanson presented on her results at the recent Open Medicine Foundation sponsored Harvard Symposium

Results

Whether they were activated or not, mitochondrial energy production; i.e. oxidative phosphorylation (the main ATP producer) was normal for both the CD4 and CD8 cells in the ME/CFS group. When pushed, the mitochondria in the ME/CFS patients’ cells quickly got energy production up to speed. That was a surprise. Usually when you push a cell or system in ME/CFS it fails- but, in this case, the T-cells responded normally.

Then came the real surprise.  Systems in ME/CFS often test out fine or at least not strongly abnormal at baseline or rest, but in this case Hanson found low glycolysis activity in both the T-helper cells (CD4) and the CD8 cells at baseline.  Simply prowling around the body, they had considerably lower levels of glycolytic activity.  When pushed, though, their glycolytic activity was normal.  The pattern was opposite to what we usually see.

That wasn’t all. It’s possible with the Seahorse to turn off different energy production pathways in order to assess how effectively the other pathways are at compensating.  When the oxidative phosphorylation pathways were turned off experimentally, the ME/CFS patients’ glycolytic pathways failed to compensate as effectively as did those of healthy controls.

Mandarano did not find problems with mitochondrial ATP production but did find issues with glycolysis

Thus no problems with mitochondrial energy production were found but three potential issues with glycolysis popped up: low glycolytic activity in both forms of unactivated T-cells, and poor glycolytic compensation with the oxidative phosphorylation pathways were turned off.

Hanson’s group next examined a critical part of energy production called the mitochondrial membrane potential. Our mitochondria need to maintain a certain membrane potential to keep up the flow of positively charged ions into the mitochondria. It does this by keeping more positively charged ions outside of the mitochondria and more negatively charged ions inside the mitochondria. Her group used a flow cytometer to assess the levels of mitochondria present and to determine how strong the membrane potential was.

The mass and membrane potential of the ME/CFS patients’ CD4 T-cells and the mitochondrial mass of the CD8 cells was normal, but the membrane potential of the CD8 T-cells – whether activated or not – were significantly impaired in the ME/CFS patients.

Four potential problems, then, were found:

  • low glycolytic activity in unactivated CD4 and CD8 T-cells
  • poor glycolytic compensation when the oxidative phosphorylation pathways were turned off
  • The mitochondrial membrane potential was impaired in the CD8 T-cells

Dr. Hanson left her presentation with the  encouraging statement that we are starting to put the pieces of the puzzle together in ME/CFS and the tantalizing suggestion that ME/CFS might be something different than what we think it is right now; i.e. keep an open mind, don’t put all your eggs in one basket, and be prepared for surprises.

Overview

Hanson and her co-authors have submitted a paper and we will get more details when their paper is published but, with these preliminary results, we have a few more data points on cellular energy production in ME/CFS. While noting that several study results are pending, maybe it’s time for a look at what we have.

It should be noted that measuring energy production is very complex. Different researchers are doing it in different ways, and I am no judge of any of them.  Researchers are using different instruments, different criteria, different kinds and numbers of patients, and they are reporting things differently. Solving those problems is one of the reasons for the NIH funded ME/CFS research centers where larger studies can use proven technologies and rigorously defined patient populations.

Check out some of the different protocols which have assessed mitochondrial functioning in isolation from the blood in ME/CFS:

Study protocols

  • Hanson’s group activated her T-cells using antibodies and IL-2 and then tested activated and unactivated cells in the Seahorse Machine
  • Tomas took PBMC’s and stressed them in the Seahorse machine
  • Stanford took PBMC’s and then used laboratory assays to test each of the complexes and flow cytometry to assess mitochondrial membrane potential
  • Fisher (unpublished) appears to have taken PBMC’s and stressed them in the Seahorse machine
  • Vermeulen measured ATP PBMC’s etc. in the lab
  • Smits measured ATP production rate in muscle biopsies

The Land of Mixed Signals

We seem to find ourselves in a familiar place – the land of mixed signals! One encouraging unmixed signal is that everyone seems to be finding something wrong – just often different things.

MITOCHONDRIA

Mitochondria Mass – Normal

  • Hanson – CD4 and CD8 (T-helper cells)
  • Fisher

Mitochondria ATP production – Normal

  • Hanson (T-cells)
  • Stanford study (not a Ron Davis study) (PBMC’s)
  • Fisher (PBMC’s)
  • Vermoulen (PBMC’s)
  • Smits (muscle biopsy)

Increased ATP Production Overall

  • Stanford
  • Preliminary results from NIH Intramural study

Reduced ATP production

  • Tomas – under both low and high glucose conditions

Functioning of Complexes – Normal

  • Stanford (I-IV)
  • Vermeulen (I-II)

Functioning of Complex V – reduced

  • Fisher
GLYCOLYSIS

Increased Glycolysis at Baseline (PBMC’s)

  • Stanford

Reduced Glycolysis at Baseline (T-cells)

  • Hanson

Reduced Glycolysis (low glucose conditions)

  • Tomas

Reduced Compensatory Glycolysis

  • Hanson
  • Tomas (?)

Glycolysis Stress Test (Glycolysis, glycolytic reserve, glycolytic capacity)- normal

  • Tomas
  • Fisher

It’s quite a muddle.  Surprisingly, though, the most consistent finding thus far is normal (or in two cases) increased mitochondrial production (!) Not many studies have directly measured glycolysis, but in these early days the results are mixed.

Isolation

cells in the blood

The most consistent result so far is normal (or increased) mitochondrial function but none of the above studies tested cells in the blood – where an inhibiting factor may lurk. (Seahorse machine cannot test cells in the blood.)

Note that all these studies are assessing the energy production of the mitochondria in isolation. None tested cells in the blood where Davis, Fluge and Mella and Prushty have found evidence that some sort of inhibiting factor may be present. The metabolomic findings which suggest problems with glycolysis are present have been assessing factors in the blood and urine as well.

Adding an exercise stress test would, of course, add another important factor. At the NIH ME/CFS Conference, Brian Walitt reported that the NIH is finding that exercise causes mitochondrial oxygen consumption (ATP production) to increase in the healthy controls but to decrease in about half of the ME/CFS patients. Several recent studies have validated that exercise impairs energy production in ME/CFS (blog coming up). Where and how the energy depletions are occurring is unclear. (Note that most of these studies examined immune cells not muscle cells.)

We obviously have long way to go to fit all the different pieces of the energy production puzzle in ME/CFS together but the good news is that an increasing amount of research is now being aimed at deciphering what’s inhibiting energy production in this disease.

The Simmaron Research Foundation’s collaboration with Maureen Hanson – which paired rigorously diagnosed patients with a respected researcher –  is just one way the Foundation is contributing to solving that puzzle.

Simmaron Patient Day Part II: The Hanson Report

Maureen Hanson has been making waves.  An ace molecular plant biologist prior to entering the chronic fatigue syndrome (ME/CFS) field, Hanson has worked on mitochondrial and gene studies in plants dating back decades. Now, with her son ill from ME/CFS, she’s turned her talents to this field, and has made a difference in a hurry.

A trusted researcher, Hanson scored one of the few XMRV grants and in a short period of time has produced studies on the gut, mitochondrial DNA, exercise, and metabolomics in ME/CFS. Last year, Hanson, created one the few chronic fatigue syndrome (ME/CFS) research centers in the U.S. (the Cornell Center for Ennervating NeuroImmune Disease, ) and this year she and her colleagues received one of the three NIH ME/CFS Research Center grants. She’s also a member of the Simmaron Research Foundation’s Scientific Advisory Board.

Last year Hanson was awarded a smaller NIH grant (R21) to do preliminary work assessing the energy production in ME/CFS patients’ immune cells using the Seahorse XF Analyzer.  In this blog we take a closer look at the work underway.

A Breakthrough Technology

It’s safe to say that the Seahorse machine is changing how researchers do research. In the mid-2000s the Seahorse folks introduced something new to the medical world called “extracellular flux (XF)” technology. A monolayer of cells is placed in a very small, 10 ml sensor chamber and then stimulated.  Every few seconds a sensor placed 200 microns above the cell monolayer takes a measurement.  Where past techniques required hours to assess oxygen metabolism, the Seahorse can do it in minutes.

This technology allows researchers to determine the energy consumption of cells by analyzing changes in oxygen and acid levels occurring in the media outside of them.  The amount of oxygen present indicates how much energy is being produced through glycolysis and by the mitochondria.

The ability to place energy stimulating or inhibiting or other drugs in the sensor chamber brings the possibilities of the Seahorse machine to an entirely new level. If the inability to produce energy turns out to be a key factor in ME/CFS, the Seahorse machine’s ability to test how drugs and other substances effect the energy production of cells could be a big boon indeed

Agilent, the company that produces the Seahorse machine, reports the machine has been used in over 250 studies. HIV researchers, for instance, recently used the machine to determine the effectiveness of the immune response in HIV patients. It turns out that in order to meet a threat, many of our immune cells undergo a huge metabolic shift as they get transformed from a resting to an active state. That shift coincides with large increases in glycolysis in particular.

A similar approach is being used in chronic fatigue syndrome (ME/CFS). Tomas’ recent Seahorse study suggested that ME/CFS patients’ immune cells (PBMC’s (T, B and NK cells, monocytes))are having severe problems producing energy. Tomas’ study opened up an important possibility but it was limited by its inability to determine which cells were having problems.

https://www.healthrising.org/blog/2017/11/11/cellular-energy-hit-chronic-fatigue-study/

Hanson is taking the next step in assessing immune functioning in ME/CFS with her R21 NIH grant. That grant gave her the funds to assess the energy production of individual immune cells separately (T, B and NK cells).  (Isabel Barao is also examining energy production in NK cells).

Each of these cell types has been potentially implicated in ME/CFS. The T-cell problems Derya Unutmaz of Jackson Labs saw are what attracted him to ME/CFS, and Mark Davis of Stanford recently found signs of unusual clonal expansion in ME/CFS patients’ T-cells.  The success some ME/CFS patients have with Rituximab suggests B-cell issues are present, and the problems ME/CFS patients’ natural killer cells have with killing have been known for decades.

T-cells are a particularly good subject because springing into action to kill other cells or to produce clones of themselves to fight invaders requires enormous amounts of energy. If energy production is flawed in ME/CFS, it’s probably going to show up in patients’ immune cells.

Glycolysis OK

Metabolomic studies suggest glycolysis might be inhibited in ME/CFS, but at the OMF’s Stanford Symposium Hanson stated that she hasn’t found impaired glycolysis. When glucose was given to the immune cells to stimulate their glycolytic processes, the cells were able to use it, but their respiratory capacity (oxidative phosphorylation) was blunted.

In another study, which the SMCI helped to fund, Hanson’s Metabolon metabolomics study found lower glucose levels (a surprise) as well as differences in fat and lipid metabolism (i.e. energy production), and in the sphingolipids that play a big role in Naviaux’s findings.

Hanson noted that low glucose levels are not a good sign, either. Low glucose levels have been associated with increased cortisol responses (possibly leading to exhaustion) and inflammation. Plus they may be able to mess with a person’s endurance.

The last sport anyone with ME/CFS is going to engage in is an endurance race.  That might make sense given that athletes with lower glucose levels tend to do worse in endurance sports. Overall Hanson’s metabolite findings suggest increased inflammation and reduced recovery from metabolic stress are part and parcel of ME/CFS. Metabolic stress, of course, is exactly what she’s measuring in her Seahorse study.

Hanson’s finding of normal glycolysis in ME/CFS patients’ T-cells mirrors the findings of Tomas’ recent Seahorse study. However, Hanson’s early findings are suggesting that, at least in the immune cells, the mitochondria are the issue.

Hanson has found that ME/CFS patients’ T-cells use less of their “respiratory capacity” when provoked than do healthy controls’ cells. If I’m reading this right, the capacity to produce energy is there, but it’s not being used.  The next step is to determine if the T-cells, when they become activated, can produce enough energy to be effective. If Dr. Hanson finds they’re not up to the task of producing adequate energy, she said, “they may also be unable to effectively respond to an immune challenge.”

Lethargic T-cells could have major implications for the immune system, as T-cells are important in just about every immune system activity. At least four different kinds of T-cells exist:  T-helper cells activate B and NK cells, T-killer cells destroy virally infected and cancerous cells, T-memory cells alert the immune system to danger, and T-regulatory cells help keep the immune system humming.  Small studies suggest that cytotoxic or killer T-cells have the same problems with killing infected cells that NK cells do.

Whether or not something in ME/CFS patients’ blood is essentially putting their cells to sleep is one of the more fascinating questions facing this field. Several researchers including Ron Davis of the Open Medicine Foundation and Fluge and Mella in Norway believe something in the blood is doing just that. Energy production issues in ME/CFS patients’ cells that have been isolated from the blood suggest that something may be wrong with the cells themselves. It’s possible, therefore, that problems may lie in both the blood and the cells.

Since the Seahorse machine allows researchers to insert different substances in the medium the cells are bathed in, I asked Dr. Hanson if she could use the machine to determine the effects ME/CFS patients’ blood may be having on their immune cells.

Dr. Hanson replied that the Seahorse machine could determine if something in ME/CFS patients’ serum affects mitochondrial function in immune cells from healthy people, but the Seahorse technology would not be able to tease out what factors in the serum are responsible.

The Seahorse requires large samples of difficult to obtain immune cells. T-cells are relatively easy to obtain; B and NK cells – not so much.  Getting Maureen Hanson the resources she needs to do her work is where the Simmaron Research Foundation comes in: it’s supplying the cells she needs to do her work.  Dr. Hanson stated that, “We are grateful to Simmaron Research for supporting the collection of additional samples from which individual cell types— such as B and NK cells—can be purified for analysis of glycolysis and oxidative phosphorylation”.

Next up, Dr Hanson will analyze the cellular energetics of those NK and B cells. Despite the Rituximab failure, B-cells are still of great interest in chronic fatigue syndrome (ME/CFS). It’s still possible, for instance, that the drug works for a significant subset of patients. Plus B-cells are heavily involved in autoimmunity. Dr. Light has proposed that energy depleted B-cells may increase the risk of an autoimmune process beginning.

The desire to examine NK cells is obvious. Reduced NK cell cytotoxicity is a hallmark of ME/CFS, and reduced cytotoxicity of T-cells appears to be present as well. Could that poor killing power be caused by the most basic of all problems – the inability to generate enough energy? Given the high energy requirements of activated immune cells, that’s a distinct possibility. Dr. Hanson’s work will take us closer than any other yet to answering that most fundamental of all questions.

 

Simmaron’s Fifth Anniversary Event Updates ME/CFS Community on Dynamic Research Underway

5th-birthday-258x300

Simmaron recently held a patient update session with its Scientific Advisory Board and key collaborators in Incline Village, Nevada. The event celebrated the Simmaron Research Foundation’s fifth year anniversary.  I don’t know if anyone would have predicted five years ago that patients would be hearing from the likes of Mady Hornig, Maureen Hanson, Konstance Knox and Elizabeth Unger but here they were in little Incline Village talking about their work.

CDC Collaboration

The surprise guest at the event was Elizabeth Unger. Dr. Unger was a fitting guest at the Simmaron’s 5th year anniversary meeting; it’s been, after all, just over five years since she took over the helm of CDC’s Chronic Fatigue Syndrome (ME/CFS) program.  Who would have thought five years ago that the head of CDC’s CFS program would show up at a Simmaron information meeting.

Certainly not Dr. Peterson. About five years ago I asked him if the CDC  had ever shown interest in his work,  and he just laughed.  His relationship with the CDC was frosty to say the least. That’s not true any longer.Dr. Elizabeth Unger

Under Dr. Reeves, the CDC developed a definition in-house that received zero support from researchers (and patients). Under Dr. Unger, the CDC has made ME/CFS experts a core feature of its work, is meeting with patient groups, has worked with CFSAC on its website, and is engaging with patients and experts in its educational materials.

Instead of a stumbling block, Dr. Unger turned out to be a collaborator who’s committed an enormous amount of time, energy and her (limited) budget to learning about ME/CFS doctors and their patients.  What a shift that has been.

Dr. Unger threw all the definitions out the window in the multisite ME/CFS expert study. Realizing that doctors, most of whom had decades of experience in this disease, were a better source of what ME/CFS was than any definition, she cleared the decks; anyone the expert doctors believed had ME/CFS, whether they met x or y definition or not, she would study. They were, by default, ME/CFS patients. Dr. Peterson thought it was a brilliant move.

At Dr. Peterson’s invitation, Dr. Unger stayed following a routine site visit to hear the presentations from Simmaron’s Scientific Board and attend the patient gathering.  At the patient meeting she had some good news; the first paper from the ME/CFS experts multisite study was finally under review for publication.

It had been a long time coming. Simmaron and Dr. Peterson are already deeply immersed in the greatly expanded second phase of the trial, and had just gotten a contract for the third phase of the study. The study was already slated to continue at least into 2017 and now will continue further.

This now immense study involving over 800 patients and controls will surely supplant the infamous PACE trial as the largest and longest ME/CFS study ever done. With a third phase slated to begin shortly, it’s going to provide an unprecedented look at a very large group of ME/CFS patients, and how they are tested and treated by doctors over time.

Dr. Unger quickly went over a few of the highlights; the greatest heterogeneity, surprisingly, was found within the ME/CFS expert’s sites, not between them. By and large, the practitioners are not seeing different kinds of patients; instead each is seeing a similarly wide variety of patients. How wide? The standard functional tests being done, for instance, indicate that some people with ME/CFS experience high rates of pain while others experience no pain at all.

The constant is that ME/CFS is producing high reductions in vitality and physical functioning but has relatively little effect on mental or emotional functioning.  Dr. Unger said the multisite studies will go a long way to helping the public understand how severe a disease ME/CFS is.

Konstance Knox  

Konstance Knox, PhD, is collaborating with Simmaron on her insect infection study at Coppe Healthcare. She posited the interesting idea of ME/CFS having a similar trajectory to Lyme Disease. Lyme Disease,she noted, first showed up in pediatrician’s offices in children with arthritis in Old Lyme, Connecticut in the 1970’s.  Eventually the children were found to be infected with bacteria carried by ticks.

KKnox

ME/CFS patients have been showing up in doctor’s offices with unexplained fatigue, post-exertional malaise, pain and debilitating symptoms for years. Could a similar scenario prevail for at least a subset of ME/CFS patients? Knox thinks it might. Her large study, using samples from 300 ME/CFS and healthy controls gathered in the NIH’s XMRV study, is looking for evidence of pathogens that aren’t always tested for in chronic fatigue syndrome (ME/CFS). They include three different kinds of Borrelia bacteria, the Powassan and Dengue viruses, and the most widespread insect borne disease in the U.S., West Nile Virus.

Each demonstrates how rapidly insect borne pathogens can invade a country. Borrelia was identified as the cause of Lyme in 1981, and according to one estimate, is believed to effect 300,000 people a year.  West Nile Virus was first found in New York in 1999 and has spread across the country.  Now the Zika virus is beginning to touch upon our southern shores in Florida as well.

In Dr. Knox’s mind, the Powassan virus is the big mystery. Carried by the same ticks that cause Lyme disease, Powassan is similar to tick-borne encephalitis virus which has long been shown to cause serious illnesses in Eurasia.

Unlike the Lyme bacteria, which needs the tick to be attached for quite some time for the bacteria to get transmitted, the Powassan virus can be transmitted in just 15 minutes. Knox found that 11% of the 2,000 ticks she studied in Wisconsin  carried Lyme disease and 6% carried the Powassan virus.  She found 55% of people infected with Lyme disease also were infected with the Powassan virus.

Dr. Knox’s preliminary data of ME/CFS patients with an acute flu-like onset found a low incidence of Lyme disease (3%) but a pretty high incidence (11%) of people who had antibodies which looked like they might be to TBEV; i.e. the Powassan virus. The NIH samples offer an opportunity to study these infections in well characterized patients and controls from multiple clinical sites.

Dr. Mady Hornig

The Hornig/Lipkin team at Columbia’s Center for Infection and Immunity (CII) isn’t just looking at ME/CFS to understand the disease. It’s mining clues from a wide range of disorders – from autism to narcolepsy – to try to understand the disease processes that are occurring. They believe the “omics” revolution – which attempts to understand diseases in terms of their genomics, proteomics, metabolomics (and probably other “omics”) – holds the key to understanding and finding the subsets present in ME/CFS.

Mady Hornig sits on the Simmaron Research Foundations Board. She and the Simmaron Research Foundation are frequent collaborators. Until they get to a cause, Dr. Hornig is unwilling to rule out any possibilities. ME/CFS could be caused by an immune response to a wide range of pathogens (which may be present or not) or to an as yet undiscovered agent. That statement suggested that Dr. Hornig doesn’t consider the earlier CII study which found little or no evidence of pathogens to be the end of the story.

Of course few researchers have looked in the tissues. Dr Chia believes he’s found enteroviruses and Dr. Duffy herpesviruses in the gut tissues of ME/CFS and/or fibromyalgia patients. Hornig and Lipkin have looked in the blood but they’re also raising money to do analyses of the flora in the stool and saliva over time. (Check out the Microbe Discovery Project  for more.) Plus, as we’ve seen, a Simmaron/Konstance Knox project is looking for evidence of insect borne illnesses that have not been tested for before.

If  pathogens are involved, the heterogeneity in the disease could reflect genetic differences in how each person responded to them, how old the person was when the infection occurred, the state of each person’s microbiome at the time, etc.  The take-away message was that different symptoms don’t necessarily mean different diseases.

The CII is doing a lot, but Dr. Hornig started out by focusing on a hot topic these days – metabolomics.  The CII team believes that metabolomics may provide the link between what’s happening in the microbiome and the rest of the body. Metabolomics uncovers the breakdown products of metabolism. If a substance, say tryptophan is not being metabolized properly in the gut, it can leave a metabolic signature in the blood that can be picked by metabolomics tests.  From the blood it’s apparently a pretty straight shot to the brain.

Marrying gut (microbiome) and blood (metabolomics) data would be the cat’s meow, and it’s begun to happen. Several small studies have been able to link altered gut bacteria to the presence of gut metabolites in the blood.  A small Solve ME/CFS Initiative study carried that idea one step forward by adding exercise to the mix. It suggested that exercise could, probably by increasing leaky gut issues, result in increased levels of gut metabolites in the blood.

Dr. Hornig believes that aberrant tryptophan metabolism in the gut could provide a major clue for ME/CFS patients.  These metabolic by-products have already been associated with several neurological diseases and are known to cause symptoms similar to those found in chronic fatigue syndrome (ME/CFS). If she finds problems with tryptophan metabolism in the gut and then can pick up their metabolic by products in the patient’s blood she can make a strong case for a gut-brain connection in ME/CFS.

While she was at it, she also noted that these bacteria can affect NAD+ and energy production.  To sum up, Dr. Hornig is gathering data on a process that could be affecting cognition, the gut and energy production in ME/CFS.

No Mady Hornig talk it seems is complete without an emotional moment. Every event I’ve seen her at has left her and others in tears at some point, and it happened again. I watched an older gentleman come over and clasp her hands. Five minutes later there they were hugging each other and sobbing away.

Top Poop Crew

Dr. Peterson and Simmaron won the top poop collector award

Dr. Peterson and Simmaron won the top poop collector award

While on the microbiome she noted, with a smile, that of all the groups they were working with, Simmaron was the best poop collector; Dr. Peterson gathered more stool samples (hundreds of them apparently) from more patients than any other doctor they were working with. (Go Simmaron :))

Maureen Hanson

Maureen Hanson, PhD, presented some  interesting news recently when she announced during an SMCI webinar that her small metabolomics had duplicated the Naviaux study’s core finding that ME/CFS was a disorder of reduced metabolism; i.e. it’s a hypometabolic disorder.

Maureen Hanson

That finding helps us understand her Simmaron talk a bit better. Hanson explored the subset question more deeply than anyone I’ve seen before.  Chronic fatigue syndrome (ME/CFS), she said, could be a bunch of different diseases, or one core pathology could be driving it.

Whatever it is, the diversity of symptoms found in the disease has produced a credibility problem because diseases which produce lots of symptoms have long been considered “psychosomatic”. The many different triggers ME/CFS and outbreaks has been associated with, and the many different bodily systems it effects, have been confusing as well.

Hanson thought it was intriguing that the symptom presentations seen in different locales appears to be similar! If ME was the result of different agents producing different diseases in different places then the locales should look very different but they don’t.  Hanson then fished out a bevy of factors which could affect symptom preSimmaron Research | #ShakeTheCFSstigmasentation; the age at which ME/CFS occurred, gender, genetic background, co-infections present, pathogen variations, treatments tried, degree of exercise attempted – all of these could conceivably tweak one disease into producing different symptoms. (Consider what happens to some people who collapse and appear to revert to a different state after overexertion or after using the wrong drug.)

She noted that her mitochondrial DNA study suggested that slight alterations in ME/CFS patients’ mitochondrial DNA could result in different symptoms. That sure presents just the tip of the iceberg with regards to genetics.  (Ron Davis and the Open Medicine Foundation will be attempting to marry genetic data and metabolomics in one of their studies.)

Hanson’s microbiome project was powered by a small NIH grant and took place in a Cornell lab famous for its microbiome work.  The project was a small one but it made a big splash and was picked up by over 50 media outlets.

The study’s finding – a reduced diversity of bacterial species (about 20% less) similar to that found in two potentially devastating gut diseases (Crohn’s and ulcerative colitis) gave Hanson the opportunity to tell the media again and again that ME/CFS is a real disease.  The study also found that ME/CFS patients’ gut bacteria tended to be more dominated by a smaller number of bacteria.

Bacteria of the Ruminococcaceae family –  important in fighting inflammation  – were significantly reduced in ME/CFS.  The representatives of another bacterial family called Enterobacteriaceae – which contains some rather nasty pathogens but hundreds of other species – doubled in ME/CFS patients.

At the genus level, Faecalibacterium prausnitzii, a butyrate bacteria, which produces an anti-inflammatory protein and protects the intestine was reduced in ME/CFS. A similar finding is found in irritable bowel syndrome.

The low butyrate findings in both Hornig and Hanson’s microbiome studies suggest they are both on the right track. That’s actually a big win given how complex (and new) microbiome analysis is, but perhaps it is not surprising given the pedigree of the labs doing the analyses.

As did a Solve ME/CFS Initiative study, Hanson also found evidence that gut materials were leaking into the blood of ME/CFS patients – a process that could spark an inflammatory process that makes its way all the way up to the brain.

[Butyrate – One neurobiologist calls butyric acid – which is produced by butyrate bacteria – “an ancient controller of metabolism and inflammation”. He reports that butyrate is the primary source of energy for the lining of the large intestine. Butyrate is such an effective anti-inflammatory that butyrate enemas (which reportedly smell horrible) and oral supplements are being used to combat inflammatory bowel diseases like Crohn’s and ulcerative colitis.  Butyrate also appears to reduce intestinal permeability – which Hornig’s/Lipkin’s and Hanson’s studies suggest many be happening in some people with ME/CFS.

Butyrate may also increase the levels of T regulatory cells which help reduce inflammation and autoimmune processes.

Hanson is a careful researcher and she spoke carefully regarding treatment. She noted that the inability of researchers at this point to clearly determine which gut species are present hampers them from recommending treatments. They can determine which families are present but because bacterial families can contain many different kinds of gut species -some of which have opposite functions – the study’s impact on treatment recommendations is not clear.

Atypical vs Typical Patients – the Peterson Subset

For many years Dr. Peterson has speculated about what he calls typical vs atypical ME/CFS patients. It’s not clear to me what the groups consist of but my sense is that  typical ME/CFS patients tend to plateau over time and they tend to have familiar co-morbid disorders such as fibromyalgia, migraine, IBS, etc. Atypical ME/CFS patients, on the other hand, tend to have other serious disorders and/or have really serious cases of ME/CFS. Whitney Dafoe and Corinne Blandino are two examples of atypical patients; Whitney because he’s so ill and Corinne Blandino because she has a strange spinal lesion.

Dr. Peterson

Dr. Hornig reported earlier that a cerebral spinal fluid (CSF) tests results had found dramatically different results.

At another event, Mady Hornig talked about the dramatic differences found in the CSF of classical versus atypical patients. Virtually all the immune factors tested were higher in the complex atypical vs the classical patients. In fact, the findings in the two subsets were so different that the atypical patients had to be removed from a study comparing healthy controls and ME/CFS patients. Simmaron and the Center for Infection and Immunity have taken a deeper look at the cerebrospinal fluid in these two types of patients.

I asked Dr. Hornig if she thought the atypical patients had a different disease or were an offshoot of more typical patients? She simply said that she thought that the atypical patients needed to be more closely watched.  Later Dr. Peterson suggested, however, that they may be profoundly different biologically.

We should know more about the similarities and differences between these two subsets soon. A Simmaron/CII spinal fluid study comparing the two in greater detail has wrapped up. The metabolomics data from the Ron Davis/Open Medicine Foundation severely ill patient study and the Naviaux study examining more typical ME/CFS patients will give us some guidance as well. Plus, the CDC will be comparing the test results of severely ill patients and healthy controls in the third phase of its multisite study.

A talk with Dr. Peterson found him in a more optimistic frame of mind than I’d seen before. While the promised funding package at the NIH hasn’t shown up yet, he was clearly impressed by the Nath Intramural study, the continuing work of the CDC, and the work Ron Davis is doing at the Open Medicine Foundation.

We didn’t talk about Ampligen and Rituximab but advances with both those drugs may make his job easier. Peterson’s stated that his patients have about a 70% response rate to Ampligen. That high percentage probably reflects two things: Dr. Peterson’s feel for who will respond to the drug, and his ability to dose this drug optimally for each patient.

At the IACFS/ME Conference, Hemispherx Biopharma will report a breakthrough in their understanding of the drug effects in ME/CFS. It appears that they’ve found a way to identify which ME/CFS patients respond to Ampligen – a finding that should help doctors and patients decide whether to try the drug, and make their next clinical trial that much easier. Dr. Patrick of Canada appears to have done the same with Rituximab – a very expensive powerful drug that many doctors are probably leery of trying in their patients without more guidance.

  • Dr. Peterson will be co-leading a session with Drs. Fluge and Mella on Rituximab and Emerging Treatments, and will be a panelist on a session devoted to diagnosing difficult cases of ME/CFS, and will be highlighting a fellowship opportunity with Simmaron, at the International IACFS/ME Conference at the end of October.

With groundbreaking spinal fluid publications, more collaborative studies lined up, and additional findings on their way to publication, the Simmaron Research Foundation (SRF) has made pivotal contributions to the rising science of ME/CFS in its first five years. The Simmaron Research Foundation is committed to translational research efforts that produce solid gains for patients. With collaborators like these, the next five years promise much.

Simmaron Research | Give | Donate | Scientifically Redefining ME/CFS