Wednesday, October 24, 2018

Symposium on the Molecular Basis of ME/CFS

At the three-day Working Group Meeting and Community Symposium on the
Molecular Basis of ME/CFS at Stanford University, sponsored by OMF, so
much scientific progress was evident. We are clearly progressing from
just data gathering to formulating new hypotheses as to the causes of
symptoms and even a possible cause of the disease. The buzz of hope
was palpable!

The Working Group Meeting brought together over 50 researchers from
around the world. Ronald W. Davis, PhD, OMF Scientific Advisory Board
Director, invited world-renowned researchers who were open to
collaboration and sharing unpublished data. As Dr. Davis said, "I
invited brilliant people with a high intellect to arrogance ratio who
are working on ME/CFS at the molecular level. The knowledge shared
this year was considerably greater than last year. The excitement to
begin new collaborations was intense. They were so engaged in planning
out their new collaborations that it was difficult to start the next
session. It felt like an explosion of ideas."

The Community Symposium gathered together patients, caregivers,
clinicians, and researchers. We welcomed nearly 300 participants at
Stanford and over 4,800 Livestream participants. The day was filled
with excellent research reports, the warm embrace of community, and
shared tremendous hope.

I want to thank the researchers for their dedication and hard work,
and everyone involved in this great event who made it such a success.
Thank you also to all the donors who made this important work
possible. Without you this progress couldn't have happened.

Below is a summary of the Community Symposium prepared by Christopher
Armstrong, PhD.

With hope for all,

Linda Tannenbaum
Founder & CEO/President

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Second Annual Community Symposium on the Molecular Basis of ME/CFS Summary
By Christopher Armstrong, PhD

During the last week of September, a 3-day Working Group Meeting on
the Molecular Basis of ME/CFS was capped off by a Community Symposium
at Stanford University. It was the second annual meeting of its kind
built upon the success of the year before with the working group
meeting stretching out an extra day beyond its predecessor. The
quantity of contributing researchers was impressive, but the quality
of the research was particularly inspiring.

The message of the year before was about trying to accumulate as much
information as possible, to gather the puzzle pieces. This year the
puzzle pieces have begun to be resolved with the next challenge to
determine how they fit together.

The Community symposium began with a welcome from Linda Tannenbaum,
OMF Founder and CEO/President, greetings from Janet Dafoe, patient
liaison, and opening remarks by Ron Davis, symposium chair.


The talks began with Dr. Raeka Aiyar, the Symposium moderator, who now
works for the New York Stem Cell Foundation (NYSCF). Stem cell
applications for research is an area that Dr. Aiyar believes has the
potential for helping understand ME/CFS and to find treatments.


Dr. Oystein Fluge gave the Keynote Address. Unable to provide specific
details about the recent Rituximab trial, Dr. Fluge went on to
elaborate on previous studies of metabolism on ME/CFS patients and
other prospective clinical trials that are underway. Their lab is
uniquely set up to allow interaction between clinical trials and
observational research with both areas concurrently informing the
other.

The current clinical trial Dr. Fluge is working on is CycloMe, an
open-label phase 2 trial looking at the effect of cyclophosphamide on
ME/CFS patients. "The results are interesting!" However, more details
are not able to be shared until publication.

The central point of their metabolism studies is that it is consistent
with several other publications from other researchers. The additional
information they provide is an inhibited pyruvate dehydrogenase
complex (PDH), an enzyme that enables the entry of sugar breakdown
products to enter the mitochondria (the powerhouse of the cell).
Interestingly, this enzyme is a central energy metabolism control
point that can determine if sugar is largely used for energy
production or if amino acids and fatty acids are being utilised
instead. The latter seems to be the consensus findings across research
groups.


Dr. Wenzhong Xiao unloads a wealth of findings from the Severely Ill
Patient Study (SIPS) he heads up at Stanford. Sleep monitoring
determined several alterations compared to healthy controls, while
morning cortisol levels were also attenuated. Together this indicates
a significant impact to the sleep/wake cycle of people with ME/CFS.
Viral pathogens have long been tied to ME/CFS with no consistent
findings. Dr. Xiao described an extensive virus search that found no
significant difference in viral pathogens between patients and
controls. The study of the microbiome revealed variations in the
bacteria of the gut, and interestingly, a neuroprotective metabolite
(3-Indolepropionate) produced by gut bacteria appears to be
significantly reduced in ME/CFS patients.


Dr. Xiao caps off his findings by displaying an integrative web of all
associated data points from the SIPS study connected to the central
diagnosis of ME/CFS. The hope is to add the data from other studies to
discover if the connected associations continue to hold.


Next up is Dr. Jonas Bergquist discussing his new study looking at
peptides and protein markers in the cerebrospinal fluid (CSF) from
ME/CFS patients, Multiple Sclerosis (MS) patients and healthy
controls. He reveals preliminary data from the study that show
elevations of protein markers indicative of neuroinflammation, cell
damage and repair in ME/CFS, and significant differences are observed
between MS and ME/CFS patients.

Secondly, Dr. Berquist screens for steroid levels and has found a
decrease of pregnenolone with non-significant downregulation of most
other steroids. Pregnenolone is a neurosteroid produced in the
mitochondria.

Thirdly, Adrenergic and Muscarinic receptor autoantibodies were
significantly elevated in plasma from ME/CFS, and this has now been
observed in two separate studies. Importantly, no such autoantibody
changes were found in the CSF.


Dr. Alain Moreau is looking into the role of circulating microRNA in
ME/CFS. MicroRNA are small molecules that circulate throughout the
body and can regulate the production of proteins and enzymes from
genes. He hypothesizes that "ME/CFS is caused by a disturbance in the
expression of microRNAs, which modulate immune functions, energy
metabolism and physiological stress response". Dr. Moreau uses a
massager arm cuff to stimulate a reaction in ME/CFS patients, a simile
to post-exertional malaise. He measures the microRNA before and after
this stimulation and measures the alteration that occurs in ME/CFS as
compared to controls. Significant variations occur between ME/CFS and
controls. Furthermore, the data is able to be split into 4 subtypes
based on the microRNA, which relates to variations in symptom
expression.


Dr. Maureen Hanson follows in a similar vein to Dr. Moreau by looking
at studying ME/CFS patients before and after an exercise challenge to
compare the dynamic response of ME/CFS patients as compared to healthy
controls. This study will focus on metabolite, gene expression and
cytokines. Similarly, a second study looking at ME/CFS patients on
Ampligen will look at symptom changes over time in conjunction with
changes in metabolites, gene expression and cytokines.

Dr. Hanson also reports on a new metabolomics study looking at ME/CFS
compared to controls. The findings align nicely with previous studies,
and upon analyzing data across other studies in the field, there were
no separate sub-groups identifiable based on the metabolites.


Dr. Ron Tompkins begins by talking about the initiation of the ME/CFS
Collaborative Research Center at Harvard (which Dr. Davis 
affectionately calls the "Stanford of the East")
. Dr. Tompkins professes his embarrassment as a Doctor by the way his community
generally responds to a disease they don't understand. Dr. Tompkins
has spent a lot of time researching the impact of significant trauma
on the body that was significant enough to kill you (a 20% mortality
rate). Through these studies he has a strong working knowledge on the
interplay of inflammation, immunity and metabolism.

The initial research they aim to begin is a thorough understanding of
muscle recovery with a multi-omic exploration of muscle biopsies from
ME/CFS patients, the first study of its kind. They also wish to begin
functional neuroimaging studies. The focus seems to be on
understanding the differences in tissues of the body as distinct from
blood plasma and immune cells.


With enhanced funding, the Research Center at Harvard would be ideal
for a setup of clinical trials to fast-track promising and potential
treatments for ME/CFS.


Michael Sikora is a graduate student under Lars Steinmetz, professor
of genetics and member of the Stanford Genome Technology Center who
are collaborating with Mark Davis. He has been working to establish
the role of T cells and the immune system in ME/CFS. They have found
the significant increase in T cells in ME/CFS patient compared to
controls indicating an activated immune response. Furthermore, the T
cell expansion signature appears distinct in ME/CFS from other
diseases like Multiple Sclerosis and Lyme disease where immune
activation is also present. Currently, they are focusing on the cause
for the immune activation, whether it's in response to an infection or
in response to self (autoimmunity).



Dr. Jarred Younger discusses his recent research on neuroinflammation.
Using a similar technique to an MRI, Dr. Younger can evaluate the
levels of metabolites in sections of the brain. Lactate is a
metabolite found as the product of sugar breakdown for energy
production (known as the process of glycolysis). Lactate was found to
be elevated in areas of the brain that are responsible for the
sickness response. "This is exactly what would happen if ME/CFS was a neuroinflammatory disorder", Dr. Younger explained. The method used
also enables the prediction of temperature in the brain, and
temperature increase is apparent in the brain of ME/CFS patients.

The same regions of the brain in which Dr. Younger had found
elevations in lactate and temperature indicative of neuroinflammation
were also previously observed to have activated microglia, which are
consistent with neuroinflammation.



Dr. Ron Davis discusses the search for biomarkers with a particular
focus on three new technologies being developed to find differences
between ME/CFS and healthy controls. First, he reintroduces the
impedance test as a marker for ME/CFS. The addition of salt to ME/CFS
and control plasma was enough to produce a significant alteration in
the ME/CFS impedance signal as opposed to the control signal. Second,
new technology produced in conjunction with San Jose State University
looks to assess red blood cell deformability in ME/CFS patients by
evaluating the speed of transit through a tiny capillary. They have
found that ME/CFS cells are significantly less deformable than healthy
cells. Finally, magnetic levitation of cells shows that ME/CFS white
blood cells are lighter than those of healthy controls. All these
instruments effectively separate ME/CFS and control plasma, red blood
cells or white cells, and each is fabricated for a very low cost. It's
possible to create a device that combines these methods of detection
to enhance specificity. All these instruments in conjunction with
metabolite tests from Dr. Robert Naviaux and Dr. Robert Phair will be
compared in a "bake-off" to determine the most effective diagnostic
for ME/CFS. The key for a successful diagnostic is that it accurately
identifies illness (low false positives and false negatives, is easy
to produce and simple enough to perform that it may be usable
anywhere.


Dr. Robert Phair is now known as the "metabolic trap guy". He comes
from a background of engineering and physiology and hopes to apply
systems engineering to human physiology. His focus is on modeling of
complex metabolic systems, with a corrent focus on substrate
inhibiting enzymes.

He emphasizes that the outbreaks of ME/CFS were a particularly
important clue to him that suggested that any genetic component
related to the illness would likely be common.

He discusses non-linear system theory as important for biology but
especially important in explaining some of the confounding elements of
ME/CFS. His hypothesis began with identifying areas of metabolism that
could form bi-stability, two steady states that can be entered into
that are functionally distinct from each other, one healthy and one
unhealthy.

First he found mutations in a gene called IDO2. IDO2 is an enzyme that
converts tryptophan (an essential amino acid) to kynurinine.
Tryptophan is also processed to seratonin. IDO2 is one of two enzymes
that process tryptophan, the other being IDO1. These two enzymes seem
to do identical things, but it's actually more complicated. At lower
levels of tryptophan, IDO1 converts tryptophan to kynurenine, but IDO2
is inactive. But IDO1 is a substrate-inhibited enzyme whereby too much
tryptophan in a cell stops its function, causing tryptophan to no
longer be processed and build up its levels in the cell. At these high
levels of tryptophan, IDO2 takes over the processing of tryptophan.
However, all the ME/CFS patients in the SIPS cohort had mutations in
IDO2 making it non-functional. Without IDO2 there is essentially a
block created that stops tryptophan converting to kynurenine and could
force it through to serotonin.

Flux experiments were initiated to measure the levels of tryptophan
and kynurenine in ME/CFS white blood cells; these showed that
tryptophan is higher and kynurenine is lower than in healthy controls,
consistent with the existence of a metabolic trap in the patients
tested. These experiments have only been conducted on 6 ME/CFS
patients and 6 healthy controls so far, and more patients will be
tested as fast as possible.

Dr. Ron Davis closes the symposium by explaining the importance of Dr.
Phair's findings but also warns about cherry-picking of data to
support a hypothesis. Good science is accomplished by forming a
testable hypothesis that makes specific predictions and doing
experiments to see if those predictions obtain. This work is still at
the beginning and will require much more exploration to determine
whether it is definitive of ME/CFS. Dr. Davis also emphasizes the need for funding at the present time. To any big donors out there, he urged, "This is the time to donate, as we may be on the precipice of a crucial finding for the illness." Dr. Davis then explained how
fundamental these pathways are to the control of a person's
biochemistry, and that It's exceptionally dangerous to begin
experimenting on one's self without more information.
Self-experimentation could have dire consequences. Dr. Davis implores
the patients to be patient.

In summary, Dr. Davis states: "A lot of progress has been made in the
last year. There is a lot more data and it is now generating testable
hypotheses. More exciting collaborations are being established.
Excellent new people are entering the field. The future is looking
even more hopeful. Our partnership with OMF has been instrumental for
this progress and for the support of this symposium. We are now on the
brink of even more exciting progress, but as always, funding is the
rate-limiting step. Now is a crucial time to donate to accelerate the
breakthroughs."

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