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A presentation by MERGE Chairman Dr Vance Spence
on 12 November 2005 at the Oak Tree Court Conference Centre, Coventry,
at the invitation of the Warwickshire Network for ME

ME Research: Making the Breakthrough

Let me thank the Warwickshire Network for ME  - a sterling group  which
actively supports biological research into ME, and campaigns for appropriate
services for people with the illness
( ) - for the
invitation to this lovely conference centre, home of the Coventry Chamber of
Commerce. I'm told there are people in the audience from as far away as
Dawlish in Devon and Stowmarket in Suffolk - illustrating the intense
interest in ME/CFS research and the pressing need for action to get to the
bottom of this illness. As many of you know, I have been ill with ME myself
for many years - I was forced to retire early on health grounds 15 years ago
- and I am presently a Senior Research Fellow (honorary) in the University
of Dundee, as well as being Chairman of MERGE. With the help of Roger
Jefcoate CBE, who is in the audience today, and the Countess of Mar, MERGE
was created with the principal aim of energising research into this
neglected illness.

First, I propose to deal briefly with some of the problems we face in trying
to execute ME/CFS research, as there are particular problems specific to
this illness which impact on "making a breakthrough". Then, I shall briefly
describe some of the current research projects and areas of interest.

The first problem - perhaps the principal problem - is that ME/CFS is not a
"clean" diagnosis. Indeed, the terms ME and CFS mean different things to
different people. As I say over and over again, this problem colours all
debate on ME, yet rather like the whiteness of a wall it is often not
recognised as a colour at all. Much of the background was described in a
( .
html) I gave to the RSE/Wellcome conference in 2003, but the essential point
is that although the term myalgic encephalomyelitis (ME) - involving an
infectious onset, specific neuromuscular symptoms and signs, and a unique
post-exercise component - has a scientific history
( )
involving epidemic and sporadic forms, "ME" today has come to be seen as a
"lay term" used by patient organisations and patients themselves, while
chronic fatigue syndrome (CFS) has been adopted by medical journals and
healthcare professionals. At present, the composite term ME/CFS is used,
though in fact it represents the uneasy union of two strange bedfellows
pres2.html), as discussed recently at the Scottish Parliament. In addition,
we find ourselves in a situation where misuse of terminology by the mass
media is common; a recent article in the UK's Daily Telegraph (daily
circulation, approximately one million) gives an example. It describes the
travails of Olympic rower Anna Hemmings. As the article says, "For Anna
Hemmings, the Sydney and Athens Olympics tell two very different stories. In
2000, the professional canoeist was a member of the British team, but just
four years later Hemmings was suffering from CFS and was so exhausted that
she slept for 15 hours a night and was sometimes too tired to wash her
hair." It goes on to describe how Anna was greatly helped by a psychological
therapy, and seems to be on the mend, which is heartening. The question is:
what illness did she have? Many people have "chronic fatigue" (between 1 and
4% of the population), and many medical conditions, such as cancer and
diabetes, have fatigue as a central complaint. Indeed, athletes at Olympic
standard like Anna Hemmings may have "burnout" due to over-training;
however, recent research (Mommersteeg et al, 2005) shows that the "burnout"
experienced by athletes differs from CFS, and is certainly not ME as
described in earlier literature. This is just one example of many media
stories - thrown out into the public arena - which have an uncertain meaning
in the context of ME/CFS.

The diagnostic mess that is ME/CFS is illustrated by our own research on
three groups of patients with quite different onsets to their illness:
"sporadic" ME/CFS cases (i.e., most of the patients in ME/CFS support
groups); people who developed illness after services in Gulf War 1; and
people who developed illness after apparent contact with organophosphates.
While all these patients were classified as having CFS (because they
fulfilled the CDC 1994 criteria for the illness), distinct psychological and
biological differences could be found between them. As this paper (Kennedy
et al, 2004) says, "The specificity of the CFS case definition should be
improved to define more homogeneous groups of patients for the purposes of
treatment and research." This view was echoed by Professor Leonard Jason who
published in 2004 an excellent review on the need for subgrouping of the
over-broad "diagnostic category" CFS which can catch widely different groups
of patients in its net. As he said, "This review suggests that there is a
need for greater diagnostic clarity and that this might be accomplished by
subgroups that integrate multiple variables including genetic, neurological,
psychological and biological domains."  At present, what patients are left
with is a "devalued" diagnosis consisting of (in one researcher's words) a
"...ragbag of common non-specific symptoms with many causes, mistakenly
labelled as a syndrome". In this respect it is worth recalling what Dr Dean
of the National Institutes of Health in the USA said in a recent debate
about ME/CFS in the USA: "There is a significant stigma attached to it...
The medical community bears some of the responsibility for invalidating
ME/CFS as a real condition"; and what Professor Anthony Komaroff stated:
"None of the participants in creating the 1988 CFS case definition and name
ever expressed any concern that it might trivialize the illness. We were
insensitive to that possibility, and we were wrong."

The problem with the definition carries over into research studies, of
course. In ME/CFS, what we see over and over again are the graphs on the
right (the upper, an ideal scenario; the lower from a real biochemical
experiment on ME/CFS patients), with the controls nicely tightly packed, and
the "CFS" patient measurements much more widely scattered. There is clearly
something going on since the patients have higher values than the controls
on average, yet the scatter is problematic, and researchers scratch their
heads when they see it. It is therefore important to select for biomedical
research studies patients that are well-categorised; i.e., have a full
clinical examination (and there is good reason to believe that neuromuscular
signs can be found in patients if such assessments are made), and, ideally,
be subsetted according to particular criteria - and the subgroups specified
by the Canadian definition of ME/CFS ( )
devised in 2003 may come to be seen as a useful starting point for such
work. For there is clearly something different about these patients; indeed,
there is substantial evidence that, despite their apparent heterogeneity,
biomedical researchers can uncover a range of interesting anomalies
( ), as
described in a recent article. Furthermore, fascinating results covering
many of the prominent symptoms of ME/CFS continue to be published by
research groups worldwide. These include reduction of brain serotonin
transporters in relation to pain (Yamamoto et al, 2003), delayed gastric
emptying (Burnett et al, 2004), and altered muscle excitability in response
to exercise (Jammes et al, 2005).

The second obstacle standing in the way of "making the breakthrough" is
funding. The diagram on the left gives a very basic outline of the origins
of medical research funding, from (on the left) larger national agencies,
such as the Medical Research Council (MRC), which allocate funds to
established research groups with a track record of success in a certain
area, on the basis of a reasonable scientific hypothesis. However, it is not
generally recognised that medical research into most if not all illness is
funded overwhelmingly from charitable sources. Take cancer: the income of
Cancer Research UK in 2003-4 was around £384,000,000, and this is only one
of  the many charities raising money for cancer. Take away the first digit
and the three noughts at the end and you are left with MERGE's approximate
income for the same period. As I've said before, the three main charitable
sources of ME/CFS research funds in the UK - the CFS Research Foundation
( ), the ME Association
( ) and MERGE ( )
- would struggle to fund between them one medium-sized clinical trial from
their aggregated annual income.

The third problem is the predominance of the biopsychosocial model of the
illness - a model defined in the Chief Medical Officer's report of 2002  as
a "...model of pathophysiology, applicable to all disease, suggests that
once an illness has started its expression is affected by beliefs, coping
styles, and behaviours, while consequential physiological and psychological
effects act in some ways to maintain and/or modify the disease process"
( ). An example is the
recent editorial in the Medical Journal of Australia which stated "
can safely conclude from these studies that graded physical exercise should
become a cornerstone of the management approach for patients with CFS",
stimulating a number of letters to the MJA, including one from Garry Scroop,
visiting Professor of Exercise Physiology who stated, "In summary, patients
with CFS are not 'deconditioned'. Neither their muscle strength nor exercise
capacity is different from that of other sedentary members of the community.
We remain unaware of any incontrovertible evidence that the various
'exercise training' programs suggested in previous articles improve either
the physiological, psychological or clinical status of people with CFS."

This model colours the perception of the illness across the board - from
official reports, such as the report to the Chief Medical Officer's report
mentioned above, to government agencies such as the Department of Work and
Pensions which is producing its new electronic guidelines in 2005, to
research funding bodies such as the Medical Research Council. The recent
large trials funded by the Medical Research Council - the FINE Trial
(designed to increase activity and challenge dysfunctional illness beliefs)
costing £1,147,000, and the PACE (Pacing, Activity, and Cognitive behaviour
therapy) trial costing £3,101,792 - are examples of the resources found for
proponents of the biopsychosocial model. Given that biopsychosocial
therapies are not cures for ME/CFS, people are suggesting that the total
spend of £4,248,792 be given directly to the patients on the trials
(£4425.82 each) so that they can challenge their own "dysfunctional illness
beliefs" in their own way. The issue was well put in an editorial called
"The discomfort of patient power" in the British Medical Journal in 2002:
"Many patients have tried cognitive behavioural therapy and report that
thinking differently does not make their disease go away, though it can
ameliorate some of the sense of privation which these illnesses often
engender. Even so, there is a consensus among patients that if resources
were allocated towards rigorous material empirical biochemical research it
would be more likely to produce a helpful insight into the nature of these
diseases, which would be preferable in their eyes to promulgating
an...incomplete paradigm as though it were a cure."

Finally, the fourth problem is that high quality biomedical research gets
( )
particularly when it conflicts with the prevailing paradigm. To continue the
example of graded exercise therapy mentioned above - widely touted as a
proven management strategy for ME/CFS patients - a recent paper from Snell
et al (2005) reported, "These results implicate abnormal immune activity in
the pathology of exercise intolerance in CFS and are consistent with a
channelopathy involving oxidative stress and nitric oxide-related toxicity."
Another recent paper has shown that exercise provokes pro-inflammatory and
anti-inflammatory cytokines in CFS patients (White et al, 2005), and another
report has described that after exercise there is a particular gene
expression in CFS patients that is not found in normal healthy people. Add
to this the patients' own reports that most are not helped by cognitive
behavioural therapy (Action for ME survey, and the 25% ME Group survey), and
one would think healthcare professionals and would be rushing to read and
implement the latest biomedical research findings. Not on your Nellie. Yet
there is indeed a growing evidence base supporting the biomedical model of
the illness, as illustrated by the comments of Professor Anthony Komaroff in
a recent newspaper article, "For years, many doctors and others dismissed
people with CFS as depressed, lazy, or just plain malingerers... Analysis of
2,000 research papers suggests that CFS is not a psychiatric illness, but a
nasty mix of neurological, immunological and hormonal abnormalities..."

Now, let us pause there. I can think of no other illnesses for which a talk
on biomedical research would need a half-hour preamble on the obstacles -
diagnosis, funding, competing models and ignoring of biomedical data -
standing in the way of "making the breakthrough". However, this is where we
patients find ourselves (for some it feels like going round in circles, as
the cartoon by Trish Campbell of the Warwickshire Network for ME
illustrates), and yet it is the base camp from which research charities such
as MERGE have to march forward. Of course, the ideal is for central (e.g.,
MRC and NHS R&D) funding of biomedical research to be provided through a
form of ring-fencing. Until then, however, we have to spend our limited
resources on novel clinical and biomedical studies that help to unravel the
biology of the illness - innovative pilot studies or seedcorn projects are
particularly important since they can give rise to the supporting data on
which future applications to major funding bodies will have to be based -
and encourage larger established research groups into the field.

In MERGE, to date we have had a several-pronged research strategy based on
the potential importance of mitochondria, immune cells, muscle, blood
vessels and genes
( ) in the
development and maintenance of ME/CFS. It is probably simplest if I describe
the strategy from the viewpoint of oxidative stress, though in reality there
are many ways to approach the body of work that is being undertaken.

Let me begin with our recently published paper (Kennedy et al, 2005) which
showed high levels of isoprostanes in ME/CFS patients, and the fact that
these were correlated with symptoms
( ).
There have now been around 12 papers from several research groups showing
raised markers of oxidative stress in these patients, but this investigation
was the first to measures isoprostanes, which are now recognised as one of
the most reliable approaches to assessing in vivo oxidative stress. It must
also be stressed that current evidence suggests that isoprostanes represent
a biomarker that has the potential to be of great importance in the
assessment of human atherosclerotic cardiovascular disease. There are
several possible sources for these oxidants, including muscle, blood vessel
endothelium and inflammatory/immune cells.

Looking at muscle, there is no question that muscle tissue is a source of
free radical generation - indeed, McArdle et al (2005) used an intracellular
probe to examine free radicals within the myotubules of muscle before,
during and after exercise. In 2005, a report from the Jammes group in France
( ) showed increased M-wave
duration in the 30-minute period after an exercise challenge in ME/CFS
patients. Jammes concluded that, "This accentuated response by CFS patients
to incremental exercise was a result of oxidative stress together with
marked alterations of the muscle membrane excitability." This research was
so important that we have funded Dr Wood and Dr Paul of Caledonian
University to replicate and extend these findings looking at M-wave and
H-wave durations in patients and healthy matched controls up to 4 hours
after exercise. In addition, we have been interested in the interaction
between muscle and the immune system and have funded a research group at
University of Strathclyde to consider the cytokine IL-6, its receptor, and a
neutralising protein, since previous research (Arnold et al, 2002) had shown
that if IL-6 was injected into CFS patients, "they experienced an increase
in somatic symptoms (e.g., aches and fatigue) whereas matched controls did
not experience any symptoms in the first 6 hours after IL-6 administration".
The Strathclyde group is interested in the relationship between IL-6 and
neutralising proteins up to 24 hours after an exercise challenge.

The blood vessel endothelium is an area that we have been interested in ever
since the publication of several papers in the early 1990s on brain blood
flow imaging and orthostatic intolerance with vascular pooling in the
extremities. The cells that line all blood vessels - endothelial cells - are
a potential source of reactive oxygen species generation via several
pathways. SPECT imaging studies by Schwartz et al (1994) showed areas of low
blood flow in the various brain regions of people with ME/CFS, and the
authors postulated that these regions of hypoperfusion were a result of a
focal infection of small cerebral blood vessels. Around the same time, Dr
Peter Rowe, Dr David Bell and others demonstrated that ME/CFS patients had
significant cardiovascular responses to standing upright, manifested by
changes in vascular volume/heart rate/blood pressure. Some psychiatrists
suggested that the cardiovascular changes to upright tilt were simply
cardiovascular deconditioning, but nothing could be further from the truth.
In an article in The Biologist in 2004, Professor Julian Stewart and I
outlined some of the "physical" arguments surrounding this aspect of the
( ). The
first thing to recognise is that the blood pressure in most ME/CFS patients
is maintained by a significant increase in heart rate, at least in the early
stages of upright posture. Professor Stewart has published some interesting
data on what happens to ME/CFS patients when they are upright, and it shows
that there is a group of patients whose leg blood is low when lying down and
it increases when upright, a wholly abnormal response and indicative of a
shift of vascular volume towards the legs. Might there be a problem with
peripheral blood vessels in ME/CFS patients? Well, since 2000 we have been
looking at how skin blood vessels respond to the endothelium-dependent
vasodilator, acetylcholine. To do this we use a novel instrument, a laser
Doppler scanner which images blood flow in the skin. In ME/CFS patients,
blood vessels are sensitive to acetylcholine driven through the skin; i.e.,
the skin blood vessels dilate more than expected, a novel if not unique
finding (i.e., most diseases show the opposite response to acetylcholine,
which is a blunted or decreased blood flow). Our series of experiments on
this aspect of vascular biology at the Vascular Diseases Research Unit in
the University of Dundee was the subject of a review
( ) in 2004,
and we have continued to research this aspect of ME/CFS patients given its
importance to understanding some of the unusual vascular phenomena which
characterise ME/CFS. In this respect we recently awarded a further grant to
Dr Faisel Khan and colleagues at the University of Dundee to continue work
on acetylcholine-mediated vasodilatation in ME/CFS patients, and especially
to look at the role of nitric oxide, prostacyclin and endothelium-derived
hyperpolarising factor (EDHF) in promoting acetylcholine sensitivity.

Inflammatory/immune cells also generate large numbers of free radicals -
superoxide, H2O2, hypochlorous acid, NO, ONOO, etc. - especially during an
infection and when cells are undergoing apoptosis or necrosis, etc. Indeed,
neutrophils kill microbes like bacteria or fungi by releasing huge amounts
of H2O2. To date, we have funded work - mentioned in the British Medical
Journal in August 2004
( ) - showing
that neutrophils in ME/CFS patients undergo early cell death (apoptosis),
significantly more so than in healthy controls
( ). As part
of further research in this area, in 2004 in conjunction with the Tymes
Trust ( ) and Search ME
( ), we awarded a grant entitled, "An
Investigation into biochemical and blood flow aspects of ME/CFS in children"
to Dr Gwen Kennedy and Professor Jill Belch, and part of this investigation
involves examining neutrophil apoptosis at both intra and extracellular
domains in children. Intriguingly, the significant developments in gene
expression in ME/CFS patients which have occurred recently - from Dr
Jonathon Kerr and Dr John Gow in the UK
( ) - are
consistent with the thrust of this, particularly increased cell membrane
prostaglandin-endoperoxidase synthase activity with downstream changes in O2
transport, increased macrophage activation, and cellular apoptotic pathway
activation, and we were delighted to be able to contribute to Dr Gow's
research with a project on the characterisation of differential gene
expression in ME/CFS.

Looking at our findings overall we see dyslipidaemia, oxidative stress and
inflammation. On balance, ME/CFS patients have a lipid profile and oxidant
biology that is consistent with cardiovascular risk, findings that may
explain some of the symptoms of the disease such as the brain symptoms
( ) that characterise
many ME/CFS patients  and some of the peripheral vascular consequences of
being upright. There is a long way to go, but progress has begun and the
body of biomedical evidence is slowly accumulating. Of course, in this talk
I have discussed only the projects for which we have been able to action
funding. A further group of projects are at the negotiation stage, and there
are some on the table that we should like to do if funding becomes available
and if researchers can be found to take on the work.

It is not generally realised that things have moved on considerably since
Darwin and Mendel in the 19th century. The age of the lady and gentleman
scientist has gone forever, and modern researchers follow funding as
hummingbirds follow nectar-bearing blossoms. A highly successful fundraiser
for cancer research told me that in the 1960s, when she began, the word
"cancer" could barely be whispered. But over years, thanks to the efforts of
people like her, there was a sea change in awareness, and contributions
began to flow in (from well people, not only patients and their families)
reaching the hundreds of millions of pounds raised today. We have to do the
same - it is ground-level backbreaking work, but only with data, data, data
will be able to answer our critics AND solve the enigma of ME/CFS.




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