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The Whittemore Peterson Institute
Building the bridges through private
and public sector collaboration
Annette Whittemore
The Whittemore Peterson Institute’s (WPI) publication
of its ground-breaking study on October 8, 2009, of
the link between a cancer-related retrovirus, XMRV, and
patients with myalgic encephalomyelitis/chronic fatigue syndrome
(“ME/CFS”) brings a desperately needed legitimacy
to a complex yet controversial and misunderstood disease
(1). News of this significant association brought hope to millions
around the world who have suffered in silence from its
devastating effects. Perhaps, just as important, the discovery
of XMRV infection in humans allows the medical world to
construct a testable hypothesis of how XMRV may cause or
contribute to illnesses across a wide spectrum of chronic
inflammatory diseases and cancers and new paradigms of
treatment and perhaps prevention.
That the discovery happened in just three years of a small
research institute’s existence is almost as amazing as the
extraordinary scientific work. This is the story of how and
why the Whittemore Peterson Institute came to be. It is a story
of multiple collaborations at every level, revealing a blueprint
for other groups of dedicated scientists, doctors, and philanthropists
to create greater progress through unique and selfless
partnerships across nontraditional boundaries. Like other
philanthropic endeavors, it began as an idea evidenced
through personal suffering and acted upon after all other
avenues had failed.
The personal decision to commit time and money to build an
institute for patients with neuroimmune diseases came from a
desperate need for medical solutions to a disease that had
been destroying our daughter’s life for over twenty years. We
were also faced with the reality that experienced physicians
were retiring without passing on their knowledge of ME/CFS
to new physicians . In addition, the existing medical
establishment lacked both knowledge and medical tools to
effectively treat patients who suffered the debilitating effects
of this neurological disease. Around the world, those who
suffer with ME/CFS have been told that their physical disorder
is a manifestation of a psychiatric disease. Subsequently,
these patients may then be denied medical support by their
government-run health care programs.
Box 1. The Historical Description
of Myalgic Encephalomyelitis
Myalgic Encephalomyelitis was first described
by Melvin Ramsey in the UK after an outbreak
in the 1950s [(5–7), see also (8)]. He coined
the term to describe the muscle pain and symptoms
of brain and spinal-cord inflammation its
sufferers experienced. In the early 1980s, an
outbreak in the United States of a disease with
the identical symptoms of ME was reported to
the CDC. With little input from the physicians
who first described the disease, a small group
of scientists, doctors and psychiatrists renamed
the disease from the earlier term, chronic
Epstein-Barr virus, to simply “Chronic Fatigue
Syndrome” (9). By emphasizing fatigue as a
symptom, which is known to be associated
with many chronic conditions, those with “CFS”
quickly became confused with others who
were simply “tired” or “burned out” from overwork.
Unfortunately for those who were truly ill,
and not merely tired, this misunderstanding has
prejudiced scientists and doctors before they
ever examined a patient with “CFS.”
Journey Through A Medical Wilderness
Our odyssey began in 1989, when my daughter, Andrea,
became ill with a mononucleosis-like illness and then failed
to return to normal health After many
months of continuous relapsing
and remitting flu-like symptoms, she was referred
to a major medical institution for evaluation. She
was given a cursory check up, then provided with a
psychological explanation for her infectious symptoms
of sore throat, severe head and nerve pain, swollen
lymph glands, night sweats, tachycardia, and muscle
aching fatigue. Even to a non-scientist that answer
seemed ridiculous. The consulting physicians could offer no
explanation for what was clearly a biological phenomenon.
I returned home with Andrea, determined to find a doctor
who knew something about the outbreak of a disease that
had occurred at Lake Tahoe, a favorite summer destination
frequented by our family. A physician and next door neighbor,
Reggie Davis, who had known Andrea as a healthy
child and saw her frequently during her illness, was convinced
that her symptoms were like those of individuals from
that outbreak. He suggested that we see Raymond Scott,
an internist in Reno, even though Andrea was only twelve.
Before allowing her to see the doctor, I scheduled an interview
with him to be sure he knew something about the disease:
I was not going to allow her to be told that her symptoms
were not real, as did the doctor who told her that she
“most likely hated her parents, her friends, and her school.”
Through it all, other physicians confirmed what I knew––that
my daughter was ill with a very real disease.
Fortunately, Dr. Scott had worked with other patients in the
Incline Village, Lake Tahoe area and knew more about CFS
than any other doctor in Reno. Although the treatments he
offered provided only symptomatic relief, her life improved
under his compassionate care. She continued this modest
improvement until she decided to enroll at the University of
Nevada–Reno. The admission policy required the measles,
mumps, and rubella (MMR) vaccination prior to starting classes.
Within five days of the MMR vaccination, Andrea had a
severe relapse and never regained her previous level of health.
Reflections
As her health continued to deteriorate, Dr. Scott became
more concerned. Soon we were on our way to another major
medical institution in California, where rounds of tests and
several physicians later, we ended the visit with a referral to
another hospital’s pain clinic where she was told she should
fill out a questionnaire everyday, then learn to live with her
pain. Just eighteen years old, Andrea was facing a lifetime of
pain that was so severe she required the use of a transcutaneous
electrical nerve stimulation unit and injections to make
it through the day.
Only after a visit to a local gastroenterologist, one year later,
did we find that much of her pain arose from a diseased gallbladder.
Within six months of her gallbladder surgery, she also
had to have her appendix removed. We began to worry that
a vital organ might soon be affected, so we followed her doctor’s
advice and sought out internist Daniel Peterson of Incline
Village. Months later, Andrea was accepted into his practice
Dr. Peterson has a passion for his work and his patients. He
is one of a small number of well-respected CFS physicians
and was one of two doctors who first alerted the Centers for
Disease Control to a possible outbreak of a new disease, then
dubbed chronic Epstein-Barr virus (EBV) (2). Dr. Peterson knew
that something was making his patients sick and keeping them
from getting well again. The CDC’s quick reply left Peterson
with the impression that the CDC didn’t know what the cause
was and that it did not think it warranted more attention.
Without serious government-backed follow-up to validate those
initial and unfortunate faulty conclusions, medical scientists
were dissuaded from researching the cause of the new disease,
while many more around the world became ill.
Patients who had what was now known as ME/CFS were
left with modest victories to cheer and little medical hope. In
1993, Nevada became one of the first states to request that
the President and Congress increase funding for research into
CFS4. In addition, the Nevada legislature agreed to include
the drug, Ampligen, which acts to stimulate the body’s antiviral
defenses, in modest recovery models for Phase III trials.
Treadmill VO2max (i.e., the volume of oxygen utilized during
exercise of maximum exertion) was used as a guide to
evaluate patient disability and response to treatment. When
Andrea turned twenty-one, she enrolled in the phase III drug
trial. Twice a week she was given an intravenous (iv) infusion
that at first caused her to experience a worsening of
her symptoms. Other days, she spent hours receiving nutrient
iv fluids that supported her health. Finally, after one year of
treatment, she began to improve with the drug and continued
to take it, off and on, for eight years.
Blood tests, developed in a laboratory in Belgium, helped
determine some of the unique traits found in many CFS
patients. After the bombing of the World Trade Center, however,
transporting blood overseas was no longer an option.
We and a few other patient advocates were approached by
one of the owners of the Belgium lab and asked to support
the establishment of a US lab that would perform the same
tests. Because most of the American patients lacked the insurance
to pay for the tests, my husband, Harvey, and I agreed
to help and soon supported the lab in its entirety. We felt
supporting this lab was critical to the ongoing work in developing
and testing therapies for patients with CFS. As a result
of supporting the lab, valuable RNase L studies and natural
killer (NK) cell work were able to continue, which eventually
led to the hypothesis that patients with CFS might be infected
with xenotropic murine leukemia virus-related virus (XMRV).
While taking Ampligen, Andrea improved to 75% of her
previous levels of energy and stamina, but despite many of
the positive outcomes, she continued to fall ill with opportunistic
infections. For unknown reasons, Andrea began to
develop reactions to Ampligen, making her too sick to continue.
Once off the drug, she began a continuous decline.
Today, without treatment she experiences daily seizures,
nausea, vomiting, severe allergies, and painful lymph-node
swelling. As a result, she requires nearly full-time help to care
for herself and her home. Instead of answers and solutions,
we were left with hopelessness.
CFS: Challenges To Overcome
The difference between the actual effects of this disease and
that which is portrayed in the popular media could not be
greater. The current CDC definition states that a patient must
satisfy two criteria:
1. Have severe chronic fatigue of six months or longer
duration, with other known medical conditions
excluded by clinical diagnosis; and
2. Concurrently have four or more of the following
symptoms: substantial impairment in short-term
memory or concentration; sore throat; tender lymph
nodes; muscle pain; multi-joint pain without swelling
or redness; headaches of a new type, pattern
or severity; unrefreshing sleep; and post-exertional
malaise lasting more than twenty-four hours.
The symptoms must have persisted or recurred during six
or more consecutive months of illness and must not have
predated the fatigue. The CDC then recommends a series of
common blood tests, but goes on to predict that:
“More than 90% of patients presenting with severe
fatigue will test at normal levels for the series of
laboratory tests listed above. Assuming that there
is nothing in the physical examination or in the
personal history of the patient that suggests a clear
direction to the doctor, no further laboratory testing
is recommended.”
With what other disease could government health officials
suggest waiting six months for a diagnosis, using tests
that will only tell you what it is not, and leave you with no
answers as to what it is or how to treat it? The CDC concludes
that because not every CFS patient has the same
abnormalities in their immune systems or brain scans, further
evaluation is not necessary. Thus, scientific answers become
even harder to obtain.
Perhaps what is missing most from the public’s awareness
is the description of the most severely ill patients, like
Andrea, who, at times, was so ill and weak that she was
unable to feed herself or walk unaided. As these patients’
immune systems weaken and various chronic infections take
hold, they live their lives between doctor’s offices and their
homes physically and emotionally isolated from their families,
friends, and communities. Many go on to develop life-threatening
complications. In a retrospective analysis, Leonard
Jason found that those diagnosed with ME/CFS died of heart
disease, cancer, or suicide at ages approximately twenty-five
years younger than the normal population. Only detailed
epidemiological studies will reveal the true complications of
long term disease and mortality resulting from the complications
of this disease.
The problems that patients experience when dealing with
the healthcare system can be as difficult as the disease itself.
Most doctors have difficulty diagnosing ME/CFS and when
they do, are at a loss as to what to do for their patients.
The lack of medical consensus is so great that most doctors
disagree on the best treatment strategies or what, if any, biological
treatments to consider. Doctors and patients are left
to their own devices, experimenting with drug treatments
that are unproven, toxic, or both. Scientific and educational
information surrounding ME/CFS is conflicting and often consists
of anecdotal observations from physicians. Additionally,
many patients are told they suffer from “faulty thinking” about
the illness and are then prescribed cognitive behavioral therapy
and graded exercise therapy.
More Than A Foundation
It was evident to me, after working with another research
foundation to study CFS, that engaging various scientists to
do related research projects was only one part of the solution
to the much bigger issues surrounding ME/CFS. This initial
research program was narrowly focused on one virus and
relied on individual researchers to apply for grants. Much like
the extramural grants of the NIH, these projects are scattered
among different unrelated researchers and not organized in
a comprehensive and coordinated manner.
One thing that I admired about the foundation’s director was
her ability to access researchers to do the work that she felt
might reveal new information. After reading about the XMRV
finding in prostate cancer, I tried to contact the group of
researchers at UCSF that had made the extraordinary new
discovery. I wanted to pay them to test CFS patient samples
using their viral-chip technology. After several attempts, I
gave up that effort and instead began to develop another
plan of action. That plan was to create a research program
within the structure of a medical research center.
Many advocacy organizations had expressed an interest in
government support of Centers of Excellence for the treatment
of patients with ME/CFS. In fact, to address the issues
of CFS, a bench-to-bedside approach was needed, requiring
nothing less than an expert institution, which would combine
translational research with patient diagnostics, treatments, and
medical training for new doctors. When it became apparent
that no one else was willing to create such a center, with the
strong encouragement of my husband, family, friends, and
political leaders.
Reflections
I agreed to act. With a promise from medical
doctors to support our efforts, I committed my time and my
family’s resources to create and build such an institute.
In early 2005, Dr. Peterson and I began working to describe
this institute’s future clinical practice. Meanwhile, my husband
discussed with John Lilley, then president of the University of
Nevada–Reno, the School of Medicine’s desire for a new
medical research building. Our Governor and good friend,
Kenny Guinn, agreed to place this project in his state budget.
Legislative leaders who understood the potential benefits to
both patients and future medical education in this state also
began to offer their support. This new research facility was to
house three significant interest groups: researchers from the
University of Nevada’s Medical School; the Nevada Cancer
Institute; and the Center for Neuroimmune Disease (now
called the WPI). That winter, I gathered scientific information
for a presentation to the 2005 state legislature, arguing
the need for such a medical center. University representatives
and Nevada Cancer Institute scientists did the same.
Passionate pleas were made by several patient advocates in
addition to our testimony. By the end of the legislative session,
ten million dollars has been allocated to support a new
research and medical office building5 (Figure 2). The main
portion of the building was built from bond money which was
based on the indirect costs of the researchers’ grants. My
husband and I committed to give or raise an additional $5
million towards WPI’s portion of the building, and soon the
construction began, bringing reality to a dream.
The Real Work Begins
Judy Mikovits and I met at an HHV-6 Foundation conference
in the spring of 2006. It was at that conference that
Dr. Peterson presented patient data describing many longstanding
CFS patients who had developed rare lymphomas.
Dr. Mikovits was intrigued and, as a seasoned scientist with
experiences in retrovirology, recognized a potential for discovering
a new disease-causing pathogen.
Shortly thereafter, I asked Dr. Mikovits to serve as the
Institute’s full-time Research Director. She immediately planned
a comprehensive research program to answer questions that
would support the development of diagnostics to help define
those who had this illness. She began by building a repository
of patient samples and organizing her studies to generate
sufficient data to justify an NIH grant, which was submitted in
June, 2007 and finally funded in October, 2009.
Having the support of University leadership––President Milton
Glick and Ole Theinhaus, Dean of the Medical School––was
also critical to our success. Experienced scientists such as
Steven St. Jeor, a CMV researcher; Greg Pari, an expert in
Kaposi’s sarcoma-associated herpesvirus (KSHV); and Ian
Buxton, a pharmacologist, offered their assistance. Soon after
moving to the University, we organized a small conference as
a means to formally introduce ourselves. Researchers from the
University, the National Cancer Institute, and the WPI came
together with ME/CFS physicians, to discuss their areas of
expertise. The following year Dr. Mikovits led the first meeting
of the Institute’s new scientific advisory board. Today,
the WPI Scientific Advisory Board engages scientists with
expertise in cancer, infectious disease, autoimmune diseases,
immunology, and virology.
WPI has had to use a combination of funding mechanisms
to pay for the many different activities neccessary for the
creation of a working institute. Like many medical research
non-profits, WPI must rely on the talents of its researchers
to receive grant support and the ability of its administrators
to raise funds from the larger community. When a disease
is not well understood and often maligned, it is an even
more daunting task. For example, it took WPI three years to
receive NIH funding for reasons unrelated to the quality of
the proposal.
Donations to the Institute come in many forms. WPI has a
yearly gala dinner which raises hundreds of thousands of dollars.
We ask private foundations, companies, and individuals
for their help in a variety of ways. We have also used yearend
gift appeals and a new Facebook Cause page to raise
money and awareness. The WPI Web site has been a source
of donations, as well. The urgent need for a continuous
source of income to support the clinical work of the Institute is
now our greatest priority.
Generous patients, hopeful for answers, make up a significant
part of the funding in this disease. They must choose
between several organizations who claim to be doing important
research work. It is difficult for most laymen to decipher
the kind of science they are funding or whether or not the
scientists are qualified to do the work. Thus, private donations
which are very competitive can be spent on research
that does not provide significant results. Educating the public
about the importance of our organization’s own research
capabilities is time consuming and requires a full time effort,
but is extremely necessary if one is to gain public support.
The Intramural NCI Program:
The Value Of Basic Research
The selection of Dr. Mikovits as the research director of the
WPI was fortuitous in that she had worked for twenty years
in the Intramural Program for the NCI as research technician,
graduate student, postdoctoral fellow and finally as head of
the NCI contractor’s lab of Antiviral Drug Mechanisms. The
NCI’s tumor virus program of the late 1970s supported the
identification of retroviral oncogenes in human tissue and of
the tumor-causing human retrovirus, human T cell leukemialymphoma
virus type I (HTLV-I) by Bernie Poiesz and Frank
Ruscetti, in the laboratory of Bob Gallo. By 1984, NCI investigators
were co-discoverers of a new retrovirus, HIV-1, which is
the causative agent of AIDS. It was natural for Dr. Mikovits to
enlist the help of her former NCI colleagues, Frank and Sandy
Ruscetti, Mike Dean and Rachel Bagni, to look for an infectious
agent. Thus, NCI’s investment in funding basic research in animal
and human virology made the discovery process possible.
Initially, the discovery process focused on the use of a viruschip
assay similar to the one used to discover xenotropic
murine leukemia virus-related virus (XMRV) in the tissue of
men carrying RNase L mutations who had prostate cancer (4).
After two and a half years of trying to make sense of the viral
chip data, we narrowed our focus to XMRV, because many
CFS patients also suffer from an RNase L defect, and initiated
a collaboration with Bob Silverman, a co-discoverer of the
virus, of the Cleveland Clinic. All patient material used in this
study were subjected to four separate XMRV assays: DNA
PCR from peripheral blood cells (PBMC); viral protein expression
in PBMC; presence of antibodies in plasma; and the
recovery of infectious virus from plasma transmitted to indicator
permissive cell lines. After five months of a rigorous review
process, the journal Science published our findings (1).
The Aftermath: Still Stuck
In Osler’s Web
By attempting to bring chronic fatigue syndrome (CFS)
research out of the shadows and squarely onto the nation’s
health agenda, we knew that we would be the object of
much criticism from both the medical establishment and those
individuals invested in other theories of disease causation.
Previous experiences had shown that some of these activities
would parallel what happened during the early days after the
discovery of HIV and AIDS.
CFS was belatedly recognized as a legitimate disease entity
by the Centers for Disease Control in 1997 but is still denied
recognition as an infectious immune disorder. The HHV6
foundation believes that HHV6 is the sole cause of CFS. A
major CFS patient advocacy organization is on record,
having concluded that a retrovirus has nothing to do with
the pathophysiology of CFS. Much of the opposition outside
of the CFS community firmly believes this disease and others
that are similar arise from psychiatric disturbances. Within
a week of the Science online publication, several scientists
publicly announced that they would not be able to replicate
the findings, negative findings were reported on blogs, and
within a month, three negative papers had been written and
submitted about the lack of XMRV in CFS.
Without directed research allocations from a Director of an
NIH institute, it can take between three to five years before
money can be allocated to study the role of XMRV in disease.
Fortunately, Robert Wiltrout, Director of the National Cancer
Institute’s Intramural Center for Cancer Research, has already
requested that the scientists in the intramural program begin
to develop reagents to determine the role of XMRV in the
development of cancer and other chronic diseases.
The other difficulties surrounding funding of governmental
research grants are numerous, including the time it takes for
the entire process to be completed. NCI has developed a
mechanism to rapidly give new research funding to existing
cancer centers. Unfortunately, when a new, non-traditional
entity such as the WPI is created, it must often delay work
until the funding is already in place. To solve these problems,
we have found it beneficial to work with other institutions
and experienced investigators who have offered to co-author
grants in a mentoring relationship. But we have also learned
a valuable lesson: a non-traditional entity may point out a
new research direction, but it must be confirmed by traditional
engrained mechanisms.
Reflections
Although the challenges have been significant, the personal
rewards one receives by helping others through the work of this
institute have been tremendous. We meet and talk often with
hundreds of individuals who are thankful that the WPI is creating
a scientific program of discovery that will improve their
lives. They have spent too many years suffering in silence, often
opting out of the medical world when they can’t find relief.
Scientific efforts to solve the many questions surrounding
neuroimmune diseases have brought a renewed interest in
the field and hope to millions throughout the world. Below
are just two of thousands of messages sent to our offices.
“Canada cheered when we heard the news.” Another patient
wrote, “I do not have words to thank you for the work you
have done. It has now been 30 years since I fell ill and I
truly never thought I would see the day this terrible knot was
untied.” Therein lies the motivation, despite all obstacles, to
continue this vital mission.
References
1. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson
DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, et al. (2009)
Detection of an infectious retrovirus, XMRV, in blood cells of patients with
Chronic Fatigue Syndrome. Science 326:585-589.
2. Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, and Schonberger
LB (1987) A cluster of patients with a chronic mononucleosis-like syndrome.
JAMA 257:2297–2302.
3. Jason LA, Corradi K, Gress S, Williams S, and Torres-Harding S (2006)
Causes of death among patients with chronic fatigue syndrome. Health
Care Women Int. 27:615–626.
4. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein
EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, et al. (2006)
Identification of a novel gammaretrovirus in prostate tumors of patients
homozygous for R462Q RNASEL variant. PLoS Pathogens 2:e25.
5. Ramsay AM and O’Sullivan E (1956) Encephalomyelitis simulating poliomyelitis.
Lancet 270:761–764.
6. Ramsay AM (1957) Encephalomyelitis simulating poliomyelitis. Public
Health 71:98–112.
7. Ramsay AM (1957) Encephalomyelitis in north west London; an endemic
infection simulating poliomyelitis and hysteria. Lancet 273:1196–1200.
8. Ramsay AM (1986) Myalgic Encephalomyelitis: A baffling syndrome with
a tragic aftermath. M.E. Association Journal 1986, UK.
9. Jason LA, Najar N, Porter N, and Reh C (2009) Evaluating the Centers
for Disease Control’s empirical chronic fatigue syndrome case definition.
J. Disability Policy Studies 20:93–100.
Building the bridges through private
and public sector collaboration
Annette Whittemore
The Whittemore Peterson Institute’s (WPI) publication
of its ground-breaking study on October 8, 2009, of
the link between a cancer-related retrovirus, XMRV, and
patients with myalgic encephalomyelitis/chronic fatigue syndrome
(“ME/CFS”) brings a desperately needed legitimacy
to a complex yet controversial and misunderstood disease
(1). News of this significant association brought hope to millions
around the world who have suffered in silence from its
devastating effects. Perhaps, just as important, the discovery
of XMRV infection in humans allows the medical world to
construct a testable hypothesis of how XMRV may cause or
contribute to illnesses across a wide spectrum of chronic
inflammatory diseases and cancers and new paradigms of
treatment and perhaps prevention.
That the discovery happened in just three years of a small
research institute’s existence is almost as amazing as the
extraordinary scientific work. This is the story of how and
why the Whittemore Peterson Institute came to be. It is a story
of multiple collaborations at every level, revealing a blueprint
for other groups of dedicated scientists, doctors, and philanthropists
to create greater progress through unique and selfless
partnerships across nontraditional boundaries. Like other
philanthropic endeavors, it began as an idea evidenced
through personal suffering and acted upon after all other
avenues had failed.
The personal decision to commit time and money to build an
institute for patients with neuroimmune diseases came from a
desperate need for medical solutions to a disease that had
been destroying our daughter’s life for over twenty years. We
were also faced with the reality that experienced physicians
were retiring without passing on their knowledge of ME/CFS
to new physicians . In addition, the existing medical
establishment lacked both knowledge and medical tools to
effectively treat patients who suffered the debilitating effects
of this neurological disease. Around the world, those who
suffer with ME/CFS have been told that their physical disorder
is a manifestation of a psychiatric disease. Subsequently,
these patients may then be denied medical support by their
government-run health care programs.
Box 1. The Historical Description
of Myalgic Encephalomyelitis
Myalgic Encephalomyelitis was first described
by Melvin Ramsey in the UK after an outbreak
in the 1950s [(5–7), see also (8)]. He coined
the term to describe the muscle pain and symptoms
of brain and spinal-cord inflammation its
sufferers experienced. In the early 1980s, an
outbreak in the United States of a disease with
the identical symptoms of ME was reported to
the CDC. With little input from the physicians
who first described the disease, a small group
of scientists, doctors and psychiatrists renamed
the disease from the earlier term, chronic
Epstein-Barr virus, to simply “Chronic Fatigue
Syndrome” (9). By emphasizing fatigue as a
symptom, which is known to be associated
with many chronic conditions, those with “CFS”
quickly became confused with others who
were simply “tired” or “burned out” from overwork.
Unfortunately for those who were truly ill,
and not merely tired, this misunderstanding has
prejudiced scientists and doctors before they
ever examined a patient with “CFS.”
Journey Through A Medical Wilderness
Our odyssey began in 1989, when my daughter, Andrea,
became ill with a mononucleosis-like illness and then failed
to return to normal health After many
months of continuous relapsing
and remitting flu-like symptoms, she was referred
to a major medical institution for evaluation. She
was given a cursory check up, then provided with a
psychological explanation for her infectious symptoms
of sore throat, severe head and nerve pain, swollen
lymph glands, night sweats, tachycardia, and muscle
aching fatigue. Even to a non-scientist that answer
seemed ridiculous. The consulting physicians could offer no
explanation for what was clearly a biological phenomenon.
I returned home with Andrea, determined to find a doctor
who knew something about the outbreak of a disease that
had occurred at Lake Tahoe, a favorite summer destination
frequented by our family. A physician and next door neighbor,
Reggie Davis, who had known Andrea as a healthy
child and saw her frequently during her illness, was convinced
that her symptoms were like those of individuals from
that outbreak. He suggested that we see Raymond Scott,
an internist in Reno, even though Andrea was only twelve.
Before allowing her to see the doctor, I scheduled an interview
with him to be sure he knew something about the disease:
I was not going to allow her to be told that her symptoms
were not real, as did the doctor who told her that she
“most likely hated her parents, her friends, and her school.”
Through it all, other physicians confirmed what I knew––that
my daughter was ill with a very real disease.
Fortunately, Dr. Scott had worked with other patients in the
Incline Village, Lake Tahoe area and knew more about CFS
than any other doctor in Reno. Although the treatments he
offered provided only symptomatic relief, her life improved
under his compassionate care. She continued this modest
improvement until she decided to enroll at the University of
Nevada–Reno. The admission policy required the measles,
mumps, and rubella (MMR) vaccination prior to starting classes.
Within five days of the MMR vaccination, Andrea had a
severe relapse and never regained her previous level of health.
Reflections
As her health continued to deteriorate, Dr. Scott became
more concerned. Soon we were on our way to another major
medical institution in California, where rounds of tests and
several physicians later, we ended the visit with a referral to
another hospital’s pain clinic where she was told she should
fill out a questionnaire everyday, then learn to live with her
pain. Just eighteen years old, Andrea was facing a lifetime of
pain that was so severe she required the use of a transcutaneous
electrical nerve stimulation unit and injections to make
it through the day.
Only after a visit to a local gastroenterologist, one year later,
did we find that much of her pain arose from a diseased gallbladder.
Within six months of her gallbladder surgery, she also
had to have her appendix removed. We began to worry that
a vital organ might soon be affected, so we followed her doctor’s
advice and sought out internist Daniel Peterson of Incline
Village. Months later, Andrea was accepted into his practice
Dr. Peterson has a passion for his work and his patients. He
is one of a small number of well-respected CFS physicians
and was one of two doctors who first alerted the Centers for
Disease Control to a possible outbreak of a new disease, then
dubbed chronic Epstein-Barr virus (EBV) (2). Dr. Peterson knew
that something was making his patients sick and keeping them
from getting well again. The CDC’s quick reply left Peterson
with the impression that the CDC didn’t know what the cause
was and that it did not think it warranted more attention.
Without serious government-backed follow-up to validate those
initial and unfortunate faulty conclusions, medical scientists
were dissuaded from researching the cause of the new disease,
while many more around the world became ill.
Patients who had what was now known as ME/CFS were
left with modest victories to cheer and little medical hope. In
1993, Nevada became one of the first states to request that
the President and Congress increase funding for research into
CFS4. In addition, the Nevada legislature agreed to include
the drug, Ampligen, which acts to stimulate the body’s antiviral
defenses, in modest recovery models for Phase III trials.
Treadmill VO2max (i.e., the volume of oxygen utilized during
exercise of maximum exertion) was used as a guide to
evaluate patient disability and response to treatment. When
Andrea turned twenty-one, she enrolled in the phase III drug
trial. Twice a week she was given an intravenous (iv) infusion
that at first caused her to experience a worsening of
her symptoms. Other days, she spent hours receiving nutrient
iv fluids that supported her health. Finally, after one year of
treatment, she began to improve with the drug and continued
to take it, off and on, for eight years.
Blood tests, developed in a laboratory in Belgium, helped
determine some of the unique traits found in many CFS
patients. After the bombing of the World Trade Center, however,
transporting blood overseas was no longer an option.
We and a few other patient advocates were approached by
one of the owners of the Belgium lab and asked to support
the establishment of a US lab that would perform the same
tests. Because most of the American patients lacked the insurance
to pay for the tests, my husband, Harvey, and I agreed
to help and soon supported the lab in its entirety. We felt
supporting this lab was critical to the ongoing work in developing
and testing therapies for patients with CFS. As a result
of supporting the lab, valuable RNase L studies and natural
killer (NK) cell work were able to continue, which eventually
led to the hypothesis that patients with CFS might be infected
with xenotropic murine leukemia virus-related virus (XMRV).
While taking Ampligen, Andrea improved to 75% of her
previous levels of energy and stamina, but despite many of
the positive outcomes, she continued to fall ill with opportunistic
infections. For unknown reasons, Andrea began to
develop reactions to Ampligen, making her too sick to continue.
Once off the drug, she began a continuous decline.
Today, without treatment she experiences daily seizures,
nausea, vomiting, severe allergies, and painful lymph-node
swelling. As a result, she requires nearly full-time help to care
for herself and her home. Instead of answers and solutions,
we were left with hopelessness.
CFS: Challenges To Overcome
The difference between the actual effects of this disease and
that which is portrayed in the popular media could not be
greater. The current CDC definition states that a patient must
satisfy two criteria:
1. Have severe chronic fatigue of six months or longer
duration, with other known medical conditions
excluded by clinical diagnosis; and
2. Concurrently have four or more of the following
symptoms: substantial impairment in short-term
memory or concentration; sore throat; tender lymph
nodes; muscle pain; multi-joint pain without swelling
or redness; headaches of a new type, pattern
or severity; unrefreshing sleep; and post-exertional
malaise lasting more than twenty-four hours.
The symptoms must have persisted or recurred during six
or more consecutive months of illness and must not have
predated the fatigue. The CDC then recommends a series of
common blood tests, but goes on to predict that:
“More than 90% of patients presenting with severe
fatigue will test at normal levels for the series of
laboratory tests listed above. Assuming that there
is nothing in the physical examination or in the
personal history of the patient that suggests a clear
direction to the doctor, no further laboratory testing
is recommended.”
With what other disease could government health officials
suggest waiting six months for a diagnosis, using tests
that will only tell you what it is not, and leave you with no
answers as to what it is or how to treat it? The CDC concludes
that because not every CFS patient has the same
abnormalities in their immune systems or brain scans, further
evaluation is not necessary. Thus, scientific answers become
even harder to obtain.
Perhaps what is missing most from the public’s awareness
is the description of the most severely ill patients, like
Andrea, who, at times, was so ill and weak that she was
unable to feed herself or walk unaided. As these patients’
immune systems weaken and various chronic infections take
hold, they live their lives between doctor’s offices and their
homes physically and emotionally isolated from their families,
friends, and communities. Many go on to develop life-threatening
complications. In a retrospective analysis, Leonard
Jason found that those diagnosed with ME/CFS died of heart
disease, cancer, or suicide at ages approximately twenty-five
years younger than the normal population. Only detailed
epidemiological studies will reveal the true complications of
long term disease and mortality resulting from the complications
of this disease.
The problems that patients experience when dealing with
the healthcare system can be as difficult as the disease itself.
Most doctors have difficulty diagnosing ME/CFS and when
they do, are at a loss as to what to do for their patients.
The lack of medical consensus is so great that most doctors
disagree on the best treatment strategies or what, if any, biological
treatments to consider. Doctors and patients are left
to their own devices, experimenting with drug treatments
that are unproven, toxic, or both. Scientific and educational
information surrounding ME/CFS is conflicting and often consists
of anecdotal observations from physicians. Additionally,
many patients are told they suffer from “faulty thinking” about
the illness and are then prescribed cognitive behavioral therapy
and graded exercise therapy.
More Than A Foundation
It was evident to me, after working with another research
foundation to study CFS, that engaging various scientists to
do related research projects was only one part of the solution
to the much bigger issues surrounding ME/CFS. This initial
research program was narrowly focused on one virus and
relied on individual researchers to apply for grants. Much like
the extramural grants of the NIH, these projects are scattered
among different unrelated researchers and not organized in
a comprehensive and coordinated manner.
One thing that I admired about the foundation’s director was
her ability to access researchers to do the work that she felt
might reveal new information. After reading about the XMRV
finding in prostate cancer, I tried to contact the group of
researchers at UCSF that had made the extraordinary new
discovery. I wanted to pay them to test CFS patient samples
using their viral-chip technology. After several attempts, I
gave up that effort and instead began to develop another
plan of action. That plan was to create a research program
within the structure of a medical research center.
Many advocacy organizations had expressed an interest in
government support of Centers of Excellence for the treatment
of patients with ME/CFS. In fact, to address the issues
of CFS, a bench-to-bedside approach was needed, requiring
nothing less than an expert institution, which would combine
translational research with patient diagnostics, treatments, and
medical training for new doctors. When it became apparent
that no one else was willing to create such a center, with the
strong encouragement of my husband, family, friends, and
political leaders.
Reflections
I agreed to act. With a promise from medical
doctors to support our efforts, I committed my time and my
family’s resources to create and build such an institute.
In early 2005, Dr. Peterson and I began working to describe
this institute’s future clinical practice. Meanwhile, my husband
discussed with John Lilley, then president of the University of
Nevada–Reno, the School of Medicine’s desire for a new
medical research building. Our Governor and good friend,
Kenny Guinn, agreed to place this project in his state budget.
Legislative leaders who understood the potential benefits to
both patients and future medical education in this state also
began to offer their support. This new research facility was to
house three significant interest groups: researchers from the
University of Nevada’s Medical School; the Nevada Cancer
Institute; and the Center for Neuroimmune Disease (now
called the WPI). That winter, I gathered scientific information
for a presentation to the 2005 state legislature, arguing
the need for such a medical center. University representatives
and Nevada Cancer Institute scientists did the same.
Passionate pleas were made by several patient advocates in
addition to our testimony. By the end of the legislative session,
ten million dollars has been allocated to support a new
research and medical office building5 (Figure 2). The main
portion of the building was built from bond money which was
based on the indirect costs of the researchers’ grants. My
husband and I committed to give or raise an additional $5
million towards WPI’s portion of the building, and soon the
construction began, bringing reality to a dream.
The Real Work Begins
Judy Mikovits and I met at an HHV-6 Foundation conference
in the spring of 2006. It was at that conference that
Dr. Peterson presented patient data describing many longstanding
CFS patients who had developed rare lymphomas.
Dr. Mikovits was intrigued and, as a seasoned scientist with
experiences in retrovirology, recognized a potential for discovering
a new disease-causing pathogen.
Shortly thereafter, I asked Dr. Mikovits to serve as the
Institute’s full-time Research Director. She immediately planned
a comprehensive research program to answer questions that
would support the development of diagnostics to help define
those who had this illness. She began by building a repository
of patient samples and organizing her studies to generate
sufficient data to justify an NIH grant, which was submitted in
June, 2007 and finally funded in October, 2009.
Having the support of University leadership––President Milton
Glick and Ole Theinhaus, Dean of the Medical School––was
also critical to our success. Experienced scientists such as
Steven St. Jeor, a CMV researcher; Greg Pari, an expert in
Kaposi’s sarcoma-associated herpesvirus (KSHV); and Ian
Buxton, a pharmacologist, offered their assistance. Soon after
moving to the University, we organized a small conference as
a means to formally introduce ourselves. Researchers from the
University, the National Cancer Institute, and the WPI came
together with ME/CFS physicians, to discuss their areas of
expertise. The following year Dr. Mikovits led the first meeting
of the Institute’s new scientific advisory board. Today,
the WPI Scientific Advisory Board engages scientists with
expertise in cancer, infectious disease, autoimmune diseases,
immunology, and virology.
WPI has had to use a combination of funding mechanisms
to pay for the many different activities neccessary for the
creation of a working institute. Like many medical research
non-profits, WPI must rely on the talents of its researchers
to receive grant support and the ability of its administrators
to raise funds from the larger community. When a disease
is not well understood and often maligned, it is an even
more daunting task. For example, it took WPI three years to
receive NIH funding for reasons unrelated to the quality of
the proposal.
Donations to the Institute come in many forms. WPI has a
yearly gala dinner which raises hundreds of thousands of dollars.
We ask private foundations, companies, and individuals
for their help in a variety of ways. We have also used yearend
gift appeals and a new Facebook Cause page to raise
money and awareness. The WPI Web site has been a source
of donations, as well. The urgent need for a continuous
source of income to support the clinical work of the Institute is
now our greatest priority.
Generous patients, hopeful for answers, make up a significant
part of the funding in this disease. They must choose
between several organizations who claim to be doing important
research work. It is difficult for most laymen to decipher
the kind of science they are funding or whether or not the
scientists are qualified to do the work. Thus, private donations
which are very competitive can be spent on research
that does not provide significant results. Educating the public
about the importance of our organization’s own research
capabilities is time consuming and requires a full time effort,
but is extremely necessary if one is to gain public support.
The Intramural NCI Program:
The Value Of Basic Research
The selection of Dr. Mikovits as the research director of the
WPI was fortuitous in that she had worked for twenty years
in the Intramural Program for the NCI as research technician,
graduate student, postdoctoral fellow and finally as head of
the NCI contractor’s lab of Antiviral Drug Mechanisms. The
NCI’s tumor virus program of the late 1970s supported the
identification of retroviral oncogenes in human tissue and of
the tumor-causing human retrovirus, human T cell leukemialymphoma
virus type I (HTLV-I) by Bernie Poiesz and Frank
Ruscetti, in the laboratory of Bob Gallo. By 1984, NCI investigators
were co-discoverers of a new retrovirus, HIV-1, which is
the causative agent of AIDS. It was natural for Dr. Mikovits to
enlist the help of her former NCI colleagues, Frank and Sandy
Ruscetti, Mike Dean and Rachel Bagni, to look for an infectious
agent. Thus, NCI’s investment in funding basic research in animal
and human virology made the discovery process possible.
Initially, the discovery process focused on the use of a viruschip
assay similar to the one used to discover xenotropic
murine leukemia virus-related virus (XMRV) in the tissue of
men carrying RNase L mutations who had prostate cancer (4).
After two and a half years of trying to make sense of the viral
chip data, we narrowed our focus to XMRV, because many
CFS patients also suffer from an RNase L defect, and initiated
a collaboration with Bob Silverman, a co-discoverer of the
virus, of the Cleveland Clinic. All patient material used in this
study were subjected to four separate XMRV assays: DNA
PCR from peripheral blood cells (PBMC); viral protein expression
in PBMC; presence of antibodies in plasma; and the
recovery of infectious virus from plasma transmitted to indicator
permissive cell lines. After five months of a rigorous review
process, the journal Science published our findings (1).
The Aftermath: Still Stuck
In Osler’s Web
By attempting to bring chronic fatigue syndrome (CFS)
research out of the shadows and squarely onto the nation’s
health agenda, we knew that we would be the object of
much criticism from both the medical establishment and those
individuals invested in other theories of disease causation.
Previous experiences had shown that some of these activities
would parallel what happened during the early days after the
discovery of HIV and AIDS.
CFS was belatedly recognized as a legitimate disease entity
by the Centers for Disease Control in 1997 but is still denied
recognition as an infectious immune disorder. The HHV6
foundation believes that HHV6 is the sole cause of CFS. A
major CFS patient advocacy organization is on record,
having concluded that a retrovirus has nothing to do with
the pathophysiology of CFS. Much of the opposition outside
of the CFS community firmly believes this disease and others
that are similar arise from psychiatric disturbances. Within
a week of the Science online publication, several scientists
publicly announced that they would not be able to replicate
the findings, negative findings were reported on blogs, and
within a month, three negative papers had been written and
submitted about the lack of XMRV in CFS.
Without directed research allocations from a Director of an
NIH institute, it can take between three to five years before
money can be allocated to study the role of XMRV in disease.
Fortunately, Robert Wiltrout, Director of the National Cancer
Institute’s Intramural Center for Cancer Research, has already
requested that the scientists in the intramural program begin
to develop reagents to determine the role of XMRV in the
development of cancer and other chronic diseases.
The other difficulties surrounding funding of governmental
research grants are numerous, including the time it takes for
the entire process to be completed. NCI has developed a
mechanism to rapidly give new research funding to existing
cancer centers. Unfortunately, when a new, non-traditional
entity such as the WPI is created, it must often delay work
until the funding is already in place. To solve these problems,
we have found it beneficial to work with other institutions
and experienced investigators who have offered to co-author
grants in a mentoring relationship. But we have also learned
a valuable lesson: a non-traditional entity may point out a
new research direction, but it must be confirmed by traditional
engrained mechanisms.
Reflections
Although the challenges have been significant, the personal
rewards one receives by helping others through the work of this
institute have been tremendous. We meet and talk often with
hundreds of individuals who are thankful that the WPI is creating
a scientific program of discovery that will improve their
lives. They have spent too many years suffering in silence, often
opting out of the medical world when they can’t find relief.
Scientific efforts to solve the many questions surrounding
neuroimmune diseases have brought a renewed interest in
the field and hope to millions throughout the world. Below
are just two of thousands of messages sent to our offices.
“Canada cheered when we heard the news.” Another patient
wrote, “I do not have words to thank you for the work you
have done. It has now been 30 years since I fell ill and I
truly never thought I would see the day this terrible knot was
untied.” Therein lies the motivation, despite all obstacles, to
continue this vital mission.
References
1. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson
DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, et al. (2009)
Detection of an infectious retrovirus, XMRV, in blood cells of patients with
Chronic Fatigue Syndrome. Science 326:585-589.
2. Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, and Schonberger
LB (1987) A cluster of patients with a chronic mononucleosis-like syndrome.
JAMA 257:2297–2302.
3. Jason LA, Corradi K, Gress S, Williams S, and Torres-Harding S (2006)
Causes of death among patients with chronic fatigue syndrome. Health
Care Women Int. 27:615–626.
4. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, Casey G, Klein
EA, Malathi K, Magi-Galluzzi C, Tubbs RR, Ganem D, et al. (2006)
Identification of a novel gammaretrovirus in prostate tumors of patients
homozygous for R462Q RNASEL variant. PLoS Pathogens 2:e25.
5. Ramsay AM and O’Sullivan E (1956) Encephalomyelitis simulating poliomyelitis.
Lancet 270:761–764.
6. Ramsay AM (1957) Encephalomyelitis simulating poliomyelitis. Public
Health 71:98–112.
7. Ramsay AM (1957) Encephalomyelitis in north west London; an endemic
infection simulating poliomyelitis and hysteria. Lancet 273:1196–1200.
8. Ramsay AM (1986) Myalgic Encephalomyelitis: A baffling syndrome with
a tragic aftermath. M.E. Association Journal 1986, UK.
9. Jason LA, Najar N, Porter N, and Reh C (2009) Evaluating the Centers
for Disease Control’s empirical chronic fatigue syndrome case definition.
J. Disability Policy Studies 20:93–100.
