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The Cause of Autism*
W. John Martin, M.D.,Ph.D.
Introduction
Autism is a diagnostic label applied to neurological disorders of early childhood
onset. It manifests as deficits in communication and in other social
interactive skills. Considerable variability exists in the severity of disease
in autistic patients, with somewhat arbitrary distinctions between autism and
childhood disintegration disorder at one end and delayed normal development at
the other extreme. Autistic patients will commonly show a wider variety of
clinical manifestations than implied by a single diagnostic label.While many millions of dollars have been
spent on autism-related research, only a few studies have provided important
insights into the underling cause, prevention and treatment of this disease.
This talk will provide a brief summary of generally accepted research views on
autism and a lengthier discussion of some of the more controversial opinions.
The argument will be presented that autism is essentially an encephalopathy of
stealth-adapted viral origin. Research findings on a stealth-adapted virus that
arose from the species of monkeys used to produce poliovirus vaccine will be
summarized. Sequencing of this virus has suggested specific therapeutic
approaches to the treatment of patients with autism and other stealth-virus
related clinical conditions. Preliminary clinical experience with some of these
approaches has been encouraging and indicates the need for formal therapeutic
trials. Studies also need to be pursued into the modes of stealth-virus
replication and transmission of what may well prove to be a major threat to the
survival of mankind.
Generally Accepted
Research Views on the Nature of Autism
1. Autism has a Genetic
Component: This is apparent from the higher incidence of autism among boys.
It is also supported by the relative concordance of disease among monozygotic
(genetically identical) twins compared to dizygotic (genetically different)
twins. Still there are numerous examples where only one of two genetically
identical twins has the disease. Genetics may well be a contributing factor to
the expression of autism, but it is clearly not the only component to this (or
these) diseases.
2. Brain Abnormalities in
Autistic Children: Head circumference has been accepted as a marker of
brain size. While normal at birth, the head circumference of 1-2 year old
autistic children is reportedly slightly enlarged. Brain imaging has also shown
enlargements in certain regions of the brain, most noticeably in parts of the
cerebellum. Equally impressive are various functional studies that show
deficits in brain activation upon certain types of sensory stimulation and in
blood flow patterns in autistic children. The question arises whether these
changes are a consequence of autism, rather than its cause. Limited
histopathological studies on brain tissue from autistic patients support the
view that certain brain cells are damaged and/or do not normally develop.
3.Biochemical Indications of a Prenatal
Disorder. As recently reported, elevated levels of one or more
neuropeptides are present in neonatal blood samples obtained from children who
subsequently were diagnosed as autistic. The source of the elevated
neuropeptides was presumed to be the brain but this was not established. The
actual levels of various neuropeptides examined differed among autistic
children, but as a group the autistic children were readily distinguishable
from normal children. Somewhat confounding, however, was that similar
elevations were consistently also found in blood samples collected from
mentally retarded children. Mental retardation had not previously been linked
with autism and clearly differs with respect to the smaller than normal head
circumference seen at birth.
Controversial Issues
Relating to Autism
1. Autism is the Result of
Vaccination. Reports of marked clinical deterioration and even the initial
onset of autism within days of receiving a vaccination has prompted the view
that the vaccine has caused the illness. Initially the focus was on
diphtheria/petussis/tetanus (DPT) vaccine but more recently it has been on live
measles/mumps/rubella (MMR) vaccine. In the case of measles, vaccine-derived
viral material has been seen using immunohistochemistry and molecular based
assays within hyperplastic lymphoid tissue present in the gastrointestinal
tract of autistic children.Similar
findings were found in non-autistic children with lymphoid hyperplasia.
Although there are reasons for concerns with live viral vaccines, including the
finding of retroviral related reverse transcriptase activity in MMR vaccines, a
primary etiological role of measles vaccine virus is not supported by data
indicating prenatal abnormalities. A detrimental effect of MMR vaccine has also
been dismissed with results of various epidemiological studies failing
to show statistically significant correlation between vaccine usage and disease
prevalence.
2. Autism is a Primary
Biochemical Disorder. Urine analyses on autistic children have shown
markedly elevated levels of various peptides as well as other types of
metabolic products.An inference is
that the levels of these chemicals would also be increased in the brain and
that they somehow interfere with normal brain function. A prime example is the
opiate-like peptides resulting from incomplete digestive breakdown of casein
and gluten proteins. This view is bolstered by noticeable clinical improvements
in some autistic children when placed on a casein and gluten free diet.
Peptides from abnormal bacterial and fungal bowel flora may also been suggested
as having neuroregulatory activity whose levels may be reduced by antibiotics.
A role for cell associated peptidase is suggested by unpublished studies that
peptidase IV inhibitory fragments may also be present in the urine of some
autistic children.
Autism: A Stealth-Adapted Viral Encephalopathy
I am
proposing that autism is primarily a prenatal infection that involves the brain
and occurs in a genetically predisposed individual. The infection renders the
person susceptible to further brain damage from vaccines and other
environmental factors. Several lines of evidence support the stealth virus
cause of autism. For example:
Blood samples from autistic children consistently induce a
readily identifiable cytopathic effect (CPE) using viral culture methods
adapted for the detection of stealth-adapted viruses. Stealth virus testing of
blood samples from autistic children has been subjected to formal “double
blind” analyses. Furthermore, cerebrospinal fluid (CSF) and gastrointestinal
biopsy have similarly yielded positive cultures.
There is good evidence for stealth virus infections among
family members of autistic children. Many of the family members will, upon
close questioning, reveal symptoms of neurological and/or immunological
dysfunction.
Autistic patients will not infrequently display positive
results in assays intended to detect conventional virus and bacterial
pathogens. As discussed below, such results can be attributed to
cross-reactivity with stealth virus components.
When will the stealth virus theory
of autism be accepted and supported by i) researches, ii) Public Health
authorities, and iii) families with affected children. The answer to the first
point is when it is clearly proven that stealth-adapted viruses, as presently
defined, do exist as novel pathogens. This challenge, as well as the goal of
eliciting official Public Health involvement, will occur when the message gets
across that the extensively sequenced prototype stealth-adapted virus is
atypically structured and that it arose as a probable contaminant of
poliovaccine production. Finally, parents will begin to focus their energies on
the stealth-adapted viruses infecting their children once they begin to see
real clinical improvements based onanti-stealth virus therapies.
Sequencing Studies on
an African Green Monkey Derived Simian Cytomegalovirus (SCMV)
These
studies unequivocally establish the origin of an atypically structured
cytopathic virus as being from SCMV. For certain regions of the stealth viral
genome, there is over 90% identity between the nucleotide sequences of the
stealth virus and that of the Colburn strain of SCMV. Yet in other regions, the
two viruses differ in a manner that is best explained by genetic instability in
viral replication and by the selection of genetic changes that favor viral survival
and avoidance of immune recognition. Of particular note is that the virus
failed to evoke an inflammatory reaction in either the patient from whom it has
been repeatedly cultured, or from the cats in which it induced considerable
brain damage. To date, the genes that would otherwise encode the major antigens
targeted by anti-CMV cytotoxic T lymphocytes have not been detected. Nor do the
viral cultures react with antibodies against several antigens shared by human
and simian CMV.
Over
120,000 nucleotide sequence data have been compiled on the stealth-adapted
virus. Long regions of contiguous sequences suggests the coding of somewhat
truncated proteins in comparison to the coding potential of the comparable
region ofthe human CMV genome. To help
clarify the extent to which these changes reflect the preexisting SCMV genome,
or are part of a mutational process occurring within a genetically unstable
stealth-adapted virus, sequencing is underway on an authentic monkey-derived
SCMV.
Even at this stage of the work, is
abundantly clear that stealth adaptation involves much more than simple
deletion/mutation of particular genes targeted by the cellular immune system.
For example, there is a striking over representation of certain genes. Of
particular interest, is the finding of multiple copies of genes implicated in
the production of, and providing receptors for, potent growth factors called
chemokines and present within the virus. This observation strongly suggests the
potential value of suppressing chemokine production in this particular patient.
Another
striking feature of the DNA analysis is the presence of particular cellular
genes adjacent to viral genes. A prime example is the three copies of a
cellular chemokine-related gene within the viral genome. These
virus-incorporated cell-derived genes do not contain normal stretches of
non-coding sequences (introns) that are present in the cell DNA. This would
indicate that the recombination process allowing cell-derived genes to become
incorporated into a replicating stealth virus had occurred at a partially
processed RNA, rather than at a DNA level. If so, it would indicate a role for
endogenouse reverse transcriptase in stealth virus assembly and replication.
Several other cell-derived sequences are more readily amplified using
polymerase chain reaction (PCR) based assays performed on
the stealth virus culture than when performed on uninfected cultures,
suggesting that the sequences may have been incorporated as part of the stealth
virus replication process.
Various bacterial-derived sequences
have also been extracted from the cultures. The bacterial sequences are of
particular interest since, along with additional data, it appears that the
virus is able to pass into, and, therefore, be potentially metabolically
empower and be transmitted by bacteria. Taken together, the data are consistent
with a viral replicative process that allows the assimilation of extraneous
sequences of cellular, bacterial and possibly fungal origins. Addressing this
situation is particularly urgent since among the potential activities of cell
derived genes, including chemokine-inducing and chemokine-receptor genes, are
the induction of malignant changes. The prospect of highly infectious bacteria
carrying cancer causing genes is a serious concern that, so far, has been
brushed aside by those responsible for overseeing the Nation’s health.
Stealth-adapted viruses that have
incorporated bacterial sequences are referred to as “viteria.” Work is underway
to confirm that such organisms can be mistaken for actual bacteria in
conventional assays for such pathogens as Borrelia
burgdoferi, Mycoplasma incognitus, Chlamydia pneumonia, etc. Many bacterial proteins have a propensity to evoke allergic reactions offering a possible explanation for such reactions among autistic children.
Stealth Adaptation as a Generic Process
CPE
generally similar to that shown with the SCMV-derived stealth-adapted virus has
been consistently seen with blood samples from many other patients. Most of these isolates do not react particularly strongly with antibody and molecular based probes that are highly
reactive with the prototype SCMV-derived stealth-adapted virus. This finding
suggests marked structural variability and probable multiple, diverse origins
of stealth-adapted viruses. Limited sequence and antibody staining data on some
of these additional isolates are consistent with origins from other
herpesviruses, including Epstein-Barr virus and human herpesvirus-6; and also
from such diverse viruses as parvovirus, adenovirus and enteroviruses. The
addition of various live viruses to positive stealth virus cultures can lead to
enhanced CPE, suggesting the possibility of reciprocal viral stimulation and
even the recombinant formation of new viral constructs. This potentiating effect has been noted using live measles and other viral vaccines. It is also reasonable to assume
that certain stealth viruses may retain some components that would normally not
be involved in evoking cellular immunity, but in the presence of a powerful
immune stimulant (such as provided by DPT vaccine) could become a target for
cell damaging immunity.
A topic
of interest is whether stealth-adapted viruses cultured from autistic children
will show any distinguishing characteristics from those cultured from patients
with other disease manifestations. Given the overall similarity in the CPE seen
when tested blood samples from autistic and non-autistic family members, it
seems likely that a similar virus is involved and that clinical manifestation
relates to sex, other genes and time and location of infection.
Implications for Patients with Autism
Specific
testing for cell derived chemokine genes, as are present in cultures of the
prototype stealth virus, has yet to be performed on stealth virus cultures from
patients with autism. Clinically, however, drugs that are known to down
regulate chemokines are finding increasing use in patients with other
stealth-virus associated diseases, including depression, attention deficit and
hyperactivity disorder (ADHD) andCFS.
Of particular interest are many of the disease modifying anti-rheumatic drugs
(DMARDS). Some clinicians have also anecdotally noted symptomatic improvement
with Acyclovir, an anti-herpesviral drug.
Progress
in this field will require disciplined clinical trials with close monitoring of
patients using both clinical markers and semi-quantitative stealth virus
cultures. In the meantime, work needs to be continued on the development of
more specific therapies that are based on a more detailed understanding of the
mode of stealth virus replication.
Positive blood cultures is a sign
of a body wide infection that can potentially cause multi-organ damage (both as
the result of direct virus damage and an evoked auto-immune response). Rather
than being viewed narrowly as a neuropsychiatric illness confined to the brain,
autism should be viewed as a generalized viral infectious process that also
involves the brain. Specific testing for endocrine disorders,
gastroenteropathy, liver damage, allergies, etc., should be part of the overall
medical profile of any stealth virus infected patient.
The
finding of a positive stealth virus culture in a child is probably sufficient
reason to avoid the intense immunological stimulation associated with DPT
vaccine and also to not add extraneous infectious viruses in the form of MMR
and live poliovirus vaccine.
Acceptance
of an infectious cause of autism can help explain the occurrence of
stealth-virus associated illness among other family members. Certainly other
family members should be tested for infection. The socially difficult issue of possible contagion to classmates, schoolteachers, non-infected family members, etc., is better
addressed than denied.
Summary
Autism
is a clinical label referring to a set of symptoms that can occur as a result
of infection with atypically structured, poorly immunogenic (stealth-adapted)
viruses. This conclusion should help reorient the clinical approach to the
diagnosis, therapy and prevention of this illness.
*Lecture prepared to be given at Catalina Island, June 9,
2001, but unable to do so for family reasons.
What are
Stealth-Adapted Viruses and Do They Exist
The accompanying article
provides a recent review of stealth viruses. Viruses are submicroscopic
infectious agents that replicate only within cells. They are comprised of an
essential nucleic acid polymer consisting of a linear string of correctly
ordered nucleotides that attaches to, and is protected by, viral proteins whose
amino acid sequences are coded by the nucleic acid polymer.While viruses are generally much smaller than bacteria, the major distinction between these life forms is that at
particular stages of their life cycle, viruses will consist of either an RNA or
a DNA nucleic acid polymer. By contrast, bacteria will consistently contain
both DNA and RNA and usually many more additional components involved in
metabolic functions, including protein synthesis, energy generation, formation
of a protective cell wall, etc. While some bacteria are still dependent on
human and/or animal cells for their replication, most bacteria can function as
free living microorganisms.
Viruses
were initially detected on the basis of the cellular damage they induced when
they co-opted cellular metabolic processes to allow for their replication.
Essentially, the viruses drained the cells existence as they tended to their
own reproduction. The virus induced cell damage was referred to a CPE. Some
viruses induce a fairly distinctive CPE in particular cell types. For other
viruses, the CPE is more subtle and may, in fact, not be seen in routine
microscopic examinations, or may be viewed as simply resulting from unexplained
toxicity of the material being tested for viral activity.
Viruses
can be further characterized by sequencing all or parts of its nucleic acid
polymer, and by using antibodies that that selectively react with the proteins
that characterize the different types of viruses. These techniques are more
narrowly focussed on the detection of viruses whose DNA or RNA sequences are
known and whose proteins have been used to generate specifically reactive
antibodies.For broader screening of as
yet unknown viruses, the tissue culture methods still provide a very powerful
tool. Molecular and immunological methods can then be used to further
characterize the cytopathic agent.
Using a
combination of molecular, immunological and tissue culture techniques, I was
able to repeatedly culture a cytopathic virus from a patient with an acute
onset neurological illness that has resulted in long term chronic fatigue
syndrome (CFS). Having seen the CPE caused by this virus, it was possible to
continually adapt the culture method to shortened the period required for its
appearance and to promote its development within the cultures. It soon became
apparent that generally similar types of CPE could be seen in cultures obtained
from patients with other neurological illnesses, including autism and
behavioral problems in children, depression and schizophrenia in adults and
neurodegenerative diseases in the elderly. Healthy medical students, used as
controls, were negative for the marked changes being seen with patients’
samples.
Unfortunately, the work fell into
the nationwide controversy regarding the very existence of CFS as an illness.
Moreover, whereas the description of a CPE occurring in cultured cells are
understandable to those who work directly with viral cultures, most physicians
and other healthcare workers are basically unfamiliar with virus culturing techniques.
Patient support groups also wanted an assay that would differentiate patient
with their particular clinical illness from patients with other diseases. The
finding of positive cultures in “non-fatigued” patients, yet not in all
patients with CFS, was a blow to the initial support received from a CFS
patient group.
African Green Monkey
Derived Simian Cytomegalovirus (SCMV).
Tissue Culture Cytopathic Effect (CPE). An important
hallmark of many, but not all disease causing viruses, is there ability to
alter the growth and overall appearance of cells that they infect. |