from the ISIS website
- shows how Toxins can damage the human DNA -
Health & the Fluid Genome
In her new book, Living with the Fluid Genome, Mae-Wan Ho writes,
"The responsiveness of genes and genomes to the environment makes clear that
the only way to keep genes and genomes constant and healthy is to have a balanced
ecology... On the other hand, it is definitely futile to think that we can go
on ruining our ecosystem and stay healthy so long as we have ‘good’
genes... Genes, unlike diamonds, are not forever."
This miniseries offers new insights into how major chronic diseases arise from
the inability to take the fluid genome seriously, and how strategies to combat
the diseases are similarly misguided and dangerous.
1. AIDS Vaccines Worse Than Useless?
2. Dynamic Genomics
3. Molecular Genetic Engineers in Junk DNA?
4. SARS Virus Genetically Engineered?
5. Endo Viruses and Chronic Disease
6. Vaccines, Gulf-War Syndrome & Bio-defence
------------------------------------------------------------------------
Dynamic Genomics
Evidence has emerged that the cocktail of drugs and environmental hazards to which
Gulf War veterans have been exposed all target a special part of the genome that’s
responsible for the immune response. The consequences are startling, and may have
far-reaching relevance for diagnosis and prevention of other chronic diseases.
Dr. Mae-Wan Ho reports.
During the Persian Gulf War, some 700 000 individuals were exposed to a whole
range of environmental hazards, including low-level chemical warfare agents, investigational
drugs (inclucing pyridostigmine bromide, used as a prophylactic against nerve
agents), organophosphate, carbamate, and other pesticides and insect repellents,
low levels of nuclear and electromagnetic radiation, toxic combustion products
from oilwell fires, diesel exhaust products and airborne particles, all collectively
known to be genotoxic, or capable of causing harm through effects on the genetic
material. The veterans were also exposed to multiple vaccinations, also of questionable
safety. A significant proportion of the veterans developed a pattern of symptoms
that have been referred to as Persian Gulf War-Related Illnesses, or Gulf War
Syndrome (GWS): rash, fatigue, muscle and joint pain, headache, irritability,
depression, unrefreshing sleep, gastrointestinal and respiratory disorders and
cognitive defects. These were eventually defined as a clinical entity in 1998
[1].
Most Gulf War I veterans (GWIVs) received oral poliovirus vaccine before deployment.
Persistent enterovirus infection has been implicated in the chronic fatigue syndrome,
one of the major disorders of GWIVs. There has already been a report that enterovirus-specific
RNA was found in the sera of patients with chronic fatigue syndrome [2]. For these
reasons, Howard Urnovitz, Scientific Director of the Chronic Illness Research
Foundation, and his colleagues decided to search for virus-specific nucleic acids
in the sera of the GWIVs by using virus-specific primers to amplify RNA sequence
[3]. The sera from 24 GWIV with GWS deployed approximately 5 years previously
were compared with serum samples from 50 controls, for the most part matched by
age, sex and race.
When the amplified RNAs were separated according to size by running the mixtures
through an agarose gel in an electric field, a striking difference between the
GWIVs and controls was seen. Controls typically gave no more than three faint
RNA bands, all less than 350 nucleotides (nt) in length. The sera from GWIVs,
in contrast, contained numerous bright bands of very large RNAs, most of them
longer than 750nt and especially longer than 2 000 nt. Most of the bands, moreover,
did not belong to either the poliovirus or enterovirus. Both viral RNAs tended
to be found more frequently in the sera of GWIVs, but the differences from controls
were not significant.
The team sequenced two of the many bands that were found only in GWIVs, one 414nt
and the other, 759nt, from three different samples. They were 99% identical between
samples, but unrelated to each other, and were not homologous (similar) to any
sequence found the public DNA database GenBank. However, short stretches of 14
to 15nt were homologous to segments in a region on the short arm of chromosome
22, 22q11.2. It is as though something had chopped up that region into pieces,
shuffled them, and joined them up together again.
Thus, 3 sequences of 15nt and 8 of 14nt in the 759nt RNA had 100% homology to
short segments of chromosome 22q11.2. Five of these segments occur only on chromosome
22q11.2. For the 414nt RNA, there were 2 sequences of 15nt and 4 of 14nt with
100% homology to the 22q11.2 region, but these segments also occur on other chromosomes,
so it cannot be excluded that other chromosome regions were also involved in this
gene shuffling exercise. Another important feature is that 6 of the segments in
the 759nt RNA and 2 of those in the 414nt RNA occur near, between, or in Alu elements
("Molecular genetic engineers in junk DNA?", this series) that are capable
of multiplying and jumping around the genome, and are hence thought to be involved
in genetic recombination or gene shuffling.
This is a surprising finding. After all, GWS is generally considered to be a ‘multifactorial’
disease, ie, a disease due to multiple causes, possibly one for each of the symptoms.
And yet, for the first time, Urnovitz and his colleagues have demonstrated that
there could be a common molecular marker for the disease.
Not only that, using the same techniques, Urnovitz and colleagues were able to
identify another unique RNA molecular marker in patients with multiple myeloma
(malignant transformation of blood plasma precursor cells) and related disorders
[4]. They analysed 65 patients with multiple myeoloma (MM) 3 with Waldenstrom’s
macroglobulinemia (WM), 2 with monoclonal gammopathy of undetermined significance
(MGUS), and 50 healthy controls.
A 713nt plasma RNA occurred in 16/18 of MM patients in relapse, 5/8 MM patients
who were untreated, 2/3 WM patients and 1ž2 MGUS patients. None of the MM patients
in remission, nor the 50 healthy controls was positive. The homology of the 713nt
RNA between four samples was > 99.7% and matched (99.6%) a 704ng sequence of
the flanking region of the peroxisome proliferator activator receptor gene, located
in the same genome region, chromosome 22q11.2. A 255nt sequence within the 713nt
RNA had a 90.2% homology with an Alu consensus sequence.
There is reasonable evidence that multiple myeloma is associated with exposure
to industrial chemicals, pesticides or other environmental insults, as in the
case of GWS.
This raises key questions: what is the origin of these RNAs? What is the possible
role of these RNAs and of chromosome 22q11.2 in these diseases? Have environmental
genotoxins played a role in causing disease? And finally, could the RNA molecular
markers offer diagnostic tools for the diseases?
Chromosome 22q11.2 has been identified as a region full of hotspots for genetic
deletions and translocations correlated with multiple myelomas and related disorders
[5], as well as with rearrangements of the immunoglobulin lambda light chains
in the normal immune response [6]. Chromosome 22 appears to be involved in the
so-called Goldenhar complex, a birth defect possibly associated with GWS.
That region is full of Alu sequences, previously thought to be nothing but junk
DNA. But it is becoming increasingl clear that they have important regulatory
functions. Alu expression is induced when cells are stressed by heat shock, or
genotoxic agents, and may be part of the detoxification response. Alu sequences
are known to be involved in genetic recombination or gene shuffling. Alu-Alu rcombinants
are generated by both extrachromosomal and chromosomal genetic mechanisms [7].
Thus, it seems reasonable to conclude that exposure to toxic substances had activated
retrotransposable Alu elements, possibly in specific parts of the genome, which
results in gene shuffling to produce the unique sequences of RNAs circulating
in the serum.
These circulating RNAs appear to be derived from white blood cells that have died,
and are enclosed in proteolipid vesicles that protect them from being broken down.
There is evidence that such plasma RNAs account for at least some of the illnesses.
They are capable of transforming the blood cells of healthy animals in a mouse
model, and are associated with immune suppression, making them more susceptible
to infections.
At a conference celebrating the Centennial of the University of Michigan Department
of Microbiology and Immunology in May 2003 [8], Urnovitz, presented the new concept
of "the dynamic genome", the idea that the genome contains "an
operating system that instructs the organism how to both use and adapt genomic
elements to the constant challenges of a dynamic environment."
This concept led to a practical breakthough, surrogate marker blood tests for
yet another condition, mad cow disease, which can be performed on live animals.
And, he also mentioned potential public health application for understanding the
role of the genome in epidemics ranging from influenza-like pandemics (SARS) to
"Gulf War syndrome, chronic fatigue syndrome, and AIDS".
What led him to the idea of the dynamic genome is the discovery that blood borne
particles, or "microvesicles" contain "non-blueprint" RNA.
In the past, they were assumed to be foreign, and hence mistaken as viruses.
He rejects the theory that a coronavirus is the cause of SARS. The virus was isolated
from lab cultures that showed sick and dying cells. "Transmissible factors
don’t have to kill a cell to be part of the disease," Urnovitz says,
"they could just dysregulate cell function without killing the host cell."
He has carried out his own analysis on the so-called SARS-related coronavirus
gene sequence. "Frankly, I do not see a virus. I see a unique and complete
rearrangement of genomic elements. For example, when I look at what is believed
to be the gene sequence coding for the spike protein of this coronavirus, I see
a complicated gene rearrangement of a region of human chromosome 7." As with
the Gulf War Syndrome, gene rearrangements like this immediately says to him,
"search for an associated catastrophic environmental event that could have
caused such genomic rearrangement."
He sees a correlation between nuclear and chemical weapons deployment over the
last 100 years and the associated occurrence of flu-like pandemics. He postulates
that when animals are exposed to nuclear or chemical weapons, entirely new regulatory
gene set are expressed and packaged into non-viral RNA regulatory microvesicles.
The risk of turning an epidemic into a pandemic is increased when the exposed
animals are migratory birds that frequent gene-swapping hot spots like southeast
China. He says, "The recent sightings in eastern China and Hong Kong of rare
migratory birds – white cranes, grey cranes, and swans – that spend
significant time feeding in the radioactive-contaminated regions of Siberia suggest
that international efforts should be focussed on not only hunting for weapons
of mass destruction but also on cleaning up the ones that have already been released
into the environment."
He rejects the common belief that vaccines are the key to stopping epidemics:
"While the current dogma states that vaccines stop viral epidemics, the historical
data do not support that claim. From smallpox to polio to HIV, all vaccine attempts
have been ineffective or hazardous to the vaccinee."
His company, Chronix Biomedical, develop screening and diagnostic tests based
on the detection of non-viral RNA regulatory microvesicles for both veterinary
and human diseases. Is it making a profit? "Not yet," he answered.
The blood test for mad cow disease, or bovine spongiform encephalitis (BSE) —the
first that can be performed on live animals—is under development in the laboratory
of Professor Bertram Brenig, Director of the Institute of Veterinary Medicine,
Georg-August University, Göttingen, Germany. Urnovitz’s collaboration
with Brenig’s laboratory has resulted in the detection of a specific RNA
unique to cows at risk for developing, or that have confirmed cases of BSE.
Urnovitz claims that the BSE blood test is 100% sensitive on all 6 BSE cows confirmed
with a licensed prion test, and 100% specific on all 46 animals from known healthy
herds. They found that 3.5% of cohort animals (two animals out of 57) showed a
positive response in the surrogate blood marker for BSE. Cohorts are animals born
and/or raised in the same herd as a confirmed BSE case within approximately 12
months before and after the date of birth of the BSE case. Positive cohort cases
may represent animals at risk for developing BSE.
If Urnovitz is right, we have to seriously rethink environmental health.
1. Fukuda K, Nisenbaum G, Stewart G, Thompson WW, Robin L, Washko RM, Noah, DL,
Barrett DH, Randall B, Herwaldt BL, Mawle AC and Reeves WC. Chronic multisymptom
illness affecting Air Force veterans of the Gulf War. JAMA 1998, 280, 981-8.
2. Clemens GB, McGarry F, Nairn C and Galbraith DN. Detection of enterovirus-specific
RNA in serum: the relationship to chronic fatigue. J Med Virol 1995, 45, 156-61.
3. Urnovitz HB, Tuite JJ, Higashida JM and Murphy WH. RNAs in the sera of Persian
Gulf War veterans have segments homologous to chromosome 22q11.2. Clin & Diagn
Lab Immunol 1999, 330-5.
4. Durie BGM, Urnovitz HB and Murphy WH. RT-PCR amplicons in the plasma of multiple
myeloma patients. Acta Oncologica 2000, 39, 789-96.
5. Calasanz MJ, Cigudosa JC, Odero MD, Ferreira C, Ardanaz MR, Faile F, Carrasco
JL, Sole F, Custa B and Gullon A. Cytogenetic analysis of 280 patients with multiple
myelooma and related disorders: primary breakpoints and clinical correlations.
Genes Chromosomes Cancer 1997, 18, 84-93.
6. Roth DB and Craig NL. VDJ recombination: a transposase goes to work. Cell 1998,
94, 411-4.
7. Makalowski W, Mitchell GA and Labuka D. Alu sequences in the coding regions
of mRNA: a source of protein variability. Trends Genet 1994, 10, 188-93.
8. "First look at genome operating system revealed at centennial celebration.
Living test for mad cow disease first application. May 14 2003, Ann Arbor, Mi
(Chronix Biomedical Press Release)
printer friendly versionRELEVANT LINKS
from the ISIS website
Vaccines, Gulf-War Syndrome & Bio-defence
Bio-Terrorism and SARS
Eating Cauliflower Mosaic Virus infected vegetables does not prove that Cauliflower
Mosaic Virus Promoter in genetically modified crops is safe
Foot & Mouth Outbreak, GM Vaccine and Bio-warfare
From BSE to GMOs - What Have We Learned? / Dr Harash Narang and BSE
GM & Biological Weapons, Scientists Call for International Watchdog
AIDS-Vaccines Trials Dangerous
GM Food Hazards and the Science War
Maurice Wilkins Talks on Social Responsibility in Science
Recent Publications
The Fluid Genome
Mae-Wan Ho
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