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Dr. Robert Garry Testimony January
24, 2002
The House Subcommittee on
National Security, Veterans Affairs, and International Relations
for the GWS Panel STATEMENT FOR HEARING RECORD
Hearing date: January 24, 2002 Submitted by: Robert F. Garry, Ph.D., Professor
Department of Microbiology and Immunology Tulane Medical School, Room 568 JBJ,
1430 Tulane Avenue New Orleans, Louisiana 70112
Date submitted: December 21, 2001
SUMMARY
This Statement concerns our research with anti-squalene antibodies,
including the discovery of these antibodies in the blood of patients with Gulf
War illness.
Our published data and additional data which has been accepted for
publication strongly suggests that Gulf War illness is closely associated with
an abnormal immune response to squalene indicated by the presence of these
antibodies. Our research also links specific lots of anthrax vaccine known to
contain squalene to the production of anti-squalene antibodies. In addition,
our research demonstrates that the blood test for detecting these antibodies,
the anti-squalene antibody assay, may be an excellent tool to aid in the
diagnosis of Gulf War illness.
U.S. Army researchers have verified our discovery of the antibodies and, in May
of this year, submitted a patent application covering their anti-squalene
antibody work. Our patent, U.S. Patent No. 6,214,566, "Method for
Detecting Anti-Squalene Antibodies," which we believe covers the same
technology, had already issued in April of this year. The Army researchers have
made a disingenuous attempt to discredit our work, and they have not yet
published any studies designed to confirm our discovery of a link between the
antibodies and Gulf War illness, though they state that such studies may be
feasible.
We believe that such confirmatory studies and additional studies should be
undertaken without delay. We also believe that the anti-squalene antibody assay
should immediately be made available under government sponsorship to all
physicians interested in using it to investigate the condition of their Gulf
War illness patients.
DATA AND OBSERVATIONS
Research data which we published in February 2000 strongly suggests that
anti-squalene antibodies are closely associated with Gulf War illness.
Specifically, we found in our study participants that 95% of the Gulf War
veterans with Gulf War illness and 100% of the non- deployed veterans with Gulf
War illness were positive for the presence of anti-squalene antibodies, while
0% of the healthy deployed veterans were positive. Additional research data
which has now been accepted for publication shows, in a limited number of
samples tested, that an increased prevalence of anti-squalene antibodies in
Anthrax Vaccine Immunization Program (AVIP) personnel correlated with
administration of lots of anthrax vaccine subsequently shown by the FDA to
contain trace amounts of squalene. Our results strongly suggest that the
production of anti-squalene antibodies is linked to symptoms of Gulf War
illness and to the presence of squalene found in certain lots of anthrax
vaccine.
Though the source of the squalene in the vaccine lots has not, to my knowledge,
been identified, squalene is used as an adjuvant in animal vaccines. The use of
squalene as an adjuvant in human vaccines has not been approved, and human
exposure to squalene in vaccines has been shown by others to cause
immunological symptoms similar to those found in Gulf War illness patients.
Gulf War illness is present both in Gulf War veterans who were deployed to the
Persian Gulf War theater of operations and in personnel who were not deployed,
including personnel who never left the United States. The absence of an
association between the presence of Gulf War illness and deployment indicates
that the causative agent or factor is not associated with the Persian Gulf.
Consistent with this observation are the results of a recent epidemiological
study finding that vaccinations that were given to both deployed and
non-deployed personnel are associated with ill health.
U.S. Army researchers have confirmed our discovery that anti-squalene
antibodies do exist and can reliably be detected, and the Army researchers
published this work in November 2000. Army representatives filed a U.S. patent
application covering anti-squalene antibody technology on May 18, 2001, and we
believe that the technology for which the patent was filed is the same
technology that was described in the November 2000 article.
A U.S. patent covering our anti-squalene antibody technology issued as of April
10, 2001. The patent is assigned to Tulane University and is licensed to a New
Orleans biomedical company. We believe that the claims awarded in the Tulane
patent cover the work that was published by the Army researchers. On May 23,
2001, Tulane's licensee wrote a letter to the Department of Defense offering to
sublicense this patented technology to the Army so that the Army researchers
could perform a study designed to confirm whether the antibodies are linked to
Gulf War illness. An Army representative declined this offer on June 6, 2001.
The journal that published the November 2000 article by the Army researchers
received the submitted article on April 18, 2000. The material submitted to the
journal on that date demonstrated that the Army researchers had confirmed our
discovery of anti-squalene antibodies. In June 2000, one of these same
researchers, an Army colonel, published a letter to the editor of the journal
which had published our original article in February 2000. In the June 2000
letter, the colonel stated that our published results constituted a "new,
unproven assay that claims to detect a novel antibody."
The colonel made this statement despite the fact that he had already
confirmed our discovery and had already submitted his findings for publication.
Further, when the colonel's article appeared in November 2000, it cited his own
letter of June 2000 to call our original findings into question. The colonel's
letter expressing an opinion which he himself had already proven to be baseless
was thus used twice in efforts to discredit our work.
The last paragraph of the November 2000 article published by the Army
researchers reads as follows:
"With the development of the ELISA using PVDF membranes, as described in
this paper, it may now be possible to undertake studies with serum from sick
and healthy individuals to determine whether naturally-occurring antibodies to
SQE [squalene] exist, and whether the appearance or amounts of such antibodies
have any relationship to normal physiologic functions or whether they are
associated with any illness."
With the serum samples available to the Army researchers, such studies would in
our opinion be very straightforward and would take a short amount of time to
complete. The Army has had its own version of the necessary test available for
more than two years but has published no such studies.
Based on the Army's actions with respect to our work, we suspect that the Army
has in fact conducted these studies and elected not to publish them. Our
published research makes a compelling case that, first, anti-squalene
antibodies exist, and second, that there is a link between the antibodies and
Gulf War illness.
Before the publication date of our research, some of our research data was
discussed in a GAO report to the Honorable Jack Metcalf entitled Gulf War
Illnesses:
Questions about the Presence of Anti-Squalene Antibodies Can Be Resolved
(GAO/NSIAD-99-5, March 1999). The GAO report specifically recommended that the
DoD conduct its own research designed to replicate or dispute our results.
The colonel's research group subsequently published a confirmatory study
that looked only at our first finding and ignored the second. A confirmatory
study of our second finding would be very easy for the Army to do in a short
time, and we find it difficult to believe that the colonel's group has not
already done such a study, since any good and inquisitive scientist with ready
access to test samples would want to do it. Instead of following the GAO's
recommendation, however, the colonel chose to publicly ignore our second
finding and to make misleading public statements that denigrated our work.
Later, when the Army and the colonel were offered the opportunity to license
our technology and finish the confirmatory work, they declined the offer.
The presence of anti-squalene antibodies in ill people and the absence of the
antibodies in healthy people is the first hard laboratory evidence that Gulf
War illness is what some might refer to as a "real disease."
It is also the first evidence that an abnormal immunological response is
under way in Gulf War illness patients. The anti-squalene antibody assay thus
represents the first laboratory test for Gulf War illness.
As such we believe that it has great clinical
value as a diagnostic aid, and it suggests that therapies designed to modulate
the immune response to antigens should be investigated in patients with Gulf
War illness.
Recent unpublished observations from the Veterans Administration indicate that
there is a significant increase in the prevalence of the neuro-degenerative
disease amyotrophic lateral sclerosis (ALS) in Gulf War veterans. The data that
we published in February 2000 shows that some of the patients who were ill with
Gulf War illness and who tested positive on the anti-squalene antibody assay
exhibited neurological symptoms. These results suggest that a possible
relationship between anti-squalene antibodies and ALS in Gulf War veterans may
exist and should be investigated.
Further research with the anti-squalene antibody assay continues on a limited
scale using private funds, but the test is not currently available to
individual physicians for investigation into the conditions of their patients.
More than two years have now elapsed since DoD researchers have had access to a
version of this test. While the DoD has proceeded with an attempt to win its
own patent on the test, in our opinion it has done nothing with the test to
help any Gulf War illness patient. It is therefore our very strong
recommendation that an agency of the U.S. government immediately commission a
large study of anti-squalene antibodies and Gulf War era veterans and other
personnel, including appropriate ALS patients. Such an investigation should be
conducted in the context of, or coordinated with, a population-based study of
Gulf War era veterans similar to the ongoing and successful Ranch Hand study of
Agent Orange. It is our further very strong recommendation that an agency of
the U.S. government immediately begin to provide the anti-squalene antibody
assay to all physicians treating patients with Gulf War illness.
REFERENCE INFORMATION
(1) Our initial study concerning anti-squalene antibodies was published in
the February 2000 issue of Experimental and Molecular Pathology. The results of
this study strongly suggest two things: (1) that humans can indeed raise serum
antibodies against squalene, and (2) that, in the people studied, the presence
of the antibodies correlated very closely with the presence of the symptoms of
Gulf War illness both in personnel who had been deployed to the Persian Gulf
theater and in personnel who had not been deployed there. A copy of this
article, entitled "Antibodies to Squalene in Gulf War Syndrome," is
attached hereto ("the Asa/Garry article").
(2) The anthrax bacillus is incapable of producing squalene, and squalene is
not present as a constituent of the growth medium used to produce the organism
for the anthrax vaccine. Squalene is widely used as a vaccine adjuvant in animals,
but it is clearly harmful to many humans when used in that manner and is not
approved for use in human vaccines.
(3) A letter to the editor published in the June 2000 issue of Experimental and
Molecular Pathology addresses the work presented in the Asa/Garry article. The
letter attempts to find fault with our testing technique, calling our test a
"... new, unproven assay that claims to detect a novel antibody ...."
The letter further states the following:
"The conclusions of Asa and colleagues, purporting to correlate
anti-squalene [sic] with Gulf War illnesses, in our opinion, rely on circular
logic. Positive results with an assay not previously validated cannot be used
as scientific proof that antibodies to the antigen exist in samples of unknowns.
It is premature to proceed directly to testing serum samples from healthy
people and sick people before conducting the fundamental validation
steps."
This letter was written by Col. Carl Alving of the Walter Reed Army Institute
of Research and John Grabenstein of the U.S. Army Medical Command. A copy of
this letter ("the Alving/Grabenstein letter"), together with our
published response and an editorial note, is attached hereto.
(4) In the November 2000 issue of the Journal of Immunological Methods, four
researchers from the Walter Reed Army Institute of Research, including Col.
Alving, published an article confirming that anti-squalene antibodies do exist
and can reliably be detected. The study described in this article reproduces
and expands upon our work and validates our anti-squalene antibody assay. A
copy of this article, entitled "Induction and Detection of Antibodies to
Squalene," is attached hereto ("the Alving article").
(5) A notation by the Journal of Immunological Methods which appears under the
title line at the top of the Alving article states that the manuscript for the
article was received by the journal from Col. Alving and his colleagues on 18
April 2000. The Alving/Grabenstein letter was published six weeks later, in
June 2000. This means that when Col. Alving and his colleague Grabenstein were
publicly characterizing our test as a "... new, unproven assay that claims
to detect a novel antibody ...," Col. Alving and his other colleagues had
already written the Alving article confirming that the new antibodies did in
fact exist.
(6) The note from the journal's editors which accompanies the
Alving/Grabenstein letter points out that this letter "... relates to
methodology. Drs. Alving and Grabenstein offer no data against the conclusions
of Asa et al."
Since the Alving article confirms that the novel antibody was indeed discovered
by our detection method, the Alving/Grabenstein letter is therefore rendered
entirely meaningless by the Alving article. Despite this, the Alving article
includes the following paragraph:
"What, if any are the potential consequences of induction of antibodies to
SQE [squalene]? A recent publication claims to have detected antibodies to SQE
in sick but not in healthy individuals (Asa et al., 2000) [the Asa/Garry
article]. However, we believe that such a conclusion may be premature, based on
a technical critique of the reported Western blot-type assay that was used
(Alving and Grabenstein, 2000) [the Alving/Grabenstein letter]."
The Alving article thus cites the Alving/Grabenstein letter, which the Alving
article itself refutes, to call into question our second discovery, that the
anti-squalene antibodies we discovered are found in sick but not healthy
individuals.
(7) After the Asa/Garry article was published, we learned that in June 1999,
investigators at the U.S. Food and Drug Administration (FDA) had assayed the
Department of Defense's anthrax vaccine for the presence of squalene.
Using a sensitive gas-liquid chromatography procedure, the FDA had identified
squalene in certain lot numbers (FAV 020, 030, 038, 043 and 047) of the
vaccine. Although the amounts of squalene found in these lots of the vaccine by
the FDA were small (parts per billion), in principle even these small amounts
may have been sufficient to induce in some vaccine recipients the immune
response that is now being manifested by the presence of anti-squalene
antibodies. The published work of other researchers has strongly linked
exposure to the anthrax vaccine and other vaccines to the development of Gulf
War illnesses.
Moreover, many pathological effects of exposure to squalene-containing vaccine
adjuvants are well known to rheumatologists, and a number of these pathologies
bear striking similarity to the signs and symptoms displayed by some ill Gulf
War era veterans.
(8) On April 10, 2001, U.S. Patent No. 6,214,566, "Method for Detecting
Anti-Squalene Antibodies," was awarded and assigned to Tulane University.
A copy of this patent is attached. Tulane has licensed the anti-squalene antibody
technology to Autoimmune Technologies, LLC of New Orleans. On May 23, 2001, the
LLC Manager of that firm wrote a letter to The Secretary of Defense with a copy
to Col. Alving offering to sublicense the patented technology to Department of
Defense researchers. On June 6, 2001, an intellectual property counsel of the
Army wrote back to decline the offer. Copies of both the May 23rd and the June
6th letters are attached.
(9) On October 22, 2001, in accordance with 37 CFR 404.6, the Department of the
Army filed a notice of the "Availability for Non-Exclusive, Exclusive, or
Partially Exclusive Licensing of U.S. Patent Application No. 09/859,389
entitled 'Detection of Antibodies to Squalene in Serum' filed May 18,
2001." On November 8, 2001, the LLC Manager of Autoimmune Technologies
spoke on the telephone with the patent attorney and the licensing officer at
Fort Detrick who were administering this license. Neither the attorney nor the
licensing officer was aware of the existence of U.S. Patent No. 6,214,566, and
neither person knew whether U.S. Patent Application No. 09/859,389 was based
upon the work done by Col. Alving and his colleagues. The LLC Manager pointed
out to both of them that, in our opinion, the work done and published by Col.
Alving's group is covered by the claims awarded in U.S. Patent No. 6,214,566.
The LLC Manager also asked for further information about the technology which
the Army was proposing to license. As of December 18, 2001, the LLC Manager had
not received this additional information, and he wrote a letter on that date to
both the attorney and the licensing officer. A copy of that letter is attached.
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