VIRUSMYTH HOMEPAGE
AGENDA FOR U.S. AIDS RESEARCH IS DUE FOR A COMPLETE OVERHAUL
By Robert Root-Bernstein
The Scientist 4 April 1994
Robert Root-Bernstein, an associate professor of physiology at
Michigan State University, contends that our ignorance concerning AIDS
is profound and that significant progress in curtailing the pandemic is
possible only if the sources of this ignorance are identified. He maintains
that the first priority of the new national AIDS task force is, therefore,
to challenge the validity of current theories about AIDS and to encourage
the asking of new questions.
A recent front-page article in The Scientist (F. Hoke, "National
AIDS Task Force Expected To Accelerate Drug Development," Feb. 7,
1994, page 1) reported that a newly formed, United States government-backed,
15-member panel intends, among other things, to improve communication between
pharmaceutical and biotech companies and thus speed development of AIDS-combating
antiretroviral drugs and vaccines.
One wonders, on one hand, what is wrong with the U.S. drug industry
that such facilitation should be necessary and, on the other, whether an
AIDS task force can, in fact, do anything that the industry is not already
doing. The task force, it seems to me, has better things to do.
In trying to imagine a more appropriate research agenda for the panel,
I find myself making three idealistic and naive (and, possibly, incorrect)
assumptions: (1) that it has been formed to push AIDS research-not politics-forward;
(2) that among its members are the equivalents of J. Robert Oppenheimer
(to protect its mission, as he did with the Manhattan Project, against
external influences) and Richard Feynman (to say, as he did in the Challenger
inquiries, what needs to be said in moments when stark reality confronts
us); and (3) that it is willing to put the lives of people with AIDS ahead
of political correctness, patronage, and economic advantage.
I hope that my assumptions are correct, but I wonder. The fact that
we still can neither treat AIDS effectively nor cure it strongly suggests
that we do not understand it. I maintain that we have not yet asked all
of the right questions about AIDS, and that our ignorance is therefore
profound. Identifying the sources and types of our medical ignorance thus
becomes the highest research priority.
A model program for accomplishing this has been developed by Marlys
and Charles Witte, two AIDS researchers in the department of surgery at
the University of Arizona Medical School, and a colleague of theirs, medical
philosopher Ann Kerwin. According to their model, ignorance comes in four
forms, each of which must be addressed as we pursue our research on AIDS:
Finally, there are the things we think we do not know but we really
do. This is hidden knowledge masquerading as ignorance.Examples of each
can readily be found in our current approach to studying AIDS, and, in
my opinion, it is the job of the AIDS task force to identify and remedy
as many of them as possible.
False Assumptions
An example of something we thought we knew, but did not, is that the
human immunodeficiency virus (HIV) is the direct cause of T-cell killing
in AIDS. Even such formerly stalwart proponents of this notion as Anthony
Fauci and Robert Gallo now admit that this is not the case. Virtually all
HIV research is now focused on finding "indirect" mechanisms
by which HIV may cause immune suppression.
We also thought we knew that HIV alone is sufficient to cause AIDS.
But such researchers as Luc Montagnier, Shyh-Ching Lo, Joseph Sonnabend,
and many others-including me-now believe that cofactors are necessary and,
therefore, that HIV by itself cannot cause AIDS.
We used to think we knew that everyone is at equal risk for HIV and
AIDS, and that a heterosexual epidemic was inevitable. But the epidemiology
of AIDS has yet to prove consistent with that view. There is no record
of tertiary (non-risk group to non-risk group) sexual transmission of AIDS
in any Western country. Indeed, every study of female prostitutes in Western
countries has led to the conclusion that those among them who do not use
drugs intravenously have almost no risk of HIV infection and that evidence
of female prostitutes acting as vectors for spreading HIV into the heterosexual
population is, at best, inconclusive.
We thought we knew that people in all AIDS risk groups proceed to AIDS
at the same rate following HIV infection, but this also has turned out
to be untrue. For young hemophiliacs, for example, the average time is
more than 15 years, while for older hemophiliacs and homosexual men, the
time to AIDS is 10 years. People who have acquired HIV through blood transfusions
have a rate nearly double that of gay men (average onset at six years),
but people who become HIV-infected during an organ transplant or cancer
chemotherapy develop AIDS, on average, in only two or three years.
We thought we knew that HIV always precedes immune suppression in people
who develop AIDS. But many studies show that lymphocyte counts are as low
in some HIV-negative gay men, intravenous drug users, and hemophiliacs
as they are in nonsymptomatic HIV-positive people-and sometimes lower.
We thought we knew that public health measures to combat AIDS-"safe
sex," clean needles for addicts, and so forth-work because they interrupt
HIV transmission. But epidemiologic studies have shown that transmission
of all suspected infections that may act as cofactors in AIDS is also interrupted.
We do not know, therefore, why public health measures work.
Other aspects of AIDS dogma have also been challenged-many of them in
the last year. For example, we now have evidence raising fears that current
vaccines, designed to spur antibody production, may be useless or even
detrimental; we have been told that significant percentages of hemophiliacs
have beaten HIV and seroreverted without resorting to antiretroviral therapies;
and, most recently, the very poor efficacy of AZT has been revealed to
us.
If such important, and previously obvious, "facts" are now
called into question, we must seriously consider how many of our remaining
notions about AIDS are similarly biased by our preconceptions and are,
therefore, not trustworthy.
A basic role that the AIDS task force must perform, then, is to make
sure that, even to the point of discomfort, we are constantly skeptical
and inquiring about the things we think we know-but really do not.
Hard Questions
The things we know we do not know are much more obvious than the things
we think we know but do not. For example, we know that we do not know how
HIV causes immune suppression. We are not even sure that HIV is sufficient
to cause AIDS without other immunosuppressive cofactors, since it is a
documentable fact that no one who gets AIDS has HIV as his or her sole
immunosuppressive risk.
Although every person with AIDS has a variety of autoimmune complications,
even including antibodies against his or her own T-cells, we know that
we do not know what role these play in AIDS. Indeed, we do not know what
triggers any human autoimmune disease, whether in AIDS or as a factor in
other syndromes. We do not know, in consequence, whether treating HIV will
be sufficient to cure AIDS, or whether AIDS may continue to destroy the
body through autoimmune mechanisms even after the virus is eliminated.
We know that alcoholism, crack cocaine use, and non-IV use of heroin
greatly increase the risk of contracting HIV. But there have been no telling
studies of the lifestyle or immunologic function of alcoholics, crack cocaine
users, or non-IV heroin addicts at risk for AIDS, nor of the mechanisms
by which these people acquire their HIV (and other) infections.
Do crack users, for example, share the very high rates of sexually transmitted
diseases, malnutrition, and bacterial and viral infections that characterize
IV-drug users and cause immune suppression in them? Do sores in the mouth
associated with crack cocaine use and oral sex with HIV-positive partners
facilitate HIV transmission? Do people who use non-IV drugs participate
more often in unprotected anal intercourse (the most efficient way to transmit
AIDS sexually) than other people? Does intercourse during menstruation
increase the probability of heterosexual transmission of HIV? Do disease
conditions that are associated with immune suppression-such as diabetes,
dialysis, anabolic steroid use, anorexia, and bulemia-pose additional risks
for contracting HIV? We do not know the answers to any of these fundamental
questions.
We must address all of these matters-the things that we know we do not
know-and many others if we are to succeed in defeating AIDS. The AIDS task
force should therefore promote, as one of its highest priorities, the investigation
of every anomalous and unexpected observation that threatens the sanctity
of the current AIDS dogma.
'Crazy Hypotheses'
The things we do not know that we do not know are, of course, the most
difficult forms of ignorance to identify. And to go about identifying them
we must invent crazy hypotheses and do unthinkable experiments. I advocate
this approach not because we can expect these hypotheses or experiments
to work, but because the history of science shows that employing them is
the most successful research strategy for addressing the unknown.
The notebooks of the great biomedical scientists-Jenner, Pasteur, Fleming,
Blumberg, and so forth-reveal a record of failed theories and botched experiments
that ultimately led to unexpected results. In disproving an incorrect theory
or in running an experiment for which there was no sound, establishment-validated
rationale, these clever scientists encouraged serendipity, the wellspring
of scientific insight. On accepting his 1976 Nobel Prize in physiology
or medicine, Baruch Blumberg said: "I could not have planned the investigation
at its beginning to find the cause of hepatitis B. This experience does
not encourage the approach to research which is based exclusively on goal-oriented
programs."
The programmatic, rationalistic converse of the Blumberg approach is
much more common, of course. But we must bear in mind the number of times
that supposedly well-founded approaches to disease have turned out to be
harmful. Physicians in the 19th century "knew" that
germs did not cause disease; it took a physical chemist named Pasteur,
working outside of the medical community, to prove otherwise. It is just
these things that make sense-but are wrong-of which we must beware; and
we can beware only if we control every theory by testing it against alternative
theories that we do not expect to be correct. Sometimes we will be surprised,
and-by being surprised-we will discover our ignorance about things we did
not know we did not know.
To nurture our curiosity and thus broaden our opportunities for serendipitous
discovery, I suggest that we cut back funding to those animal models and
test-tube studies that do not behave like human AIDS and, instead, put
more effort into modeling what really happens in human beings. No one,
for example, has ever mimicked in an animal the entire range of immunosuppressive
agents that bombard a blood-transfusion patient: anesthetics; surgery;
multiple blood transfusions contaminated not only with HIV but also with
cytomegalovirus, Epstein-Barr virus, and hepatitis C virus; opiate analgesics;
and high-dose antibiotics. No one has yet modeled such IV-drug-user risks
as multiple, concurrent infections with sexually transmitted diseases;
bacterial infections from unclean needles; constant re-exposure to alloantigens
(blood, lymphocytes, tissue) on unclean needles; persistent drug addiction;
chronic antibiotic use; and malnutrition. No one has repeatedly reinoculated
chimpanzees or macaques rectally with semen containing HIV, herpes viruses,
and mycoplasmas, while concurrently exposing them to inhalant nitrites,
antibiotics, and other drugs, as has typified so many men and women who
have contracted AIDS sexually.
So another of the functions that the AIDS task force must take on is
to make sure that no assumption goes unchallenged, and to provide sufficient
freedom for nonconformist research that might well yield serendipitous
surprises. Let's start with messy reality instead of assuming that HIV
is the entire answer.
Hidden Knowledge
Finally, there are the things that we do know, but we think we do not.
Most important, we think that we do not know of any cure for AIDS at present,
but, really, we do. That there is a cure is clearly evident all around
us-the hundreds of documented cases of people who have been infected with
HIV, who have developed T-cell deficiencies, and who have subsequently
returned to a normal immunologic status, lost all signs of HIV, and remain
healthy. There are people who have had antibody to HIV for more than 10
years who display no signs of immunologic damage. And there are those rare
cases of people who have had full-blown AIDS for more than a decade and
are still alive.
These people are living proof that there are things about AIDS that
we do not know we know; they are walking data banks, waiting to be tapped,
waiting to reveal to us the knowledge that we possess but are unaware of.
We need to uncover the hidden knowledge that is within our reach by studying
these people to find out whether the strains of HIV that have infected
them are nonpathogenic and therefore protective against pathogenic strains;
whether they are genetically different from other human beings; or whether
they have treated themselves differently and so hold the clues to treatment
of other HIV-infected people.
Limited formal studies and much anecdotal evidence suggest HIV have
been treated with retroviral drugs; most have drastically altered their
lifestyles to eliminate ongoing immunosuppressive risks, including re-exposure
to HIV and other sexually transmitted diseases; they have ceased drug use;
and most have adopted high-nutrition diet supplements to boost immune function.
These people may be telling us that we know how to treat AIDS successfully
through risk elimination and immunologic boosters rather than antiretrovirals
or HIV vaccines. One reason we do not know that we know this is because
these people have succeeded by ignoring mainstream medical advice, and
their knowledge is therefore outside the structure of biomedical science.
I suggest that whatever these survivors know must be combined with what
the world of official biomedical investigation knows and become a focal
point of AIDS research as soon as possible. We must refocus AIDS research
on seroreverters, long-term survivors of HIV infection, and long-term survivors
of AIDS.
Of course, we must also place whatever knowledge we get in such unorthodox
ways back into a standard scientific form:
What we do not know that we know tends to be expressed in terms of anomalies-things
that do not fit our expectations-and are therefore generally overlooked
or ignored. The AIDS task force should pursue studies involving these survivors
and see how much of AIDS can be prevented by focusing on cofactors.
An Open Field
Recognizing the extent of our scientific ignorance of AIDS leads me
to conclude that we have narrowed our focus too precisely. AIDS is more
complex than just HIV. It includes everything that predisposes people to
HIV infection, everything that can synergistically work with HIV once present,
and everything that can cause immune suppression in people at risk for
AIDS independently of HIV. Recognizing this increased complexity does not
displace HIV from its place at the center of AIDS research, but it does
provide a wide range of new targets for prevention and treatment.
The useful function that an AIDS task force can play is to make sure
that the utmost reaches of our ignorance are quickly and efficiently identified.
We will not do that by staying in the rut that has been gouged out during
the past decade, but rather by deviating from it.
A diversity of opinion and of research has never hurt science. Dogmatism
and politically motivated programs often have. The AIDS task force can
foster one or the other, but not both. *
Robert S. Root-Bernstein, an associate professor of
physiology at Michigan State University, East Lansing, is the author of
Rethinking AIDS: The Tragic Cost of Premature Consensus (New York, Free
Press, 1993) and Diversity (Cambridge, Mass., Harvard University Press,
1989). He is a former MacArthur Fellow (1981-1986).
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