FOR U.S. AIDS RESEARCH IS DUE FOR A
By Robert S. Root-Bernstein
Scientist 4 April 1994
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.
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:
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.
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,
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 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
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
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,
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.
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.
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
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.
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.
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
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.
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.
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.
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.
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
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.
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.
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
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.
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.
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. *
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)