INTERVIEW DAVID RASNICK
A Real Scientist
By Mark Gabrish Conlan
Protease expert Dr. David Rasnick takes on the HIV/AIDS
myth and the protease inhibitor hype.
Virtually no one who isn't a biochemist directly involved in research
on protease enzymes and the pharmaceuticals that inhibit them has ever heard
of the Gordon Conferences on Proteolytic Enzymes, held every other year
in New Hampshire. But the 1994 Gordon Conference featured a presentation
on a topic that two years later would become the hottest AIDS story worldwide:
the use of protease inhibitors to control the alleged "AIDS virus,"
British researcher John Kay presented the results of a clinical trial
in which 400 people with AIDS were given two grams a day of a protease inhibitor
made by Hoffmann-LaRoche called Ro 31-8959 (now being sold under the generic
name saquinavir and the trade name Invirase). After 18 months of this regimen,
the patients who received the protease inhibitor showed no clinical improvement
whatsoever over the study's control group. Kay asserted that the reason
for these disappointing results was that the patients on the inhibitor initially
improved, but subsequently their HIV evolved resistance to the inhibitor.
He also announced that Roche was imposing a blackout on further discussion
of these results because they were so disappointing, and to this day the
study has not been published in the scientific press.
David Rasnick, Ph.D. -- a man who had been working on proteases his entire
professional life, ever since he won his Ph.D. from Georgia Tech in 1978
for studying them - challenged the blithe assertion that mutations in HIV
were responsible for the long-term failure of the protease inhibitor. He
noted that there are eight different places -- "substrates," they're
called in science -- where proteases are needed in the reproductive cycle
To help produce a new HIV particle, the proteases have to cut apart eight
bonds between nine different proteins in the right sequence and at the right
time. Dr. Rasnick pointed out that, according to the literature produced
by the manufacturers of HIV protease inhibitors, even the mutations that
successfully blocked inhibition of one of those protease cycles had little
or no effect on the other seven -- and even if a mutation occurred that
successfully blocked inhibition of all eight sites, he doubted that the
result would be a functional virus that could infect anything.
"I went on to propose that the HIV protease inhibitors were performing
as designed -- blocking HIV production -- without being undermined by the
emergence of drug-resistant mutant strains," Dr. Rasnick recalled in
an article in the August 1996 issue of the newsletter Reappraising AIDS.
"The reason that these drugs did not alleviate AIDS is that HIV is
not the cause of AIDS. During private discussions, none of my colleagues
found any flaws with my reasoning and even thought it was right. I left
the meeting thinking that these fellows would continue the analysis where
I left off. Well, that, of course, didn't happen. The HIV protease mutation
hypothesis has become more entrenched with time."
Two years after the Gordon Conference debacle, HIV protease inhibitors
have become a worldwide growth industry. According to Cameron Lee of ACT
UP Golden Gate, the Merck drug company is currently building two entire
factories just to manufacture its protease inhibitor, Crixivan (indinavir).
Abbott Laboratories, manufacturer of the protease inhibitor Norvir (ritonavir)
- which Dr. Rasnick claims is even more potentially toxic than the other
two - made $10 million profit off Norvir the first three weeks it was on
the market. To get around the alleged "mutation" problem that
rendered the protease inhibitors clinically useless when they were tested
on their own, doctors are being told to prescribe them as "combination
therapies" with the nucleoside analogue drugs, such as AZT, that have
their own major toxicities and also do little or nothing to lengthen the
lives or improve the clinical health of the people taking them.
While Dr. Rasnick has had reasonable doubts about whether HIV could cause
AIDS for years, the hype surrounding the protease inhibitors appears to
have pushed him out of the scientific closet and led him to "come out"
as an AIDS dissident. In this interview, he discusses the potential toxicities
of the protease inhibitors, explains why he thinks they will be useless
in fighting AIDS, and vividly describes the fear, intimidation, and terror
that operate at all levels of AIDS, including among the scientists themselves,
to prevent rational discussion of alternatives to the HIV/AIDS model and
the use of highly toxic chemotherapies as Western medicine's standard treatments
Mark Conlan for Zenger's magazine: What specifically
Dr. David Rasnick: Proteases are one of the largest classes of
enzymes. Like all enzymes, they are proteins. The proteases are divided
into four main classes: serine proteases, cysteine proteases, metalloproteases
and aspartyl proteases. I've worked on all four classes.
HIV protease is an aspartyl protease. There's a human aspartyl protease,
renin, that's involved in the regulation of blood pressure. The gut proteases,
like cathepsin-D and the stomach protease pepsin, are aspartyl proteases.
There are also serine proteases in your gut, like tripsin and chymotripsin.
They help you digest the food. It's not clear what cathepsin-D does in the
gut. It's not secreted. It's actually in the membranes, the surface of the
gut. But it's important.
The reason I emphasize cathepsin-D is that it is also susceptible to
the HIV protease inhibitors, though it's many orders of magnitude less sensitive
than the HIV proteases. At the dosing levels that patients receive of these
HIV protease inhibitors, they're sufficient to inhibit virtually all the
cathepsin-D in a patient's gut.
I know for a fact that cathepsin-D is essential for life because of my
own research, which had nothing to do with AIDS. I work with a lot of people
that work on proteases. There's an animal study that is not published yet.
This fellow came to our lab some months ago and gave a seminar. He did a
gene knock-out on mice. These people are able to eliminate specific individual
genes from these mice, and then when they eliminate that gene, the proteins
associated with that gene are not present. One reason they do this is to
test various hypotheses about the functions of those genes, and the proteins
This fellow did a gene knock-out in mice where he totally eliminated
the protease enzyme cathepsin-D. It didn't affect their development at first.
They were born, and they did fine until after they were weaned. Then, about
20 days after they were born, they spontaneously died -- 100 percent of
them. Based on this experiment, cathepsin-D is the only protease that I
know of that is absolutely essential to life.
Let me tell you the pathology involved when there was no cathepsin-D
in these animals. There were two very interesting coincidences -- I'm going
to say "coincidences" because I don't want to use any causal language
here, but it's very suggestive. First, the animals that didn't have any
cathepsin-D, after they were weaned and they died spontaneously, their intestines,
their guts, just withered away and disappeared. The animals essentially
starved to death, because they couldn't digest food anymore. A second feature
is that their lymph glands -- a very important immune tissue -- atrophied
I don't want to make the implication that this necessarily has anything
to do with AIDS, but it's very suggestive. You've got this enzyme, cathepsin-D,
which if it's not present, the small intestine and the lymph glands wither
away and die. The atrophy of the lymph glands might have a profound effect
on them if they lived long enough, but that's not what kills them. The gut
thing is what kills them.
Besides doing a knock-out to get rid of the gene that creates an enzyme,
another way to make it not present is to inhibit it, obviously. It has the
same effect. I wasn't even thinking in terms of AIDS. I was thinking in
terms of inhibitors, and I was thinking to myself during this seminar, "Boy,
the last thing I want to do is inhibit cathepsin-D in the gut." Certainly
I don't want to do it on a chronic basis, because it seems to be absolutely
essential for the life of these animals. They die without it. So it makes
me very worried that anybody would be taking HIV protease inhibitors at
high concentrations for a long period of time.
Zenger's: Is there actually a chance that the HIV protease inhibitors
would inhibit enough cathepsin-D in the human body to matter?
Dr. Rasnick: Cathepsin-D is about 100,000 to 1 million times less
sensitive than the HIV proteases to the Roche HIV protease inhibitor Invirase
(saquinavir), for example. So, as a person who makes drugs, I would ordinarily
say, "That's a tremendous difference there, so it would be no problem."
I wouldn't even worry about it inhibiting human enzyme, except for one problem:
the doses that they're giving AIDS patients.
They're giving them anywhere from two to seven grams of protease inhibitors
a day, and all of this is in pill form. It gets down in the gut, and it's
very highly concentrated there before it gets into the blood. Then it gets
absorbed, gets diluted out in the bloodstream and other places, to the point
that it won't affect any other aspartyl protease that I'm aware of in those
concentrations. But it will in the gut.
As a matter of fact, there's enough of it in the gut, when the AIDS patients
take these protease inhibitors -- at least based on the kinetics, the potency
of these compounds -- to inhibit virtually all of the human enzyme in the
gut. Now, I don't know if that's what leads to the toxicity of these things
-- the diarrhea, liver problems, and kidney stones -- or not. I can't say
that for a fact.
But my guess is that HIV protease inhibitors taken orally in the large
doses they're using would have a long-term toxic effect from the inhibition
of cathepsin-D. Nobody's taken them long enough to know what the long-term
effects of these inhibitors are. They've only given them to people long
enough to get the acute effects, the things we talked about before. I don't
know what the long-term toxicities would be, but boy, I sure would keep
an eye out to follow that up.
Zenger's: In the September 1996 issue of Zenger's, I published
the listed side effect for the protease inhibitors, from the package inserts
for the Roche drug Invirase (saquinavir) and the Merck drug Crixivan (indinavir).
You've also mentioned the possible toxicities from these drugs.
Dr. Rasnick: Oh, they definitely have well-documented toxic side
effects. But you can be awfully misled by those inserts. What happens is
that everything that's ever been reported during a clinical trial is included
in those inserts, regardless of how rare it is, and there's no distinction,
typically -- at least I'm not aware of them -- of the relative importance
of these side effects, unless they're tremendously noticeable. Then they'll
have a second little area, and they'll write on that separately.
Generally, the package inserts are just a grab-bag of everything that
any physician, anybody, has written down during the clinical trials. And
you can be terribly misled in two ways. One is that it makes these things
look horribly, horribly dangerous, because you can just read off this litany
of things. The drug may or may not be dangerous, but it has nothing to do
with the litany of things. It has to do with the frequency and severity
of all these things, and there's no indication in that. So it can make you
overestimate the toxicity of these things.
It can also make you underestimate the toxicities, or ignore the principal
toxicities, because they don't make any distinction. The vast majority of
the toxicities with these protease inhibitors, so far at least, are intestinal
problems like diarrhea or cramps or something. That represents the vast
majority of people who have adverse reactions, about 40-45 percent.
Zenger's: So you're saying that, from your understanding and your
experience of how protease inhibitors work, you think the most significant
items on that list, the ones to be genuinely concerned about, would be the
gastrointestinal and digestive items?
Dr. Rasnick: So far. That could change, but those are the major
ones that have been reported in the literature, and I don't think anybody
disputes that. What the long-term consequences are, I don't know. Not many
people know about the potential effect on cathepsin-D, because that study
has not yet been published. So there's no way for them to know that unless
they happen to be protease people that also know the guy who did the knock-out.
But that's got me concerned in the long term, because even if you lower
the dose somewhat, so that you reduce the the acute effects, the imminent
diarrhea and all that sort of thing, the long-term effect concerns me. I
don't know if it's going to be a problem or if it's not going to be a problem,
but from what I've seen with those animals which have no cathepsin-D at
all, and it's lethal to them, it certainly is worth paying attention to.
Zenger's: You said that the problem with these drugs inhibiting
cathepsin-D occurs when they're taken in pill form. Would you suggest that
the drugs would be less likely to have this effect if they were given intravenously?
Dr. Rasnick: They wouldn't have that effect if they were given
intravenously, because it would bypass the gut entirely. But a simpler way
to circumvent this whole problem, and also to reduce the dose, would be
to use suppositories. Then you're down in the lower gastrointestinal tract,
where cathepsin-D is not an issue -- plus the absorption efficiency is much
higher than if you take it orally.
The problem is, in the United States, people don't even think about using
suppositories. It would not be a problem in Japan, where they prefer suppositories.
But in the United States, sociologically, that would not be as appealing,
especially when these people have to take these things four to eight times
a day, depending on their regimen.
Any time you have to administer something by injection, IV or subcutaneous,
that throws in all sorts of complications. One thing it does is make it
far more dangerous. You can OD much quicker by doing IV. Also, when you
IV, you have a much greater chance of introducing infectious agents, bacteria
and viruses. And it's not nearly as convenient. You also have to have a
special prescription for the syringes, and all the same things that diabetics
have to go through. It would probably increase the expense of these things
ten times -- and they're already expensive.
Zenger's: In your article in the August 1996 Reappraising AIDS,
you said that after the HIV/AIDS model was announced -- or, as I like to
say, "politically proclaimed" -- in 1984, you, as a biochemist
with extensive experience in protease, immediately thought that inhibiting
HIV protease would be a way to go to battle this virus. Now you say that,
looking back on it, you're glad you didn't get involved in that particular
Dr. Rasnick: First of all, I don't believe HIV has anything to
do with AIDS. So it's pointless to make inhibitors for anything that has
to do with HIV if it has nothing to do with AIDS. From a technical standpoint,
it's absolutely a brilliant strategy to prevent the replication of infectious
HIV. It works in vitro. It probably works in people, if the silly thing
is there. But if it doesn't matter whether you inhibit it or you don't inhibit
it, it doesn't matter how brilliant it is. The problem is, you've got to
have a virus that matters, and the reason I was glad I got out of it is
I would have been working on a virus that doesn't matter.
If the virus mattered -- if HIV were the cause of AIDS -- the people
making these protease inhibitors ought to be given wonderful prizes, raised
up on people's shoulders and marched around the world, because they've come
up with a marvelous, marvelous way of blocking HIV. And we will find out
in about a year, I would guess -- a year from last spring -- if these things
are going to have any effect at all on the course of the disease that matters
I'm not talking about viral load. I'm not talking about CD4. I'm talking
about the number of people who survive because of these inhibitors, who
would be dead if they had not taken these inhibitors. We don't know that
yet. There are no published data on that. Abbott gave a little abstract
back in January or February of this year. They made this big to-do about
the HIV protease inhibitors having a desirable clinical effect, prolonging
the lives of AIDS patients and reducing the morbidity -- how sick they are
-- with these things. But it has never been published.
And the very interesting thing is that the Vancouver AIDS conference
this past summer, where you would have thought there would have been a big
follow-up on this, and we would have been presented with these extraordinary
data -- you know what happened in Vancouver? Everybody retreated to the
surrogate markers: the viral load, CD4 and stuff like that. They're pulling
back from that big claim.
Zenger's: What they've done is, instead of testing the protease
inhibitors against placebos -- against nothing -- they have tested a combination
of a protease inhibitor and AZT and another nucleoside analogue, against
the nucleoside analogues alone. And in a previous issue of Reappraising
AIDS [March 1996], Paul Philpott suggested that the reason for the results
they got -- that patients did better on the combinations involving the protease
inhibitors than they did on combinations that were solely nucleoside analogues
-- is that the protease inhibitors might also be inhibiting the kinase enzymes
that the body needs to break down the nucleoside analogues.
Dr. Rasnick: I don't think so. They could be reducing the toxicity
of AZT, if they inhibited those enzymes. I don't know if they inhibit those
enzymes. I'd be suspicious if they did, because I know what they do. Nucleoside
analogues like AZT and the other ones [ddI, ddC, d4T, 3TC] are phosphate-free
derivatives. They come without the phosphates attached.
In order for them to have their antiviral activity -- and also anticellular
activity; you cannot separate the two -- they have to be phosphorilated,
and that's what kinases do. Kinases are enzymes that put phosphates on things.
That turns these nucleosides into nucleotides. Nucleotides are nucleosides
with phosphates attached. Then, when you have the phosphates on there, the
nucleotides can interact with the reverse transcriptases, and with DNA polymerases
of all sorts.
If you interfered with the ability of these kinases to attach the phosphorus
chains to the nucleosides, you would essentially take the AZT out of circulation.
It wouldn't be available to do anything, really. It would probably just
go to the liver and be degraded. But, since the body is always turning nucleosides
into nucleotides, if you inhibit that process, you may prevent the production
of the active AZT nucleotide, but then you're also going to prevent the
conversion of natural nucleosides into nucleotides. I could picture it being
toxic that way.
Zenger's: So what you're saying is basically that protease enzymes
and kinase enzymes are sufficiently different chemically that it is highly
unlikely that one substance would inhibit both.
Dr. Rasnick: Highly unlikely. The only way that you could answer
that is to do an assay for the kinase. These are common assays. You throw
in various concentrations of the protease inhibitor, and see if it has any
effect at all on the kinase activity. It's an easy assay to do. I personally
don't think these protease inhibitors would have an effect on kinases. but
then I also wouldn't have guessed that they'd have an effect on the cytochrome
p450 enzymes in the liver, either -- and they do, or at least some of them
do: the Abbott inhibitor Norvir (ritonavir), for example.
Cytochrome p450 is a whole family of liver enzymes that are involved
in detoxifying drugs. They actually get rid of anything that's ingested
in the body that the liver is not happy with by oxidizing them and making
these water-insoluble molecules very water-soluble. Then, once they're water-soluble,
they dissolve and can be eliminated in the urine. The liver does that on
almost every kind of molecule you can imagine. There are some molecules
that are resistant to the liver's enzyme, but the liver is a better chemist
than any human chemist around.
Unfortunately, some of these HIV protease inhibitors interfere with the
ability of these enzymes to do their job. You can picture what happens from
there. When you have all of these drugs that your liver is normally trying
to eliminate from the body, and then it can't eliminate them, the concentrations
are going to build up. Then you will start seeing toxic effects even at
doses that would ordinarily be perfectly safe, because the liver cannot
eliminate it anymore. This is particularly dangerous for AIDS patients because
they are often taking almost a whole drugstore's worth of pills every day.
It's not a trivial issue.
Zenger's: In your article in Reappraising AIDS, you talked
about how you find it fascinating that the HIV/AIDS model has survived as
long as it has, despite --
Dr. Rasnick: -- no evidence for it! There is literally no evidence
for it, you know? The best pieces of evidence against the HIV/AIDS hypothesis
are the 100,000 scientific papers that have been published on it. I haven't
read all 100,000 - thank God. If there is a just God, I will not have to
read all 100,000 of them. I have read hundreds of them, though, and they
all assume this stuff. I've got a huge library on this whole thing, and
I can find nothing - not one paper - where there is any evidence at all
that supports the HIV hypothesis of AIDS. There's lots of speculation, and
there's lots of assumptions and hypotheses, but there's no evidence. There
are no data.
I know many of my colleagues, especially in the protease field, who work
on HIV protease inhibitors. They will tell you privately that they're not
going to work. They have no confidence in these things, and the data are
not there. They'll tell you that privately. They even volunteer that. Publicly,
they won't say anything like that. They have a private life, their private
thoughts; and then they have their public, commercial, or academic mind.
Zenger's: I think that's largely because the government, the pharmaceutical
industry, the World Health Organization, all the people in authority, all
the people with money to hand out for research, have made this an institutional
"truth." The way Peter Duesberg's funding was taken away from
him, and his reputation was trashed in the scientific community, seems to
have had a chilling effect, to the point where he's been seen as a kind
of example. All these scientists who are confessing privately that they
don't think this will work may very well just be aware and afraid of the
potential consequences that would result if they took that position publicly.
Dr. Rasnick: If that's the situation, then I'm very angry, because
it means that my profession, the profession of science, is populated largely
by cowards. It means that the integrity and courage that I would think would
be part of the job of being a scientist is in very short supply. I've thought
about this a lot, and I don't think you can really do science -- really,
really, honest to God do science -- without a level of integrity and a certain
level of courage.
To do science means that you go, as they say in Star Trek, "where
nobody has gone before." That's essentially it. If you know where you're
going, you're an engineer. If you don't know where you're going, you're
a scientist. In order to do that, it requires a certain amount of courage;
and in order to carry out your job, it takes a certain amount of integrity.
People have to be able to trust what you say and what you do. And you have
to have the ability to critique your own work, to the point where you would
believe it if somebody else told these things to you.
So I guess, even if you're right in what you're saying, that's a serious
indictment of the whole enterprise. It means that it's set up wrong. We've
got people in the institutions -- masses of people -- doing science, that
should not be doing it. I think the institutions themselves contribute a
lot to that. Just their sheer size can squash people.
Another problem is the fact that they're segregated into specialties,
and there's no ability for an overview, a global view of issues. We're always
relying on our colleague specialists. The virologists rely on the biochemists.
The biochemists rely on the virologists. The physicians rely on all of us
to be right, you know. The government relies on the experts, and so on.
We don't cross over, and we don't doubt what the other people say.
In the early days, in 1984, when Robert Gallo made that pronouncement
that HIV was the probable cause of AIDS, I assumed he knew what he was talking
about because he was a virologist and I was not. I didn't have any background
in virology, so I just had to accept on faith that he knew what he was talking
about. The non-virologists assumed that he knew what he was talking about.
As it turned out, the virologists didn't assume that -- at least not
at first. But since he made that claim in public before his papers were
published, they never got a chance to critique it in the literature. You
never got to hear the scientific debate among his peers, so it looked like
there was no opposition at all. The other virologists never had an opportunity
to challenge it.
I'm a scientist with 20 years' experience, and there's only two things
that I'm absolutely certain of in science. Absolutely, with no doubt in
my mind. One is that AIDS is not contagious. It's not a thing that you can
"catch" from anybody. And the other thing is it's not caused by
a virus, in particular HIV.
The only reason why I'm absolutely convinced on that is because "HIV/AIDS"
is the most studied thing in all of science. Absolutely the most studied
thing in all of science. The fact that it's so well studied -- and you can't
find a grain of literature that even supports it, much less proves the hypothesis
-- finally has satisfied me enough I would risk my life on that statement.
The only reason I'm that confident is because billions of dollars have been
spent on it, and have proved it to be the case!
Zenger's: In other words, the fact that 12 1/2 years and $40+
billion, and hundreds of thousands of scientific man-hours, have been spent
on this and have produced absolutely nothing --
Dr. Rasnick: Well, no. It's produced $40 billion worth of evidence
that HIV is harmless! I mean, what we got from our $40 billion is enough
evidence to satisfy me as a scientist, as a man, as a taxpayer, as anything
that you want to say, that AIDS is not contagious and that it's not caused
by HIV. That's what we've got for our $40 billion. That's the positive "spin."
There is another consequence to this $40 billion. People have to spend
it. It's not easy to spend 40 billion bucks. You can't flush it down the
commode to spend it, you know. So if you've got all this money available
to you, and you have to spend it up, what do you have to do?
You have to do your experiments really fast. You can't think them through
clearly. You can't think of all the ramifications. You have to make all
these assumptions. You just do your experiments. You don't do controls.
You do them the quickest, fastest way that you can. You write the results
and send them in. So then you start on your next experiment. You do the
whole same process over and over again.
So as a consequence of this tremendous amount of money, it means that
we're doing shoddy work because we have to spend that money. Since there's
only a finite number of scientists and people around that can spend the
$40 billion, they're busting their butts to spend that money.
As a consequence, the published AIDS literature is some of the shoddiest
work I've ever seen in my professional life, and I'm convinced a lot of
it has to do with the excess money. They can't spend it fast enough! It's
piling up, so they have to write faster and faster -- and think less and
less, do fewer and fewer controlled experiments, and just assume everything
is fine and dandy.
AIDS is now institutionalized. If AIDS were to go away tomorrow, it would
be a catastrophe for the people that depend on it, you know. It's a multi-billion
dollar industry. There are people who have reputations, whole institutes.
Gallo now is the leader of the Human Retroviral Institute, a totally pointless
institute. It has no function at all. Retroviruses are harmless, and yet
you've got this whole institute to research them. So they don't want to
see this go away, obviously.
Abbott makes $1 million on their blood tests. They don't want to see
that go away. And the companies that make AZT and the protease inhibitors,
they don't want to see that go away. All of the little AIDS organizations,
the little people in the community who've now risen up and now have status:
they don't want to see it go away. It's become comfortable, and it's a sociological
The AIDS thing -- the hysteria, the stupidity, the institutional craziness
-- would all disappear if the fear disappeared. The whole thing is kept
together by fear, intimidation, terrorism and brutality. Think about it.
If you're an HIV-positive pregnant woman and you tell your doctor, "I'm
not going to take AZT," he'll want to throw you in jail and threaten
to take your child away!
It's fear all the way through. Even scientists, people like me, are subjected
to fear and intimidation. You're supposed to be open, and be able to talk.
I can talk to my own colleagues, freely and openly, on virtually every topic
in science -- even about whether there are deities or not -- except alternatives
to HIV as the cause of AIDS. It's astounding! It's incredible! When I went
to school, I was taught that only happened 1,000 years ago!
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