A Real Scientist

By Mark Gabrish Conlan

Zenger's 1998

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," HIV.

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 of HIV.

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 for AIDS.

Mark Conlan for Zenger's magazine: What specifically are proteases?

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 they produce.

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 as well.

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 field. Why?

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 to people.

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 thing.

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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