By Peter H. Duesberg and Bryan J. Ellison
From the discovery of tobacco mosaic virus through the polio epidemic, scientists have found and legitimately blamed many viruses for a variety of diseases, each having passed the acid test of Koch's postulates. But for every truly dangerous virus, many more perfectly harmless passenger viruses can be found in humans and animals. NIH-sponsored polio research during the late 1950s proved the point. Researchers trying to isolate new strains of poliovirus accidentally found numerous closely related passenger viruses - -such as Coxsackie and echoviruses - that, like polio, infected the digestive system. Scientists classified some of these viruses as "orphans" - viruses without corresponding diseases. The virus hunters could not bring themselves to believe microbes could exist without being harmful and expected even these "orphan" viruses would someday find appropriate sicknesses.
When trying to blame a passenger virus for a disease, how-ever, one nagging problem haunts the virus hunter: The laws of virology dictate that the illness will strike the victim soon after infection. When microbes infect a new host, they cause sickness within days or weeks at most. In order to cause disease, viruses need to grow into sufficient numbers to take over the body; otherwise, the host's immune defenses will neutralize the invader and prevent disease altogether. The rate-determining step of such fast, exponential growth is the generation time of the virus. Since the generation time of all human viruses is between eight and forty-eight hours, and since the infected cell produces one hundred to one thousand viruses per day, viruses multiply exponentially, increasing in numbers hundred- to thousandfold per day. Within a week or two, one hundred trillion (1014) cells can be produced-one for each of the one hundred trillion cells in the human body.
Therefore, if scientists wish to convict an innocent virus, they must invent a new property for it that allows the virus to violate the laws of virology. For example, they can hypothesize a "latent period" of months or years between the time the virus invades the body and the appearance of symptoms - hence, a "slow" virus.
However, the slow virus concept has never been reconciled with the short generation time of viruses and the immune system. Once the virus lies totally dormant, an intact immune system will never allow any virus to be reactivated to multiply into numbers that would threaten the host.
For a virus to be reactivated, the. immune system first must be destroyed by something else - the real cause of a disease. A reactivated virus would just contribute an opportunistic infection. Thus, there are no slow viruses, only slow virologists.
A conventional virus could, however, be slow acting in a defective immune system. Indeed, some exceptional victims suffer pre-existing health problems that prevent their immune systems from reacting decisively against the virus, allowing it to continue growing and damaging the host for a long period of time. This can happen with virtually any type of virus, but it is extremely rare. When such a chronic infection does occur, as with a small percentage of hepatitis cases whose immune system is damaged by alcoholism or intravenous drug addiction, the virus keeps growing abundantly in the body and can easily be found by experimental tests.
Other germs, like herpes viruses, can hide out in some recess of the body, breaking out periodically to strike again when the immune system passes a seasonal low. In both examples, only the weakened immune system of the host allows the infection to smolder or occasionally reappear from hibernation. By contrast, a slow virus is an invention credited with the natural ability to cause disease only years after infection - termed the latent period - in previously healthy persons, regardless of the state of their immunity. Such a concept allows scientists to blame a long-neutralized virus for any disease that appears decades after infection. The slow virus is the original sin against the laws of virology.
The slow-virus or latent-period concept, now used to connect HIV with AIDS, can be traced back to the days of the war on polio. The researcher who popularized this modern myth is today an authority for AIDS researchers and one whose career epitomizes the evolution of the virus hunters over the past three decades.
Dr. Carleton Gajdusek is a pediatrician who has worked as a virologist at the NIH for decades. Having spent a great deal of time studying contagious childhood diseases around the world, Gajdusek was sponsored by the NFIP and sent to New Guinea in 1957. There, a doctor with the local health department introduced him to a disease called kuru, a mysterious ailment that attacked the brain, rendering the victim increasingly spasmodic or paralyzed until death within months. The syndrome existed only among the thirty-five thousand tribal villagers in one set of valleys, mostly the Fore tribe. Before Gajdusek's arrival, no outsider had ever described kuru, although the Fore tribesmen told him the condition had begun appearing a few decades earlier.
Gajdusek's initial study assumed the disease to be infectious. He reported that the natives routinely cannibalized the brains of relatives for ritual purposes, a practice that they told him had begun around the same time as the arrival of kuru. Gajdusek later explained to one interviewer that cannibalism "expressed love for their dead relatives," and that it also "provided a good source of protein for a meat-starved community." Gajdusek decided that kuru was transmitted by the eating of deceased victims' brains. Yet when he searched for a virus, he ran into a baffling absence of evidence. None of the typical signs of infection could be found in the patients. Their bodies showed no inflammation and no fever, no changes were registered in their supposedly infected spinal fluid, their immune systems failed to react as if any microbe had invaded the body, and those people with suppressed immune defenses had no greater risk of catching the disease. Another scientific group soon arrived from Australia and concluded that kuru might be genetically inherited.
Upon arriving back in the United States, Gajdusek was hired by the NIH to work at its institute for studying neurological disease. While continuing to monitor kuru incidence, he devoted his time to laboratory study of the condition. Word of his discovery of kuru meanwhile made its way to England, where another virus hunter was investigating a sheep disease known as scrapie, which involved symptoms of brain degeneration. The English researcher suggested to Gajdusek that kuru might be caused by a slow virus, one with a long latent period.
Gajdusek was immediately hooked by the revolutionary idea, despite his own "misgivings" that genes, toxins, or nutritional deficiencies might be the cause of kuru. Again determined to find an elusive virus, he tried to transmit kuru from victims to chimpanzees. But none of the animals became sick when injected with blood, urine, or other bodily fluids from kuru patients, nor from the cerebrospinal fluid that surrounds the brain, which should have been full of the alleged brain-destroying virus. Indeed, the monkeys contracted no disease even from eating kuru-affected brains - the authentic animal model of cannibalism.
Only one bizarre experiment did work, in which the brains of kuru patients were ground into a fine mush and injected directly into the brains of live monkeys through holes drilled in their skulls. Ultimately, some of the experimental monkeys suffered coordination and movement problems. Surprisingly, though, even this extreme method could not transfer kuru to dozens of other animal species. And no virus could be seen in the brain tissue, even using the best electron microscopes.
At this point, one might expect Gajdusek would have suspected something was seriously wrong with his virus hypothesis. If evidence for the invisible virus could not be found anywhere but in unpurified brain tissue, if it did not elicit any defensive reactions by the body, and if it could not be transmitted in pure form to animals, then probably no virus existed at all. The homogenized brain tissue of dead kuru patients - full of every imaginable protein and other compounds-should in itself be toxic when inoculated into monkeys' brains.
Nevertheless, the sick monkeys convinced Gajdusek and his colleagues he had found a virus. Since he could not isolate it apart from the brain tissue, he decided to study the virus and its structure with a standard experiment: He would define which chemical and physical treatments would destroy the microbe, thereby gathering clues about its nature. But to his astonishment, almost nothing seemed to harm the mystery germ. Powerful chemicals, acids and bases, boiling temperatures, ultraviolet and ionizing radiation, ultrasound-no matter how he treated the brain tissue, it still caused "kuru" in his lab monkeys. Further tests also proved that no foreign genetic material, which all viruses require for their existence, could be found anywhere in kuru-affected brains.
Employing the strongest virus-destroying treatments, Gajdusek had failed to render the kuru brain tissue harmless in his experi-ments. His results lent themselves to one obvious interpretation: No virus existed in the first place, so it could not possibly be destroyed. But Gajdusek clung to his virus hypothesis. Despite his disappointing experiments, he turned the results upside down and argued that the "kuru virus" was actually a new type of super-microbe or, as he put it, an "unconventional virus." This new virus also needed to act as a slow virus, since long periods of time elapsed between an act of cannibalism and the onset of kuru; he liberally suggested latent periods extending into years or even decades.
At an earlier time, and in another context, Gajdusek probably would have been ignored by orthodox scientists. But he offered this hypothesis to a generation of scientists dominated and impressed by virus hunters. The year was 1965, polio had largely disappeared, and the burgeoning ranks of NIH-funded virologists welcomed any new research direction on which to use their skills. Thus, they embraced Gajdusek's slow virus hypothesis enthusiastically. They listened uncritically when he claimed a similar unconventional virus caused Creutzfeld-Jakob disease, a rare brain disorder that seems to strike mostly Westerners having undergone previous brain surgery (obviously such medical operations might well be suspected as the real cause). Gajdusek proposed slow or even unconventional viruses as the causes of a huge laundry list of nerve and brain disorders, ranging from scrapie in sheep to multiple sclerosis and Alzheimer's disease in humans, and he was taken seriously even though he offered no proof. Entranced, his peers awarded him the 1976 Nobel Prize for medicine, specifically for the kuru and Creutzfeld-Jakob viruses he has yet to find. And the NIH promoted him to head its Laboratory of Central Nervous System Studies.
In the meantime another crucial, if embarrassing, bit of information has emerged as a challenge to Gajdusek's virus-kuru hypothesis. The published transcript of his Nobel acceptance speech, in a 1977 issue of Science magazine, included a photo ostensibly showing New Guinea natives eating their cannibalistic meal. The photo is not very clear. When colleagues asked Gajdusek if the photo truly showed cannibalism, he admitted the meal was merely roast pork. According to Science, "He never publishes actual pictures of cannibalism, he says, because they are 'too offensive.'" Unconvinced, anthropologist Lyle Steadman of Arizona State University has investigated and directly challenged Gajdusek, claiming "there is no evidence of cannibalism in New Guinea." Steadman, who spent two years doing fieldwork in New Guinea, noted that he often heard tales of cannibalism but when he probed, the evidence evaporated."
Gajdusek, angered by the hint of malfeasance, has insisted that "he has actual photographs of cannibalism, but he would never publish them because they 'so offend the relatives of the people who used to do it.'" This statement contradicts his earlier claims that the tribesman proudly ate their dead relatives out of respect, quitting the practice only in deference to outside pressure from government authorities. For evidence of cannibalism, Gajdusek also cited Australian arrests of tribesmen for the alleged crime - which, as it turned out, were based on hearsay accusations. So perhaps New Guinea natives stand falsely accused of ritual cannibalism.
In addition, few people outside of Gajdusek's original research team have ever personally witnessed kuru victims. This means we also depend on his own descriptions and statistics for our knowledge of the disease itself, particularly since he claims cannibalism and kuru both ceased to exist within a few years after his 1957 trip. Phantom viruses, transmitted through phantom cannibalism, cause phantom disease.
Yet Gajdusek has reshaped the thinking of an entire generation of biologists, his seductive message of slow viruses having landed on eager ears. He and the virus hunters inspired by him have built careers chasing viruses and attributing them to latent periods in order to connect them to noninfectious diseases.
SMON, the nerve-destroying disease that struck Japan during the 1960s, became one unfortunate example. Japanese virologists, greatly impressed with Gajdusek's accomplishments, spent years searching for slow viruses they presumed would cause the disease and thereby delayed finding the true cause - a prescribed medication.
Another example of a pointless virus hunt involved diabetes. Beginning in the early 1960s, some scientists tried to blame this noncontagious syndrome on the virus that also causes mumps. The evidence has been pathetically sparse, forcing virologists to point to occasional children who become diabetic after they have also suffered mumps or, if they really stretch their case, to argue that both mumps and diabetes become most common during the same annual season in one county of New York.
Having become soldiers without a war, veteran polio virologists invaded the diabetes field as well, proposing since the early 1970s that Coxsackie viruses may cause the disease. Antibodies against several strains of these harmless viruses, first discovered as by-products of polio research, have been found in a few diabetic children. But between 20 percent and 70 percent of young diabetics have never been infected, and the remainder have already neutralized the virus with their immune systems long before the onset of diabetes. Apparently, an equal percentage of non-diabetic children have also been infected with these Coxsackie viruses. Needless to say, none of the above viruses meets Koch's postulates for causing diabetes.
Hilary Koprowski, like Gajdusek, typifies the modern virus hunter. Although Koprowski's virology career began earlier, Gajdusek's work helped rescue Koprowski from the obsolescence that threatened polio researchers after the war on polio. Like so many of his colleagues, he found his newest calling in the war on AIDS.
Koprowski's work on viruses started at the Rockefeller Institute in New York. By the late 1:94os he moved across town to the Lederle pharmaceutical company, where he worked feverishly to develop a polio vaccine. By 1954 he had invented one, but Jonas Salk was announcing the field trials for another vaccine, and Koprowski's already-tested product was shunted aside by Salk's public acclaim. Koprowski left Lederle in I957 to take a position as director of the privately endowed Wistar Institute of Pennsylvania, where he began tests on humans and stepped up the campaign to get approval for his vaccine. By now Albert Sabin had tested his own polio immunization on millions of people in foreign countries, completely overshadowing Koprowski's equally successful but less-promoted vaccine. Nevertheless, Koprowski's day did arrive. His vaccine became the standard used by the World Health Organization in America during the late 1950s and 1960s.
In the meantime he spent several years studying the rabies virus and creating a vaccine against that virus, which attacks the brain and nervous system. But because rabies is relatively rare, Koprowski's vaccine never achieved the stardom of other immunizations. More important, however, his rabies research placed him squarely in the field of neurological diseases just in time to meet up with Gajdusek's kuru work. The news of slow viruses enticed Koprowski with visions of groundbreaking science. He quickly realized that the notion of slow viruses could become a useful tool, allowing him to source slow, noninfectious diseases to viruses, so long believed to be fast-acting agents. He participated as a "program advisor" in Gajdusek's first major conference on slow and unconventional viruses held in 1964 at the NIH head-quarters in Bethesda, Maryland. From that point forward, Hilary Koprowski joined the new virus-hunting trend from which he would never turn back.
His first big opportunity to take a crack at slow viruses came at the end of the 1960s. Subacute sclerosing panencephalitis (SSPE), a mouthful of a name for such a rare condition, attacks a small number of schoolchildren and teenagers each year, causing dementia, learning disabilities, and finally death. Doctors first recognized SSPE in the 1930s, and by the 1960s the virus hunters were searching for an SSPE germ. At that time, the most fashionable viruses for research belonged to the myxovirus family, which included the viruses that caused influenza, measles, and mumps. Animal virologists therefore started by probing for signs of myxoviruses. Excitement mounted after trace quantities of measles virus were detected in the brains of SSPE patients, and in 1967 most of the victims were found to have antibodies against measles. The facts that SSPE affected only one of every million measles--infected people and that this rare condition appeared from one to ten years after infection by measles were no longer a problem: Researchers simply hypothesized a one- to ten-year latency period. Little wonder they could also easily rationalize that one virus could cause two totally different diseases.
Koprowski's foray into SSPE research began in the early 1970s. He began isolating the measles virus from dying SSPE victims, a nearly impossible task because their immune systems had long before completely neutralized the virus (some SSPE cases, more-over had never had measles, merely the measles vaccine). His characteristic patience nonetheless paid off, yielding a tiny handful of virus particles from some patients that could be coaxed to begin growing again, if only in laboratory cell culture. In other patients only defective viruses that were unable to grow had remained so many years after the original measles infection. Rather than concluding the measles virus had nothing to do with SSPE, he employed the new logic of virus hunting to argue that a defective measles virus caused SSPE!
Koprowski continued this line of SSPE research for several more years. But in 1985 Gajdusek himself entered the SSPE fray, publishing a paper with leading AIDS researcher Robert Gallo in which they proposed that HIV, the supposed AIDS virus, caused SSPE while remaining latent. With hardly a blink, several leading virologists jettisoned the old measles-SSPE hypothesis in favor of a newly popular, but equally innocent, virus.
Multiple sclerosis (MS), the notorious disease that also attacks the nervous system and ultimately kills, has provided yet another opportunity for the virus hunters. First, they blamed the measles virus starting in the 1960s, since many MS patients had antibodies against the virus. Ten years later others suggested the mumps virus, which is similar to measles. The early I980s brought the coronavirus hypothesis of MS, the category of virus better known for causing some colds. In 1985, with Gajdusek stealing his thunder for SSPE, Koprowski also published a scientific paper that year in Nature with Robert Gallo, in this case arguing that some virus similar to HIV now caused MS. Unfortunately for Koprowski, even this hypothesis was abandoned within just a few years.
PHANTOM VIRUSES AND BIG BUCKS
Most virus hunters prefer chasing real, if arguably harmless, viruses as their deadly enemies. But Gajdusek's "unconventional" viruses - the ones neither he nor anyone else have ever found - have been making a comeback in recent years. Given the abundance of research dollars being poured into biomedical science by the NIH and other agencies, opportunistic virus hunters have been finding creative ways to cash in. One increasingly successful method utilizes modern biotechnology to isolate viruses that may not even exist.
Hepatitis, or liver disease, has yielded profitable virus-hunting opportunities in recent years. Hepatitis can be a truly painful affliction, starting like a flu but progressing to more severe symptoms, including high fevers and yellow skin. At least three varieties seem to exist. Hepatitis A is infectious, spread through unsanitary conditions, and is caused by a conventional virus. Hepatitis B also results from a virus (discovered in the 1960s) and is transmitted mostly between heroin addicts sharing needles, among sexually active and promiscuous people, or in the Third World from mothers to their children around the time of birth.
A third type of hepatitis was found in the 1970s, again restricted to heroin addicts, alcoholics, and patients who have received blood transfusions. Most scientists assumed these cases were either hepatitis A or B, until widespread testing revealed neither virus in the victims. Roughly thirty-five thousand Americans die each year of any type of the disease, a fraction of those from this "non-A, non-B hepatitis," as it was known for years. Today it is called hepatitis C. This form of hepatitis does not behave as an infectious disease, for it rigidly confines itself to people in well- defined risk groups rather than spreading to larger populations or even to the doctors treating hepatitis patients. Yet virologists have been eyeing the disease from the beginning, hoping one day to find a virus causing it.
That day arrived in 1987. The laboratory for the job was no less than the research facility of the Chiron Corporation, a biotechnology company located directly across the bay from San Francisco. Equipped with the most advanced techniques, a research team started its search in 1982 by injecting blood from patients into chimpanzees. None of monkeys contracted hepatitis, although subtle signs vaguely resembling infection or reddening did appear. For the next step, the scientists probed liver tissue for a virus. None could be found. Growing desperate, the team fished even for the smallest print of a virus, finally coming across and greatly amplifying a small piece of genetic information, encoded in a molecule known as ribonucleic acid (RNA), that did not seem to belong in the host's genetic code. This fragment of presumably foreign RNA, the researchers assumed, must be the genetic information of some undetected virus. Whatever it was, liver tissue contains it only in barely detectable amounts. Only about half of all hepatitis C patients contain the rare foreign RNA. And in those who contain it, there is only one RNA molecule for every ten liver cells - hardly a plausible cause for disease.
The Chiron team used newly available technology to reconstruct pieces of the mystery virus. Now they could test patients for antibodies against this hypothetical virus and soon discovered that only a slight majority of hepatitis C patients had any evidence of these antibodies in their blood. Koch's first postulate, of course, demands that a truly harmful virus be found in huge quantities in every single patient. His second postulate requires that the virus particles be isolated and grown, although this supposed hepatitis virus has never been found intact. And the third postulate insists that newly infected animals, such as chimpanzees, should get the disease when injected with the virus. This hypothetical microbe fails all three tests. But Koch's standards were the furthest thing from the minds of the Chiron scientists when they announced in 1987 that they had finally found the "hepatitis C" virus.
Now more paradoxes are confronting the viral hypothesis. Huge numbers of people testing positive for the hypothetical hepatitis C virus never develop any symptoms of the disease, even though the "virus" is no less active in their bodies than in hepatitis patients. And according to a recent large-scale study of people watched for eighteen years, those with signs of "infection" live just as long as those without. Despite these facts, scientists defend their still-elusive virus by giving it an undefined latent period extending into decades.
Paradoxes like these no longer faze the virus-hunting research establishment. Indeed, rewards are generally showered upon any new virus hypothesis, no matter how bizarre. Chiron did not spend five years creating its own virus for nothing. Having patented the test for the virus, the company put it into production and began a publicity campaign to win powerful allies. The first step was a paper published in Science, the world's most popular science magazine, edited by Dan Koshland, Jr., professor of molecular and cell biology at the University of California at Berkeley. Edward Penhoet, chief executive officer for Chiron, also holds a position as professor of molecular and cell biology at the University of California at Berkeley. The NIH-supported virology establishment soon lent the full weight of its credibility to the hepatitis C virus camp. As Chiron's CEO boasted, "We have a blockbuster product." A regulatory order from the Food and Drug Admin-istration (FDA) to test the blood supply would reap enormous sales for Chiron.
Their big chance presented itself in late 1988 as a special request from Japanese Emperor Hirohito's doctors. The monarch was dying and constantly needed blood transfusions; could Chiron provide a test to make sure he received no blood tainted with hepatitis C? The biotech company jumped at the opportunity, making for itself such a name in Japan that the Tokyo government gave the product its approval within one year. The emperor died in the meantime, but excitement over Chiron's test was fueled when the Japanese government placed hepatitis C high on its medical priority list. Chiron's test kit now earns some $60 million annually in that country alone. By the middle of 1990, the United States followed suit. The FDA not only approved the test, but even recommended the universal testing of donated blood. The American Association of Blood Banks followed suit by mandating the $5 test for all 12 million blood donations made each year in this country - raking in another $60 million annually for Chiron while raising the nation's medical costs that much more. And all this testing is being done for a virus that has never been isolated.
Profits from the test kit have generated another all-too-common part of virus hunting. With Chiron's new income from the hepatitis C test, Penhoet's company bought out Cetus, another biotech company, founded by Donald Glaser, who, like Penhoet, also holds a position as professor of molecular and cell biology at the University of California at Berkeley. And Chiron made an unrestricted donation of about 12 million to the Department of Molecular and Cell Biology at the University of California at Berkeley that generates $100,000 in interest each year.
Unfortunately for Peter Duesberg, who belongs to the same department, his supervisor is yet another professor who consults for Chiron Corporation - and displays little sympathy for Duesberg for challenging modern virus hunting by restricting his academic duties to undergraduate student teaching and by not appointing him to decision-making committees. Such conflicts of interest have become standard fixtures in university biology departments.
The modern biomedical research establishment differs radically from any previous scientific program in history. Driven by vast infusions of federal and commercial money, it has grown into an enormous and powerful bureaucracy that greatly amplifies its successes and mistakes all the while stifling dissent. Such a process can no longer be called science, which by definition depends on self-correction by internal challenge and debate.
Despite their popularity among scientists and their companies, "latent," "slow," and "defective" viruses have achieved only little prominence as hypothetical causes of degenerative diseases before the AIDS era. Their hypothetical role in degenerative diseases, which result from the loss of large numbers of cells, remained confined to rare, exclusive illnesses like kuru and hepatitis C.
However, because latent, slow, and defective viruses cannot kill cells, such "viruses" eventually achieved prominence as hypothetical causes of cancer and thus entered the courts of health care and medical research. The next chapter describes the terms under which these viruses were promoted as causes of cancer and how some of these terms were eventually used to promote latent, slow, and defective viruses as causes of degenerative diseases including, above all, AIDS.