The Coming Plague (40 page)
Authors: Laurie Garrett
Baltimore believed in oncogenes. He also believed that retroviruses were capable of inserting themselves permanently in animal germ line DNA, right alongside these oncogenes, and being passed on in that form via sperm or eggs to the next animal generation. In this way, he reasoned, virally induced cancers could be inherited. Baltimore cautiously predicted that human retroviruses would be found that, as theorized by Huebner and Todaro, triggered cellular oncogenes.
Having shared the 1975 Nobel Prize with Howard Temin and another leading microbiologist, Renato Dulbecco, Baltimore turned his attention broadly to the role of retroviruses and the more traditional RNA viruses in cancer.
“What is cancer?” he asked in 1978.
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“This question is at the heart of present efforts to control this disease, and the most manipulable model systems for studying it have been virus-induced cancers. That viruses cause cancer in animals is a certainty; that they do so in humans is less certain but probable.”
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“This question is at the heart of present efforts to control this disease, and the most manipulable model systems for studying it have been virus-induced cancers. That viruses cause cancer in animals is a certainty; that they do so in humans is less certain but probable.”
Temin and Baltimore, working independently, had already shown that two retroviruses caused cancer in animals: Rous sarcoma (in chickens) and Rauscher mouse leukemia viruses. Other animal retroviruses, by virtue of their ability to get inside and disrupt cellular DNA, were shown to be associated with cancer: avian leukosis virus (leukemia in chickens), Moloney leukemia virus (in mice), Kirsten sarcoma virus (in mice), Gibbon ape leukemia virus, cow and feline leukemia viruses, visna virus (in sheep), mammary tumor virus (in mice), and a host of so-called foamy viruses (found in monkeys, cats, and cattle).
Faced with these discoveries, Joshua Lederberg said that the only reasonable way to look at viruses was to recognize that “the very essence of the virus is its fundamental entanglement with the genetic and metabolic machinery of the host.”
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During the early 1980s, the genetic engineers discovered that those genetic entanglements could be deliberately manipulated in hundreds of different ways, allowing scientists to learn what tasks a given gene sequence normally performed by moving, switching off, turning on, or mutating that sequence. This could be done by inserting artificially constructed plasmids into cells, or by attaching genes to bacteriophagesâminuscule viruses that infect bacteria.
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In California, Michael Bishop and Harold Varmus were in pursuit of oncogenes. In their laboratories at the University of California, San Francisco, long-haired, bearded Michael Bishop and his taller, leaner bespectacled counterpart Harold Varmus formed a Mutt-and-Jeff team that zeroed in on the Rous sarcoma virus. It was such a potent cancer-causing agent that all chicken muscle cells in petri dishes could be transformed to cancer cells within twenty-four hours of infection. Researchers at Rockefeller University had previously discovered that the virus contained a gene they called src (for “sarcoma”) that seemed to cause the tumor transformation of infected cells.
Between 1976 and 1983, Bishop and Varmus discovered that
src
was, indeed, a potent cancer-causing virus product that was a near-duplicate of a gene normally present in chickens. To differentiate between the two, Bishop and Varmus designated the viral oncogene
v-src
and the normal cellular oncogene
c-src
.
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The pair of energetic young researchers then asked just how widespread was the
c-src
oncogene in the animal world. To the surprise of many, they quickly discovered
c-src
in the DNA of other birds, animals, insects, and humans.
9
src
was, indeed, a potent cancer-causing virus product that was a near-duplicate of a gene normally present in chickens. To differentiate between the two, Bishop and Varmus designated the viral oncogene
v-src
and the normal cellular oncogene
c-src
.
8
The pair of energetic young researchers then asked just how widespread was the
c-src
oncogene in the animal world. To the surprise of many, they quickly discovered
c-src
in the DNA of other birds, animals, insects, and humans.
9
Why would humans and chickens share a common geneâone that caused cancer, no less? Varmus and Bishop quickly discovered that
c-src
was the genetic blueprint for the manufacture of a protein that ended up nestling on the inner lining of the cell membrane. There, it acted as a kinase, chemically altering passing proteins by adding phosphate ions to specific amino acids. This radically changed the biochemical reactivity of the proteins, and the impact was so profound that nearly every aspect of cell
structure and activity was adversely affected. The discovery “sent the thrill of recognition down the spines of biochemists,” Bishop said,
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because they had long recognized that nearly every essential activity inside a human or animal cell was affected by phosphorylation.
c-src
was the genetic blueprint for the manufacture of a protein that ended up nestling on the inner lining of the cell membrane. There, it acted as a kinase, chemically altering passing proteins by adding phosphate ions to specific amino acids. This radically changed the biochemical reactivity of the proteins, and the impact was so profound that nearly every aspect of cell
structure and activity was adversely affected. The discovery “sent the thrill of recognition down the spines of biochemists,” Bishop said,
10
because they had long recognized that nearly every essential activity inside a human or animal cell was affected by phosphorylation.
Other researchers quickly discovered that the same pattern held true for a variety of cancer-causing retroviruses: the viruses carried genes that mimicked oncogenes that were commonly found in the DNA of all animals, humans, even insects. And those oncogenes controlled very powerful enzymes that could alter hundreds of different essential proteins inside cells, causing the cells to transform into cancer.
“The genes of retroviruses assume principles that are very similar to what we call jumping genes,” Varmus explained. “And they, too, have evolved mechanisms for getting around, for picking up new genes, for making mutations. And carrying out evolutionary changes.”
The retroviral genes “jumped” better along the cellular genome than did the “garden-variety oncogenes” inside the cell, Varmus asserted. And they had the ability to insert themselves into host DNA, reproduce right along with the host cell, and, as Varmus put it, “carry out God-knows-what.”
Scientists hypothesized that normally oncogenes were switched on only at given times in an animal's development. For example, as a fetus grew, such wild cellular activity might be key to its development from a fertilized egg to a baby.
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Bishop hypothesized that these oncogenes acted “as a keyboard on which many different carcinogens can play, whether they be chemicals, x-rays, the ravages of aging, even viruses themselves. With the revelation that there were a limited number of genes in cells that were affected, it became natural to see them as a keyboard on which many different causes of cancer play. It's not an endless keyboardâit's a keyboard of perhaps less keys than a standard piano keyboard. And out of this comes the manifestation of cancerâthe melody, if you wish. An enemy has been foundâit is part of usâand we have begun to understand its lines of attack.”
The discovery of oncogenes would cause a shift in thinking among cancer experts worldwide, prompting many to wonder for the first time just how many human tumors were started by microbes.
And, sure enough, in 1979 researchers at the U.S. National Cancer Institute, the Tokyo Cancer Institute, and Kyoto University discovered a retrovirus that caused cancer in human beings. Dr. Robert Gallo and his NCI colleagues found evidence of a virus inside the T cells (disease-fighting white blood cells) of a twenty-eight-year-old African-American man who had come to Bethesda, Maryland, in 1979 from his Alabama home for experimental cancer treatment. The NCI group quickly found two other individuals who suffered T-cell lymphomas and seemed to be infected with a virus: an immigrant woman from the Caribbean and a Caucasian man who had traveled extensively in the Caribbean and Asia.
Two years earlier Kiyoshi Takatsuki, an epidemiologist with the Tokyo
Cancer Institute, had discovered groups of people living on outer Japanese islands who apparently had cancer involving their immune systems' T cells.
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The Japanese researchers dubbed the disease adult T-cell leukemia or ATL. Gallo's laboratory isolated their virus and named it HTLV, or human T-cell leukemia virus.
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The Gallo group also identified the existence of an oncogene in the HTLV virus that gave the microbe the ability to produce leukemia.
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Attempts at collaboration between the Japanese and American researchers went awry and Yorio Hinuma and Mitsuaki Yoshida of Kyoto University announced discovery of a different virus in the Japanese leukemia patients, named ATLV, or adult T-cell leukemia virus.
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Cancer Institute, had discovered groups of people living on outer Japanese islands who apparently had cancer involving their immune systems' T cells.
12
The Japanese researchers dubbed the disease adult T-cell leukemia or ATL. Gallo's laboratory isolated their virus and named it HTLV, or human T-cell leukemia virus.
13
The Gallo group also identified the existence of an oncogene in the HTLV virus that gave the microbe the ability to produce leukemia.
14
Attempts at collaboration between the Japanese and American researchers went awry and Yorio Hinuma and Mitsuaki Yoshida of Kyoto University announced discovery of a different virus in the Japanese leukemia patients, named ATLV, or adult T-cell leukemia virus.
15
Ultimately, Mitsuaki Yoshida led a Tokyo Cancer Institute study in 1980 that compared ATLV and HTLV and found them identical. They furthermore showed that Japanese monkeys (
Macaca fuscata
), Indonesian rhesus monkeys, and African green monkeys captured in Kenya and held in captivity in Germany had antibodies to ATLV/HTLV, and that the virusâor a monkey version of the human virusâcould be transmitted from one cocaged animal to another.
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The finding posed several questions, the researchers wrote, including “Are monkeys the natural reservoir of ATLV? Is ATLV transmissible from monkeys to humans through a certain vector? What is the mode of infectious transmission of ATLV in monkeys?”
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The finding, and questions it posed, would be echoed with other diseases in coming years.
Macaca fuscata
), Indonesian rhesus monkeys, and African green monkeys captured in Kenya and held in captivity in Germany had antibodies to ATLV/HTLV, and that the virusâor a monkey version of the human virusâcould be transmitted from one cocaged animal to another.
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The finding posed several questions, the researchers wrote, including “Are monkeys the natural reservoir of ATLV? Is ATLV transmissible from monkeys to humans through a certain vector? What is the mode of infectious transmission of ATLV in monkeys?”
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The finding, and questions it posed, would be echoed with other diseases in coming years.
The following year, 1981, David Golde at UCLA found a patient who was suffering from a particularly aggressive type of blood cancer, hairy-cell leukemia, so named because the damaged white blood cells appeared “hairy” under the microscope. Golde discovered that something in the blood of this patient was capable of producing the “hairy” effect on human T-cell lymphocytes grown in the laboratory. Golde named the patient's cell line MO.
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Several scientists wondered why Golde's cell line grew so well in test tubes, since heretofore it had been nearly impossible to raise human T cells in the laboratory. Robert Gallo and UCLA's Irvin Chen both thought the lab growth capability plus evidence that “something” from the MO cells could transform other human lymphocytes indicated that an infectious cancer-causing agent was involved.
The hunt was on.
Chen discovered a second cancer-causing retrovirus in the MO cells, which was dubbed HTLV-II (Gallo's first virus was then redesignated HTLV-I).
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Chen concluded that HTLV-II had no oncogene, however, and the cancerous behavior of the MO cells seemed to be caused by a defective form of the virus that had emerged in the laboratory as a result of culturing conditions. The finding was confirmed within weeks in three other laboratories.
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Chen concluded that HTLV-II had no oncogene, however, and the cancerous behavior of the MO cells seemed to be caused by a defective form of the virus that had emerged in the laboratory as a result of culturing conditions. The finding was confirmed within weeks in three other laboratories.
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The impact of these findings was striking. The U.S. National Cancer Institute, for example, would quickly shift resources toward cancer virology,
encouraging scientists to search for other cancer-causing human viruses and to further elucidate the link between oncogenes and microbes.
encouraging scientists to search for other cancer-causing human viruses and to further elucidate the link between oncogenes and microbes.
“We have found oncogenes. We have sequenced those oncogenes. And we have learned that we have these genes in our human genomes normally. That's both frightening and exciting,” National Cancer Institute director Dr. Vincent De Vita said in 1981. “We've put one billion dollars into viral oncology research. Jim Watson asked me to say was it useful or not. What value would I place on it? Every nickel we've spent or committed so far has been worth it. We've had dividends beyond imagination.”
That year De Vita ordered all the work in the NIH's Frederick Laboratory facility switched to the pursuit of links between viruses, oncogenes, and cancer. Thanks to the new molecular biology technologies, it was now possible to conduct such searches with a reasonable degree of speed and efficiency. One segment of known DNA or RNA from, for example, HTLV-I could be used as a probe to search quickly for the presence of its genetic mates in all sorts of animal and human cells.
The notion that cancer could result from a contagious process was extraordinary, particularly in view of how hard cancer patients and scientists had fought for centuries to dispel precisely that notion. Ever since medical science had learned to differentially diagnose cancer, people had feared the disease's victims. Prejudice and shame often went hand in hand with the biological horrors of cancer.
That cultural perspective had begun to shift in the 1960s when the public recognized the link between cancer and a host of chemical toxins, particularly those contained in smoked tobacco. While fears of contagion were erased, they were replaced by apprehension and a considerable amount of anger directed at the sources of chemical carcinogens.
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During the mid-1970s, most Western countries had erected government infrastructures devoted to the regulation and control of human exposure to such chemical carcinogens, monitoring food, water, air pollution, pesticides, auto emissions, industrial waste, housing materials, and so on.
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During the mid-1970s, most Western countries had erected government infrastructures devoted to the regulation and control of human exposure to such chemical carcinogens, monitoring food, water, air pollution, pesticides, auto emissions, industrial waste, housing materials, and so on.
By the time molecular biologists zeroed in on oncogenes and retroviruses, the political and consumer power of the environmental movement was quite considerable, particularly in North America and the Scandinavian countries. That explains Michael Bishop's hesitancy to overemphasize the role of viruses in causation of human cancers. His “keyboard” metaphor for triggering oncogenes with a variety of carcinogensâhormones, chemicals, and microbesâwas an important way to reconcile the previous emphasis on chemical origins of cancer with the new insights into viral mechanisms of pathogenesis.
In years to come epidemiologists would strive to understand how such viruses were spread, who gave HTLV-I, for example, to whom. Japanese and German researchers would discover antibodies to HTLV-I in African monkeys and chimpanzees, as well as hunters in Kenya.
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It would quickly be apparent that HTLV-I infections of human beings were clustered in
populations not only in Japan
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and the Caribbean
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but also in Surinam
25
and Italy.
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It would quickly be apparent that HTLV-I infections of human beings were clustered in
populations not only in Japan
23
and the Caribbean
24
but also in Surinam
25
and Italy.
26
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