Later, Hunter and other researchers realized that the middle T protein he’d been studying was not actually a purified single protein, but rather was contaminated with other proteins, a common occurrence in lab research at the time. It wasn’t middle T that was the kinase, it was the contaminant. But that realization didn’t alter the shock of finding tyrosine on the receiving end of a phosphate. Hunter’s discovery had turned everyone’s attention to this once-ignored amino acid called tyrosine, and that was what mattered. A new concept had been born: Tyrosine kinases were major determinants in driving the growth of cells, including malignant ones. This understanding would prove to be a major step forward for cancer researchers. In the hunt for cancer’s underlying mechanism, finding tyrosine was like a tracker finding an animal’s footprint or a broken branch. They knew they had caught the right trail.
BACK IN SCOTLAND, Lydon continued his postdoctoral work at Dundee and continued to absorb all he could about kinases from the lab next door until 1982. By that point, having spent most of his life in Scotland and northern England, he was ready for warmer, if not greener, pastures, and he accepted a job at Schering-Plough, the Paris-based pharmaceutical company. His boss was a medical doctor from Switzerland named Alex Matter.
As Lydon was finishing up at Dundee, Druker was in his first year of medical school and taking a course on the history of cancer therapy. He slowly began musing about what it would take to improve cancer treatment, wondering whether it might be possible to create medicines that affected cancerous cells differently from how they affected normal cells.
Like pieces on a chessboard assembling for checkmate, discoveries and researchers were slowly coming together. The mutant chromosome, the translocation, the tyrosine kinase. Nick Lydon, Alex Matter, Brian Druker. The next advancing move came from a colony of mice in Bethesda, Maryland.
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A CHEMICAL AMPUTATION
In 1965, Herb Abelson was in his mid-twenties and had just graduated from medical school, and he had a serious problem. He was a prime candidate to be drafted to serve as a general medical officer for the Vietnam War. But Abelson was vehemently against the war and had no desire to be shipped off to the jungles of Southeast Asia. Yet he also had no desire to flee to Canada. The solution was to join either the Coast Guard or the National Institutes of Health.
During the war, the National Institutes of Health (NIH) became a refuge for smart medical doctors like Abelson who did not want to serve overseas. Employees at the NIH were part of the Public Health Service, which was considered a military position. A doctor working there could safely avoid being sent to Vietnam. With approximately 15,000 med school graduates and only 100 NIH job openings, it was the cream of the crop that ended up there. This hotbed of talent ended up making enormous strides in the treatment and understanding of cancer, as well as many other diseases. Considering the circumstances leading to his NIH arrival, the contribution Herb Abelson was about to make to the understanding of how CML develops and the leap in cancer treatment that ultimately resulted from that explanation could easily never have happened.
Fortunately, his arrival at the NIH also coincided with an era of solid support for young scientists with new ideas. In today’s risk-averse climate, the average age of a first-time National Cancer Institute grant recipient is in the early forties, with younger applicants routinely denied funding to investigate new ideas. In 2010, less than 4 percent of R01 grants—the oldest and most common NIH award, for up to $250,000 per year up to five years—went to scientists under age 36. The average age of R01 recipients has continued to increase during the past thirty years, even as the average age of newly minted PhDs has remained constant. But conditions and caution were quite different in the 1960s and ’70s. Abelson, like Nowell and Hungerford, was young at a time when youth was considered an advantage in making medical breakthroughs.
Abelson was assigned to work under a biologist named Jack Dalton, who had a hands-off style that left his charges free to pursue whatever struck their curiosity. Like Rous fifty years earlier, Abelson was particularly curious about viruses that caused cancer.
The world already knew a lot about viruses by the time Abelson came to the NIH. Most crucial here was the fact that although viruses, which can’t reproduce on their own outside of a host, don’t qualify as living things, they do have genetic material. Once a virus finds its way inside a living being, be it plant, animal, or human, that genetic material is replicated over and over. Sometimes, such as with HIV, the virus that causes AIDS, that replication, left untreated, eventually kills the host. Other times, the body eradicates the virus on its own, as is usually the case with the influenza virus. Sometimes, the host grows accustomed to a virus, its presence proving undisruptive to the host’s normal goings-on.
But many other crucial facts had not yet come to light when Abelson joined the NIH. Temin had not created his focus assay or found the hidden mechanism that allowed RNA viruses to replicate. Erikson had not yet identified the protein made by the killer gene in RSV, and Hunter had not uncovered tyrosine’s involvement in cancer. No one had a clue about the cellular origin of oncogenes. The chromosome banding techniques that would allow Rowley her seminal observation were nonexistent. These three threads of research—the Philadelphia chromosome, the role of kinases in cancer, and the source of the cancer-inducing gene in cancer-causing viruses—remained utterly distinct. And the research Abelson was about to begin was another completely unrelated strand of science. He was interested in pulling apart the process by which viruses caused cancer, charting their course inside a cell. That investigation wasn’t necessarily about genes. For Abelson, it wasn’t necessarily about anything more than asking a question and seeing where his attempt to answer it would lead.
Elsewhere at the NIH, other draft avoiders were experimenting with toxic chemotherapy regimens, desperate for some step forward in the treatment of cancer. Cancer treatment had gained significant ground since the introduction of corticosteroids (synthetically manufactured versions of hormones produced by our adrenal glands) and antifolates (drugs that thwart folic acid, a chemical essential to the production of DNA) in the 1940s. These chemicals extended the survival time for many cancer patients, though always incrementally. Any attempt to improve treatment by combining drugs was trial by error, trying different drugs given in varying regimens and waiting to see what happened. At the NIH, determined doctors injected patient after patient with one concoction after another, hopeful that each new mix would be better at killing the cancer without killing the patient. Behind thin curtains, patients moaned in their hospital beds, either from the pain of the cancer expanding in their bodies or the toxic side effects of the drugs. Though strides were made during those years that would help steer decades of cancer care to come, frustration was much more common than success.
Far from those hallowed halls, Abelson was busy at the lab bench, where he homed in on the Moloney virus, which caused leukemia in mice. Moloney virus is what’s known as a simple RNA virus. Simple RNA viruses, which often cause cancer, come in two varieties. One type contains all the genes required for replication. These viruses often cause tumors in animals, and are found most commonly in domesticated animals such as cats, food animals such as chickens, and laboratory animals. Almost always, the virus is found because of the tumor it causes; pet owners, farmers, and scientists see the lesions, not the infection. The viruses do exist in the wild but are encountered less frequently because the close contact required to spot them is much rarer. These tumors usually have a long latency period; they are very slow to induce disease.
The second type of simple RNA virus is less common but carries a more immediate danger to its host. These are the viruses that, when they replicate, capture genes from the host. By the time the virus infects a new host, though, the captured gene has become an oncogene. RSV was an example of this simple RNA virus. The virus had captured src from a host during replication, and once inside the viral genome, the gene had become
an oncogene that caused cancer in chickens. This transport, a hostage from one ship who turns criminal by the time of the next piracy, was the process that Bishop and Varmus would spot with their radioactive DNA flashlight, the src probe that had enabled them to find the normal, proto-oncogene version of src in the genome of healthy chickens, the very animal later infected by a virus containing a cancer-causing version of src.
When Herb Abelson was deep into his lab work at the NIH in the 1960s, he knew nothing about this. The concept of oncogene capture was years away. In fact, the very notion of oncogenes—healthy genes with the capacity to turn malignant—was a completely foreign concept to lab researchers like Abelson. He knew about the common simple RNA viruses; he was using one in his experiments. He knew nothing about the rarer kind that could lift a gene from its host and thereby trigger a deadly disease. But he was about to witness one taking over his colony of mice.
EVERY VIRUS HAS a target cell type, a certain organ that it most wants to infect. Abelson knew that the Moloney virus hit the thymus gland first. From there, a type of leukemia called lymphocytic leukemia—a cancer of the T-cell portion of the immune system—spread to the rest of the body.
Abelson wanted to see if he could get the virus to target a different part of the mouse’s body—if he could, as the science jargon goes, “increase the host range” of the virus. If the road was blocked, would the driver find an alternative route or just call it a day? The reason for the experiment was simple: He was curious. He had an inkling that testing whether he could force the virus into a new path of attack might show him something about how cancer happens, though he wasn’t sure what.
He injected 163 newborn mice with prednisolone, a powerful steroid that shrinks the thymus and other parts of the immune system. He was chemically amputating the thymus from the mice. Then, when the animals were between one and eight weeks old, he injected them with Moloney virus. Without the thymus present, what kind of cells would the virus gravitate toward? Would it replicate in another part of the body, or would it fail to infect, leaving the mice cancer free?
In the days that followed, Abelson visited his mouse cages looking for signs of cancer, his heavy brow still as he took each animal in his hands to peer through its fur. Leukemia developed in more than 100 animals. Twelve of the mice developed lymphosarcomas, hard tumors in their lymph nodes, where lymph, part of the immune system, gathers. “That was pretty unprecedented,” said Abelson. “These large tumors had never been seen.” The cancer was affecting the B cells of the immune system instead of the T cells, the original target. What’s more, unlike the slow-growing cancer caused by the Moloney virus, this malignancy developed rapidly, with a startlingly short latency period. All of the animals were dead within weeks.
B cells and T cells are lymphocytes, one of the varieties of white blood cells that make up the immune system. Both B and T cells have receptors on their surface that recognize foreign substances, called antigens, with each receptor tuned to a different antigen. But though their functions overlap, B and T cells are distinctly different. The majority of T cells are either helpers or killers, the helpers triggering the killers into action to annihilate invaders like viruses, some bacteria, and some cancer cells. Helper T cells can also activate B cells, which produce bacteria-fighting antibodies and new immune cells that remember new invaders. B and T cells also reside in different parts of the body. B cells grow entirely in the bone marrow, whereas T cells, though sprouted in the marrow, mature in the thymus. Their differences in function and location are such that a virus that causes cancer in T cells does not necessarily have the same ability in B cells. So finding B-cell cancer in mice injected with a virus known to cause T-cell cancer was very odd.
Abelson wanted to know more about the anomalous hard nodules that had grown in the lymph nodes of some of the mice in his colony. Was the virus inside the mice still Moloney or was it something different? Was the virus able to cause a different type of cancer when its usual pathway was thwarted, or had the virus itself been altered when it infected the chemically amputated mice, changed irrevocably into a deadly new virus that killed mice far more rapidly than its predecessor? To find out, he would inject that extracted virus into new mice—thymuses intact—and see what kind of cancer they got.
Abelson extracted tumors from a few of the lymphosarcoma mice and passed them through filters so fine that only the virus would pass through. Abelson infected a new, healthy colony of mice with the purified sample. Then he waited to see what kind of cancer would develop. If they got slow-growing thymus cancer, Abelson could be fairly certain that the Moloney virus had come through the experiment unscathed, and that, simply, in the absence of a thymus to land on, the virus had entered another cell type; it had taken the alternative route. But if the healthy mice still got tumors in their B cells—the type of immune cell in which cancer had arisen in the chemically amputated mice—then the virus couldn’t possibly be the same one he’d started with.
The answer came quickly: All of the mice developed B-cell tumors. Again, they were dead within weeks. Clearly, the agent he’d injected into the second colony wasn’t the Moloney virus. It was something different, some altered version. Abelson had found a new virus.
Eventually, the Abelson virus, as it came to be called, would play a central role in the story of the Philadelphia chromosome and CML. The virus was a valuable research tool not so much because of the cancer that it caused but rather because it gave scientists a controlled way to study how cancer develops. There were three key features that made the virus the perfect model for exploring cancer transformation. First, its pedigree was known, so there were no questions about where the virus had come from that might cast doubt on promising research findings. Second, the virus caused cancer that progressed rapidly, allowing experiments to be completed in weeks or months rather than years. Third, the cancer it caused was one of the blood, easier to study than solid tumors of internal organs because they can be extracted with syringes rather than with surgery.
In 1969, when Abelson presented his work at the annual meeting of the American Association of Cancer Research (AACR), the significance of the virus was wholly unsuspected. In fact, the response belittled his findings. Some more seasoned researchers criticized Abelson for playing around in the lab when he should have been dutifully studying the scientific literature and following a more well-worn path. “I was berated by the president of AACR, and disparaged about it,” Abelson recalled.
But much like David Hungerford with his predilection for recording his observations simply for the sake of recording them, Abelson wasn’t worried about where his work was leading to, and neither were his supervisors or those providing the money. It was enough that the science was solid, that it answered some questions and raised new ones.
And it turned out that Abelson wasn’t really interested in pursuing those questions any further. Rather, he found himself gravitating toward treating pediatric cancer, and so, in the early 1970s, he left the NIH to complete his medical training at Boston Children’s Hospital.
He still yearned for the excitement of laboratory research, though, and didn’t want to cut himself off completely from that kind of work. So he joined a lab at MIT, across the river in Cambridge, where he worked during his residency. He stored away his samples of the virus that now bore his name and moved on to other pursuits.
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STRIPPING AWAY THE FUR AND THE FAT
One floor below Abelson’s new lab bench, David Baltimore was feeling impatient. Fresh off his and Howard Temin’s groundbreaking discovery of reverse transcriptase—the enzyme that enabled RNA-based viruses to convert their genetic information into DNA that could then be replicated inside a host—he was eager to put the finding to good use.
Locating the mechanism that enabled RNA viruses to replicate portended a new era for understanding cancer because it created the ability to investigate those viruses at the molecular level. “I was convinced that mouse viruses were
going to make the difference, that the ability to manipulate the genetics of the mouse gives you a research range that you can’t get any other way,” said Baltimore. “But having had no experience with such viruses, I didn’t have a system to work with, and I didn’t know what system would be best.” Each step forward in this uncharted terrain meant inventing new steps, new ways to grab hold of the landscape, new methods for tilling the earth. Cloning held so much possibility for studying how cancer occurred, but researchers had to find ways to exploit the technology first.
Whereas the Colorado-based lab of Ray Erikson—the man who, with Marc Collett, had discovered the Src kinase encoded by the cancer-causing src gene in the Rous sarcoma virus—was infused with the slow pace of his country upbringing, leaving him contented with taking seven or eight years to answer a question, Baltimore, born and raised in New York City, valued quick results. “Life is too short to sit around for years and years to get an answer to anything,” said Baltimore. “Simplicity and speed are things you don’t hear a lot about, but to me, they are central elements to research.” Now determined to exploit reverse transcriptase as a cancer research tool, Baltimore—whose success had already brought him renown, with the funding and resources to prove it—stocked his lab with postdoctoral talent that would help him gain ground quickly.
When Naomi Rosenberg joined the Baltimore lab in 1973, she wasn’t particularly interested in reverse transcriptase. The first person in her rural Vermont family to attend college, Rosenberg’s early childhood interest in science had withered during boring high school classes. Later, having come to terms with the slim career options afforded by her chosen college major of Latin, she decided to give biology another try. She was hooked. Veering far from the paths of her cabinet-maker father, pottery-making mother, and poetry-writing brother, Rosenberg found her calling in the microscopic world of viruses. “The idea that something so small could have such devastating consequences—I just find it fascinating,” Rosenberg said.
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