by Sam Kean
It was an ingenious inversion of a classic experimental strategy. For decades, biologists have been altering a cancer cell’s genes and injecting the cells into a few standardized strains of mice. The “different cancers into same strain” experiments have allowed cancer biologists to observe how alterations in cancer genes might affect their growth, metabolism, and metastasis. But what effects might variations in the host’s genome have? Adams’s “same cancer into different strains” experiment switched the locus of attention from seed to soil.
In New York and Boston, meanwhile, researchers such as Joan Massagué and Robert Weinberg were also investigating “host factors.” In a suggestive experiment, Weinberg and his colleagues studied a cohort of mice whose lungs they had sprayed with thousands of dormant cancer cells. Some mice were exposed to an inflammatory stimulus—the kind that might occur during pneumonia, say—and only in those did the “micro-mets” wake up and turn aggressive. It called to mind a fascinating, if overlooked, experiment that Mina Bissell had done back in the 1980s. Researchers had known for generations that if you injected a chick’s wing with a certain cancer-causing virus a tumor would grow there. Bissell showed that, when you injected one wing and injured the other, this other wing would grow a tumor, too. On the other hand, if you injected a chick while it was an embryo, there would be no tumor at all. “Back then, it was fashionable to think of cancer only as an oncogene-driven automaton,” Bissell told me. “But here the automaton could be switched on and off by its local environment.” It wasn’t just the seed that mattered; changing features of the soil could affect whether it would ever germinate.
Massagué and his students were making advances of their own, notably in an experiment in which they depleted various types of immune cells in mice that carried dormant cancer cells. Some of these cell types belong to the “adaptive immune” system, which learns to identify new pathogens and to target them when they next appear. (The adaptive immune system, associated with T cells and B cells, is why vaccines work, and why people seldom get chicken pox more than once.) But the most striking effect occurred when the experimenters depleted another type of cell, the “natural killer,” or NK, cell. These cells belong to our “innate immunity”—they can’t learn anything new but arrive preprogrammed to destroy sick or aberrant host cells. Massagué’s team had implicated these cells as crucial surveyors and controllers of cancer metastasis.
Adams’s particular interest was in host genes, rather than cell types, that might affect metastasis. In early 2013, Louise van der Weyden, a postdoc in Adams’s lab who also happens to be his wife, created a suspension of mouse melanoma cells—a coffee-dark slurry—and injected it into a few dozen mouse strains. Some weeks later, she counted the number of visible mets in the lungs for each strain and rushed the data to Adams’s office.
Even within that small cohort, Adams recalled, the differences were obvious. Some of the mice had developed hundreds of mets—a fusillade of black pinpricks. In still others, the lungs had visibly blackened with metastasis. Yet some mice had developed just a few mets. Adams has a photograph of those mouse lungs above his desk. “Here was the same cancer exerting such different effects in different host environments,” he said.
Two years later, van der Weyden had inoculated 810 mouse strains with the melanoma cells and scrutinized the physiology of metastasis in each. Fifteen strains were either moderately or extremely resistant. Twelve of those 15 strains had gene variations that affected immune regulation, again suggesting the potent role of that system in a cancer’s ability to spread and invade. Even within the resistant group, one mouse strain stood out. Exposed to the dose of cancer cells used in the study, normal mice developed about 250 mets. Mice of this resistant strain, however, developed only 15 to 20 mets on average. And some of these mice hardly developed any mets at all; their lungs looked pristine and uncolonized even two months after the exposure.
Was this resistance to metastasis peculiar to melanoma, which is a type of cancer well known to provoke an immune response? Adams and van der Weyden tested three other types of cancer: lung, breast, and colon. In all of them, the mouse strain was resistant to the formation of metastases. Notably, the strain carries a variant in a gene called Spns2, which, through a cascade of events, increases the concentration of immune cells, notably NK cells, in the lungs—the very cells that Massagué’s lab had identified as a powerful restrictor of metastasis.
David Adams’s father never suffered a recurrence of melanoma; he died from prostate cancer that had spread widely through his body. “Years ago, I would have thought of the melanoma versus the prostate cancer in terms of differences in the inherent metastatic potential of those two cell types,” Adams said. “Good cancer versus bad cancer. Now I think more and more of a different question: why was my father’s body more receptive to prostate metastasis versus melanoma metastasis?”
There are important consequences of taking soil as well as seed into account. Among the most successful recent innovations in cancer therapeutics is immunotherapy, in which a patient’s own immune system is activated to target cancer cells. Years ago, the pioneer immunologist Jim Allison and his colleagues discovered that cancer cells used special proteins to trigger the brakes in the host’s immune cells, leading to unchecked growth. (To use more appropriate evolutionary language: clones of cancer cells that are capable of blocking host immune attacks are naturally selected and grow.) When drugs stopped certain cancers from exploiting these braking proteins, Allison and his colleagues showed, immune cells would start to attack them.
Such therapies are best thought of as soil therapies: rather than killing tumor cells directly, or targeting mutant gene products within tumor cells, they work on the phalanxes of immunological predators that survey tissue environments, and alter the ecology of the host. But soil therapies will go beyond immune factors; a wide variety of environmental features have to be taken into account. The extracellular matrix with which the cancer interacts, the blood vessels that a successful tumor must coax out to feed itself, the nature of a host’s connective-tissue cells—all of these affect the ecology of tissues and thereby the growth of cancers.
Cancers, like mussels, proliferate in congenial habitats, and, like mussels, they can create microenvironments that help them resist predators. Seed therapies kill cells—something like spraying a lake with a mussel poison. Soil therapies, by contrast, change the habitat. When I asked Adams about the kind of clinical trial that excited him because of its therapeutic potential, he discussed an unusual study in which patients who are diagnosed with a primary melanoma—such as his father—will donate blood so that researchers can identify their genetic markers and their immune-cell composition. By studying how they fare over time, we might learn which patient populations are particularly susceptible or resistant to certain cancers. We’d have a better sense of which patients need aggressive treatment. And we might learn something about how to treat them—how to alter a susceptible patient’s immunological and histological profile to resemble that of a resistant one.
“Cancer is no more a disease of cells than a traffic jam is a disease of cars,” the British physician and cancer researcher D. W. Smithers wrote in The Lancet, in 1962. “A traffic jam is due to a failure of the normal relationship between driven cars and their environment and can occur whether they themselves are running normally or not.” Smithers had overstepped in his provocation. The uproar that ensued was clamorous and immediate; Smithers complained that he had been “lacerated by Occam’s razor.” By arguing that cellular relationships were responsible for cancer’s behavior, he had committed the cardinal sin of multiplying the factors that oncologists had to consider. “To deny the importance of cells in tumor growth would be like denying the importance of people in some problem in sociology,” he later clarified. Cancer cells were a necessary condition for disease but not a sufficient one. His real aim was to get beyond oncology’s obsession with its internal-combustion engine—the cellular automaton and its genes—and on
ly since his death has the field started to come to grips with his message.
You ride the subway one morning. The train is delayed at 59th Street, and a man in a Yankees cap sneezes on you. At work later that week, you feel the chill entering you quietly, on little cat feet. You take a cab home, now sniffling, cursing the C line and retracing your steps: the culprit with the cap; the empty seat that should have raised suspicion; that slightly moist steel bar you should never have touched. What you do not think about are the six other passengers, sitting nearby, who also got sneezed on. None of them is sick.
This is medicine’s “denominator problem.” The numerator is you—the person who gets ill. The denominator is everyone at risk, including all the other passengers who were exposed. Numerators are easy to study. Denominators are hard. Numerators come to the doctor’s office, congested and miserable. They get blood tests and prescriptions. Denominators go home from the subway station, heat up dinner, and watch The Strain. The numerator persists. The denominator vanishes.
Why didn’t the denominators get sick? The pathogen exposure was the same; the hosts were different. Yet even the term pathogen is misleading. A pathogen is defined by its ability to be, well, pathogenic. That’s not an inherent attribute, however; it’s a relationship, an interaction with the host. Ruslan Medzhitov, an immunobiologist at Yale, has spent much of his life studying host-pathogen interactions. “You can inject the same virus into different hosts and get vastly different responses,” he says. It’s the soil that determines the nature of the illness.
And that returns us to the problem with the early detection paradigm. Suppose we could install tiny sensors in people that would regularly scan their blood to find circulating tumor cells, conducting an ongoing “liquid biopsy.” We’d be catching cancers earlier than ever before. But, as with the doctors in Seoul, we might also end up overtreating more cancers than ever before. That’s because circulating tumor cells might augur metastatic cancer in some patients, while in others the mets never seem to take hold. Why don’t the mets take hold? The old answer was: the cancer wasn’t the right kind of guest. The new question is: should we be looking, too, for the right kind of host?
A few months ago, a forty-year-old woman came to my office in a state of panic. She had had a hysterectomy as a treatment for endometriosis. Pathologists, examining her uterus postoperatively, had found a rare, malignant sarcoma lodged in the tissue—a tumor so small that it could not be seen on any of her preoperative scans. She had consulted a gynecologist and a surgeon, both of whom had recommended an aggressive procedure to remove the ovaries and the surrounding tissue—a scorched-earth operation with many long-term consequences. Once these tumors spread, they had reasoned, there’s no known treatment. Patients diagnosed with these sarcomas tend to have a sobering prognosis, with most surviving only two to three years after the symptoms appear.
But that’s a completely different scenario, I said to her. In her case, the tumor was detected incidentally. There were no symptoms or signs of the cancer. If we sampled 10,000 asymptomatic women, we have no idea how many such malignancies would be found incidentally. And we have no clue how those tumors, the ones found incidentally, behave in real life. Would the alliances formed between the woman’s tumor cells and her tissue cells enable widespread metastatic dissemination? Or would these encounters naturally dampen the growth of the tumor and prevent its spread? Nobody could say. We err toward risk aversion, even at the cost of bodily damage; we don’t learn what would happen if we did nothing. It was a classic “denominator” problem, but my response seemed supremely unsatisfactory.
She looked at me as if I were mad. “Would you sit and do nothing if someone found this tumor in you?” she asked. She decided to go ahead with the surgery.
Anna Guzello went in the opposite direction, as I recently learned when I checked back with her oncologist, Katherine Crew. Guzello had agreed to take the estrogen-blocker tamoxifen. But she refused chemo, and even Herceptin, despite being HER2-positive. Frustratingly, though, Crew wasn’t in a position to say with any confidence what was going to happen.
For decades, our standard explanation for those who make up our “denominators”—i.e., people who meet the criteria of the diagnostic test, who are at risk for a disease, but who may not actually have it—was stochastic: we thought there was a roll-of-the-dice aspect to falling ill. There absolutely is. But what Medzhitov calls “new rules of tissue engagement” may help us understand why so many people who are exposed to a disease don’t end up getting it. Medzhitov believes that all our tissues have “established rules by which cells form engagements and alliances with other cells.” Physiology is the product of these relationships. So consider our internal-denominator problem. There are tens of trillions of cells in a human body; a large fraction of them are dividing, almost always imperfectly. There’s no reason to think there’s a supply-side shortage of potential cancer cells, even in perfectly healthy people. Medzhitov’s point is that cancer cells produce cancer—they get established and grow—only when they manage to form alliances with normal cells. And there are two sides (at least) to any such relationship.
Once we think of diseases in terms of ecosystems, then, we’re obliged to ask why someone didn’t get sick. Yet ecologists are a frustrating lot, at least if you’re a doctor. Part of the seduction of cancer genetics is that it purports to explain the unity and the diversity of cancer in one swoop. For ecologists, by contrast, everything is a relationship among a complex assemblage of factors.
I talked to Anthony Ricciardi, professor of invasion ecology at McGill University, in Montreal. Ricciardi, a biologist, grew up on the banks of Lake Saint-Louis, which bulges out from the Saint Lawrence River—the route through which the mussels metastasized to the Great Lakes. “I was familiar with much of what was living in that lake, having played in it as a child and later studied it as a student,” he told me. “And I had never seen a zebra mussel before. Then, one day in June 1991, while I was working on a research project, I turned over a rock and there was one of them attached to it. It took me a few seconds to recognize what it was. And then I found a few more. That’s when I had a premonition of the invasion to come.”
I asked him why those freshwater mussels went into hyperdrive when they came to our lakes. “You’ve got to understand the dynamics of invasion ecology,” he said. “It’s a series of dice rolls. Most organisms introduced into a new environment will fail, often because they arrive in the wrong place at the wrong time. Vast, vast numbers will die. Piranhas were dumped into the lake for years, but they can’t establish, because the temperature isn’t right for them. People will release marine species like flounder, but the salinity isn’t right for them.” His language, even his tone, was eerily reminiscent of Joan Massagué’s; he might have been describing the waves of cellular death during the establishment of metastasis. “There isn’t one factor but a series of factors that determined how and why the mussels took hold,” he went on.
“But, over all, would you say the temperature of the water was the key?” I asked.
“The water temperature’s a factor. The water chemistry would also have contributed.”
“So a combination of the temperature and the salinity?”
“But also the calcium content. That’s absolutely important.”
I added that to my list of drivers: “Temperature, salinity, calcium . . .”
“And the fact that there weren’t any well-adapted predators. The native fish in these lakes will hardly touch the mussels. Neither will most ducks.”
“Ducks?”
He sighed, as if tasked with explaining an immensely complex theorem to a child. “There are many contributing factors, although some of these factors are clearly more important than others. There are probabilities attached. It’s all context-dependent.”
And so it went. For a cancer geneticist like me, it was an exercise in frustration. Every time I tried to pin down a principal cause for the Dreissena invasion, I was presented with
another contender. Disheartened, I gave up.
Perhaps we all gave up. Considering the limitations of our knowledge, methods, and resources, our field may have had no choice but to submit to the lacerations of Occam’s razor, at least for a while. It was only natural that many cancer biologists, confronting the sheer complexity of the whole organism, trained their attention exclusively on our “pathogen”: the cancer cell. Investigating metastasis seems more straightforward than investigating non-metastasis; clinically speaking, it’s tough to study those who haven’t fallen ill. And we physicians have been drawn to the toggle-switch model of disease and health: the biopsy was positive; the blood test was negative; the scans find “no evidence of disease.” Good germs, bad germs. Ecologists, meanwhile, talk about webs of nutrition, predation, climate, topography, all subject to complex feedback loops, all context-dependent. To them, invasion is an equation, even a set of simultaneous equations.
Still, at the ASCO meeting this June, on the shore of Lake Michigan, I was struck by the fact that seed-only research was increasingly making room for research that also sifted through soil, even beyond the excitement surrounding immune therapies. Going further and embracing an ecological model would cost us clarity. But over time it might gain us genuine comprehension.
Taking the denominator problem seriously beckons us toward a denominator solution. In the field of oncology, “holistic” has become a patchouli-scented catchall for untested folk remedies: raspberry-leaf tea and juice cleanses. Still, as ambitious cancer researchers study soil as well as seed, one sees the beginnings of a new approach. It would return us to the true meaning of “holistic”: to take the body, the organism, its anatomy, its physiology—this infuriatingly intricate web—as a whole. Such an approach would help us understand the phenomenon in all its vexing diversity; it would help us understand when you have cancer and when cancer has you. It would encourage doctors to ask not just what you have but what you are.
