And that returns us to the problem with the early-detection paradigm. Suppose we could install tiny sensors in people which 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 ten thousand 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.

“Hulk no can be mad at Mr. Puppy Face.” Facebook

Twitter

Email

Shopping

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 St. 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. ♦