remember brian’s song?

maladies_coverHistorical records of cancer date to 2500 BC, when tumors were described in a medical compendium compiled by Imhotep. Under the heading Treatment, he states ominously “there is none.” That is where the recorded human history of cancer starts, and in three millennia it didn’t get much better: a 1760s text lists “remote sympathy” as treatment.

By the late 1800s, surgery was the primary treatment option for some cancers. Whereas the emphasis had once been on a surgeon’s speed—to reduce the conscious patient’s suffering—the introduction of anesthetics meant surgery could semi-humanely last for hours. Unsurprisingly, doctors found all manner of ailments that could now be cured through the applications of surgical touch; cancer was just one of them.

Noting that cancers often recurred after mastectomies, surgeons of the late 19th and early 20th centuries began removing more and more tissue in the hopes of clearing all the cancer. It was a gruesome contest and destructive game of one-upsmanship. In radical mastectomies, surgeons removed chest muscles, lymph nodes, bones—as much tissue as they could without killing the patient; survivors, lacking postural muscles, were left with a peculiar slouch and concave chest. That this happened was awful enough, but what’s worse is that the radical surgeries didn’t help: if the cancer had not yet metastasized, even a “lumpectomy” was effective; if it had metastasized, even the most radical of surgeries was unlikely to remove it all.

Surgery was not a panacea, and one reason cancer is difficult to cure is that it has a more diffuse and amorphous cause than most diseases. We all carry genes that are precursors to cancer. Occasionally cell mutations cause those genes to be activated, potentially leading to unchecked cell growth and cancer. But we also have the opposite: genes that stop or slow tumor growth; mutations can sometimes cause these tumor suppressors to become inactive. This means that what we call cancer is not a unitary thing in the way that “the flu” is infection with an influenza virus; cancer is a heterogenous and idiosyncratic bundle of cell mutations, including those that cause unchecked cell growth and those that destroy tumor suppressing cells. No two cancer cases are the same, because each cancer is a web of mutations accumulated from multiple rolls of the genetic dice.

Consider a hypothetical cancer case. An asbestos particle is inhaled, which causes localized inflammation and swelling, leading to a mutation in a single lung cell that, a decade later, causes unchecked cell growth. Our hypothetical person is a smoker, so a second mutation occurs elsewhere in the lungs. Later they have some chest x-rays taken, leading to a third mutation. Still later, another mutation occurs that makes the cells mobile, and the cancer mestatasizes. It’s treated by chemotherapy, which kills almost all the cells but for a few that develop mutations making it resistant to the chemo drug, and the cancer returns.

That last part is important (and to me, novel). I assumed that when cancer recurred, it was because the drugs did not entirely clear the cancer. This is true in a literal sense, but it’s not necessarily the case that the dose wasn’t strong enough to eradicate it: instead, chemical-resistance mutations might have rendered the drug ineffective, even at larger doses. The importance of “identifying cancer early” is not just because metastasized cancer is diffused, but because by the time it metastasizes there are so many mutations built up that we might not be able to account for them all in treatment.

However, in some cases we actually can unravel those mutations. The underlying genetic cause of some forms of cancer has been identified, in which case even advanced and metastasized cancers can sometimes be reversed. In the future, cancer treatments will likely be individualized: we’ll genetically sequence each patient’s cancer, identify the mutations, and develop a combination of treatments targeted to that specific “brand” of cancer. Each combination of mutations—and thus each particular treatment—may be totally novel and never seen again.

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In public health, “cures” alone do not solve epidemiological problems. Treatments for cholera and tuberculosis were discovered in the 20th century, but incidences of those diseases were already decreasing by the end of the 19th century as preventative measures were implemented. But the causes of cancer are more indirect and delayed than the causes of cholera and tuberculosis. John Snow needed a few days of work to isolate the Broad Street pump as the source of the cholera epidemic; to figure out that smoking increases rates of lung cancer, we needed epidemiological statistics collected across decades.

Sometimes we can determine some very specific preventative measures: stop smoking or stop being a chimney sweep (one of the first people to identify carcinogens discovered that chimney sweeps had a high frequency of scrotal cancer, because soot would get buried deeply in their nether regions, where it would stay for weeks, months, or years, eventually causing skin cancer). But carcinogens don’t really “cause” cancer in the same direct way that influenza viruses “cause” the flu. You might develop lung cancer decades after you inhale some asbestos particles, but in truth all those asbestos particles did is increase the likelihood of cell mutations leading to cancer, and it’s typical that multiple cell mutations are required for cancer to grow—that is, we need a mutation that unleashes cell growth to happen in concert with another mutation that deactivates genes that regulate tumor suppression. Did asbestos cause that hypothetical person’s cancer, if asbestos was responsible for only one of multiple mutations? This sort of diffusion—temporal and causal—I think, makes cancer hard to wrap your head around, in the same way we’re bad at intuiting the power of compound interest; it just doesn’t mesh with the timescales and 1:1 correspondence we can grasp intuitively.

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Side note I: Some cancers have unexpected treatments. The prostate depends on testosterone, meaning that some prostate cancers can be treated by castration. Likewise, some breast cancers can be treated by removing the ovaries (or any other means of blocking estrogen). These facts are interesting on their own, but what’s real mind-blowing is that the first doctor who treated breast cancer by removing ovaries did so (a) before anyone had a good idea what the ovaries actually did, (2) before estrogen had been discovered, and (d) based only on information he’d gotten from Scottish farmers, who had gleaned a relationship between cow ovary health and milk production.

Side note II: Many moons ago, tobacco industry scientists famously performed studies where tar from cigarette smoke was painted on the backs of mice, who developed tumors. In the 1980s, when cigarette manufacturers were being sued, a corporate honcho claimed—in court and under oath—that millions of dollars had been spent on these studies to “try to reduce tumors on the backs of mice.” I love the audacity of that lie.


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