The Pill That Could · Philadelphia, 1960

Philadelphia, 1960, part 2

Four years old, because in 1956 a Swedish-Indonesian team — Joe Hin Tjio and Albert Levan — had published a paper showing that humans have forty-six chromosomes. This was a surprise. The textbooks of the time said forty-eight. They had said forty-eight for decades. The number had been counted, by various people using various methods, and they had all gotten forty-eight, and it had become one of those facts that everyone knew and no one rechecked. Tjio and Levan, working with a hypotonic-shock technique that swelled cells and spread their chromosomes apart cleanly, recounted, and got forty-six, and were right. (The earlier counts had been done on cells in which the chromosomes were too clumped to count accurately, and people had simply miscounted, repeatedly, in a direction that subsequent counts then anchored to.)

So as of 1956, the field knew how many chromosomes a human has. As of 1959, in a paper by Jérôme Lejeune in France, the field knew that one extra copy of chromosome 21 produced Down syndrome — the first time a specific chromosomal abnormality had been linked to a specific human condition. As of 1960, the field had a few methods for getting cells to divide and for spreading and staining their chromosomes. It had a small number of practitioners, mostly young, mostly working in just a few labs around the world.

It did not have, at this point, any clear understanding of what chromosomes had to do with cancer.

* * *

Cancer, in 1960, was understood in broad strokes and almost no detail.

The broad strokes were these. Cancer is a disease of the body's own cells. A cell that is supposed to grow only in certain circumstances starts growing in others; a cell that is supposed to die at a certain point doesn't; a population of these cells expands, takes up space, interferes with the work of organs, and eventually kills the person. Different cancers come from different starting cells — leukemia from blood-forming cells, breast cancer from the cells lining the milk ducts, and so on — and behave differently because of it. Some cancers are linked to specific exposures: tobacco smoke and lung cancer; certain chemical dyes and bladder cancer; ionizing radiation and basically everything. Some cancers are linked to viruses, at least in animals. (Peyton Rous had shown in 1911 that a virus could cause a tumor in chickens, a finding so far outside the conventional wisdom that it took the field about fifty years to take seriously.) Some cancers run in families.

What the field did not have, in 1960, was a mechanism. There was no agreement on what was actually happening, at the level of the cell, when a cell turned cancerous. The major hypotheses were several. Maybe cancer was a virus, like Rous's sarcoma virus, that just hadn't been found in most cancers yet. Maybe it was something about cellular metabolism, a permanent shift in how a cell handled energy. Maybe it was a mistake in the body's defenses, an immune system failing to recognize and kill abnormal cells. Maybe it was something genetic, written into the DNA, although what exactly might be written there and how it would have gotten there were not at all clear.

There was an old hypothesis, sitting in the literature, due to a German biologist named Theodor Boveri. Boveri had proposed in the early 1910s, working with sea urchin eggs, that abnormalities in the chromosomes might cause cells to behave like cancer cells. It was a careful argument, made on the basis of clean observations, and it had aged reasonably well. It was not, however, an argument anyone was actively pursuing in 1960. Boveri had died young; the methods to test his idea in human cells had not existed for most of the intervening half-century; and the consensus, to the extent there was one, was that cancer was probably more complicated than that.

Then, in the late 1950s, a new piece of information started to creep into the literature. People who looked at chromosomes from cancer cells — and there were not many people doing this, but there were some — kept finding that the chromosomes were a mess. The numbers were wrong. There were too many of some, too few of others, fragments that didn't belong, occasional ones that looked deformed. This was a curious thing, but the obvious interpretation was that cancer cells, being already disordered, were probably bad at copying their chromosomes properly, and the chromosomal mess was a consequence of being a cancer cell rather than a cause. The chromosomes were a downstream symptom, like the fever in a sick person — a sign of the disease but not its source.

The way you would distinguish between symptom and cause, if you wanted to, would be to find a cancer in which the chromosomal abnormality was the same in every patient. If chromosomes go wrong randomly because the cell is sick, you'd expect a different mess in every case. If something specific in the chromosomes is causing the disease, you'd expect to see the same specific thing every time.

* * *

Nowell and Hungerford had been looking at leukemia samples — the easiest cancer to study, because the cancer cells circulate in the blood and can be drawn through a needle — and they had been looking at the chromosomes from those samples carefully. They had noticed, in patients with one particular kind of leukemia, that one chromosome looked unusually small. Not different sizes in different patients. The same too-small chromosome, in the same place in the karyotype, in patient after patient.

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