The Pill That Could · Philadelphia, 1960

Philadelphia, 1960, part 3

The leukemia in question was chronic myeloid leukemia. CML. The same disease that, thirty-three years later, would have Brian Druker sitting in his Portland clinic with nothing to offer.

CML in 1960 was, as in 1993, a fatal disease. The available treatments — busulfan, an alkylating agent that knocked white cell counts down at the cost of considerable toxicity; splenectomy, removal of the swollen spleen, which provided some symptomatic relief — extended life by months, sometimes a year or two, and did not change the eventual outcome. CML patients in 1960 mostly died of CML, in their fifties or sixties or, often enough, much younger.

There was, however, something useful about CML for what Nowell and Hungerford were trying to do. CML produces a great many abnormal white cells, circulating freely. You could draw a tube of blood from a CML patient and have, almost without effort, a high yield of the very cells you wanted to look at. PHA wasn't even strictly necessary — although it helped — because some of the CML cells were already actively dividing. The disease was, from the perspective of a young cytogeneticist trying to read cancer chromosomes, an unusually cooperative subject.

So they read them. Patient by patient. They looked at samples from a handful of people with CML. In every one, the same small chromosome. A piece of it, looking at it through the microscope of 1960, appeared to be missing.

* * *

The paper appeared in Science in the autumn of 1960. It is short. The total length, by modern standards, is barely a long paragraph — about a page of journal text, with a small figure showing a karyotype. Its conclusions are stated carefully, in the conditional language of a paper not wanting to overreach. The authors note that they have observed an unusually small chromosome, present in the cells of patients with chronic granulocytic leukemia (which was the more common name for CML at the time), absent in the same patients' normal cells when those could be obtained, and consistent across the cases they had been able to examine. They suggest that this finding may be relevant to the understanding of the disease.

They do not claim to have found the cause of cancer. They do not claim to have shown that CML is a chromosomal disease. They report what they have seen and let the field draw its own conclusions.

The field's first conclusion is that this is interesting but perhaps not entirely surprising. People have been seeing chromosomal abnormalities in cancer cells for a while; here is another one. The novelty of Nowell and Hungerford's paper, when it is appreciated, is not that the chromosomes are abnormal but that they are consistently abnormal — the same abnormality in every patient. This is the feature that distinguishes a cause from a symptom, at least potentially. It is the first time anyone has shown such a thing in a human cancer.

A few years later, at one of the small conferences where the new field of cytogenetics was working out its conventions, the practitioners agreed on a naming system for newly discovered chromosomal anomalies. The system was simple: name the anomaly after the city in which it was first reported. The small chromosome from the CML patients, having first been described in Philadelphia, became the Philadelphia chromosome. It is, as far as I can tell, the only piece of human anatomy named after the city of Philadelphia.

* * *

Now here is the thing about the Philadelphia chromosome.

It was the first specific, reproducible genetic abnormality ever linked to a specific human cancer. In a field that had been arguing for decades about whether cancer had genetic causes at all, it was a clear data point on the side of yes. It is, with the benefit of hindsight, one of the most important findings in twentieth-century cancer biology.

It also did, in the immediate term, almost nothing.

It did almost nothing because nobody could do anything with it. The tools to ask the obvious follow-up questions did not exist. What does the missing piece do? — unanswerable; you couldn't isolate it, couldn't read it, couldn't even reliably tell what was missing as opposed to what was abnormal in some other way. What protein is encoded there? — unanswerable; the relationship between specific stretches of chromosome and specific proteins, in humans, was known in only a handful of cases, and not this one. Could you make a drug that fixes the problem? — laughable; the field had no drugs that targeted specific genes or specific proteins, didn't really have the concept of doing so, and wouldn't develop the necessary toolkit for two more decades.

So the Philadelphia chromosome went into the literature, was cited respectfully, became a piece of standard knowledge about CML, and sat there. Doctors learned to look for it; finding it confirmed the diagnosis of CML in ambiguous cases. Researchers occasionally wrote review articles about it. It was a fact in good standing.

What it wasn't was a useful fact. It told you what was wrong, in some general sense, but not specifically enough to act on. It was as if you had been told that a particular kind of car always broke down because of a problem in the engine, and you opened the hood to find the engine encased in concrete. There was nothing to do with the information.

The interpretation that hardened, in the years after 1960, was that the small chromosome had simply lost a piece. A deletion, in the language of the field. A chunk of chromosome 22 had broken off and been lost, and that loss was somehow involved in the disease — perhaps because something important had been on the missing piece, perhaps because the loss had disrupted some balance. Either way, the missing piece was gone, and there was nothing further to be done.

This interpretation was not exactly wrong, but it was missing something important, and the something important would not be found for thirteen more years, when a researcher in Chicago, on a sabbatical, with a new staining technique that revealed banding patterns inside chromosomes, looked at the Philadelphia chromosome and at the cells it came from and saw something nobody else had noticed.

The missing piece wasn't missing.

It was somewhere else.

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