The Pill That Could

Chapter 1: Philadelphia, 1960

The microscope is a Zeiss, the slide is a smear of cells from a man with leukemia, and the man looking down the eyepiece is David Hungerford. It is the autumn of 1959 or the spring of 1960; the dates are not perfectly clear in the historical record, and Hungerford himself, asked years later, gave slightly different versions. What is clear is what he is looking at.

He is looking at a single cell, frozen in the moment of dividing in two. The cell has been treated with a chemical that arrests division partway through, at the stage where the chromosomes have already condensed but haven't yet been pulled to opposite ends of the cell. They sit in the middle of the field, scattered, like loose grains of rice. There are forty-six of them, which is what there are supposed to be in any normal human cell, and which is also a number that the field has only known for a few years.

Hungerford counts them, the way he has counted them in thousands of cells before. He matches them up. Chromosomes come in pairs — twenty-two matched pairs plus the two sex chromosomes, X and Y in a man, X and X in a woman — and matching them is most of the work. You look at length and at the position of the centromere, the pinched-in waist where the two halves of the duplicated chromosome are held together. You group the pairs from longest to shortest. You write the result down.

In this cell, in this leukemia patient, twenty-one of the autosomal pairs match cleanly. The smallest pair — the chromosomes labeled 22, the shortest of the autosomes, which are the chromosomes that aren't sex chromosomes — should look the same as each other. They don't. One is the right size. The other is too small. A piece of it, a noticeable piece, is missing.

Hungerford makes a note. He goes back to his microscope.

* * *

You can find Peter Nowell, in the photographs from this period, looking like a young man trying to look a little older. He is in his early thirties. He is a pathologist by training, on the faculty at the University of Pennsylvania School of Medicine, in West Philadelphia. He is tall and slightly formal in a way pathologists of his generation often were. He is also, by accident more than design, in the middle of a small revolution in how people study human cells.

The accident is this. A few years earlier, Nowell had been trying to get a clean look at human white blood cells under a microscope. White blood cells — leukocytes, which is the source of the word leukemia, blood that has gone white in some specific way — are the cells that are diseased in the leukemias, and they are also the cells you can most easily get hold of in a clinical setting, because you can draw blood from a patient's arm. The trouble is that when you spin down a tube of blood, what you mostly get is red cells. The white cells are buried in there, and getting them out cleanly is fiddly.

There is a substance called phytohemagglutinin — PHA, in everyday lab usage — which is extracted from kidney beans and which clumps red blood cells together, so that they fall to the bottom of a tube and leave the white cells suspended above them. PHA was being used, around 1960, as a way to separate white cells from red. Nowell was using it for that. Then he noticed that something else was happening. Some of the white cells, after exposure to PHA, started to divide.

This was not supposed to happen. White blood cells circulating in the body, generally speaking, don't divide. They are made elsewhere — in the bone marrow, in the lymph nodes, in the thymus — and the cells you draw from a vein are mature cells doing mature-cell things, not dividing. To see chromosomes you need cells that are dividing, because chromosomes are only condensed and visible during division. The rest of the time the genetic material is decondensed into something more like loose thread, and you can't see anything useful.

PHA, in other words, was solving a problem the field hadn't quite figured out it had. Before PHA, if you wanted to look at human chromosomes, you had to get cells from bone marrow (which required a needle in a hip bone) or from a tumor (which required a tumor and a surgeon) or from a cell line grown in culture (which only worked for some kinds of cells). After PHA, you could draw a tube of blood, add the bean extract, wait a couple of days, and have a population of dividing cells that you could then arrest in mid-division and stain and look at. It made human cytogenetics — the study of human chromosomes — practical for ordinary patients in ordinary hospitals.

Nowell published the PHA finding in 1960. He was not the only one to notice the effect, but he was early, and he was thorough, and the technique spread. It is, in retrospect, a finding that probably should have made him famous on its own. It is also what made his next finding possible.

* * *

David Hungerford was, in 1960, finishing his PhD at the Institute for Cancer Research, the small institution in Fox Chase, just north of the city, that would later become Fox Chase Cancer Center. He had spent his graduate years learning to read chromosomes. This was, in 1960, a relatively rare skill. The field of human cytogenetics, as a recognizable field, was four years old.

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