The Pill That Could · The Translocation

The Translocation, part 2

The technique was called Q-banding, for quinacrine. Within a year or two it was joined by G-banding, which used a different stain (Giemsa, a dye that had been used in microscopy for nearly a century) after a brief treatment with an enzyme called trypsin, and which produced a similar barcode in ordinary visible light. By 1971, at a conference in Paris, the cytogenetics community had agreed on a standardized nomenclature. Each chromosome was divided into bands. Each band had a number. You could now describe a region of a chromosome — a specific stretch of a specific chromosome — with the same precision a surveyor would describe a piece of land.

This was the technique Rowley brought back from her sabbatical year. It was being adopted across the field, but slowly, because it took practice, and because the published photographs in textbooks all still showed the unstained version. She had spent her year in Oxford getting good at it. She came home to Chicago in 1972 with the ability to read the barcode of a chromosome in a way that, in the United States, very few people could yet match.

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Before going further, it is worth pausing on what a chromosome actually contains, because the rest of this story depends on it.

Inside a chromosome is DNA. Inside the DNA is a sequence of letters — four chemical bases, A, T, G, and C, repeated in long strings, tens of millions of letters in each chromosome. In humans, the total length of the DNA across all forty-six chromosomes is something like six billion letters.

Stretches of those letters spell out what are called genes. A gene is a section of DNA that contains the instructions for making a particular protein. Proteins are the molecules that do most of the work of being alive — the enzymes that catalyze chemical reactions, the structural fibers that hold tissues together, the receptors that sit in cell membranes and listen for signals, the transporters that move things in and out of cells. There are perhaps twenty thousand protein-coding genes in the human genome (the field will not have a confident count until the early 2000s, but the rough order of magnitude is settled).

The flow of information goes one way. The DNA is read, by a series of molecular machines, to produce RNA — a closely related molecule that serves as a working copy. The RNA is read, by a different molecular machine, to produce protein. The protein folds into a particular shape and does its particular job. DNA to RNA to protein. This is sometimes called the central dogma of molecular biology, a name proposed by Francis Crick in the late 1950s, slightly tongue-in-cheek (he meant it more as a working assumption than a theological commitment), and the name has stuck.

If a gene is broken — if its DNA sequence is altered, or if it is moved to a region of the chromosome where it gets switched on at the wrong time, or if it is fused to a piece of another gene — the protein it makes will be different. Sometimes the difference is harmless. Sometimes the protein is no longer made at all. Sometimes the protein is made in larger amounts than usual, or smaller, or in the wrong cells, or at the wrong moments. Sometimes a new protein is created, made of pieces of two genes that should not be near each other, with properties neither of the originals had.

This last possibility — a fusion protein, made by accidentally joining two genes — is one of the things that can happen when a chromosome breaks and is repaired wrong. The cell has machinery for repairing broken chromosomes, but the machinery is not perfect. If a break occurs in the middle of a gene, and the chromosome rejoins to the wrong partner, the result can be a gene whose first half comes from one chromosome and whose second half comes from another. The protein made from such a gene is a hybrid. Whether it does anything useful, anything dangerous, or nothing at all depends entirely on which two genes were involved.

In 1973, all of this is known in principle but not in detail. Genes have been identified in bacteria, in yeast, in fruit flies. In humans they are mostly inferred. The molecular tools to read a human gene letter by letter — the techniques that will become known as DNA sequencing — are still a few years away. The field is in a curious position: it knows what genes are, it knows what proteins are, it knows how DNA codes for protein, and it knows almost nothing about which specific human genes do which specific things. The map is mostly blank.

What you can do, in 1973, is look at chromosomes. And with banding, you can look at them well enough to see when one of them has been rearranged.

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Rowley, looking at her CML cells with Q-banding, was seeing two things at once.

The first was the Philadelphia chromosome itself, the small chromosome 22, with a noticeably shorter long arm than its partner. This was familiar; this was what Nowell and Hungerford had described in 1960. With banding, Rowley could now see exactly which bands of chromosome 22 were missing. The break was on the long arm, in a band the new nomenclature labeled q11 (the q referring to the long arm, the 11 to the position of the band). The piece beyond the break — the distal portion of the long arm — was gone.

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