The Pill That Could · BCR-ABL

BCR-ABL, part 2

The implications spread quickly. The cellular version of v-src — called c-src, with the c for cellular — was not, in itself, a cancer gene. It was a regular gene doing a regular job. The viral version differed from it in a few details, and those details were what made it cause cancer. Cancer-causing genes, in other words, were not foreign agents introduced from outside. They were ordinary cellular genes, present in every healthy cell, that became cancer-causing when something specific went wrong with them.

Bishop and Varmus would receive the Nobel Prize for this in 1989. By then, the same logic had been applied to many other viral oncogenes. Each of them — v-myc, v-ras, v-fms, v-erb, and so on, including v-abl — had been shown to have a normal cellular cousin. The cellular cousins were given the same names with a c- prefix. The category of “cellular oncogenes” came into being, although the more careful word, used by people who wanted to distinguish the cancer-causing version from the normal version, was “proto-oncogene” — a normal gene that, when altered, becomes capable of driving cancer.

This was the conceptual move that the Philadelphia chromosome story needed. If the Philadelphia translocation had broken in the middle of a gene, and joined that gene to a piece of another gene, the result might be doing something analogous to what the Rous virus had done: creating a slightly altered version of a normal cellular gene, with new and dangerous properties.

The hypothesis sharpened. If you wanted to find the cancer-causing event in CML, you could look for proto-oncogenes near the breakpoints on chromosomes 9 and 22.

* * *

The third thread is shorter, and weirder, and closer to a punchline.

In 1979, a young researcher named Tony Hunter at the Salk Institute in La Jolla, California, was trying to study the protein made by an oncogene from a different tumor virus, the polyoma virus. The protein was being phosphorylated — chemical phosphate groups were being attached to it by some kind of enzyme — and Hunter was trying to find out where on the protein the phosphates went.

A brief side note on phosphorylation, because the rest of the chapter depends on it.

A phosphate group is a small chemical tag, a single phosphorus atom surrounded by oxygens, that cells use as a kind of universal switch. Enzymes called kinases attach phosphate groups onto specific spots on specific proteins; other enzymes, called phosphatases, take them off again. The presence or absence of a phosphate at a given spot can change the shape of the protein, change its activity, change which other proteins it sticks to, change where in the cell it goes. It is the cell's main way of relaying signals — of saying things have changed, do something different now — quickly and reversibly. Most of the proteins in any cell at any given moment have phosphates being added and removed continuously, in elaborate patterns that encode what the cell is up to.

Phosphates can be attached to several different kinds of amino acid — amino acids being the small building-block molecules that proteins are made of — but in 1979, the consensus was that essentially all biological phosphorylation happened on two amino acids in particular: serine and threonine. There was a small literature on a third amino acid, tyrosine, but it was quiet, and most working biochemists assumed that if any phosphorylation happened on tyrosine, it was rare and probably unimportant.

Hunter, working with the polyoma protein, ran his samples on a special two-dimensional plate that separates phosphorylated amino acids by their chemical properties. He had done this many times. The serine and threonine spots were where they always were. But there was an extra spot, in a place where, by his understanding, no spot should be. He went back and ran the experiment again, more carefully this time, with fresh buffers. The same extra spot appeared.

It turned out to be phosphotyrosine. Hunter had found, by what was widely understood to be partly accident and partly very careful technique, that the polyoma oncoprotein was phosphorylating tyrosines.

He went back and looked at the famous v-Src protein, which had been studied for years. v-Src had been known to have kinase activity since 1977; the assumption had been that it phosphorylated serines or threonines, like every other kinase known at the time. With the right method, Hunter saw that v-Src was phosphorylating tyrosines too.

Within a year or two, the same was shown for v-Abl. The Abelson virus protein, the cancer-causing gene from the leukemia virus that had given ABL its name, was a tyrosine kinase. So was its cellular counterpart, ABL itself. So were a growing number of other oncoproteins.

It was striking. Of the many things an oncogene could in principle have turned out to be, a disproportionate number of them were turning out to be tyrosine kinases. The class — a relatively rare type of enzyme that hardly anyone had been thinking about a few years earlier — was suddenly central to cancer biology. Whatever was special about tyrosine phosphorylation, it seemed to be the kind of signal that, if it got stuck in the on position, could push a cell toward becoming a tumor.

* * *

Now de Klein in Rotterdam.

In 1982, the situation around CML looked like this. The Philadelphia chromosome had been described twenty-two years earlier. Rowley had reinterpreted it as a t(9;22) translocation nine years earlier. The breakpoints had been mapped to specific bands — q34 on chromosome 9, q11 on chromosome 22 — with the new banding techniques. ABL, the cellular cousin of the Abelson viral oncogene, had recently been mapped to chromosome 9, in roughly the right region. It was a tyrosine kinase. It was a proto-oncogene. And the question that suggested itself — obvious in retrospect, less obvious at the time, the kind of question that requires several different threads to have already been pulled before anyone can think to ask it — was whether the Philadelphia translocation broke chromosome 9 inside the ABL gene.

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