acquisition of aggressive new powers in the cell – overshadowed all else. ‘My reaction to this unanimity of opinion was intransigent disbelief,’ wrote Harris in a
review for the journal of the Federation of American Societies of Experimental Biology, FASEB. He figured that, with or without the agency of a virus, the rate at which mutations occur naturally in
our cells is such that if malign mutations were always dominant – that is, able to override any other operating instructions in the cell – hardly a child would be born without a tumour
already forming.
In experiments run by fellow cell biologists Georges Barski and Francine Cornefert that seemed to confirm the virologists’ theories of the driving forces in cancer, Harris was struck by
something the two scientists had dismissed in the interpretation of their results. Their experiment involved fusing malignant mouse cells with normal mouse cells to see which set of instructions
prevailed. When, in due course, a tumour developed, they concluded that the genetic material from the malignant cell had dominated that of the normal cell. The fact that the resulting tumour cells
had a depleted number of chromosomes they thought was of no consequence. Harris did not agree. Could it be, he wondered, that in becoming malignant the cells had
lost
genes that might have
suppressed cancer, rather than
gained
genes that encouraged malignancy? It was exactly the question posed a few years later in Texas by Alfred Knudson, looking at the evidence from
retinoblastoma cases.
Over the next few years, Harris and his colleagues at Oxford – in collaboration with a lab in Stockholm that had the best materials to play with – explored this question by fusing
malignant cells with normal cells of various different types. They demonstrated conclusively that for the hybrid cells to produce tumours, something in the DNA had to be lost – something that
presumably was suppressing the malignant growth while it was still present. They published their findings in
Nature
in 1969, two years before Knudson’s retinoblastoma studies –
and well before it was possible to home in on the individual gene or genes that might be responsible.
But Harris and Knudson were up against the limits of technology in proving their theories; they were ahead of their time and their ideas caused barely a ripple in the cancer community.
THE FIRST TUMOUR-SUPPRESSOR GENE IS FOUND
That began to change in the late 1970s when cytologists – scientists who study the structure and function of cells – noticed that in the tumour cells of children
with retinoblastoma, chromosome 13 was unusually short: it seemed to be missing a large chunk of DNA. What is more, in those children with a family history of retinoblastoma, all the cells in their
bodies had a truncated chromosome 13. It gave researchers a place to look for the offending gene, and suddenly a hotly competitive race was on to find it and clone it. This promised to be the
novelty everyone was seeking – something that might explain the many anomalies that were thrown up by their pursuit of oncogenes.
But though the discovery had narrowed the field considerably, finding the retinoblastoma gene remained a Herculean task, for chromosome 13 is a mighty bundle of DNA some 60 million base pairs
long. Furthermore, scientists weren’t even sure whether they were looking for a single gene or a clutch of genes that normally worked in concert to suppress tumours. They got their answers by
an almost impossible stroke of luck. Arriving at Bob Weinberg’s lab in the mid-1980s, a young postdoc named Steven Friend announced he wanted to clone the retinoblastoma gene. As Weinberg
tells it, he met this request from his new recruit with frank astonishment: ‘
What?
How on earth are you going to do that? You don’t know anything about cloning; nobody knows
exactly where it is in chromosome 13.’ But Friend was not deterred. ‘Don’t worry. I’ll do
review for the journal of the Federation of American Societies of Experimental Biology, FASEB. He figured that, with or without the agency of a virus, the rate at which mutations occur naturally in
our cells is such that if malign mutations were always dominant – that is, able to override any other operating instructions in the cell – hardly a child would be born without a tumour
already forming.
In experiments run by fellow cell biologists Georges Barski and Francine Cornefert that seemed to confirm the virologists’ theories of the driving forces in cancer, Harris was struck by
something the two scientists had dismissed in the interpretation of their results. Their experiment involved fusing malignant mouse cells with normal mouse cells to see which set of instructions
prevailed. When, in due course, a tumour developed, they concluded that the genetic material from the malignant cell had dominated that of the normal cell. The fact that the resulting tumour cells
had a depleted number of chromosomes they thought was of no consequence. Harris did not agree. Could it be, he wondered, that in becoming malignant the cells had
lost
genes that might have
suppressed cancer, rather than
gained
genes that encouraged malignancy? It was exactly the question posed a few years later in Texas by Alfred Knudson, looking at the evidence from
retinoblastoma cases.
Over the next few years, Harris and his colleagues at Oxford – in collaboration with a lab in Stockholm that had the best materials to play with – explored this question by fusing
malignant cells with normal cells of various different types. They demonstrated conclusively that for the hybrid cells to produce tumours, something in the DNA had to be lost – something that
presumably was suppressing the malignant growth while it was still present. They published their findings in
Nature
in 1969, two years before Knudson’s retinoblastoma studies –
and well before it was possible to home in on the individual gene or genes that might be responsible.
But Harris and Knudson were up against the limits of technology in proving their theories; they were ahead of their time and their ideas caused barely a ripple in the cancer community.
THE FIRST TUMOUR-SUPPRESSOR GENE IS FOUND
That began to change in the late 1970s when cytologists – scientists who study the structure and function of cells – noticed that in the tumour cells of children
with retinoblastoma, chromosome 13 was unusually short: it seemed to be missing a large chunk of DNA. What is more, in those children with a family history of retinoblastoma, all the cells in their
bodies had a truncated chromosome 13. It gave researchers a place to look for the offending gene, and suddenly a hotly competitive race was on to find it and clone it. This promised to be the
novelty everyone was seeking – something that might explain the many anomalies that were thrown up by their pursuit of oncogenes.
But though the discovery had narrowed the field considerably, finding the retinoblastoma gene remained a Herculean task, for chromosome 13 is a mighty bundle of DNA some 60 million base pairs
long. Furthermore, scientists weren’t even sure whether they were looking for a single gene or a clutch of genes that normally worked in concert to suppress tumours. They got their answers by
an almost impossible stroke of luck. Arriving at Bob Weinberg’s lab in the mid-1980s, a young postdoc named Steven Friend announced he wanted to clone the retinoblastoma gene. As Weinberg
tells it, he met this request from his new recruit with frank astonishment: ‘
What?
How on earth are you going to do that? You don’t know anything about cloning; nobody knows
exactly where it is in chromosome 13.’ But Friend was not deterred. ‘Don’t worry. I’ll do
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