Clinical Medical Research Award
Alfred Knudson, Jr., Peter Nowell, and Janet Rowley
For incisive studies in patient-oriented research that paved the way for identifying genetic alterations that cause cancer in humans and that allow for cancer diagnosis in patients at the molecular level.
In 1960, Peter Nowell discovered the "Philadelphia chromosome." It was only four years earlier that the precise number of human chromosomes had been fixed at 46 and chromosome studies were, by today's standards, quite primitive. After photographing chromosomes under a microscope, researchers literally cut them up, like paper dolls, and arranged them according to size, thereby producing a karyotype. Nowell, a tumor biologist in the pathology department at the University of Pennsylvania School of Medicine, was interested in the relationship between cancer and alterations in genes (although he had no proof there was one).
One day while "diddling around with leukemic cells in culture," and rinsing them with tap water, Nowell noted that cells were dividing. Staining them with a special dye made the cells' chromosomes more visible. Nowell collaborated with the late David Hungerford who, he says, "knew more about chromosomes than I did," and together they made the startling observation that individuals suffering from chronic myelogenous leukemia (CML) had an abnormally small chromosome in the tumor cells.
At a time when the idea that cancer had a genetic basis was widely disbelieved, Nowell's results provided the first clear evidence that a particular genetic defect in a single chromosome can lead to a population or clone of identical cells that accumulate in numbers to form a deadly malignancy. What made Nowell and Hungerford notice the Philadelphia chromosome, named after the city in which they worked, was its size. The tiny Philadelphia chromosome became a clear and consistent marker of CML, a cancer of the myeloid or bone marrow cells, with broad implications for diagnosis and prognosis of disease.
But even so, many researchers continued to believe that genetic aberrations were the result, not the cause, of malignancy. It would be more than a decade before other cancers were found to be associated with other, consistent chromosomal abnormalities. Likewise, more than a decade passed before scientists understood exactly why the Philadelphia chromosome was so small.
Janet Rowley, who has spent her entire professional career at the University of Chicago, would be the one who understood. In 1961, Rowley went to Oxford with her husband, who was on sabbatical. She got a grant to study chromosomes and, when she returned to Chicago, even though she had "no special interest in chromosome abnormalities in hematological diseases," the course of her research was set by her ready response to clinical colleagues who frequently asked her to study their patients. "I came to realize that there were many questions about chromosome changes in patients that would be rewarding to study," noted Rowley, and for the next decade she labored over the microscope looking at chromosomes in leukemic cells.
It is worth noting that in science nothing is quite as powerful as a prepared mind armed with new technology and in the early 1970s geneticists perfected the art of "banding," a new way of visualizing chromosomes with great clarity. Rowley was ready. Using banding technology, she discovered that the tiny Philadelphia chromosome was missing a piece of itself.
In fact, she showed that in patients with CML, a crucial segment of chromosome 22 broke off and moved to chromosome 9, where it did not belong. Moreover, a tiny piece of chromosome 9, which carried an oncogene, had moved to the breakpoint on chromosome 22. Rowley had identified the first "translocation" in cancer, providing clear evidence that the cause of CML could be related to the fact that by moving from one chromosome to another, the aberrant segment of chromosome 22 was no longer sitting next to genes that controlled its behavior.
Rowley and her colleagues subsequently identified several other signal chromosome translocations, including one characteristic of acute myeloblastic leukemia. Quickly picking up on her lead that translocations contribute to malignancy, scientists around the world joined the search for chromosomes that either switched genetic material or, in some cases, lost it altogether in a process known as "deletion." A whole new area of cancer genetics opened up.
Not content to rest on her laurels, Rowley is still in the forefront. Using yet newer techniques for detecting abnormal chromosomes (called spectral karyotyping), Rowley found a chromosomal rearrangement that characterizes one of the childhood leukemias, and her work continues.
In addition to its implications for accurate cancer diagnosis, understanding the genetics of cancer at the level of chromosomes and genes is now opening the door to the design of drug and radiation therapy that encourages the hope that very specific therapies will be developed for specific diseases.
Explaining why some tumors are hereditary and others appear to be "sporadic" was one of the great conundrums of cancer biology—until Alfred Knudson, Jr., came up with the "two-hit" hypothesis that provided a unifying model for understanding cancer that occurs in individuals who carry a "susceptibility gene," and cancers that develop because of randomly induced mutations in otherwise normal genes. Like many significant conceptual leaps in science, Knudson's two-hit hypothesis was met with skepticism when he first published it in 1971.
Knudson, who has been affiliated with the Fox Chase Cancer Center in Philadelphia since 1976, was studying children with retinoblastoma, a cancer of the eye, noting differences between the 40 percent of cases with heritable tumors and the 60 percent of non-heritable cases. "Most people assumed that retinoblastoma genes were inherited in a dominant fashionthat is, if you had the gene, you would get the cancer," Knudson said. But he observed the variable number of tumors that develop in individuals who inherit one retinoblastoma gene, and proposed that a second mutation, after conception of the child, was necessary for a tumor to develop. The same gene, known as RB1, is involved in children with the non-hereditary form, but both mutations, or hits, occur after conception.
The hits can occur in many waysfrom an environmental toxin, dietary factors, radiation, or the kind of random mutation that sometimes occurs during the intricate process of normal cell replication. Knudson proposed that retinoblastoma develops either because both copies of a key gene are lost, or because they are inactivated and unable to function.
In essence, Knudson, far ahead of his time (and ahead of his own hard data) hypothesized that some genes' normal role in life is to behave as anticancer or tumor-suppressor genes that keep cell division under healthy control. At first, the strength of his hypothesis rested on a complex mathematical model, but was supported in 1976 when Knudson and others showed that some patients with hereditary retinoblastoma are missing a segment of chromosome 13 in all of their cells. In 1986, other scientists applied the tools of molecular technology to clone the gene, RB1, so that its function as a tumor-suppressor gene could be studied in detail.
One of the most significant achievements of molecular genetics in the past few years has been the identification of a number of tumor-suppressor genes that, when mutated, lose their ability to control cell division. Malignancy is the result. Although Knudson's initial studies were directed at relatively rare tumors, including retinoblastoma and Wilms' tumor (another childhood cancer with heritable components), it is now apparent that his two-hit hypothesis explains the etiology or origin of many common forms of cancer, and is one of many defining concepts behind all of modern cancer biology.