Albert Lasker
Clinical Medical Research Award

Award Presentation by the Jury Chairman

Dolly the Sheep may be the world's most famous clone, but the most infamous clones are the ones that produce cancers in human beings. Cancer begins when one cell in the body undergoes a genetic change that endows that cell and its clonal descendants a growth advantage vis-a-vis other cells. Over time, the cancer clone accumulates other mutations that help it to grow. Two classes of genes are targets of the mutations that convert normal cells to cancer clones. One class comprises the proto-oncogenes discovered by Bishop and Varmus in 1976. These are cellular genes that normally stimulate cell growth. The second class of cancer-causing genes are the tumor suppressor genes. They have an opposite action: They produce proteins that normally inhibit growth. When the proto-oncogenes and the tumor suppressor genes operate normally, the cell cycle (about which Ira Herskowitz so eloquently spoke) is exquisitely controlled, cell division proceeds in an orderly fashion, and cancer does not occur. Under the normal conditions of cell growth, the proto-oncogenes are the accelerators of the cell cycle, and the tumor suppressor genes are the brakes. Or, in the parlance of Wall Street, the proto-oncogenes are the Bulls, and the tumor suppressor genes are the Bears.

Cancer occurs when mutations create an imbalance between the accelerating actions of the proto-oncogenes and the braking actions of the tumor suppressor genes. Mutation in a proto-oncogene acts in a dominant fashion and converts the normal version of the gene to an oncogenic form that produces a hyperactive growth-stimulating protein. This sequence of events was demonstrated by several scientific groups, including those led by Bob Weinberg and Mike Wigler in the early 1980s in classic experiments on Ras. Mutation in a tumor suppressor gene acts in the opposite way, causing cancer in a recessive fashion by inactivation of the tumor suppressor protein. This inactivation requires that both copies of the same gene be disrupted, an event that is referred to as "two hits." In order for a single cell to evolve into a cancer clone, mutations must occur in various combinations, involving the dominant activation of three or four proto-oncogenes plus the recessive inactivation of three or four tumor suppressor genes. In all, scientists have identified over 100 genes that cause cancer in humans—75 proto-oncogenes and 25 tumor suppressor genes. It is now established beyond any doubt that alterations in our genes are the fundamental initiating event in human cancer. The genetic paradigm for cancer is here to stay.

This year's Lasker Award in Clinical Research celebrates the accomplishments of three scientists who provided the first convincing evidence that human cancers arise from mutations in our genes, setting the stage for our present understanding of the genetic basis of cancer. The pioneering work of Peter Nowell, Janet Rowley, and Al Knudson was done in the 1960s and 1970s. Their insights were way ahead of their time, decades before the tools of molecular biology were available to confirm their hypotheses.

Our story begins 40 years ago at a time when our knowledge of cancer genetics was simply nonexistent. In 1958, Peter Nowell, then a newly minted instructor in pathology at the University of Pennsylvania, teamed up with the late David Hungerford to apply the primitive techniques of cytogenetics to the study of chromosomes in patients with leukemia. Within two years, Nowell and Hungerford discovered the first chromosomal abnormality in human malignancy—a piece of the smallest chromosome, no. 22, was missing in 9 out of 10 patients with chronic myelogenous leukemia. The important conceptual point was that this genetic change was present in all the cells of this neoplasm. This led Nowell and Hungerford to advance the audacious proposal that cancer could arise from a mutation in a single cell. In other words, cancers could be clonal. The discovery of the Philadelphia chromosome had immediate clinical application in the diagnosis and management of patients with leukemia, and it opened a new field of research cancer—cytogenetics. Nowell went on to study chromosomal changes in other tumors, and this led him to advance the theory of the clonal evolution of tumor progression. He proposed that carcinogenesis occurred in multiple steps. The progression of the ancestral tumor cell to a full-blown cancer results from the sequential acquisition of additional mutations that confer a selective growth advantage to the original clone. This powerful theory, originally published in 1976, is widely accepted today. It has been verified most elegantly by Vogelstein and colleagues in their molecular analysis of the multiple mutations in oncogenes and tumor suppressor genes that occur in human colon cancers.

One other brief comment about Peter Nowell, and this relates to his remarkable attachment to Philadelphia and Penn. He was born in Philadelphia, left home briefly to attend college for four years at Wesleyan University in Connecticut, returned to Philadelphia to enter medical school at Penn in 1948, and has remained there for the last 50 years. Such municipal and institutional fidelity is almost unequaled in this peripatetic age.

I say almost unequaled because our next honoree, Janet Rowley, has outdistanced Peter by four years in both municipal and institutional fidelity. Janet was born in Chicago, went to college at the University of Chicago where she read all the Great Books, obtained her M.D. degree from the University of Chicago, and did her internship in Chicago. Except for two sabbaticals at Oxford, she has been affiliated with the University of Chicago for 54 years. Despite this interminable love affair with Chicago, I'm told that Janet's favorite Frank Sinatra song is not "Chicago," but "New York, New York." Janet, today New York honors you.

Stimulated by Nowell's discovery of the Philadelphia chromosome, Janet began her scientific career in 1962 by analyzing the chromosomes from patients with different types of leukemias and lymphomas. She describes the 10-year period between 1962 and 1972 as "the era of chromosomal chaos." The techniques for identifying chromosomes were primitive. Except for Nowell's Philadelphia chromosome, no one had been able to discover a second consistent chromosomal change in any cancer. The Philadelphia chromosome stood alone as a medical curiosity for more than a decade, and many disillusioned biologists began to question whether it was really the cause of the myelogenous leukemia. Maybe it was an epiphenomenon that was secondary to the process of transformation.

Finally, in the early 1970s, new staining techniques were developed by Swedish scientists that allowed each human chromosome to be identified on the basis of its unique pattern of bands. Cytogeneticists could now bring order to the chromosomal chaos. Janet is the scientist who first saw the light in 1972 when she looked into the microscope and discovered that the Philadelphia chromosome was not a simple deletion of chromosome 22, as everyone supposed. Rather, it was a reciprocal translocation between pieces of chromosome 22 and chromosome 9. The result was that the DNA from the end of chromosome 9 moved to the end of chromosome 22, and conversely the DNA at the end of chromosome 22 moved to the end of chromosome 9. In the Philadelphia chromosome, this exchange of DNA creates a new hybrid oncogene that stimulates cell growth. This chromosomal rearrangement was the first somatic translocation to be identified in any malignant or nonmalignant disease in man or animals.

Janet speculated that nonrandom chromosomal rearrangements in tumor cells might provide the crucial signposts that point to the locations of new cancer-causing genes. This proposal, bold at the time, has turned out to be an understatement. More than 70 translocations are now known to cause cancers in humans. In each case the translocation breakpoint has been molecularly cloned and shown to produce an activated oncogene or an inactivated tumor suppressor gene. More than half of these 70 genes are new ones that were not previously known to the scientific community. Janet herself identified 10 of these 70 translocation breakpoints, including the translocation in follicular lymphoma that led to the cloning of the now-famous Bcl-2 gene that regulates the cell suicide program. When Bcl-2 is activated by a chromosomal translocation, lymphomas occur because the cells fail to die. Cancer cells must not only show uncontrolled growth; they must also find a way to avoid programmed cell death, which is the body's way of eliminating cells that don't obey the rules. This newly appreciated aspect of malignancy is now being unraveled by Stanley Korsmeyer in St. Louis and Suzanne Cory in Melbourne, thanks in large part to the careful cytogenetics of Janet Rowley.

Throughout her career, Janet led the world in applying the latest technologies of cytogenetics and molecular biology to clinical medicine. She pioneered the use of DNA-based techniques to diagnose patients, to follow their progress, and to develop more effective treatment protocols targeted to particular subgroups.

In 1985, Mike Bishop, the doyen of the tumor retrovirologist, noted in one of his refreshing review articles that studies of tumor chromosomes were no longer "mere amusements for the myopic microscopist," because they often provide useful clues for the molecular biologist. Nowell pointed out to Bishop that "we microscopists had known all along that these were important clues, but had to wait for the retrograde retrovirologists to provide us with the means to exploit them." Peter obviously made his point, and a decade later in another of his inimitable reviews Bishop wrote in reference to Janet Rowley's classic 1973 paper on the Philadelphia translocation: "Those of you who persist in thinking of cytogenetics as simply peering through a microscope should read the crucial paper by Rowley: it is a gem of ingenuity." No one could have said it better!

And now to Al Knudson. Al differs from Peter and Janet in two ways. First, he is not a cytogeneticist, and second, his strong point is not fidelity—at least in the municipal and institutional sense. Quite the opposite, in fact. For the first 44 years of his life, Al bounced back and forth like a ping pong ball between Los Angeles and New York. Born in Los Angeles. College at Caltech. Medical school in New York at Columbia P&S. Back to L.A. for an internship in Pasadena. Back to New York Hospital for a residency in pediatrics. Back to L.A. for a second residency at L.A. Children's Hospital, followed by a Ph.D. in genetics at Caltech, and chairmanship of the department of pediatrics at City of Hope in Duarte. And then back to New York as Dean at Stony Brook. Too bad for Al that there were no frequent flyer miles in those days.

In 1969, Al got tired of coast-to-coast travel and moved to the middle of the U.S. where he could get to either coast in a hurry. I'm proud to say that he settled in Texas, where he became Associate Director of the M.D. Anderson Hospital and Professor of Biology at UT Medical Center in Houston. After 10 years, Al apparently decided that life in middle America was too middle-of-the road. He yearned for a seacoast. Resuming his peripatetic ways, he moved back to the east coast—this time to Philadelphia and to the Fox Chase Institute for Cancer Research. He has now spent 22 years in the same city at the same institution. In 30 years he'll catch up to Peter and Janet.

During his many trips back and forth between L.A. and New York, Al had plenty of time to think, and he began to ponder the problem of pediatric cancers, a problem that had intrigued him since his early days as a pediatric resident at New York Hospital. He had seen and read about rare cases of retinoblastoma, neuroblastoma, and Wilms' tumor that occurred in newborn babies. This early onset suggested to Al that the number of predisposing events in these pediatric tumors must be quite small. When Al moved to the M.D. Anderson hospital in 1969, he was no longer distracted by the folderol of L.A. Within two years he proposed a novel genetic theory, based on a complex mathematical model, to explain how tumors of the eye arose in retinoblastoma. As a card-carrying pediatrician and geneticist, Al knew that retinoblastoma appeared clinically in two forms —a familial form in which a tumor-causing gene is transmitted from parent to offspring and a sporadic form in which affected children have no family history. He proposed that retinoblastomas required two mutations that arise differently in the sporadic and familial forms. In children with the familial form, the first mutation, which Al called the first hit, was inherited; it was present in the germline and thus found in every cell in the body. The eye tumor did not develop until a somatic cell—in this case a retinal cell—underwent a second mutation, which he called the second hit. This second hit would be triggered by an environmental insult, such as radiation, a chemical, or some dietary factor. In children with sporadic retinoblastoma, there was no inherited mutation. The two hits must both occur in the same retinal cell in both copies of the same gene. The likelihood of the same retinal cell undergoing two independent mutations in the same gene would be extremely rare. This formulation immediately explained why children with the inherited form of the disease developed multiple tumors in both eyes at a very early age, whereas children with the sporadic form typically developed only one tumor in one eye at a much later age.

Knudson's two-hit model, so elegant in its simplicity yet so powerful in its ability to predict, provided the first unifying explanation of how hereditary and sporadic forms of the same cancer could involve the same gene. The two-hit model of 1972 also predicted that malignancies can occur because of a loss or inactivation of both copies of a gene that normally functions to inhibit cell growth, which we now call a tumor suppressor gene. The idea that cancer in humans would be caused by a loss of gene function and that hereditary and sporadic forms of cancer could both involve the same gene were heretical. If 1962–72 was the decade of chromosomal chaos, then 1972–82 was the decade of hereditary heresy. Like a fine Bordeaux wine, Al's new ideas had to ferment and age for many years before the molecular biologists were willing to taste and experiment.

Direct confirmation of the two-hit model came in 1986, 15 years after its formulation, with the cloning of the retinoblastoma gene by Dryja, Friend, and Weinberg. Today, we know that the retinoblastoma gene product, the RB protein, is a master regulator molecule of the cell cycle. The Knudson model has now been validated in thousands of experimental and clinical systems and provides the conceptual foundation for our current views of the crucial role of tumor suppressor genes in cancer. The discovery of tumor suppressor genes, such as p53, the two breast cancer genes BRCA1 and BRCA2, and the familial polyposis gene APC, is directly traceable to Knudson's ideas. The most frequent tumors in human—cancer of the colon, breast, lung, and prostate—all involve mutations in tumor suppressor genes.

It is extremely rare in biomedical science for a single idea to be so influential in changing the direction of an entire field. It must be especially gratifying to Al—the consummate pediatrician, medical geneticist, and cancer biologist—to know that cancer centers throughout the world are routinely performing DNA-based tests of tumor suppressor genes for diagnosis and counseling of patients from cancer-prone families.

As a final footnote, it's personally gratifying to me to note that all three clinical discoveries that we celebrate today were made by scientists trained in medicine whose initial stimulation came from their contact with patients. Their research accomplishments epitomize the dictum that "medicine is the tutor of biology." In this sense, our awardees are superb models for young physicians who aspire to careers in creative patient-oriented research.