Theories of Genes and Cancer

Theories of Genes and CancerThe Wind in the TreesIn the recently 1950s, ray Nowell and David Hungerford, dickens pathologists from Philadelphia had effect an unusual chromosomal pattern in continuing myelogenous leukemia (CML) stalls. In CML cells, Novell found that mavin copy of chromosome 22 had its head lopped off. Novell c anyed this irregularity the Philadelphia chromosome after the place of discovery.In 1973, a hematologist in loot named Janet Bowley followed this study, looking for the missing pieces of the Philadelphia chromosome. She found a pattern. The missing head of chromosome 22 had attached itself to the tip of chromosome 9. And a piece of chromosome 9 had attached itself to chromosome 22. This ancestral event was called a translocation the transposition of both pieces of chromosomes.Bowley found this same translocation in the cells of every CML patient. Cancer was not disorganized chaos, but an organized chromosomal chaos resulting from specific, identical innovations. Chromosome translocation jakes create new genes called chimereticular activating system by fusing two genes formerly located on two different chromosomes. The CML translocation, Rowley postulated, had created such a chimera.***In 1969, Alfred Knudson, a patrimonialist at MD Anderson Cancer Center in Texas, wanted to capture a pattern of inheritance of pubic louse by studying retinoblastoma, an hereditary eye crabmeat. Retinoblstoma has two distinct variants, an inherited familial form and a periodic form. Children who suffer from the familial form may drive home strong family histories of the disease, and they typically develop tumors in both eyes. Children with the sporadic form never have a history in the family and ceaselessly have a tumor in precisely one eye.By studying cohorts of children with the two types of cancers, Knudson detect the cohorts developed cancers at different speeds. hereditary retinoblastoma cancer develops at early ages, typically b etween 2 to 6 months old. Sporadic retinoblastoma cancer develops at older ages, typically between ages 2 to 4 years old.Humans inherit two copies of every gene, one from each p bent. Knudson postulated that both copies of the Retinoblastoma (Rb) gene needed to be inactivated through renewal to develop retinoblastoma. Some children inherit one mutated version and one common version of the Rb gene. The inherited conversion is the first hit. These children are therefore predisposed to the cancer, and only a single additional genetic mutation is needed for them to develop the cancer. So they develop cancer at preceding ages. Sporadic retinoblastoma develops at later ages because two independent mutations have to stash away in the cell. Knudson called this the two-hit guess of cancer. For certain cancer-causing genes, two mutational hits are needed to produce cancer.At first glance, Knudsons two-hit theory seemed at odds with the src gene, which only required one activated copy to cause cancer. The answer is because the two genes perform two different functions. The src gene creates a hyperactive kinase that provokes staring(a) cell division to cause cancer, while the Rb gene performs the striaback function. It is a cancer suppressor gene, or an anti- transforming gene. It requires two mutation hits to inactivate such a gene.A Risky PredictionRisky prescience is a process scientists used to validate untested theories. For instance, the return of Halleys comet in 1758 validated Newtons law of gravity.The first risky prevision involved Varmus and Bishops supposition on oncogenes. In the late 1970s, Varmus and Bishop had shown that the precursors of oncogenes, also called proto-oncogenes, already existed in all normal cells. They hypothesized that mutations in such proto-oncogenes caused cancer. To taste that they were right, we needed to the mutated versions of such proto-oncogenes within the cancer cells.How does one find such a gene? The MIT cance r biologist Robert Weinberg had an idea. If he transfers a fragment of the DNA containing the activated oncogene from the cancer cell into normal cells, then the activated oncogene should speed the normal cells to divide and proliferate, producing a foci turn out of the normal cells in the petri dish. By repeating this process and dividing the DNA fragments into smaller and smaller fragments, he should be able to isolate the culprit.In the summer of 1979, a graduate learner in Weinbergs lab named Chiaho Shih went through the experiment using mouse cancer cells. He verified that the method worked for mouse cancer cells. They then locomote on to human cancer cells.Three years later in 1982, Weinberg isolated a gene called ras from human cancer cells. The mutated ras gene encoded a hyperactive protein permanently locked on. It was the long-sought native human oncogene, captured out of a cancer cell.Meanwhile, two other scientists, Mariano Barbacid, and Michael Wigler had also indep endently discovered the ras gene in 1982.The second risky prediction the hypothesis that retinoblastoma was caused by the mutation of two copies of Rb genes. Thad Dryja, an ophthalmologist and geneticist, suspected that the mutation responsible was likely a deletion of the gene. To prove the hypothesis, Dryja wanted to prove that the two copies of the Rb gene were deleted from the cancer cells.Week after week, Dryja extracted the chromosomes from his massive collections of tumors and ran his essay set against the chromosomes. Eventually, he saw a blank seat in his probes. A piece of DNA was missing in probe H3-8 of the tumor cells. Dryja took his probe to Steve Friend who had a collection of normal cells in Weinbergs lab. Friend applied the H3-8 probe to normal cells and isolated the gene on that location. Both copies of the Rb genes were indeed deleted from the cancer cells.The third risky prediction involved the hypothesis that activated oncogenes cause cancer. We already knew that (1) activated oncogenes were symbolise in cancer cells, and (2) they could be isolated from the cancer cells. To prove causation, we have to prove that activated oncogenes can create cancer in an animal.In 1984, using transgenic mouse technology, Philip Leders team at Harvard created transgenic mice with an activated c-myc gene expressed in the breast cells. The mice developed small tumors in their breast late in life after pregnancy.To test the roles of environmental stimuli and other oncogenes, Leder created a second OncoMouse with ras and myc expressed in breast cells. The mice developed exact distinct tumors in their breasts in months, pregnancy not required. Scientists had created real, living tumors in an animal.The Hallmarks of CancerPhilip Leders experiment showed that scientists had created real tumors by manipulating two genes, ras and myc, in an animal. But activating two potent proto-oncogenes did not create the replete(p) syndrome of cancer in every cell of the mouse. It raised further questions about(predicate) the genesis of cancer.In 1988, using human specimens, a physician named Bert Vogelstein set out to describe the number of genetic changes required to start cancer.Vogelstein examine how normal cells progress to cancer cells in colon cancer. He found a consistent pattern in his colon cancer samples. The genetic progression of cancer was a multi-step process. The transitions in the stages of cancer mirrored the transitions in genetic changes. Cancer cells did not activate or inactivate at random. Instead, the shift from a pre-malignant state to an invasive cancer correlated with the activating and inactivation of genes in a strict and stereotypical sequence.Cancer cells are caused by mutations of genes in their DNA. Besides uncontrolled growth, cancer cells also can resist devastation signals, grow their own blood vessels, and metastasize passim the body.In January 2000, Robert Weinberg and Douglas Hanahan wrote the seminal pap er, The Hallmarks of Cancer that gave the six essential changes in cell physiology that collectively cause cancerSelf-sufficiency in growth signals mess up pedal stuck onInsensitivity to growth-inhibitory signals- brakes dont workEvading of programmed cell death (apoptosis) wont dieLimitless replicative potential uncontrolled growth sustained angiogenesis having its own blood supplyTissue invasion and metastasis