Chapter 3 Chapter 3 Clues: The Search for Proto-Oncogenes

By the mid-1970s, Ames and countless other researchers studying chemical carcinogens had a general and simple description of the origin of human cancer.Once they accepted this new idea, they started spreading the word.They believe that cancer is caused by chemical and physical factors that damage the genes of cells inside human tissues.At the same time, another school of cancer researchers took a very different view, the complete opposite.They believe that chemical research is not convincing, and infectious factors are the root cause of cancer.This school of thought portrays cancer as an infectious disease, spread by microbes rather than caused by mutagenic chemicals or radiation.

The alleged microbes are viruses—subcellular forms of life.Virus particles, wrapped in protein and lipid coats, are only the size of genetic packages and wander from cell to cell.After the virus particles are adsorbed to the cell surface, they inject their own genes into the cell interior.Thereafter, the injected viral genes begin to replicate themselves.These newly replicated viral genes quickly assemble into a new assembly—a new virus particle that occupies the chemical space reserved by the host cell for its own use.The progeny virus particles then break through the infected cell and begin to seek out new cells to colonize.

It seems that the only function of viruses is to replicate themselves as much as possible.During the replication process, the virus and its progeny can kill many cells and damage many tissues.Viruses can cause respiratory infections, rabies, measles, mumps, rubella, smallpox, and cold sores.Every virus is devastated everywhere. But some viruses behave in a different way: Instead of destroying tissue, they cause cancer. In 1909 Peyton Laws of the Rockefeller Institute in New York discovered the first tumor virus.He found that when virus particles extracted from the connective tissue of one chicken were injected into another chicken, the latter also produced tumors.Cancer-inducing virus particles can also be extracted from the tumor.Rous sarcoma virus is indeed capable of unlimited transmission in chicken flocks.Virus multiplies inside each infected chicken cell, prompting tumor formation

In the 1930s, new oncoviruses were discovered that caused skin cancer in rabbits.Subsequently, mouse breast cancer virus and leukemia virus were discovered successively.A relative of Rous sarcoma virus can cause leukemia in chickens.By the 1950s, several more leukemia viruses had been identified in mice. These findings lead to a simple conclusion.A tumor virus can invade a cell somewhere in the body.Instead of multiplying inside the cell and then killing the cell, the virus allows the cell to survive.The virus laying down the butcher knife is not becoming a Buddha. This is just a move for the virus to live in the new host for a long time.Once it's settled inside a cell, the virus tampers with the host's growth-control mechanisms, driving the cell and its descendants to relentless expansion.Even though a virus particle is thousands of times smaller than the cell it infects, it can usurp control of the cell and manipulate its behavior.An infectious tumor virus particle drives cells to proliferate and form tumors by driving them to grow and divide infinitely.

Tumor virus particles take over cells, providing a clear and powerful explanation for the origin of human cancer.But attributing human cancers to infection with tumor viruses remains problematic.The work of epidemiologists presents the most intractable contradiction to this view.These studies clearly show that most human cancers behave differently than infectious diseases.If the geographic distribution of cancer cases is plotted on a map, they appear to be randomly distributed geographically, rather than occurring in densely packed small groups like an epidemic. Those who advocate the tumor virus theory can justify themselves.They hypothesize that human tumor viruses are ubiquitous in the human population, and that, like bacteria that colonize the skin and gut, these viruses are usually harmless.But in rare cases, the virus is activated in some unknown way, bursting out in silence, causing cancer, with serious consequences.The notion that cancer is always an isolated event that pops up here and there rather than a massive epidemic fits the observation that it is widespread and haphazardly evil.

By the early 1970s, those who advocated the tumor virus theory began to use new molecular biological methods to strengthen their views.By isolating cancer viruses into their molecular forms, oncology virologists have begun to understand in detail how viruses successfully turn normal cells into cancerous ones.Their motivation for this research is simple: to make the human cancer virus theory more credible. Like all other self-replicating organisms, tumor virions carry many different genes.Unsurprisingly, some viral genes are dedicated to viral replication.These "replicating" genes act as templates that allow the virus to replicate itself inside the infected cell.In addition, oncoviruses appear to carry special genetic information that enables them to transform an infected host from normal growth into rapidly growing cancer cells.Therefore, it is the genes carried by the virus that cause the cancer.

The finding strengthens the argument that cancer is a disease caused by genes, but it does little to bridge the gap between the chemical and viral theories of cancer.Chemical carcinogen researchers continue to insist that oncogenes in tumor cells do not originate from viruses, but arise spontaneously from cancer cells.They are the result of genetic changes in normal cells caused by chemicals or radiation.Those who believe in viruses insist that all tumor cells carry foreign oncogenes—genes imposed on those cells by invading tumor viruses. However, there is a common thread that unites the two factions.Both acknowledge that there is a small population of genes at work inside the cell that allow the cell and its progeny to grow out of control.They call such cancer genes "oncogenes" (oncogenes), which echoes the word ".ncology" (oncology), which refers to the profession of tumors. In Greek, ".nkos" means a piece or a mass .fallen good people

The debate reached a fever pitch.It is difficult to reconcile the two sides of the debate about the origin of human cancer.It turns out that both theories have played an important role in unraveling the mystery of cancer's origins.In fact, there is a way to bridge the gap between the two factions.The reason is as follows: Maybe oncogenes are indeed crucial to the occurrence of cancer, but the oncogenes that cause cancer may not be brought by viruses that invade cells, but chemical carcinogens that damage normal cell genes may play a role. The genes then become potent oncogenes, acting like the oncogenes brought into cells by infectious tumor viruses.

The idea is fascinating, but obviously unverifiable.Like most unprovable insights, it was dismissed as whimsy with no scientific value.The pantheon of cancer research is littered with the wreckage of dozens of theories about the origin of cancer, and this one doesn't seem to have a better fate. It is believed that a human cell, whether normal or cancerous, carries tens of thousands of genes in its DNA.There may be a small group of genes that, when mutated in response to chemical carcinogens, drive cells to grow out of control.At this moment, none of the existing technologies can undertake the task of finding the small number of mutated genes inside cancer cells.

Surprisingly, however, it was the researchers of the viral oncogene who found the cellular oncogene.The discovery of this class of genes sparked a massive revolution in cancer research that continues to this day. The answer comes from the Rous sarcoma virus, often referred to as RSV. After 1909, Rouse abandoned the study of RSV because he believed that it was not relevant to understanding the origin of human cancer.Over the next 60 years, RSV was only occasionally involved by other researchers. In 1966, the elderly Rous won the Nobel Prize in Medicine and Physiology for his research work more than half a century ago.

The 1960s saw a resurgence of interest in oncoviruses, thanks in part to a new generation of young researchers eager to use DNA analysis techniques to dissect the causes of cancer.Among them were Harold Varmus of San Francisco and J.Michael Bishop and his colleagues sought to understand how RSV grows in infected chicken cells and, in particular, how RSV turns these cells from normal growth into cancerous ones. Warmus and Bishop drew on the work of other researchers who set out to isolate the RSV genome.Like other viruses, RSV carries genes it uses to replicate itself in infected cells.These replicators instruct the cell to produce hundreds or even thousands of progeny virus particles identical to the one that caused the infection in the first place. But in the end, it was another gene of RSV that jumped into people's eyes.It is the gene that the virus uses to turn an infected normal cell into a cancerous cell -- a viral oncogene.In "sarcoma" (sarcoma), the viral gene is called src (pronounced Shaq).All the evidence suggests that when src enters a cell via an infectious RSV particle, it sounds the charge, driving the cell and its progeny to relentless growth. The origin of the src gene in RSV remains a mystery. Other relatives of RSV, although they have the same replication genes and can reproduce in infected chicken cells like RSV, cannot turn infected chicken cells into tumor cells, nor do they have the src gene.This phenomenon makes people regard src as a tool for RSV to induce carcinogenesis. After observing RSV and its relative viruses, most geneticists have concluded that only RSV is a true natural virus, while their relative viruses have lost the src gene for some reason and become related carcinogenic defects. mutant virus.Viruses are known to often lose genes by abusing their gene-replication machinery. However, the facts of this case seem to point in another direction. Relative viruses of RSV are widely distributed, but RSV with src oncogene is unique, and only Rous himself was isolated once at the beginning of this century. RSV seems to be the oddity, while its relatives represent the norm.Perhaps a relative virus acquired the src gene from some external source and became RSV. So where is the src gene sacred?Most likely, the upper SV ancestor snatched the src gene from another oncovirus.The gain gave RSV something it didn't have before, namely, inducing cancer. The Warmus-Bishop joint experiment quickly confirmed the existence of gene theft, but the true source of the stolen genes was surprising.Their research team developed a technique to detect the src gene in viral and cellular genomes.Armed with this skill, the researchers began searching for other places where the src gene might show up. In 1975, a researcher at the laboratory unearthed a most unexpected treasure in a routine experiment.He used their new technique to analyze the genes of normal chicken cells as well as chicken cells infected with RSV.The expected result should be: there is no src oncogene in normal cells, but infected cells have at least one src gene, that is, the src gene that RSV virus imports into the cell. However, this estimate is quite wrong.The src gene was clearly present in both uninfected and virus-infected cells.Normal chicken cells possess at least one src long before infection with RSV. Their discovery sparked a revolution in 1976 after it was reported publicly in the Th year.The discovery led to a complete shift in thinking by researchers.It means that the gene was likely originally a cellular gene that was abducted by an RSV ancestor and then incorporated into the RSV genome, used by the virus to turn normal cells into cancerous ones. So there is a new idea as follows. Before Rouse discovered the RSV virus in 1909, RSV was still completely unknown to humans.Its direct ancestor is a related virus that can multiply in chicken cells but cannot turn them into cancerous cells.When the virus grows in an infected chicken cell, under certain conditions, through a certain genetic event, a src gene of the cell is incorporated into its own viral genome. The src gene is a normal chicken gene.Prior to the theft, src was functioning in some normal areas of chicken cell growth and was not involved in cancerous morass.But once src became part of the RSV genome, the virus corroded src, changing src from Jekyll to Hyde." A normal cellular gene was regenerated into a potent oncogenic factor. Soon, the researchers discovered that all birds had at least one normal src gene in their genomes.Later, the src gene was also found in the genomes of all vertebrates including humans.That said, the src gene is part of the normal genetic equipment of all vertebrates.In the following years, a variant of the normal src gene was discovered in distantly related animals, including fruit flies. The distribution of normal src genes in such a diverse range of animal genomes means that the common ancestor of all these organisms already possessed some variant of the src gene more than 600 million years ago.Subsequent organisms retain this gene simply because it plays an integral role in the life of the organism.If the src gene were not so important, at least some animal populations would have abandoned it at some point in evolution.However, src is apparently everywhere. Thus the src gene has two faces.Under normal circumstances, it acts as a template for a specific function in the cells of all animals.However, after it is seized by RSV, src acts as an oncogene, turning RSV into a potent oncogenic factor. src and The 19th century British novelist R. L． In Stevenson's novel (Dr. Jekyll), a kind and gentle doctor Jekyll takes a drug and turns into another ugly and murderous person named Hagrid. ——Translator's Note The relationship of RSV can explain a peculiar event-gene theft in a chicken coop on Long Island in 1909.A few months later, the tumor-ridden flocks came to Rouse's attention. But there is an even more important circumstance that overshadows viruses, and their genetic diversity.The Warmus-Bishop team dubbed the regular form of the src gene a "proto-oncogene," suggesting that it has the potential to transform into an oncogene under the right circumstances.Their terms imply that at least one potential cancer-causing factor is lurking in the genomes of chickens and even humans. Thinking about the origins of cancer has revolutionized.For the first time, the idea that disease is rooted deep in normal cells has shown its plausibility.It seems that every cell has buried within its normal genome a root of self-destruction—a gene meant for normal life.black sheep Before long, Varmus-Bishop's lab and other researchers were taking a closer look at other viruses that could cause tumors like RSV.These other viruses can infect chickens, mice, rats, monkeys and even cats.They both belong to the retroviruses and are distant relatives of each other. (HIV, the virus that causes AIDS, discovered a few years later, is also a distant relative of these oncogenic retroviruses.) The various retroviruses that cause cancer in animals have a history that is strikingly similar to RSV.Each arose from a previous virus that did not rapidly develop tumors in infected host animals; The proto-oncogene was selected, and the effective carcinogenic ability was obtained.Viruses engineer these captive genes into potent oncogenes. The proto-oncogenes and src stolen by these different viruses are different, and they are each given unique gene names. These names reflect the source of the virus in which the gene was first discovered: myC is in avian myelocytoma (avlan myelocytomatosis) was first isolated. s is from murine sarcoma virus and in is from feline sarcoma virus.Soon, the number of genes on the list increased to more than 20 species. Now, the example of src can be extended and summarized as one point: the genome of animals contains many proto-oncogenes, most of which have no relationship with src.Like src, each proto-oncogene is widely distributed within the animal kingdom.Therefore, Chuan y[ and Zhou wb, originally found in chicken DNA, can also be found in **A of all other mammals.Proto-oncogenes of various types appear to be found in the genomes of all vertebrates. That is to say, in the human genome, there is a group of potential oncogenes - proto-oncogenes.They play an integral role in the reproduction of human cells.In the hundreds of millions of years of evolutionary history of animal genomes, these genes have gone through vicissitudes without changing their original intentions, which fully demonstrates their importance. It will take nearly a decade to reveal exactly what these normal genes do.At this moment, their normal role remains puzzling.The discovery of proto-oncogenes has an even more significant implication: They are candidate targets for chemical carcinogens.Proto-oncogenes in animals are occasionally activated by retroviruses to become oncogenes; perhaps, mutagenic carcinogens can also activate proto-oncogenes in humans.Rather than being stolen from their old home in the cell's chromosomes by passing retroviruses and modified, human proto-oncogenes may have been modified in situ by aggressive carcinogens.Different approaches lead to the same goal, and the result may be the same - to produce powerful oncogenes. Thus, for a few years in the mid-1970s, a light dawned on the mystery of cancer.The reason why retroviruses have such powerful abilities is that they often mess around in the gene pile of the host cell, and when they happen to be able to have unexpected gains-proto-oncogenes.Viruses open another window to these genes—dozens out of the thousands in the human genome.While the notion that oncogenes play a key role in causing cancer has yet to be proven, those who seek to prove that cancer is rooted in genes, even if there is no hard evidence, rejoice.Soon, they unexpectedly obtained enough evidence.This evidence turns a fascinating hypothesis into a solid fact.