Chapter 2 Chapter 2 Clues to the Origins of Cancer: How the Outside World Influences the Cell's Inside

In order to understand the root of cancer, let's put aside the discussion of cells and genes and turn to a completely different direction, that is, the science of studying and describing human beings and human diseases-epidemiology.Epidemiologists study the incidence of cancer in large groups of people, and cancer epidemiologists study the incidence of cancer in different populations.Their work is almost always driven by a central question: How exactly do different behaviors or environments affect the incidence of a particular cancer?Cancer incidence has become an interesting scientific subject only recently.Cancer remained a relatively rare disease until the 19th century, which can be explained by the fact that cancer occurs mainly in older people.In the early nineteenth century, life expectancy in many European countries was only 35 years.Many people may develop cancer later in life, but they end their short lives early due to infectious diseases, malnutrition or accidents.

As for the rare cases of encountering cancer, most of them are attributed to accident or God's will.But some of the evidence accumulating since the last decade of the eighteenth century has led to another view: cancers are linked to a patient's particular experiences or lifestyles.Some doctors came up with this new idea by starting to document specific tumors that occurred in specific populations. The most famous of these, and perhaps the earliest, was made in 1775 by the London physician Percival Potter (perCIV. lp. ti).He described cancer of the scrotum in a man who had worked as a chimney sweep in his early years.Porter proposed the first cancer whose pathogenesis is closely related to special factors or environments.Soon, also in London, a surgeon reported that snuffing

Various reports scattered throughout the nineteenth century reinforce this view.Miners at the pitchblende mines in eastern Germany died of lung cancer, a disease that is extremely rare in a large part of the population.By the early 20th century, those who worked with the newly discovered X-rays were found to be prone to skin cancer and leukemia.Women who applied luminescent radium to watch hands were diagnosed with tongue cancer from frequent licking of bristles.Since the early 1950s, the incidence of lung cancer among smokers has been increasing, usually 20 to 30 times higher than that of non-smokers.

There are also huge differences in the incidence of cancer between countries.The incidence of liver cancer in some parts of Africa is 18 times that of the UK.The probability of Japanese suffering from stomach cancer is 11% higher than that of Americans.Colon cancer rates in the United States are 10 to 20 times higher than in some parts of Africa.These marked differences were not due to genetic predisposition.When people move from one part of the world to another, their children quickly develop high rates of cancers typical of the new location. It is clear from the above that, for many cancers, the unprovoked spontaneous breakdown of human tissue has become an unconvincing explanation.Another theory is more convincing: External factors affecting the body—lifestyle, eating habits, or the environment—play an important role in the development of cancer.This great shift in thinking that began in the early 20th century coincided with another revolution in our understanding of infectious disease. In the last decades of the 19th century, Robert Koch and Louis Pasteur discovered that many fatal diseases could be traced to specific, accidental factors: bacteria and viruses.Since then, human diseases are no longer the effect of random and unpredictable natural forces, but have their own special known causes.

This major breakthrough allows us to redefine and clarify the problem of cancer.Now we can put the cancer mystery in more precise terms: How exactly do lifestyle and eating habits specifically affect the behavior of tissues deep within the body?Unraveling this mystery requires describing both normal and cancerous individual cells, and the mechanisms within them that drive their growth.Such simplification—the condensation of complex phenomena into a single underlying mechanism—soon became a central theme of contemporary cancer research, and would remain its glory well into the late 20th century.Cancer Factors and Target Genes

The idea that cancer is not the random, spontaneous deterioration of human tissue but its activation has fundamentally changed the thinking of many cancer researchers.If external factors drive cancer, perhaps we can identify these factors and study how they work.Perhaps, the whole process from the initial oncogenic factor to the development of cancer can be revealed.So, until the end of the 19th century, scientists all over the world tried to recreate cancer in laboratory animals—mice, rats, rabbits.Year after year, but no success. In the first decade of the 20th century, Japan achieved its first success.Katsuzaburo Yamami took inspiration from earlier studies of chimney sweeps in Europe.Originally Percival Potter found a high incidence of scrotal cancer among chimney sweeps in London, but decades later, studies by others found much lower rates of scrotal cancer among chimney sweeps in continental Europe.It appears that this difference is related to personal hygiene practices.British chimney sweeps, like many of their 18th-century compatriots, rarely bathed, while those on the Continent bathed frequently.It appears that creosote tar from London flues that sticks to the skin of English chimney sweeps causes cancer if not washed off quickly.

In response, Sanji repeatedly smeared coal tar on the rabbit's ears.Many months later, skin cancer developed on the rabbit's ear.And other researchers failed to induce cancer because they either gave up too soon or didn't think about the need to apply the substance repeatedly. Yamaji's experiments directly show that cancer can be induced in the laboratory as desired by special factors.Rabbit ear tumors—and perhaps all other tumors—can have a definite cause.But this epiphany can only lead to another pivotal question: How exactly do chemicals, like the one in coal tar, cause cancer? Cancer-causing chemicals -- chemical carcinogens -- somehow get into the body Tissue cells, which promote tumor growth.So the cancer itself is not the invader, the real invader is the carcinogen (in this case, coal tar).

The discovery that X-rays can also cause cancer adds to the mystery.After Wilhelm Roentgen's discovery in 1895, X-ray tubes were widely used for bone imaging and treatment of various diseases.Technicians who operate X-ray machines and the many genes responsible for X-ray red eye color have been studied extensively.After X-ray irradiation, the eye color mutation gene becomes a template, and the eyes lose their pigment and become almost pure white.This white-eyed trait can be passed on to future generations indefinitely. By the end of World War II, it was discovered that certain chemicals could mutate fruit flies.Patients exposed to radiation developed skin cancer and leukemia.How could these two disparate factors—chemicals and X-rays—be insidiously linked so that both can induce cancer?Both are harmful and both damage human tissue and kill cells.But what does killing cells have to do with cancer?The manifestation of cancer is the proliferation of tissue cells, which runs counter to the failure of tissue cells caused by harmful factors.

By the 1930s, the coal tar problem was better understood through the combined efforts of American chemists and cancer researchers.They found that coal tar is actually a mixture of hundreds or even thousands of different chemicals.So chemists separated the tar into its many chemical components, which were given to cancer researchers, who went on to test each component for its carcinogenic potential in laboratory animals.They found that some of the ingredients have a strong carcinogenic effect.Now the mystery of chemical carcinogens can be formulated more precisely: Certain chemical constituents, such as 3-methylcholanthracene and xylylenepropanthracene—and, of course, X-rays—cause cancer.

But such progress has done little to address the fundamental question of how these or other chemicals induce cancer.As is often the case in cancer research, the giant leaps in solving this particular problem came from studies with no apparent link to cancer.This time, the strongest conclusions came from genetic studies of fruit flies.By the early 20th century, fruit flies were thought to possess a genetic system very similar to that of humans. Not least, the flies' genes can be easily replaced.The offspring of a pair of fruit flies are often identical to their parents.But in the 1930s, Hermann Müller discovered that x-rayed fruit flies produced offspring that sometimes had very different traits.These entirely new traits are often passed on to the next generation of fruit flies, which are then passed on from generation to generation.

Muller's conclusion is that the genetic material once thought to be passed on with great detail and precision from one generation to the next is actually very fragile and volatile.Geneticists call this mutagenic.In some unknown way, the X-rays act on the genetic material and alter its informational content.Therefore, the scientific thinking and vocabulary should be: X-rays can cause gene mutations. Unpredictable genetic changes induced by X-rays are often fatal.But in rare cases, these genetic changes -- mutations -- didn't affect the flies' growth and development, and they remained healthy and strong despite the altered genes.A well-studied example of a gene that normally specifies the color of red eyes has been studied.After X-ray irradiation, the eye color mutation gene becomes a template, and the eyes lose their pigment and become almost pure white.This white-eyed trait can be passed on to future generations indefinitely. By the end of World War II, it was discovered that certain chemicals could mutate fruit flies.Some of these are the highly active azithrils that were used in gas warfare during World War I.As before, the second and subsequent generations of a fruit fly exposed to chemicals passed on altered forms of genes that dictate traits such as eye color, limb or hair development. Around 1950, several geneticists combined the accumulated information on chemicals, X-rays, and mutations to come up with a unified, conclusive theory, although it was still speculative in practice.The theory goes like this: X-rays and certain chemicals can cause cancer. X-rays and chemicals can also cause genetic mutations.Thus, these carcinogens cause genetic mutations in the animals affected by them.In other words, carcinogens (that is, factors that cause cancer) are actually mutagenic factors (factors that cause mutations), and there is an inextricable relationship between these two processes. Implicit in this reasoning is the premise that fruit fly genes share the same behavioral patterns as human genes.By the 1950s, this theory had become increasingly attractive.Drosophila genes and human cells have been found to possess DNA molecules.Moreover, cells in all complex organisms, from worms to flies to humans, are organized in a very similar way.Thus, generalization from one organism to another has a solid foothold. Mutations caused by these mutagenic factors also cause a little confusion.Geneticists study those mutated genes that are passed down through generations in an organism.But in the case of cancer, the mutagen appears to damage only those cellular genes at specific locations within the body.Based on this, it can be deduced that once the gene of a target cell is damaged, the mutant cell will expand rapidly in the body like a wild horse, and sooner or later a large number of offspring cells that are considered to be tumors will be produced. There seem to be two systems of inheritance here: one that describes the transmission of genes from an organism's mother to its offspring, and one that describes the transmission of genes from a cell within a tissue to the cells of that tissue's descendants.In the latter case, the genes altered by the mutagenic carcinogen usually have no chance of being passed on to the next generation of organisms.No matter how badly damaged the genes of gut, brain or lung cells are, they never affect the genetic makeup of an organism's offspring. This dichotomy can be stated more simply: mutations in germ cells (sperm or eggs) are passed on to offspring; mutations in cells elsewhere in the body (somatic cells) are not.This stuff, known as somatic mutation, apparently plays a key role in causing cancer. After Watson and Crick discovered the double helix structure of DNA in 1953, inferences about genes and mutations could be expressed in a more precise vocabulary.If the information contained in the gene is encoded in the form of DNA base sequence, then the mutation is the change of the DNA structure, that is, the change of the DNA base sequence that makes up a single gene.If the theory that carcinogens are equal to mutagenic factors is valid, then cancer cells must contain DNA molecules with altered base sequences.These altered DNA sequences store information that normal cells do not, and somehow direct cancer cells to grow out of control. The carcinogen-mutagen theory is fascinating because it reduces the complex phenomenon of carcinogenesis to a single underlying mechanism.But it will take another 30 years of research to confirm the theory.It has often been the case that genetic inferences are much more advanced than the available evidence.Mutagens confirmed to be carcinogens In the 1930s, it was already known that many chemical substances used in experimental animals had carcinogenic effects.Before long, cancer researchers started a family workshop, trying to induce tumors in animals again.They usually choose mice and rats.Like intermountain rabbits, their biology bears some resemblance to humans, and they can reproduce in large numbers, with repeated application of chemicals over many months.This method of testing for potential carcinogens was especially necessary as the chemical industry began putting hundreds or even thousands of chemical ingredients on the market after World War II. By the 1960s, this testing method had picked up many substances identified as causing cancer in rodents.Many of these are suspected to be carcinogenic to humans as well, but in most cases this suspicion can never be proven because the suspected carcinogen must not be consciously applied to humans.Chemicals believed to cause cancer in rodents are often withdrawn from the market and, when permitted for common use, their use is severely restricted. Rodent carcinogen tests have revealed many cancer-inducing chemicals.These potential carcinogenic chemicals vary in molecular structure.After entering the organism and the cells of the organism, they combine with different target molecules inside the cells, and change or even damage the target molecules in some way.The diversity of chemical carcinogens means that there is an equally rich variety of target molecules inside human cells. It is also recognized from experiments that different chemicals have very different carcinogenic effects on experimental animals.Sometimes it takes several hundred milligrams of a chemical for many months to induce cancer.Other chemicals require only a few micrograms, one or two injections, to develop cancer in mice or rats.The coefficient of variation for this carcinogenesis is as high as 1 million or more.One of the most carcinogenic chemicals found in tests is the naturally occurring aflatoxin.It is produced when peanuts and grains become moldy due to improper storage.For rodents, even a very small amount of aflatoxin has a strong inducing effect on liver cancer, and an epidemiological survey in Africa showed that it is equally dangerous for humans. It is baffling that so many chemicals have been implicated as carcinogens, complicating rather than simplifying the question of cancer's origins.How can mountains of evidence be condensed into a few simple principles?How, exactly, can the carcinogen-mutagen theory be illustrated in terms of what these chemicals do? In the mid-1970s, geneticist Bruce Ames of the University of California, Berkeley, provided an answer to this mystery.Ames' early research focused on the workings of bacterial genes.Because the genes involved in bacterial function closely resemble those of more complex life forms, Ames' work, like much of bacterial genetics, has broad implications.Bacterial genes are encoded in DNA molecules and are just as easily damaged by mutations as human genes.X-rays and many chemicals that damage human genes can have the same effect on bacteria. Studying bacterial genes has a significant benefit over studying human or mouse genes.How quickly and cheaply bacteria can grow.They can start breeding in 20 minutes, whereas mice take months to prepare.Therefore, the achievements of bacterial genetics greatly promoted the genetic research in the 1960s and 1970s. Ames was trying to come up with a simple way to measure the relative mutagenic power of different chemicals.He applied the chemicals to the genes of Salmonella bacteria grown in petri dishes.In his most widely used experiment, a mutation in a key gene allowed mutant bacteria to multiply into colonies that were clearly visible in petri dishes; unmutated bacteria were unable to do so.So, to accurately gauge the effect of a potential mutagen, one simply injects the chemical into a Petri dish containing the appropriate bacteria, mutates the bacteria's genes, and counts the number of colonies that appear on the calculator.Increased colony numbers directly reflect the mutagenic potency of the test chemical. Ames rounded up a large collection of known carcinogens and tested them one by one using his bacterial mutation assay.Analysis of the test results yielded encouraging correlations.Chemicals that are highly mutagenic to bacteria are equally effective at inducing tumors in experimental rodents; chemicals that lack significant mutagenesis also appear to lack carcinogenicity. The carcinogen-mutagenic factor theory is no longer a castle in the air, and for the first time has a little experimental basis.Moreover, a chemical's ability to cause cancer appears to stem from its ability to damage the genes of the body's cells.There is indeed a close connection between mutagenicity and carcinogenicity. The method, known as the Ames Test, has another bonus.Now, scientists can measure the cancer-causing potential of a newly discovered chemical within a day or two.At that time, testing the safety of chemical ingredients on humans was slammed. Instead, rodents were used as test subjects. The test also took several years, and the Ames test was a hundred times cheaper.A single positive result from the Ames test can almost seal the future fate of the tested chemical. Of course, things are not really that simple.Some chemicals are responsible for rising cancer rates in rodents and humans, even though they tested negative in the Ames bacteria test.Asbestos and alcohol are notable examples.Of course, there are also chemicals that are highly effective against genetic mutations in bacteria but have little carcinogenic effect on mammals. Therefore, it can be expressed as follows: Mutagenic factors enter cells, damage genes, and cause cancer.Soon, it was found that many carcinogens directly act on DNA molecules, especially the bases in the two strands of the double helix.By altering the base structure, they directly affect the information content of the DNA, which is exactly what mutagenic factors are intended to do. Thus, through the contributions of Ames and others, the carcinogen-mutagen theory gained strong support: Many carcinogens create mutant genes by damaging DNA.However, this is just one of many theories about the origin of cancer. As long as one key evidence is missing, it cannot override other theories and become the truth.If carcinogens cause cancer by changing genes, then cancer cells must carry mutated genes.These mutant genes must be found.If not, the carcinogen-mutagen theory is out of the question, along with dozens of other failed theories that have attempted to explain this complex disease.