2020年11月11日星期三

what does a hemorrhoids look like,"The King of Diseases" 2

    There is also a nutritional anemia that Minot's research team has not studied. It breeds in the Mumbai weaving factory owned by British merchants thousands of miles away. The factory is managed by the local minions who press bones and suck the pulp. The wages here have been maintained at an extremely low level, resulting in the workers living in abject poverty, malnutrition, and lack of medicines. Therefore, in a moral sense, this is another "pernicious" anemia. In the 1920s, British doctors performed physical examinations for these workers to study the effects of this chronic malnutrition. They found that many of them, especially the women, had severe anemia after giving birth (this is another "colonial charm"-creating a certain misery in a large population, and then proceeding to sociology or medicine. experiment of).

    In 1928, the young British doctor Lucy Wills had just graduated from the London School of Gynecology and went to Mumbai with a grant to study this anemia. Wells is an alternative among hematologists. She is driven by a strong curiosity and is willing to venture to a faraway country and dream of solving a mysterious anemia. She knows Minot's work. But she found that the anemia in Mumbai is different from the anemia studied by Minot, and it is impossible to reverse the condition by taking Minot's "mixed food" or vitamin B12. Surprisingly, she found that using dark-colored yeast sauce, which was becoming popular among the “diet therapy admirers” in the UK and Australia at the time, could cure this anemia. Wells was not sure which key chemical nutrient in the yeast sauce played a role, so he called it the "Wells factor."

    It was later proved that the "Wells factor" turned out to be folic acid, which is a vitamin-like substance commonly found in fruits and vegetables (the yeast sauce is rich in folic acid). DNA replication is required when cells divide-DNA is a chemical substance that carries all the genetic information in a cell. Folic acid is a key component of DNA. Therefore, folic acid is essential for cell division. Cells in the human body divide to produce blood cells at the most alarming rate. Every day, more than 300 billion cells are produced. Therefore, the production of blood is particularly dependent on folic acid. When folic acid is scarce (as in Mumbai, where men and women have no money to eat vegetables), the bone marrow stops producing new blood cells. Millions of semi-mature cells spew out, like semi-finished products stuck on the "production line". The bone marrow has become a factory that cannot function normally, a physiological factory that is malnourished, which is strangely reminiscent of the weaving factory in Mumbai.

    Farber was busy studying the connection between vitamins, bone marrow and normal blood in the early summer of 1946. In fact, his first phase of clinical trials inspired by these aspects has evolved into a terrible mistake. Lucy Wells once found that if folic acid is taken for patients with nutritional deficiencies, they can restore normal blood production. Farber does not know if children with leukemia can get their blood back to normal if they take folic acid. Following this far-fetched idea, after he obtained some synthetic folic acid, he recruited a group of leukemia children to line up for experiments and began to inject folic acid into them.

    But in the following months, Faber discovered that not only did folic acid not prevent the development of leukemia, it accelerated the progression of leukemia. One patient's white blood cell count almost doubled. Another patient's leukemia cells surged into the bloodstream and caused malignant cells to leak out of the skin. Farber hurriedly terminated the experiment. He called this phenomenon "acceleration", as if a dangerous object accelerates to the ground in free fall.

    Faber's experiment angered the pediatricians at Children's Hospital. This synthetic folic acid not only exacerbates the condition of leukemia, but may also cause the death of sick children. But Faber is interested in that since folic acid can promote the development of childhood leukemia cells, what will happen if he can cut off the supply of folic acid in sick children with a certain drug? For example, a kind of "antifolate" (folate antagonist)? Can a chemical that blocks the growth of white blood cells stop leukemia?

    Minot and Wells’ observations begin to fit into a fuzzy picture properly. If the bone marrow was a busy cell factory in the beginning, then the bone marrow infiltrated by leukemia is a factory that runs overspeed, frantically "manufacturing" cancer cell parts. Minot and Wells can open the bone marrow production line by adding nutrients to the body. So, by cutting off the supply of nutrients, can it be shut down? Can we learn from the anemia of the workers in the Mumbai textile factory and redo medical exploration in the Boston hospital?

    On the long road from the underground laboratory of the Children's Hospital back to his residence on Emory Street in Brooklyn, Farber kept thinking about such a drug.His home is laid out with dark wooden boards, and dinner is usually casually sent. Farber’s wife, Norma, is a musician and writer who always talks about opera and poetry; while Farber talks about autopsy, drug trials and patients. When he returned to the hospital at night, Norma's crisp piano sound echoed behind him. The prospect of anti-cancer chemicals troubled Faber, who imagined it and yearned it with an obsessive enthusiasm. But he didn't know what the medicine would be, or what he would call it. The concept of "chemotherapy" as we now understand it was not yet applied to anticancer drugs. Faber dreamed of such a vivid "anti-vitamin" treatment, which did not exist at the time.

    The folic acid used in Faber’s first disastrous drug trial came from an old friend of his, the chemist Yelapragada Subbarao (Yellapragada Subbarao), most of his colleagues called He "Yella". He can be regarded as a pioneer in many ways, as a cell physiologist with a background of physicians and a chemist who accidentally broke into the field of biology. His personality of "taking dangers seriously" also indicates his twists and turns in science. Subalao arrived in Boston in 1923, penniless and unprepared. At that time, he had just completed his medical training in India and received a scholarship to pursue a degree at the Harvard University School of Tropical Hygiene. However, he found that the weather in Boston is far from the "tropical". In the cold and violent winter in Boston, Subbarao did not have a license to practice medicine in the United States, so he could not find a job as a doctor. He could only live in the Brighamand Women's Hospital as a night shift concierge. The job content included opening the door. , Change the sheets and clean the potty.

    However, this kind of work gave Subbarao an opportunity. He made friends and established contacts in the hospital, and was soon transferred to the Department of Biochemistry to work as a researcher and work day shift. His initial project was to purify molecules from living cells and do chemical "dissection" on them to determine their composition. Essentially, it was to perform biochemical dissection of cells. Although this kind of work requires more persistence than imagination, the results are remarkable. Subalao purified a molecule called ATP, which is the energy source of all living things (ATP carries "chemical energy" in cells); he also purified another molecule called "sarcosine", which is Energy carrier in muscle cells. Any one of these achievements should be enough to guarantee him a faculty position at Harvard University. But Subbarao is a foreigner with a serious accent and withdrawn personality. He likes to go out at night and is vegetarian. He lives in a studio apartment in the downtown area and only associates with other "nocturnal animals", such as Farber. In 1940, due to lack of faculty and recognition, Subbarao was angrily transferred to the Lederle Labs under the American Cyanamide Company in northern New York, in charge of a chemical synthesis researcher group.

    At the Rieter Pharmaceutical Factory, Yela Subbarao quickly restarted his original strategy, focusing on developing synthetic versions of natural chemicals in cells, hoping to use them as nutritional supplements. In the 1920s, another drug company Eli Lilly (EliLilly) was already making money by selling concentrated vitamin B12 to treat malnourished pernicious anemia. Subalao decided to focus on the treatment of other anemias, the neglected folate deficiency anemia. But by 1946, after experiencing many failures to extract folic acid from pig liver, Subalao changed his mind and started synthesizing folic acid from scratch with the help of a group of scientists.

    The chemical reaction to synthesize folic acid brought an accidental bonus. Because there are several intermediate steps in this reaction, Subbarao's team can make a slight adjustment to the formula to create variants of folic acid that are closely related to the molecular structure. These variants have some unexpected properties. Usually, enzymes and receptors react by "recognizing" the chemical structure of cell molecules, but "bait molecules" that closely mimic the natural molecular structure will bind to receptors or enzymes to prevent them from having other reactions. Like a counterfeit key blocking the keyhole. Therefore, certain molecular analogs developed by Subalao can act as folic acid antagonists.

    These are the "anti-vitamins" that Faber dreams of. Faber wrote to Subbarao and asked him if he could use "folate antagonists" to treat patients with leukemia. Subalao agreed. At the end of the summer of 1947, the first batch of antagonists was sent from Rieter's laboratory in New York to Faber's laboratory.

    Faber's Book of War

    For thousands of years, patients suffering from this disease have become almost any experiment imaginable. In order to find an effective treatment to treat this thorny disease, no matter the fields, forests, pharmacies or temples, they were all scoured. Almost all animals have contributed without exception, regardless of hair or skin, teeth or toenails, thymus or thyroid, liver or spleen.

    ——William Bainbridge (William Bainbridge)

    Finding a way to eradicate this scourge... can only be left to accidental attempts and uncoordinated research.

    ——The Washington Post in 1946

    Dorchester, seven miles southwest of Boston’s Longwood Hospital, is a typical New England suburban town. It is bordered by a smoky industrial area to the west and the gray-green bay of the Atlantic Ocean to the east. The zone survives arbitrarily. In the late 1940s, waves of Jewish and Irish immigrants settled here, including boat builders, iron casters, railway engineers, fishermen, and factory workers, moving into brick houses with wooden walls. The residential area goes up along the winding Blue Mountain Avenue. Dorchester was completely renewed and became a typical suburban residential city. Along the river, there are parks and playgrounds, as well as a golf course, church and synagogue. Every Sunday afternoon, families and families gather in Franklin Park, walking on leafy paths, or watching ostriches, polar bears and tigers at the zoo.

    On August 16, 1947, living in a residential area across from the zoo, the child of a Boston shipyard worker fell strangely ill. The child's name is Robert Sandler. He is only two years old and has a low-grade fever for more than two weeks. His body temperature fluctuates from high to low, accompanied by increasing lethargy, and his face is pale. His twin brother Elliott is healthy, lively and lovely.

    Ten days after Sandler's first fever, his condition deteriorated significantly, his body temperature rose, and his face changed from ruddy to a strange milky white. He was taken to Boston Children's Hospital. His spleen (a fist-sized organ responsible for storing and producing blood, located in the chest cavity and usually hard to feel) was visibly enlarged, and it hung down like a stuffed bag. Faber observed his blood under a microscope and found that thousands of immature lymphoid leukemia primitive cells were dividing frantically. Their chromosomes keep condensing and unfolding, like a fist clenched and loosened.

    When Sandler arrived at the Children's Hospital, Faber had just received the first package from Rieter Labs a few weeks ago. On September 6, 1947, Faber began to inject pteroyl aspartic acid (PAA) into Sandler, which was the first folic acid antagonist produced by Rieter. (At the time, clinical trials of drugs usually did not require the patient's consent—not even for toxic drugs. Parents were occasionally informed about the trials to be conducted in general, and children were almost never informed or consulted. The "Nuremberg Rules" on human experiments require the subjects to give their explicit and voluntary consent. The rules were drafted on August 9, 1947, less than a month before the PAA test. Did Farber in Boston hear about it? Past this "rule that requires patient consent" is unknown.)

    PAA has little effect. In the following month, Sandler became less and less energetic; he started to limp as he walked, which was the result of leukemia compressing the spinal cord. He also developed joint pain, which then metastasized to his whole body, which was extremely painful. Then the leukemia broke out in one of his thigh bones, causing fractures and causing unexplained pain. By December, the condition seemed hopeless. The tip of Sandler's spleen became heavier due to the effects of leukemia cells, and even dropped into the pelvis. He was depressed, listless, swollen, pale, almost dying.

    However, on the day of December 28, Faber received a new type of folate antagonist, aminopterin, from Subalao and Kelter, whose structure is slightly different from PAA. As soon as the drug arrived, Faber immediately injected it into the boy, hoping to at least bring some relief to the boy's cancer.

    The result was remarkable. Once climbed to an astronomical white blood cell count (10,000 in September, 20,000 in November, and close to 70,000 in December), it suddenly stopped under the action of the drug and stood still. What's even more surprising is that the count began to drop, and the leukemia blast cells gradually decreased in the blood and almost disappeared. On New Year's Eve, the count dropped to 1/6 of the peak, close to the normal level. The cancer cells have not completely disappeared. Although malignant white blood cells are still present under the microscope, it has been temporarily relieved and frozen in the boy's blood in this cold winter in Boston.

    On January 13, 1948, Sandler returned to the hospital for a follow-up visit. This was the first time he entered the clinic by himself in two months. His spleen and liver have shrunk significantly, so Farber pointed out that his clothes "have become very loose in the abdomen." His bleeding has stopped and his appetite is wide, as if he wants to make up for the delicacy he has missed for six months. By February, Faber noticed that the child's agility, nutrition and activity level were comparable to his twin brother. In just a month or so, Robert Sandler seemed to be exactly like Elliott Sandler again.

    Sandler's condition appeared to be relieved, unprecedented in the history of leukemia, which allowed Faber to carry out a series of busy treatments. In the early winter of 1948, more children came to his clinic: a three-year-old boy with a sore throat, a two-and-a-half-year-old girl with lumps in the head and neck, etc., all of whom were eventually diagnosed with childhood acute lymphoblastic leukemia. The supply of folic acid antagonists from Yella is abundant, and patients urgently need these drugs for treatment, so Farber hired some more doctors to assist him, including hematologist Louis Diamond and a group of assistants: James Wolff (James Wolff), Robert Mercer (Robert Mercer) and Robert Sylvester (Robert Sylvester).

    The failure of Farber's first clinical trial angered the children's hospital. The second clinical trial now pushes the hospital's patience to a corner. The hospital passed a vote that the atmosphere in the leukemia ward was too radical and too risky to be conducive to medical education, so it decided to withdraw all pediatric interns from the leukemia chemotherapy ward. This decision actually left the Faber team in a "lone alone" situation. Farber and his assistants can only take care of all the work of the sick. As a surgeon pointed out, children with cancer are usually "crammed into a ward in a remote corner of the hospital." The pediatrician believes that since they are not far from death, why not be more kind and gentle, "let them die peacefully." A clinician suggested that Fabersin’s “chemicals” should only be used as the last resort to save children’s lives. This made Faber couldn't help but recall his previous life as a pathologist. He couldn't help but sneered: "At that time, the only medicine you need is antiseptic liquid."

    Faber transformed the back room of a ward near the bathroom into a temporary consulting room. His few assistants were also placed in the vacant back room, stairwell, and office of the pathology department. The hospital's support is insignificant. Faber’s assistants have to sharpen the bone marrow needles themselves. This ancient and outdated practice is like letting the surgeon sharpen the knife on the whetstone. His staff pay attention to details and meticulously track and record the patient's condition: every blood count, every blood transfusion, and every fever must be recorded in detail. If leukemia can be defeated, Faber hopes to record every minute of this battle for future generations, even if no one wants to witness it with his own eyes.

    The winter of 1948 was dreary and gloomy, and strange cold came to Boston. The snowstorm broke out, bringing Faber's clinic to a standstill. The narrow asphalt road on Longwood Avenue was filled with muddy rain and snow; the basement passage was not warm enough even in autumn, and now it is freezing to the bones. It is no longer possible to inject folic acid antagonists every day, and the Faber team had to go back and implement three injections a week. In February, the wind and snow weakened and the daily injections resumed.

    At the same time, the news that "Faber can treat childhood leukemia" spread like wildfire, and more and more children came to seek medical treatment. Case after case has shown an incredible pattern-folate antagonists can promote the decline of leukemia cell counts, and sometimes even make them disappear completely-at least temporarily. There are also cases of remission like Sandler. The two boys were able to return to school through the treatment of aminopterin. Another 2.5-year-old girl who had been in bed for seven months was also able to "play and run around." The blood returned to normal, almost allowing the children to resume their fleeting normal childhood life.

    But the same fate is still inevitable: after a few months of remission, cancer will inevitably recur, and even Yella's most powerful medicine can do nothing. These leukemia cells will return to the bone marrow and burst out into the blood. Even the most active folic acid antagonists cannot stop their growth. Robert Sandler's condition improved a few months after taking the medicine, but he died in 1948.

    However, even if it is only a temporary relief, it is still a real relief, which is of great historical significance. By April 1948, Farber's treatment team had enough data to publish a preliminary medical report in the New England Journal of Medicine. The team has treated 16 children, of which 10 have been effective. Five children (about one-third of the initial population) are still alive four or even six months after diagnosis. For leukemia, six months of survival is almost eternal.

    Faber’s paper was published on June 3, 1948. It has seven pages and is packed with tables, numbers, micrographs, laboratory measurements, and blood cell counts. The text of the paper is rigid, correct and not emotional, scientific. Extremely strong. However, it is as fascinating as all great medical papers, and as enduring as all outstanding novels. Reading now, the situation at that time seems to be vivid: In the busy days of the Boston Clinic, the life of the patient is hanging by a thread, and Faber and his assistants are busy looking for new medicines for the treatment of this terrible disease that is fleeting and recurring from time to time. The plot of this story is ups and downs, with a beginning, a development, and unfortunately, an ending.

    A scientist recalled that the reaction of the medical community to this paper was "suspicion, disbelief and anger." But for Farber, his research provides tantalizing news: cancer, even the most malignant, can be treated with one drug or one chemical. In the six months between 1947 and 1948, Faber saw a door open. Although the time was short, the door was full of temptation. Only then the door closed again. However, he glimpsed a brilliant possibility through the porch. Through active chemical treatment, an aggressive systemic tumor disappears, which is definitely an unprecedented precedent in the history of cancer. In the summer of 1948, one of Faber’s assistants performed a bone marrow biopsy on a child with leukemia who had been treated with aminopterin. The results were incredible. He wrote: "The bone marrow looks so normal, it makes people think that leukemia can be'cured'."

    Faber's dream is indeed so. He dreamed that a specific anti-cancer drug would kill malignant cells, regenerate normal cells, and return to their physiological space; he dreamed of a whole set of anti-cancer drugs that could destroy tumor cells; he dreamed of curing with chemicals After treating leukemia, this experience of treatment can be applied to more general cancer treatments. Faber threw a challenge book in the field of anti-cancer medicine, and a whole generation of doctors and scientists were involved in this war.

    The hidden plague

    The metaphors we have chosen to describe the universe in a small way reflect ourselves.

    ——Stephen Jay Gould (Stephen Jay Gould)

    The medical industry has known this disease for more than 3000 years. However, for more than 3,000 years, humans have been knocking on the door of the medical field, seeking a "cure".

    ——Fortune Magazine, March 1937

    Now, it's the turn of cancer to break in.

    ——Susan Sontag

    "Illness as Metaphor"

    We tend to think of cancer as a "modern disease" because the metaphors used for it are very modern. This is a kind of "overproduction", a disease of explosive growth. Its growth cannot be stopped and it has fallen into an uncontrollable "deep". Modern biology encourages us to imagine the cell as a "molecular machine". Cancer, on the other hand, cannot stop its initial command (growth), and has transformed into an indestructible, self-driven automatic device.

    As Susan Sontag strongly advocated in the book "Metaphors of Disease": Cancer is a "typical suffering of the 20th century". This concept reminds people of another type that is also considered to be The "symbol of an era" disease-tuberculosis that raged in the 19th century. Sontag emphasized that these two diseases are similarly "filthy", "this is from the original meaning of the word-unlucky, bad, and sensually disgusting." Both will drain the life force and cause the patient to delay death; in these two diseases, "near death" can reflect the essence of the disease more than "death".

    Although the two have these similarities, tuberculosis belongs to another century after all. The Victorian romantics elevated tuberculosis (or "tuberculosis") to an extreme manifestation of pathology-fever, non-stop, difficult to breathe, and extremely compulsive. This is the poet’s disease: John Keats is in a small room, overlooking the Spanish Steps of Rome, and is gradually dying; or Byron, who is infatuated with romance, dreams of dying from this disease, Make his lover feel bad. In 1852, Thoreau wrote: "Death and disease are often beautiful, just like... the flushing of the face caused by tuberculosis." In Thomas Mann's "The Magic Mountain" In Mountain), this kind of "face flushing" released passionate creativity on its victims-a kind of sober, enlightening, and cathartic power, which seems to be full of the essence of the times.

    Cancer, by comparison, is full of more contemporary images.As the surgeon and writer Sherwin Nuland wrote: Cancer cells are a desperate "individualist", "in any sense they are an unruly person. ". The term "metastasis" is used to describe the migration of cancer from one site to another. This word is a peculiar combination of "meta" and "stasis". Latin means "beyond peace". This is a state of runaway and partial instability that captures the unique instability of modern times. Sex. If tuberculosis used to kill patients by pathologically hollowing out the internal organs (mycobacterium tuberculosis gradually emptied the lungs), then cancer caused the patient to suffocate by filling the body with too many cells; its meaning Complementing the consumption of tuberculosis is an "excessive" metamorphosis. Cancer is a disease of expansionists; it invades tissues, establishes territory in a hostile environment, seeks "sanctuary" in one organ, and then transfers to other organs. It is crazy for survival and full of creativity; it is cruel, shrewd and cunning; it fights every inch of the land, and it has a sense of defense. Sometimes, it seems to be teaching us how to survive. Facing cancer is facing a similar species, which is even more suitable for survival than us.

    Cancer is a desperate, vicious specter of modern horror. This image is so memorable because it is at least partly real. Cancer cells are an amazing metamorphosis of normal cells. Cancer is a very successful invader and colonizer, partly because the traits on which it succeeds are the same as the traits on which we as a species depend for success.

    Like normal cells, cancer cells also grow according to the most basic and fundamental single cell splitting into two. In normal tissues, this process is carefully regulated, and growth is stimulated by specific signals, and then suppressed by other signals. However, in cancer, cells grow unscrupulously, spawning generations of cells. Biologists use the term "cloning" to describe cells from the same genetic ancestor. We now know that cancer is a clonal disease. Almost every known cancer (malignant tumor) originates from the same progenitor cell. After it has obtained unlimited cell division and viability, it has produced infinite descendants. This is the countless cycles and repetitions of Wei Ersha's motto "cells come from cells".

    However, cancer is not just a simple clonal disease, it is a "combination of cloning and evolution" disease. If only growth does not evolve, cancer cells will not have the powerful ability to invade, survive and metastasize. Each generation of cancer cells creates a small number of cells that are genetically different from the parent cell. When chemotherapy drugs or the immune system attack cancer cells, mutated cloned cells can resist the attack and grow, so that the fittest can survive. This gruesome process of mutation, selection, and overgrowth continues unremittingly and evolves cells that are more and more adapted to survival and growth. In some cases, these mutant cells will speed up the absorption of other variants. Genetic instability is like a "perfect madness", providing more incentives to create mutant cloned cells. Therefore, cancer's application of the "basic logic of evolution" is different from any other disease. If we humans as a species are the ultimate product of Darwinian selection, then this incredible disease lurking in our body is also the ultimate product of Darwinian natural selection.

    This metaphorical temptation may take us far. But this is inevitable when discussing the topic of cancer. When I started writing this book, I imagined that my "project" was to write a "history" of cancer. But then it was inevitable to feel that what I wrote was not a certain “thing” but a certain “person”. My theme has gradually evolved into something like a "person", like a mysterious, distorted mirror image. This is not so much the history of a disease as it is a biography of a more personal and fleshy disease.

    Every biographer must face the birth of his "biography": where did the cancer "born"? How old is it? Who was the first person to record it as a disease? Therefore, we need to redo the opening chapter.

    Edwin Smith (Edwin Smith) is not an ordinary person. He is half a scholar, half a hawker, good at counterfeiting antiques, and a self-taught ancient Egyptologist. In 1862, he bought (some say he stole) a piece of Egyptian papyrus more than four meters long from an antique dealer in Luxor, Egypt. The papyrus was in poor condition, and the broken and yellowed pages were full of scribbled ancient Egyptian text. Now, this manuscript is believed to have been written in the 17th century BC, and it transcribed a manuscript from 2500 BC. The copyist seems to be a restless "man copying man", scribbled and often makes mistakes, so he often uses red ink on the edge of the paper to correct the mistakes.

    This ancient manuscript was translated in 1930 and is now believed to be the teachings of Yin Hetian, the great doctor of ancient Egypt in 2625 BC. Imhotep is one of the few non-royal Egyptians known to us in the ancient Egyptian dynasty. He is a Renaissance master and a central figure in the Egyptian Renaissance movement. As a high-ranking official of King Djozer, he dabbled in neurosurgery and demonstrated his skills in the field of architecture. He did the earliest research on astrology and astronomy. Even if the ancient Greeks marched on the land of Egypt hundreds of years later, facing this great wise man who was like a raging fire, they believed that he was an ancient mage and put him together with his god of medicine, Asclepius. Asclepius merged into one.

    However, the surprising thing about Smith's papyrus is not the content of magic and religion, but the lack of records of magic and religion. Although immersed in the world of spells, spells, and charms, Imhotep used aloof, unmodified scientific vocabulary to describe fractures and spine ectopic positions, as if he was writing a modern surgical textbook. The 48 cases described on the papyrus include hand fractures, porous skin ulcers, and skull fractures. These are all regarded as medical problems rather than mysterious phenomena. For each case, he made anatomical description, diagnosis, summary and prognosis.

    This ancient doctor lit a beacon for the world, and it was under its shining that cancer emerged for the first time as an independent disease. In describing the 45th case, Imhotep put forward: “If you examine a patient’s chest for a bulging lump and find that the lump has exceeded the range of the chest; if you put your hand on the chest and find that the lump is cold, use your hand When you touch it, there is no heat, no coarse particles, no liquid, and no secretion, but when you touch it, it feels swelling, you should say to him: "This is a lump case... on the breast A raised tumor means that there are lumps in the chest that are large, widely distributed, and hard; touching them is like touching a spherical package, or you can compare them to immature hemats, which are hard to touch It's cold again.'"

    The bulging lumps on the breasts, hard and cold, and dense like river mangos, lurking under the skin to spread-it is difficult to find such a vivid description of breast cancer. In each case on the papyrus, there is a concise treatment discussion, even if it is an expedient measure to treat the symptoms but not the root cause, such as pouring milk through the ear, applying ointment to the wound, and applying ointment to the burn. . But for the 45th case, Yinhetian fell into an unusual silence. Under "Treatment", he only wrote a short sentence: "There is no cure."

    After admitting medical incompetence, cancer almost disappeared from ancient medical history. Other diseases have left their mysterious footprints in legends and historical annals by circulating outbreaks on a global scale. In 1715 BC, a violent plague, possibly Typhus, ravaged the port city of Avaris, killing a large number of people. In the 12th century BC, smallpox broke out in some areas, and the smallpox made Ramses V's face pockmarked. In the Indus Valley, tuberculosis fluctuates like seasonal floods. However, if cancer still exists in the gaps of these large-scale epidemics, then it only exists in silence, leaving no trace in the medical literature or other literature.

    Two thousand years after Yin Hetian described tumors, we heard the news of cancer again. This time it was also hiding in silence, becoming a hidden shame. The Greek historian Herodotus wrote a book called "History" (Histories) around 440 BC, which records that the Persian queen Atosha suddenly contracted an unusual disease. Atosha is the daughter of Cyrus and the wife of Darius. Darius not only inherited the throne of the Achaemenid dynasty, but also inherited the ruling means known for his brutality. The land spanned from Lydia in the Mediterranean to Babylon in the Persian Gulf. During the reign of Queen Atosha, she found a bleeding lump on her breast, which may be caused by a particularly malignant inflammatory breast cancer (in inflammatory breast cancer, malignant tumor cells invade the lymph nodes of the breast, causing Redness).

    As long as Atosha is willing, doctors from Babylon to Greece will flock to wait on the side of the bed. But on the contrary, she is self-closed, grumpy and puzzling. She wrapped herself in the sheets and imposed isolation. Darius's doctor probably tried to treat her, but to no avail. In the end, a Greek slave named Democedes persuaded her-let him help her remove the tumor.

    Soon after the operation, Atosha mysteriously disappeared from Herodotus's text. For Herodotus, she was just a small plot twist. We don’t know if her tumor recurred, or how and when she died, but Demusidis’ resection was at least temporarily successful, and he freed Atosha from the pain. , Survived. Attosha's heart is full of fanatical gratitude and territorial ambition. It turned out that Darius had been planning to conquer the neighboring Scythia (Scythia). And Demusidis, who was bent on returning to his hometown, urged Atosha to lobby her husband and conquer Greece to the west. The turn of the Persian Empire from east to west, and the subsequent series of Hippocratic Wars, became a decisive moment in the early history of the West. Therefore, it can also be said that Atosha’s tumor quietly raised a thousand sails. Cancer, even as a secret disease, left its fingerprints in the ancient world.

    But Herodotus and Imhotep are storytellers after all. Like all stories, their stories have gaps and contradictions. The "cancer" described in the story may be a real tumor, or it may be just an abscess, ulcer, wart or mole. Only those malignant tissues that have been preserved for various strange reasons in history constitute unquestionable cancer cases. If you want to observe cancer face to face and see this ancient disease clearly, you need to go back to that remote millennium cemetery. It is located in the southern Peruvian plains blown by wind and sand.

    This plain is located on the northern edge of the Atacama Desert. This is a dry, desolate strip of land, stretching for thousands of kilometers, falling on the huge leeward side of the Andes extending from southern Peru to Chile, where it is constantly being blown by warm, dry breeze. Since historical records, it has never rained here. It is hard to imagine that human beings once lived here and flourished for a while. But it did happen: hundreds of tombs scattered on the plain—small shallow pits dug in the clay, and carefully arranged with rocks. For thousands of years, dogs, storms, and tomb robbers dug up these shallow graves and unearthed history.

    The mummified remains of members of the Chiribaya tribe are buried in the tomb. The Kolibayas did not take any special preservative measures on the remains of the deceased, but the blessed and perfect climate is very suitable for making them into mummies. The clay sucked up water and liquid from under the corpse, while the wind dried the tissue on it. The corpse is often placed in a sitting position, thereby quickly freezing in time and space.

    In 1990, a desiccated grave with about 140 bodies caught the attention of Arthur Aufderheide, a professor at the University of Minnesota at Duluth. The professor is a pathologist, but his specialty is paleopathology, which focuses on the study of ancient specimens. This field is different from Faber's specialty. The object of anatomy is not a patient who has just died, but a mummy found at an archaeological site. Offdheide uses small sterile milk containers to store these human specimens in a dome-shaped basement at the University of Minnesota. There are nearly 5,000 tissues, dozens of biopsy specimens, and hundreds in his storage cabinet. Broken skeleton.

    Offdheide pieced together a makeshift dissection table at the Kolibaya cultural site and dissected 140 corpses within a few weeks, one of which had an unusual discovery. This mummy is a young woman about 35 years old, with her feet curled up, sitting in a shallow clay grave. When Offdheide checked her, his fingers felt a hard "bulb" on her left upper arm. The corpse is well preserved, only due to the thin and wrinkled skin that has been dried for thousands of years, but the most striking thing is the lump, which has been preserved intact and filled with spicules. There is no doubt that this is a malignant bone tumor-a cancer that has been preserved in a mummy for thousands of years. Offdheide suspected that the tumor had penetrated the skin while the woman was still alive. Even a small osteosarcoma can cause unimaginable pain. He believed that the pain this woman was suffering must be painful to the heart and lungs.

    Offdheide is not the only archaeological pathologist to find cancer in a mummy specimen. (Bone tumors can form hardened and calcified tissues, so it is very likely to be preserved for hundreds of thousands of years, and the state of preservation is also the best.) He said, "Malignant tissues preserved in mummies have also allowed us to discover other types of cancer. The oldest of these is an abdominal cancer that occurred in Dakhleh, Egypt, around 400 AD." In other cases, the archaeological pathologist did not find the actual tumor, but only the traces left by the tumor in the body. Some skeletons are full of pores caused by cancer in the skull or shoulder bones, all of which come from the metastasis of skin cancer or breast cancer.In 1914, a team of archaeologists found a 2000-year-old Egyptian mummy in the catacombs of Alexandria, with a tumor on it that had invaded the pelvis. The archaeologist Louis Leakey, who unearthed the earliest known human skeleton, also found a mandible dating back 2 million years at a nearby site, with unique characteristics of southeastern Africa The traces left by the lymphoma (but the pathological origin of the tumor has never been confirmed). If this discovery does represent a scar left by an ancient malignant tumor, then cancer is far from a "modern disease", but one of the oldest diseases ever seen on human specimens. Probably the oldest disease.

    However, the most striking discovery is not that "cancer already existed in the distant past", but that cancer is fleeting and very rare. I once asked Offdeheide about this question, and he smiled and said: "The early history of cancer is the early history of very few cancers." Mesopotamians know migraines; Egyptians know epilepsy. In "Bible Leviticus", a disease similar to leprosy is mentioned-"tsara'at". In Hindu Vedic medicine, there is a term specifically describing "edema" and there is a goddess who specializes in managing smallpox. Tuberculosis is even more ubiquitous. The ancients were very familiar with it. Just like the Eskimos had various names for ice, there were also specific words corresponding to various phenotypes of the disease. But even common cancers, such as breast cancer, lung cancer, and prostate cancer, are clearly "absent" in history books. In the vast history of medicine, with very few exceptions, there is no book on cancer, and there is no god who guards cancer patients.

    There are several reasons behind the absence of cancer in history. Cancer is an age-related disease, and its incidence sometimes increases exponentially with age. For example, the risk of breast cancer is 1 in 400 women in their 30s, while women in their 70s will have breast cancer in 1 in 9 people. In ancient society, people were threatened by diseases such as tuberculosis, cholera, smallpox, leprosy, plague or pneumonia for a long time, and often died before they had cancer. Even if cancer exists, it is submerged in other diseases. In fact, the rise of cancer in the world is the result of "double negation": cancer becomes a common phenomenon only when all other "human killers" are eliminated. Doctors in the 19th century often associated cancer with civilization, believing that the rush and disorder of modern life stimulated pathological changes in the body to some extent, leading to cancer. This inference is correct, but it does not constitute causality-civilization does not cause cancer, but exposes cancer by extending human life.

    "Longevity" is certainly an important factor in the prevalence of cancer in the early 20th century, but it may not be the only factor. Our ability to detect cancer early and accurately determine the cause of cancer death has been greatly enhanced in the last century. The deaths of children with leukemia in the 1850s were attributed to abscesses or infections (or to Bennett’s "blood suppuration"). Surgery, biopsy and autopsy techniques have further strengthened our ability to diagnose cancer. The imported mammography can detect early signs of breast cancer, which greatly "increased" the incidence of breast cancer. This result may seem contradictory, but it can be perfectly explained-X-rays allow people to diagnose early tumors.

    Finally, changes in the structure of modern life have fundamentally changed the scope of cancer manifestations. The incidence of certain types of cancer has increased, and the incidence of certain types has decreased. For example, stomach cancer, which was very common in some people before the end of the 19th century, may be the result of several carcinogens (found in pickling reagents and preservatives) and worsening of bacterial infections (endemic and infectious) . After the introduction of modern refrigeration technology (and improvements in the field of public health may reduce endemic bacterial infections), the incidence of gastric cancer seems to have decreased. In contrast, the incidence of lung cancer in men increased sharply in the 1950s, as a result of the increase in the number of smokers in the early 20th century. While women started smoking in the 1950s, the incidence of lung cancer in this population has not yet reached a peak.

    Demographic and epidemiological changes have had huge consequences in different periods. Roswell Parker pointed out in 1900 that tuberculosis is by far the most common cause of death in the United States. Then came the pneumonia, which was called "captain of the death penalty" by the famous medical scientist William Osler of Johns Hopkins University, followed by dysentery and gastroenteritis. Cancer still lags behind, ranking far in seventh place. However, in the early 1940s, cancer was advancing all the way, rushing to second place after heart disease. In the same period, the life expectancy of Americans has increased by about 26 years, and the proportion of people over 60 has almost doubled, and this is the age when most cancers begin to take off.

    Although ancient cancer cases are rare, we still can’t forget the tumor that grew on the bones of a 35-year-old female mummy discovered by Offdheide. This woman must have wondered why there is a sharp pain on the bone, why there is a slow bulge on the arm. Seeing this kind of tumor, people must feel that they have encountered a powerful monster in infancy.

    burden

    The black cholestasis does not change, and cancer develops.

    —Galen, 130 BC

    Therefore, we know nothing about the truth of cancer and its nature. At this point, we are no different from the ancient Greeks.

    -Francis Carter Wood, 1914

    It is bad bile, bad habits, bad bosses, bad genes.

    ——Mel Greaves (Mel Greaves)

    "Cancer: The Evolutionary Legacy" (Cancer, The Evolutionary Legacy), 2000

    Disease, from some perspectives, only exists if we perceive it, name it, and respond to it.

    -C.E. Luxembourg (C.E. Rosenberg)

    Even an ancient monster needs a name. To name a disease is to describe a certain condition of suffering, which is an act of language first and then medicine. Before the patient became the subject of medical examination, he was only a narrator, telling the pain he had experienced, as if he had just visited the kingdom of disease. In order to get rid of the trouble of a certain disease, people must start with the story of telling and understanding the story of the disease.

    The names of ancient diseases are condensed stories in themselves. Typhus is a fierce disease, accompanied by unstable fever and sweating. The name of this disease comes from the Greek word "tuphon" (father of all winds). The modern term typhoon (typhoon) also comes from this. "Influenza" comes from the Latin word "influentia", because in the imagination of medieval doctors, the cyclical outbreak of influenza was affected by the proximity of stars and planets to or away from the earth. Tuberculosis (tuberculosis) is transformed from the Latin "tuber". "Tuber" refers to swollen glands, clumps like small vegetables. Lymphatic tuberculosis is called "scrofula", which comes from the Latin word meaning "little piglet". Its symptoms are a series of enlarged glands arranged in rows, which reminds people of a group of suckling piglets.

    In the Hippocrates era around 400 BC, the term "karkinos" to describe cancer first appeared in medical literature. It came from the Greek word "crab". The tumor, as well as the swollen blood vessels spreading all over it, reminded Hippocrates of a crab waving its feet and digging in the sand. This picture is very strange (rarely cancers really look like crabs), but also very vivid. Later writers, including doctors and patients, added modifications to it. In the eyes of some people, the hardened and dim surface of the tumor makes people think of the hard shell of a crab. Some people feel that the tumor spreads quietly in the body, like a crab walking under the skin. For others, the sudden sting of cancer is like being caught by the big claws of a crab.

    There is also a Greek word that also intersects with the history of cancer, and that is "onkos"-people sometimes use this word to describe tumors; the modern oncology term "oncology" is born out of this word. "Onkos" means a weight or load in Greek, or more generally a burden-cancer is conceived as a burden on the body. On the Greek stage, the word "onkos" is also used to describe the mask of a tragic character, which often wears a heavy cone on its head, symbolizing the psychological burden it bears.

    Although these vivid metaphors are likely to resonate with our modern understanding of cancer, what Hippocrates called "karkinos" is actually very different from the cancers we now know. Hippocrates’ "karkinos" are mostly large epidermal tumors that can be seen with the naked eye, such as breast cancer, skin cancer, jaw cancer, neck cancer and tongue cancer. He did not even distinguish between malignant tumors and non-malignant tumors. Hippocrates' "karkinos" includes any kind of swelling imaginable: such as nodules, carbuncles, polyps, protrusions, tuberculosis, pustules, and glands. He put all kinds of bumps indiscriminately into the same pathological category.

    The Greeks did not have microscopes.They have never imagined that there is an entity called a "cell", let alone a cell. It is also impossible for them to think of the concept of "karkinos is uncontrolled cell growth". However, they knew well about fluid mechanics: waterwheels, pistons, valves, gutters and sluices all originated from the water science revolution of irrigation and canal excavation, and what Archaemedes found in the bathtub bears his name The law of naming pushed this revolution to the apex. This focus on hydraulics has also penetrated into Greek medicine and pathology. In order to explain all diseases, Hippocrates introduced a whole set of theories based on liquid and its volume, and freely applied this theory to the explanation of pneumonia, abscess, dysentery and hemorrhoids. Hippocrates proposed that the human body is mainly composed of four fluids called "body fluids", including blood, black bile, yellow bile and mucus. Each of these body fluids has its own unique color (red, black, yellow, white), viscosity and basic characteristics. When the human body is in a healthy state, these four liquids are in complete balance (but may not be stable). When you are sick, it will manifest as an excess of some kind of body fluid in the body, which disrupts this balance.

    Claudius Galen was an influential Greek doctor and a prolific writer who practiced medicine in Rome around 160 AD. He pushed Hippocrates' theory of body fluids to the extreme. Galen, like Hippocrates, classifies all diseases according to whether various body fluids are excessive. He believes that the redness and swelling caused by inflammation are all caused by excessive blood; while tuberculosis, pustules, mucositis and lymphatic tuberculosis that are cold, white, and moist are all attributed to excessive mucus. Jaundice is attributed to excessive yellow bile; as for cancer, Galen believes that the culprit behind the scenes is the most malignant and worrying black bile of the four body fluids. [Also attributed to the greasy, viscous body fluid of black bile, there is only another metaphorical disease-depression. In fact, depression was called "melancholia" in the Middle Ages, and it got its name from the Greek words "melas" (black) and khole (bile). Therefore, depression and cancer, two mental and physical diseases caused by black bile, are entangled because of their inherent characteristics. Galen believes that cancer is caused by black bile stasis. Because it is trapped somewhere and cannot be vented, it condenses into a tangled mass. In the 16th century, British surgeon Thomas Gale mentioned Galen’s theory that “black cholestasis does not dissolve, and cancer develops”. He believed that “if the body fluids are hot, it will cause ulcers, and this is why , The color of these tumors will be darker."

    This short, vivid description has a profound impact on future oncology research, far beyond Galen's (or Gale's) intentions. According to Galen's theory, cancer is a systemic malignant state, which is caused by excessive secretion of black bile in the body. Tumors are nothing but local appearances caused by deep dysfunction in the body, a kind of physiological imbalance throughout the body. Hippocrates once expressed a profound opinion that cancer "better not be treated, because the patient will live longer." 500 years later, Galen explained his teacher's brilliant thinking with a series of wild physiology conjectures. Galen pointed out that the problem with surgical treatment of cancer is that black bile is everywhere, just like other liquids, it is inevitable and permeates everywhere. You can remove the cancer, but the bile will flow back to its original place, just as sap penetrates the branches of a tree.

    Galen died in Rome in 199 AD. However, his influence on medicine lasted more than a thousand years. The metaphorical nature of the black bile carcinogenic theory is so tempting that it firmly occupies the minds of doctors. Therefore, surgical removal of the tumor is considered to treat the symptoms but not the root cause, and only fools can do it. Generations of surgeons have added their own observations to Galen's observations, further consolidating this theory. "Don't be led astray and perform surgery," John of Arderne wrote in the mid-14th century. "Surgery will only humiliate you." "Those who pretend to be able to treat cancer by cutting, digging out, and removing are nothing more than converting a non-ulcer cancer into an ulcer cancer... In my medical career, I have never seen a case. I have not heard of anyone who has cured cancer with resection surgery.” Perhaps the most influential surgeon in the 15th century, Leonard Bertipaglia, added his own admonition. .

    Galen may inadvertently do a good deed for future cancer patients, at least temporarily benefiting these patients.In the Middle Ages when there were no anaesthetics and antibiotics, most surgical operations were performed in a dark room of a clinic, and more commonly performed in the back room of a barber shop-the patient was secured with a strap and the scalpel was rusty. , Often lead to life-threatening catastrophic consequences. The 16th-century surgeon Ambroise Pare described using a soldering iron heated by coal fire to scorch tumors, or use sulfuric acid ointment to burn tumors. Even a small scratch on the skin, after such treatment, will quickly purify and cause fatal infection. Tumors often cause heavy bleeding under mild stimulation.

    The 18th-century German doctor Lorenz Heister once described the mastectomy performed in his clinic as a sacrificial ritual: "Many women can muster great courage. Come to accept this kind of surgery, you won’t even groan. But some other women screamed, and even the most fearless doctors would be discouraged, which would hinder the continuation of the operation. In order to perform this kind of surgery, the surgeon must have a firm personality. Don't be disturbed by the patient's screams."

    It is conceivable that many patients would rather give up the opportunity to perform this "fearless operation", and give their fate to Galen-try to take systemic medicine to remove black bile. As a result, the drugstore was quickly filled with breathtaking cancer drugs: lead preparations, arsenic extracts, wild boar teeth, fox lungs, sharp ivory, shelled castor, white coral on the seabed, vomiting Roots, senna leaves, and bits and pieces of laxatives and laxatives, as well as alcohol and opiates to deal with intolerable pain. In the 17th century, pastes made with crab eyes were very popular and could sell for 5 shillings a pound-people hoped to fight poison with poison. The medicinal ointments and treatments of this era have become more and more strange-goat dung, frogs, crow's feet, stinky chamomile, tortoise liver, holy water; or hand blessings, and lead plates to compress tumors. All in one.

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