American Physician, Biological Scientist and Author, Awarded Pulitzer Prize for his book, The Emperor Of All Maladies: A Biography of Cancer
American Physician, Biological Scientist and Author, Awarded Pulitzer Prize for his book, The Emperor Of All Maladies: A Biography of Cancer
The daughter of Lithuanian immigrants, born with a precocious scientific intellect and a thirst for chemical knowledge, Elion had completed a master's degree in chemistry from New York University in 1941 while teaching high school science during the day and preforming her research for her thesis at night and on the weekends. Although highly qualified, talented, and driven, she had been unable to find a job in an academic laboratory. Frustrated by repeated rejections, she had found a position as a supermarket product supervisor. When Hitchings found Trudy Elion, who would soon become on of the most innovative synthetic chemists of her generation (and a future Nobel laureate), she was working for a food lab in New York, testing the acidity of pickles and the color of egg yolk going into mayonnaise. Rescued from a life of pickles and mayonnaise?
The most logical conclusion from these facts is that while some combination of genes and environments can strongly influence g, this combination will rarely be passed, intact, from parents to their children. Mendel?s laws virtually guarantee that the particular permutation of genes will scatter apart in every generation. And environmental interactions are so difficult to capture and predict that they cannot be reproduced over time. Intelligence, in short, is heritable (i.e., influenced by genes), but not easily inheritable (i.e., moved down intact from one generation to the next).
There are not over two dozen funds in the U.S. devoted to fundamental cancer research. They range in capital from about $500 up to about $2,000,000, but their aggregate capitalization is certainly not much more than $5,000,000.? The public willingly spends a third of that sum in an afternoon to watch a major football game.
Three profoundly destabilizing scientific ideas ricochet through the twentieth century, trisecting it into three unequal parts: the atom, the byte, the gene.
Whether epidemiology alone can, in strict logic, ever prove causality, even in this modern sense, may be questioned, but the same must also be said of laboratory experiments on animals. ?Richard Doll
But despite such parallel metaphors, tuberculosis belongs to another century. TB (or consumption) was Victorian romanticism brought to its pathological extreme?febrile, unrelenting, breathless, and obsessive, it was a disease of poets: John Keats involuting silently toward death in a small room overlooking the Spanish Steps in Rome, or Byron, an obsessive romantic, who fantasized about dying of the disease to impress his mistresses. Death and disease are often beautiful?like the hectic glow of consumption, Thoreau wrote in 1852. In Thomas Mann?s Magic Mountain, this hectic glow releases feverish creative force in its victims?a clarifying, edifying, cathartic force that, too, appears to be charged with the essence of its era.
By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site. In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed?cancer?s primordial ancestor. A decade passes. The small collection of ras-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene. Another decade passes. yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivated a tumor-suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene. Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood/ vessels to grow; another mutation within the blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen.
Cancer, as we now know, is a disease caused by the uncontrolled growth of a single cell. This growth is unleashed by mutations?changes in DNA that specifically affect genes that incite unlimited cell growth. In a normal cell, powerful genetic circuits regulate cell division and cell death. In a cancer cell, these circuits have been broken, and the unleashed cell cannot stop growing.
Estrogen is the principal hormone secreted by the ovaries. As with testosterone for the normal prostate, estrogen was soon demonstrated to be a vital factor for the maintenance of normal breast tissue. And like prostate cancer, breast cancer was also thought to be sustained by estrogen. Given these analogies, physiologists theorized that acute estrogen deprivation (in this case by ovarian removal) choked the growth of these hormone-dependent breast cancer cells.
Gliomas appeared on the same side of the brain that the phone was predominantly held, further tightening the link. An avalanche of panic ensued in the media.
I began this as a hypothetical story of cancer. The genes, carcinogens, and the sequence of mutations in this story are all certainly hypothetical. But the body at its center is real. This man was the first patient to die in my care during my fellowship in cancer medicine at Massachusetts General Hospital. Medicine, I said, begins with storytelling. Patients tell stories to describe illness; doctors tell stories to understand it. Science tells its own story to explain diseases. This story of one cancer?s genesis?of carcinogens causing mutations in internal genes, unleashing cascading pathways in cells that then cycle through mutation, selection, and survival?represents the most cogent outline we have of cancer?s birth.
If there's a seminal discovery in oncology in the last 20 years, it's that idea that cancer genes are often mutated versions of normal genes.
In an age of increasingly mechanized production, the genesis of scientific knowledge remains an unyieldingly, obstreperously hand-hewn process. It is among the most human of our activities. Far from being subsumed by the dehumanizing effects of technology, science remains our last stand against it.
In the folklore of science, there is the often-told story of the moment of discovery: the quickening of the pulse, the spectral luminosity of ordinary facts, the overheated, standstill second when observations crystallize and fall together into patterns, like pieces of a kaleidoscope. The apple drops from the tree. The man jumps up from a bathtub; the slippery equation balances itself. But there is another moment of discovery?its antithesis?that is rarely recorded: the discovery of failure. It is a moment that a scientist often encounters alone. A patient?s CT scan shows a relapsed lymphoma. A cell once killed by a drug begins to grow back. A child returns to the NCI with a headache.
It is hard to look at the tumor and not come away with the feeling that one has encountered a powerful monster in its infancy
Life may be chemistry, but it?s a special circumstance of chemistry. Organisms exist not because of reactions that are possible, but because of reactions that are barely possible. Too much reactivity and we would spontaneously combust. Too little, and we would turn cold and die. Proteins enable these barely possible reactions, allowing
Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung. The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. occasionally, he senses something moving under his rib cage when he walks. Another year passes, and the sensations accelerate. The man visits a physician and a CT scan is performed, revealing a rind-like mass wrapped around a bronchus in the lung. A biopsy reveals lung cancer. A surgeon examines the man and the CT scan of the chest and deems the cancer inoperable. Three weeks after that visit, the man returns to the medical clinic complaining of pain in his ribs and his hips. A bone scan reveals metastasis to the pelvis and the ribs. Intravenous chemotherapy is initiated. The cells in the lung-lining tumor respond. The man soldiers through a punishing regimen of multiple cell-killing drugs. But during the treatment, one cell in the tumor acquires yet another mutation that makes it resistant to the drug used to treat the cancer. Seven months after his initial diagnosis, the tumor relapses all over the body?in the lungs, the bones, the liver. On the morning of October, 17, 2004, deeply narcotized on opiates in a hospital bed in Boston and surrounded by his wife and his children, the man dies of metastatic lung cancer, a sliver of asbestos still lodged in the periphery of his lung. He is sixty-two years old.
One leukemia doctor wrote, I know the patients, I know their brothers and sisters, I know their dogs and cats by name.? The pain is that a lot of love affairs end.
Sandeep Jauhar?s Doctored is a passionate and necessary book that asks difficult questions about the future of medicine. The narrative is gripping, and the writing is marvelous. But it was the gravity of the problem?so movingly told?that grabbed and kept my attention throughout this remarkable work.
Surgeons walked around with their scalpels dangling from their pockets. If a tool fell on the blood-soiled floor, it was dusted off and inserted back into the pocket?or into the body of the patient on the operating table.
The developments of the summer of 1976 drastically reorganized the universe of cancer biology, returning genes, again, to its center. Harold Varmus and Michael Bishop?s proto-oncogene theory provided the first cogent and comprehensive theory of carcinogenesis. The theory explained how radiation, soot, and cigarette smoke, diverse and seemingly unrelated insults, could all initiate cancer?by mutating and thus activating precursor oncogenes within the cell. The theory made sense of Bruce Ames?s peculiar correlation between carcinogens and mutagens: chemicals that cause mutations in DNA produce cancers because they alter cellular proto-oncogenes. The theory clarified why the same kind of cancer might arise in smokers and nonsmokers, albeit at different rates: both smokers and nonsmokers have the same proto-oncogenes in their cells, but smokers develop cancer at a higher rate because carcinogens in tobacco increase the mutation rate of these genes.
The most striking finding, though, is not that cancer existed in the distant past, but that it was fleetingly rare. When I asked Aufderheide about this, he laughed. The early history of cancer, he said is that there is very little early history of cancer. The Mesopotamians knew their migraines; the Egyptians had a word for seizures. A leprosy-like illness, tsara?at, is mentioned in the book of Leviticus. The Hindu Vedas have a medical term for dropsy and a goddess specifically dedicated to smallpox. Tuberculosis was so omnipresent and familiar to the ancients that ?as with ice and the Eskimos?distinct words exist for every incarnation of it. But even common cancers, such as breast, lung, and prostate, are conspicuously absent. With a few notable exceptions, in the vast stretch of medical history there is no book or god for cancer. There are several reasons behind this absence. Cancer is an age-related disease?sometimes exponentially so. The risk of breast cancer, for instance, is about 1 in 400 for a thirty-year-old woman and increases to 1 in 9 for a seventy-year-old. In most ancient societies, people didn?t live long enough to get cancer. Men and women were long consumed by tuberculosis, dropsy, cholera, smallpox, leprosy, plague, or pneumonia. If cancer existed, it remained submerged under the sea of other illnesses, manifesting only when all the others ceased. Indeed, cancer?s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed.
There is a difference between the cost of a drug and the price of a drug. A pill of Gleevec?I mean, the chemical that we call Gleevec?can be synthesized.
To take care of cancer patients is an enormous privilege, but it also involves deploying everything in your toolbox: the emotional, the psychological, the scientific, the epidemiologic.
W”hler?s experiment demolished vitalism. Organic and inorganic chemicals, he proved, were interchangeable. Biology was chemistry: perhaps even a human body was no different from a bag of busily reacting chemicals?a beaker with arms, legs, eyes, brain, and soul.