The Emperor of All Maladies, A biography of Cancer by Siddhartha Mukherjee.

The Emperor of All Maladies, A biography of Cancer by Siddhartha Mukherjee was 41 of 2020. 

Intense, might read again, so many things to be noted and remembered. The subject of the book, daily morphed into something that resembled an individual - an enigmatic, if somewhat deranged, image in a mirror, so this is not a history but a biography.  Dedicated to Robert Sandler (1945-48) one of Farber's first patient  and to those who came before and after him by being the first to: "receive injection of controversial amniopterin; he began to show results; until then leukemia was considered to be absolutely fatal. His recovery gave hope that we could hold cancer at bay, and even cure it, and this could be extended to other cancers. "

Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well and in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place. —Susan Sontag

Author's Note - Two characters stand at the epicenter of this story Sidney Farber, father of modern Chemotheraphy and Mary Lasker, the Manhatten socialite of legendary social and political energy, who joins Farber in his decade-long journey enabling funds. 

 Prologue : Earlier cutting more meant curing more, the understanding has morphed, often radically from decade to decade, and today it is known to be caused because of the  uncontrolled growth by mutations (changes in DNA that specifically effects genes) of a single cell. 

Part One: “Of blacke cholor, without boyling”

Cancer is an age related disease - sometimes exponentially so and therefore there is no book or God for cancer. Civilization did not cause cancer, but by extending human life spans - civilization unveiled it, it is lesser among children, and increases with increase in age group. It was in the time of Hippocrates, around 400 BC, that a word for cancer first appeared in the medical literature. Karkinos, from the Greek word for 'crab'. Another Greek word would intersect with the history of cancer - onkos, a word used occasionally to describe tumors, from which the discipline of oncology would take its modern name. Cancer even when it begins locally, is inevitably waiting to explode out of its confinement, like the big bang. A 'systematic' illness, crablike and constantly mobile, it could burrow through invisible channels from one organ to another, often a humoral disease. Antiseptic and Anesthesia's discovery helped surgery. 

The first medical description of cancer was found in an Egyptian text originally written in 2500 BC, "A bulging tumor in the brest....like touching a ball of wrappings", Discussing treatment, the ancient scribe noted:is none. When medicines and operations failed, doctors reorted to the only established treatment for cancer, borrowed from Galen's teachings,an intricate series of bleeding and purging rituals to squeeze the humors out of the body, as if it were an overfilled, heavy sponge.  The anatomist Andreas Vesalius (1514-1564) tried to discover the source for black bile, the fluid throught to be responsible for cancer. Unable to find it, Vesalius launched a new search for Cancer's real cause and cure. Medieval surgeons attacked cancer using primitive surgical methods. Johannes Scultetus (1595-1645) describes a mastectomy, the surgical removal of breast cancer, using fire, acid and leather bindings. Between 1800 and 1900 surgeons devised increasingly aggressive operations to attack the roots of cancer in the body. In the 1890s, Williams Stewart Halsted at Johns Hopkins University devised the radical mastectomy - an operation to extirpate the breast, the muscle beneath the breast and the associated lymph nodes. When radium was discovered by Marie and Pierre Curie, oncologists and surgeons began to deliver high doses of radiation to tumors. Yet radiation was itself carcinogenic. Radiation therapy catapulted cancer medicine into its atomic age - age replete with both promise and peril. A powerful invisible knife, curing at times and causing at others, it dampened the initial enthusiasm of scientists. Madame curie died from a leukemia caused by decades of X-ray exposure. Ehrlich was looking for a 'curative substance" not mearly palliative acting favourably on one or the other symptom. During world war two hundreds of tons of mustard gas were released on the Bari harbor in Italy during an air raid. The gas decimated normal white blood cells in the body, leading pharmacologists to fantasize about using a similar chemical to kill cancers of white blood cells. Chemotherapy - chemical warfare on cancer cells - was inspired, literally, by war. In 1947 Sidney Farber discovered a folic acid analog called aminopterin that killed rapidly dividing cells in the bone marrow. Using aminopterin, Farber obtained brief, tantalizing remissions in acute lymphoblastic leukemia. One of Farber's first patient was two-year old Robert Sandler one of the twin, to whom this book is dedicated. 

Part Two: An Impatient War

Community of scholars were focused on generating knowledge to improve the public health. That's a great activity. Can we call that a war? 

Mary Lasker became the "fairy godmother"of cancer research, she would coax and strong-arm the nation to initiate a War on Cancer.   Faber's patient, Einar Gustafson- known as Jimmy - a baseball fan became the unofficial mascot for children's cancer. The Jimmy fund founded in 1948, was one of the most powerful cancer advocacy organizations, with Ted Williams a vocal supporter. A new cancer ward was build in Boston. Sidney Farber and Mary Lasker had begun a 'crusade' against cancer. At the National Cancer Institute (NCI) in the 1960s physicians Emil Frei and Emil Freireich forged a strategy to cure acute lymphoblastic leukemia using highly toxic drugs. They tried combining four drugs; vincristine, amethopterin, mercaptopurine and prednisone acronymed as VAMP.  Henry Kaplan, a physician-scientist, used radiation therapy to cure Hodgkin's lymphoma. The cures of lymphoblastic leukemia and Hodgkin's lymphoma invigorated the war on Cancer, raising the possibility of Farber's 'Universal cure'. The simple principle - the meticulous matching of a particular therapy to a particular form and stage of cancer - which was given a dure merit in cancer therapy.   Inspired by the early victories of chemotherapy, cancer advocates, lead by Lasker and Farber, urged the nation to launch a war on cancer. Induction, Intensification, Maintenance, Cure was the process. Li had stumbled on a deep and fundamental principle of oncology: Cancer needed to be systematically treated long after every visible sign of it had vanished.  Peyton Rous who was awarded noble prize came us with the cause and clarity that relatively few viruses have any connection with the production of neoplasms. Cancer could be caused by something inherent in the cell, such as a genetic mutation. Two superficial theories where thus stituched audaciously - and prematurely - into one comprehensive whole. One offered a cause: Virus caused cancer the second offered a cure: particular combinations of cytotoxic poisons would cure cancer. 

 

Part Three: “Will you turn me out if I can’t get better?”

In God we trust, all others must have data. Radiotherapiss, chemotherapists, and surgeon fought viciously for power and information. The war on cancer seemed, at times, to have devolved into a war within cancer. 

If prostate cancer could be starved to near death by choking off testosterone, can doing that to estrogen save ovaries? 'Antiestrogen' was in development. The movement to restore sanity and sanctity to the end-of-life care of cancer patients emerged, predictably, not from cure- obsessed America but from Europe. It's founder was Cecily Saunders, a former nurse. Though the word care, was not used, Pallative care, the branch of medicine that focused on symptom relief and comfort, had been perceived as the antimatter of cancer therapy, the negative to its positive, and admission of failure to its rhetoric of success. The workd palliate comes from the Latin palliare, "to cloak" - and providing pain relief was perceived as cloaking the essence of the illness, smothering symptoms rather than attacking disease. In 1974, three pronged approach to cancer was brought out by NCI "Treatment, Rehabilitation and Continuing Care"

In 1970, the Laskerites published a full page advertisement in the New York Times, coaxing Nixon to support their war. Many scientists criticised the war on cancer as premature, arguing that a political cure would not lead to a medical cure. Lasker's use of canny advertising and potent imagery still inspires generations of advocates, including Greenpeace.

A shift in research emphasis, from research on treatment to research on prevention, seemed necessary.

Part Four: Prevention Is the Cure

 In 1775, the London surgeon Percivall Pott observed that scrotal cancer occurred disproportionately in adolescent chimney sweeps and proposed a link between soot and scrotal cancer, launching the hunt for preventable carcinogens in the environment. Innovative studies in the 1950's established the link between cigarette smoking and lung cancer. Yet early warning labels affixed on packages in the 1960s avoided the word 'cancer'. Explicit warning labels were not required until decades later. Although smoking rates have fallen in most developed nations, active marketing and bold political lobbying allowed the tobacco industry to flourish in others, creating a new generation of smokers and of future cancer victims. Master Settlement Agreement (MSA) was signed by Cigarette manufacturers restricting advertising, trade, lobbying etc. Another method was attacking precancer rather than cancer. Papanicolaou brought out pap smear , the use of which was not to find caner, but to detect its antecedent, its precursor - the portent of cancer. The difference in the behaviour of tumors is not just a consequence of quantitative growth, but of qualitative growth. Just because a tumor is small does not mean that it is premetastatic. In 1982 Frei found a cure for breast cancer called STAMP - Solid Tumor Autologous Marrow Program. Peter joined him and got this approved.

An era of oncology was coming to a close, and the field had turned its entrancement with universal solutions and radical cures, and was grappling with fundamental questions regarding underlying principles governing the root behaviour of a particular form of cancer. What was common to all cancer and what made breast cancer different from lung or prostate cancer. 

Part Five: “A Distorted Version of Our Normal Selves”

Quest to combact cancer turned inward, towards basic biology, toward fundamental mechanisms. Rous's theory of virus causing cancer warranted the need for a vaccine, while, Boveris theory of it being because of mysterious problem lurking in chromosomes offered no cure. Spiegelman's conjecture about human retroviruses turned out to be the cause of different disease - HIV. 

Genes are units of inheritance, they shuttle properties - traits - from one generation to another. Genese are transferred with the help of RNA - Ribonucleci acid. Harold Varmus and J. Michael Bishop discovered that cancer is caused by the activation of endogenous precursor genes that exist in all normal cells. Cancer, Varmus wrote, is a 'distorted version' of our normal selves. Their proto -oncogene therory provided the first cogent and comprehensive theory of carcinogenesis.The cancer cell was a broken, deranged machine. Oncogenes were its jammed accelerators and inactivated tumor suppressors its missing brake. Proto-oncogenes need to be activated through mutations which are rare, and tumor suppressor genes need to be inactivated .Cancer was not genetic just in its origin, but in its entirety. The cloning of ras and retinoblastoma—oncogene and anti-oncogene—was a transformative moment in cancer genetics. In the decade between 1983 and 1993, a horde of other oncogenes and antioncogenes (tumor suppressor genes) were swiftly identified in human cancers: myc, neu, fos, ret, akt (all oncogenes), and p53, VHL, APC (all tumor suppressors). Retroviruses, the accidental carriers of oncogenes, faded far into the distance. Varmus and Bishop’s theory—that oncogenes were activated cellular genes—was recognized to be widely true for many forms of cancer. And the two-hit hypothesis—that tumor suppressors were genes that needed to be inactivated in both chromosomes— was also found to be widely applicable in cancer. A rather general conceptual framework for carcinogenesis was slowly becoming apparent. The cancer cell was a broken, deranged machine. Oncogenes were its jammed accelerators and inactivated tumor suppressors its missing brakes. Working with collaborators across the globe Robert Weinberg, of MIT discovered distorted genes in mouse and human cancer cells. Scientists have sequenced the entire genome (all 23,000 genes); making it possible to document every genetic change (relative to normal genes). Dots represent mutations in genes found in colon cancer, with commonly mutated genes becoming "hills" and then "mountains".

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.

How many “rules,” then, could Weinberg and Hanahan evoke to explain the core behavior of more than a hundred distinct types and subtypes of tumors? The question was audacious in its expansiveness; the answer even more audacious in its economy: six. “We suggest that the vast catalog of cancer cell genotypes is a manifestation of six essential alterations in cell physiology that collectively dictate malignant growth.” 1. Self-suf iciency in growth signals: cancer cells acquire an autonomous drive to proliferate— pathological mitosis—by virtue of the activation of oncogenes such as ras or myc. 2 . Insensitivity to growth-inhibitory (antigrowth) signals: cancer cells inactivate tumor suppressor genes, such as retinoblastoma (Rb), that normally inhibit growth 3. Evasion of programmed cell death (apoptosis): cancer cells suppress and inactivate genes and pathways that normally enable cells to die. 4. Limitless replicative potential: cancer cells activate specific gene pathways that render them immortal even after generations of growth. 5. Sustained angiogenesis: cancer cells acquire the capacity to draw out their own supply of blood and blood vessels—tumor angiogenesis. 6. Tissue invasion and metastasis: cancer cells acquire the capacity to migrate to other organs, invade other tissues, and colonize these organs, resulting in their spread throughout the body. Notably, Weinberg and Hanahan wrote, these six rules were not abstract descriptions of cancer’s behavior. Many of the genes and pathways that enabled each of these six behaviors had concretely been identified—ras, myc, Rb, to name just a few. The task now was to connect this causal understanding of cancer’s deep biology to the quest for its cure.

The mechanistic maturity of cancer science would create a new kind of cancer medicine, Weinberg and Hanahan posited: “With holistic clarity of mechanism, cancer prognosis and treatment will become a rational science, unrecognizable by current practitioners.” Having wandered in the darkness for decades, scientists had finally reached a clearing in their understanding of cancer. Medicine’s task was to continue that journey toward a new therapeutic attack.

Part Six: The Fruits of Long Endeavors

Umbilical blood contains one of the richest known sources of blood forming stem cells - Stem cells can be stored in cryobanks and used for a bone marrow transplant to treat leukemia in the future.  Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s. 

To target cancer cells with novel therapies, scientists and physicians needed new vulnerabilities that were unique to cancer. The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles’ heels of cancer. First, cancer cells are driven to grow because of the accumulation of mutations in their DNA. These mutations activate internal proto-oncogenes and inactivate tumor suppressor genes, thus unleashing the “accelerators” and “brakes” that operate during normal cell division. Targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately. Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways. Cancer cells divide and grow because they are driven by hyperactive or inactive signals in these critical pathways. These pathways exist in normal cells but are tightly regulated. The potential dependence of a cancer cell on such permanently activated pathways is a second potential vulnerability of a cancer cell. Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth. These include the capacity to resist death signals, to metastasize throughout the body, and to incite the growth of blood vessels. These “hallmarks of cancer” are not invented by the cancer cell; they are typically derived from the corruption of similar processes that occur in the normal physiology of the body. The acquired dependence of a cancer cell on these processes is a third potential vulnerability of cancer. The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new heel. 

 In the 1990s, Barbara Bradfield was among the first women to be treated with a drug. Herceptin, that specifically attacks breast cancer cells. She is the longest survivor of that treatment, with no hint of her cancer remaining. Similarly Gleevec was for chronic myeloid leukemia or CML. In the decade since the discovery of Gleevec, twenty-four novel drugs have been listed by the National Cancer Institute as cancer-targeted therapies. Dozens more are in development. The twentyfour drugs have been shown to be effective against lung, breast, colon, and prostate cancers, sarcomas, lymphomas, and leukemias. Some, such as dasatinib, directly inactivate oncogenes. Others target oncogene-activated pathways—the “hallmarks of cancer” codified by Weinberg. The drug Avastin interrupts tumor angiogenesis by attacking the capacity of cancer cells to incite blood-vessel growth. Bortezomib, or Velcade, blocks an internal waste-dispensing mechanism for proteins that is particularly hyperactive in cancer cells.

“Cancer at the fin de siècle,” as the oncologist Harold Burstein described it, “resides at the interface between society and science.” It poses not one but two challenges. The first, the “biological challenge” of cancer, involves “harnessing the fantastic rise in scientific knowledge . . . to conquer this ancient and terrible illness.” But the second, the “social challenge,” is just as acute: it involves forcing ourselves to confront our customs, rituals, and behaviors. These, unfortunately, are not customs or behaviors that lie at the peripheries of our society or selves, but ones that lie at their definitional cores: what we eat and drink, what we produce and exude into our environments, when we choose to reproduce, and how we age.

The bedlam of the cancer genome, in short, is deceptive. If one listens closely, there are organizational principles. The language of cancer is grammatical, methodical, and even—I hesitate to write—quite beautiful. Genes talk to genes and pathways to pathways in perfect pitch, producing a familiar yet foreign music that rolls faster and faster into a lethal rhythm. Underneath what might seem like overwhelming diversity is a deep genetic unity. Cancers that look vastly unlike each other superficially often have the same or similar pathways unhinged. “Cancer,” as one scientist recently put it, “really is a pathway disease.”

The sequencing of the cancer genome represents the genetic anatomy of cancer. And just as Virchow made the crucial leap from Vesalian anatomy to the physiology of cancer in the nineteenth century, science must make a leap from the molecular anatomy to the molecular physiology of cancer. We will soon know what the mutant genes are. The real challenge is to understand what the mutant genes do. This seminal transition from descriptive biology to the functional biology of cancer will provoke three new directions for cancer medicine. The first is a direction for cancer therapeutics. Once the crucial driver mutations in any given cancer have been identified, we will need to launch a hunt for targeted therapies against these genes. The second new direction is for cancer prevention. To date, cancer prevention has relied on two disparate and polarized methodologies to try to identify preventable carcinogens. Like cancer prevention, cancer screening will also be reinvigorated by the molecular understanding of cancer. Indeed, it has already been. The third, and arguably most complex, new direction for cancer medicine is to integrate our understanding of aberrant genes and pathways to explain the behavior of cancer as a whole, thereby renewing the cycle of knowledge, discovery, and therapeutic intervention. One of the most provocative examples of a cancer cell’s behavior, inexplicable by the activation of any single gene or pathway, is its immortality. Rapid cellular proliferation, or the insensitivity to growth-arresting signals, or tumor angiogenesis, can all largely be explained by aberrantly activated and inactivated pathways such as ras, Rb, or myc in cancer cells. But scientists cannot explain how cancers continue to proliferate endlessly. Most normal cells, even rapidly growing normal cells, will proliferate over several generations and then exhaust their capacity to keep dividing. What allows a cancer cell to keep dividing endlessly without exhaustion or depletion generation upon generation? An emerging, although highly controversial, answer to this question is that cancer’s immortality, too, is borrowed from normal physiology.

Taken to its logical extreme, the cancer cell’s capacity to consistently imitate, corrupt, and pervert normal physiology thus raises the ominous question of what “normalcy” is. We are inherently destined to slouch towards a malignant end. Indeed, as the fraction of those affected by cancer creeps inexorably in some nations from one in four to one in three to one in two, cancer will, indeed, be the new normal—an inevitability. The question then will not be if we will encounter this immortal illness in our lives, but when.

Atossa's war

 Cancer, we have discovered, is stitched into our genome. Oncogenes arise from mutations in essential genes that regulate the growth of cells. Mutations accumulate in these genes when DNA is damaged by carcinogens, but also by seemingly random errors in copying genes when cells divide. The former might be preventable, but the latter is endogenous. Cancer is a flaw in our growth, but this flaw is deeply entrenched in ourselves. We can rid ourselves of cancer, then, only as much as we can rid ourselves of the processes in our physiology that depend on growth—aging, regeneration, healing, reproduction. Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature. These are related impulses—one might seek to understand nature in order to control it—but the drive to intervene is unique to technology. Medicine, then, is fundamentally a technological art; at its core lies a desire to improve human lives by intervening on life itself. Conceptually, the battle against cancer pushes the idea of technology to its far edge, for the object being intervened upon is our genome. It is unclear whether an intervention that discriminates between malignant and normal growth is even possible. Perhaps cancer, the scrappy, fecund, invasive, adaptable twin to our own scrappy, fecund, invasive, adaptable cells and genes, is impossible to disconnect from our bodies. Perhaps cancer defines the inherent outer limit of our survival. As our cells divide and our bodies age, and as mutations accumulate inexorably upon mutations, cancer might well be the final terminus in our development as organisms.

It is possible that we are fatally conjoined to this ancient illness, forced to play its cat-and-mouse game for the foreseeable future of our species. But if cancer deaths can be prevented before old age, if the terrifying game of treatment, resistance, recurrence, and more treatment can be stretched out longer and longer, then it will transform the way we imagine this ancient illness. Given what we know about cancer, even this would represent a technological victory unlike any other in our history. It would be a victory over our own inevitability—a victory over our genomes.