intro’d to Siddhartha here:
Soon we’ll cure diseases with a cell, not a pill – ted2015
dominance for model – antibiotics: have disease, take medicine, kill something
so seductive was this idea.. so potent was the metaphor of lock and key .. a transformation like no other.. we’ve spent the last 100 yrs trying to replicate that model.. and it’s worked.. but only partly.. ie: a person in wichita fiddling with 10-15 phone lines
what if we reorganized this approach.. the natural world gives us another sense.. organized upwards..: all self-regulating semi-autonomous units: cell, organs/organisms, environments
rather than killing things (w pills) – which eventually runs ceiling of that approach… grow things natural re-organizing (w cells)
so thinking about immune system.. the organismal capacity.. and the environment
most carcinogenic environment .. prison
need to change the physiology of the organ..
7 min – what’s really at stake is not the medicine.. but the metaphor: not killing something but growing something
11 min – dying to form cartilage… the most efficient repairers of fractures..
self-organizing ness. people… most efficient repairers of self.. if set free
we had gone hunting for pills and found theories
could your pill be a cell, could med be an organ created outside of body…. could we store organs.. could your medicine be an environment
could you apply this outside of medicine
a nother way ness
when scientist builds model.. trying to show in metaphor.. antibiotics really distorted how we thought about medicine for 100 yrs.. we need new models.. that’s what’s at stake..
the reason we haven’t had transformative impact.. perhaps not so much about more powerful drugs.. but perhaps more that we don’t have powerful ways of thinking about medicines
and/or people – science of people ness
mechanisms, models, metaphors
so.. imagining the metaphor where the cell is a human – (ie: most efficient repairer of fractures in our humanity) – and wondering if setting enough of us free (in a petri dish of sorts – rat park ish) we might facilitate a mechanism/model/metaphor – that is deep/simple/open enough to re-grow/organize all of us toward a more natural (and less unhealthy) state.
Siddhartha Mukherjee (Bengali:born 1970) is an Indian-born American physician, scientist and writer best known for the 2010 book, The Emperor of All Maladies: A Biography of Cancer, for which Mukherjee won a Pulitzer Prize. The book was the basis of a 2015 film documentary, Cancer: The Emperor of All Maladies, by Ken Burns for PBS Television. It was named one of the 100 most influential books written in English since 1923 by TIME and one of the 100 notable books of 2010 by The New York Times Magazine.
Currently, he is an assistant professor of medicine at Columbia University and staff physician at Columbia University Medical Center in New York City. He has been the Plummer Visiting Professor at the Mayo Clinic in Rochester, the Joseph Garland lecturer at the Massachusetts Medical Society and an honorary visiting professor at Johns Hopkins School of Medicine.
A hematologist and oncologist, Mukherjee is also known for his work on the formation of blood and the interactions between the micro-environment (or “niche”) and cancer cells. Recently, the Government of India has conferred its fourth highest Civilian Award Padma Shri upon Mukherjee.
book links to amazon
in u.s. 1 in 3 women and 1 in 2 men will develop cancer during their lifetime.
cancer, 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, unleashing a cell that cannot stop growing.
that this seemingly simple mechanism – cell growth without barrier – can lie at the heart of this grotesque and multifaceted illness is a testament to the unfathomable power of cell growth.
“Cell division allows us as organisms to grow, to adapt, to recover, to repair—to live. And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair—to live at the cost of our living. Cancer cells can grow faster, adapt better. They are more perfect versions of ourselves”
malignant growth and normal growth are so genetically intertwined that unbraiding the two might be one of the most significant scientific challenges faced by our species..
or.. perhaps.. learning .. as you say.. to prevent malignant growth.
cancer is built into our genomes: the genes that unmoor normal cell division are not foreign to our bodies, but rather mutated, distorted version of the very genes that perform vital cellular functions……… if we seek immortality, then so, too, in a rather perverse sense does the cancer cell.
part 1 – of blacke cholor, w/o boyling
he (farber) would try to use the knowledge he had gathered from his pathological specimes to devise new therapeutic interventions. (coming up from the basement of autopsy ness)
yet all this knowledge only amplified the sense of medical helplessness..
it gave physicians plenty to wrangle over at medial meetings.. but it did not help their patients at all.. (an oncologist recalled)
sounds very Ed ish.. very perpetuate\ing not us ish.. a mission we don’t know how to or don’t really want to give up.. so the disease lives on..
in 1847 – name changed to leukemia..greek word for white.. white blood cells..
if cells only arose from other cells (virchow’s cellular theory) then growth could occur in only two ways: by increasing cell numbers or by increasing cell size
virchow finding – hyperplasia in its extreme form…as he examined the architecture of cancers, the growth often seemed to have acquired a life of its own, as if the cells had become possessed by a new and mysterious drive to grow…. growth in a new form.. he called it neoplasia..
cancer was a disease of pathological hyperplasia in which cells acquired an autonomous will to divide. .. created masses of tissue (tumors) that invade organs/tissues.
but once pathologists stopped looking for infectious causes and refocused their lenses on the disease, they discovered the obvious analogies between leukemia cells and cells of other forms of cancer.
adults on ave have about 5000 white blood cells … per microliter of blood… carla’s contained 90 000 cells per microliter
we would push her deeper into the abyss to try to rescue her. for carla, the only way out would be the way through.
despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured.
science begins with counting. to understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it.
? measure ness.. objective ness..
maybe that’s why we have a chance for something diff today.. we don’t have to be objective.. ish..
if cancer medicine was to be transformed into a rigorous science, then cancer would need to be counted somehow – measure in some reliable, reproducible way.
i see what’s being said. but i don’t think anything can be reliable.. and i wonder if this is part of what’s keeping us from things..
if leukemia could be counted, farber reasoned then any intervention – a chemical sent circulating through the blood, say – could be evaluated for its potency in living patients. he could watch cells grow or die in the blood and use that to measure the success or failure of a drug. he could perform an ‘experiment’ on cancer.
wondering .. about numbers.. and us..
wondering about things we can’t see.. measure..
wondering what we’re missing
the idea mesmerized farber. in the 1940s and 50s, young biologists were galvanized by the idea of using simple models to understand complex phenomena. complexity was best understood by building from the ground up. single-celled organisms such as bacteria would reveal the workings of massive, multicellular animals such as humans.
the most iconic of these new drugs were the antibiotics. penicillin, that precious chemical that had to be milked to last droplet during ww2 1939… in 1942,, when merck had shipped out its first batch.. 5.5 grams..it was 1/2 entire stock of antibiotic in america. a decade later.. being mass produced so effectively.. price sunk to 4 cents a dose.. 1/8 cost of 1/2 gallon milk
in 1949.. streptomycin.. purified out of a clod of mold from a chiken farmer’s barnyard.. time mag: remedies in our own backyard.
thinking of csu prof’s combustion book..
new drugs appeared at an astonishing rate: by 1950 more than half meds in common medical use had been unknown a decade earlier… eve more significant that these miracle drugs, shifts in pubic health and hygiene also drastically altered the national physiogonomy of illness.
tedyouth – inserts to airplanes.. see what can happen when we free art ists first.. any problems we’re getting credentialed for.. on a mission for.. well become irrelevant.. no?
1910 to 1940.. largely due to better sanitation and public hygiene efforts… life expectancy rose from 47 to 68…. hospitals proliferated.. 45 to 60 nearly 1000 new… 35 to 52 # of patients 7 mill to 17 mill
when a dr has to tell a patient that there is not specific remedy …patient apt to … wonder whether dr is keeping abreast of the times… in new/sanitized suburban towns, young generation thus dreamed of cures.. of a death-free, disease-free existence.
this durability ness… fed into consuming durables…illness now ranked 3rd in list of ‘worries’ behind finances and child rearing as #1… w/this obsession fertility rises.. baby born every 7 sec…
of all diseases, cancer had refused to fall into step in this march of progress.
radical mastectomy via william halsted in 1890s… discovery of x rays in early 1900s
scientifically, cancer still remained a black box, a mysterious entity that was best cut away en bloc rather than treated by some deeper medical insight.
to cure cancer (if it could be cured at al), drs had only two strategies: cutting it out or incinerating it w/radiation
decade later.. no further findings.. only been able to make treatment more humane..
fortune article: cancer: the great darkness, the authors suggested, was as much political as medical..
systemic neglect of cancer research: not over 2 dozen funds in us devoted to it.. they range from 500 to 2 mill.. aggregate not more than 5 mill. the public willingly spends a 1/3 of that in an afternoon to watch a major football game.. this stagnation of research funds stood in stark contrast to the swift rise to prominence of the disease.
1900 to 1916 – cancer related mortality grew by 29.8 percent… edging out tb. by 1926.. nation’s 2nd common killer behind heart disease…. 1937 – cancer problem fierce contagion in media
1927 – 5 mill reward to arrest human cancer….. roosevelt signs national caner institute act… created national cancer institute.. perfect.. except for.. 1938.. war breaks out… scientists, lobbyists, physicians, and surgeons fell off public radar..
ie: not able to use words: breast or cancer.. in the times.. all this when farber enters 1947
this isolation was key to farbers’ early success. insulated from the spotlights of public scrutiny, he worked on a small, obscure piece of the puzzle..
minot had shown that replacing a single molecule could restore the normalcy of blood in this complex hematological disease.
colonial fascination.. create conditions of misery in a population, then subject it to social/medial experimentation.
when cells divide, the need to make copies of dna – the chemical that carries all the genetic info in a cell…
subbarao purified a molecule called atp, the source of energy in all living beings…... but couldn’t get into yale….. but did get precisely the antivitamins that farer had been fantasizing about (after he gave folic acid to leukemia patients and found it accelerated their deaths…
1947 – robert sandler – given antifolate
if leukemia was going to be beaten farber wanted every minute of that battle recorded for posterity – even if no one else was willing to watch it happen
document everything ness… even if and because no one is paying attention..
by april 1948 there was just enough data to put together a prelim paper for the new england journal of medicine..
the paper was received, as one scientist recalls, with skepticism disbelief and outrage. but for farber, the study carried a tantalizing message: cancer, eve in it most aggressive form, had been treated with a medicine, a chemical. in six months between 1947 and 1948, farber thus saw door open briefly, seductively – then close tightly shut again…
he dreamed of malignant cells being killed by specific anticancer drugs, and of normal cells regenerating and reclaiming their physiological spaces..
it is a disease of overproduction, of fulminant growth – growth unstoppable, growth tipped into the abyss of no control. modern biology encourages us to imagine the cell as a molecular machine. cancer is that machine unable to quench it initial command (to grow) and thus transformed into an indestructible, self-propelled automation…..
sonsan sontag argued so powerfully in her book illness as metaphor, of an other disease..tb..
recommended to overdrive
both drain vitality; both stretch out the encounter with death; in both cases dying even more than death defines the illness.
cancer, in contrast, is riddled with more contemporary images. the cancer cell is a desperate individualist, ‘in every possible sense, a nonconformist,’ as the surgeon-writer sherwin uland wrote. the word metastasis, used to describe the migration of cancer from one site to another is a curious mix of meta and stasis – beyond stillness in latin – an unmoored, partially unstable state that captures the peculiar instability of modernity..
if tb once killed by hollowing out lungs.. cancer kills by filling body w/too many cells.. the pathology of excess. cancer is an expansionist disease; it invades through tissues, sets up colonies in hostile landscapes, seeking sanctuary in one organ and then immigrating to another , it lives desperately, inventively, fiercely, territorially, cannily, and defensively – at times, as if teaching us how to survive. to confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are.
learning from cancer..
cancer is phenomenally successful invader and colonizer in part because it exploits the very features that make us successful as a species or as an organism.
cancer, we no know, is a clonal disease.
wilde… most people are other people
if growth occurred w/o evolution, cancer cells would not be imbued w/their potent capacity to invade, survive, and metastasize…. when a chemotherapeutic drug or the immune system attacks cancer, mutant clones that can resist the attack grow out. the fittest cancer cell survives.
bad strafish.. wars.. terrorism.. et al
it felt inescapably, as if i were writing not about something but about someone. my subject daily morphed into something that resembled an individual an enigmatic, if somewhat deranged, image in a mirror.. so not history but biography of cancer…
1862 – edwin smith… finds papyrus… of 2625 bc ..imhotep (physician)…. the surprising feature of the smith papyrus is not magic and religion but the absence of magic and religion.
if cancer existed in the interstices of these massive epidemics, it existed in silence, leaving no easily identifiable trace in the medical literature – or in any other literature.
… we once more hear of cancer. and again, it is an illness cloaked in silence, a private shame.
if atossa had desired it, an entire retinue of physicians from babylonia to greece would have flocked to her bedside to treat her. instead she descended in to a fierce and impenetrable loneliness. she wrapped herself in sheets, in a self-imposed quarantine…..
someone cuts it out of her.. and in frenzy of gratitude.. for life..she gets this territorial ambition… pleads w/her husband to invade greece.
it was atossa’s tumor, then that quietly launched a thousand ships.. cancer, even as a clandestine illness, left it s fingerprints on the ancient world..
a thousand-year-old cancer preserved inside of a mummy…
there are several reasons behind this absence (of cancer from earliest days). cancer is an age-related disease – sometimes exponentially so…. in most ancient societies, people didn’t live long enough to get cancer…. can’cer’s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed. 19th cent dr’s often linked cancer to civilization: cancer, they imagined, was caused by the rush and whirl of modern life…. civilization did not cause cancer, but by extending human life spans – civilization unveiled it.
didn’t people used to live longer than we do now?
A patient, long before he becomes the subject of medical scrutiny, is, at first, simply a storyteller, a narrator of suffering—a traveler who has visited the kingdom of the ill. To relieve an illness, one must begin, then, by unburdening its story.”
400 bc word for cancer first appeared in medical lit as karkinos… greek word for crab….. another greek word intersects with the history of cancer – onkos… used to describe tumors… greek for a mass or a load, or more commonly a burden; cancer was imagined as a burden carried by the body.
Depression and cancer, the psychic and physical diseases of black bile, were thus intrinsically intertwined.)
so.. story is part (perhaps first step) to curing illnesses .. and one’s we can’t seem to cure have been silenced by shame..
hippocrates had once … that cancer was best left untreated, since patients live longer that way.
the problem w/treating cancer surgically, galen suggested, was that black bile was everywhere, as inevitable and pervasive as any fluid. you could cut cancer out, but the bile would flow right back, like sap seeping through the limbs of a tree.
the surgical removal of tumors – a local solution so a systemic problem – was thus perceived as a fool’s operation.
deep enough ness…
no matter how diligently vesalius pored through the body, he could not find galen’s black bile… vesalius had started his anatomical project (digging up/finding and then studying dead people) to save galen’ theory, but in the end he quietly buried it.
late 1800s.. that he was applying sewage cleanser to his patients appears not to have struck him as even the slightest bit unusual. – he’s observed sewage disposers cleanse their waste with a cheap, sweet smelling liquid containing carbolic acid..
he (halsted) found that it (cocaine – was being used as anesthetic) produced much more than a transitory numbness: it amplified his instinct for tirelessness; it synergized with his already manic energy. his mind became, as one observer put it, clearer and clearer, with no sense of fatigue and no desire or ability to sleep.
frustrated by repeated failures, moore had begun to *record the anatomy of each relapse, denoting the area of the original tumor, the precise margi of the surgery, and the site of cancer recurrence by drawing tiny black dots on a diagram of a breast-creating a sort of historical dartboard of cancer recurrence…and to mooore’s surprise, dot by dot, a pattern had emerged. the recurrences had accummulated precisely around the margins of the original surgery, as if minute remnants of cancer had been left behind by incomplete surgery and grown back. mammary cancer requires the careful extirpation of the entire organ moore concluded. local recurrence of cancer after operation is due to the continuous growth of fragments of the principal tumor.
cancer teaching us (a bit earlier).. of antifragility…
halsted would excavate his way past it . instead of stripping away the thin pectoralis minor, which had little function, halsted ecided to dig even deeper into the breast cavity, cutting through the pectoralis major the large, prominent muscle responsible for moving the shoulder and the hand. halsted was not alone in this innovation…
a macabre marathon was in progress. halsted and his disciples would rather evacuate the entire contents of the body than be faced with cancer recurrences.
yet halsted accepted all these consequences as if they were the inevitable *war woulds in an all-out battle
*collateral damage ness
by 1898, it had transformed into a profession booming w/self-confidence, a discipline so swooningly self-impressed with its technical abilities that great surgeons unabashedly imagined themselves as showmen… (radical surgery…)
halsted’s mastectomy may have been a florentine mosaic worker’s operation, but if cancer was a chronic relapsing disease, then perhaps cutting it away, even with halsted’s intaglio precisions, was not enough….. one needed to track not immediate survival, or even survival over 5-10 months, but survival over 5-10 yrs….. halsted had operated on enough … for cancer storehouse.. at hopkins
there was a deep conceptual error.
deep enough matters. and quiet/still enough matters.. to get to deep enough.
halsted’s ability to cure patients w/breast cancer obviously depends on the sort of cancer – the stage of breast cancer – that he confronts. the woman w/metastatic cancer is not going to be cured by a radical mastectomy, no matter how aggressively and meticulously halsted extirpates the tumor in her breast: her cancer is no longer a local problem.
in contrast, woman w/small, confined cancer does benefit from operation.. but for her, a far less aggressive… so halsted’s mastectomy a peculiar misfit in both cases.
too much too early for the woman w/local breast cancer, .. too little too late for the oman with metastatic cancer..
but if one looked closely, the roots had persisted. (even in radical surgery)
rather than address the real qquestio raised by the data – did radical mastectomy trule extend lives – they clutched to their theories even more adamantly.
the ultimate survival from breast cancer, in short, had little to do with how extensively a surgeon operated on the breast; it depened on how extensively the cancer had spread before surgery.
as george crile, one of the most fervent critics of radical surgery, later put it, if the disease was so advance that one had to get rid of the muscles i order to get rid of the tumor, then it had already spread through the system – making the whole operation *moot.
huge… irrelevant ness
cancer was beginning to tire him out. trials, tables, and charts had never been his forte; he was a surgeon, not a *bookkeeper. it is esp true of mammary cancer, he wrote, that the surgeon interested in furnishing the best stats may in perfectly honorable ways provide them….. exemplified his growing skepticism about putting his own operating to a test. he instinctively knew that he had come to the far edge of his understanding of this amorphous illness that was constantly sliiping out of his reach.
*bookkeeper – all of us.. as commonplace book ness
he wanted new and open anatomical vistas where he could practice his technically brilliant procedures in peace, not debates about the measurement and remeasurement of end points of surgery.
what halsted could not prove, despite his most strenuous efforts, was far more revealing. after nearly two decades of data gathering having been levitated, praised, analyzed, and reanalyzed in conference after conference, the superiority of radical surgery in “curing ” cancer still stood on shaky ground. more surgery had just not translated int more effective therapy.
even the word radical was a seductive conceptual trap. halsted had used it in the latin sense of ‘root’ because his operation was meant to dig out the buried subterranean roots of cancer. but radical also meant ‘aggressive, innovative and braze’ and it was this meaning that left its mark on the imaginations of patients. what man or woman, confronting cancer, would willingly choose non-radical, or ‘conservative’ surgery.
whoa. to Ed ness. to life ness.
radical surgery, on historical wrote soon fossilized into dogma..
shrug off the responsibility of a cure altogether. undoubtedly, if operated upon properly the condition may be cured locally, and that is the only point which the surgeon must hold himself responsible one of halsted’s disciples announced at a conference in baltimore in 1931. the best a surgeon could do in other words was to deliver the most technically perfect operation. curing cancer was someone else’s problem.
whoa.. thinking of Ed and fisch – enemy is us ness.. and dealing with today ness even if bandaid. and thinking of Paul’s doc.. syriza et al.. and being .. not afraid. and how deeply we need.. a nother way.
eve in its widest sense and english surgeon wrote in 1929, the measure of operability depends on the question: is the lesion removable and not on the question: is the removal of the lesion going to cure the patient. surgeons often counted themselves lucky if their patients merely survived these operations.
or these tests… or degrees.. or.. this debt.. this day.. this month..
to arrive at that sort of logic – the hippocratic oath turned upside down – demands either a terminal desperation or a terminal optimism. in the 1930s, the pendulum of cancer surgery swung desperately between those two points.
proof became irrelevant and trials impossible to run. the more fervently surgeons believed in the inherent good of their operations, the more untenable it became to put these to a formal scientific trial. radical surgery thus drew the blinds of circular logic around itself for nearly a century.
brave enough for ..good bye cycle.. as the day. every day.
halsted asking student to head up new dept – i know you didn’t know anyhing.. but we believe that you can learn.
like young cushing inherited halsted’ intaglio surgical technique – the slow separation of brain from tumor, working now here, now there, leaving small, flattened pads of hot, wrong-out cotton to control oozing.. but not halsted’s penchant for radical surgery..
nearly all pioneers in the medical x ray labs in the u.s. died of cancers induced by the burns.. – washington post, 1945
in mid 1880s pierre curie used minuscule quartz crystals to craft an instrument called an electrometer, capable of measuring exquisitely small doses of energy
the curies – (pierre and marie) found the first signal of a new element – an element many times more radioactive than uranium…1902..x rays…
marie’s hands.. painful legacy..as if the tissue had been burnt from the inside.. would eventually burn into her bone marrow.. leaving her permanently anemic..
radium was attacking dna… this ability of x rays to selectively kill rapidly dividing cells did not go unnoticed.. esp by cancer researchers.. – ie: grubbe
x rays could only be used to treat cancer locally, with little effect on tumors that had already metastasized.
a new branch of cancer medicine, radiation oncology, was born, x ray clinics mushroomed
one could double and quadruple the doses of radiant energy, but this did not translate into more cures. instead, indiscriminate irradiation left patients scarred, blinded, and scalded by doses that had far exceeded tolerability.
making radium watches.. women licking radium brushes.. 1920s
marie curie dies of leukemia 1934.. grubbes fingers amputated.. dies of multiple forms of cancer..
a more discriminating therapy was needed, especially for cancers that were nonlocalized.
cancer was often a humoral disease. crablike and constantly mobile, it could burrow through invisible channels from one organ to another… it was a systemic illness..
the trouble lies in finding a selective poison- a drug that will kill cancer without annihilating the patient. systemic therapy without specificity is an indiscriminate bomb.
deep enough ness – 2 needs
experimenting w/dyes… wohler’s experiment demolished vitalism – vital essence that can’t be duplicated..
the dyes seemed able to discriminate among chemicals hidden inside cells – binding some and sparing others.
the other inhabitants of ehrlich’s train compartment had dozed off to sleep. but this rant in a train compartment was one of medicine’s most important ideas in its distilled, primordial form. ‘chemotherapy’ the use of specific chemicals to heal the diseased body, was conceptually born in the middle of the night.
scribbled in the middle of the night ness…
with cancer it was the similarity of the cancer cell to the normal human cell that made it nearly impossible to target.
ehrlich.. observing mustard gas.. left mean anemic and in need of transfusions of blood.. often up to once a month. they were prone to infections. their white cell counts often hovered persistently below normal.. that their bullet would eventually appear out of that very chemical weapon seemed like a perversion of specific affinity, a ghoullish distortion of ehrlich’s dream.
every experiment is a conversation with a prior experiment..
in 1948 – jimmy fund: 231 000.. in comparison, in 1944, manhattan project spent 100 mill every month at the oak ridge site. in 1948, americans spent more than 126 mill on coca cola alone.
to measure the genius of the jimmy campaign in dollars.. is to miss its point.. for farber, the jimmy fund campaign was an early experiment – the building of another model…..
for any illness to rise to political prominence.. it needed to be marketed, just as a political campaign needed marketing. a disease needed to be transformed politically before it could be transformed scientifically.
if farber’s antifolates were his first discovery in oncology, then this critical truth was his second. it set off a seismic transformation in his career that would far outstrip his transformation from a pathologist to a leukemia dr. this second transformation – from a clinician into an advocate for cancer research – reflected the transformation of cancer itself. the emergence of cancer from its basement into the glaring light of publicity would change the trajectory of this story. it is a metamorphosis that lies at the heart of this book.
part 2 – an impatient war
perhaps only one cardinal sin: impatience. because of impatience we were drive out of paradise, because of impatience we cannot return – franz kafka
or can we..
all of this demonstrates why few research scientists are in policymaking positions of public trust. their training for detail produces tunnel vision, and men of broader perspective are required for useful application of scientific progress – michael shimkin
in 1831 – alexis de tocquevillie, the fresh aristocrat, toured the us and was astonished by the obsessive organization energy of its citizens…. they form a society.. more than a century after tocqueville … farber instinctively grasped the truth behind tocqueville’s observation. if visionary changes were best forged by groups of private citizens forming societies, then farber needed such a coalition to launch a national attack on cancer….
there was… one person for this.. mary woodard lasker
advertising was merely a carrier for info and reason, and for the public to grasp its impact, info had to be distilled into its essential elemental form…. advertising as a lubricant of info and .. and need for elemental *iconography would leave a deep an lasting impact on the cancer campaign
*iconography – perhaps today.. modeling.. beyond icon ness… because: rev of everyday life ness.. in reverse ness
inquiry – a luxury of peacetime. the war demanded something more urgent and goal-directed…. ie: the atomic bomb.. the product of the manhattan project
on aug 7 1945, the morning after hiroshima bombing, the nyt gushed about the extraordinary success of the project… uni prof’s who are opposed to organizing, planning and directing research after the manner of industrial labs.. have something to think about now.. a most important piece of research was conducted on behalf of the army in precisely the means adopted in industrial labs. end result: an invention was given to the world in three years, which it would have taken perhaps half a century to develop if we had to rely on primadonna research scientists who work alone.. a *problem was stated, it was solve by teamwork, by planing, by competent direction, and not by the mere desire to satisfy curiosity.’
*problem – oh my. bad/wrong problem.. maybe only works for bad/wrong problem ness… and/or.. imagine if we did it for something that really mattered.. to all of us.
the congratulatory tone of that editorial captured a general sentiment about science that had swept through the nation. the manhattan project had overturned the prevailing model of scientific discovery. the bomb had been designed, … by a focused swat team of researchers sent off to accomplish a concrete missions. a new model of scientific *governance emerged from the project- research driven by specific mandates, timelines, and goals.
*governance – ugh… and at 100 mill a month..
a lesson bush (vannevar bush) had learned from all of this was that goal-directed strategies, so useful i wartime, would be of limited use during periods of peace.
because of the time..? or the purpose..? ie: things that matter.. things of war..
the laskerites – wanted a manhattan project for cancer…
bush’s cult of open-ended curiosity-driven inquiry – interesting science – had ossified into dogma. to battle cancer, that dogma needed to be overturned.
for the first time, an academic oncologist felt as if he had a community. the cancer doctor was not the outcast anymore..
leukemia treated w/a single drug would inevitably grow resistant to the drug
li was accused of experimenting on people, freireich said. but of course all of us were experimenting, … to not experiment would mean to follow the old rules – to do absolutely nothing.
li had stumbled on a deep an fundament a principle of oncology: cancer needed to by systemically treated long after every visible sign of it had vanished. [he got fired for continuing treatment when people thought the women were cured.. but the reading was still not at zero]
this strategy – which cost min chiu li his job – resulted in the first chemotherapeutic cure of cancer in adults..
the academic stodginesss of the leukemia consortium – its insistence on progressively and systematically testing one drug combo after another – was now driving freireich progressively and systematically mad.
try explaining zubrod’s strategy of sequential, systematic, and objective trials to a woman whose daughter has just slumped into a coma and died, ‘ freireich recalled.
what we needed was quite the opposite of a systematic approach – an intuitive and inspired leap of faith into the deadly abyss of deadly drugs..
if leukemia was a model form of cancer, then skipper had been studying the disease by artificially inducing leukemias in animals – in effect, by building a model of a model.
a model is a lie that helps you see the truth – howard skipper
skipper liked to think about cancer not as a disease but as an abstract mathematical entity.
skipper found: chemo killed a % of cells; combos of drugs gave synergistic effects on killing
using drugs in concert dramatically lowered the chance of resistance and increased cell killing… w/several drugs and several iterative rounds of chemo in rapid-fire succession, skipper cured leukemias in his mouse model..
equity…everyone getting a go – everyday.. do-over ad infinitum
the regimen…vamp – each letter for one of drugs… and… vamp means: improvise/patch up, cobble together from bits and pieces that might crumble apart any second; one who promises but doesn’t deliver; front of boot, part that carries full brunt of force during a kick
doctors are men who prescribe medicines of which they know little, to cure disease of which they know less, in human beings of whom they know nothing. – voltaire
not just dr’s .. all of us. everything is experiment.
when frei and freireich presented the prelim plan for vamp.. the audience balked… freireich recalled, it was a terrible catastrophic showdown. we were laughed at and then called insane, incompetent, and cruel. ….. frei and freireich it was felt were making an unauthorized quantum leap. the group refused to sponsor vamp.. at least not until the many other trials had been completed.
frei wrangled a last minute compromise: vamp would be studied independently as the nci, outside the purview of the algb. the idea was preposterous freireich recalled. to run the trial we would need to split w/the algb, the very group that we had been so instrumental in founding. zubrod wasn’t pleased w/the compromise: it as a break from his cherished – cooperative – model.
worse still, if vamp failed, it would be a political nightmare for him, if the children had died, we’d be accused of *experimenting on people at this federal installation of the nci, freireich acknowledged.
the vamp trial was finally launched in 1961
almost instantly, it seems like an abysmal mistake – precisely the sort of nightmare that zubrod had been trying to avoid.
his (friereich) paternal, possessive instincts were aroused: these were my kids. i really tried to take care of them.. the nci, as a chile, watched tensely – for its life, too, was on the line.
at end of three excruciating weeks.. a few somehow pulled through.. then unexpectedly…. there was a payoff.. the normal bone marrow cells began to recover gradually, but the leukemia went into remission. the bone marrow biopsies came back one after another – al w/o leukemia cells.
this – after near complete devastation – was a remission so deep that it exceeded the expectations of everyone at the nci
once again, after nearly catastropic dip in counts – like a drop from a cliff w/a thread tied to your ankles…. the bone marrow recovered and the leukemia vanished..a few days later, the bone marrow began to regenerate…
by 1962.. f and f treated 6 patients w vamp…critics were slowly turning to converts…. 1964 – astonishment slowly gave way to buoyancy .. opinionated harvard-trained hematologist.. and one of most prominent earl opponents of vamp wrote. the mood among pediatric oncologists changed virtually overnight from one of compassionate fatalism to one of aggressive optimism
1963 – on return from one of those triumphant conferences celebrating success… patients w/ minor complaints
in 1880s virchow had observed leukemia cells could occasionally colonize the brain… had to look at spinal fluid… a clear liquid that circulates in direct connection with the brain, is a surrogate for examining the brain…. the overheated, standstill second when observations crystallize and fall together in to 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 discover of failure. it is a moment that a scientist often encounters alone.
findings in failings.. helping gain sight toward the sync.. of us
no cancer was found in the body. but the leukemia cells had invaded the nervous system, causing a quick, unexpected demise…. leukemia cells were growing explosively in the spinal fluid by the millions, colonizing the brain.
it was the consequence of the body’s own defense system subverting cancer treatment. the rain and spinal cord are insulated by a tight cellular seal called the blood-brain barrier that prevents foreign chemicals from easily getting into the brain. …. evolved to keep poisons from reaching the brain. but the same system had likely also kept vamp out of the nervous system, creating a natural ‘sanctuary’ for cancer w/in the body
story of leukemia – the story of cancer – isn’t the story of dr’s who struggle and survive, moving from one institution to another. it is the story of patients who struggle and survive, moving from one embankment of illness to another…. if history of medicine is told through the stories of dr’s it is because their contributions stand in place of the more substantive heroism of their patients.
hodgkin .. underestimated the value of careful observation – by compulsively studying anatomy alone, he had stumbled upon the most critical revelation about this form of lymphoma: hodgkin’s disease had a peculiar propensity of infiltrating lymph nodes locally one by one….. a local disease on the verge of transforming into a systemic one…. via extrapolation..
devita – the unorthodoxy of their (zubrod, f&f) approach – the maniacs doing cancer research, as he called it – had instantly fascinated him.
terror of vamp – death by infections… terror of mopp – death by nausea…. what if vamp had not been intensive enough
the agent responsible for carrying the cancer, rous concluded, was not a cell or an environmental carcinogen, but some tiny particle lurking w/in a cell…… a virus….mono
rous lambasted idea that cancer could be caused by something inherent to the cells, such as a genetic mutation. … and .. belief in that acts as a tranquilizer on those who believe it… rous had his own tranquilizer.. viruses cause cancer.. and many in his audience , in no mood for caveats and complexities, were desperate to swallow his medicine……. two superficial theories: 1\ viruses caused cancer 2\ combos of cytotoxic poisons would cure cancer
on searching for a cure before knowing the cause..
garb’s book – and he becomes laskerites messiah.. religious movements/cults founded on : a prophet, a prophecy, a book and a revelation
missing element – a revelation – a sign that would auger the future and capture the imagination of the public
moon landing… mary lasker begins to refer to a programmatic war on cancer as the conquest of inner space – as opposed to outer space instantly unifying the two projects..
apollo11 – shifts public perception of science… laskerites coined a phrase to describe this analogy.. they called it a moon shot for cancer
full page add in washington post – 1969 – open letter to nixon
when a disease insinuates itself to potently into the imagination of an era it is often because it impinges on an anxiety latent w/in that imagination…. every era casts illness in its own image. society, like the ultimate psychosomatic patient, matches its medial afflictions to its psychological crises; when a disease touches such a visceral chord, it is often because that chord is already resonating.
1950s – fear of annihilation from outside – cold war.. horror movies – the thermometer of anxiety in popular culture.. alien invasions.. parasitic occupations of the brain.. body snatching…
by early 1970s.. locus of anxiety – shifted to inside… : the exorcist,…. cancer epitomized this internal horror.. an internal alien
we are fickle even about fear..
these metaphorical shifts… powerful… a strategic alignment of power..
in past had pleased to the nation for funds for cancer. now, pleaded for the nation for a more coordinated attack on cancer.. colossally empowered in the public imagination…. part of american dream..
impatient, aggressive, and goal driven,.. nixon.. was inherently partial to impatient aggressive, and goal driven projects.
level of funding unprecedented in history of nih.. of american science..
landers’s answer to that questions.. not merely medical cure.. but political.. ‘if enough citizens *let their senators know they want bill s 34 passed, it will pass..
so.. does this not work..? we seek to cure.. not to loads of mail and ensuing b creation/support.. no?
people saying not a good way.. to focused. inside the box.. but nixon facing next election.. makes it happen.. bittersweet for laskerites… mary and farber excluding themselves..
the act, then, was an anomaly, designed explicitly to please all of its clients, but unable to satisfy and of them
73 farber dies..his last hrs spent discussing future of jimmy fund..and direction of war on cancer. his papers were neatly arranged in shelves all around him… new boo o advance in leukemia just arrived
2005 – carla in full remission
part 3 – will you turn me out if i can’t get better
73 bad yr for war on cancer.. devolves into a war w/in cancer
Cancer didn’t move centrifugally by whirling through larger and larger ordered spirals; its spread was more erratic and unpredictable.
on mastectomy’s being forced..
by late 1976.. chemo patients not relapsing.. einhorn had cured a solid cancer by chemo…. following pages about side effects.. nausea.. smuggling in marijuana to tide them through effects…. cisplatin touted as epic chemo product of late 70s… the ie of how curing cancer involved pushing patients nearly to brink of death.
in 70s young drs who opposed vietnam war flooded to the nci… enrollment in fed research program.. exempted draft.. so soldiers of one battler channeled to another…. big boost of energy…trial and error on huge scale
if prostate cancer could be starved to near-death by choking off testosterone, then could hormonal deprivation be applied to starve another hormone-dependent cancer… ie: breast cancer..
palliative care (medicine) from london via saunders
john cairns resurrected the task of measuring progress in the war on cancer… he was coming from overgranularity… wanted to pull away from details and offer a bird’s eye view.
Since the illness was man-made, its solution could also be man-made.
so many smoke – hard to say cancer and smoking a correlation
long before lung cancer grew overtly and symptomatically out of a smoker’s lung auerbach found, the lung contained layer upon layer of precancerous lesions in various states of evolution – like a prehistoric shale of carcinogenesis…… a disease unfolded slowly in time – auerbach..
1961 0 american cancer society, amer heart assoc and national tb assoc sent joint letter to pres kennedy… he assigned to his surgeon general, luther terry… who spent childhood in tobacco.. and academic life in cancer..
in medical circles, link between tobacco and cancer such stale news.. most began to focus on 2nd hand smoke as risk
meta analysis.. using all trials
report released… jan 1964 – on sat.. so wouldn’t mess up stock market..
in nation obsessed w/cancer the attribution of a vast preponderance of a major cancer to a single, preventable cause might have been expected to provoke a powerful and immediate responses… but not so..
ever since flawed attempts to regulate alcohol during prohibition, congress had conspicuously disabled the capacity of any federal agency to regulate an industry.
cigs had narrowly escaped being defined as a drug. thus., even if the surgeon general’s report provided a perfect rational to control tobacco industry, there was little that washington would to, or importantly, could do to achieve that goal.
1950s – any policing was just on word smithing…
john blatnik… finds that couldn’t regulate tobacco.. but could reg ads.. so… ads add health disclaimer..
yet in congress.. diluted meeting after meeting… so came up with disclaimer that all must use.. so not unfair to ads… taking out words death, cancer…
“an unabashed act to protect private industry from government regulation.” Politicians were far more protective of the narrow interests of tobacco than of the broad interest of public health. Tobacco makers need not have bothered inventing protective filters, Drew wrote drily: Congress had turned out to be “the best filter yet.
iconoclastic – a person who attacks cherished beliefs or institutions.. – describing john banzhaf – who in 1966 – found law that said equal airtime for opposing views…
amer cancer soc, amer lung assoc… and others.. didn’t support him… yet he won his case..
last cig commercial.. jan 1 1971
p 270 – on cig companies not only knowing about dangers.. but squashing reports that proved it..
tobacco industry uses its wealth to influence politicians to create a favourable environment to promote smoking
It remains an astonishing, disturbing fact that in America—a nation where nearly every new drug is subjected to rigorous scrutiny as a potential carcinogen, and even the bare hint of a substance’s link to cancer ignites a firestorm of public hysteria and media anxiety—one of the most potent and common carcinogens known to humans can be freely bought and sold at every corner store for a few dollars.
in tradition of all good tests, ames’s test transformed the unobservable and immeasurable into the observable and measurable.
“Carcinogens, Ames suggested, had a common, distinctive functional property: they altered genes.”
just as reading this Saul tweets this:
You know cancer causing genes are smart buggers when they mess w/ DNA’s double helix structure.
Original Tweet: https://twitter.com/skap5/status/680045826861871104
on the need for human gene categorization… 1950s.. dna structure still largely undiscovered.. .. move to systematically organie varint blood atigens.. hoping to link them to human disease.. blumberg.. 1964
p 280 – discovery of hbv (by blumberg) was an embarrassment to the nci.. had yet to find a single cancer – associated virus…
the cycle fo death and repair, appeared to be responsible for the cancer – a blow to hte notion that viruses directly cause cancer..
blumberg had thus made a critical link from cause to prevention. he had identified a viral carcinogen, found a method to detect it before transmission, then found a means to thwart transmission.
strangest among preventable carcinogens… not a virus but a bacterium
marshall’s experiments…. the long incubation period had been critical – found when he was too busy to look sooner
can’t pinpoint underlyings of cancer, ie: diabetes: abnormal insulin; coronary heart : clot, …
on attacking pre cancer – papanicolaou – greek cytologist… most intensive study… penniless of the boat.. 1913. – 1928 – new cancer diagnosis… (288) – pap smear.. and scoffed at at conferences… another scoffing and he dives back into his smears w/ nearly monastic ferocity. (1928 to 1950) – 1950 at party.. he verbalizes strand of thought he had been spinning internally for nearly a decade… pap not to find cancer but pre cancer..
1952 – 150 000 women receive pap smears – 557 found pre cancer .. couldn’t have seen/known otherwise..
fed into re emergence of salomon’s.. mammography… (delayed by nazis mid 1930s)
mammography trials/flawed all over the world.. finally finalized in 2007 in sweden – 1976 – 42 000 women – benefits those over 55..? (302) mammogram.. not a particularly good tool for detecting early breast cancer..
a static pic can’t capture this qualitative growth.. seeing a small tumor and extracting it from the body doesn’t guarantee our freedom from cancer – a fact that we still struggle to believe…
Like any portrait, it is drawn in the hopes that it might capture something essential about the subject—its psyche, its inner being, its future, its behavior.
“All photographs are accurate,” the artist Richard Avedon liked to say, “[but] none of them is the truth
1980s – missing element … a deeper understanding of carcinogenesis – a mechanistic understanding that would explain the means by which normal cells become cancer cells.
my task was to repossess imagination from death.
(after.. if a man die.. it is because death has first possessed his imagination.. – william carlos williams
easy to repossess imagination w/false promises; much harder to do so with nuanced truths.
on susan sontag’s … myelodysplasia (what killed her).. caused by high-dose chemo that she had received for the other cancers.. her new dr telling her same info w/o choking off possibility of a miraculous remission…
trial running was the principal currency of academic advancement, and volley after volley of trails were launched…1980 ish
vamp – intensive attack – grew… aids showed up… men who’s white blood cells – immune system – had dropped because of chemo.. 1981-2
sontag pens it.. illness as metaphor… arguing that aids, like cancer , was becoming not just a biological disease but something much larger.. a social political category replete with its own punitive metaphors.
on delays on drugs.. because insurance et al won’t cover – as experimental/investigation slapped on as label….. even though… 1177 papers 1993 alone, entire wards dedicated to the procedure…
then tables turn.. becomes lucrative.. but then patients don’t want to be put through placebo ish trials.. just want the drug
1999 – bezwoda misleading/scam from work in johannesburg
on treatment being like … being dropped from plane.. by people in white coats that don’t know what they’re doing… they are making parachutes not map-making…
[1st impulse while reading was a reminder of csap scores… and how they weren’t really comparing anything comparable from yr to yr]….. in effect, creating a frozen, static population so that cancer mortality could be compared directly from one year to the next.
flat line cancer..was t truly inanimate? … or two equals in opp directions..
instead, he (bailar) had chronicled a dynamic, moving battle in midpitch against a dynamic, moving target
the quest to combat cancer thus turned inward, toward basic biology, toward fundamental mechanisms..
deep enough ness…
part 4 – prevention is the cure
part 5 – a distorted version of our normal selves
it is in vain to speak of cures, or think of remedies, until such time as we have considered of the causes.. cures must be imperfect, lame, and to no purposed, wherin the causes have not first been searched. – robert burton.. the anatomy of melancholy
you can’t do experiments to see what causes cancer. it’s not an accessible problem and it’s not the sort of thing scientists can afford to do.. i hermann, cancer researcher , 1978
what can be the why of these happenings? – peyton rous, 1966
i mull over the type of cancer to study in the lab, and i find myself gravitating toward leukemia. i may be choosing the lab, but my subject of research is governed by a patient. carla’s diseases has left its mark on my life.
the cells technically speaking, are immortal. the woman from whose body they were once taken has been dead for thirty yrs..
on virchow missing essence of the cause. inflammation makes cells divide in response to injury, but this cell division is driven as a reaction to an external agent such as a bacteria or a wound. in cancer, the cell acquires autonomous proliferation;it is driven to divide by an internal signal…he failed to fathom that the true disturbance lay within the cancer cell itself.
a revolution in the understanding of normal cells was sweeping through biology in the early twentieth century. the seeds of this revolution were planted by a retiring, nearsighted monk in an isolated abbey in brno, austria, who bred pea plants as a hobby.
in the early 1860s, working alone, gregor mendel had identified a few characteristics in his …… biological organisms transmit ‘instructions’ from one cell to its progeny by… his primitive lampit microscope, w/which he could barely peer into the interior of cells, had no power to reveal the mechanism of inheritance. mendel did not even have the name for this unit of inheritance; decades later in 1909, botanists would christen it a gene…mendel’s studies left a provocative question hanging over biology for half a century…
so genes had to be carried on chromosomes – the threadlike structure identified by flemming three decades earlier…
mendel: genes move from one gen to next; morgan: carried on chromosomes; avery: in bacteria, genes transmitted laterally – via dna
What scientists had formerly disregarded as a form of cellular stuffing with no real function—a “stupid molecule,” as the biologist Max Delbruck once called it dismissively—turned out to be the central conveyor of genetic information between cells, the least stupid of all molecules in the chemical world
never nothing going on ness
by mid 1940s.. 3 decades after word.. seeing nature of functionality… functionally: a gene was unit of inheritance; physically: carried w/in cell as chromosome; chemcially: composed of dna
genes carried instructions to build proteins… the workhorses of the cell..
*proteins (discovered in 1940s) carry out the bulk of cellular functions. they form enzymes, catalysts that speed up biochemical reactions vital to the life of the cell. *proteins are receptors for other proteins or molecules, responsible for transmitting signals from one cell to next… create structural components.. regulate other proteins.. coordinating life of cell.
*so.. perhaps chip as (artificially augmented, artificially inseminated, placebo ish) protein
beadle and tatum found that a gene ‘works’ by *providing the blueprint to build a protein. a protein is a gene realized – the machine built from a gene’s instructions. but proteins are not created directly out of genes…
*ie: helping to see what’s already there.. so.. listening to and trusting.. that/us
in late 50s..from paris and caltech and cambridge.. discovered the he genesisi of proteins from genes requires an intermediary step – a moleculre call .. *rna
* or perhaps chip as aa/ai/? rna
RNA is the working copy of the genetic blueprint. It is through RNA that a gene is translated into a protein. This intermediary RNA copy of a gene is called a gene’s “message.” Genetic information is transmitted from a cell to its progeny through a series of discrete and coordinated steps.
first, genes located in chromosomes, are duplicated when a cell divides and are transmitted into progeny cells. next, a gene, in the form of dna, is converted into its rna copy. finally, this rna message is translated into a protein.
the protein, the ultimate product of genetic info, carries out the function encoded by the gene.
in the eye cells of the prgeny fly, thes gens id deciphered, ie: converted int an intermediate rna message. the rna message in turn instructs the eye cells to build the reid pigmenint… et al..any interruption in this info flowmight disrupt the transmission …
This unidirectional flow of genetic information—DNA → RNA → protein—was found to be universal in living organisms, from bacteria to slime molds to fruit flies to humans. In the mid-1950s, biologists termed this the “central dogma” of molecular biology.
mutants.. from copying error.. during cell division..
link between x rays and mutations..radiation causes cancer.. since x rays also cause mutations.. could cancer be a disease of mutations..
what caused mitosis to turn so abruptly from such an exquisitely regulated process to chaos…. what had failed was a kind of biological imagination...
temin imagined creating cancer in a petri dish… in 1958 .. succeeded… (previous could only look at rous’s because only way you could see.. like looking for keys..lost in house.. under street corner lampstand..)
temin’s imagination that allowed him to look… and re imagine
temin believed that the cell and its interaction with the virus, had all the biological components necessary to drive the malignant process. the ghost was out of the organism.
biological info, the dogma proposed, only travels down a one way street from dna to rna to proteins.. how on earth, temin wondered, could rna turn around acrobatically and make a dna copy of itself, driving wrong way
Temin made a leap of faith; if the data did not fit the dogma, then the dogma—not the data—needed to be changed.
.. we have to re imagine data as well.. ie: self-talk as data..
termin had an inkling, but his proof was so circumstantial.. so frail.. he could barely convince anyone… the hypothesis earned him little but ridicule and grief..
Standing unknowingly at the edge of a molecular revolution, he wanted silence.
RNA into DNA. Even the thought made him shiver: a molecule that could write history backward, turn back the relentless forward flow of biological information
Temin was not just talking about viruses. He was systematically dismantling one of the fundamental principles of biology.
The genes of retroviruses, they postulated, exist as RNA outside cells
RNA viruses infect cells, they make a DNA copy of their genes and attach this copy to the cell’s genes. This DNA copy, called a provirus, makes RNA copies, and the virus is regenerated, phoenixlike, to form new viruses. The virus is thus constantly shuttling states, rising from the cellular genome and falling in again—RNA to DNA to RNA; RNA to DNA to RNA—ad infinitum
so this is what we do.. we intersect that.. to detox ourselves.. from perpetuate\ing not us ness.
the conference (where all this was presented) epitomized the virtually insurmountable segregation between cancer therapy and cancer science. (embraced by scientists.. largely ignored by oncologists)
It was as if a sealed divider had been constructed through the middle of the world of cancer, with “cause” on one side and “cure” on the other.
spiegelman having to prove that human cancers had retrovirus genes hidden inside them…. the more he found.. the more funds were sent his way… but in his frenzied hunt… he had hpushed .. so hard.. that he saw … what did not exist.. the hundreds of millions spent . could not make it happen..
spiegelman was half right half wrong – retroviruses turn out to be cause of diff disease (hiv) – not cancer..
the genetic alteration, Temin proposed, need not originate in a virus. The virus had merely brought a message into a cell. To understand the genesis of cancer, it was that culprit message—not the messenger—that needed to be identified
deep enough ness
src – sarcoma… was the answer to temin’s puzzle… the cancer causing message.
The virus, in effect, was no more than an accidental courier for a gene that had originated in a cancer cell—a parasite parasitized by cancer. Rous had been wrong—but spectacularly wrong. Viruses did cause cancer, but they did so, typically, by tampering with genes that originate in cells.
from the back and forth dna to rna to dna to rna
Science is often described as an iterative and cumulative process, a puzzle solved piece by piece, with each piece contributing a few hazy pixels of a much larger picture. But the arrival of a truly powerful new theory in science often feels far from iterative. Rather than explain one observation or phenomenon in a single, pixelated step, an entire field of observations suddenly seems to crystallize into a perfect whole. The effect is almost like watching a puzzle solve itself
self-organizing one ness… the dance…
mutations induced by chemicals or x rays caused cancer not by ‘inserting’ foreign genes into cells, but by activating such endogenous proto-oncogenes.
for nearly six decades, the rous virus had seduced biologists – spiegelman most sadly among them – down a false path. yet the false path had ultimately circled back to the right destination – fro viral src toward cellular src and to the notion of internal proto-oncogenes sitting omnipresently in the normal cell’s genome.
cancer was intrinsically loaded in our genome, awaiting activation. .. our own genetic ‘oncos’ fatal burden of our genes
monster not slain only seen in a new/clearer way
cancer created in mouse
blood vessels are created to heal wounds. Nothing is invented; nothing is extraneous. Cancer’s life is a recapitulation of the body’s life, its existence a pathological mirror of our own. Susan Sontag warned against overburdening an illness with metaphors. But this is not a metaphor. Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves
most people are other people… and that’s our cancer..
cancer not disorderly chaos but orderly… name it in 6 rules
part 6 – the fruits of long endeavors
umbilical blood.. richest known sources of blood forming stem cells….. often flushed down a sink
the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity…
these two traditional Achilles’ heels of cancer—
as cure… zoom dance, ni ness. ness… if it’s a replica of us.. beat it by more of being us ness.. no?
nuance of achilles’ heels..from new finding in 80s:
1\ genes: growth via accumulation of mutations….. targeting these hyperactive genes, while sparing their modulated normal precursors, might be a novel means to attack cancer cells more discriminately.
2\ pathways: proto-oncones and tumor suppressor genes.. lie at hubs of cellular pathways… the potential dependence of a cancer cell on pathway is a potential vulnerability
3\ acquired capabilities: relentless cycle of mutation, selection, survival .. creates other properties besides uncontrolled growth… hallmarks of cancer.. not invented by cancer.. so this dependence a vulnerability as well..
In his book Invisible Cities, Italo Calvino describes a fictional metropolis in which every relationship between one household and the next is denoted by a piece of colored string stretched between the two houses. As the metropolis grows, the mesh of strings thickens and the individual houses blur away. In the end, Calvino’s city becomes no more than an interwoven network of colored strings
on neu.. not being forgotten.. reconnected…
scientific uncertainty is no excuse for inaction.. we cannot wait for proof..
dying people don’t have time or energy. we can’t keep doing this one woman, one drug, one company at a time – gracia buffleben
The project, having generated an interminable trail of legal memos, was quietly tabled..
unyoked at last from the institution that had forestalled his collaboration, he …
summoning all the nonchalance he could muster…. drucker walked over to legal….. the layers absentmindedly signed on the dotted line. everyone just humored me.. no one thought even faintly that this drug might work.
(even drucker) was amazed
on drug not working.. ie: not making money.. and spending money on so few patients…
The development of Gleevec paralleled the birth of the patient chat room on the Internet; by 1999, patients were exchanging information about trials online. In many cases, it was patients who informed their doctors about Druker’s drug and then, finding their own doctors poorly informed and incredulous, flew to Oregon or Los Angeles to enroll themselves in the Gleevec trial
4 min mile: What Bannister proved was that such notions about intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits
drucker laughing about increasing cancer in the world.. because people who had it were living longer…
p 442 – on targeted therapy being a cat and mouse game.. cancer would shift its foot..
the red queen telling alice.. the world keeps shifting so quickly .. she has to keep running just to keep her position… this is our predicament w/cancer…
smoking, this model argues, is entwined into our social dna just as densely and as inextricably as oncogenes are entwined into our genetic material (study with stopping to smoke in group as opposed to alone)
The bedlam of the cancer genome, in short, is deceptive. If one listens closely, there are organizational principles.
underneath what might seem like overwhelming diversity is a deep genetic unity.
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
as doll suggests and a satosa epitimizes, we might as well focus on prolonging life rather than eliminating death. this war on cancer may best be won by redefining victory
“There are far more good historians than there are good prophets,” Klausner wrote. “It is extraordinarily difficult to predict scientific discovery, which is often propelled by seminal insights coming from unexpected directions
When truly radical discoveries appear, their impact is often not incremental but cataclysmic and paradigm-shifting.
sync matters.. so perhaps we leap frog
but with cancer, where no simple, universal, or definitive cure is in sight – and is never likely to be – the past is constantly conversing with the future.
Her illness had tried to humiliate her. It had made her anonymous and seemingly humorless; it had sentenced her to die an unsightly death in a freezing hospital room thousands of miles away from home. She had responded with vengeance, moving to be always one step ahead, trying to outwit it
something essential about our struggle against cancer: that, to keep pace with this malady, you needed to keep inventing and reinventing, learning and unlearning strategies
alive ness. embracing uncertainty keeps us alive.
Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished.
Cancer, 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, unleashing a cell that cannot stop growing.
Every generation of cancer cells creates a small number of cells that is genetically different from its parents. When a chemotherapeutic drug or the immune system attacks cancer, mutant clones that can resist the attack grow out. The fittest cancer cell survives.
Down to their innate molecular core, cancer cells are hyperactive, survival-endowed, scrappy, fecund, inventive copies of ourselves.
The secret to battling cancer, then, is to find means to prevent these mutations from occurring in susceptible cells, or to find means to eliminate the mutated cells without compromising normal growth
2015 film documentary, Cancer: The Emperor of All Maladies
episode 1 – magic bullets
uncontrolled growth of single cell.. attacks parts of body
leukemia.. cancer of the blood.. cancer in liquid form
sydney farber first to try chemical poison.. that starved white blood cells.. robert sandler..
had tried to treat leukemia.. to stop growth of white blodd cells..
child leukemia.. 100% death usually w/in 3 months.. made it urgent.
to leave the autopsy room and go front and center to make a diff
4 fluids.. needed to be in balance.. black bile melancholia.. was said to have caused cancer… then … no trace of black bile found
then … find when someone is sick.. it’s because something is going wrong inside body…
bone marrow.. where normally produce blood is like your lawn. cancer is like weeds..
47 – sandler receives first dose – goes into remission
limited understanding of what cancer was.. honeybomb (1847) explained cells.. irreducible form of every element… every cell came from a previous cell – that changed understanding of what cancer was
cancer cells clearly came from perfectly normal cells that had been changed..
1\ if tumors – collection of abnormal cells.. should be able to cut from body
1868 – holstead… puzzle.. even when breast removed.. cancer could reappear.. he believed escaped from edge.. so had to cut wider
radical surgery – big operation more likely to cure big cancer.. significant # of patients still had cancer spread.. like it had leapfrogged the surgeans work
2\ another therapy.. turn of 20th cent.. 1896 – grubay.. radiation.. x rays… could they burn out tumors.. invisible knife so could get to those areas.. realizing radiation is also poison..
marie curie – radium.. spawn an industry .. radiation clinics.. a new treatment for cancer..
harmful effects: burn/scar/blind/cause cancer.. grubay fell victim to radiation poisoning.
radiation only worked when cancer localized..
3\ so needed a 3rd approach.. a systemic treatment for systemic disease.. chemi therapy – that can find the cancer wherever it is
1870 – paul ehrlich digs deeper.. selective affinity… could chemicals be pointed at diseased cells and not others.. he called these… magic bullets..
mustard gas in ww1… (killed/blinded/et al many.. ) but also found chemicals in gas targeted on white blood cells..
1942 ww2 – rediscover mustard gas.. set out to see if it would work on cancer.. worked in secret.. nitro mustard… 1946 – wartime lifted.. yale guys reveal.. goodman and gillman
farber reads this.. and says can’t wait… (sandler case)… remissions.. then death – sandler dies 49 – before 4th bday
irony of oncology.. the very drugs that treat the cancer can be cancer causing
the drugs we gave him caused the leukemia
40s – still believed cancer was single disease.. needing single cure
farber likes – march of dimes – to eradicate polio w/in decade raised 200 mill led to research..
farber gets some money.. uses for new kind of hospital… and jimmy fund… (48).. on truth or consequences et al.. jimmy cans everywhere.. (52) cancer hospital opens.. jimmy fund clinic
mary lasker – wealthy socialite.. aids.. says we spend more on chewing gum than cancer research.. she was outraged by disease and illness – her husband had made a fortune selling lucky strike cigarettes… he helped her raise money. she called money frozen energy.. what’s the money doing.. she would complain about this all the time.. she created a public force around cancer.. hepburn et al.. then husband dies of colon cancer.. she seeks govt money.. needs a scientist.. gets farber..
he and lasker concluded.. needed an all out coordinated attack against cancer.. focused on nci – national cancer institute.. (55) efforts had succeeded.. nci becomes center.. zubroad (a try anything approach) center dr (fry and frieriech)…. progress was slow.. problem was resistance.. cancer can find a way to bypass action of drug
give 2 drugs at same time.. emergence of resistance prevented.. by how much of each dose.. longer remissions.. but still relapsed
david nathan arrives… these kids were going to die.. but we were making it worse
(62) trial called vamp – for 4 drugs – if 2 drugs caused kids to bleed to death.. what would 4 do..?
lord (64) – one of first children ever cured of leukemia – from vamp study… nathan wants to continue this.. farber didn’t.. rift.. farber really hated to hurt a child.. i will not injure 2 children to save one
still in an era to fix one cancer but still causing another.. ie: luca dies at 6
lasker goes to white house.. wanting 100 mill… linden.. flirts.. lasker refuses..says lady bird is her best friend… gets money..
(69) – nixon .. lasker.. conquest of inner space (71) – intro a bill for 400 mill for cancer research.. lasker asks friend ann landers to have people write congressmen.. passed 75 to 1.. house 350 to 5.. 1.6 billion in first year alone.. based on an entity of a promise.. to cure cancer..
today .. child leukemia.. survival rate of 95%
on chipping away at uncertainties.. knowing the right thing to do…
(73) – emergency signal in jimmy clinic – farber dead.. of heart attack.. thomas farber.. his son.. survived by jimmy
episode 2 – the blind men and the elephant
the extraordinary relationship – cancer patient and dr – siddhartha
one great theme over last 100 yrs – i’m not taking this anymore.. i’m going to try something else..
(71) – u.s. declares war on cancer – nixon… declaring war on something you didn’t understand at all was nuts… that was the hubris – siddhartha
70s 80s… seemed at times to be war w/in cancer.. ie: dr’s fighting.. et al
radical mastectomy – dr’s could be fired if didn’t do that.. hard to try anything else.. based on theory that cancer spreads outward… bernard fisher.. finally challenges mastectomy.. he believed.. no orderly pattern.. idea that breast cancer was local was not so.. it was systemic.. randomized procedure – half lumpectomy – so most hated.. he said: in god we trust.. all other must have data.. he was denied grant funding.. et al .. other dr’s couldn’t admit they could be wrong.. the women.. were finding out… maybe an alternative..
rose kushner – led rally.. patients began flocking to her study.. when results released (85) – unequivicable… survival same.. no matter how much you took out of breast.. so radical mastectomy was out.. fisher had overthrown one of central dogmas: cutting more is curing more
these stories last a long time.. only when you really can’t justify it anymore do we throw it out
dr lori wilson – breast cancer… howard uni… 2013 – wilson get cancer herself.. diff cancer in each breast
have to solve fundamental mystery of disease: what causes healthy cells to suddenly begin dividing w/o restraint
up till 70s an empirical approach.. use things that kill living cells.. successful.. but now by 70s almost terror in field that unless we understand what’s going on deep inside.. won’t get the next generations of medicines – siddhartha
approaches have been made w/o understanding.. then silos in a field of cancer research…
idea of viral carcenogensis – 1908 – patten rouse – virus causing disease.. showed could transfer cancer from chicken to chicken… so people looking for this in humans.. couldn’t find one.. then (57) – field hospital in uganda.. observed abdominal tumors.. seemed contagious.. (burkett) – taken to la lab.. found virus.. scared people.. but said – now maybe can be prevented.. ie: vaccine against cancer.. became consuming focus – 60s 70s.. 100s of mill of dollars spent on single idea… scant support for ones who wanted to look at other causes.. in end … after 100s of millions.. nothing found
next – cancer caused by chemicals in environment 1775 – (pott) even older than viral theory.. patients had been chimney sweeps.. most had soot lodged under skin..
ww1 soldiers given cigarettes in trenches to relieve stress.. became addicted.. brought it home w/them.. lung cancer on rise.. 1900 – less than 1% 1930 – 15% 1945 20% and rising… 40s interview many.. one question about smoking.. only 1 common association.. cigarettes
we can’t overcome a problem by denying the answer
longest running scientific fraud in history… smoking.. to lung cancer… finally 64 – declare smoking hazardous.. chemical awareness grows.. but still low on understanding…
to solve cancer.. may have to understand the nature of life itself..
2 independent causes.. viruses.. chemicals.. then maybe too .. genes
clues were ignored.. till 67 – bruce ames.. made discovery.. i was thinking differently than others.. i was biochemist and.. testing for mutigenes.. agents w/greatest power to mutate where same ones to cause cancer.. mutation…. things that cause cancer create mutations in genes..
everything thinks have to have a resolution… so these 3 to one.. (bishop & farness) – tackle the riddle..
the extra gene causing virus.. sarc.. so why does cell have cancer gene.. discovery – gene was taken from normal genes..
52 min – the fact that sarc existed in all – birds, chickens, emu, people… see through the darkness a glimpse. of clear theory of cancer.
ie: there are genes in your body that control normal cellular growth and if you disrupt these genes.. you essentially begin to unleash cancer..
important thing.. viral/chemical.. weren’t wrong. just not sufficient.. like blind men and elephant… siddhartha –
oncogenes.. weinberg… the manic ness of this profession 90% shows nothing.. what drives one is ongoing curiosity… 78 – goes looking for cancer gene… how to do it came to weinberg as cross longfellow bridge on snowy day.. took year.. but worked..first human oncogenes.. rass… the trigger.. so then maybe if we attack the oncogenes…
euphoria.. if we could attack what’s diff…we have not conquered.. only seen it more clearly..
the vulnerability is already in us.. the very genes that keep you alive will kill you – siddhartha
(86) – war on cancer had spent billions..great stride scientifically.. but there was a deep chasm between the lab and the clinic…
baylor – we had solid documentation that we hadn’t made great strides.. tension of money spending.. push for radical chemo
bone marrow transplants… increase.. becomes a business.. 5 times dose.. and eventually find.. didn’t work – peters
15000 women.. got totally out of hand..
1:16 – a crisis of faith – siddhartha
when you treat cancer important to know what you can/can’t be sure of – juliano – uncertainty is part of treating cancer
can we understand what’s broken… then create something to attack that.. what is an oncogene-specific study
like car w/gas pedal stuck… cells growing uncontrollably
1:28 – 1\ if oncogene is present – fast growth 2\ how to target this..
antibody… targeted missiles made in body … find one that could target oncogene…
1:35 – druker – why don’t we figure out why the light is stuck on.. and fix it that way.. rather than smashing the light.
promise of new approach – lab to clinic to lab… (93) – barabra – first success for targeted oncogene… women wanted drug.. not to be part of trials… deny patients medicines… doing something too early always a formula for disaster.. genentech activism.. refused medicine and death.. (95) – set down w/activists…
herceptin proof of principle.. what gets us through is the data.. have to be own worst critic.. but if data keeps telling you.. you have to believe it..
(98) – druker finally given ok – 100% response rate for leukemia… receptin like 4 min mile… wasn’t possible before.. but really..
you break the idea of the limit..
all that research now being used to make drugs.. help people.. targeting oncogenes is working
scientists collabing.. mapping of all genes.. between the monster and the robot.. lies the best – siddhartha
episode 3 – finding the achilles heel
gleevec catching popular imagination – cure cancer world had been waiting for
mid 70s – discovery that genes caused cancer.. vogelstein ..research mutated genes of colon cancer. slow moving.. easy to monitor over time… created a timeline.. begin to think of cancer having a history
vogelstein helped to see that cancer is a multi step process… sidd
clinton – entire human genome project.. turning point.. finally gave catalog of all genes.. google map.. zipcodes.. so could search systematically…
2005 – cancer genome atlas.. an incredible gene scientist effort.. to understand possibility of what can go wrong… spring 2008 – now could infer truth… as more results.. some excitement produced anxiety…
pointed out genes are much more complex.. – sidd
abnormalities not oncogenes but tumor suppressor gene – fail to stop cells from dividing.. oncogene like an accelerator.. tumor suppressor like breaks.. all cells have both defects
dealing w/tip of iceberg.. push cures even further away.. could see more clearly .. but chaotic.. like rubix cube.. one side can be fine.. but rest are now toxic – ldk
work for a while.. then stop working… because of: resistance…. cancer cells are constantly mutating.. so genetic diversity of cancer grows… transforms idea of treatment from static idea to dynamic idea – sidd
may not be the same disease in anyone.. a moving target.. cancer becomes resistant to whatever drug we are using
incremental progress has come at high price.. to recoup.. pharma put successful drugs at high price.. from 5000 a year to 100 000 a year or more….getting cancer is one of worst economic things that can happen to you in the u.s.
in us where drug companies set price.. many don’t get to.. in places govt sets it.. often used.. in developing .. not even available.. solution to problem of cost.. lies in understanding mechanisms… whole system if inefficient.. what we need to do is perform more basic research.. but finances tight.. we’re not limited by ideas but by resources.. we’ve got to figure out how to turn that around..
after all these years.. vast majority still treated with chemo..
30 in – stage 4 – i know they will die.. in the time we live and the tools we have.
let’s do this first: free art-ists.
most cancer is predictable.. once it comes back.. that’s it… open ness.. is very helpful.. – cole… for decades paliative care was slim.. obsessed with cure.. healing is sometimes helping people have a good death
movement toward palliative care.. 1960s london.. today part of training in us
for some people it is a war.. and for others they don’t want to fight.. but not defeat.. rather.. negotiation. .. what to do .. sidd
starting asking for prevention rather than cure – 2000s – had long been forgotten…
it will take a more imaginative strategy.. to get people to stop smoking..
smoking ads.. suing for health care costs… obesity… will become leading preventible cause of cancer.. but don’t know what causes most of cancers..
most – probably result of accidental copying errors..
so many things paraded through media as cause.. fear takes hold..
epidemiology – trying to reconstruct… to find cause.. ie: nun’s w/o children so hormones; snuff; … trying to understand behavior.. why higher is some places even if just moved there.. why do some act like disease.. in clusters..
53 min – our tools are good enough…
old suspect has re emerged – viruses… vaccines for some.. hpv vaccine can wipe out cancer of the cirvics
57 min – mamogram.. breast cancer industry built around that concept.. yet – instrument turned out to be too blunt an instrument… false positive diagnosis.. led many to surgery/chemo et al… ethically/economically difficult to stop
vrca – chromosome 17 –
can’t be one size fits all. has to be focused on individual…
cancer mortality down 20% in u.s. over last 2 decades
on having to determine significant mutations.. not all are significant
1:07 – key is to hit a cancer w/multiple drugs simultaneously..
only about 200 genes.. funnel to 12 pathways…
w/cost plummeting.. where we’re going individualized approach like infectious diseases.. if very bad infection.. dr will take sample of bug .. grow it.. pick an antibiotic or two or three and mix together an hope it cures it.. that’s what we’re trying to do in oncology
1:11 – immune system:
cancer is literally evolution in a bottle. all forces.. all history in life.. that plays out at billion times speed of evolution.
if cancer exploits the power of evolution to survive.. perhaps only a commensurate weapon can overcome it.. the human immune system.. an extraordinary set of defenses…
first explored 19th cent surgeon … william coley.. tumor seemed to vanish of own accord after serious infection.. birth of cancer immunotherapy.. hoping to trigger fever that would overwhelm the cancer.. steven rosenberg since 1970s… self-cure.. answer had to lay in patients own immune system…. sooo..
1:16 try to identify cells that were attacking the cancer and use them to develop a cancer treatment..
first 66 patients.. no sign of cure.. 67th .. worked..
1:17 – could you educate to attack cancer cell and not normal cell. sidd
remove tumor.. find t cells fighting tumor… take cells out.. grow them out.. turn a few cancer fighting sells into an army.. then put them back in
1:22 – immune system might be holding itself back from attacking cancer cells – allison – can remove breaks.. free immune system to attack cancer..
on being attacked for saying such things as.. i think immune system might solve this..
for many decades we’ve concentrated on the tumor.. rather than the host immune response… ie: patient and tumor..
fruits of jim allison’s work.. has made it generic..
1:25 – another novel approach.. immune system as surveillance… but often blind.. and miss them… so we have to redirect that t cell.. a new gene forces it to see.. ie: taking off blindfold.. re engineering t cells..
let the cells do the work they were designed to do..
emily whitehead (2012).. first child.. 4th person to receive this treatment… how well it will work in kids is only possible to know by doing it
on educating immune system to see/kill cancer
immune system is there for whole trip.. patience that respond to it will respond for a long time..
1\ revolution – understanding disease
2\ ongoing – putting understanding into practice
cycles of hope and despair have moved us forward… if the cancer cell is evolving .. then so are we – sidd
tweet shared shortly after i finished Siddhartha’s book:
in obama sotu – jan 2016 – via (biden’s) immunology
placebo- artificial – rna.. to get our natural process working again.. imagine a turtle..
to call the score in such a test “intelligence,” especially when the score is uniquely sensitive to the configuration of the test, is to insult the very quality it sets out to measure.
And so it goes, interposing linguistic discrimination on genetic variation, mixing biology and desire.
Mukherjee points as an object of inquiry far apter than intelligence in understanding personhood.
via Thomas Seyfried:
higher blood sugar faster tumor is going to grow.. because it’s going to ferment the sugar.. prime fuel for fermentation..
people say.. what’s the mechanism.. we showed the mechanism.. ie: slide: anti-tumor effects of calorie restriction: 1\ anti angiogenic (mukherjee) 2\ anti-inflammatory (mulrooney) 3\ pro-apoptotic (mukherjee)
on last slide.. see that it’s actually purna.. any relation..? not finding any via siddhartha’s wikipedia page