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Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Friday, November 06, 2015

Recently our Hematology/Oncology group held its annual retreat at Asilomar. Asilomar is a California state park and conference center on the Pacific coast, and a delightful place to hold a meeting. We’ve been going there for a quarter century or so, and it is a great place for professionals to meet away from the hurly-burly of daily existence.


Faculty, fellows and post-docs mix in a pleasant environment, learn from each other and create new collaborations. We also take long walks on the beach watching the sun set over the Pacific, or play golf at the nearby public links during our mandatory afternoon break.


We were not the only professional group there that week. Because everyone eats in a common dining hall, one gets to mingle with folks from other organizations. That weekend we were one of four groups, including the IRLSSG, the CCRH, and the OPA. If you are not up on your organizational acronyms, the CCRH is the California Coalition for Rural Housing. The IRLSSG is the International Restless Leg Syndrome Study Group, busy holding its Science Summit. “I certainly hope none of them is upstairs from me,” said one of my colleagues. “Those guys will keep you awake with all that tapping.”


The OPA, it turned out, was the Organization for Professional Astrology. They looked quite a bit different from the other groups. The women wore long, flamboyant scarves and multi-colored coats, and the men tended towards equally flamboyant facial hair. Our group was full of post-docs wearing blue jeans and T-shirts, and let me tell you, we looked pretty shabby by comparison.


I so wanted to crash their party. But duty prevailed, and I hung around with my Onco-homies instead, learning about circulating tumor DNA and novel organoid culture methods and oncogene addiction’s effects on the immune system. All very interesting, of course, but nothing to match the astrologers’ agenda for sheer pizzazz.


I found that agenda online at the OPA website: Day one was devoted to the theme of “Transition from the Cardinal Cross to the Mutable Cross.” I do not have a clue what this means, but then I suspect they might find oncogene addiction’s effects on the immune system equally mysterious. We are all fairly ignorant outside our specialties.


The breakout sessions were fascinating, and included “The Astrology of Twins,” “Astrology and Kabbalah,” “The Death Chart,” and “Unaspected Planets.”  A planet is unaspected when it isn’t connected to other planets by a major aspect (Conjunction, Square, Opposition, Trine, or Sextile, as my readers will immediately recognize).  Astrologers really dig astronomy. They hug it like a lamprey hugs a sturgeon, sucking it dry of meaning.


The Astrology of Twins breakout forthrightly faced a problem area for astrologists. If you seriously believe (and I have not a clue whether most astrologers are frauds or merely seriously delusional) that the location of the planets at the moment of one’s birth determines your fate—who you marry, your financial success, the date of your death—then identical twins pose a problem. They are born with the same star chart, yet demonstrably differ in terms of marital, financial, and actuarial success. They represent, one would think, a pretty telling prima facie argument against accepting astrology.


Astrologers have thought mightily about this problem. They have decided that it is not really a problem after all. First, the few minutes between one birth and the next is all you need, apparently, to affect your astrologic destiny. Plus, the astrologers say, our astrologic charts map potential, and I may choose to act out one part of my chart’s potential while my feckless twin Fred (that scoundrel) acts out another part of the chart. They believe in free will of a sort. And that explains why Fred and I marry differently and die differently.


If this all sounds like absolute nonsense, well, then, that’s because it is. Karl Popper’s definition of science comes to mind: real science doesn’t prove, it falsifies. That is to say, it sets up crucial tests of a hypothesis, and if the tests fail you move on. Popper was skeptical of Freudian psychiatry for exactly this reason: it could explain everything. There was never any serious attempt at falsification. Astrology is Freudian psychiatry on speed.


Here’s a Popperian falsification experiment, carried out in England and reported in 2003 in the Journal of Consciousness Studies (of whose existence I was previously unconscious—way too many scientific journals out there). Take 2000 Brits born in March of 1958, many within minutes of each other (so-called “time twins”).  Follow them a long time, and measure over 100 characteristics, including “occupation, anxiety levels, marital status, aggressiveness, sociability, IQ levels, and ability in art, sports, mathematics and reading.”


The hypothesis would be that “time twins” should be more alike than those born further apart, under different star charts.


Surprise! No correlation. Absolute falsification. But you knew that already. The President of the Astrological Association of Great Britain, asked to comment, said the work should be treated with “extreme caution” and accused the authors of attempting to “discredit astrology.” As if that was even possible.


The OPA had a session devoted to this issue as well, entitled “Predictive Astrology.” I quote from the précis for this session: “Astrology is very good at predicting the types of experiences you will have in a lifetime but the actual events can be more difficult to pin­point. In this workshop we will synthe­size five major factors in determining experiences/events in a person’s life. The five factors are the natal promise, secondary progressions, solar arc progressions, transits, and eclipses. It may seem confusing and complicated to put all of these factors together in a birth chart but in this workshop we will breakdown each factor and look at it individually and as part of the collective whole.”


Well, OK, who doesn’t want to know more about their natal promise, and who hasn’t stayed up all night worrying about their solar arc progression? It gives me the heebie-jeebies whenever I think about it, but somehow I manage to cope.


I would have loved to have been a fly on the wall at another session. The conference organizers gave the same solar chart to four different astrologers, had them cast their charts independently, and then presented them. Howlingly entertaining, I suspect, but I was stuck learning about boring science-y stuff.


Astrology once was science-y. Johannes Kepler, in addition to his great contributions to astronomy , was imperial mathematician for the Holy Roman Emperor, and made his salary composing star charts for the Emperor Rudolf II. What’s more, he actually appears to have believed it. He wrote a friend "Regard this as certain, Mars never crosses my path without involving me in disputes and putting me myself in a quarrelsome mood." I can relate: that happens to all of us. Here’s a series of Jupiter-Saturn conjunctions from his De Stella Nova:

But science moved on, in part because Kepler and others were ultimately unable to reconcile astrology and astronomy. The astrologers, though, love to reference Kepler, and there is even a Kepler College, which supplies online education in pursuit of its “mission of offering the best astrological education available online.”



It’s easy to laugh about the OPA. It is so nonsensical, so farcical, so divorced from reality that one cannot think of OPA and Kepler College without breaking into a smile. But just as the OPA and the Stanford Heme-Onc Retreat co-existed peacefully at Asilomar, so to do we co-exist in the wider society. And not always so peacefully.


Each of those folks has the same number of votes as those of us who exist in the reality-based universe. In living memory, a President and his First Lady (the Reagans) invited an astrologer to the White House--indeed kept her on a monthly retainer.


Who knows, maybe the astrologer gave the President better advice tham the Secretary of State or the National Security Advisor. But still, it gives you pause. Donald Regan, the President’s Chief of Staff, wrote in his memoirs that the astrologer chose the dates for summit meetings, presidential debates, and (here my oncology antennae perk up) the date for the President’s 1985 cancer surgery.


The astrologer, Miss Joan Quigley of San Francisco, titled her memoir What Does Joan Say?--supposedly Ronald Reagan’s habitual question to Nancy whenever the fate of the world was at stake. 


That Americans are shamefully ignorant of modern science--and not just ignorant but on occasion actively opposed to its teachings--is pretty obvious, and pretty scary. Scary, too, because scientists are now being viewed by parts of our political class as just another special interest group, to be ignored when our findings differ from the biases and interests of larger voting populations. I worry about the future of a country whose leaders glory in their ignorance.


Anyways, enough griping by an old fuss-budget scientist and physician. Our meeting broke up on Friday, but the OPA hung around another day. Saturday night, according to their website, they had a celebration, with music, a raffle with “incredible” prizes (Astrology software, which I suspect made “incredible” factually correct), free readings, and “a trip to Neptune... and much more!“


Never been to Neptune, other than with NASA’s New Horizons’ interplanetary probe. The trip isn’t in my division’s budget. And “much more”—what was that? They did look like they knew how to party. Maybe I should have hung around.

Thursday, October 29, 2015

Recently I’ve been reading Peter Singer’s The Most Good You Can Do. Singer is a philosopher and bioethicist who belongs firmly to the utilitarian tradition dating back to Jeremy Bentham. “The most good you can do” is Singer’s modern-day twist on the Benthamite “greatest good for the greatest number.”


To Singer, the “greatest good” is human life, more particularly life lived without fear, illness, or starvation. Singer argues that we should be “effective altruists” in pursuit of this greater good. By “effective altruist” he explicitly means performing cost-benefit analyses that assign our charitable giving to those causes that demonstrably save the most lives or do the most to reduce human suffering.


Once one accepts this basic premise, certain things follow. One should support, with one’s benevolence, those causes that intentionally support these goals. It is not just, says Singer, that we should prioritize anti-blindness campaigns that target childhood trachoma over art museums. Within charitable causes targeting illness, a childhood vaccination program in Sub-Saharan Africa should be prioritized over flying two children who are conjoint twins from a poor country to a rich country for expensive first-world surgery.


Singer explicitly uses the example of just such a case, performed at Stanford’s Lucille Packard Children’s Hospital. As I bike by Packard every morning on my way to clinic, this example is particularly close to home. It is not that it is bad to spend your money this way, per se, but for the cost of shipping the conjoint twins across the ocean, performing modern surgery, using an ICU, and all the other paraphernalia of modern medicine, one could have saved far more lives. It was not, in short “the most good you can do.”


Effective altruists, says Singer, make choices, and those choices should be both economically rational and global in nature. Those who judge charitable organizations, like Charity Navigator, should not judge based on what percentage of the money they raise goes to the charitable goal, but rather based on what the goal actually is, and how effectively the money is used in pursuit of that goal. In contrast to Charity Navigator, which dislikes money spent on organizational infrastructure, Singer favors infrastructure that allows one to do “the most good you can do.”


The Lancet Article

More or less when I was finishing Singer’s book, I came across a fascinating article in The Lancet on the Global Burden of Disease Study 2013 (GBD2013). GBD 2013, funded by the Gates Foundation, attempted to bring together all available epidemiologic data to “enable comparisons of health loss over time and across causes, age-sex groups, and countries,” to quote the paper (Lancet 22 August 2015;386:743-800)


The tools used by the investigators were DALYs (Disability-Adjusted Life Years) and HALE (Healthy Life Expectancy. To jump to the paper’s punch line, between 1990 and 2013 life expectancy at birth rose by 6.2 years, from 65.3 years in 1990 to 71.5 years in 2013. DALY’s decreased, HALE increased, and the world is a remarkably healthier place than it was just a generation ago.


But that’s not the whole story. Again, to quote the paper, “For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing.” To put this in context, when one eliminates or significantly reduces easily preventable causes of death (infectious diarrhea) people grow old and get old people’s diseases. If you die of a preventable childhood illness through lack of vaccination, you don’t smoke, eat too much fat, and develop congestive heart failure five decades later.


What is astonishing about this paper is the suggestion that most of the world is now making the transition, accomplished in high-income countries over 50 years ago, to chronic disease. This transition has not come about by chance, but rather by the concerted efforts of governments, the World Health Organization, and private foundations (the Gates Foundation and a host of others).


The Gates Foundation, in spending its billions of Microsoft dollars, explicitly chose a Singerian “most good you can do” approach, focusing on infectious diseases in low- and middle-income countries, with stunning success. Their success, and the larger success celebrated by GDB 2013, is largely through the application of old, cheap technologies rather than through the development of new technologies (though the Gates Foundation has been a great supporter of vaccine research).


In addition to public health measures, the rising tide of economic success on a global level, the result of much-maligned globalization, must surely be playing some part in this story.


An Old Tension

As a physician I look at The Lancet article and say “hurrah for public health.” To increase the average life span by 6.2 years in a 23-year period on a global basis is an astonishing success. Think of it: for every four years that passed, average lifespan improved by more than a year. That must be unprecedented in human history, outside of a few more limited settings, but certainly has never previously occurred on a global basis. It provides stunning support for the “effective altruism” approach.


The Gates Foundation, as I have mentioned, intentionally avoided the cancer problem as being too messy and intractable. Its support of HPV and Hepatitis B vaccines will certainly have important cancer prevention effects, but those will roll out over the decades.


As a doctor who treats cancer for a living, what is one to make of these results? Well, the reduced DALYs for acute diseases are partially offset by the increased DALYs for more chronic disease, as one would expect. Oncologists are not going out of business, nor are cardiologists or neurologists, in the Singerian utopia. We are still mortal, we still age.


On a global basis, we are in the midst of an explosion in cancer cases in Low and Middle Income Countries (LMICs), partly the consequence of people living longer and partly the consequence of picking up bad Western habits (Camels and McDonald’s).


So public health measures are all well and good, but what am I supposed to do with the 37-year-old triple-negative breast cancer patient sitting in my clinic whose liver metastases just blew through front-line chemotherapy? Or the same patient, in an office in Bangladesh or Tanzania?


Singer’s book is focused on charitable giving, not patient care. I have no doubt that he would consider the appropriate choice, at both the individual and health care system levels, as really no choice at all: “the most good you can do” would re-direct resources to where they could lengthen life the most, and that place is not third-line chemotherapy. The moral calculus is all on the side of vaccinating children or providing mosquito netting to their parents.


This is not a new argument, of course. The tension between public health measures (which treat populations in a cost-effective manner) and individual health care (which focuses, sometimes expensively and often for too long, on the patient in front of you) is a real one. In the United States and many other countries it is hard-wired into the payment systems and into the bureaucracies that manage health care.


There are deep historical reasons why the CDC and Medicare are dueling organizations, rather than living under one roof, but that is not my focus here. My ethical responsibility, one embodied in the Oath of Hippocrates I swore many years ago, is to the patient sitting in front of me in clinic. I am supposed to keep that patient out of harm’s way, not some other doctor’s patient half a world away. It is also, under the laws of the state of California, my legal responsibility.


There are many diversions in this argument. ASCO has recently and quite explicitly moved in the direction of including cost-benefit analysis in clinical decision-making, in its “Conceptual Framework to Assess the Value of Cancer Treatment Options.”


Similarly, the movement towards limiting heroic measures, use of hospice care, and advanced care planning all represent attempts to avoid the unnecessary and even punitive experiences shared by dying cancer patients. 


But these are arguably not Singer-like “most good you can do” prescriptions. Rather, they all live comfortably within a context Hippocrates would have understood, all focused on the patient sitting in front of you: don’t subject your patient to drugs that will bankrupt his family and usually won’t work. Don’t subject your patient to diagnostic tests that have little value and some real risk. Make sure that your patient has the opportunity for a good death, surrounded by those she loves, rather than a miserable wasting away, intubated and in pain in an ICU.


What is the Most Good We Can Do?

But there is, in addition to the doc who cares for Mrs. Smith, another part of me, a part that resonates with “the most good you can do” argument. And at a global level, in cancer, we have a pretty good idea of what constitutes “the most good you can do.”


If I speak just of breast cancer (and I can speak intelligently of little else) it is pretty clear that fairly simple local-regional control measures would save more lives than any other intervention. I say “fairly simple,” though there is nothing simple about it: an operating room presumes the steady flow of electricity, of teams of nurses and surgeons and anesthesiologists, of pathologists to read the slides, and radiation oncologists with not inexpensive machinery. Many of these, taken for granted in high-income countries, are simply unavailable to most in low-income countries.


After surgery, one could make the case for flooding the world with tamoxifen, and perhaps—perhaps—1980s-style off-patent chemotherapy, presupposing one could test for estrogen receptor. Tamoxifen has probably saved more lives on a global basis than any other cancer drug.


But past that point things get very expensive and the gains progressively smaller. HER2-targeted adjuvant therapy almost makes the cut from an efficacy standpoint, but is totally out of reach for the vast majority of the world’s HER2-positive patients from a financial standpoint. And forget mTOR inhibition and CDK 4/6 inhibition and second-generation HER2-targeting, whose expenses and unproven benefits in the adjuvant setting all would fail “the most good you can do” sniff test.


Recently some of my Stanford colleagues published a cost-benefit analysis in the Journal of Clinical Oncology (Durkee BY et al. J Clin Oncol 33, 2015, epub ahead of print Sep 8 2015) looking at the addition of pertuzumab to a standard taxanes+trastuzumab combination. This three-drug combination is a big deal in metastatic HER2-positive breast cancer, bringing median survival from 40 months up to about 56 months. We seldom see survival improving by more than a year in the metastatic setting, in breast cancer or any other disease. But the price paid for the improved survival comes in at an astonishing $713,219 per quality-adjusted life year.


Things change, of course: drugs go off patent and get cheaper, and countries that were previously impoverished undergo economic takeoff and create robust health care systems, its citizens now sufficiently well off to obtain that which was previously denied. This is certainly happening in many places.


Advocacy can play a role as well. Singer, in discussing the British charity Oxfam, notes that some of its most effective work has involved advocacy, specifically influencing governments in low- and middle-income countries to “do the right thing” on behalf of its citizens.


The obvious advocacy issue in oncology involves drug patents. If a drug is highly effective at saving lives, but is out of reach for large proportions of a population, then the moral calculus favors eliminating or significantly limiting patent rights, as occurred in Sub-Saharan Africa with HAART for AIDS/HIV.


Such advocacy requires an “on the ground” understanding of how the health care system works, as well as a sophisticated and nuanced understanding of the benefits of therapeutic interventions. Revoking the patent for an mTOR inhibitor in Zimbabwe would not pass the sniff test, for many reasons. But perhaps for trastuzumab? Maybe, maybe not: I would love to see a cost-benefit analysis on this. Administering a year of Herceptin involves more than just the cost of the drug. It require effective and somewhat complex infrastructure.


“The most good you can do” is a concept that many of us will not be totally comfortable with. I’m certainly not, my Hippocratic tradition still warring with my cost-benefit public health instincts. But certainly we can start a dialog on what it would involve, both at home and abroad.

Sunday, September 13, 2015

You may have read just recently of the discovery of a new human species, Homo naledi, in the Rising Star cave in South Africa. The find has its fascinations. The skeletons were found deep in a cave complex, 200 meters from the cave’s mouth and 30 meters underground, by two spelunkers. To get to the resting place, the underground explorers had to traverse claustrophobia-inducing terrain: dark, narrow spaces, stony chutes and ladders, and the wonderfully named Dragon’s Back, a rock wall that led to a stalactite-filled chamber where the bodies were interred.

Once there the two cavers found bones. Lots of bones, ultimately bones from at least 15 members of Homo naledi. Archeologists go into states of rapture over the tiniest of skeletal remains. As has been often said, the physical evidence for many of our ancestors could fit comfortably inside a shoebox, with room left over for the shoes. This profusion of skeletal remains is astonishingly rare.


A single finger bone found in a Siberian cave is all that remains of the Denosivan species (partial precursors of modern Melanesians). But Homo naledi is represented by more than 1,550 bones, adults and children: a veritable archeological gold mine, with their resting place not yet fully excavated.



Wonderful Mystery

How those bones got to that crypt is a wonderful mystery. Predators did not carry the bones there, as they lack teeth marks. Nor did some ancient deluge deposit them there, as they lack any surrounding sediment. They are clustered in a small space and wonderfully undisturbed. The archeologists suspect that their own kind carried them there.


The skeletons have not yet been dated, though their anatomic characteristics suggest they might be two million years or more old, somewhere between Australopithecus africanus and Homo habilis. The species itself, while having many modern characteristics, has a tiny braincase, only 560 cc for the males and 465 cc for the females. They must have been a curious sight, their tiny little heads (less than half the size of our own) propped on top of five-foot bodies.


These were not animal kingdom geniuses. Yet somehow, perhaps—and it is just a perhaps, barely even an educated guess—they already thought in terms of placing their kin in a special final resting place.


If this is true, I find it astonishing. Extrapolating motive to two million year-old ancestors is foolhardy--foolhardy beyond belief. Yet I would like to believe that one of the things that makes us human, and perhaps made us human, a part of our earliest intellectual toolkit, right up there beside tool-making, is that we care, and cared, for our dead.


‘Mental Time Travel’

Evolutionary psychologists have suggested that an important part of what makes us human is our mental ability to move seamlessly backwards and forwards in time. This “mental time travel” allows us to project and predict; it was a valuable tool for a species on the make.


The other great apes, our closest relatives, do not have it, so it must have evolved at some point in the past few million years. Was a starting point remembering our dead? Caring for old Uncle Fred even after the old man stopped moving? Understanding, in some grim way, the finality of death?


I cannot imagine those ur-humans had much in the way of ceremony. They could not exchange much other than unintelligible grunts, and those small brain cases, with their tiny amounts of RAM, probably did not lend themselves to funeral oratory or even a decent post-burial wake. Indeed, their small brain capacity has led some to question the very idea that their location suggests intentional burial. But they did have the makings of culture. We know that because they passed on tool-making from generation to generation.


I am not a great fan of funerals. As an oncologist I have had too many dead to remember, and too many that I wanted to forget. The few patients’ funerals I have attended have all left me in melancholic moods I find hard to shake. The worst have been for those who made that progression from professional client to friend to someone I loved.


But the outpourings of grief that I have experienced at these funerals have convinced me that there is something quite human in our feelings for the dead.


Anthropologists have written weighty tomes on the funeral ceremonies surrounding the dead; ceremonies that have existed in every recorded human culture and which long predated the first written records. Ancient Homo sapiens and Homo neanderthalensis clearly cared for the dead in ways instantly recognizable to us. And now, perhaps, Homo naledi joins their ranks.


So intrinsic is this behavior, such a part of our intellectual and social package, that we see nothing unusual in it, but unusual it is, and not a little bit illogical. A funeral, by definition, serves no obvious Darwinian function. It cannot affect the species’ fitness to reproduce. The genetic flow is in the wrong direction. The energy required to bury one’s dead, the opportunity cost associated with it, might even have had a negative impact on a peripheral species clawing out its ancient existence in Sub-Saharan Africa.


And yet no civilization in human history has failed to honor their dead. And few things, I suspect, horrify us more than a failure to honor them, and honor them as individuals. I am always made vaguely nauseous, and somewhat horrified, by a picture of a mass burial at a concentration camp, not so much because of the fact of their deaths, as for the wholly anonymous nature of those emaciated, intermingled bodies. In contrast I feel a rightness, even righteousness, in the rows of graves one sees at an Arlington or Gettysburg or Normandy cemetery.


Again, I cannot explain it in rational terms. The dead do not care where they lie, or how I feel about them. But I suspect that these feelings are hard-wired, have deep roots in our shared history, and may have roots that extend back to Homo naledi and beyond. That when I stood by my father’s grave, after his long battle with prostate cancer had come to its inevitable end, my grief, my sorrow at never having the chance to talk with him again, the sense of loss that continues to this day, were all part of what makes me human.


Did Homo naledi, like us, feel grief at the passing of their kin? I think it is likely, because grief or something quite like it is common among higher social animals, not just humankind. But if our South African ancestors took the next step, and consciously placed their dead in a specific place, they were doing something new in the history of life on this planet, something transcending mere grief. Perhaps, in that act of remembrance, we see the origins of the mental time travel that so characterizes the human species.


How did they understand death? It is an interesting question, an unanswerable at this remove. Human children, developmentally, do not have an adult’s understanding of what death means until around the age of seven, which implies some particular combination of size and development. Was H. naledi as mature as a seven year-old?


John Donne wrote “Any man’s death diminishes me, because I am involved in mankind.” Did they feel diminished by their loss? Or did the burial, in some way, make them feel more involved with what then passed for mankind? Did the opportunity cost of dragging your relative to that underground complex make you feel closer to those who remained behind, the social bonds strengthened?


Perhaps caring for our dead, paying visible testament to their passing, is part of the larger act of caring for each other that represents one of our better qualities. Indeed, it may be the portal through which that which is best in us traverses the generations.


“Naledi” is the Lesotho language’s word for “star,” so Homo naledi means “star man.” Homo naledi, indeed: Star man.

Sunday, August 23, 2015

Lately I’ve been reading stories about traitors. I don’t mean traitors in the political sense, those who sell out their country for money or ideology or some other vague motive. I must admit they don’t interest me very much; they seem relics of the Cold War or some other half-forgotten conflict. The traitors I see popping up everywhere are traitors to their profession.


We all make mistakes. To say “nobody’s perfect” is to not say very much. If a civil engineer miscalculates stress loads and a building or a bridge collapses, he may not be a very good engineer, or may be a pretty good engineer who had one horrible day. But it is likely he is horrified by what has occurred.


Physicians make mistakes regularly, simply because of the sheer volume of data they confront and the innumerable decisions they must make on a daily basis, decisions made on inadequate data and our imperfect understanding of human biology. Others often catch these mistakes before they can cause real harm (“others” usually being nurses, without whom the health care system would be a deadly shambles).


These errors may be acts of sloppiness or miscalculation or just having a bad day, but they are not treason to the profession. They need fixing, but rarely affect the moral essence of a profession, its ethical raison d’etre.


Nor am I talking about the evil men and women do that is divorced from their profession: being a professional—in any profession-- does not prevent one from committing drug abuse, or rape, or murder, or cheating on one’s spouse, or being an embezzler. As wrong as these are, as horrid as they may make someone, they are still at some remove from one’s profession.


What I am talking about is something else, something darker.


Take this story from my local paper: three serving California Highway Patrol officers and three retired officers as well as a defense lawyer were arrested and charged in the murder of a young man they suspected of stealing valuable antiques. The lawyer was the mastermind of the conspiracy, and the police officers either participated in the murder or its cover-up. The attorney wanted to “send a message,” according to the story.


Or take the staff and officers of the American Psychological Association. A 542-page report, commissioned by the organization, recently concluded that the APA had worked with the US Government to enable the torture of detainees. The APA has announced the departure of most of its staff leadership, including its CEO and (I kid thee not) its ethics director. The APA task force worked with the Pentagon and the CIA, its goal being to “curry favor” with the U.S. Defense Department, according to the report.


Several years ago I read about Robert Courtney, a Kansas City pharmacist who diluted chemotherapeutic agents, giving patients suboptimal doses of their prescribed agents (Taxol and Gemzar, according to the paper). The purpose was financial; Courtney was said to be worth more than $10 million.


Or, if you want to get much closer to home, consider the tale of Dr. Farid Fata of Detroit. Fata, a medical oncologist, was convicted last month of administering chemotherapy to patients who did not, in fact, have cancer. He agreed with prosecutors that as many as 553 patients might have been victims of his scheme. He was sentenced to 45 years in prison for Medicare fraud.


Speaking to the court, according to the Detroit News, Fata said “I stand before you ashamed of my actions…it all went wrong. I cannot bring back the past. My quest for power is self-destructive… They came to me seeking compassion and care…I failed them.”


The paper also interviewed several of his victims, who as a group did not think 45 years (in essence, a life sentence) nearly enough punishment. One, a retired auto plant supervisor, walks with a cane related to chemotherapy-induced peripheral neuropathy. “I’ve got to live with this the rest of my life. He’ll probably live longer than me.”


What all these case have in common is the treasonous behavior of those who committed the acts described. What do police do? They maintain law and order. What do lawyers do? They serve society’s goal of justice. What do psychologists do? They heal troubled minds. What do pharmacists do? They guarantee the purity of our drug supplies. What do oncologists do? They provide compassionate and appropriate care to cancer patients.


The cops and the lawyer who murdered the young man in California betrayed the foundations of their profession, betrayed the very concept of law and justice. The APA officials who, perhaps out of a misguided sense of patriotism, helped the CIA torture their fellow human beings, betrayed not only their profession but also the very Enlightenment values that serve as the basis for their profession. The oncologist who gave chemotherapy to someone who didn’t have cancer so that he could bilk the government was so far away from “first, do no harm” that one cannot even think of him as a physician.


Fata was turned in by a colleague and by his business manager. The colleague saw a patient of Fata’s who didn’t have cancer but received chemotherapy and was concerned that this might just have been the tip of the iceberg. Instead of ignoring it, he contacted their business manager, who contacted the FBI.


The Detroit News quotes the colleague (Dr. Soe Maunglay) as saying “It is very difficult to process and it is overwhelming at the same time. It was very, very disappointing to see not even an oncologist, a human being doing this type of …tortuous activity. So I was questioning my faith in humanity, as everybody would have.” Dr. Maunglay is a member of ASCO, and I thank him for standing up for his profession, and for humanity.


Finally, you may have read about Khalid al-Assad. Mr. Assad was the retired chief of antiquities at Palmyra, in Syria. Syria is currently in the throes of horrors we can barely even imagine: a brutal civil war, made worse by the emergence of the Islamic State (ISIS), an organization that thinks nothing of beheading civilized men. One of the people beheaded was my son’s high school classmate, who had devoted his life to helping Syrian refugees.


Khalid Al-Kassid had given his life to finding and protecting glories of ancient Palmyra, a civilization on the far eastern edge of the Roman Empire. In addition to murdering the innocent, ISIS believes in destroying “idolatrous” antiquities, or looting and selling them if they are not to be blown up. Al-Kassid had, news reports say, hidden some of the irreplaceable legacies of this past civilization.




The ISIS thugs interrogated the 82-year-old for a month in the belief that he would reveal where Palmyra’s treasures were hidden. I hate to think what he went through. When he continued to refuse his captor’s demands he was beheaded, and his body tied to a pole on a city street.


It is easy to reduce professions to their technical components, as if ICD-10 codes equated to medicine. If cops are defined as people who ride around in patrol cars, and lawyers as people who file legal briefs, and pharmacists as people who fill prescriptions, and doctors as those who write them, and archeologists as people who dig up old things, in short if one ignores the ethical component that makes a profession a profession, then in no time at all one finds oneself in a world made up of murderers and torturers and poisoners, with nothing to hold on to. A world where ISIS is the tragic norm.


Some men betray their profession, and some hold to their profession’s moral compass and do not. Some of the latter pay a terrible price for their courage. Let us celebrate those who do not, and in the process maintain our civilization, or at least that part of it which is worth saving.

Monday, July 06, 2015

I was, I suspect, almost the last person to hear Kelly Clarkson’s number one hit song “Stronger,”  which topped the charts a couple of years ago. In case you haven’t listened to it yet, it has as the catchy refrain “What doesn't kill you makes you stronger, stronger.”


If that sounds familiar, that’s because it is a line from the 19th century German Philosopher Friedrich Nietzsche’s 1888 great hit, Twilight of the Idols. Clarkson, of course, first came to the attention of the American public through her victory on TV’s American Idol. And American Idol, of course, is now in its final year: Twilight of the Idols, indeed. Sometimes irony is piled on irony.

John Maynard Keynes famously wrote “Practical men, who believe themselves to be quite exempt from any intellectual influences, are usually the slaves of some defunct economist.” To which, apparently, we can now add: songwriters are slaves of some defunct philosopher.


Nietzsche loved catchy aphorisms. His works are full of them. But this is one that never made much sense to me, in either a physical or emotional sense. Imagine being in a horrible automobile accident, with a plethora of broken bones, a pneumothorax requiring a chest tube, a ruptured spleen, and a concussion. “That which doesn’t kill me, makes me stronger?” Yeah, right.


Does anyone really believe such nonsense? Certainly not Nietzsche himself, succumbing to the dementia that condemned him to an asylum, leading to his premature death at the age of 44.


Well, perhaps Nietzsche and his acolyte Clarkson mean it in the emotional or metaphorical sense of “Sure, I’ve been through hard times, but it has made me a stronger, better person.” The world is full of people with post-traumatic stress disorder who might beg to differ. Emotional wounds frequently hurt as much or more as the physical ones, and can take a lifetime to heal. So Nietzsche and Clarkson are two remarkably silly people to spout such balderdash.


Or so I had thought, until recently, when I discovered the emerging literature on senescence.


Senescence (from Latin: senescere, meaning "to grow old") has two meanings, one at the general and one at the cellular level. In the popular mind, senescence refers to age-related deterioration: the grey hair, wrinkles and loss of memory that I am so familiar with.


But at the cellular level senescence refers to age-related loss of division. In 1961 the Wistar Institute’s Leonard Hayflick noted that normal fetal cells would divide a certain number of times (up to about 60) and then hit a wall. That wall is now called the Hayflick limit, and represents the point at which cells senesce. They don’t die, at least not right away. They just stop dividing.


In humans (though not in all organisms) the Hayflick limit is linked to telomere shortening. Though they no longer divide, senescent cells remain metabolically quite active. They have a specific secretome, pumping out pro-inflammatory molecules as well as potent pro-survival signals. They grow older and older, but cling tenaciously to life. Their secretome affects surrounding normal cells, poisoning them with their decrepitude.


The Greeks had a myth that encapsulates this view of cellular senescence. In it, Eos, the goddess of the dawn, falls in love with a handsome youth named Tithonus. Knowing that Tithonus will inevitably die, Eos asks Zeus to make her lover immortal. Zeus, who as Greek gods go had a pretty sinister sense of humor, rendered Titonus immortal but not eternally young.


Tithonus lives forever, but in a progressively shriveled, ever-more miserable state. Tennyson’s poem on Tithonus includes these lovely lines:


The woods decay, the woods decay and fall,

The vapours weep their burthen to the ground,

Man comes and tills the field and lies beneath,

And after many a summer dies the swan.

Me only cruel immortality

Consumes: I wither slowly in thine arms.


Is all this inevitable? Are we condemned to “wither slowly”? Maybe, maybe not. Yi Zhu and colleagues at Scripps recently published a paper in Aging Cell describing a new approach to identifying drugs that would specifically eliminate senescent cells. The first two drugs they came up in their screen were dasatinib (a Src kinase inhibitor already in the clinic) and quercetin, a natural compound found at most nutrition stores. Dasatinib eliminates senescent human fat cell progenitors, while quercetin takes down senescent endothelial cells and bone marrow stem cells. I’m partial to quercetin because I am co-author of a very old quercetin paper.


The authors call these compounds “senolytics”, and senolytics in aging mice work wonders, improving heart function, exercise endurance, bone function and overall survival. Sometimes a single course is enough. Take that, Zeus!


But what about senescence in cancer? Here is where things get interesting for an (old) cancer doctor. I never thought of cancers as getting old, or senescent, particularly because immortality is one of their classic hallmarks. This immortality stems from the almost universal over-expression of telomerase by human cancers.


But cancers, paradoxically, frequently include senescent cells. Oncogenes trigger senescence; indeed there is something the biologists call oncogene-induced senescence, or OIS. Work from the 1990s on emphasized OIS as an important barrier to cancer progression, preventing the transition from early pre-invasive disease to more aggressive invasive cancers. Senescence, in this view, is an evolutionary fix, a valuable negative feedback loop: turn on an oncogene, and you get senescent cells, and the cancer fails to take off.


This view is changing, or at least becoming more nuanced. OIS has its own senescence-associated secretory phenotype, a witch’s brew of cytokines, growth factors, and proteases. You would think that old age was a good thing in cancer, but not always: recent work suggests that the OIS secretome in HER2-positive breast cancer (for one recent example) can promote growth, invasion, and metastasis by their non-senescent fellow-traveler cancer cells. The cytokine IL-6 plays an important role in this nastiness, and may represent a therapeutic target.


So cancer cells can take Nietzsche and Clarkson to heart: that which doesn’t kill me makes me stronger. Senesce all you want, because those senescent cells can make you stronger if you are an oncogene-induced cancer. Those old souls Kelly Clarkson and Freddy Nietzsche were wise: they’re singing the cancer cells’ song. Stronger, stronger.



About the Author

George W. Sledge, Jr., MD
GEORGE W. SLEDGE, JR., MD, is Chief of Oncology at Stanford University. His OT writing was recognized with an APEX Award for Publication Excellence in the category of “Regular Departments & Columns.”