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

 

                            Palmyra

 

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.

 

 


Thursday, June 11, 2015

I am no racing fanatic. I have never been to the track, know virtually nothing about horses, and can go years without seeing the Kentucky Derby on TV. I have never seen the Preakness, and the Belmont Stakes only rarely. I have never placed a bet in my life. While I find them quite beautiful, I am aware of the price these highly inbred animals pay for our amusement. But like many I was caught up in the recent Triple Crown mania and its protagonist, American Pharoah. 

 

In the days leading up to the Belmont stakes I read an article saying that it was unlikely, indeed almost scientifically impossible, for American Pharoah to triumph, no matter how good a race he ran. The odds were stacked against him. The tight schedule of Kentucky Derby to Preakness to Belmont took too much out of even the best of horses. Other horses, having missed one or both of the other two races, simply had greater reserves, more stamina, and more stored glycogen to burn. It had been thirty-seven years since the last Triple Crown winner for a reason. In fact, the odds were against any horse winning the Triple Crown.

 

Certainly his trainer must have shared that concern, and the jockey that rode American Pharoah. They had been in the same situation before, winning the first two races only to lose the third. One might hope that this time things would be different this time, but what were the odds? Upsets weren't just common, they were ubiquitous. 

 

As I sat in front of my television over the weekend, my mind drifted to the ASCO annual meeting I had just attended. As at every ASCO, I had caught up with old friends, attended talks, gone to innumerable side-meetings, and inhaled the Onco-zeitgeist. 

 

Some years ASCO seems unalloyed triumph. Some years are years of consolidation. This was the latter, though "consolidation" barely seems to describe the forward progress of the checkpoint inhibitor juggernaut. 

 

If a prize were given for "drug of the year" at ASCO, surely nivolumab would be the winner. The pride of the plenary session was Jedd Wolchok's presentation of the combination of nivolumab and ipilimumab for melanoma. The combination's median progression-free survival of 11.5 months easily beat out either single agent nivolumab (at 6.9 months) or ipilimumab (a piddling 2.9 months). Median overall survival for the combination has not yet been reached, but it was clear to all that we have passed an inflection point in the history of metastatic melanoma. 

 

And not just melanoma. The Checkmate 057 nonsquamous non-small cell lung cancer trial (do we really have to say “nonsquamous non-small cell lung cancer” from here on out?) compared nivolumab with docetaxel in the second-line setting, and demonstrated a survival advantage, as well as the impressive "tail of the curve" effect we have seen repeatedly in immune checkpoint inhibitor trials. And there was nivolumab in hepatocellular carcinoma, with a 19% response rate, including complete responses: amazing for this disease. Nivolumab also looked like it might have a place in small cell lung cancer, a disease that has gone many a year since finding a new champion. 

 

And not just nivolumab. Pembrolizumab is a star in Mismatch Repair (MMR) deficient colorectal cancer, with a 62% response rate (and inactive in MMR-proficient colorectal cancer, which makes for interesting biology). And pembro, like nivo, looked interesting in small cell lung cancer. 

 

Recently a friend told me that he had called a major pharmaceutical company to speak to an individual involved in a trial he was opening. The voice at the other end of the phone asked: "Is he in Immuno-Oncology or Rest of Oncology?" Imagine having that conversation five years ago. Times have changed. 

 

I think of the Annual Meeting's immune checkpoint story as the first leg of the Triple Crown, its Kentucky Derby, if you will. But what about the other two races in oncology's Triple Crown?

 

Value

If I had to chose a topic for this year's Preakness race I would chose the word "value." Value kept coming up, both in the Plenary session, in other sessions I attended, and in conversations in the halls of the McCormick convention center.

 

Len Saltz gave his "Perspectives on Value" in the Plenary session, noting the astonishing cost of the new checkpoint inhibitors. The price of Ipi, for instance, is "approximately 4,000 times the cost of gold" on a weight for weight basis. Cancer drug prices bear little relationship to value, or to the cost of production, or even the cost of the research that goes into the making of the drugs. The prices are, quite simply, "what the seller thinks the market will bear." 

 

These comments made their way to that altar of modern capitalism, the Wall Street Journal, whose well-insured readers no doubt considered Len's comments heretical. But the Value meme has taken hold in the oncology community, and I suspect will remain a concern and challenge for doctors and patients, just as it did for many speakers in many sessions. ASCO has taken some first awkward steps toward defining value, a difficult but necessary transition. 

 

Defining value is tricky business, of course. I look at those first Ipilimumab patients in melanoma, some now a decade out and still in remission, and think "what a wonderful time to be an oncologist." Decades of research, the cynicism of most of us (about both melanoma and immunotherapeutic approaches), preceded this wonderful merger of science and clinical practice. I repeatedly find myself saying, "How cool is that?"

 

I love the basic science, the clinical-translational elements of the story, and the very real patient benefits, but I dread the financial consequences. A presentation that caught my eye was Aasthaa Bansal's study of the health effects of bankruptcy in cancer. It is quite simple: if you file for bankruptcy you are far more likely to die of your cancer. The adjusted hazard ratio for death was 1.79. Since health care costs are a leading cause of bankruptcy it is only a small stretch from the 4000-times-gold cost of a checkpoint inhibitor to, not just the poorhouse, but also the mortuary. Scary, but also an indictment of our dysfunctional American health care system.

 

"Value" too often ends up being about money, and rapidly devolves into sterile cost/benefit analyses. But what physicians value most is their time. While you can cost out time, doctors resent the unforgiving, irreplaceable, forever-gone nature of lost time. It is a major "value" issue. I saw this everywhere at this year's ASCO. There was a full education session devoted to the bureaucratic inefficiencies that waste our time. And, in the New Drugs in Oncology pre-meeting session, which I co-chaired, Tony Tolcher spoke eloquently of the ridiculous and unnecessary time burdens inflicted on clinical researchers.

 

These time-sucks are largely self-inflicted wounds. It is easy to blame the government, or the makers of electronic health records, or Pharma and the remora-like CROs attached to them, but we put up with this nonsense. If we are not quite losing the "Value" Preakness, we are certainly not winning it. 

 

Which leads me to the Belmont Stakes, the third leg of the Triple Crown. I heard about this race mostly in side conversations with colleagues. The basic story was this: "I have no control over my life." Physicians in general, and oncologists in particular, have suffered a progressive loss of autonomy. They now feel firmly in the grasp of hospital bean counters who view them as interchangeable widgets, and information technology geeks who look on them as not very smart data entry specialists. 

 

By chance, Dana Farber was transitioning from one electronic health record system to another while the Annual Meeting proceeded, and no one I met from Harvard thought it anything other than a massive waste of their time. Knowing the fate that awaited them I offered my condolences. The modern EHR is non-intuitive, treats doctors as secretaries, fails in its basic promise of inter-hospital connectivity, and is sold to hospitals for its billing benefits rather than for its timesaving characteristics. What's not to love?

 

I also heard from a young oncologist bullied by superiors over work RVUs. This doctor covered her salary, but that apparently was not enough: more was expected. She had gone into academic medicine in hope of a research career, and now she saw that career vanishing. The needs of the hospital corporation outweighed the needs of the individual. The time she needed to write protocols, produce papers, and perform research were considered unimportant. She was a widget, a part in the machine.

 

This is not just a complaint of the academics I met. All over the country the old private practice groups are disappearing, swallowed up by corporations. Few of the doctors I know are happy with these transitions. One I spoke to belonged to a practice that had been purchased by a large health care company, which then decided that the purchase had not met the corporate definition of a positive cost: benefit analysis. They had simply decided to stop paying physician salaries until the books balanced. The practice got out from under the corporation, at great cost, and now resides under the umbrella of an academic health organization, the lesser of two evils.

 

Happy?

If the first leg of the Triple Crown was science, and the second value, let's call the third leg, for want of a better word, "happiness." Happiness is undervalued as a reason to come to work every day. Physicians burn out, or at least the ones I see leaving the profession, because they are no longer happy. By and large they still love their craft, adore their patients, and are thrilled by the scientific and clinical advances. The reasons they went into their profession are still there.

 

But I heard, over and over again, their unhappiness, and sometimes a feeling of desperation. I don't think I was projecting (really, I don't). These seem to be general stresses brought on by a change by medicine to something more corporate, more dollar-dominated. Perhaps more efficient as well; the old way of doing things was anything but efficient. But certainly we have arrived at a place where physician autonomy now resides in a very narrow space.  

 

I saw bewildered-looking fellows navigating McCormick Place for the first time: enthusiastic, delighted to be in Chicago, a bit confused about what they had gotten themselves into. An old friend, standing next to me, turned and asked, "If you had to do it all over again would you still be an oncologist?"

 

I don't mean to leave this admittedly peculiar and particular view of the Annual Meeting on a down note. Nor do I mean to suggest that everyone is swigging Prozac cocktails, beating their collective chests, and wailing at the moon. They are not. But happy? Less so now than ever. 

 

I do not think that there is anything inevitable in life, other than death and taxes, and I am not even sure about those. One of my favorite quotes is from Pericles of Athens’ famous funeral oration: "The secret to happiness is freedom, and the secret to freedom is courage." As a profession we need to find our courage, seize our freedom, and then we will, perhaps, find happiness.

 

American Pharoah won the Belmont stakes, blowing away the field. No one was even close when horse and jockey crossed the finish line: he led by more than five lengths. Courage and heart still mean something, and nothing is impossible. He joins War Admiral and Seattle Slew and Secretariat in horse racing's version of immortality.


Thursday, May 14, 2015

If you want to see what the future holds for us, let me suggest two recent articles. The first, published in the March 5th issue of the MIT Technology Review by Antonio Regalado, is called “Engineering the Perfect Baby.”  The second, published in Nature just a week later by a group of concerned scientists, is called “Don’t Edit the Human Germ Line.” Both discuss recent advances that, for all practical purposes, turn science fiction into science. It’s an interesting story.

 

The story goes back three years to the development of CRISPR/Cas-9 technology for gene editing by Jennifer Doudna and Emmanuelle Charpentier. CRISPRs (short for Clustered Regularly Interspaced Short Palindromic Repeats) are short DNA segments in which segments of viral DNA are inserted, which are then transcribed to a form of RNA (cr-RNA). This viral-specific cr-RNA then directs the nuclease Cas9 to the invading complementary viral DNA, which is cleaved.

 

We do not think of bacteria as either needing or having an immune system, but CRISPR/Cas9 functions as one in the prokaryote/bacteriophage arms race. It is elegant and simple, a profoundly cool invention far down on the evolutionary tree that somehow failed to make it to mammals.

 

Doudna and Charpentier had the exceedingly clever, and in retrospect quite obvious, idea that this could be used to edit specific DNA sequences. I say “in retrospect quite obvious,” but it is the sort of retrospective obviousness that turns previously obscure professors working in equally obscure fields into Nobel laureates, as their 2012 Science CRISPR/Cas-9 paper certainly will.

 

Molecular biologists love this technology, and for good reason. With CRISPR/Cas-9 one can add or subtract genes almost at will. The technology, while not perfect (more on this later), is a straightforward, off-the-shelf tool kit that allows practically anyone to manipulate the genome of practically any cell. It is a game changer for laboratory research. The technology has launched an astonishing number of papers, several new biotech start-ups, and (already) the inevitable ugly patent lawsuits over who got there first.

 

Because bacterial DNA and human DNA are forged from the same base elements, what one can do in E. coli one can do in H. sapiens. Whether it is wise for H. sapiens to reproduce E. coli technology is the real question.

 

What Regaldo’s article suggests, and what the Nature article confirms, is that we are close to a tipping point in human history. It is easily conceivable that CRISPR tech can be used to edit the genes of human germ-line cells. We will, in the very near future, be able to alter a baby’s genome, with almost unimaginable consequences.

 

Is this a line we want to cross? Some, unsurprisingly, find this prospect disturbing. The authors of the Nature paper suggested a moratorium on gene editing of human stem cells until we can be work out all of the important practical and ethical issues. Let us slow down, they say, take a deep breath, think things through, and then proceed with caution.

 

A wonderful idea, but a bit too late, as it turns out. March was so last month. A group of Chinese investigators at the Sun Yat-Sen University in Guangzhou took human stem cells (defective leftovers from a fertility clinic) and used CASPR/Cas-9 to introduce the b-globin gene. b-globin mutations are responsible for beta thalassemia, which afflicts a significant population of patients.

 

The paper was published in the April 18 issue of Protein & Cell (a journal I had never heard of before), reportedly after having been rejected by Nature and Science on ethical grounds. It is rather like when Gregor Mendel published his article on the genetics of peas in Proceedings of the Natural History Society of Brünn, only now we have PubMed and the world is a very small place. I suspect Protein & Cell’s impact factor just took a quantum leap upwards.

 

The paper suggests we are not quite there yet: of the 86 embryos where the authors used CRISPR/Cas-9 to introduce the gene, only 4 “took”, and many had off-target mutational events, not a good thing if you are trying to eliminate a genetic defect. In other words, don’t expect this to be available at your local fertility clinic next week.

 

But if not next week, then maybe next year, or the year after: this field is moving at light speed, and the Chinese doctors were (or so a recent Science article suggests) using last year’s techniques. Lots of very smart people are piling into the field. This will soon be feasible, then eventually trivial, technology.

 

And as for a moratorium on gene editing of human stem cells? It might stick for a while, but I am not sanguine about its long-term prospects. I think it is a given that any moratorium will eventually fail.

 

To answer why this is the case, just look at the history of attempts to limit the use of new technologies:

 

First, the atomic bomb. In 1945, after the first nuclear explosion at Alamogordo, a group of Manhattan Project scientists, led by Leo Szilard (who famously first thought of the nuclear chain reaction that would occur once one split the uranium atom), petitioned the President to halt the use of the bomb. The petition, dated July 17, 1945, stated “the nation which sets the precedent of using these newly liberated forces of nature for purposes of destruction may have to bear the responsibility of opening the door to an era of devastation on an unimaginable

scale.”

 

The powers that be were not amused. The US government had spent two billion 1945 dollars developing the A bomb as a war measure, it faced the likelihood of an invasion of Japan with untold potential casualties, and it had little sympathy for Japanese civilians. It also saw the bomb as a long-term source of political and military power. The niggling objections of the atomic scientists (and by no means all objected) were ignored, and literally within weeks Hiroshima and Nagasaki ushered in the Atomic Age, in all its frightful glory.

 

That decision tells you that technologies rapidly get out of control of those who create them. In the Atomic Age, one at least needed a well-heeled nation-state to back you if you wanted to build a bomb, a partial barrier (though only partial: impoverished Pakistan, two generations later, is capable of immolating its neighbors). And nation-states, since 1945, have thankfully not used these weapons on other nation-states, though nuclear proliferation sadly continues.

 

But in the Genome Era, just about any college biology graduate soon will be able to insert genes that eliminate defects or increase function. For practical purposes, Lichtenstein and Monaco could be the biologic equivalent of today’s nuclear powers five years from now. Unless the moratorium is worldwide, all you would need to do would be to fly somewhere that didn’t share the biomedical ethical stance of the Nature authors. And if I knew I carried a deadly genetic defect, I would do anything to save my children from the same fate.

 

By the way, you might say that comparing the atom bomb to CRISPR/Cas9 is a somewhat ridiculous comparison given the relative significance of the two. And you would be right, though perhaps not in the way you might first think: CRISPR/Cas9 is likely to be far more significant in the long run. A technology that allows a species to intentionally evolve new characteristics is far more important for the history of that species. Gills, anyone? Chlorophyll rather than melanin in your skin? All those pesky vitamins we don’t make ourselves? Edit them in.

 

The somewhat more pertinent analogy, and one commented on by many, is the Asilomar conference. After Cohen and Boyer performed the first recombinant DNA experiments, there was a similar terror of Dr. Frankenstein experiments by mad scientists. The city fathers of Cambridge, Massachusetts, appropriately frightened by the proximity of Harvard and MIT, passed a law banning the use of recombinant DNA technology within its city limits.

 

The then-small community of molecular biologists met at the Asilomar conference center (near San Francisco) in 1975 and voluntarily developed limits on certain types of genetic experiments until their safety could be determined. It was a highly moral stance by the leaders of a new biologic revolution, but also a highly practical one, as it decreased public opposition to recombinant DNA technology.

 

The moratorium turned out to a brief one (no one, to my knowledge, has ever been killed by recombinant DNA, at least not yet), and with its lifting the biotech industry was born, and we never gave those early qualms a second thought.

 

I’ve been to Asilomar several times: my Oncology division at Stanford holds its annual scientific retreat there. It is a lovely state park on the Pacific coast, and a great place to hold a conference: watching the sunset over the ocean at Asilomar is an awe-inspiring experience.

 

But Asilomar is just not the right model for what is happening today. Molecular biology is ubiquitous, a global enterprise carried on by tens or hundreds of thousands of scientists, not the small handful in the 1970s. A few academic scientists no longer drive it; big pharma and biotech call the shots, and can be expected to remain highly ethical just so long as no obscene profits can be made from a new technologic development.

 

Jennifer Doudna has suggested that we need an Asilomar equivalent for CRISPR/Cas9 gene editing of embryos, and indeed there has already been a preliminary meeting of scientists, lawyers, and bioethicists in Napa Valley’s Carneros Inn earlier this year. By the way, the Carneros Inn is even nicer than Asilomar: one should always hold scientific retreats at great resorts in wine country. It greatly improves the meeting outputs.

 

The Asilomar scientists had what were, in essence, short-term concerns: will recombinant DNA, let loose on the world, be the scientific equivalent of the Four Horsemen of the Apocalypse? Well, no, and we knew the answer quickly.

 

But CRISPR-Cas9 stem cell germ-line editing, once the technical wrinkles are worked out, is a technology whose medical and social implications will take generations to play out. The pressure to use it for medical purposes will be enormous. Edit out or fix a gene that causes some dreadful neurodegenerative disease (a Huntington’s chorea or its equivalent) and no one will notice the difference for forty or fifty years. These diseases will go away, and who will miss them? And who among my great-grandchildren will even care, it having been something they have always lived with?

 

Perhaps (one already knows the objections) we should not assign God-like powers over creation to ourselves, but how long will that dike hold when a Senator’s or a billionaire’s or a dictator’s misbegotten embryo needs genomic resuscitation?

 

And edit in something that makes one smarter or faster or—dare I say—cuter? Cosmetic editing will be popular the moment we figure out how to do it. Pretty much the first law of the consumer electronics industry is that every new technical advance (viz: VCR, CD-ROM, streaming video) is used almost immediately for pornography. I can only imagine what will happen with gene editing.

 

I simply do not trust us not to use CRISPR/Cas-9 germ-line editing. There is a certain technologic imperialism that renders it inevitable. We always want to play with the cool new toys, and this one will be really, really easy to play with. What will my descendants look like? Probably not like me. And there are those who would say that is a good thing.


Monday, February 02, 2015

I’ve had this conversation a hundred times. My patient, still stunned by her recent breast cancer diagnosis, asks the “why me?’ question. She doesn’t smoke, or drink to excess, and has lived a pretty unexceptionable life. Her family history is devoid of breast or ovarian cancer. And yet here she sits, her life forever altered by the Latinate-sounding words of a pathology report, and she has no idea why she is here.

I can’t help her, not in any meaningful sense. I explain that most women do not have a family history or an inherited predisposition. I explain that we have a number of risk factors related to the internal hormonal milieu, things like early menarche and late menopause and breast feeding and the number of childbirths, but I cannot mount any enthusiasm for these as personal risk factors for her. There are hundreds of women walking by my clinic every day with the same risk factors, and most will never get breast cancer.

 

When you get right down to it, I usually end up saying, it’s just bad luck.

 

I thought about these doctor-patient interactions while reading the recent paper in Science by Cristian Tomasetti and Bert Vogelstein of Johns Hopkins. The authors performed a fairly simple analysis, matching up the number of stem cell divisions in a given organ with the reported incidence of that organ’s cancer. They concluded that there was a clear and fairly strong relationship between the two: the more stem cell divisions, the greater the likelihood of cancer.

 

They concluded that only a third of the variation in cancer risk between different tissues was attributable to either the environment or an inherited predisposition. The majority is due to “bad luck.”  “Bad luck” now enters the scientific literature as the cause of most human cancer.

 

The paper has already, in the month or so since its publication, elicited a striking range of responses—one would almost say, of emotions—in both lay and scientific circles. Google “bad luck and cancer” and you will see a mountain of references. The article induced an almost visceral response in readers, or at least in newspaper editors.

 

And among scientists, who have been quick to respond to the paper (for an elegant analysis read the recent Cancer Letter interview with Barnett Kramer).  One unhappy cancer biologist told me “this just proves that they’ll publish anything in Science.”

 

Part of the reaction is based on the paper’s technical elements. Because of a paucity of data on stem cell divisions in breast and prostate cancer—two rather common human cancers—these were left out of the analysis. Also, the take-home message that two-thirds of variation in cancer risk is due to random mutations in normal stem cells has attracted attention. Two thirds of variation in risk is not the same thing as saying two-thirds of human cancer is due to “bad luck.” Not all tissues are created equal in terms of their cancer incidence, so a correlation coefficient between “all cancer types” is not the same as “all cancers.” The Science press release, interestingly, made this mistake.

 

But what rendered many apoplectic was the “lessons learned” aspect of the correlation. If most cancer is “bad luck,” then cancer primary prevention efforts will inevitably prove futile. And indeed, many news outlets drew exactly this message from the paper, and from interviews with the authors. The paper itself is much more nuanced, but nuance makes for bad headlines.

 

It is an unfortunate message. Lung cancer, the leading cause of cancer death in the United States, is largely preventable. Cervical cancer, a viral disease, is largely preventable, as is hepatocellular carcinoma. Large percentages of head and neck cancer, esophageal cancer, bladder cancer, and skin cancer (among others) are largely preventable. If the public views lung cancer as “bad luck,” why quit smoking? If cervical cancer is “bad luck,” why bother to vaccinate your twelve-year-old daughter? Why put on sunscreen if skin cancer is “bad luck”?

 

“Bad luck” absolves one of responsibility, and therefore of any need to live one’s life in a healthy way. If a man with a gambling addiction goes broke at the racetrack, “bad luck” is a useful excuse. If a two pack-a-day smoking habit, another addictive behavior, leads to small cell lung cancer, “bad luck” implies the smoker is not responsible.

 

The other problem with the paper is the very concept of “bad luck.” A public that believes in ghosts to a greater degree than evolution may take an essentially supernatural view of “bad luck.” “Bad luck” may not, in the universal hierarchy, be at quite the same as divine will or destiny or fate. But some of my patients believe that there is a degree of supernatural intent at work there, cancer as cosmic payback for a youthful indiscretion, or a family curse at work.

 

The world is full of superstitions, and many of these are medical: the belief, enshrined by generations of ER doctors, that the full moon floods the emergency room with crazies, or that Friday the 13th increases the trauma load. Statistically not the case, a PubMed search assures me, but I’ve heard it affirmed dozens of times. For what it’s worth, the only strong correlation I ever saw in the ER was with the Super Bowl or the World Series: heart attacks could wait until the end of the game.

 

In Ireland there is a common belief that a Saturday hospital discharge is bad luck, and associated with rapid readmission: “Saturday flit, short sit.” Some 13.7% of patients interviewed for a study published in the Irish Medical Journal would refuse a Saturday discharge, and 40% of doctors would humor them.

 

One thinks of Shakespeare’s lovely line in Hamlet: “There’s a special providence in the fall of a sparrow.” At some level we want our lives to have a special providence, even our personal catastrophes: “I got cancer because I was doomed to get cancer” may be more satisfying than what the authors of the Science paper actually meant: a stochastic process, a probabilistic event without any deeper meaning.

 

In short, we mean “bad luck” in the sense first described by Pascal in the seventeenth century. Pascal, attempting to understand games of chance, rendered the supernatural natural: you lost that card game because the odds were against you, not the gods. Kiss the dice for good luck all you want, but when they roll on the table randomness prevails.

 

Pascal was an essentially gloomy philosopher/mathematician: though religiously devout, his blinding mathematical brilliance had the effect of stripping the universe of mystery.  He was also terrified by what he saw through the telescope: “Le silence éternel de ces espaces infinis m'effraie.” The eternal silence of these infinite spaces frightens me:  he believed the universe to be essentially random, but did not like what it implied.

 

Nor was he the only great scientist who detested randomness, The great 20th century debate between Bohr and Einstein over quantum theory largely boiled down to the issue of randomness. “God does not play at dice,” Einstein famously said. Bohr supposedly responded “Albert, stop telling God what to do with his dice.”

 

But even Bohr allowed for the possibility of good luck, keeping a horseshoe above his door, as was then a common superstition in Denmark. Asked whether he really believed that it brought him good luck, he replied “Of course not…but I am told it works even if you don’t believe in it.”

 

It’s a principle that I can endorse. So, after a second opinion, as we shake hands and prepare to leave the room, my last words to the patient are always “best of luck to you.”

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.”