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Cancer Clinical trials History Medicine Skepticism/critical thinking

Vincent DeVita: We need more freedom to be mavericks. Orac: Not so much

One of my favorite television shows right now is The Knick, as I described before in a post about medical history. To give you an idea of how much I’m into The Knick, I’ll tell you that I signed up for Cinemax for three months just for that one show. (After its second season finale airs next Friday, I’ll drop Cinemax until next fall.) The reason why I’m bringing up The Knick (besides I love the show and need to bring it up at least once a year) is because an article by Malcolm Gladwell published earlier this week in The New Yorker entitled Tough Medicine, which is a commentary based on a new book on cancer by a veritable god of cancer research, Vincent T. DeVita, Jr., immediately resonated with a storyline in this season of The Knick. I haven’t yet read The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable–and How We Can Get There by Vincent T. DeVita and Elizabeth DeVita-Raeburn, but I would like to. I can tell, though, that there will be parts of the book I find annoying, at least if Gladwell’s take on the book is accurate as he semi-approvingly describes DeVita as railing against the cautiousness and incremental nature of today’s cancer research. On the other hand, the article does conclude with Gladwell demonstrating a better understanding of the disadvantages of what DeVita is proposing than it seems that he will in the beginning. In fact, it is Gladwell who seemingly ends up being more reasonable than his subject, although he does appear share DeVita’s apparent assumption that potentially all cancer patients are savable if only we try hard enough.

The Brave Maverick Doctor versus the clinician-scientist

Here’s where my reference to The Knick comes in. (Because it seems mandatory these days, I’ll issue a spoiler alert right now. Skip to the next section if you don’t want to be exposed to major plot points from the show.) The Knick is a TV series set in the fictional Knickerbocker Hospital in lower Manhattan and takes place more than a century ago, the first in 1900, the second in 1901. Its main character, Dr. John Thackery (brilliantly portrayed by Clive Owen) is a surgeon clearly patterned on one of the veritable gods of American surgery, William Stewart Halsted, whose contributions to surgery, including blood transfusions, sterile surgical gloves, local anesthesia, an emphasis on the delicate handling of tissue, cancer surgery, and the surgical residency program, are legendary. He was also a cocaine and morphine addict, but managed to function well in spite of his addictions. Thackery is also an addict, but doesn’t function nearly as well.

The fictional Dr. Thackery is a type of doctor to whom I’ve referred as the Maverick Doctor, or Brave Maverick Doctor when I’m in a sarcastic mood. Such doctors can be bold, reckless even. They believe in their own rightness, thinking that their training as physicians should be enough for society to trust their judgment to do what they believe to be right and bristle at anything they view as constraining their freedom of medical judgment in any way, such as evidence-based treatment guidelines. When they’re right, as, for example, William Halsted and Vincent DeVita frequently were, they can push the envelope of medicine faster than anyone. There’s a very good reason why, for example, DeVita is one one of editors of the main textbook of oncology owned by most oncologists, myself included. Unfortunately,when Brave Maverick Doctors are wrong (the far more frequent situation), as, for example, Stanislaw Burzynski is wrong, they are frequently very, very wrong and can do great harm. Not surprisingly, there is a disturbingly high percentage of quacks among Brave Maverick Doctors. Think Mark Geier. Think Rashid Buttar. Think Andrew Wakefield. You get the idea. Indeed, there is a whole medical organization dedicated to Brave Maverick Doctors, the American Association of Physicians and Surgeons (AAPS).

Relevant to DeVita’s book and Gladwell’s article, one of the central themes of The Knick is the conflict between the innovation of Brave Maverick Doctors and its inherent risk. This conflict is embodied in the character of Thackery, who is often bold to the point of recklessness in his pursuit of curing disease. On the other side, the slow, methodical accumulation of scientific knowledge is represented by Dr. Levi Zinberg at Mt. Sinai Hospital. Thackery is all about trying new things, almost regardless of the cost or risk, while Zinberg is all about collaboration and the careful, incremental, scientific advancement of medicine. In the first season, for example, Thackery comes to view Zinberg as a competitor, even going so far as to become obsessed with identifying different blood types before Zinberg does, after having been informed that that’s what Zinberg was working on. Zinberg, for his part, offers collaboration leading to the slow, systematic accumulation of knowledge. He even shares his laboratory notes with one of Thackery’s junior surgeons, Bertram Chickering, Jr., to show his good faith, telling Chickering to feel free to show the notes to Thackery.

In the second season, this conflict is even more prominent. In episode 3 this season, The Best with the Best to Get the Best (whose title, ironically, is about eugenics, which makes its first appearance in the series here), for personal reasons Chickering decides to leave the Knick and take a position at Mt. Sinai working for Zinberg. There, his experience with Thackery comes into immediate conflict with the way things are done at Mt. Sinai, where he is disappointed when Zinberg assigns him a laboratory project working with a new gland extract (adrenaline) instead of letting him operate right away. When Chickering suggests accelerating the testing of the new gland extract in animals from mice to larger animals or even humans, he is told in no uncertain terms,”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”

Dr. Bertrand Chickering, Jr. (right) runs into a little conflict by wanting to move too fast for his new team and is told, ”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”
Dr. Bertrand Chickering, Jr. (right) runs into a little conflict by wanting to move too fast for his new team and is told, ”Dr. Zinberg is very specific about his protocols. Start on mice. Present our findings. Then on to rats, then guinea pigs, then cats, dogs, and pigs, and only then to humans.”

This conflict comes to a head when Chickering’s mother is diagnosed with inoperable laryngeal cancer. He tells Zinberg of his mother’s condition and that he is determined to seek out new experimental procedures to save her life. Zinberg replies by cautioning him not to let his emotions get the better of him. This leads him to seek out Dr. Algernon Edwards, a brilliant African-American surgeon hired early in the first season by the Knick’s board of directors over Thackery’s objections (which were based on racism, of course) who had ultimately won Thackery’s respect. Edwards tells Chickering of a paper by Pierre Curie, and says he can translate it from French if Bertie locates a copy, which he does. The procedure involves injecting the tumor with mercury and zinc and then zapping it with electricity. This leads to an episode entitled, appropriately enough, There Are Rules, where Chickering, breaking the rules, persuades Edwards to help him, saying, “I don’t have the luxury of two years of study.” It is about as succinct an expression of the inherent conflict in medical research between risk and careful scientific study as you’ll ever see.

And help him Edwards does. The two operate on Chickering’s mother at Mt. Sinai in secret, with Chickering’s father in the room, unable to watch. Not surprisingly, the surgery does not go well. The tumor does not soften as predicted, and the two surgeons get into bleeding and do damage to Mrs. Chickering’s airway while trying to separate the tumor from surrounding structures. They are also discovered by a janitor, who informs Zinberg, who bursts in a few minutes later demanding to know what the hell is going on. To his credit, when Zinberg sees the situation, he refrains from further scolding and leaps in to help as much as he can. Unfortunately, they can’t save Mrs. Chickering, who dies on the table. Thus ends Chickering’s tenure at Mt. Sinai. He resigns before Zinberg can fire him; not surprisingly he winds up back at the Knick with Thackery, who has actually become slightly less reckless.

This fundamental conflict between careful, slow scientific progress and the need to do something for patients who are suffering now and going to die soon is a theme Gladwell revisits in his article. Of course, most clinical researchers are not a Dr. Thackery or a Dr. Zinberg, who really are archetypes more than anything else. Most physician-scientists and clinical researchers fall somewhere in between these extremes. What seems to bother Gladwell and Dr. DeVita is that over the last three decades the balance in medicine has clearly moved away from the Thackerys and towards the Zinbergs, which leads DeVita to make the same sorts of misguided arguments that I’d discussed being made for right-to-try laws, the Saatchi bill, and the 21st Century Cures Act, all of which seek to remove patient protections in the name of letting Maverick Doctors “innovate” more.

Brave Maverick Oncologists and the wild, wild West of the 1960s

When I referred to Vincent DeVita as a “god” of oncology, I was only exaggerating slightly. If you don’t believe me, go back and read a post I wrote two years ago that uses one of DeVita’s review articles as a jumping off point to discuss how chemotherapy went from a near-fringe idea to being validated as a successful treatment for a number of cancers. It’s a good overview of the history of chemotherapy, a history that DeVita lived right in the middle of and whose success he was very much a part of. Now 80 years old, DeVita uses his book to look back at the history of cancer chemotherapy, and the anecdote that Gladwell chooses to start his article is very telling:

In the fall of 1963, not long after Vincent T. DeVita, Jr., joined the National Cancer Institute as a clinical associate, he and his wife were invited to a co-worker’s party. At the door, one of the institute’s most brilliant researchers, Emil Freireich, presented them with overflowing Martinis. The head of the medical branch, Tom Frei, strode across the room with a lab technician flung over his shoulder, legs kicking and her skirt over her head. DeVita, shocked, tried to hide in a corner. But some time later the N.C.I.’s clinical director, Nathaniel Berlin, frantically waved him over. Freireich, six feet four and built like a lineman, had passed out in the bathtub. Berlin needed help moving him. “Together, we pulled him up, threw his arms over our shoulders, and dragged him out through the party,” DeVita writes, in his memoir, “The Death of Cancer” (Sarah Crichton Books). “Out front, Freireich’s wife, Deanie, sat behind the wheel of their car. We tossed Freireich in the backseat and slammed the door.”

Half a century ago, the N.C.I. was a very different place. It was dingy and underfunded—a fraction of its current size—and home to a raw and unruly medical staff. The orthodoxy of the time was that cancer was a death sentence: the tumor could be treated with surgery or radiation, in order to buy some time, and the patient’s inevitable decline could be eased through medicine, and that was it. At the N.C.I., however, an insurgent group led by Frei and Freireich believed that if cancer drugs were used in extremely large doses, and in multiple combinations and repeated cycles, the cancer could be beaten. “I wasn’t sure if these scientists were maniacs or geniuses,” DeVita writes. But, as he worked with Freireich on the N.C.I.’s childhood-leukemia ward—and saw the fruits of the first experiments using combination chemotherapy—he became a convert.

You get the idea. Back in 1963, men were men, women were women, and the sheep ran scared. Or something. Maybe it was Mad Men, but with oncologists and cancer researchers instead of advertising executives. Or maybe the NCI was the wild, wild West, populated by nothing but Maverick Doctors. As I will discuss, the wild frontier turns out to be a very good metaphor for cancer research as practiced 50 years ago, at least in terms of the attitudes of the physicians at the forefront back then compared to the way things are done now.

Having established early NCI of the early 1960s as the wild West, Maverick doctor bona fides of the era, Gladwell next relates anecdotes from DeVita’s book in which a Maverick doctor shows those cautious, pointy-headed professors how curing cancer is done, starting with one of DeVita’s own accomplishments when he decided to try to replicate Frei and Freirich’s success with childhood leukemia in an adult malignancy. Back in the early 1960s, Hodgkin’s disease, too, was also a virtual death sentence, with very little that doctors could do to save the lives of patients diagnosed with the disease. Over a few beers one night, DeVita and a colleague named Jack Moxley mapped out a protocol based on what Frei and Freireich were doing with leukemia. Because of the ability of cancer cells to mutate and develop resistance under the selective pressure of chemotherapy, they estimated that they needed four drugs, each working through a different mechanism, so that the cells that survived one wave would be killed by the next. They then plotted how often the drugs could be given and how high the doses would need to be. Obviously, the doses needed to be high enough to kill the cancer cells but not so high that the patient died. Ultimately they settled on a regimen called MOMP: three eleven-day rounds of nitrogen mustard, Oncovin (a brand of vincristine), methotrexate, and prednisone, interspersed with ten-day recovery cycles.

This story is the very essence of science-based medicine combined with “maverick-y-ness. Here, two oncology fellows carefully examined the medical literature regarding chemotherapy drugs and what was known about the biology of Hodgkins’ lymphoma at the time and came up with what seemed to be a reasonable combination of drugs. It’s not something that could be done today in the same way, but as I will explain, contrary to what DeVita and Gladwell seem to think, that’s not a bad thing. In the meantime, let’s look at what happened:

“The side effects were almost immediate,” DeVita writes:

The sound of vomiting could be heard along the hallway. Night after night, Moxley and I paced outside the rooms of our patients, fearful of what might happen. Over the weeks that followed, they lost weight and grew listless, and their platelet counts sank lower and lower to dangerous levels.
Then came the surprise. Twelve of the fourteen patients in the initial trial went into remission—and nine stayed there as the months passed. In most cases, the tumors disappeared entirely, something that had never before been seen in the treatment of solid tumors. In the spring of 1965, DeVita went to Philadelphia to present the results to the annual meeting of the American Association for Cancer Research. He stood up before the crowd and ran triumphantly through the data: “ ‘Our patients were, therefore,’ I said, savoring the dramatic conclusion, ‘in complete remission.’ ”

What happened? An illustrious cancer expert named David Karnofsky made a narrow point about the appropriateness of the term “complete remission.” After that, nothing: “There were a few perfunctory questions about the severity of the side effects. But that was it.” History had been made in the world of cancer treatment, and no one seemed to care.

Why did DeVita’s work receive such a lukewarm reception? It’s hard to say. It could well have been the natural reticence and skepticism that scientists exercise upon hearing radical new results. It could well have been that the audience thought the data too good to be true. Whatever the reason, Gladwell next discusses the next stage of DeVita’s career, when after finishing his fellowship at the NCI he went to Yale to do another year of residency before coming back to the NCI. A stronger echo of Dr. Chickering’s experience leaving the Knick and taking a position at Mt. Sinai would be hard to imagine:

When his first go-round as a clinical associate at the N.C.I. was up, DeVita took a post as a resident at Yale. At what was supposed to be a world-class hospital, he discovered that the standard of care for many cancers was woefully backward. Freireich had taught DeVita to treat Pseudomonas meningitis in leukemia patients by injecting an antibiotic directly into the spinal column—even though the drug’s label warned against that method of administration. That was the only way, Freireich believed, to get the drug past the blood-brain barrier. At Yale, DeVita writes, “you just didn’t do that kind of thing. As a result, I watched leukemic patients die.” Leukemia patients also sometimes came down with lobar pneumonia. Conventional wisdom held that that ought to be treated with antibiotics. But N.C.I. researchers had figured out that the disease was actually a fungal infection, and had to be treated with a different class of drug. “When I saw this condition in patients with leukemia and pointed it out to the chief of infectious diseases at Yale, he didn’t believe me—even when the lab tests proved my point,” DeVita continues. More patients died. Leukemia patients on chemotherapy needed platelets for blood transfusions. But DeVita’s superiors at Yale insisted there was no evidence that transfusions made a difference, despite the fact that Freireich had already proved that they did. “Ergo, at Yale,” DeVita says, “I watched patients bleed to death.”

Elsewhere, DeVita relates how he had originally wanted to do a fellowship at Yale too but decided to come back to the NCI after a year because of his experiences at Yale.

It’s hard to judge this story without knowing a bit more, but notice how DeVita said that Freirich had taught him to treat Pseudomonas meningitis with intrathecal antibiotics. Had he yet published a convincing clinical study showing that intrathecal antibiotics worked better? I searched for Freireich’s publications on Pseudomonas infections from the 1960s; all I could find was an analysis of 54 episodes of multiple organism sepsis in leukemia patients from 1965, which isn’t applicable to the problem. A search for Freirich’s name and just “meningitis” only revealed this case report from 1968 on Listeria monocytogenes meningitis. In other words, as far as I can ascertain, Freireich had apparently not published his experience with the use of intrathecal antibiotics for meningitis in leukemia patients at the time DeVita was at Yale. Similarly, I was not able to find papers by Freireich on fungal infections before 1968. So why on earth would the doctors at Yale believe DeVita? Why should they have? If it’s not published, then why would they do it? On the other hand, Freireich had published several papers on the effectiveness of transfusions by the late 1960s, one in the New England Journal of Medicine in 1959.

Whether or not he was off base criticizing his colleagues at Yale in the late 1960s, DeVita does note something that I’ve noted myself, as have many others, namely that new ideas are often resisted and that clinical practice doesn’t always change. He noted that he couldn’t do a combination-chemotherapy trial in the US because it went against the grain at the time, necessitating doing it overseas. He also cites the example of Bernie Fisher, who had shown that there was no difference in survival in breast cancer between radical mastectomy and much less invasive breast-conserving surgery followed by radiation therapy, and how he had had difficulty enrolling patients to his studies because of resistance from surgeons.

What DeVita neglects to note is that eventually data did win out, and our practice changed. Indeed, I myself have never even done a radical mastectomy because the procedure had been obsolete years before I did my surgical residency. Heck, my practice has changed radically, in response to clinical trials, just since I first became an attending in 1999. As I like to point out, change in science-based medicine is messy. It often takes more time than we think it should, particularly in retrospect. But eventually we do change practice in response to data and science. At the heart of this change, the question is always: How much new evidence is required before a critical mass of physicians are convinced to change practice? Not all conservatism in medicine is bad. One need only point to the debacle that resulted from the much too rapid adoption of high dose chemotherapy and bone marrow transplantation for advanced breast cancer that became popular in the 1990s, only to be shown to do no good and cause a lot of harm when decent randomized clinical trials were done.

Innovation versus practice guidelines

A second key anecdote from DeVita’s book related by Gladwell involves DeVita’s experience with how a new regimen that he developed was altered as it spread from the NCI to other cancer centers, in this case Memorial Sloan-Kettering Cancer Center (MSKCC). Basically, over the next few years, DeVita and colleagues refined the MOMP regimen, which became MOPP: two full doses of nitrogen mustard and vincristine on the first and the eighth days, and daily doses of procarbazine and prednisone for fourteen days, followed by two weeks of rest. The results of a second trial, published in 1970, showed MOPP to be superior to MOMP.

What puzzled DeVita was how tepid the response was at MSKCC when he presented his work there. Indeed, oncologist after oncologist there told him MOPP “didn’t work.” Why was that? Ironically enough, it was the product of the very same sort of tinkering that DeVita had used seven years earlier to develop MOMP:

Baffled, he asked one of the hospital’s leading oncologists, Barney Clarkson, to explain exactly how he was administering the MOPP protocol. Clarkson answered that he and his colleagues had decided to swap the nitrogen mustard in DeVita’s formula for a drug called thiotepa. This was a compound they had developed in-house at Memorial Sloan Kettering and felt partial to. So MOPP was now TOPP. DeVita writes:

They’d also cut the dose of procarbazine in half, because it made patients nauseous. And they’d reduced the dose of vincristine drastically because of the risk of nerve damage. They’d also added, at a minimum, an extra two weeks between cycles so that patients would have fully recovered from the toxic effects of the prior dose before they got the next. They gave no thought to the fact that the tumor would have been back on its feet by then, too, apparently.

These alterations had not been tested or formally compared with DeVita’s original formula. They were simply what the oncologists at Memorial Sloan Kettering felt made more sense. After an hour, DeVita had had enough:

“Why in God’s name have you done this?” he asked.

A voice piped up from the audience. “Well, Vince, most of our patients come to us on the subway, and we don’t want them to vomit on the way home.”

Here were physicians at one of the world’s greatest cancer hospitals denying their patients a potentially life-saving treatment because their way felt better.

So basically, the doctors at MSKCC had altered the protocol, and the resultant protocol, TOPP, didn’t work. What would have been appropriate, if the oncologists at MSKCC really thought their protocol was an improvement, would have been to do a clinical trial comparing MOPP to TOPP head to head, but they didn’t do that. They just changed DeVita’s protocol as they saw fit and started using it. For them to conclude that TOPP didn’t work, it must have been very obviously different from the results reported by DeVita with MOPP, because there was no control group and no clinical trial. Worse, if DeVita’s account is to be believed, the oncologists at MSKCC didn’t even differentiate their new protocol from DeVita’s original protocol or figure out that the reason that their protocol didn’t work was because of their alterations.

One might think that this sort of experimentation would indicate that perhaps there should be some clinical guidelines that made sure that MOPP, which had been validated as effective in clinical trials, should be administered the same way, but that’s exactly the opposite of what DeVita argues, according to Gladwell:

But here “The Death of Cancer” takes an unexpected turn. DeVita doesn’t think his experience with the stubborn physicians at Memorial Sloan Kettering or at Yale justifies greater standardization. He is wary of too many scripts and guidelines. What made the extraordinary progress against cancer at the N.C.I. during the nineteen-sixties and seventies possible, in his view, was the absence of rules.

And:

Clinical progress against a disease as wily and dimly understood as cancer, DeVita argues, happens when doctors have the freedom to try unorthodox things—and he worries that we have lost sight of that fact.

Where have we heard these arguments before? Oh, yes. I remember. They’re the same arguments made by proponents of the Saatchi Bill and the misguided 21st Century Cures Act. The central idea behind all of these policy ideas is that we somehow have to “free” doctors and researchers to “innovate,” rather than “shackling” them. The impetus for these ideas is, in essence, worshiping at the altar of the cult of the Brave Maverick Doctor. It is the Great Man (or Woman) theory of the history of medicine, in which breakthroughs come not so much because of the gradual accretion of knowledge, with each new scientific finding building on what has been discovered before, but because of singular individuals with the vision and the bravery to see what needs to be done and the cleverness, intelligence, and will to do it.

DeVita vs the FDA

Gladwell notes that the angriest part of DeVita’s book is his chapter about the FDA, where he argues that the FDA has somehow fundamentally misunderstood innovation. I rather suspect a lot of DeVita’s hostility comes from two experiences he had in his life. First, he describes a prolonged battle to save his friend Lee, who developed advanced prostate cancer. DeVita kept pushing to get him into clinical trial after clinical trial, to get experimental therapies off protocol, and basically to try anything that could be tried, ending when he couldn’t get his friend an experimental drug called abiraterone. His friend died He later learned that abiraterone was so effective that the clinical trial was halted early and now clearly believes that he could have saved him, even though there is no cure for advanced prostate cancer. (Abiraterone significantly prolongs life, but is not a cure.) Even so, abiraterone was no cure. Another incident is that DeVita, ironically enough, was the father of the Ted DeVita, the “boy in the bubble,” who developed aplastic anemia and lived well over eight years in a plastic bubble before succumbing.

Specifically, he objects to the FDA’s mandate to require that all new approved drugs be safe and efficacious, pointing out that this “gatekeeping” function of the FDA can hinder progress. I’ll have to wait to read the book to see if DeVita’s argument is more compelling than how Gladwell represents it, but I was underwhelmed, as not a single example of how “progress” had been hindered was provided, only hypothetical examples. In one, he suggests that cancer is like a door with three locks, each with a different key. If a drug “opens the first lock,” it would be a breakthrough but wouldn’t cure the cancer by itself. So DeVita asks:

So how do you get it through a trial that requires proof of efficacy—especially if you don’t yet know what the right keys for the two remaining locks are? Since cancer comes in a dizzying variety of types and subtypes, each with its own molecular profile, we want researchers to be free to experiment with different combinations of keys.

The problem with this analogy is that it is disappointingly simplistic given who is making it and that the time to work out the preliminary answer to this question is in preclinical research leading to the development of this drug and others, not in human beings. Moroever, as represented by Gladwell, this argument completely ignores the incredible genetic heterogeneity of even a single cancer, where different cells, even in the same tumor, might have different combinations of these locks. He also criticizes the FDA for approving drugs for very specific indications, including specific cancers and even specific stages of cancers, complaining, “The vital insight gained by using an approved drug in a different way for a different tumor has been lost.” No, it has not. In this age of precision medicine based on genomics, if anything, we’re becoming more open to trying drugs designed for one tumor in another tumor based on the genetic abnormality it targets rather than the tissue of origin of the tumor. The FDA is struggling, as we all are, with the question of how to target therapy to the individual characteristics of the tumor. New forms of clinical trials are being tested. New regulatory frameworks are being developed.

To his credit, Gladwell points out exactly what’s wrong with DeVita’s argument for more freedom to tinker, specifically the paradox at the heart of it. First, he notes that the breakthroughs at the NCI in the 1960s and 1970s were the product of a freewheeling intellectual climate and a relative lack of rules over what could and could not be done in clinical trials. Indeed, it’s quite true that no one could do now what DeVita did 52 years ago. At the same time, it was that very same climate that allowed the oncologists at MSKCC muck up DeVita’s effective chemotherapy regimen by turning MOPP into TOPP. The problem with such a freewheeling atmosphere without rules is that, for it to be a net benefit, there have to be more doctors like Emil Freireich and Vincent DeVita than there are like Barney Clarkson, as Gladwell notes. Personally, having been in medicine in one form or another for 30 years now, I am not nearly so confident that there aren’t a lot more Barney Clarksons than Vincent DeVitas. In fact, I’m quite sure that there are and that, contrary to DeVita’s claims that an extra 100,000 more patients a year could be cured if we just used all the wonderful drugs out there to their fullest potential, opening medical practice and research to the sort of “innovation” DeVita proposes would end up harming far more patients than it would ever help.

Let’s just put it this way. By DeVita’s definition, Stanislaw Burzynski is “innovating” with his “make it up as you go along” form of “personalized gene-targeted” cancer therapy combined with his antineoplastons. After all, “innovation” is very difficult to identify, except in retrospect, after we know what works and what doesn’t, who is a Stanislaw Burzynski-style maverick and who is a Vincent DeVita-style maverick.

wild_wild_west_by_aspeckofdust

The problem with mavericks and nostalgia

‘Cause the good ole days weren’t
Always good
And tomorrow ain’t as bad as it seems

– Billy Joel

 

DeVita’s complaints about medicine are not uncommon. I tend to hear complaints like his from (mostly) an older generation of physicians who came of age in terms of their medical career during times when physician autonomy was perceived to be much closer to absolute and constraints on doing research less onerous, in other words, in a more freewheeling “wild West” sort of atmosphere. Given that, I can’t help but think that there is more than a little nostalgia, a pining for the “good old days,” in DeVita’s book. I also can’t help but wonder if Gladwell was rather selective in his quoting of DeVita, given that in an NPR interview just one month ago promoting his book, DeVita said very little that was so critical of the state of cancer research.

Be that as it may, I tend to view new fields of medical research as being rather like the American frontier. The first ones in are the hardiest and bravest, the ones willing to take the most risk, such as trappers and mountain men. They clear the way for the next wave, and as new arrivals keep coming, civilization intrudes. There are more and more laws and rules, and there is no longer absolute freedom. Eventually, what was once frontier is now little different from the states where all the settlers came from, and the original trailblazers have either moved on or struggle to fit in. Cancer research is rather like that. Back in its “wild West” period, because so little was known about cancer and so few effective treatments existed outside of surgery for certain specific cancers, there was an “anything goes” culture because, or so it was perceived, there was much to gain and very little to lose by trying almost anything. So men like DeVita (and, yes, unfortunately is was almost all men back then) did. Also, the less that’s known, the more variability in care is acceptable, because we don’t know what the best existing treatment is. The more we learn, the greater the risk in practicing outside of evidence-based guidelines because doing so becomes more likely to harm than help.

We are all products of our time and experiences, and DeVita is no different. He became a cancer researcher in a specific time and place, and his life experiences, particularly with his son with aplastic anemia and his friend with prostate cancer shaped his views. Think of it this way: DeVita, as brilliant as he is and as deserving as he is of all the respect he gets, was nonetheless very fortunate very early in his career. After all, his first attempt at innovation through tinkering happened to be a smashing success. There was no guarantee at the time that this would be the case. Indeed, it’s not hard to imagine an alternative history, in which his first attempt at multimodality chemotherapy was so toxic that it killed most of his patients before their cancers could or was simply ineffective and toxic. Would DeVita view giving physicians unfettered freedom to “tinker” so favorably if that had been the case? After all, in other hands, such tinkering resulted in an ineffective treatment combination.

One thing I like about The Knick is that it shows that one maverick can easily produce both outcomes: disaster and greatness. In other words, it’s a mistake to separate mavericks into Freireich-style mavericks and Clarkson-style mavericks. Any single maverick, for any given bit of “tinkering,” can produce Freireich or DeVita results or he can produce Clarkson-style results. Indeed, when Brave Maverick Surgeon John Thackery does his “tinkering,” sometimes, he’s successful, as when he successfully separates a pair of conjoined twins this season. More often, Thackery fails miserably. Two of the more dramatic failures occurred late in the first season when Thackery outright killed a girl transfusing her with his own blood based on his incorrect hypothesis of what determined different blood types and in the second season when, while trying to treat a man’s addiction by ablating part of his brain with an electrical probe, he inadvertently damaged part of the brain that resulted in a locked in patient, about as horrible an outcome as can be imagined. (If you don’t know what locked in syndrome is, read this or watch The Diving Bell and the Butterfly. It’s arguably a fate worse than death.) This season, when Chickering, following the lead of his mentor, tries an experimental treatment on his mother, disaster ensues. The converse can also happen, as in the first season when Dr. Zinberg develops the “illuminating intrascope,” which allows doctors to look inside their patients without making large incisions. (Basically, it was a precursor to what we use today as the laparoscope.) This conflict appears poised to play itself out in the season finale tonight, as the synopsis includes this: “Thackery eschews Zinberg’s (Michael Nathanson) advice at Mt. Sinai and opts for a dramatic, and risky, alternative course of action.”

Same as it ever was.

Unlike 50 (or 115) years ago, medicine today is, for better or worse, largely a “team sport.” This is particularly true when it comes to serious diseases like cancer. For instance, in my specialty, breast cancer surgery, it’s uncommon that I am the only physician involved in the care of my patients with breast disease. It happens for patients undergoing a biopsy and for patients with ductal carcinoma in situ whose tumors are hormone receptor negative and who are thus not going to benefit from estrogen-blocking therapy. Even in both of these cases, at the very least a pathologist is also involved. The care of the rest of my patients involves a combination of surgery, radiation oncology, and medical oncology.

The collaborative nature of cancer care today can be frustrating to some doctors. In addition, there is a certain type of personality that views evidence-based guidelines as “being told what to do.” It’s not hard to find these doctors; indeed, just peruse the feed for Kevin, MD, and it won’t take more than a few days for you see them, and if you peruse the AAPS Twitter feed, you’ll see them in spades. Truly, the appeal of the cult of the Brave Maverick Doctor is strong. It’s just disappointing to see a physician as eminent as Vincent DeVita worshiping at the altar of the cult of the Brave Maverick Doctor.

Few physicians are as brilliant as Dr. DeVita or Dr. Freireich, and even brilliant maverick doctors “tinkering” the way DeVita did tend to be wrong far more often than they are correct. That’s why, as The Knick puts it, there are rules. Reasonable people can disagree over how strict those rules need to be, but there have to be rules.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

154 replies on “Vincent DeVita: We need more freedom to be mavericks. Orac: Not so much”

I skipped a lot of this because we just finished binge-watching season one. We ordered TMN, which carries HBO Canada, for the express purpose of watching The Knick, because my mother will not shut up about it. 🙂

Why this show isn’t nominated for a slew of awards is beyond me. In addition to Owen, Cara Seymour is particularly good as Sister Harriet, who bears more than a passing resemblance to a nun I once knew. Then again, The Wire never got nominated for awards, either.

I need to watch “The Knick”.

That “back in the good ol’ days” phenomena seems almost universal in many career fields. In the extreme, an engineer might yearn for a slide rule, but, honestly, how realistic is that for practical use today? DeVita wants to see giant strides in cancer treatment like he remembers happening in his time. He wants to see cancer conquered. I think that realization of one’s mortality and not being here to see a dream happen brings about these yearnings. If it inspires others, great. But if it’s more like “back when I was your age, I walked 20 miles uphill each way to school in the snow every day”, well, time for rolling of eyes.

Recently I was listening to a woman lament the lack of OBs skilled at vaginal breech and assisted delivery. My uncle is 75 and a retired OB who practiced in Toronto. He was considered the go-to guy for breech and instruments. He doesn’t lament the passage one iota. The good ol’ days scared the daylights out him half the time.

And every one of the maverick believers- woo-bent or not- thinks that s/he will be that one in a million who truly does transform science, initiating the much lauded paradigm shift.

Those are not good odds.

Don’t they see that?

I think we’re also dealing with men (and as Orac says, it is mostly men) whose attitude is “you can’t tell me what to do! Damn it, stop arguing and follow my instructions!” It sounds as though DeVita expected other doctors to do things his way, just because he was a doctor and said so–but wasn’t prepared to give his colleagues that same amount of respect, even when they were more experienced than he was. Yes, it’s very human for him to take for granted that he knows better than other people, but it’s also very human for them to take for granted that they know better than he does.

Maybe you should distinguish mavericks who are right from those who are wrong, but this would require intelligence, which cannot be objectively evaluated by administrations.
In the meantime people like DeVita have saved millions of lives,
whereas the step-by-step approach has given that:
http://seer.cancer.gov/statfacts/html/pancreas.html
http://seer.cancer.gov/statfacts/html/corp.html
http://seer.cancer.gov/statfacts/html/urinb.html
http://seer.cancer.gov/statfacts/html/brain.html
Fortunately, if the number of cancer scientists increases at the actual steady pace, there will be more people living from cancer than dying of it before the two degrees Celsius global warming is reached.
What we need is a paradigm shift:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799276/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567024/

Maybe you should distinguish mavericks who are right from those who are wrong, but this would require intelligence, which cannot be objectively evaluated by administrations.

Uh, did you actually…oh, you know…read my actual post? I spent a lot of time discussing mavericks who are right versus those who are wrong, why it’s hard to tell the difference except in retrospect, and how a single maverick can fall into either category, depending on what he’s working on.

I mean, seriously. Did you actually bother to read my post? Your comment suggests that you didn’t.

Uh, did you actually…oh, you know…read my actual post?

Well, there’s a Billy Joel quote in the middle!

Orac:

For some reason, I keep getting waylaid to an ad which then shoves me over to an ‘about blank’ and doesn’t go to the site.
Why that?
Do you have to go through this 7 times to break the spell?

A long and thoughtful piece. We have to take the time and trouble to read and digest such pieces.
Daniel Corcos didn’t.

@ Orac # 8
“It’s hard to tell the difference except in retrospect”
No it’s not so hard, if you take enough time for your evaluation. But telling that somebody is a maverick, any bureaucrat can do it, and it’s not scientific evaluation.
“how a single maverick can fall into either category, depending on what he’s working on”. It’s not clear what you mean here. Clearly there are mavericks who don’t have any chance to find anything because they are stupid. And there are people that cannot find anything because they follow the herd.

For some reason, I keep getting waylaid to an ad which then shoves me over to an ‘about blank’ and doesn’t go to the site.

Yah, I can’t remember the redirect site, but it’s completely broken and rendered SB more or less unusable on this iPad until I installed the “Refine” browser plugin.

It’s not clear what you mean here. Clearly there are mavericks who don’t have any chance to find anything because they are stupid. And there are people that cannot find anything because they follow the herd.

Read the post. Until you show me evidence that you’ve bothered to read what I wrote, I see no point in engaging you further, and I see no evidence in your comments that you’ve gone beyond the title and maybe a couple of paragraphs.

@ Peter Dudgale
If you have taken the time and trouble to read and digest Orac’s prose, you would have noticed that he actually did not read DeVita’s book. But this should not prevent the minions to argue that Orac has not been read with the attention he deserves.

you would have noticed that he actually did not read DeVita’s book This is relevant here, how exactly?

I just read the entire post (as I said above, I didn’t initially because we have yet to start season 2 of The Knick) and it appears as though you’re the only one here missing the point.

@ Delphine
If you read the whole thread, you will see that Orac and one of his minions accuse me to criticize Orac’s post without having read it. This is quite funny, because they have no “evidence” for this, and because the post is about a book that Orac has not read. Did I miss your point?

The first sentence of your #7. The post contains examples of mavericks who were right versus those who weren’t.

Was the post about a book that Orac has not read? We must be reading a different post.

Perhaps you would like to read my first ever thesis, on Philip Roth and misogyny. Don’t hate me for not reading every single word Roth has ever written. Also, I was 21.

Kreboizen @13 hit the nail on the head: the problem isn’t that Daniel Corcos hasn’t read the post, it’s that he thinks that he’s the one-in-a-million maverick who’s idea is actually correct. But he’s not content to wait and be vindicated in hindsight, so he insists that people of “intelligence” should be able to see his brilliance before he’s provided evidence via the boring old peer-review system.

Clearly there are mavericks who don’t have any chance to find anything because they are stupid. And there are people that cannot find anything because they follow the herd.

And then there are people who learn to strike the balance between research that is innovative while still being supported by the current state of knowledge (and, preferably, some preliminary data.) We call them “competent scientists.”

In reality I don’t believe that Orac is reviewing the book or Dr. DeVita’s work but looking at how we come to know what we know and how we change what we know.

We have a sphere of knowledge that has developed overtime and changes incrementally as new insights are brought to bear. Most people are comfortable with this and will fight tooth and nail for this system. Along comes a maverick that states that everything you think you know is wrong. The maverick is typically reviled by the masses and indeed sometimes killed for his/her impious thoughts.

I have a rule for music that I think would apply here: 95% of all music is crap and only 5% is ok or better. Of the ok music only 5% is better than ok. You can see the progression here.

So for any maverick probably 95% is crap and 5% is ok or better. Of course just because a maverick puts forth a crapy idea does not make them stupid.

My maverick days ended at age 12 after deciding to cook an uncracked egg in a microwave despite repeated admonitions not to do this.

One blown off microwave door later, with scalding egg burns on arms (not a lot, but it was hot), the maverick was tamed.

“As I like to point out, change in science-based medicine is messy. It often takes more time than we think it should, particularly in retrospect. But eventually we do change practice in response to data and science. At the heart of this change, the question is always: How much new evidence is required before a critical mass of physicians are convinced to change practice? ”

I noticed that change is often function of generational change, not of amount of evidences. Only when generation with old ideas die out, new idea can take root. This indicates that only young generation is hope for the change.

“There was no guarantee at the time that this would be the case.”

We human like to do reverse rationalization even though there is no guarantee that same rationale will work in future. In hindsight, some one always looks like genius. Politicians are specially good at taking credit for success they never had real plan for.

@Daniel Corcos – You need to go back and re-read (or read) the first paragraph carefully: the OP isn’t about Dr. DeVita’s book, its about Malcolm Gladwell’s article “Tough Medicine,” which includes excerpts from the book.

@ Sarah A
I have published in what you call the old peer-review system (Blood, Current Biology, Cancer Medicine, Oncogene, Journal of Immunology) and have got hard criticism from people like you, even when I found the first evidence of the role of the B cell receptor in lymphoma and the role of oncogenes in driving genetic instability. People in the heard first say “it cannot be true”, then “your results can be explained otherwise” then when everybody agrees on the fact that it is true, that the discovery has been made by somebody else (preferentially an american who used the machine that goes Bing).

The first sentence of your #7. The post contains examples of mavericks who were right versus those who weren’t.

Yep. Then he goes on to be addressing a point that mavericks are either stupid or not, which is totally not what I argued at all. One more time, even brilliant mavericks are usually wrong more often than they are right.

“My maverick days ended at age 12 after deciding to cook an uncracked egg in a microwave despite repeated admonitions not to do this.”

Happily there were no nuking ovens around when I was 12. When I was 12 I stuck a screwdriver into a tube radio to see how it worked. When I came to I was up against the wall on the other side of the room with a smoking screwdriver in my hand.

But then all children are mavericks.

Daniel Corcos:
“@ Orac # 8
“It’s hard to tell the difference except in retrospect”
No it’s not so hard, if you take enough time for your evaluation. ”

That made me laugh.

At least acknowledge that it goes Ping and not Bing. Unless there’s a new machine that does indeed go Bing. There ended up being a lot of machines present when I gave birth and before the mask went over my face I can assure you that none went Bing. Only Ping.

Delphine,

Its the perfect time for Bing and David Bowie to sing Little Drummer Boy (what a strange duet).

@ Orac
That’s not what I am saying. If an idea is good, you can tell if it is good or not even when it is not demonstrated. It may be difficult to prove, there can be technical difficulties, but you should not expect Leo Szilard constructing an atomic bomb with his hands to understand that his idea is correct. Leo Szilard who also predicted the way science would be killed by bureaucracy:
http://www.deepseanews.com/2010/07/how-to-retard-scientific-progress/

@ Delphine
I must admit you are right. When I hear it now it’s clearly a Ping.

If an idea is good, you can tell if it is good or not even when it is not demonstrated

The Hindenburg is a good example.

Ah, I see now. Corcos has a bug up his butt about “bureaucracy.” This explains much.

As for telling if an idea is “good” or not, well, no, in biomedical science particularly that is not nearly as easy as you make it sound. Many “good” ideas go down in flames when tested, and, quite frankly, we scientists have quite the terrible record predicting which ones will survive experimental testing and which ones won’t, particularly the “big” ideas that buck the mainstream, most of which will fail.

“It’s hard to tell the difference except in retrospect”
No it’s not so hard, if you take enough time for your evaluation. ”

That made me laugh.

Me too.

One wonders if the grant application process is being conflated with identifying “good” and “bad” mavericks. 🙂

Ah, I see now. Corcos has a bug up his butt about “bureaucracy.” This explains much.

This is why brave mavericks publish with ResearchGate: Game. Changed.

Orac
Actually, the grant application process is biased toward projects giving preliminary results, i.e., it does not favor people with ideas, but people with a working technology that give experimental results, which can be presented as if the results were relevant to a real question. It is not surprising then that you will find more trials on homeopathy than on innovative methods that will need a lot of settings. It is not surprising either than people like Farber and DeVita have achieved such success, when most today’s cancer scientists are at a standstill, as shown by the death curves on my links.
“Many “good” ideas go down in flames when tested, and, quite frankly, we scientists have quite the terrible record predicting which ones will survive experimental testing and which ones won’t, particularly the “big” ideas that buck the mainstream, most of which will fail.”
Actually, the two “big” ideas I had the opportunity to address experimentally were proven to be correct.

Delphine – As a Philip Roth scholar, perhaps you can understand one reason why, in the Australian faith-healer thread, when someone mentioned “sexual intent” in toward food in describing a woo site, my reaction was: Eeeeeeeew!

@ Vincent DeVita,

Dear Sir,

Can alternative medicine help satiate a hunger for more effective 21st century medicine?

Furthermore, is it true that:

alternative medicine is a flavor of conjecture;
conjecture is an ingredient of creativity;
creativity is a recipe for hypotheses;
a hypothesis feeds medical science;
medical science nourishes mankind; then
knowledge grows.

Evidence is for bureaucratic sheeple! Superior intelligent people are just right by default, actually demonstrating something is just an unnecessary formality. /s

Actually, the two “big” ideas I had the opportunity to address experimentally were proven to be correct.

Then you were exceedingly fortunate. It’s also, I suspect, why you appear to suffer from the same blind spot that DeVita does and now assume your lucky experience is generalizable and that it’s to easy tell the difference between a “good” maverick and “bad” maverick. Would that it were true! You then use that assumption to assume that, if only we would unleash the maverick, we’d have cures for pancreatic cancer, endometrial cancer, bladder cancer, brain cancer, etc.

Would that it were true!

In this, DeVita shows more insight than you. He consistently describes cancer as a “devious” foe, as one that will not yield to just one strategy. He is correct.

John Wheeler (physicist of note) had a theory that it was OK for successful scientists in their late career to go Emeritus and start promoting partly-baked maverick ideas — indeed, it’s almost obligatory for them.

He reckoned that science does benefit from fringe ideas, on account of the (say) 5% that aren’t bogus, and it was better for people like him (with nothing to lose) to promote them, rather than for young scientists to sacrifice their careers.

As a Philip Roth scholar….

Simply recalling the couch in “Goodbye, Columbus” sets off a pretty strong “Eeeeeeeew” in me, but that may have something to do with other associations.

Daniel Corcos: Even Einstein–the genius who won a Nobel prize for, among other things, showing that despite the long-accepted experimental evidence that light is made up of waves, light is made up of particles–didn’t get everything right.

General relativity was demonstrated experimentally, first in 1919 and consistently over the decades since. Einstein was still wrong about quantum mechanics. Please, consider the possibility that you are no more brilliant or infallible than Einstein.

@Vicky
I don’t claim to be infallible. What I am saying is that if you wait for providing evidence that will convince all people you cannot succeed. What many people consider today as “evidence” in science is proper utilization of the machine that goes ping. By the way, Einstein would still be unknown if the reviewers of his papers have asked for experimental “evidence”.
@ Orac
“In this, DeVita shows more insight than you. He consistently describes cancer as a “devious” foe, as one that will not yield to just one strategy. He is correct.” Let’s see. What I can tell you is that I can protect mice from chemotherapy induced myelosuppression. And I am expecting to face a lot of criticism and bureaucracy before the method being applied to human.

@ Narad
Researchgate is a den of mavericks like James Allison, Drew Pardoll and Mitch Nussenzweig. I wanted to post the links, but apparently it is considered as spamming.

alternative medicine is a flavor of conjecture;

Cite?

conjecture is an ingredient of creativity;

Cite? I can create a lot of stuff that isn’t true. See ChemE, for example.

creativity is a recipe for hypotheses;

Cite?

a hypothesis feeds medical science;

Cite?

medical science nourishes mankind;

Well, I’ll accept that, but only if there is evidence. Or do you disagree?

then knowledge grows.

Cite?

May the gods of HTML protect me.

@ Daniel Corcos

If an idea is good, you can tell if it is good or not even when it is not demonstrated.

Err… No.

I had plenty of apparently good ideas in my life, only to be proven an !diot when they were put to the test.

I suffer from a form of recall bias where I mostly remember my failures; to me, a success is nothing to brag about and soon forgotten.

With all due respect, I suspect you have a bad case of recall bias, too, but in the other direction. You had these two “big ideas” which have been vindicated, but you may forget all these little apparently good ideas which didn’t pan out.

You may be lucky to be surrounded by colleagues who are very good at brainstorming and playing the sounding board for new ideas. So good ideas are filtered through.
Or you could be one of these rare humans who are very good at introspection and self-analysis.

But for the rest of us puny mortals, only time and testing it will tell if an idea was good or very stupid.

I sympathise with the pain of dealing with bureaucrats. I really do. My director is spending more time writing reports than doing science, and we had to pass on hiring good people because of some well-meaning labor laws.
As for scientists stealing other scientists’ discoveries… It’s not just the Americans. And the scientific community should really spend more efforts in cleaning its act. But that’s the world we have been dealt.

What I can tell you is that I can protect mice from chemotherapy induced myelosuppression. And I am expecting to face a lot of criticism and bureaucracy before the method being applied to human.

“If you’re a mouse and you have cancer, we can take good care of you.” Judah Folkman

herr doktor bimler

John Wheeler has reasonable point given the reality of the effects on career of proposing off- the-wall ideas as a young scientist, but I dont’ think that’s what De Vita is doing here. However there is also a very real problem that a lot of eminent men (and it does seem to be a particularly male propensity) do this not in that spirit, but on the assumption that their past success makes them infallible.

@ Helianthus
You have to distinguish ideas and methods. An idea can be good and never give rise to a method that works. That’s life. But one has to try. If an idea is foolish, you can tell it from the beginning, even if the guy is Columbus and if he discovers America.
@ Krebiozen
Lack of a mouse model was the reason I could not pursue cell inflation assisted chemotherapy. Let’s see what they will say now. Probably something like “you have not proven that it will work on humans”.

It’s really not that complicated.

People who experience “creativity” (insight, intuition, non-linear problems solving, whatever) are not strangers to hard work.

People who succeed only by working hard are, however, strangers to creativity.

So, Orac describes someone as “lucky”. One has to wonder what is being expressed there, if not resentment based on not understanding how it works. Creative people don’t resent those who succeed only by working hard, but they do resent the resentment.

The other type of person in this little universe of characteristics is the good manager, who knows how to use both. If there’s a problem here, it’s that we tend to assign individuals to roles for which they are not suited.

@ Daniel Corcos

But one has to try.

I agree, but it was sort of my point.
An idea may have merits, but until you try it, assigning a judgement value to it is fraught with unseen consequences.

OK, now I’m getting close to the “principe de précaution”, and it’s a concept a positively hate. It’s mainly used as an excuse to do nothing.

If an idea is foolish, you can tell it from the beginning, even if the guy is Columbus and if he discovers America.

Aïe. You just added another level of complexity.

Columbus’ idea was right – there was riches to be found by sailing West – but for the wrong reasons. Or, as another point of view, he was wrong – you can not reach India/China by sailing West – but by serendipity Columbus found something completely unrelated to the original objective, but still worth the expenses: a whole new continent and its natural resources, waiting for someone to grab them.

If your point was that providing free reign to explorers and researchers is fostering innovation and discovery, Columbus is a great example (well, maybe not from the POV of the native Amerindians, but I digress).
And it’s a point I agree with.

Bur following your assertion on how good ideas stand by themselves, Columbus’ example is actually counter-productive, because he got good results despite starting with a foolish idea.
So what’s the point of judging if an idea is good or not?

If I understood your previous posts correctly, you are bemoaning the excess of criticism and bureaucracy in the innovation process.
That’s an interesting reversal of Orac’s position:
– Orac’s main point is that people coming with bad ideas, for whatever reason, for scientific/medical advances are a dime a dozen, whereas truly game-changing ideas are occurring much more rarely; thus he is advocating caution and the need for building the idea’s case by incremental evidence, because there is no real way to know if an idea is good or bad before testing it, and the trend is toward bad ideas.
– your point is that most criticism/bureaucracy is only delaying innovation.
But how do you distinguish between bad criticism and critics who actually have a point?
Similarly, how do you draw the line between needed and excess regulation? To put it simply, would you like to be remembered as the guy who introduced the new Mediator (or Vioxx, or Thalidomide)?

And I am expecting to face a lot of criticism and bureaucracy before the method being applied to human.

As well you should. That’s the way it works, and that’s more a good thing than a bad thing. Humans aren’t mice and they aren’t mathematical models. If you’re wrong you could well hurt people—badly. That’s why we have so many rules governing clinical trials. Consider the principle of clinical equipoise.

http://respectfulinsolence.com/2010/09/20/balancing-scientific-rigor-versus-patien/

However there is also a very real problem that a lot of eminent men (and it does seem to be a particularly male propensity) do this not in that spirit, but on the assumption that their past success makes them infallible.

Yes, this. Or, if not infallible, very much more likely to be right than reality would suggest. It’s confirmation bias of the highest order. They remember the hits and forget that the hits are far outnumbered (at least for most people) by the misses.

So, Orac describes someone as “lucky”. One has to wonder what is being expressed there, if not resentment based on not understanding how it works. Creative people don’t resent those who succeed only by working hard, but they do resent the resentment.

What nonsense. Being “lucky” and working hard are not mutually exclusive. After all, hard work can make its own luck. The problem is that “innovative” ideas are a dime a dozen—heck, there’s even a journal dedicated to them, Medical Hypotheses, which is dedicated to “provocative” ideas and ends up publishing a lot of dubious stuff as a result—and only a small minority of them will be successfully validated, no matter how much work is put into them. It has nothing to do with envy and everything to do with the reality of how science works.

Helianthus @59 — about Columbus: My understanding is that he had accepted an estimate for the size of the earth that was much too small, and hence greatly underestimated the distance west to China. If they hadn’t bumped into the new world, they probably would have all died.

Weirdly, the size of the earth is really not all that hard to measure — Eratosthenes’ first attempt is thought to have given a reasonably accurate value — so you’d think a good estimate would have been available to Columbus.

“In this, DeVita shows more insight than you. He consistently describes cancer as a “devious” foe, as one that will not yield to just one strategy. He is correct.” Let’s see. What I can tell you is that I can protect mice from chemotherapy induced myelosuppression.

Also, I forgot to mention. I came of scientific age in the 1990s, when angiogenesis inhibition was going to cure all cancers by targeting the one common pathway. We all know how that turned out. Of course, Judah Folkman, one of my scientific heroes, kept things in perspective and was frequently cautioning people that his spectacular results in mice didn’t necessarily mean that angiostatin or other antiangiogenic therapy would cure cancer in humans.

As Orac point out in this entertaining post, Vincent DeVita’s son Ted DeVita had aplastic anaemia.

Off topic, does a suppressed immune system from aplastic anaemia affect the incidence of Autism Spectrum Disorders?

There is no aplastic anaemia reported by people with Autism spectrum disorder yet.

http://www.ehealthme.com/cs/autism+spectrum+disorder/aplastic+anaemia

It is then logical, but professionally dangerous, to ask the question:

Does forced immunity (i.e., immune-system stimulation) through vaccinations affect the incidence of Autism Spectrum Disorders?

In my opinion, only brave maverick doctors pursue this question.

Johnny says (#53),

Cite? x 5

MJD says,

Do you review articles for Wikipedia?

The prose you request citations for comes from a book that I authored in 2011. (RIP Lilady)

@Orac,

Thanks to you and the minions I now have the willpower to avoid speaking of that which should not be spoken, at least here at RI.

“so you’d think a good estimate would have been available to Columbus.”

It was. He ignored it, and the experts who criticized his plan based on that knowledge. But there was also a lot of uncertainty. Even so he won the needed backing, after some noted failures. Perhaps it was a matter of motivated reasoning since if he had accepted the larger number the trip would have been near impossible.

I think we would know if there was *any* association of autism with aplastic anemia. You tend to die from aplastic anemia unless you seek medical treatment, making the prior post even more of a non sequitur

Dr. Corcos does have one point worth discussion. It doe indeed seem that contemporary grant-giving practices are leading to a pernicious conservatism in grant applications. This seems to be obtaining in every field, not just experimental medicine. In fact I think this issue has in the past been discussed here. [Did you check for this Dr. Corcos?]

However, the grant-giving process is mostly aside from the issues specific to the discussion started by the OP. While there do seem to be some barriers to free research and discussion, this does not affect the generally supportable conclusion that seeking to be a ‘maverick’ is at best of ambiguous utility to cancer research.

There is also, I will add, no need to criticize positions not actually said in the OP, and that conflation of highly various issues concerning innovation in research is highly unscientific.

I’m no fanboi of Orac or of anyone else. But zebra’s imputation of “resentment” to Orac based on a highly tendentious interpretation of one sentence is an unambiguously asshole move.

Just a few points. Ideas must be distinguished from methods. An idea remains good even when the methods do not work. This is/was the case for monoclonal antibodies. If the initial failures were considered as a proof that it was a bad idea, we would not have all these drugs. A bad idea, as trying to reach India believing the earth smaller than it is, remains a bad idea, even if serendipity sometimes occurs.
Secondly, the “principe de précaution”. I don’t mean to say that we have to rush on the patients. Of course, everything has to be done to ensure safety before use in humans. But it is costly. So the problem is rather the complete lack of ability, not mentioning the competition and conflict of interest, of scientists in charge of evaluation to distinguish bad from good ideas.

RJ — Thanks!

In my capacity as Voice of Reason on climate-change discussion threads one often runs across denialists who claim that “scientists” (they usually use scare quotes) used to think the earth was flat — their point being that the scientists who now tell us that the climate is warming rapidly because of greenhouse gases could just be just as wrong.

The argument would be idiotic even if its premise were true, but even the premise is wrong. It’s hot, steaming lumps of burning stupid all the way down!

Ach, a little word salad here and there, but you get my point.

I like mine with balsamic vinegarette on the side.

I’m not quite sure how my comment relates to your intellectual agenda, but you’re welcome!

My understanding is that he had accepted an estimate for the size of the earth that was much too small, and hence greatly underestimated the distance west to China. If they hadn’t bumped into the new world, they probably would have all died.

YOU’RE WELCOME, GUYS.

Srsly, though, you’re going to have to be nice to the Gypsies for a while now.

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