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."
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.
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.
The problem with mavericks and nostalgia
'Cause the good ole days weren't
And tomorrow ain't as bad as it seems
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.
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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.
In early November this hit the news:
A leap from mouse model directly to humans, and it worked.
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:
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:
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!
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.
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.
The maverick scientist protests too much methinks.
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.
I figured that it something like that.
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.
Orac # 16
The term "evidence" occurred five times. Is that proof?
@ 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.
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).
It's actually an English invention.
Agree, but administrators in any country love it.
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.
"@ 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.
Its the perfect time for Bing and David Bowie to sing Little Drummer Boy (what a strange duet).
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:
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.
Here I disagree. The Hindenburg was a Zeppelin, not an idea.
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.
One wonders if the grant application process is being conflated with identifying "good" and "bad" mavericks. :-)
This is why brave mavericks publish with ResearchGate: Game. Changed.
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!
I should follow for you the advice you gave me for See Noevo
but I could not resist.
Researchgate is a den of mavericks:
A den of mavericks
@ Vincent DeVita,
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
Evidence is for bureaucratic sheeple! Superior intelligent people are just right by default, actually demonstrating something is just an unnecessary formality. /s
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.
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.
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".
"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.
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.
Cite? I can create a lot of stuff that isn't true. See ChemE, for example.
Well, I'll accept that, but only if there is evidence. Or do you disagree?
May the gods of HTML protect me.
@ Daniel Corcos
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.
"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.
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.
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
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.
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)?
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.
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.
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.
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.
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
Do you review articles for Wikipedia?
The prose you request citations for comes from a book that I authored in 2011. (RIP Lilady)
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!
YOU'RE WELCOME, GUYS.
Srsly, though, you're going to have to be nice to the Gypsies for a while now.
Dr. Corcos, if you really think that there is some anti-intellectual disease at the top that disables reasonable evaluation of potentially innovative research, you're going to have to make this case in much greater detail than you have. You can't convince me by a series of anecdotes, nor of personal abuse to those that disagree with you.
I'm not a fanboi of the scientific establishment either. If you have a case I'm prepared to be convinced (and I think others here feel the same way). If you have detailed case studies and comparative sociological analyses, you're going to need to write a book to make it cogent to me, though. Not a few blog comments and personal abuse.
Your comparison with Folkman's failure does not stand, because angiogenesis inhibition is a strategy directed against the tumor, and tumors evolve. But a strategy directed toward normal cells does not present the same problems. What is needed is just to check that the same objectives are achieved in mice and humans (temporarily preventing cell division) and we have some reasons to think it can work the same way.
Daniel Corcos 69
"scientists in charge"
And that's the problem. You need good managers, but you put people in charge based on other criteria. Maybe some not-so-great scientists would be better at what you are talking about.
It appears to me that a significant point of confusion here is the vagueness of the phrase "good idea" vs "bad idea." We usually apply those terms to ideas that can reasonably be evaluated ahead of time using common sense: driving drunk = bad idea, calling a cab = good idea.
But biomedical research doesn't work that way - it's not a question of "good idea" or "bad idea," its a question of "true hypothesis" vs "false hypothesis." The topics involved are way too complex to be able to tell whether a hypothesis is likely to be true ahead of time - if that weren't the case there would be no need to do the research in the first place! At the same time, there needs to be some sort of system in place for allocating limited research dollars based on how likely a given proposal is to generate useful information, hence the dreaded grant committee. But even expert reviewers don't (or shouldn't) judge grant proposals based on whether it sounds like a good or bad idea, they judge it based, in large part, on how well the hypothesis is supported by the existing literature.
And that, it seems to me, is a big factor that people like DeVito forget about when pining for the good old days. They assume that the reason they were able to make such huge, ground-breaking discoveries while later progress in the field became more incremental was because they had less regulation and/or because they were more "creative" - they don't seem to consider that they had the advantage of being able to pick the low-hanging fruit in a largely unexplored field. Modern researchers have the advantage of the body of knowledge that pioneers like DeVito generated, but that also means that out-in-left-field ideas are less likely to pan out, precisely because DeVito et al helped to push back the limits of what consititutes "left field." When I come to think about it that way, it's almost as if DeVito is lamenting the fact that his protegees don't have the (viable) option of completely ignoring everything he did.
Of course, significance and innovation are also factors in the grant process, and part of the hell of grant writing is striking that balance between "innovation" and "feasibility." As I remarked earlier, successful researchers find a way to strike that balance, they don't whine about how unfair it is that their genius goes unrecognized by the hide-bound bureaucracy.
Your approach might work in a world of literally unlimited resources. In the world we live in, someone has to decide which ideas get the lab workers, equipment, mice, chemicals, and so forth for those rounds of testing.
In the specific case of medical applications for human patients, there are ethical as well as financial reasons to ask things like "Is this more likely to help the patient than to hurt them? And what kind of help, versus what kind of harm?"
I suspect you've never been offered a medication by a doctor who said "this will probably ease your symptoms and may reduce disease progression, but it has about one chance in a thousand of killing you or causing significant brain damage." But at least the doctor who says that knows about the risk, and is telling their patients, so the patient can decide, not just saying "There's a fine new medication, make an appointment with the front desk for the first dose."
Orac is demonstrating the misunderstanding that I described:
Yes. They are the result of people who aren't creative playing at creativity. They think that it is all about just being "innovative", and you say they are "lucky", because of course they hit on the right answer only by chance.
But that just isn't the case in the history of science and art at least. It may well happen sometimes, and some things came about through just trial and error, but there really have been transcendent insights by individuals who put themselves in the position to make those leaps. From the shoulders of giants, as they mostly acknowledge.
Now, can that experience lead to a kind of hubris? Of course; who can easily accept being a one-hit wonder? Who can easily go through the whole process again without some kind of conviction that the outcome will repeat?
That's the struggle, and you can't expect most to achieve some kind of saint-like humility given our hero-worshipping Galt-exalting culture.
You seem to be denouncing Galt-exaltation. Why then does almost every post of yours scream that everyone but you is wrong and everything would be OK if everyone would just look at it your way.
If I had to guess based on your comments here I would have taken you for a Rand sympathizer (not a true follower). Because every single one of your posts screams LISTIN TO MEEEEEE!
There's a version of "Crescat scientia vita excolatur" that was reworked for squirrels, but it's not coming to me at the moment.
Helianthus @63 and rs @66 make some very good points about the wishful thinking Columbus engaged in, and his sheer luck that the Americas were in his way.
Supporting evidence needed for your claims that "innovative" ideas are the result of "people who aren't creative playing at creativity.
@ RJ #74
Let me clarify my point. What I am saying is that the reward system as it is now does not favor ideas. It favors productivity in terms of publications. How it translates in terms of cancer cure can be evaluated globally by the links that I put at my post #7. If we relate this absence of efficiency to the number of scientists working on cancer, doubling every twelve years, we can conclude to a total failure. Why it is so is for me quite obvious. There is not enough benefit trying to answer a question.
When you realize that there is an issue important to solve, the first thing is to address the question theoretically, then to try to set the methods for addressing the question. Setting the methods for addressing a question is too much effort and is not rewarded enough compared to the risk taken. What people usually do now is to learn methods and then see what they can do to publish results that seem to answer a question.
Yes, simple-minded dichotomies as a rule aren't complicated. Or of any value whatever.
So why do you (or Orac, or anyone) make your posts if you don't want people to listen to you?
And do you make comments that you don't believe to be correct?
I don't get it.
@ Sarah A
I don't doubt that there are "successful researchers" who "can find a way to strike that balance" but the links that I posted at #7 show that these "successful researchers" are not so successful after all because what we can see is a failure. A hypothesis can be good as long it has not been shown to be false, but maintaining that a system works when obviously it does not is unscientific.
"Your approach might work in a world of literally unlimited resources."
Not at all. It is personalized medicine and the exponential number of scientists involved in a Ponzi scheme which require unlimited resources.
What I am saying is that the reward system as it is now does not favor ideas. It favors productivity in terms of publications.
And what we* are saying is that you are wrong because you are setting up a false dichotomy - to succeed in science you have to have ideas and publications. It's easy to have ideas without publications, but you can't get publications without ideas. No doubt you'll sniff that what gets published nowadays doesn't come up to your standards of what constitutes an "idea," but that's just too bad - the word "idea" doesn't mean "sweeping paradigm shift that will revolutionize the field," and frankly, as a mere PhD student I find it somewhat embarrassing that I have to point out how childish and simplistic an idea that is to a senior researcher.
* I should probably speak for myself, but it seems unfair to take sole credit for what several different commentors have pointed out
Guidelines are more agreeable than rules.
It might be more productive to have maverick doctors document their views, differences, the basis of their proposals, and their results for the record rather than to distrain them so broadly, so early on.
Just think if MDA had monitored all of B's patients early on, many questions could have been settled earlier. Instead MDA et al just threw rocks early onbefore patients, much less their data existed, for cases that were hopeless. Especially if B's data taking was incomplete or biased.
As for maverick patients, the FDA and paternalistic drs seem to routinely violate their rights. At some level, there is a group of patients and families that have more innate capability to better address these situations. Here, medical pandering becomes interference and distraint.
The current medical model can be excruciatingly ineffective for those that need dramatic improvements in prognosis ***now***. The 1-2 typical trial changes seem laughable to me. I needed to find several dozen changes to plug gaps, many gaps readily apparent along the way (the answers usually less so).
We've seen a lot of the well insured corporate elite go their deaths these past 5 yrs or so, after a lot of money and misery with cancer. Typically nasty and brutish, often short too.
There is still plenty of room for daVita's view in the patients world. At most, the guidelines might be proffered in second opinions, such as the insurance company
Not to speak for DC, but I am sympathetic to (if not necessarily in complete agreement with) his position, and I think you are misinterpreting. He is not talking about "succeeding in science" as an individual, but the success of this particular project.
In fact, I think you could say that his complaint is that there isn't a project in the sense that we saw with say the US space program. I call it a management problem; he may find that terminology too closely associated with less exalted enterprises like engineering and business, but still.
@Daniel Corcos - You have a very strange idea of what constitutes a "failure." Many cancers (as well as other diseases and conditions) that used to be death sentences are now treatable and even curable (for all practical applications of the term "cure.") You're alleging that the real research which brought that about is a failure because you're comparing it to a fantasy in which Brave Maverick Doctors will be recognized as the geniuses they are and given the unlimited freedom and resources that will allow them to discover The Cure (TM)
WTF? Are you serious? Anti-angiogenic therapy is aimed at normal cells: The vascular endothelial cells. Indeed, I can show you slides and figures from the 1990s that touted this as its big advantage, that it targeted normal cells, not the tumor cells, and vascular endothelial cells are genetically much more stable than tumor cells.
My analogy stands.
Back when I was a young, freshly-minted scientist, I thought that brave maverick ideas would change the face of science and win me a Nobel Prize.
I quickly learned that for every brave maverick idea that worked, there were hundreds of thousands that disappeared without trace.
As I got older I worked out that the skill was to recognise the ideas that had sound foundations from those that were mostly pie in the sky. Nowadays, whenever I hear of brave maverick doctors it mostly brings to mind thoughts about failure of self criticism.
Anti-angiogenic therapy is aimed at cancer cells because they should die in the absence of blood supply. So if cancer cells escape because they adapt there is not much you can do.
@ Sarah A
I just refer you to the links I have posted. What I mean is that there were much more progress in the after-war period than there is now, although the Ponzi scheme of cancer scientist number has reached an unsustainable pace. And this I relate it directly to management problems very similar to what has described Laurence Peter. And it is not a problem of not recognizing genius but a problem of not using intelligence.
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.
John Wheeler may have under-estimated just how lazy and broken journalism would become. It is easier to fill space between the advertisements by describing at length the quirky persona and eminent career of someone proposing a partly-baked idea, than the quality of that idea.
Must credit I. J. Good for to recognising that ideas fall along an entire continuum of bakedness:
Pundits and journalists like Maverick Scientists because the sad reality of "science as a branch of management" -- with PIs trying to direct small armies of graduate students and research assistants in what little time they have left from filling in grant applications -- does not provide a satisfying narrative, or fill their need for heroic personalities.
As a Philip Roth scholar, perhaps you can understand one reason why, [...] when someone mentioned “sexual intent” in toward food in describing a woo site, my reaction was: Eeeeeeeew!
Live and let liver.
"As I got older I worked out that the skill was to recognise the ideas that had sound foundations from those that were mostly pie in the sky. Nowadays, whenever I hear of brave maverick doctors it mostly brings to mind thoughts about failure of self criticism."
Do you mean that ideas that had sound foundations could not originate from mavericks?
Hearing that research into treating/curing cancer is a "total failure" reminds me of this:
I'm also reminded of the malevolent nitwit on another forum who proclaims that our system for investigating and developing cancer treatments is a failure because we do not devote resources to validating "proven" cancer cures like those of Royal Rife, Rene Caisse, Harry Hoxsey etc.
Hearing about Brave Mavericks affects me now in the same way as tales of Brave Whistleblowers. There are relatively few examples of the real thing, while many more are tangled up in cults of their own personality.
Actually, it's way more complicated than that.
@ Dangerous Bacon
I confess that the links I have posted are a little bit extreme. However, in the survival results you show, many of the trends are due to better detection.
My previous answer is apparently still in moderation.
And you continue to ignore the obvious: of course the early days of any research field are going to be where the fastest progress is made, because a) that's when all the low-hanging fruit gets picked, and b) each incremental advance is proportionally bigger when you're starting in a field where little or nothing is known. When you're at the bottom rung of a ladder, taking one step upwards doubles your height from the ground, but when you're on the 20th rung, taking another step upwards only takes you 5% higher. The question is, what is your evidence that research performed in the post-war period "used intelligence" (whatever the heck that's even supposed to mean) better than current research? For that matter, how exactly do you think the current system should be changed? Everything you've said thus far is vague whining about how the current system is a "Ponzi scheme" that "doesn't favor ideas."
Yup. In retrospect, going back and reading my post, that's one point I really wish I had hammered on more instead of making that analogy to the frontier days. Early on in a field, all the "easy" and "obvious" stuff is there for the discovery. That doesn't mean it's "easy" in the sense that, given what was known at the time, it didn't take genius and hard work to reach that low-hanging fruit. It just means that there's so much more room for breakthroughs and improvements. As a field matures, the advances become more incremental because it builds on what has been discovered before.
Perhaps you should have read the first part of my post. The bit where I said that for every brave maverick idea that worked there were hundreds of thousands that sank without trace.
I also wanted to affirm Sarah A's comment that in the early days of an new field the advances seem to be large, but later they seem to become incremental. This is a result of the low-hanging fruit phenomenon, but also of the fact that there are lots of discoveries to be made. We could look at the DeVita example. Combination chemotherapy appeared to be a significant advance in cancer treatment, whereas going from there to combinations that address the specific genetic make-up of the tumour and with reduced side effects seem to be so much incremental fiddling. The result of the second for the patients is better than the former. Incremental advances, while less exciting, are no less useful.
I saw the other day over at Pharyngula that Paul Davies is continuing with his eccentric notion that cancers are reversions to a Precambrian phenotype, because cancers all look like Edicarian biota or placozoa. Despite a few doses of respectful insolence, Davies is still Mathsplaining to oncologists and evo-devo geneticists about their failures to understand genetics properly:
Between that, and some of the cr@p I've read at PNAS over the years, I'm going to go with the idea that science literature already has far more mavericks than it needs.
@ Sarah A
Ok, what I wrote requires clarification.
Firstly, the early successes due to "easy" discoveries compared to the (failure, oops, sorry) incremental advance "because it builds on what has been discovered before" (a new interpretation of "standing on the shoulders of giants") is far from being a generalized phenomenon.
These discoveries seem to be « easy" only retrospectively. And there are many obvious approaches of changing treatments according to cell kinetics and chronobiology that could be done on theoretical grounds but are not because clinical trials are so difficult and expensive, which limit them to new molecules that can finance them.
Now for the current system, which I have named the Dilbert pyramid, a mix between Peter principle, where people are promoted until they reach the level of their incompetence, and Dilbert principle, where management is performed by the least competent (in order to limit the amount of damage, according to Scott Adams).
What I have discovered is that, in France, the hard bench work is done by the bottom of the hierarchy, and the probability to obtain a promotion is related to the ability to obey the boss. So, the most creative and independent scientists are discarded, realizing a Dilbert configuration, but with a different explanation. At the next step, top management is more likely to be done by people performing intense self-promotion, i.e. the least able to manage a community of people, realizing again a Dilbert configuration.
Now for the Ponzi scheme: the pyramidal nature of these hierarchies makes that either people are led to loose their job in an intense and stupid competition, or that there are more and more « science workers ». A mix between the two is occurring, with competition ruining science ethics, and the number of science workers following an unsustainable growth.
I did not put any link but I am sure you can use wikipedia.
Those who publish in PNAS cannot be mavericks. Medical Hypotheses is the appropriate channel.
"oh sh!t, we all hung over
Hutz was here on layover"
-from an arabic folk song
Those who publish in PNAS cannot be mavericks.
I am shocked, shocked to find sarcasm going on at RI!
I was thinking of Williamson's "Larval Transfer" paper. And Frederickson's epigenetic-expressions-of-positive-thinking exercise in statistical malpractice. But the examples kept multiplying.
More seriously, I think that Paul Davies is wrong and that he has also made an error in referring to Haeckel. However, I am more sympathetic to Davies than to Myers. By showing this picture from the Bible, Myers does not even realize that he provides the strongest argument for an "atavistic" model of cancer. How can cancer develop so many distinct features, if not as a consequence of a toolkit acquired during evolution? I have argued elsewhere that genetic instability can be the consequence of cell cycle deregulation and the cause of the acquisition of other traits as the consequence of SOMATIC evolution, and therefore cancer is primarily a disease of cell multiplication. However, presented as Myers has done, I would be surprised if Davies is not comforted in his idea of cancer being the consequence of features acquired during the evolution of multicellular organisms.
However, I am more sympathetic to Davies than to Myers.
Do not taunt the Orac.
My understanding is that many of the 'tools' cancer uses are already present in the human genome, particularly those associated with embryonic development; angiogenesis and metastasis for example. There are presumably also various old deactivated genes that mutations in a tumor could resurrect as atavisms, just as birds still have the genes to produce teeth, but to frame this as the key element in cancer seems a bit of a stretch to me.
just as birds still have the genes to produce teeth
I dunno if mutations that cause "tiny bumps and protuberances" in the beaks of chicken embryos are a good example of supposedly deactivated but still-viable genes. Unless viewed through the eye of wistful thinking, those beak malformations do not look a lot like the teeth of actual ancestral birds.
Absolutely untrue, at least until recently.
For example, Linus Pauling published some of his early highly dubious work claiming that vitamin C cures cancer in PNAS. That's because, until quite recently, if you were a member of the NAS you could publish pretty much anything you wanted to in PNAS. You could also recommend pretty much anything to be published there.
It was because of the abuse of PNAS as a dumping ground for whatever scraps of research or Brave Maverick Ideas that NAS members wanted published that a few years ago the journal tightened up its peer review process and clamped down on such shenanigans—not entirely adequately, IMHO.
OK, perhaps some of the genes to produce teeth. My point is there are plenty of genes and pseudogenes in DNA for cancer to co-opt and re-purpose.
So basically, for you, a maverick is somebody who is wrong. In this case a maverick cannot have a good idea. This sounds like a circular reasoning.
For me, a maverick is somebody unknown to the NAS, who comes with an original idea, and who can be right or wrong, but still, progress in science comes from new ideas.
I agree, but the challenge is to find how many INDEPENDENT events are required for explaining the cancer phenotype. Gene instability may explain the accelerated occurrence of other features, but it would be good if we know what is the relation between the various features.
I already told you, Dr. Corcos, what you need to do if you have some definite theses about what is wrong with the grant-giving process. As a researcher you should not need me to tell you.
Write a book. Get together with some like-minded researchers and produce detailed case studies and comparative sociological analyses.
Your vague impressions are unconvincing. That's all you've given here. Your quick and continued resort to personal abuse makes them still the less convincing.
zebra, I would like people to read me, sure, but I'd like my writing to be worthy of reading. While I view my impressions and opinions as generally sound, I don't insist on the correctness of my sociological impressions to the point that anyone who disagrees - especially when those impressions are not fully fleshed out - is an idiot who just doesn't get that. My evidence is never strong enough; it would be stupid to behave that way.
By extension, it is stupid for you to behave that way. I'm interested in what other people have to say. Why aren't you? I'm not very strongly convinced by my own amateur sociological generalizations, because that would be stupid. And when you act like your vague sociological theses are theorems that somehow only you can understand, you are behaving stupidly.
No, son, you're exhibiting what the Catholics call the sin of pride. I'm not a believer, but I join the Catholics in understanding this pernicious moral character flaw. You don't seem like you're an idiot - why do you act like one?
Concerning the grant-giving process, I don't have much to add to what had been said before by Peter Lawrence and Leo Szilard, which I refer to in my post #36.
Although I agree with them, for me this is not the main cause of trouble, which I describe in more details in the post #106 as the Dilbert pyramid. Shortly, if every biomedical scientist needs younger ones (PhDs and post-doc) to do his work, this leads to a Ponzi scheme. If you are not convinced that there is an exponential growth of scientists, type cancer on pubmed and you will see the trend. But the number of papers is only one indication, since there are more and more authors on one paper.
The system now collapses by different ways: there is not enough money to do research and competition is fierce; obtaining grants becomes more important than answering important questions; bright students are driven away from research due to the absence of positions; short term successes are preferred and benefits related to scientific misconduct exceed risks; and finally as in Dilbert's principle top positions are more likely to be held by the least-competent people.
The solution to this problem is to separate training from production, by limiting PhD numbers and hiring technicians. Again, not doing that is preferring short-term to long-term goals.
PS. Where did I resort to "personal abuse"?
RJ writes (#118),
Write a book. Get together with some like-minded researchers and produce detailed case studies and comparative sociological analyses.
The times are a changin - Bob Dylan
Having played in the books and patents game, I've found that blogging is a very effective, and satisfying, communication medium for instant feedback.
The Scienceblog Respectful-Insolence is a wonderful place to discuss whatever "floats your boat" but beware - do not taunt the Orac (reference #111).
@ Daniel Corcos,
It would be unorthodox if you were placed in Orac's penalty box (i.e., instant moderation) but it would be immensely entertaining.
You've abused those that disagree with you form the first post, and in most of the posts. If you cannot see this it's not my job to educate you.
You posit this 'Dilbert pyramid' of yours by your vague subjective impressions. I'm not convinced. Not good enough. As I said before, I think there is a critique to be made of excessive conservatism in science, but you are not willing to put it in cogent form. Goodbye, Dr. Corcos.
Daniel Corcos says (#119),
The solution to this problem is to separate training from production, by limiting PhD numbers and hiring technicians.
Having worked with intellectual property for many years, my experience with education level and innovation is as follows:
PhD = incremental improvements (i.e., me-too products and methods). More often a people manager; and
<PhD = surprisingly innovative and sometimes pioneering. A people manager want-to-be.
With respect to American for-profit and non-profit companies, the best money is in managing people not innovation.
Well, there's always crowd-funding like the poor ME/cfs researchers are forced into doing.
Or you could hook up with Google like Dr. Thomas R. Insel did. Although I don't know if he is a maverick or not. Seems as if he will continue the same path he's been on for years.
"You’ve abused those that disagree with you form the first post"
Too much insolence, or not respectful enough?
I think it's time to dig out the Sagan quote:
"They laughed at Einstein, they laughed at the Wright Brothers. But they also laughed at Bozo the Clown."
Is there a source for that? Here's John Sladek from 1974 (in The New Apocrypha):
Not a Roth scholar, that was like 23 years ago and I thought I was edgy and smart. Now I know I'm edgy and smart, but I also know I'm not a Roth scholar.
No, son, you’re exhibiting what the Catholics call the sin of pride. I’m not a believer, but I join the Catholics in understanding this pernicious moral character flaw. You don’t seem like you’re an idiot – why do you act like one?
I'm so turned on right now.
The times are a changin – Bob Dylan
With respect to American for-profit and non-profit companies, the best money is in managing people not innovation.
Wrong, it's not an either/or, and you cynicism is unattractive.
The version of "You Ain't Goin' Nowhere" from Greatest Hits Volume 2 seems to be much more apropos.
W—quote has Broca's Brain as attestation for the full version.
So I stumbled in here with some sort of post about smuggling vodka to the former Kafiristan, which is sort of where I'm from, but now I have no idea where it's gone.
I really do need to pick one of my old languages up, though.
W—quote has Broca’s Brain as attestation for the full version.
Ah, so Sagan's original has Columbus, Fulton and the Wright brothers; it has mutated a bit over the years.
What matters is that my man Sladek has precedence.
some sort of post about smuggling vodka to the former Kafiristan,</i
That has my full attention already.
@ DF and HDB
I never laughed at Bozo the clown.
Now, nobody likes a good laugh more than I do, except perhaps my wife and some of her friends.
Come to think of it, most people like a good laugh more than I do, but that is beside the point.
Daniel Corcos says (#137),
I never laughed at Bozo the clown.
I never laughed at Ronald McDonald.
@DF and HDB,
Who are your least favorite clowns?
Wow... the minions have us talking about clowns now, they are very clever with distractions.
Are you trying to ruin my jokes?
herr doktor bimler,
That was presumably a reference to the song 'They All Laughed', which refers to all three.
Daniel Corcos says (#139),
Are you trying to ruin my jokes?
Sometimes laughter is the best medicine.
Oops, a dangerous statement here at RI so let me rephrase:
My apology, your humor is much appreciated.
You with your vapidities dare to accuse the others of making distractions
I have to agree with DC on the "hire technicians not PhD's", but then I'm the guy who says we need fewer "doctors" and more practitioners trained to the needed tasks.
The ponzi scheme description is really not unique to this field though-- the academy has been that for a long time. A better parallel is the whole privatizing education movement (K12) in the USA, because you can teach for two years and then become the principal of your very own charter school. At higher levels, there is at least some residual inertia in creating new institutions.
@RJ: Still no clue what you are talking about. If it's something I said, what is it?
That was presumably a reference to the song ‘They All Laughed’, which refers to all three.
I have learned something new, thanks!
Me too. That song was used in a UK TV commercial a few years ago, which is why I'm familiar with it (it's not to my usual musical tastes) , but I hadn't directly connected it to Sagan's quote, having been distracted by Bozo the Clown.
This is I hope my last thing to say to zebra, the non-contributing time sink. Just look at your recent comment. You think it's appropriate, based on limited anecdotal evidence and vague impressions, to refer to academia as a Ponzi scheme. Where's your evidence? Isolated anecdotal reports won't do. That's all you have.
You have a excessively loving opinion for your plausible but unexamined hypotheses, and then abuse others who try to point this out to you. You don't know as much as you think you do, because no-one knows as much as you think you do.
Because your claims serially have no real evidence, you get upset when people point out that you don't know these things. You're a twerp, full of excessive self-regard. You don't have to consider what I'm saying; only if you wish to be a serious, worthwhile person.
I've just read Devita's book. Although I don't agree completely with what he says, he makes some very strong points about the regulatory burden imposed by the FDA on cancer drug development:
(1) Single patient IND applications are excessively burdensome. These were instituted into law in 1987, ironically to allow access of HIV patients to drugs, but also added cancer patients. This was more burdensome for cancer patients because of the much larger types of cancer and numbers of drugs so IND applications could not be simply copied.
(2) The NCI and FDA had a system prior to 1987 where experimental drugs were classified by the NCI into A, B, and C classes. Class C drugs were accessible to oncologists for individual patients and provided free of charge by pharma. According to Devita, pharma was willing to do this because it was seen as a stepping stone to ultimate FDA approval.
(3) FDA regulators rely overly on survival as the endpoint for approval of drugs. This delays approval of drugs that obviously cause excellent responses (for example, PLX4032/vemurafenib) and force 100's of millions of dollars to be invested in demonstrating a survival benefit, when that money could have been invested in overcoming resistance. Another example was that the FDA held up cisplatin approval for 3 years because a regulator insisted on testing as a single agent and demonstrating survival.
(4) Related to #3, the FDA likely would not have approved/allowed research with MOPP which cured Hodgkin's because, although each single agent caused tumor regressions (and thus destroyed a large proportion of cancer cells temporarily), this is generally insufficient to prolong survival. Thus it is possible/likely that combining agents that do not prolong survival individually could possibly cure cancer.
(5) The FDA is approving drugs too narrowly and is effectively controlling the research on regulatory grounds without really considering the science. For example, drugs are being developed/approved only in narrow setting (specific subtype of non-small cell lung cancer, or only after failure of taxanes and doxorubicin in breast cancer), when there is no biological reason these drugs wouldn't work in other settings (all types of non-small cell lung cancer, or any line of chemotherapy).
I find these arguments compelling and his vision for drug regulation would clearly limit the Burzynski's of the world from peddling their snake oil.
Devita tells a story of a former trainee, RSK Young (nicknamed in the NCI as 'Risky Young') who, though promising at NCI, is inclined away from science toward regulation and law who becomes a key player at the FDA. According to Devita, at one meeting Dr. Young shakes the FDA regulation guidebook and shouts 'this is the bible.' At another juncture, Young uses his lunch break to testify as a concerned citizen against approval of cisplatin because single-agent survival benefit wasn't demonstrated, although it had already done stuff like this. Wow.
DeVita is behind the times on this issue. The FDA is already addressing this problem, as I've pointed out in my multiple posts on right-to-try laws. Single patient INDs should soon be much easier to obtain. Even despite that, it's actually rare for the FDA to turn down a single patient IND. So I don't think DeVita is really raising much of a point there that isn't already being addressed.
I have a big problem with this complaint: Frequently, response or a surrogate endpoint like disease-free survival doesn't correlate with overall survival. See: Avastin in breast cancer, which produced good PFS when combined with standard-of-care chemo. Also, the FDA does allow provisional expedited approval of drugs based on an improvement in PFS, but that has to be followed up with studies verifying an improvement in OS. Again, see: Avastin in breast cancer, which, despite succeeding at prolonging PFS, failed this second test.
This, too, is being addressed already through the FDA's personalized/precision medicine initiative.
I get the feeling from reading your characterization of DeVita's complaints that he is a bit behind the times, as I suspected.
You still haven't offered anything substantive beyond your characterizations-- why is your unsupported claim any more valid than mine?
You do realize that this thread is just a conversation, and you are not a qualified peer reviewer for some publication, right?
Lots of people express their views and only engage further if someone strongly disagrees. Which, contrary to your bizarre claims about my behavior, so far hasn't happened but once.
Regarding #1, I've never used a single patient IND. I hope it gets easier, but Devita's description of the pre-1987 process where the NCI scientists were gatekeepers sounds much better. Devita seems to like right-to-try laws, but I don't like them. I'll see what the FDA comes up with.
Regarding #3, I don't think Devita is arguing for approving on PFS, but on response rate. i.e. when you definitely know that a drug can kill a significant tumor fraction it should be approved. Prolonged survival (or even cure) could be achieved through combinations.
Regarding #5, I'm not sure what the FDA is doing through precision medicine, but it's damn hard to enroll a patient in some of these registration trials. One trial we ran was almost impossible to enroll in because (for regulatory not scientific reasons), the eligibility was (a) only one prior line of therapy and (b) resistance to both anthracycline and a taxane. After a year of negotiation with the FDA and multiple amendments (submitted to hundreds of IRBs at each site), this stricture was modestly loosened.
And speaking of precision medicine, it is classic government process that while this is being pushed, the common rule is being modified by HHS to make that very research more difficult, more expensive, and require more regulatory oversight.
The regulatory burden is too high. Sometimes I'm fed up and just want to do basic research. Blast it.
It is not clear that response rate would give better information as compared to PFS. The issue is side-effects (including long-term side effects) vs. tumor response. Personalized therapies will require simultaneous combination therapy targeted to distinct pathways in order to prevent drug resistance, but the risk is drug interaction and then unpredictable side effects.