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Learning from Animals: Evolutionary Medicine with a Twist

In 2005, cardiologist Barbara Natterson-Horowitz was called to the zoo to examine a non-human patient, an emperor tamarin with heart failure.  She was surprised when the veterinarian told her not to look her patient in the eyes because eye contact could cause capture myopathy. In this condition, when an animal is captured, restrained, and feels threatened, there is a catastrophic surge of adrenaline that damages muscle tissues and can kill. It was described decades ago, but medical doctors don’t read the veterinary literature. It wasn’t until the early 2000s that American doctors began to recognize a similar phenomenon in human patients, takotsubo or stress-induced cardiomyopathy.

She began to wonder whether animals got other human diseases. She quickly learned that they did. Jaguars get breast cancer and may carry the same BRCA1 gene that plagues Ashkenazi Jewish women, rhinos get leukemia, penguins get melanoma, gorillas die from ruptured aortas, and koalas are in the midst of an epidemic of sexually transmitted chlamydia.  Wild dragonflies infected with parasites become obese and develop a form of metabolic syndrome. Pretty much every human disorder occurs in animals too.

With the help of writer Kathryn Bowers, she distilled her findings into a book: Zoobiquity: What Animals Can Teach Us About Health and the Science of Healing.  It’s a good read: informative, well argued, spiced with intriguing trivia, and more entertaining than a trip to the zoo.

If veterinarians and human doctors collaborated on a routine basis, what might they learn from each other? A doctor working on a novel therapy for melanoma asked a veterinarian “Do dogs get melanoma?” He had promising results in a mouse model with induced cancers, but needed to study the treatment in animals with spontaneously occurring tumors, intact immune systems, and a longer life span. Dogs do indeed get melanoma, and in the ensuing collaboration a vaccine was developed that dramatically prolonged their survival rates.  Human applications are being investigated.

What about sex? The oldest penis on record belonged to a crustacean that lived 425 millions years ago. Animal studies shed light on human erectile dysfunction and premature ejaculation. Animals routinely engage in homosexual couplings, oral and anal sex, interspecies sex, and masturbation.

Human drug addicts are not alone: animals seek and respond to chemical rewards in the lab and in the wild. Human emotions evolved to influence behavior and fitness. Everything from gambling to compulsive shopping can be viewed in terms of beneficial animal activities like foraging and hunting. SIDS might be related to a response in young animals called “fear” or “alarm” bradycardia. Lessons learned from reducing the weight of obese pets and zoo animals might inform human dieting efforts. Humans engage in self-mutilating behaviors like cutting; self-injury also occurs in animals and probably represents grooming gone awry.  Humans develop anorexia nervosa; eating disorders also occur in animals when stress and fear inhibit feeding.

The pathogens from animal diseases can adapt to humans, as in the case of HIV. A sexually transmitted disease in animals can become a human disease where infection is by ingestion, like brucellosis. Pathogens can affect host behavior. Advanced syphilis may promote the spread of spirochetes by compromising judgment and increasing sexual appetites along with egomania, impulsiveness and disinhibition; Al Capone, Napoleon and Idi Amin were syphilitics and the author speculates that their disease may have facilitated their power grabs.

Teenage risk-taking behavior is paralleled in young animals undergoing the transition to adult life. Bullying, gangs, peer oppression, and self-destructive behavior are not limited to humans. Understanding animal behavior could shed light on possible ways to influence human behavior.

An epidemic of dead crows in New York City coincided with the human outbreak of a mosquito-borne disease identified by the CDC as St. Louis encephalitis. An astute veterinarian realized that the bird deaths were not compatible with that diagnosis. He was ignored at first, but eventually the CDC admitted that it was wrong, and the true diagnosis was a virus not previously recognized in the US: West Nile virus. In the wake of this misdiagnosis, agencies are calling for the routine involvement of veterinarians in evaluating public health crises.

Although Carl Zimmer has pointed out some misconceptions  about evolution in her book, Dr. Natterson-Horowitz makes a good argument for evolutionary medicine with a twist. Rather than speculating about our ancestors, we can study our living animal relatives for clues about human diseases and behaviors. Rather than speculating about how traits like homosexuality evolved, we can study how they affect survival in animals today.

There is only one medicine and one biology. Terms like “alternative medicine” or “veterinary medicine” create  false dichotomies.  There is much to be gained from a regular collaboration between people doctors and animal doctors.

 

 

 

Posted in: Book & movie reviews, Evolution, Veterinary medicine

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78 thoughts on “Learning from Animals: Evolutionary Medicine with a Twist

  1. Ben Kavoussi says:

    Great article. I am sure that some rudimentary knowledge about health and disease might have come from observing, experimenting and dissecting domesticated animals. Galen is reported to have worked on live pigs.

    It is very true that terms like “alternative” or “veterinary” medicine create false dichotomies.

  2. If I remember correctly, I believe takotsubo’s, as mentioned in the story, is the pathophys of “dying of a broken heart.”

  3. carassius says:

    I hate to have my first post here to be so cynical. But, as a veterinarian, I feel I really need to say, “Duh!” I’m a bit older than the typical recent graduate (I’ve only been a veterinarian for about three years). My veterinary curriculum included a fair bit of ‘One Medicine’ philosophy wherever possible. I guess many people don’t realize how many diseases share commonalities regardless of species and that we can also learn from what traits, symptoms, and processes aren’t shared. Zoonotic diseases alone are enough to fill a nice sized textbook. I would hope that human medicine would look to include some of this philosophy also.

  4. Simon says:

    I too am a veterinarian currently doing a PhD in human infectious diseases to try and bridge the gap- vets tend to be very on the ball about “One Health” in a way I don’t see as often in doctors. I guess it’s because here, in the UK, vets take an oath to protect human health first and animal health second, so so-called veterinary public health is a big deal.
    And while I agree with the motives behind your “false dichotomy” label my hackles are somewhat raised by you comparing alternative medicine to veterinary medicine! Veterinary medicine is a subset of medicine that is clearly defined by our target market- just like paediatrics or geriatric medicine. Alternative medicine is defined as medicine that isn’t medicine.

  5. windriven says:

    @Simon

    I think you misinterpreted Dr. Hall’s comment about veterinary medicine. I read it quite the opposite of the way you seem to have taken it.

  6. Janet Camp says:

    I’ve always been confused about the mission of veterinary medicine. Small animal vets, indeed, seem to function as doctors for pets. Some large animal vets mostly take care of horses that are pets or “athletes”. But some vets mostly (or additionally?) take care of “food animals”. They prescribe and administer vaccines, antibiotics, etc., that keep animals healthy (or at least prevent them dying before slaughter) for the sole purpose of surviving in confinement until slaughtered for human consumption.

    I eat meat occasionally, so this isn’t about a PETA-attitude or anything. I am simply wondering how large animal vets see their mission to those animals in contrast to vets who are pretty much doctors to household pets.

    Does veterinary medicine (theoretically anyway) exist to benefit humans or for the benefit of other animals? I’ve often wondered about the term itself. To examine (vet) animals–but to what purpose? To benefit humans or for the animals themselves? There is overlap, I’m sure, but I guess I’m interested in a vet’s primary purpose when it comes to food animals.

  7. Harriet Hall says:

    @Simon,

    “comparing alternative medicine to veterinary medicine”

    I did no such thing! Please lower your hackles.
    I thought I made it quite clear that veterinary medicine is a subset of real medicine, and anyone familiar with my writings knows that I’ve said repeatedly that there is no such thing as alternative medicine, most recently here: http://www.sciencebasedmedicine.org/index.php/fairy-tale-science-and-placebo-medicine/

    The two have nothing in common except that the way some people think about the terminology creates a false dichotomy.

  8. DVMKurmes says:

    @Janet Camp; In general, the answer to your question (Do veterinarians exist to benefit animals or humans) is both. When a small animal veterinarian vaccinates a pet against Rabies, it protects both the animal and the humans exposed to it. You do have a point though that industrialized food animal production raises some serious questions about both the animals welfare and the benefit to humans. Is cheap meat really worth creating drug resistant strains of bacteria? Should we really push dairy cattle to their physiological limits for cheap milk? I’m not sure that organized veterinary medicine has adequately addressed these type of questions.
    The “veterinarian’s oath” does answer your question in a general sense, that protecting animal health and welfare should benefit society. It is interesting that we have eliminated things like bovine tuberculosis and brucellosis, while we may be inadvertantly increasing exposure to other pathogens.

  9. ConspicuousCarl says:

    Animals get the same diseases, and they sometimes get the same scam treatments. Some idiot at my job recently declared that her dog was cured by an acupuncturist. Freaks.

  10. jas23 says:

    Dr. Tracey McNamara was the New York veterinarian to whom you referred: *She* is a female.

  11. Jacob V says:

    My wife and I are horse owners and my wife is very involved with the local back country trail riding groups. From our discussions with other horse owners and riders it appears that perhaps at least half of the horse owners we know use and accept a number of vet/scam practices. The most common appear to be animal chiropractic and acupuncture as well the use of many expensive supplements that have no evidence of effectiveness. The one I’m still waiting for is the “Equine Power Band!” for the prevention of lameness, joint strain and hoof problems!! And of course the saddest part of all of this is that many of the people offering VET/SCAM are equine veterinarians themselves.

  12. Ray Greek MD says:

    There is no doubt that humans and animals share traits, some of which are medically relevant. But multiple head to head studies have revealed that animal models are not predictive modalities for human response to drugs and disease. Yet, this is the very reason the FDA and EPA require animal testing and the justification the NIH proffers for funding animal models. Very few scientists are bold enough to propose invasive studies of, say monkeys, in order to merely expand the knowledge base (basic research). There is almost always a claim that such research will cure humans of a dreaded disease.

    Zoobiquity was also discussed in various science journals with more or less the same accolades. Considering the high-impact ratings of these journals and the emphasis on science and prior possibility emphasized on this site, these uncritical reviews are unfortunate. For a scientific critique of animal models be they occupants of zoos or labs or the homes of humans, I refer you to an article, titled Animal models and conserved processes, that we just published in the journal Theoretical Biology and Medical Modelling – available at http://www.tbiomed.com/content/9/1/40/abstract. (The provisional pdf is available but it appears some of the figures are missing. The article can be understood without them and the final version will be up in the next month or so.) In this article, we discuss what can and cannot be learned from animal models even when they share conserved processes per Kirschner and Gerhardt. I am sure the reader will enjoy Zoobiquity more than our article but such is the difference between an in-depth examination of evolved complex systems and a superficial examination of a complicated science subject in a feel-good puff piece.

    If anyone connected with Science-Based Medicine, for example staff, contributors, or readers, would like to pursue this topic in the form of a point-counterpoint in the literature, please contact me at drraygreek@gmail.com. In the past, editors of MedLine-indexed journals have asked me to participate in such a debate but they, and I, were unable to find anyone to oppose my position. I find this a sad reflection on the character of physician-scientists who unhesitatingly and reflexively support the use of animal models. It is also a sad commentary on the medical wing of the skeptic community. (See http://www.opposingviews.com/i/society/animal-rights/orac-debates for more.) If Dr Hall is correct (http://www.sciencebasedmedicine.org/index.php/poor-scientific-arguments-in-the-service-of-animal-rights-activism/) and I cherry pick the literature and am an activist not a scientist, then this would be an excellent opportunity to expose my perfidy. Surely a peer-reviewed journal would offer a level playing field. But if science-based responses to my position remain lacking, as opposed to straw man arguments and ad hominems, which are in ample supply, this is indeed a poor commentary on people professing to be skeptics.
    Ray Greek

  13. Calli Arcale says:

    “koalas are in the midst of an epidemic”

    From what I’ve read, it might be more appropriate to call it a pandemic. It is now to the point where it represents a serious threat to the survival of the species. Of course, the species is also suffering quite a lot of other challenges right now, the biggest being massive habitat loss and the crippling fragmentation of what’s left — with much of that fragmented habitat being riddled with busy streets. Syphilis and vehicle collisions are now major causes of koala mortality, and the population is collapsing.

    Janet Camp:

    I have a relative who is a large animal veterinarian. He’s in Iowa, so most of his patients are dairy cows and beef cattle. His job is to keep the animals healthy, for the animals’ sake, for the sake of the wider population of cattle (infectious disease is a problem), for the sake of the animals’ owners (who could go bankrupt if they all get sick), and for the sake of the consumers who will ultimately purchase products made from the animals. It is not merely a matter of seeing that they survive until slaughter, or of maximizing milk production. It’s more complicated than that, and even farmers raising steers for beef generally care about their animals, and not just in a financial sense. The fact that it will be slaughtered doesn’t make its life any more pointless than if it were a wild animal destined to someday be eaten by a pack of wolves. Everything that lives dies; if the intervening time can be made more comfortable, that is worthwhile regardless of how short the life is destined to become.

    Some decisions are different with food animals, to be sure. If the animal has a disease that renders it unfit for human consumption, then the owner must decide whether to keep it as a pet or euthanize it now and send it to the rendering plant. If the animal has a disease or injury where it is still fit to eat but treatment will change that, again, the owner must decide. It’s not practical to keep all such animals as pets; it can be a difficult decision, but a food animal is more likely to be put down than a pet is. For obvious reasons. Not because people don’t care, exactly, or because they are worthless, but simply because you can’t save them all, and if you’re going to be in this business, sooner or later you will be confronted with that reality.

  14. Harriet Hall says:

    @Ray Greek,

    “If Dr Hall is correct (http://www.sciencebasedmedicine.org/index.php/poor-scientific-arguments-in-the-service-of-animal-rights-activism/) and I cherry pick the literature and am an activist not a scientist, ”

    Apparently you have confused me with Dr. Gorski. I haven’t said anything about you, and this post is about learning from the biology that is common to humans and animals. I didn’t claim that all animal models are predictive of human responses and neither I nor Zoobiquity addressed animal rights or the use of animals in drug testing.

    Your comment is a blatant attempt to hijack the discussion and use it for your personal agenda. I don’t appreciate it.

  15. Ray Greek MD says:

    Tsk tsk Dr Hall. The link is to an article by Dr Gorski, yes. But scroll down and you will find a comment by one Harriet Hall. Reproduced below:

    # Harriet Hall on 03 Mar 2008 at 2:16 pm
    AFMA/EFMA/JFMA is analogous to the cholesterol skeptics (THINCS) organization in that they both start with a conviction, cherry pick the literature to find support for that conviction, and try to substitute activism for the scientific process.
    Their own words betray them: “we seek to demonstrate.” That’s what pseudoscience does. Real science doesn’t seek to demonstrate, it asks questions.

    It certainly appears that I honestly represented what you wrote. Science is about looking deeper and not assuming that, say, your commenter got it wrong just because the link does not immediately scream your name. For those unfamiliar with the issue, I am president of AFMA, the 501c3 referred to by Dr Hall. The other groups are sister organizations in other countries. Dr Hall, please don’t pretend you did know the relationship especially after I co-authored a controversial article that appeared in Skeptic, the magazine you contribute to and have commented in numerous venues where you also write and or comment.

    As to the book and your own position on animal models as predictive modalities, as I stated, the book was reviewed and the authors interviewed in numerous places. Based on these interviews and what the book actually says, the authors do indeed think animal models are predictive and they most certainly do discuss drug development. Moreover, based on your comments above and based on the statement “I didn’t claim that all animal models are predictive” it certainly appears you hold the position that animal models can be predictive modalities for human response to drugs and disease. Such is even implied in your response to me – “all animal models.”

    As to the “all animal models” part of the statement, that is a dodge as animal models as a class are either predictive modalities or they aren’t (they either have a high enough positive and negative predictive values to qualify as predictive or they don’t). And if you want to break it down into individual species, again one cannot say that the species predicted whatever, toxicity, the pathophysiology of HIV/AIDS, efficacy of a drug and so forth based on single examples. THAT is cherry picking and the fallacy of insufficient statistics to boot! Studies examining individual species as well as the animal model per se have shown that animal models are not predictive unless one also wants to allow astrology and fortunetelling as “predictive” modalities. The positive and negative predictive values (PPV and NPV) of all are about the same. A good example is the use of nonhuman primates (NHPs) to test for teratogenicity. Most NHPs responded to thalidomide as humans did, but when tested for other chemicals, some of which were known human teratogens, the PPV and NPV were around 0.5. (See http://www6.miami.edu/ethics/jpsl/archives/all/TestingThalidomide.html for more.)

    Moreover, please do not pull out the old canard that “prediction” really means what one generates from a hypothesis. You have the same education I do and know the difference between PPV/NPV and predictions made from hypotheses. No one claims that the predictions generated from hypotheses are predictive modalities like CT scans, exercise tolerance tests, blood tests, and animal models.

    Nice straw man about animal rights, however. Where exactly in my “hijacking attempt” did I mention that again? Oh, and as to the hijacking, the title of the book and the topic of your blog was Zoobiquity: What Animals Can Teach Us About Health and the Science of Healing. That is pretty straightforward! Drug development per se was not mentioned in the blog but it is in the book and what pray tell does one want to learn from these animals? Targets for drugs and pathophysiology of disease! Both fall squarely under the rubric of using animals as predictive models. If you want to deny that animal models are predictive and instead say that they are only used as heuristics or for basic science, then you had plenty of space to do so and by not doing so it is not exactly a leap of logic to go from “What Animals Can Teach Us About Health and the Science of Healing” to a comment regarding animals used as predictive models. They are merely different ways of saying the same thing. Moreover, the book supports this view.

    Next time Dr Hall, actually read the link before commenting, avoid fallacies like straw man arguments, and knock off the feigned righteous indignation. The use of animal models to teach us about health and healing is no more my personal agenda than it is yours. It is a controversial topic that is science-based and effects medicine, just like the book and just like various topics covered on this website. My comments were on the exact topic you wrote about! You just don’t want the challenge of having to prove that animal models are successfully used exactly how scientists claim they are used – to predict human response to drugs and disease. You want to present a fluff piece and avoid the real issue. You want to support the status quo and hope that it is correct because you clearly have not researched it. I find THAT offensive Dr Hall and I don’t appreciate your reluctance, or perhaps inability, to defend your position. It is one thing to be a shruggie but another altogether to advocate for a position based on ignorance. Maybe you should go back to discussing CAM and homeopathy. The intellectual challenge there is, shall we say, not great.

  16. Harriet Hall says:

    Ray Greek wants to start a fight. I will not indulge him. I will simply point out that his views are indeed “controversial.” See: http://speakingofresearch.com/tag/ray-greek/

  17. Ray Greek MD says:

    Ah yes, the old ad hominem. When without facts, attack character. Dr Hall has provided a link to an advocacy site, how nice. I wonder if the site will reflect reality or advocate for a position regardless of facts? Below are links to articles I have co-authored that explain my position, all of which are in peer-reviewed journals and most are indexed on PubMed. None are advocacy groups, but maybe some will find peer-reviewed journals almost as credible as the special interest group linked to by Dr Hall.

    Are animal models predictive for humans?
    http://www.peh-med.com/content/pdf/1747-5341-4-2.pdf

    Is the use of sentient animals in basic research justifiable?
    http://www.peh-med.com/content/pdf/1747-5341-5-14.pdf

    The History and Implications of Testing Thalidomide on Animals http://www6.miami.edu/ethics/jpsl/archives/all/TestingThalidomide.html

    Complex systems, evolution, and animal models
    http://www.afma-curedisease.org/pdf/2011_Studies_in_article_Preprint_version.pdf

    An analysis of the Bateson Review of research using nonhuman primates
    http://www.dovepress.com/an-analysis-of-the-bateson-review-of-research-using-nonhuman-primates-peer-reviewed-article-MB

    Animal models in an age of personalized medicine
    http://www.futuremedicine.com/doi/full/10.2217/pme.11.89

    The Nuremberg Code subverts human health and safety by requiring animal modeling
    http://www.biomedcentral.com/content/pdf/1472-6939-13-16.pdf

    Animal models and conserved processes
    http://www.tbiomed.com/content/9/1/40/abstract

    I am perfectly happy to encourage everyone to read the material and decide for themselves. But accusing me a wanting a fight is like accusing everyone that blogs on this site of wanting a fight with CAM people. I think what we all want is a fair presentation of the arguments so we can refute the fallacies and outright errors in order to decrease suffering specifically and promote science-based skepticism in general. Debating issues accomplishes this. To quote the executive editor of this site: “During a live debate we can see how the candidates think and what they know and believe about scientific issues. They can also be pushed on specific points if they give evasive answers.” That is what happens in live debates as well as back and forth debates in the scientific literature. And this is exactly what Dr Hall has refused to do. She is not alone in her position.

    Can anyone imagine the science-based medicine community or skeptic community in general refusing to debate creationists or CAM? Especially under the conditions I have stipulated (see http://www.opposingviews.com/i/society/animal-rights/orac-debates) or in the scientific literature? Such refusals raise serious questions about the claims being made and about the character of the people involved. If I am right and animal models are not predictive modalities but are being passed off as such, then great harm is happening (to humans) as a result and nobody is doing anything about it. If I am wrong, in light of all the articles that at least some qualified people took seriously enough to publish, then someone should refute my position and be done with me. There is an ethical imperative either way. Let the record show that at least two physician-bloggers on Science-Based Medicine have ignored this imperative.

  18. ConspicuousCarl says:

    Ray Greek MD on 12 Sep 2012 at 2:10 am

    Moreover, based on your comments above and based on the statement “I didn’t claim that all animal models are predictive” it certainly appears you hold the position that animal models can be predictive modalities for human response to drugs and disease. Such is even implied in your response to me – “all animal models.”

    You appear not to understand the concept of “some, but not all”.

    animal models as a class are either predictive modalities or they aren’t

    This is just an obtuse statement. “Crash test dummies are either predictive modalities as a class or they are not, you can’t cherry pick and say they are good for car accidents but bad for stab wounds.”

  19. DugganSC says:

    I think it’s pretty obvious that not all animal results translate to humans (even among the same species, there’s variation. There’s a cute Urban Legend about the differences of cats and dogs at http://www.snopes.com/critters/mishaps/drugcat.asp ), but correspondingly, there isn’t a 100% match between individual humans, so I fail to see the argument. There’s some basic biology that we all hold in common. There’s some which varies by species. There’s some that varies by individuals of the species (the fellow who’s fasting and runs 5 miles a day will likely absorb the medicine differently than the guy carrying 50 lbs of excess weight due to seldom entering the state of sobriety). Ultimately, we try to learn what we can from the results we see.

    Darn it, now I have MC Frontalot’s “Origin of the Species” running through my head…

  20. DugganSC says:

    The above should refer to similar species when speaking of cats and dogs. *facepalm* Need more coffee…

  21. BillyJoe says:

    “…and vehicle collisions are now major causes of koala mortality”

    There is a saying (I don’t know if it is true) that an animal found in road kill is not going extinct.
    In other words, if they are being killed on the roads, there must be plenty of them about.

  22. Calli Arcale says:

    BillyJoe — I don’t want to derail the thread too much, but you could also say that about tuna. If tuna is commonly found on menus it must not be going extinct. And yet several species are actually in very serious danger due to overfishing; their current prevalence on the road doesn’t mean they will still be so abundant on the road in ten years. It depends. There are still enough koalas to supply roads with corpses; one cannot assume this will remain the case, and population surveys suggest an alarming decline in the past decade. (Also, roadkilled koala wasn’t as common in the past as it is now. This is not merely due to an increase in automobile traffic; they didn’t used to cross roads so often, since they could just go from treetop to treetop without touching the ground.)

    Regarding the validity of animal models, they may not be perfect, but they are among the best models we have. As the old adage goes, all models are wrong; some are useful. That animal models are imperfect is no justification for abandoning them. You don’t quit science just because it’s hard. The key is to understand (and constantly seek to improve the understanding) the strengths and weaknesses of a specific model in a specific application.

  23. Ray Greek MD says:

    I apologize for the formatting. I need to learn how to do this.

    # ConspicuousCarl on 12 Sep 2012 at 5:23 am
    You appear not to understand the concept of “some, but not all”.

    “animal models as a class are either predictive modalities or they aren’t”

    This is just an obtuse statement. “Crash test dummies are either predictive modalities as a class or they are not, you can’t cherry pick and say they are good for car accidents but bad for stab wounds.”

    The difference between some and all in this context is two-fold. First, Dr Hall clearly holds that at least some animal models are predictive models as she differentiated between the two. That was/is the issue in contention: are any animal models predictive for humans in terms of drug and disease response. Whether she thinks 1% or 100% are predictive is irrelevant. I maintain that none are. But wait, it gets worse! Second, most people make this exact argument and what they mean is either that animal model A did not predict human response for outcome P but did predict outcome Q and therefore was predictive for one but not the other. This reveals an ignorance of the fundamentals of how positive predictive value (PPV) and negative predictive value (NPV) are derived, as single instances of agreement are immaterial in terms of the predictive value of the model.

    An example. Assume a med school has 200 faculty and staff. It has an NCAA Division I football team hence there is a general interest in the sport. All 200 people wager on which team will be the ultimate #1 at the end of the season. It is highly probable that at least one will pick the winner. So can we say that the med school always predicts the winner? No, this would be a fallacy (conversion fallacy, I think) as if we are to assess the ability of the med school faculty as a whole to pick the winner, they would get one pick (not up to 200). So, picking an animal model that gave the same outcome as humans and saying that “the animal model” predicted the outcome is fallacious. What about individual species? Thalidomide causes more or less the same limb defects in rabbits as humans. Does this make “the animal model” predictive? No, see above. Does it make the rabbit model predictive? No. In order for the rabbit model to be a predictive modality for teratogens one would need to produce data on numerous chemicals that could be plugged into the formula for PPV and NPV. Unless rabbits can be shown to have a history of replicating human response, they are not predictive modalities despite an occasional correct answer. Showing a shared response in retrospect does qualify as predictive and is not helpful in terms of keeping bad drugs off the market; an oft-cited reason for animal modeling.

    The use of PPV and NPV is not controversial despite being misunderstood by many. See essentially any of my above-mentioned articles for more on this.

    So, when I stated that the models either are or are not predictive I mean exactly that. Model A either is or is not a predictive modality for outcome P. In the crash test dummies example you are using, you list two general ways crash test dummies can be used and suggest one way could be predictive for human outcomes while the other is not. This is true. Likewise animal model A could be tested for predictive ability for human outcome P and fail, but qualify as predictive for human outcome Q. I agree that such is logically possible. My statement/position is much broader! I am saying that there are reasons, in the form of evolutionary biology and complexity science, to strongly suggest that animal models per se, be it the practice of animal modeling or the use of individual species/strains, will never qualify as predictive modalities in terms of human response to drugs and disease. Granted, animal species A will occasionally exhibit the same outcome to a perturbation such as a drug or disease as a subset of humans. This occurs with about the frequency to be expected from chance alone. That is not a predictive modality. It does not have, and indeed will never have, a high enough PPV or NPV.

    The article I provided links to explain all this in depth. I do not expect everyone to digest all this from comments on a blog. If for no other reason, I am not capable of explaining it in such short space. But also because this is a trans-disciplinary inquiry. An understanding of the fundamentals, and maybe more, of evolutionary biology, complexity science, philosophy of science, and the empirical evidence is required. In my experience (I have no systematic reviews :) ), very few people have this background. However, despite their ignorance they are happy to weigh in in issue. Kirschner said in a lecture in 2010 that: “In 1940 no one knew how phenotypic variation was generated, but nevertheless people had strong views on its nature.” (Available at
    http://www.youtube.com/watch?v=lbcpLPcXw9M) Having strong views is fine. I have presented mine. Refusing to defend those views, especially when the issue involves life and death (and when one fails to comprehend even the fundamentals of the topic), is not. How would the bloggers and commenters here react if manufacturer of woo Y were presented with evidence that the product did not work but refused to debate the issue? What about if they were condescending and mocked the people using the real science? Which side is arguing science here and which is burying its head in the sand?

  24. Ray Greek MD says:

    # DugganSCon 12 Sep 2012 at 7:27 am
    I think it’s pretty obvious that not all animal results translate to humans (even among the same species, there’s variation. There’s a cute Urban Legend about the differences of cats and dogs at http://www.snopes.com/critters/mishaps/drugcat.asp ), but correspondingly, there isn’t a 100% match between individual humans, so I fail to see the argument.

    Thank you. We present this same theme in our personalized medicine article at
    http://www.futuremedicine.com/doi/full/10.2217/pme.11.89

    Allow me to outline the argument and why it is important. The FDA and EPA require animal models for testing new chemicals for safety. The FDA requires efficacy testing as well. This, despite the fact that many studies have shown there is no correlation between species in terms of their response to chemicals/drugs. Drugs that are safe and efficacious in some humans kill some animals and vice versa. (See our conserved process article
    http://www.tbiomed.com/content/9/1/40/abstract
    for more on where animal models can be used. We don’t claim they are worthless!) The Pharma pipeline is drying up in part because a very high percentage of drugs fail to pass the irrelevant animal tests. The Pharma literature is full of scientists opining that if the animal model paradigm is not stopped, drug development will halt due to financial concerns. Even the National Cancer Institute has said that society has lost cures for cancer because of animal model. So, one reason to have this discussion is that the paradigm is not cost neutral; it is damaging human health.

    A second reason to have this discussion is that roughly 50% of NIH grants fund animal models of human disease. Most of these grant applications link outcomes in the model to outcomes in human patients promising in essence that if they cure cancer in their mouse model, society will have a cure to some form of human cancer. This is fraud and results in more promising research modalities NOT receiving the funding they need. Ever try to get a grant for observational human research? The pie is finite. Fund X and Y will not get funded.

    The premise all of the above is based on is the ability of animal models to be predictive modalities for human response to drugs and disease. This is stated many times in many places in regulatory literature as well as the science literature. If this premise is false, as I claim it is, then the whole process should be abandoned because of both direct and indirect harm to humans. Leave the animal-ethics issue off the table. Using animal models to predict human response to drugs and disease harms humans under the guise of helping them and thus should be abandoned. If scientists want to do basic research with animals, let them apply for a grant that says as much. I have no scientific issues with using animals in basic research. But that is not what is happening.

    Our books and articles flesh all this out. I am also happy to go into more depth in a point-counter point or live debate. But that does not look promising.

  25. David Gorski says:
    animal models as a class are either predictive modalities or they aren’t

    This is just an obtuse statement. “Crash test dummies are either predictive modalities as a class or they are not, you can’t cherry pick and say they are good for car accidents but bad for stab wounds.”

    Indeed. It’s ridiculous to lump all animal models into a “class.” There are too many such animals used for too many purposes. Some animal models are more reliable than others. Such generalizations reveal more about the good Dr. Greek than and his ideology-inspired lack of nuance than they reveal about the actual utility of animal models.

    More importantly, Dr. Greek appears to be arguing that we should abandon current tools in favor of tools that don’t exist yet, such as computer models cell culture models that predict human response better than animal models and, of course, the various “-omics” of personalized medicine, which have not as yet been validated as reliable predictors of human responses. Why does he do this? Because he’s an animal rights activist and believes that animal research is inherently wrong. (If I’m mistaken about this, then perhaps Dr. Greek would describe for us when animal research, in his opinion, morally justifiable.) His arguments, particularly his article on personalized medicine, are not persuasive to someone who’s actually doing biomedical research and knows the issues involved in personalized medicine.

  26. David Gorski says:

    I have no scientific issues with using animals in basic research.

    That’s nice. Define basic research as opposed to translational research that uses animals. (Hint: Translational research involves a lot more than “predicting human responses,” and basic research is, I suspect, a much broader definition that Dr. Greek appreciates.)

  27. Ray Greek MD says:

    Again, sorry about the formatting. Can someone please direct me to a url that explains how you guys make your posts look like they do? Thanks!

    # Calli Arcaleon 12 Sep 2012 at 1:50 pm
    Regarding the validity of animal models, they may not be perfect, but they are among the best models we have. As the old adage goes, all models are wrong; some are useful. That animal models are imperfect is no justification for abandoning them. You don’t quit science just because it’s hard. The key is to understand (and constantly seek to improve the understanding) the strengths and weaknesses of a specific model in a specific application.

    No one is suggesting that animal models be abandoned because they are not perfect. I have explained many times where animal models can be used and why they can be used for such endeavors and not others. For example, see
    http://www.tbiomed.com/content/9/1/40/abstract

    http://www.peh-med.com/content/pdf/1747-5341-5-14.pdf
    or either of the books
    Animal Models in Light of Evolution
    FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed

    The issue is whether the model fulfills its function. If it does, then fine but if it does not AND there is a cost to using it, for example people are harmed or money could be used for research that has a history of better results in terms of applicability, then the modality should be abandoned or fixed. I maintain that it cannot be fixed because animals and humans are evolved complex systems that are differently complex. This is not a controversial position. My conclusion is unpopular but I am not sure that even it is controversial outside a small circle. I have attended evolutionary biology conferences and complexity conferences where I had a booth and sat there and explained my position to the scientists that stopped by. Almost all asked why I was doing this, as my facts were solid, from their perspective as evolutionary biologist or mathematicians involved in complexity and hence uncontroversial. So what was my poiont? When I explained that animal models are really being used exactly as I explained, as predictive models, they were shocked. Now granted, they weren’t concerned enough to speak out publically or join the AFMA board but they assured me that they were on my side and wished me success. Shruggies!

    Selling animal models as predictive modalities when they are really tools for basic research is fraud when done in order to obtain government funding and just plain wrong from any perspective. If the claim is that model X does Y and model X does not do Y then the reasons for supporting Y dissolve. To say that model X is the best we have is disingenuous if model X is supposed to predict the pathophysiology of HIV and does not. That is like saying since we have no real cure for pancreas cancer we should use acupuncture because its the best we have. Medicine gave up trephination for treating schizophrenia long ago despite not having any really good treatments. The issue not “what else is available?”, the issue is does the modality do what is claimed. Getting bad information is worse than no information. many treatments have gone to market based almost entirely on animal data and poor clinical trials.

    This is not an ethereal argument. Over 90% of drugs fail after animal testing and this drives up the cost of other drugs as well as keeping otherwise good drugs from patients. Read the Pharma literature: Nature Reviews Drug Discovery, Drug Discovery Today, Drug Discovery World, Drug Discovery & Development. All will have articles saying point blank that animal models are not predictive and are a big part of the drug development problem facing Pharma. People are dying because of this! Drug targets are identified in animal models that go on to fail in clinical trials. Toxicity is assessed in animal models and go-no go decisions are made based on the results. Animal models are not being used to generate hypotheses; they are used as predictive modalities. And scientists acknowledge this.

    Again, if scientists want to use animal models in basic research, an example of where animal models are NOT being used as predictive modalities, then they need to say so and stop claiming there is direct line between results in mice and in humans. Even the animal model community admits they increase their odds of grant approval by linking basic research to human disease. I am not guilty of the Nirvana fallacy here. I am merely holding scientists to the claims they themselves have made.

  28. DugganSC says:

    Hmm… although I think he makes a good point above that the current medicine model where results must be shown in animals before humans fight screen out drugs where they fail to find an animal that it works on. That said, you need something before you skip to human trials. ^_^ But, of course, that’s not germane to the actual topic of the article, which is trying to note health traits in animals that correspond to humans that we can make use of.

  29. David Gorski says:

    One notes that Dr. Greek still can’t seem to define basic research compared to translational research that uses animals as a means of studying scientific principles that could be translated to human health. This is not a trivial question, and Dr. Greek seems completely incapable of addressing it in a serious manner. In reality, the use of animals as “predictive models” that Dr. Greek keeps harping on is not nearly as large a slice of the pie when it comes to using animal models as he seems to think it is. I’ve pointed this out before elsewhere.

    One also notes that Dr. Greek has not answered the question of whether he has moral objections to the use of animals in basic science research.

  30. David Gorski says:

    That said, you need something before you skip to human trials. ^_^

    Indeed. Whenever Dr. Greek is asked what he would substitute for the use of animal models in biomedical research, his answer always seems to be cell culture models, computer models, and, most recently, the sorts of “omics” approaches that scientists are currently trying to turn into “personalized” medicine. Of course, cell culture models are certainly not more reliable than animal models in terms of predictions, and computer models are entirely dependent upon understanding the system well enough to program them to be robust enough to be useful. Similarly, the various “omics” models are now producing a flood of data that we don’t yet know how to analyze in a sufficiently detailed, robust, and predictive fashion to use them to predict human drug responses, much less human toxicities and responses that aren’t obvious. Certainly they are not sufficiently “predictive” yet by Dr. Greek’s own criteria!

    But, of course, that’s not germane to the actual topic of the article, which is trying to note health traits in animals that correspond to humans that we can make use of.

    True that. Harriet wasn’t really discussing animal research at all! Certainly, she was not discussing the kind of “predictive animal models” that Dr. Greek is so obsessed with attacking. Yet more evidence of his single-mindedness. He turns the comments after a fun little post by Harriet into a battleground in which he attacks his bête noire. That reminds me. By engaging him in my last few posts, contributed to the derailing of the discussion. Sorry about that, Harriet. I’ll try to be good from now on. :-)

  31. Ray Greek MD says:

    Again, apologizes for the formatting and the typos I am sure are in here somewhere.

    # David Gorskion 12 Sep 2012 at 3:53 pm
    “animal models as a class are either predictive modalities or they aren’t”
    Indeed. It’s ridiculous to lump all animal models into a “class.”

    That is exactly the opposite of what I am doing. There are scientists whose job it is to make just such classifications. For example,
    Handbook of Laboratory Animal Science Second Edition Animal Models. Volume II. 2nd edition. Edited by Hau J, van Hoosier Jr GK. Boca Rotan: CRC Press; 2003

    The above could be easily expanded. David, are you really saying that classifying models is unimportant? Or are you making a straw man by claiming that my position is that ALL animal models fall into the same class? I have gone to great lengths to explain that animal models can be classified into numerous categories and that most are scientifically viable. But when the very people using the model make the claim that the model in a predictive modality then it should be judged accordingly.

    # David Gorskion 12 Sep 2012 at 3:53 pm
    There are too many such animals used for too many purposes. Some animal models are more reliable than others. Such generalizations reveal more about the good Dr. Greek than and his ideology-inspired lack of nuance than they reveal about the actual utility of animal models.

    That is completely false. The above-mentioned books and scientists use more or less the same classification scheme that I do. They break down the categories into subcategories, which is useful for their purposes but rarely for mine, but all of them acknowledge that animals as predictive models for human response to drugs and disease is a real category and the most common use of animal models. Nuance is accomplished by categorizing models and separating uses. Your comment really does not make sense. You are smarter than that.

    # David Gorskion 12 Sep 2012 at 3:53 pm
    More importantly, Dr. Greek appears to be arguing that we should abandon current tools in favor of tools that don’t exist yet, such as computer models cell culture models that predict human response better than animal models and, of course, the various “-omics” of personalized medicine, which have not as yet been validated as reliable predictors of human responses.

    Thanks but I don’t need you help in explaining my position. I have stated many times that the above list does not predict human response. Read my blog or books or anything else I have written. Actually some of the above does already exist. There are personalized medicine tests that are used daily and as I understand the field of breast cancer, genotyping is routine. But the above is NOT what I am saying should replace animal tests. I am saying we don’t drill holes into the skulls of schizophrenics just because we do not as of yet have a cure for schizophrenia. The “that’s all we have argument” does not carry any weight when what we have does not work and has risks. Animal models are not predictive modalities. Period. If they are being used as such then that is bad science and should cease. I favor funding your above list as those modalities at least have a chance of someday predicting human response while using one evolved complex system to predict perturbations for another at the level of organization relevant to drugs and disease response does not have a chance.

    # David Gorskion 12 Sep 2012 at 3:53 pm
    Why does he do this? Because he’s an animal rights activist and believes that animal research is inherently wrong.

    I am philosophically an animal rightist, but where exactly are all those activities that would qualify me as an activist? I oppose abortion after 32 weeks and support it before that time period. Does that make me an abortion activist? I oppose genital mutilation does that make me an activist on that issue? I think not. Any “activism” I did on animal rights I stopped as soon as we formed AFMA (1999) so people that were not animal rightists would feel comfortable joining us in a scientific examination of animal models regardless of the ethics. In a small way this has been a success. The board had had and currently does have scientists with no animal concerns whatsoever. I will grant you can attempt to make me into an animal rights activist—you will fail, but at least you can make a prima facie case—but try that with Niall Shanks or Mark Rice.

    But lets assume I am an absolute animal rights terrorist, out there doing terrorist things every night between midnight and 4AM. OK. What does that imply for my position? As I think I might have read on this site and one like it, claims have to stand or fall on their own merit. I might be Hitler, but even if I am, even Adolph was right when he said 2 + 2 = 4. If I wanted to make philosophical arguments I would not be doing what I am doing. Moreover, why am I acknowledging that most categories of animal use are scientifically viable? If my strategy is to sway people to a scientifically invalid way of thinking, why grant anything at all to the opposition?

    # David Gorskion 12 Sep 2012 at 3:53 pm
    (If I’m mistaken about this, then perhaps Dr. Greek would describe for us when animal research, in his opinion, morally justifiable.)

    I am an animal rightist. The only morally justifiable use for sentient animals, IMO, is the same as it is when assessing human-based research. This is not earthshattering news! But look at where this gets you. I am openly saying that research that I find morally repugnant is scientifically valid. Mmmmm. Hard to paint me as a having an agenda, engaging in motivated reasoning, or being irrational in general when I acknowledge what could be called facts against interest. If I wanted to fool people into thinking animal-based research was bad, why not tell a big lie as opposed to what you consider a smaller lie: that animal models just fail as predictive models. As I understand it, people are more likely to believe a big lie than small one. UNLESS, gosh darn it, I am presenting the science as I see it and no one is addressing said science but is instead attacking my philosophy. Is this an example of poisoning the well?

    # David Gorskion 12 Sep 2012 at 3:53 pm
    His arguments, particularly his article on personalized medicine, are not persuasive to someone who’s actually doing biomedical research and knows the issues involved in personalized medicine.

    Well David that is what debates are for. I find most people that are involved in personalized medicine think exactly how I think on this issue and the value of personalized medicine in general. Last time I checked, there were around 50 drugs that now have gene-based labeling. THAT is personalized medicine and lives are being saved as a result. But since you think am wrong on all this lets take it to a forum amenable to a thorough analysis not a “my friends agree with me and your friends agree with you” level of discussion. Let do science!

    # David Gorski on 12 Sep 2012 at 4:07 pm
    I have no scientific issues with using animals in basic research.
    That’s nice. Define basic research as opposed to translational research that uses animals. (Hint: Translational research involves a lot more than “predicting human responses,” and basic research is, I suspect, a much broader definition that Dr. Greek appreciates.)

    I wrote an article on the topic. See
    http://www.peh-med.com/content/pdf/1747-5341-5-14.pdf
    But again, if you have issues and want to show where I am wrong on all this I have certainly given you plenty of invitations to do so. At some point you either have to prove your position, disprove mine, or accept the fact that you are damaging your reputation by committing the same mistakes and fallacies you criticize in the CAM community and elsewhere. I have set up a better than level playing field for you
    http://www.opposingviews.com/i/society/animal-rights/orac-debates
    and yet you still opine without consequences in these blogs. Even your supporters have issues with this. All I ask is that we have moderators and a panel of mutually acceptable experts to call the fallacies and so forth. You should be thrilled with this! Experts from the relevant field to correct misrepresentations and mistakes. I think this debate would expose how little you know about complexity science and evolution and how often you use fallacies in your arguments on this issue. So far, I see no evidence that I am wrong as you are certainly not jumping at the opportunity put me in my place.

  32. Ray Greek MD says:

    The usual disclaimers re typos and formatting

    # DugganSCon 12 Sep 2012 at 4:23 pm
    Hmm… although I think he makes a good point above that the current medicine model where results must be shown in animals before humans fight screen out drugs where they fail to find an animal that it works on. That said, you need something before you skip to human trials. ^_^

    Why? Would you test new drugs on car engines? Of course not. There is no prior plausibility for thinking such would be useful. But with animal testing we have prior plausibility against it from evolutionary biology and complexity science AND we have empirical evidence that decisively proves it does not work. However, microdosing as currently performed could be expanded to be used in all aspects of drug testing.

    # DugganSCon 12 Sep 2012 at 4:23 pm
    But, of course, that’s not germane to the actual topic of the article, which is trying to note health traits in animals that correspond to humans that we can make use of.

    I disagree. The basis for observing animals, the basis for zoobiquity, is prediction. If anyone wants to claim that the point of the book and article was that animals can be used as heuristics*—an aid in learning or discovering new things—then by all means do so. But that is not what I got out of the book or the various article where the book and or concept was discussed. Furthermore, if all agree that animal models are not predictive modalities and they are just used as heuristics then say so. But since almost no one will say that then the prediction issue is relevant.

    *The following a definition of heuristic. Sorry I forgot where it came from. Some online dictionary.
    1. serving to indicate or point out; stimulating interest as a means of furthering investigation.
    2. encouraging a person to learn, discover, understand, or solve problems on his or her own, as by experimenting, evaluating possible answers or solutions, or by trial and error: a heuristic teaching method.
    3. of, pertaining to, or based on experimentation, evaluation, or trial-and-error methods.

    # David Gorskion 12 Sep 2012 at 4:54 pm
    One notes that Dr. Greek still can’t seem to define basic research compared to translational research that uses animals as a means of studying scientific principles that could be translated to human health. This is not a trivial question, and Dr. Greek seems completely incapable of addressing it in a serious manner. In reality, the use of animals as “predictive models” that Dr. Greek keeps harping on is not nearly as large a slice of the pie when it comes to using animal models as he seems to think it is. I’ve pointed this out before elsewhere.
    One also notes that Dr. Greek has not answered the question of whether he has moral objections to the use of animals in basic science research.

    Sorry guys I did not take typing classess in high school and can only go so fast without even more typos than usual. I am addressing the posts sequentially.

    Now, however, I am going to eat lunch and will address more comments afterward.

  33. Scott says:

    In order to produce the nice quotes, you can use

    [blockquote]text you want to quote here[/blockquote]

    But replace the [ with less-than, and the ] with greater-than, symbols.

  34. Ray Greek MD says:

    Thank you Scott for the tutorial. We will see if I do it right.

    Some of the following questions were addressed in a comment that is “awaiting moderation.” I seem to get that about every other comment. I will try to add some details and hope the original comment is posted before this one.

    # David Gorski on 12 Sep 2012 at 4:54 pm
    One notes that Dr. Greek still can’t seem to define basic research compared to translational research that uses animals as a means of studying scientific principles that could be translated to human health. This is not a trivial question, and Dr. Greek seems completely incapable of addressing it in a serious manner.

    Oh, I don’t know, David. Writing a 12,000+ word article that was published in a PubMed-indexed journal might be seen by some as addressing it in a serious manner.
    http://www.peh-med.com/content/pdf/1747-5341-5-14.pdf
    I could cut and paste the contents but you could also read the thing before expressing an opinion as to what I think.

    This is what debates are for. I lay out my position. You actually read what I have written and address the specifics. Then I reply, then you, and so forth. It is unreasonable to ask me to reproduce every article I have written so you don’t have to copy the url onto your browser OR so you can then continue to ignore what I have said just as you are currently ignoring what I have previously written. Even when it is specifically on the point you are concerned about.

    For the record, I define basic research the same way it is has traditionally been defined by the people doing such research. I think we cite 5 or so examples in the above-mentioned article. The following is from Linden. Journal of Biomedical Discovery and Collaboration 2008, 3:3 doi:10.1186/1747-5333-3-3
    http://www.j-biomed-discovery.com/content/3/1/3
    and is more or less how we defined basic research in the article.

    The Frascati definition (1963) for basic research is: “Experimental or theoretical work undertaken primarily to acquire new knowledge of phenomena and observable facts without any particular application or use in view. It is usually undertaken by scientists who may set their own agenda and to a large extent organise their own work [4].” This definition is similar to three interpretations of blue skies research: “Excellent curiosity-driven science, free from boundaries [5].” “Innovative and creative research that might lead to outcomes unimagined at the outset [6].” “Addresses fundamental, curiosity driven science [7].”
    4. Organisation for Economic Cooperation and Development (OECD): The Measurement of Scientific and Technical activities: Proposed Standard Practice for Surveys of Research and Development Paris OECD; 1963.
    5. National Environment Research Council: Blue Skies Review Final Report London: NERC; 2007.
    6. Braben DW: Pioneering Research – a risk worth taking New Jersey: John Wiley and Sons; 2004:174.
    7. House of Commons – Select Committee on Science and Technology: Blue Skies Research House of Commons Tenth Report; Sessions 2006–2007 HC470:39.

    The above are pretty standard definitions for basic research. Most people that take issue with the above are people trying to have their cake and eat it too. They want the grant money that accompanies calling their research applied or predictive or translational but also want to justify failure by switching and then calling their research basic research.

    In terms of translational research, I wrote the following in my blog in January. Available at
    http://www.opposingviews.com/i/society/animal-rights/chimeric-monkeys-and-translational-research

    Translational medicine is certainly a buzzword in medical research these days. Briefly, most basic research has not translated into treatments for patients. This is the case despite the fact that a vast majority of NIH grants go to basic research and must be considered in light of the fact that over 50% of NIH grants go to animal-based basic research.(Greek and Greek 2010) Moreover, the last two decades have seen a huge increase in NIH funding and hence in grant money to basic researchers. Therefore, people in politics and elsewhere are attempting to change this obvious waste of resources, but the way they are going about it will be self-defeating. My concern with NCATS is that it will turn into exactly what the rest of the NIH currently is, namely an organization that funds animal-based research over all other options. Much of what is currently being called translational research is simply animal-based basic research that has been relabeled as translational research. The reason for this is simple. The medical university system in the US depends on the money from animal-based research. Universities receive billions of dollars in overhead from animal-based projects, which they can use for whatever they wish. They form a vast lobby that demands the gravy train continue. Pictures of cute monkeys help. Translational research works for research from the basic sciences of physics and chemistry where sound scientific ideas and principles merely need to be developed. It does not work for developing perpetual motions machines or extrapolating drug and disease response between species.

    We can parse the definitions, it appears a lot people have trouble differentiating translational from basic research when animal models are used, but regardless, at some point an animal model is either claimed to be predictive or it is not. If it is claimed to be a predictive modality, it should be judged on that basis. But if it was claimed to be predictive for the grant then later claimed to be merely basic research, that is fraud as well as dishonest.

    # David Gorskion 12 Sep 2012 at 4:59 pm
    That said, you need something before you skip to human trials. ^_^
    Indeed. Whenever Dr. Greek is asked what he would substitute for the use of animal models in biomedical research, his answer always seems to be cell culture models, computer models, and, most recently, the sorts of “omics” approaches that scientists are currently trying to turn into “personalized” medicine.

    You know, I cannot recall ever saying that. Such is the stock and trade of animal rightist activists but not me. I just don’t think I have ever said the above could replace animals. Two reasons for that: 1. My argument is exactly the opposite from the 3Rs and replacement argument outlined by you. I am saying that animal models are not predictive and hence should be abandoned for such purposes. 2. I have pointed out numerous times, usually criticizing animal activists, that cell cultures, in silico etc are not in fact predictive for ADMET etc, for the most part. I have said that basic research could be performed with all of the above but that is different from what you have attributed to me.

    In the post awaiting moderation I think I mention microdosing. I will say again that in terms of predictive technologies making more thorough use of microdosing is how I would test drugs currently. Right now, microdosing is just used for PK but the concept could be used for PD. This is irrelevant to the issue of animal models however, as using a Ouija board to predict human response to drugs should not be considered even if absolutely nothing else is available simply because the Ouija board cannot predict human response. Neither can animal models.

    David Gorski on 12 Sep 2012 at 4:59 pm
    Of course, cell culture models are certainly not more reliable than animal models in terms of predictions, and computer models are entirely dependent upon understanding the system well enough to program them to be robust enough to be useful.

    And this is THE problem. It does not matter if cell culture etc ect are not predictive for human response. If whatever technology or bioassay does not have a high PPV and NPV, then it is not predictive. Period. There is no such thing as “nonpredictive modality A being a little more predictive than non-predictive modality B.” The modality either qualifies as predictive or does not. It does not have to have a PPV of 1.0 but, for medical science, it does need something in 0.9 neighborhood. David, you know this. A CT scan has a PPV of 1.0 for pneumothorax. I don’t know what the PPV would for using, say, chest percussion or visual asymmetry of the chest to diagnose a pneumo but I bet both would be very low. Which is why neither is used even in extreme circumstances. The decision to place a needle in a patient’s chest to relieve a possible tension pneumo is probably going to be made on the basis of acute distress and history more than anything else. (I am out of my field with the pneumo example and clearly in David’s, so if he says the example is wrong, I defer to him, but hope the concept is still understood.)

    The point is I have never claimed that predictive modalities exist to replace animals that are unsuccessfully as predictive models. You David, have attributed that to me in some of your previous posts and I have explained what I wrote above in reply. Something is not sinking in which is why I say you are spouting off without consequence in these blogs and am criticizing you for refusing to bring nonsense like that to a live debate or in the journals. Being proven wrong in front of your peers in a live debate is different from ignoring such proofs in the blogosphere. As quoted previously: “During a live debate we can see how the candidates think and what they know and believe about scientific issues. They can also be pushed on specific points if they give evasive answers.” Nonsense does not usually survive a crowed amphitheater full of smart, educated people.

    David Gorski on 12 Sep 2012 at 4:59 pm
    Similarly, the various “omics” models are now producing a flood of data that we don’t yet know how to analyze in a sufficiently detailed, robust, and predictive fashion to use them to predict human drug responses, much less human toxicities and responses that aren’t obvious. Certainly they are not sufficiently “predictive” yet by Dr. Greek’s own criteria!

    As I stated, some are and some are not but again my argument does not rest on finding replacements to a modality that does not work in the fist place. I am not offering a cure for cancer, I am saying animal models cannot predict efficacy or safety for testing cures and hence should not be so used. Just as, even though we have no cure for schizophrenia, I oppose performing trephination on those patients. For someone who harps on prior plausibility, this does not seem to be making a dent.

    David Gorski on 12 Sep 2012 at 4:59 pm
    But, of course, that’s not germane to the actual topic of the article, which is trying to note health traits in animals that correspond to humans that we can make use of.
    True that. Harriet wasn’t really discussing animal research at all! Certainly, she was not discussing the kind of “predictive animal models” that Dr. Greek is so obsessed with attacking. Yet more evidence of his single-mindedness. He turns the comments after a fun little post by Harriet into a battleground in which he attacks his bête noire. That reminds me. By engaging him in my last few posts, contributed to the derailing of the discussion. Sorry about that, Harriet. I’ll try to be good from now on.

    If you still do not see the connection between the two, and indeed what the book and concept of zoobiquity actual claim, then I either I have made my points inadequately or you have failed to understand them. Either way, you still have not addressed my position and in addition you have misrepresented it. That would not fly in a live debate or in peer reviewed journals. I doubt there will be such consequences here.

    On my computer it appears the post related to this one is still in limbo. That one should be read before this one but I am sure everyone can deal with it.

  35. lilady says:

    Tsk, Tsk, Tsk Dr. Greek: Are you that desperate to garner attention for your animal rights movement, that you have posted here numerous times…challenging bloggers to debate you?

    Odd, isn’t it, that none of the readers of Dr. Hall’s blog, have found anything that she has stated in her review of the book “Zoobiquity: What Animals Can Teach Us About Health and the Science of Healing”, that remotely resembles what you only *think* Dr. Hall stated.

    I really don’t mind your obvious and blatant thread derailing and the self-promotion of articles you have written, along with the links. That being stated, I do object to your vicious and unwarranted attacks of Dr. Hall.

    You really need to take some time away from your animal rights movement activities. IMHO, those activities have beclouded your ability to understand how medical doctors/veterinarians can share information about diseases and disorders that affect humans as well as animals.

    Now about West Nile Virus, which is a zoonotic disease that affects humans, birds and animals. Why don’t you Google “sentinel chickens” to see how they are used throughout the world to monitor the presence of the WNV in mosquito populations. Chickens, when used as “sentinels”, do not get ill or die from WNV encephalitis, but the presence of antibodies to WNV in their blood, enable public health officials to issue alerts and to determine if aerial or ground spraying is necessary How many human and animal lives have been saved, because of the testing of sentinel chickens for the presence of antibodies, Dr. Greek?

  36. David Gorski says:

    Oh, I don’t know, David. Writing a 12,000+ word article that was published in a PubMed-indexed journal might be seen by some as addressing it in a serious manner.

    Actually, I did read it, all 12,000+ painful words of it. I found it tendentious and lacking in understanding in how research is done “on the ground” in real research labs, particularly the understanding of how translational and basic research frequently blur together. As for the rest. If you don’t think that cell culture, “omics,” etc. are more reliable than animal research, tell me, are these your words?

    Anything that is humanbased is, ipso facto, going to be more reliable than anything animal-based. Examples include human embryonic stem cell research; epidemiological studies of patterns of human disease and their associations with environmental causes; in vitro research using human cells and tissues; the use of gene chips or microarrays to study patterns of gene expression in humans; clinical research; autopsies; mathematical and computer modeling; post-marketing drug surveillance; basic scientific research in the fields of biology, physics and chemistry; and technology-based research methods such as those using positron emission tomography, functional magnetic resonance imaging, and others; these are viable means for discovering truths about human disease and drugs.

    And this:

    If scientists are sincere about conducting medical research with the aim of benefiting humans, then they should immediately stop using animals as predictive models for human responses to drugs and disease. The NIH and other funding organizations should consider transferring the current funding that is going to animals as predictive models to human-based research that is consistent with the concept of personalized medicine. This would include developing predictive human-based ADMET and efficacy testing, studying diseases both in intact humans and in tissues obtained from humans, developing software to aid in these pursuits, and generally following the scientific principles that have been set forth for advancing the field of personalized medicine.

    Sure, you might not have said explicitly that cell culture, computer models, and the “omics” of personalized medicine are better than animal models, but in context your writings have certainly given the impression that that that’s what you think. Why not just own it? Until you do, I don’t see much point in sparring with you further. Sure, you come off as having a lot of book knowledge but not much practical knowledge that comes from actually doing research. (One notes that the first thing you do is to quote definitions, apparently being unable to synthesize a definition in your own words, something that virtually any translational scientist can do.) It all sounds very impressive; that is, unless you’re a scientist actually doing research.

  37. rokujolady says:

    Dr Greek: seriously, man. TL;DR.
    Also, as a computer programmer, I’m compelled to say that if you don’t know every detail of a complex system, you can’t simulate it with a computer. We test on animals because biology is wonderfully, ridiculously complicated. More than any computer system in existence, more than any rube goldberg machine. If computers were anywhere near being able to give the same amount of data as even a nematode we’d have to be worrying about a lot more than the welfare of real animals.
    Did you argue that? I don’t know because I was bored and skimming after the first few clauses.

  38. Harriet Hall says:

    It seems to me that Dr. Greek’s argument is refuted by the history of medicine. There are many lists of medical advances that depended on animal experimentation, for instance:

    http://cflegacy.research.umn.edu/iacuc/public_media/medadvances.cfm and
    http://speakingofresearch.com/facts/medical-benefits/

    Would insulin have been discovered and developed for human use without animal experimentation? How many lives have been saved by that alone? Weren’t dog experiments predictive of the human response to the drug insulin?

  39. lilady says:

    @ Dr.Hall:

    How about the “One Health Initiative” as featured here…

    http://speakingofresearch.com/facts/veterinary-benefits/

    “….Veterinary medicine and human medicine have followed similar developmental paths. This is true for a number of reasons, not the least of which is that veterinary patients and human patients may suffer from the same disease problems and benefit from the same diagnostic and therapeutic methods. Today’s medical scientists see no division between the disciplines of medicine and veterinary medicine, interpreting medical science as a continuum of form and function which while varying across species, is more alike than not. This philosophy is embodied in the current concept of the “One Health Initiative”, now a major focus of the American Veterinary Medical Association (AVMA) in concert with the American Medical Association (AMA), the Centers for Disease Control and the American Society of Tropical Medicine & Hygiene….”

  40. Ray Greek MD says:

    # David Gorski on 12 Sep 2012 at 9:12 pm
    If you don’t think that cell culture, “omics,” etc. are more reliable than animal research, tell me, are these your words?

    Oh, I definitely think human-based studies are more reliable than animal-based research. I have said so many times in very straightforward terms. And this is why you lose these encounters, David and why, after the dust settles and it all finally dawns on you, you refuse to play any more. I made a huge deal out of the fact that there are no modalities, be they animal or technological or whatever, that are predictive for human in terms of ADMET etc in drug development. I also made a huge deal out of the fact that in order to qualify as a predictive modality in medical science, PPVs and NPVs in the 0.9 neighborhood are required. So, in light of all that verbiage and after reading the basic science article, what do you do? You bait and switch. You replace my position on animal models and other models as predictive modalities with the reliability of models. HUGE difference!

    In science, and the humanities for that matter, words have meaning. A modality can have a higher PPV than another and still not qualify as predictive. But said modality would qualify as being more reliable. Not predictive, just more reliable. And the difference, while real, is inconsequential if one needs a predictive model. You sat though the same lectures I did when learning about PPV, sensitivity and so on in medical school. And you make decisions every day based on those factors. You know the difference. So when I discuss whether a modality qualifies as predictive and you change the subject to reliability, you know darn good and well what you are doing.

    Furthermore, you claim to value clear thinking and realize the importance of avoiding fallacies. Yet when pressed, and you are pressed because you have no evidence that animal models qualify as predictive modalities despite being so represented by scientists, or that my position is wrong, you resort to the same kinds of fallacies used by creationists and CAM practitioners. Shame on you David Gorski! For you this is just about money and ego but for some it is about life itself. If you had an argument to make, you would have made it long ago. Questioning my motives is not an argument. Bait and switch is not an argument. Ad hominems are not arguments and neither are straw man fallacies. Take away all that and your posts have been devoid of content. You have presented NOTHING that even begins to call my position into question.

    I realize that a lot of people probably have not followed this discussion, as it has gotten rather technical. But anyone that professes to use critical thinking skills can assess the difference between the reliability of a model and whether it qualifies as a predictive modality and judge whether you broke the rules. Forget the fact that you have not explained how one system that is differently complex from another can predict the outcomes to perturbations for the second complex system. Forget the fact that you have not explained why animal models should even be considered as possibly predictive in light of all the human differences to drugs and diseases that have resulted in our current emphasis on personalized medicine. And, ignore the fact that evolution has used many small differences to form new traits and that any one of these, when placed into the context of an intact complex system should raise serious doubts regarding inter-system extrapolation. No, ignore all that. When push came to shove you resorted to fallacies to try and save face. This is why I am willing to do just about anything to debate you but will always require a panel of experts to call you on the fallacies and support my explanation of complexity science and evolutionary biology since you clearly either do not appreciate these areas or pretend not to understand the significance because you know where it will lead.

    Take another look at all this, David. I am offering to allow experts that we both agree to, to be the final word on disagreements of fact in their area of expertise. I am offering to video my presentation so there will be no surprises and provide all the papers referenced so the experts can make sure I am not cherry picking or misrepresenting or whatever else you have accused me of. I will also give you the video so you can know exactly what my claims are and can prepare to address them specifically. I kind of doubt Barack is going to give Mitt such terms for their debates. Can’t Gish gallop in a video screened by the panel. Can’t quote out of context when the same panel has to approve the quote. Can’t avoid the issue when the panel asks for specifics. Nope. If anyone had this good of an offer regarding a position he was confident in he would take it in a heartbeat.

    And what is your issue with definitions? I quote people in order to avoid idiots debating me on such points. When I write, if I can find a point I want to make coming from another person’s writings I will use it rather than my own words every time. That way, if people like you want to question the fundamentals of science because they cause problems for your position, you have to accuse the expert I am quoting of being an animal rights activist or having motivated reasoning or of not being a real scientist or whatever. (Want to question my definition of basic research? In the article, we quoted Arthur Kornberg. Argue with him or other equally prestigious individuals who agree with his definition!) Saves me from debating every single point that even a high school biology student already understands.

    I see others are weighing in. I will try to address their comments shortly.

  41. Ray Greek MD says:

    # Harriet Hall on 12 Sep 2012 at 9:45 pm
    It seems to me that Dr. Greek’s argument is refuted by the history of medicine. There are many lists of medical advances that depended on animal experimentation, for instance:
    http://cflegacy.research.umn.edu/iacuc/public_media/medadvances.cfm and
    http://speakingofresearch.com/facts/medical-benefits/

    1. Those lists are compiled by people with a vested interest in the outcome of this discussion. One of the rules of critical thinking is to see if the source of the so-called facts could be using motivated reasoning or just plain lying. While a vested interest does not disqualify the position, such an interest means a skeptic should not just take the site’s word for the position. (For example, I have a vested interest in this issue because of my philosophical position on animal rights that might cloud my judgment and while this does invalidate my position it does necessitate that my position be proven, not merely relied on without scrutiny.)

    Would you, Dr Hall, use quotes from a homeopathy site without scrutinizing the claims? Probably should not do so from this site or any other site then. Moreover, this is exactly what I am talking about when I say that when it comes to animal-based research, skeptics forget everything they have ever learned and just follow along like sheep. Having been nerds most of our life, we skeptics are finally in a society of like-minded people so lets not rock the boat. Oh, it’s OK to debunk homeopathy and creationism because all the other skeptics are doing that. But lets not challenge any traditional and widely accepted, yet unproven, positions of the collective as that might get us in trouble. It seems that most skeptics believe that the worst thing that can happen to them is to be called a crank. That’s unfortunate as a lot of brilliant scientists were first called cranks.

    2. Lets assume many medical advances in history relied on animal models. So what? My position is not, contrary to Dr Gorski’s claim, that animal models are useless. My claim lies solely with prediction. Consider the following from our book Animal Models in Light of Evolution.

    The purpose of this book is to address the ability, or lack thereof, of animals to predict human response and to see what other roles they may have in research and testing. We will argue that claims concerning the great utility of animals as predictive models of human biomedical phenomena are unsupported by evidence and are compromised by both methodological issues and issues arising from basic biological theory. p24

    We are about to begin a detailed analysis of the roles played by animals in biomedical research. This is a good place to make clear, once again, what we are interested in, and what we are not. There can be no doubt whatsoever that if you wish to make discoveries about rats and mice you will be forced of methodological necessity to perform careful scientific studies of R. rattus and M. musculus respectively. In fact, in writing this book, we are the beneficiaries of the results of careful scientific studies of animals. There is no doubt that careful biological studies of rats and mice can help clarify the general contours of mammalian biology. Such studies can also play a valuable heuristic role by prompting new ways of thinking about human biological problems of interest. The issue we are concerned with is this: notwithstanding these cautions, are animal models predictive of human outcomes in, say, toxicology, drug discovery, and the study of the causes and cures of human diseases? p28

    This book is not intended to be a criticism of the use of animals in the context of basic biological research. There can be no doubt that careful studies of animals have prompted important hypotheses about basic biological principles, and there can be no doubt that studies of animals have contributed greatly to our scientific understanding of life, and there is little doubt that these studies will continue to illuminate these matters in the future (items (7) and (9) above). p30

    We remind the reader once again that the target of our criticism of animal-based research is restricted to the practice of predictive modeling. We do not dispute that there are legitimate roles for animal test subjects in other kinds of experimental investigation—for example basic biological research aimed at increasing the sum total of human knowledge. Animal experiments in the context of basic research may enrich our knowledge of specific phenomena in mice, and, if painting is permitted with a broad enough brush, they may help delineate some of the important contours of mammalian biology, from which lessons about the Eukaryotes and even life itself might be forthcoming. p351

    As I have stated once or twice just in this series of comments, animals can be used successfully in many scientific endeavors. The paper I referred to earlier, “Animal models and conserved processes,” that we just published in the journal Theoretical Biology and Medical Modelling – available at http://www.tbiomed.com/content/9/1/40/abstract
    outlines many areas where animals can be so used. But drugs and disease act the level of a complex system where very small differences can result in very diverse outcomes. The following are NOT examples of animals being used to predict human outcome to disease or drugs even though animals and humans have these properties in common.
    A. Discovery that the heart circulates blood in a circle.
    B. Discovery that the lungs oxygenate the blood.
    C. Discovery that insulin is produced in the pancreas and the pancreas is affected by diabetes.

    These are examples of basic biological properties that exist in many species and phyla. I could provide hundreds of more examples. This is one of the areas we have always acknowledged as productive for using animal models. The problem lies in going beyond this level of organization in a complex system. For example, the pancreas was linked to diabetes based on autopsies before animal models gave such evidence. Indeed, because Bernard used what appears to have sloppy technique in dissecting the liver and pancreas, he and others thought the liver was the problem in diabetes and a huge controversy ensued with some advocating for the liver and others for the pancreas. Even today, some animal models do not manifest insulin or glucose abnormalities in response to diabetes.

    # Harriet Hall on 12 Sep 2012 at 9:45 pm
    Would insulin have been discovered and developed for human use without animal experimentation? How many lives have been saved by that alone? Weren’t dog experiments predictive of the human response to the drug insulin?

    To begin, insulin was arguably discovered in humans but dogs were used to obtain a sample large enough to purify, at least somewhat, and administer back to dogs and humans. Even Banting and Best admitted they did not discover insulin but purified it enough to try on humans and other dogs. They stated that they had provided evidence from the lab to essentially confirm autopsy findings. Regardless, insulin derived from pigs and cattle at slaughter did treat diabetics for decades and many lives were saved. (A thorough examination of the history of diabetes and insulin is beyond the scope of my comments but is nevertheless very informative in terms of where animal models are and are not useful or predictive.)

    Again, this is immaterial to my position. The fact that animals can be used as bio-factories, for example for the production of insulin or monoclonal antibodies, is something we have acknowledged many times. Animals also respond to hypoxia as do humans (eventual death) and to many of the chemicals in the body: epinephrine, insulin etc. These are shared biological properties and many were discovered in animals. The hoxbox is another example and the conserved process paper discusses what can and what cannot be learned from animal models that share conserved processes or other traits.

    This topic, like science in general, is not amenable to “explanation by sound bite.” Try explaining organic chemistry in a 4000-word essay. You can’t! Try explaining evolution to a creationist using the “comments on a blog method.” Again, no joy! That is why most people do not yell at the organic teacher that he is wrong when they are just starting the class. First they actually learn the material and then, maybe, eventually, question some of the traditional answers, dig deeper, and find anomalies etc. Likewise, we have covered all this in numerous places and if anyone wanted to actually learn about our position, as opposed to just reflexively disagreeing with us because we question what is in reality dogma, they might find the question they are asking now to be a waste of time and unrelated to our position. For example, suggesting that insulin saves lives and that our position must therefore be false reveals profound inattention to what I have been writing, just plain obstinateness, or an ad populum or other appeal to emotion. First learn, then question.

    The prediction question is not about whether exsanguination is bad for mammals; it is about the pathophysiology of HIV, which differs considerably between humans and chimps, and the response to drug such as TGN1412. When response to drugs and disease is examined, animal models are seen to fail as predictive models. But animals still respond to many perturbations just as we humans. We both fall out of airplanes and hit the ground. That does not make animal models predictive modalities for coronary artery disease, AIDS, Vioxx, thalidomide, or even penicillin. When studying a complex system, understanding the level of examination is key.

    This is all from me for today. If there are no more comments, this will be my last post. Thanks to everyone who commented, even those with whom I disagree! And thanks to the editors for allowing the discussion!
    I will leave you with the following from Animal Models in Light of Evolution</italics (p358)

    Our position can be summarized as follows: Living complex systems belonging to different species, largely as a result of the operation of evolutionary mechanisms over long periods of time, manifest different responses to the same stimuli due to: (1) differences with respect to genes present; (2) differences with respect to mutations in the same gene (where one species has an ortholog of a gene found in another); (3) differences with respect to proteins and protein activity; (4) differences with respect to gene regulation; (5) differences in gene expression; (6) differences in protein-protein interactions; (7) differences in genetic networks; (8) differences with respect to organismal organization (humans and rats may be intact systems, but may be differently intact); (9) differences in environmental exposures; and last but not least; (10) differences with respect to evolutionary histories. These are some of the important reasons why members of one species often respond differently to drugs and toxins, and experience different diseases. Immense empirical evidence supports this position.

    1. Harriet Hall says:

      @Ray Greek,

      “insulin was arguably discovered in humans but dogs were used to obtain a sample large enough to purify”

      References, please! Who is arguing that? Everything I could find showed that insulin was discovered in dogs. For instance
      http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html
      Note that this is a Nobel Prize website, not an advocacy website.
      Insulin was discovered in dogs, and the response of diabetic dogs to insulin predicted the response of human diabetics, and animal insulin was injected into humans for decades and saved countless lives.

      You can argue that animal experiments do not always predict human responses, and that they shouldn’t be required in every case, and that they should be used with great care to rule out situations where animals are significantly different (obviously you don’t do vitamin C studies in animals that make their own) but you can’t argue that they are “never” or even “seldom” predictive. They have proven their value over and over in predicting human responses to everything from insulin to vaccines to organ transplants. You have an agenda and are succumbing to confirmation bias.

  42. DugganSC says:

    So, to make a long story short, my impression from the debate is that Dr. Greek acknowledges animal models, whether observation or through direct testing, have indeed helped advance medicine, but our current model for drug testing, where drugs must be tested and succeed on animals first, may be causing us to lose therapies and drugs that might be tested in other manners. Computer modeling and the “-omics” (which I’ll admit I’m not entirely following, but am guessing is probably some sort of meta-analyses on a high level) may provide better ways of predicting the effects of a drug or therapy. Currently, these alternate methods have not shown themselves to be effective enough, but results are promising enough to continue research into them while we employ our current model of animal testing because so far it’s the solution with the highest reliability.

    Is that an accurate summary?

  43. David Gorski says:

    So, to make a long story short, my impression from the debate is that Dr. Greek acknowledges animal models, whether observation or through direct testing, have indeed helped advance medicine, but our current model for drug testing, where drugs must be tested and succeed on animals first, may be causing us to lose therapies and drugs that might be tested in other manners

    Yes and no. At every point, Dr. Greek tries to downplay the usefulness of animal models, even in basic research, as he did for the use of dogs in the development of insulin therapy for diabetes. One wonders if he thinks animals were useful in the development of transplantation surgery. So, yes, Dr. Greek attacks “predictive models,” but he does his best to cast doubt on other forms of animal research, only grudgingly admitting its utility in blindingly obvious cases. His organization’s manifesto stated:

    Americans For Medical Advancement (AFMA)/ Europeans For Medical Advancement (EFMA)/ Japanese For Medical Advancement (JFMA) is a mainstream science-based research and educational institute dedicated to improving policy and decision-making regarding the use of the animal model in biomedical research.

    AFMA/EFMA/JFMA opposes animal-modeled research as a modality for seeking cures and treatments for human disease based on overwhelming scientific evidence that findings from animal models cannot be reliably extrapolated to humans. We seek to demonstrate, through rigorous research and analysis, that the reliance on animal-modeled research, as well as other pseudoscientific endeavors, harms rather than helps humans, and prolongs human suffering by inhibiting medical progress.

    That’s far broader than just using animals to predict human responses to drugs.

  44. DeepBluSci says:

    David, you’re spot on in your analysis of Greek. What he often does to avoid having to “grudgingly admit” the usefulness of animals in a particular field of research is to simply not mention any facts that may contradict his message.

    For example in the case of insulin above he writes that “To begin, insulin was arguably discovered in humans but dogs were used to obtain a sample large enough to purify, at least somewhat, and administer back to dogs and humans. Even Banting and Best admitted they did not discover insulin but purified it enough to try on humans and other dogs. They stated that they had provided evidence from the lab to essentially confirm autopsy findings. ”

    Actually the first evidence that the pancreas was somehow involved in diabetes came from human autopsies, but many the major findings following that were made in animals. For example, Oskar Minkowski and Joseph von Mehring firmly established through experiments in dogs that the pancreas was was involved in regulating blood sugar and that this role was distinct from it’s role in digestion, confirming the association that was suggested by the autopsies (after all the damaged pancreas could easily have been a consequence of diabetes). Eugine Opie subsequently pinpointed through autopsy the islets of langerhans as the structures in the pancreas that were lost in diabetes, but this built on the earlier work of Minkowski and Mehring. Several researchers, including Ludwig Zulzer and Nicolea Polescu, have been credited with isolating insulin and using it to treat diabetes in the period 1906-1921 (Polescu in particular deserves far more credit for his work), before Banting, Best and their colleagues got involved. These early studies of the isolation of insulin and it’s use in lowering blood sugar levels were all carried out in animals.

    A couple of points occur to me:

    1) Minkowski, Mehring, Zulzer, Polescu, Banting, Best et al. did a lot more than just confirm the observations (though “clarify the observations” would be the more accurate term) they extended the knowledge considerably.

    2) Does it really make a difference to the discussion on the merits of animal research whether Banting and Best (and Collip and Macleod) really were the first to isolate insulin and use it to treat diabetes. The important thing is that all the scientists who accomplished this (some better than others) in the years 1906-1922 did so through animal studies.

    It’s a good example of how Greek operates.

    The discussion of what constitutes basic Vs applied Vs transational research is perhaps one the most tedious out there, though unfortunately important to science policy discussion. I often wish that the terms had never been invented, or at least not defined as they often are, as anyone with any real experience of science will know damn well that there are no demarkation lines between them.

  45. Ray Greek MD says:

    hello all
    And to think I had assumed everyone would be over all this by today.

    # DugganSCon 13 Sep 2012 at 8:59 am
    Is that an accurate summary?

    Sorry, but no. When animal models are used as predictive modalities and fail then they should be abandoned. I appreciate your good intentions here DugganSCon, but why is this so hard to comprehend? I am being serious. Where am I going wrong? You seem to be a serious person and yet I am not communicating effectively with you. I assume a certain level of education on this site but maybe I am making a false assumption. Not everyone is familiar with PPV and NPV or simple statistics. Let me approach this from a different direction.

    If modality X is used to, and claimed to be successful at, function Y but research shows it does not fill that purpose, why use it? For example, drug development is somewhat like flying a plane. If the instruments work 80% of the time, a far higher percentage than the PPV and NPV for animal models, those instruments would not be used. Now, those instruments might be more reliable than instruments that only give an accurate representation of reality 60% of the time but the pilot could never rely on or even use instruments that were correct only 80% of the time. The pilot could never make decisions based on those instruments. People would die.

    Ditto for animal models. Toxicity testing is the easiest example so I will use it. Studies have shown animal models have PPV and NPV of around 0.5 for toxicity. Here’s what that means and what it does not mean. For any toxic effect manifest in animal models, there is a 50% chance it will be seen in humans. That is the same percentage you would see with a coin toss. Now, what does that buy you in terms of developing that drug? Absolutely nothing. Every drug has toxic effects, some very severe, in some species or strains and if we did not develop those drugs on that basis, there would be no drugs. On the other hand, many species have been tested for infamous examples of toxicity in humans and in some of those cases no animal model was ever found that reproduced the effect. Moreover, a NPV of 0.5 does not ensure safety or even “give us an idea” of whether the drug is safe.

    So to say animal models are the best we have is meaningless. Even if true, regarding the reliability of in vitro etc, which I doubt, the tests are misleading and offer nothing of value. I have written extensively on this and shown that the people most concerned about this are in Pharma. Gorski et al are not arguing with me when I say animal models are not predictive they are arguing with the people that actual develop the product. (The real controversy here is how microdosing should be implemented/expanded, not the value of animal models in drug development.)

    I have used drugs in my examples as they are easier to explain but the same applied to disease pathophysiology. HIV being a prime example.

    The use of animals in basic research makes no claim of prediction hence is not judged on the basis of prediction. Neither is the use of animals for spare parts for humans, for learning about diseases in the same species, or when they are used as bioreactors. These uses are scientifically viable regardless of your views on ethics. BUT, the reason people go apoplectic when I point all this out is that basic researchers claim their models are predictive in their grant applications and sell their research to congress and society on that basis. Take away the direct link between results in mice and curing Mom and society would not allow most animal experiments. I reference all this the books and articles.

    Our claim is actually very modest scientifically speaking. But the implications for grants and the egos that go with NIH grants is far-reaching indeed.

    Thanks for the question! If i am still not communicating effectively, please direct me.

    # David Gorski on 13 Sep 2012 at 11:00 am
    Yes and no. At every point, Dr. Greek tries to downplay the usefulness of animal models, even in basic research, as he did for the use of dogs in the development of insulin therapy for diabetes.

    See the quotes above from Animal Models in Light of Evolution. Does not sound like downplaying to me. I am not downplaying the role of dogs in the purification of insulin but to claim no one knew about insulin until Banting and Best is inconsistent with history. I am touchy about attributing breakthroughs to animal models when the real story is much more complicated. Such is how nonsense is started and maintained. As Goldacre says “I think you will find it’s a bit more complicated than that.” (Hope I got that right.)

    # David Gorski on 13 Sep 2012 at 11:00 am
    One wonders if he thinks animals were useful in the development of transplantation surgery.

    This is David changing the subject. AFMA and I have one issue: prediction. Because people like David refuse to address that subject and instead want to debate everything except that, I do occasionally address basic science and history. Probably should not but such is life. So lets assume everything I have ever said about basic science and history is wrong. What does that imply about my position on prediction? Nothing.

    If someone wants to debate the role of animals in basic science or what advances were dependent upon animal models historically, I am happy to participate. But ONLY after we have settled the prediction issue. Because every time I take on a historical issue or basic science, when my opponent has his back against the wall he will always come back with: “Well, animals really do predict human outcomes, anyway. I don’t care what you say about it. THAT’S why we do it.” Mature? No. Reality? Yes! So if anyone wants to discuss the polio vaccine, penicillin, diabetes and so forth, either stipulate animal models are not predictive modalities at the level of drug and disease response or participate in a debate on that issue.

    # David Gorski on 13 Sep 2012 at 11:00 am
    So, yes, Dr. Greek attacks “predictive models,” but he does his best to cast doubt on other forms of animal research, only grudgingly admitting its utility in blindingly obvious cases. His organization’s manifesto stated:
    Americans For Medical Advancement (AFMA)/ Europeans For Medical Advancement (EFMA)/ Japanese For Medical Advancement (JFMA) is a mainstream science-based research and educational institute dedicated to improving policy and decision-making regarding the use of the animal model in biomedical research.
    AFMA/EFMA/JFMA opposes animal-modeled research as a modality for seeking cures and treatments for human disease based on overwhelming scientific evidence that findings from animal models cannot be reliably extrapolated to humans. We seek to demonstrate, through rigorous research and analysis, that the reliance on animal-modeled research, as well as other pseudoscientific endeavors, harms rather than helps humans, and prolongs human suffering by inhibiting medical progress.
    That’s far broader than just using animals to predict human responses to drugs.

    No. I wrote it and it means prediction. Nothing more. BTW, the above manifesto is very old. JFMA and EFMA are not really functioning anymore. Several years ago we changed the above to:

    Americans For Medical Advancement (AFMA) is a not-for-profit organization that promotes biomedical research and the practice of medicine based on critical thinking and our current understanding of evolutionary and developmental biology, complex systems and genomics.
    Our primary concern is the advancement of investigative methodologies that lead to effective cures and treatments for human diseases. As such, AFMA is opposed to research modalities that have been shown to be scientifically invalid—specifically, the use of animals as predictive models (also known as causal analogical models) for humans relative to drug and disease response.
    While an immense body of empirical evidence has supported this conclusion for decades, new knowledge about genes, gene regulation, gene expression and gene networks—gained in large part as a result of the Human Genome Project—has significantly increased our understanding of why animals cannot be used to predict human response to drugs or the pathophysiology of human diseases.
    Despite the development of an all-encompassing theory as to why animals are not predictive, there remains—much to the detriment of human health and medical progress—extraordinary resistance to abandoning the use of animals as predictive models. (For the reasons why, click on OPPOSITION)
    The goal of AFMA, therefore, is to educate the scientific community, as well as the general public, of the urgent need for a move away from the ineffective animal model to research modalities that truly reflect the enormous strides we have made in our knowledge of living systems.

    Might want to check the website occasionally, David if you are really trying to portray current information. You cannot intuit what is on the website or in the books and articles.

    # Harriet Hallon 13 Sep 2012 at 11:55 am
    @Ray Greek,
    “insulin was arguably discovered in humans but dogs were used to obtain a sample large enough to purify”
    References, please! Who is arguing that? Everything I could find showed that insulin was discovered in dogs. For instance
    http://www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html
    Note that this is a Nobel Prize website, not an advocacy website.

    As stated above, if anyone wants to debate insulin and diabetes I am happy to comply but only after the prediction issue is settled. If you want to go to the mat on the history of insulin discovery, you will lose. And references? That is ripe! I have offered links to the articles that explain all this is much more detail than I can do in this forum so read all that before asking for more. Further, where are David’s references on anything? I have offered papers published in peer-reviewed journals that have references out the wazoo. The Nuremberg paper, or maybe its the the conserved process paper, has over 300 as I recall. If you want a real debate on insulin and diabetes complete with references and even the original papers, some are in German, then comply with the above and I will show up for whatever. But asking me for references when you and David are not even pretending to support your opinions with anything except “here’s what I found on the Internet” is a little much.

    # Harriet Hallon 13 Sep 2012 at 11:55 am
    You can argue that animal experiments do not always predict human responses, and that they shouldn’t be required in every case, and that they should be used with great care to rule out situations where animals are significantly different (obviously you don’t do vitamin C studies in animals that make their own) but you can’t argue that they are “never” or even “seldom” predictive.

    Dr Hall, I am not trying to be rude here but you are way over your head in all this. Gorski is just being disingenuous, and maybe really is somewhat deficient in a couple of areas, but you are missing the big points. Take a refresher curse on philosophy of science and intro to statistics then rejoin the conversation. Words have meaning especially in medical science. As a family practitioner I doubt you have the training in science that specialists have. I am not anti-FP! I did my internship in FP and have family and friend who are smarter than me who went into FP. But the training is different. Your statement above reveals a lack of understanding of some of the fundamentals of science. Sorry! But you brought all this up. I doubt you really understand what zoobiquity was all about but that does not excuse your taking a position that inconsistent with science. As I sated earlier, in order to comprehend all this one needs knowledge that is transdisciplinary. I did not have this knowledge until I worked with Shanks! It took me about 10,000 hours of reading what he told me to read and discussing it all with him in order for me to become competent. (Shanks had a PhD in Philosophy of Science.) A lot of all this goes back to philosophy of science and most physicians and even scientists in general just don’t have the background. You don’t need to understand complexity science and philosophy of science to criticize homeopathy.

    # Harriet Hallon 13 Sep 2012 at 11:55 am
    They have proven their value over and over in predicting human responses to everything from insulin to vaccines to organ transplants. You have an agenda and are succumbing to confirmation bias.

    Well, maybe we can agree on one thing. Either I am wrong, for whatever reasons, or I am right in which case harm is being done by a failed paradigm. Now, one way to resolve situations like this is through a debate in the peer-reviewed literature, complete with experts in the relevant areas. But guess what? I have offered to do that and no one on your side wants to play. So we definitely have a situation where one of us is right and one is wrong and the consequences are very real. But I am the one that is willing to pursue it through the usual channels and your side is whimpering on the sidelines, blogging without consequences, failing to address my arguments, misrepresenting my position, and then changing the subject.

    Come on Dr Hall! Your side excoriates woo every day. If I am woo-full then expose me in public. My only issue is that whatever the forum, we have mutually agreed upon experts in the relevant fields and allow them to determine things like:
    whether a modality can be “sometimes predictive”
    what does complexity science imply for trans-species extrapolation at the level of organization where drugs and disease manifest
    are my references correct in terms of saying what I claim
    have animal models been empirically shown to fail as predictive models
    etc etc

    The above could be accomplished with: a mathematician or physicist working on, or just competent in, complexity; a PhD philosopher of science; a clinical physician from academia; an evolutionary biologist; a basic researcher from one of the hard sciences; a statistician—although that is overkill—and maybe representatives from a couple of more areas.

    Want to play?

    # DeepBluScion 13 Sep 2012 at 12:18 pm
    David, you’re spot on in your analysis of Greek. What he often does to avoid having to “grudgingly admit” the usefulness of animals in a particular field of research is to simply not mention any facts that may contradict his message.

    See above quotes from Animal Models in Light of Evolution.

    Actually the first evidence that the pancreas was somehow involved in diabetes came from human autopsies

    Thank you, that was my only point. I acknowledged animal played a role.

    The discussion of what constitutes basic Vs applied Vs transational research is perhaps one the most tedious out there, though unfortunately important to science policy discussion. I often wish that the terms had never been invented, or at least not defined as they often are, as anyone with any real experience of science will know damn well that there are no demarkation lines between them.

    Odd that you should say that as my division of animal models into predictive and nonpredictive uses accomplishes exactly that.

  46. Ray Greek MD says:

    oops! left out an end quote apparently. sorry!

  47. Harriet Hall says:

    Let me see if I understand this correctly. Dr. Greek is willing to discuss whether studying diabetic animals predicted human responses to insulin, but only after we have agreed with him that studying animals doesn’t predict human responses to anything.

  48. evilrobotxoxo says:

    Dr. Greek: a question for you. If a new drug came out that worked great in cell culture models, but 90% of the rats who it was given to developed tumors and died, would you recommend human clinical trials? Please try to give a clear yes/no answer and explain your reasoning succinctly.

  49. Chris says:

    Dr. Hall:

    Insulin was discovered in dogs, and the response of diabetic dogs to insulin predicted the response of human diabetics, and animal insulin was injected into humans for decades and saved countless lives.

    I am straying off topic, especially since I am ignoring Dr. Greek tl/dr bits. I recently read Breakthrough: Elizabeth Hughes, the Discovery of Insulin, and the Making of a Medical Miracle. It was fascinating. It goes to the use of dogs, and onto contracting with meat packers to get enough pancreases to make insulin. It is also the human story of what those who had diabetes had to endure in order to live.

  50. Harriet Hall says:

    Thanks, Chris! That sounds like the kind of book I really enjoy reading. My library doesn’t have it, but I’ve asked them to get it for me by Interlibrary Loan.

  51. David Gorski says:

    Let me see if I understand this correctly. Dr. Greek is willing to discuss whether studying diabetic animals predicted human responses to insulin, but only after we have agreed with him that studying animals doesn’t predict human responses to anything.

    Oh, that’s hilarious! But it’s typical of Greek, and a ploy to which I say, “Sorry, Dr. Greek. You don’t get to make the rules of discussion here.”

    It’s equally hilarious that Greek claimed I was “changing the subject” when I brought out the issue of transplantation. The issue of transplantation and surgery in general are very relevant to this discussion. Huge swaths of surgery were developed in animal models, which were used to refine surgical techniques and test the effects of different operations on physiology, complications, and the like.

    Perhaps my favorite (but by no means the only) example of this is the Blalock-Taussig shunt, the development of which was dramatized in the HBO movie Something The Lord Made, starring Alan Rickman and Mos Def as Alfred Blalock and Vivien Thomas, respectively. Blalock was a pioneering surgeon, and Thomas was his African-American technician, which brought up all sorts of racial issues in the 1940s-1960s, which drove some of the drama. The rest of the drama was about the process of scientific discovery that began with “blue babies” who had a constellation of heart defects known as the Tetralogy of Fallot, and how in the 1940s Alfred Blalock and cardiologist Helen Taussig came up with a concept how to ameliorate the problem and vastly prolong the survival of children with Tetralogy of Fallot. (Completely fixing the problem was not possible at that time because there was no heart-lung machine yet.) Here’s a description:

    Most interesting from a science standpoint, it portrays brainstorming sessions, where Blalock and Thomas discuss possible ideas of (1) how to induce the blue baby syndrome in dogs, in order to produce an animal model of the defect, without which they could not develop a surgical procedure to ameliorate the cyanosis; and then (2) how to correct the condition in the animal model; and then finally (3) how to operate on a child’s heart, construct the shunt proposed by Taussig, and have the patient survive the operation. These scenes are presented with great gusto and give a sense of the tough work involved in medical research, as together Blalock and Thomas try out different procedures on dog after dog, only to have them die, one of them quite unexpectedly after they had thought they had hit upon the right technique. They also have to invent a variety of new surgical instruments in order to carry out the then difficult and technically challenging procedure. All of this was done after overcoming years of neglect in the Department of Surgery at Johns Hopkins that had left the surgical research labs in an appalling state of neglect as Blalock strugged to refocus the department on surgical research, in the process turning it into a research powerhouse.

    Eventually, as we know from history, the two men eventually did come up with a workable animal model of the blue baby syndrome and an operation to reverse the lack of oxygen in the arterial blood. In November 1944, a critically 15 month old girl with blue baby syndrome named Eileen Saxon was near death, and she became the first patient upon whom Blalock was to try this new operation. Indeed, when just how nervous Blalock was at what he was about to attempt was obvious, and the palpable bewilderment and shock of Blalock’s colleagues and residents when he invited Thomas into the operating theater showed just how different attitudes were then. Thomas stood next to Blalock for the whole case and guided him through it, as he had done the operation in the animal laboratory many more times than Blalock had.

    No doubt Greek will claim that, because the idea came first from humans, it’s not “predictive,” but in reality, this is a near-perfect example of animal research being predictive in that (1) Blalock and Thomas understood the pathophysiology in the human; (2) figured out a way to recreate the pathophysiology in a dog; and (3) figured out how to correct it in a dog. The result of their having figured this out was predictive in that the same procedure that worked in dogs worked in human babies.

  52. lilady says:

    Dr. Hall and Dr. Gorski have effectively addressed and debunked all of Dr. Greek’s specious and uninformed arguments against using research animals for the benefit of humans.

    Here, from the California Veterinary Medicine Website is their statement about Animal Research…for the benefit of humans AND the benefit of animals:

    http://www.cvma.net/doc.asp?ID=2403

    “….“These animals are heroes. Their contribution to discovering life-saving advancements in medicine and science—for both pets and humans—is enormous,” said Jon Klingborg, DVM, president of the California Veterinary Medical Association (CVMA). “Thanks to the last century of animal research, we have achieved life-saving treatments for people and animals. As veterinarians, we are able to treat more ailments and prevent more diseases, and that allows us to keep our pets living longer and healthier.”

    Without animal research, millions of dogs, cats, birds, and farm animals would be dead from more than 200 diseases, including anthrax, distemper, rabies, feline leukemia, and canine parvo virus, according to Americans for Medical Progress (AMP), a nonprofit group that supports the responsible and humane use of animals in biomedical research. Today, those diseases are largely preventable, thanks to vaccines and treatments developed in animal research….”

  53. Ray Greek MD says:

    # Harriet Hall on 13 Sep 2012 at 3:12 pm
    Let me see if I understand this correctly. Dr. Greek is willing to discuss whether studying diabetic animals predicted human responses to insulin, but only after we have agreed with him that studying animals doesn’t predict human responses to anything.

    That’s sad Dr Hall. Truly. I have stated ad nauseam that animals and humans share traits and properties but that in terms of being predictive modalities, animal models are not predictive modalities for drug and disease response. (And the claim as predictive modalities is exactly how animal models are sold to society.) I specifically stated that humans and animals react the same way to numerous perturbations and linked to a paper explaining the role conserved processes play in this. In order to misrepresent my position the way you have in the above, you are either playing a role or lack the reading comprehension skills present in the average 6th grader.

    Furthermore, I don’t want to debate history or basic research; your side wants to discuss all those things. Look back at the old posts and tell me who is bringing up topics other than prediction. It’s not me. I offered to participate in such a debate because your side apparently wants to discuss it in more depth. My issue has always been whether animal models are predictive modalities for human response to drugs and disease. In order to get my debate I am willing to participate in what your side apparently wants. But only after the prediction issue is settled.

    Again, I suggest you take some refresher curses before continuing with your comments. As I have explained a single instance of correlation does not mean a modality is predictive otherwise astrology and fortunetelling would qualify. Even if I classified insulin produced in the pancreas and used by the same body as a drug, as opposed to basic biological process shared among mammals, a single instance of sharing a response is not the same a being a predictive modality. Go back to that 2X2 table we all learned in medical school and notice that when calculating PPV one needs a history of predictions not a single prediction in order to determine whether the modality is predictive.

    You have confused, out of ignorance or purposefully—I don’t know which is less flattering—the use of the word “predictions,” which are generated by hypotheses, and “predictive modality” which is what you used every time you ordered a stress tolerance tests or PSA or CT scan. If you continue making such mistakes you have no reason to expect to be taken seriously in this discussion.

    I am taking the comments in order and will post when my response get long enough.

  54. Calli Arcale says:

    Ray Greek:

    No one is suggesting that animal models be abandoned because they are not perfect. I have explained many times where animal models can be used and why they can be used for such endeavors and not others.

    Really? Then clearly I misunderstood you when you said this:

    First, Dr Hall clearly holds that at least some animal models are predictive models as she differentiated between the two. That was/is the issue in contention: are any animal models predictive for humans in terms of drug and disease response. Whether she thinks 1% or 100% are predictive is irrelevant. I maintain that none are.

    That seem to pretty clearly say that you don’t think any animal models are predictive. At all. In your response to me, you drew a curious distinction between basic research and some other type of research that you didn’t really specify. You said:

    Selling animal models as predictive modalities when they are really tools for basic research is fraud when done in order to obtain government funding and just plain wrong from any perspective.

    I call this a curious distinction because you seem to think there is something fundamentally different between basic research and whatever this other type of research is that fraudulently obtains government funding and is basically wrong. There isn’t. Science is science, no matter what the question being studied might be. Guinea pigs are the classic example of an animal model; they revealed the true cause and treatment of scurvy. That wasn’t just basic research; the scientists were actually trying to test a theory about beriberi and inadvertently stumbled upon the only other animal that gets scurvy. They promptly abandoned the beriberi research to work out exactly how to cure the guinea pigs’ scurvy. That research translated exactly into humans — in this case, the particular animal turned out to be a perfect predictor for this particular disease. Rare as that is, it’s scientific gold when it happens.

    To be honest, you seem to be dancing around a central claim that you seem unwilling to directly voice. You are good at writing large walls of text. I’m verbose too; I understand the temptation. But you might be better understood if you aimed for more concise language.

  55. Ray Greek MD says:

    # evilrobotxoxoon 13 Sep 2012 at 3:20 pm
    Dr. Greek: a question for you. If a new drug came out that worked great in cell culture models, but 90% of the rats who it was given to developed tumors and died, would you recommend human clinical trials? Please try to give a clear yes/no answer and explain your reasoning succinctly.

    Tamoxifen. Succinct enough? There are numerous drugs that fulfill your criteria and worse but that are used very successfully in medicine. Matter of fact, almost every drug on the market will kill some animal or result in toxicity in some animal model. Penicillin kills some strains of guinea pigs and hamsters. Want to pull it from the market? So not only would I take your hypothetical drug to clinical trials I would start with Phase 0 (microdosing) and expand the microdosing protocol as I have described elsewhere.

    # David Gorski on 13 Sep 2012 at 4:06 pm
    It’s equally hilarious that Greek claimed I was “changing the subject” when I brought out the issue of transplantation. The issue of transplantation and surgery in general are very relevant to this discussion. Huge swaths of surgery were developed in animal models, which were used to refine surgical techniques and test the effects of different operations on physiology, complications, and the like.

    That is wrong on so many levels. 1. Where in my posts did I equate response to disease and drug with surgeries? 2. You are cherry picking. How did intracranial-extracranial bypass work out in humans? How about radial keratotomy and the cardiopulmonary bypass machine before John Kirklin modified it and flow rates were changed based on human data? All worked well in animal models but not humans. 3. No references. 4. Conversion fallacy. 5. Saying you are not changing the subject is not the same as not changing the subject.

    But come on David, take all these pearls and bring them up in a debate.

    # David Gorski on 13 Sep 2012 at 4:06 pm
    Perhaps my favorite (but by no means the only) example of this is the Blalock-Taussig shunt

    After our prediction debate lets publically debate what you said about the BT shunt. For a surgeon, you are leaving out a few somewhat important details. But thats the problem, David. You will never put yourself in a position where you can be held accountable for spouting nonsense or misrepresenting facts, history, and positions.

  56. Ray Greek MD says:

    # Calli Arcale on 13 Sep 2012 at 5:45 pm

    I suggest you read the books and articles I have referred to. I take you at your word and acknowledge that this is weighty stuff. In my experience (I have no systematic reviews on this) it takes a vast majority of people about three times of thoroughly going through all this to understand what I am saying and, as importantly, what I am not saying. This is such an emotion-generating issue most people hear or read what they think they are going hear or read; not what I actually say. I have asked people who hung in there and finally comprehended the position how to speed the process but have not had any suggestions. Most people say they really did read X when I wrote Y and see it in retrospect. But they say there was just nothing to do to facilitate the process except keep studying the material. Sorry! If you are not really interested in the topic I can understand not wanting to put the time in. But if you want to understand it, it takes time. I alluded to this in my first blog post in 2010:

    The Internet has been an outstanding educational resource. We wrote two books essentially before the Internet as we know it now and three since. The three latter books are much better, in part because of the facts and articles we could access via the World Wide Web. That having been said, science education is not conducive to learning via Internet. Many controversies can be studied using the Internet, for example creation versus evolution, the validity of complimentary and alternative medicine, and the use of animals in science. But in order to really understand the nitty gritty science behind all these subjects one needs to go back to the last century. One needs to read books. There is no reason a person who is lacking in advanced science education cannot read and understand science-related topics. However, jumping in without adequate background may not be productive.

    Thanks for your comment!

  57. Harriet Hall says:

    Tamoxifen? I don’t think so. Check your facts.
    In fact, it undermines your argument. You are complaining about the requirement for animal testing for drug approval, saying that a drug might not be approved because it doesn’t work in the test animal even though it works in humans. Presumably tamoxifen was tested in animals and it passed the tests.

    In fact, doesn’t the approval process undermine your whole argument that animals are too different to serve as predictive models? Aren’t animal studies routinely used to predict the safety and effectiveness of drugs, allowing them to proceed to human testing?

    A lot of drugs have different effects in some animals, but a lot of them have the same effects in some animals as in humans. Seems to me the lesson is that we must choose our test animals carefully, with the guidance of veterinarians who understand the similarities and differences. Cooperation with zoologists was the whole point of Zoobiquity.

  58. evilrobotxoxo says:

    @ Dr. Greek: If you would take a novel drug candidate that in therapeutic doses gave 90% of rats tumors and give it to humans, even in small doses, without even using the animal model to explore the mechanism first, then you have made it perfectly clear to even the most untrained observer that you are either a true ideologue or a true idiot.

    I’ve read most of your posts here, and you fall prey to several errors in logic and/or understanding. First, you talk about the PPV and NPV of “animal models.” You explicitly deny to Dr. Gorski that you are lumping all animal models into a single class, but talking about the PPV and NPV of “animal models” is lumping all models into a class and using a statistic to describe them. People like me who work with animal models for a living spend a lot of time trying to determine the predictive validity of specific model systems. It’s not like your insight that animal models have variable predictive validity is new; the only new parts that you contribute to the discussion are incorrect, namely 1) your error in lumping them all together and 2) your mistaken belief that the criteria for diagnostic tests in a single patient should apply to scientific experiments.

    Another critical error you make is in discussing quantitative estimates of the PPV and NPV in the context of drug testing. PPV and NPV are dependent on what set of compounds is being tested. You say that the PPV and NPV are around 0.5, but this is the estimate of those numbers derived from compounds that were tested in both humans and animals, i.e. the selected subset of compounds with known pharmacological activity that passed preliminary animal safety testing. Nobody knows what the PPV and NPV would be for the set of all drug candidates, or for the set of all possible compounds in the Sigma catalog. Human testing of all those compounds has never been performed and never will. However, your quoted PPV and NPV values are systematically biased to be lower than the relevant values (i.e. the PPV and NPV for all drug candidates) because drugs that are found to be overtly toxic or pharmacologically ineffective in animals are never tested in humans. The PPV and NPV for the set of all compounds in the sigma catalog would be even higher because the vast majority of those would either have no effect (like water) or be universally toxic in some obvious way (like sodium hydroxide powder), while all drug candidates simultaneously possess the possibility of toxicity (if they possess any biological activity at all) and the possibility of being nontoxic (if someone is bothering to test them).

    Finally, you keep wanting to have a debate and bemoaning the fact that no one will debate you. I’m a physician-scientist who does laboratory work with animals on a daily basis, and I feel that I am qualified to debate you. However, I will not. I can’t speak for why Dr. Gorski, Dr. Hall, or anyone else would refuse, but I suspect their reasons are similar to mine. I am not intimidated by your profound intellect or afraid of being publicly shamed when you expose me as a mountebank toting a hollow idol. Less interestingly, perhaps, I have evaluated your claims, and I find that they simply do not merit a commitment of my time beyond writing this post. If there were a large subset of our society who shared your views, to the point where it threatened the integrity of the scientific enterprise (as with creationism, anti-vaxers, etc.), then I would feel an obligation to engage you. Fortunately, it appears that virtually no one cares what you think. Feel free to have the last word; I will not respond to you (or think about you) again.

  59. Ray Greek MD says:

    # Harriet Hall on 13 Sep 2012 at 6:33 pm
    Tamoxifen? I don’t think so. Check your facts.

    Tamoxifen, was developed as a birth control pill based on rat studies. Didn’t work in women. In fact it increased the chance for pregnancy.(1,2) No toxicities were observed in preclinical studies (1) when it was thought to be a birth control pill, but after tamoxifen was released as a cancer treatment, more studies were done and a strain of rat was shown to develop liver tumors. White writing in Current Drug Metabolism, 2003:

    Tamoxifen, a non-steroidal antiestrogen, is the class representative of a group of drugs that include toremifene, droloxifene and idoxifene. Tamoxifen has been successfully used worldwide as adjuvant therapy in the treatment of women with breast cancer. However, such therapy results in a slightly increased risk of endometrial cancers. Lifetime exposure of rats to high closes of tamoxifen results in a high incidence of liver tumors. . . . The observation of Greaves et al. [28] that tamoxifen administration resulted in liver tumors in rats was quickly confirmed by other groups [29-31]. . . . At present, the rat is the only animal species where the formation of liver tumors in response to tamoxifen has been reported. No liver tumors are found in rats similarly treated with toremifene [33-35] or droloxifene [36], suggesting a mechanism of action that might be unique for tamoxifen [37,3 8].(3)

    An editorial in Nature Reviews Drug Discovery 2003:

    In Tamoxifen’s case, a drug first developed as a potential contraceptive languished for many years before its present application was found. Furthermore, its propensity to cause liver tumours in rats, a toxicity problem that thankfully does not carry over into humans, was not detected until after the drug had been on the market for many years. If it had been found in preclinical testing, the drug would almost certainly have been withdrawn from the pipeline.(4)

    Animal studies played a minor role in the development of tamoxifen. According to D. N. Richardson of the Imperial Chemistries Industries PLC, the developer of the drug, writing in Drug Design and Delivery: “No laboratory tests for anti-tumour activity were carried out for Nolvadex [tamoxifen] until after the activity in human patients had been confirmed.” (5)

    This is what I have been saying. Test enough species and strains and you will find one that gives whatever response: cancer, anticancer, hepatotoxicity, no toxicity. There is no way to know beforehand which species will mimic the human response. For that matter, there is no way to know which species will mimic which response for which humans as humans vary so much.

    1. Tucker M, Adam H, Patterson J: Tamoxifen. In Safety Testing of New Drugs Laboratory Predictions and Clinical Performance. Edited by Laurence D, McLean A, Weatherall M. London: Academic Press; 1984: 125-162.
    2. Jordan VC, Robinson SP: Species-specific pharmacology of antiestrogens: role of metabolism. Fed Proc 1987, 46:1870-1874.
    3. White IN: Tamoxifen: is it safe? Comparison of activation and detoxication mechanisms in rodents and in humans. Curr Drug Metab 2003, 4:223-239.
    4. Editorial. 2003. Follow the yellow brick road. Nat Rev Drug Discov 2 (3):167.
    5. Richardson DN: The history of Nolvadex. Drug Des Deliv 1988, 3:1-14.

    # Harriet Hall on 13 Sep 2012 at 6:33 pm
    In fact, it undermines your argument. You are complaining about the requirement for animal testing for drug approval, saying that a drug might not be approved because it doesn’t work in the test animal even though it works in humans. Presumably tamoxifen was tested in animals and it passed the tests.

    I never said the drug would not be approved I said it would not be developed. Many drugs are the market because they were developed despite the animal studies and more have had toxicities discovered after marketing. Some of the toxicities did not manifest in humans, eg tamoxifen, while others did but an animal model that mimicked the toxicity was found only in retrospect. We discuss some of the “toxic in animals but not humans” drugs in our first book. The point is that even the drug developers do not believe the animal models, which I have also mentioned. Obviously, companies vary and some will shelve a drug based on animal models quicker than others. But all agree the animal model is not predictive. Also, I am not the only one that said society has lost drugs. Pharma and the NCI have also said this.

    # Harriet Hall on 13 Sep 2012 at 6:33 pm
    In fact, doesn’t the approval process undermine your whole argument that animals are too different to serve as predictive models? Aren’t animal studies routinely used to predict the safety and effectiveness of drugs, allowing them to proceed to human testing?

    No, my whole argument is that studies have been performed and conclusively demonstrated that animal models are not predictive for perturbations in humans, eg toxicities from the perturbation of administering drugs, and that everyone except basic researchers accept this. Consider the following.

    Elias Zerhouni, former director of NIH and current head of R&D at Sanofi was quoted in the June 25, 2012 issue of Forbes as saying: “R&D in pharma has been isolating itself for 20 years, thinking that animal models would be enough and highly predictive, and I think I want to just bring back the discipline of outstanding translational science, which means understand the disease in humans before I even touch a patient.”

    Sharp and Langer 2011:

    The next challenge for biomedical research will be to solve problems of highly complex and integrated biological systems within the human body. Predictive models of these systems in either normal or disease states are beyond the capability of current knowledge and technology.(Sharp and Langer 2011)

    A Reuters article on MSNBC discuses a computer-based method for predicting drug toxicity. The chip would test for activation of genes and proteins in various human tissues:

    “If things are going to fail, you want them to fail early,” Dr. Francis Collins, the director of the National Institutes of Health (NIH), told Reuters on Friday. “Now you’ll be able to find out much quicker if something isn’t going to work.”
    Collins said a drug’s toxicity is one of the most common reasons why promising compounds fail. But animal tests — the usual method of checking a drug before trying it on humans — can be misleading.
    He said about half of drugs that work in animals may turn out to be toxic for people. And some drugs may in fact work in people even if they fail in animals, meaning potentially important medicines could be rejected.(Reuters 2011)

    Alan Oliff, former executive director for cancer research at Merck Research Laboratories in West Point, Pennsylvania stated in 1997: “The fundamental problem in drug discovery for cancer is that the [animal] model systems are not predictive at all.” (Gura 1997)

    Littman and Williams of Pfizer writing about using humans as models for other humans in Nature Reviews Drug Discovery 2005:

    Experimental medicine is the use of innovative measurements, models and designs in studying human subjects for establishing proof of mechanism and concept of new drugs, for exploring the potential for market differentiation for successful drug candidates, and for efficiently terminating the development of unsuccessful ones. Humans are the ultimate ‘model’ because of the uncertain validity and efficacy of novel targets and drug candidates that emerge from genomics, combinatorial chemistry and highthroughput screening and the use of poorly predictive preclinical models . . . Experimental medicine in contemporary drug development is a business strategy that relies on experiments in humans for the purpose of demonstrating the mechanistic activity of new drugs at safe doses (exposures) and linking that activity to efficacy in patients. This strategy is very much a part of the ‘learning’ phase of early drug development that helps weed out drug failures early and precedes the ‘confirmation’ late phases of development in which high costs demand higher levels of success . . . In the new paradigm, studies in humans increase confidence in the relevance of novel drug targets and largely replace the animal efficacy models that are often poorly predictive of the efficacy of novel agents with unprecedented mechanisms of action (see below) . . . Until or unless a predictive preclinical model can represent each of these subtypes, humans will remain the ‘ultimate model organism’….
    Why should experimental medicine become more involved in the validation of
    novel drug targets? First, causes of attrition during the clinical phases of development have changed since the early 1990s. At that time, 40% of attrition was due to poor bioavailability and pharmacokinetics. By 2000, these factors caused the attrition of only about 10% of failed compounds. In fact, by that time 62% of compounds entering Phase II trials failed at some point prior to registration and 30% were due to lack of efficacy (Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nature Rev. Drug Discov. 3, 711–715 (2004)). More recent data looking at the success rate of compounds between 1997 and mid-2004 suggest that about 30% of the failures occur during Phase III. For the large number of compounds with unprecedented mechanisms of action entering Phase II there are two reasons for failure due to lack of efficacy. These are inadequate pharmacology (not rigorously testing the drug target) and the lack of predictability of animal models, particularly in some therapeutic areas such as oncology and the neurosciences (Leaf, C. Why we’re losing the war on cancer — and how to win it. Fortune 9, March (2004)). The risk of expensive Phase II failure due to these two factors can be reduced in the future through appropriate human studies using modern biomarker technologies.
    There are many examples of drugs that were effective in standard animal disease models but lacked efficacy in human disease. Xenograft models of cancer are a prime example . . . Even in the inflammation area, in which animal models tend to be more predictive of disease in humans, there are examples of failure due to lack of efficacy with adequate testing of the drug target. Leukotriene B4 (LTB4) antagonists, for example, were active in animal models of inflammatory arthritis, yet failed to achieve efficacy in rheumatoid arthritis (Polmar, S., Diaz-Gonzalez, F., Dougados, M., Ortiz, P. & de-Miguel, G. Limited clinical efficacy of a leukotriene B4 receptor (LTB4) antagonist in patients with active rheumatoid arthritis (RA). Arthritis Rheum. 50, S239 (2004)). In neuroscience, dopamine D4 antagonists showed activity in animal behaviour models that predicted efficacy of older dopamine D2 antagonists in schizophrenia, but these D4 antagonists were not efficacious in humans (Tarazi F. I., Zhang K. & Baldessarini R. J. Review: dopamine D4 receptors: beyond schizophrenia. J. Recept. Signal Transduct. Res. 24, 131–147 (2004)). N-methyl-d-aspartate (NMDA) antagonists seemed to be active in preclinical models of stroke but this did not translate convincingly into a therapeutic effect in humans (Ikonomidou, C. & Turski, L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 6, 383–486 (2002)).
    Given these statistics and examples it makes sense to move the rationale for efficacy of novel drug targets to one based on evidence in humans. The key questions are whether this can this be done efficiently and how experimental medicine can contribute to this to provide benefit during clinical development. The hypothesis put forward here is that advances in molecular diagnostics and biomarker technologies will underpin the success of this new paradigm . . . Improved preclinical models have not materialized, and so human experimentation is still the ultimate model, although we would hope that preclinical models will in time improve. (Littman and Williams 2005)

    Opar:

    Drug-induced liver injury (DILI) is the primary reason why companies abandon compounds during development, and risks of idiopathic DILI even as low as 1 in 100,000 treated patients can lead companies to withdraw approved drugs. . . . “Animal models fall short, so a lot of people believe the solution is to humanize drug development,” says Paul Watkins, director of the Hamner-UNC Institute for Drug Safety Sciences and a member of the MIP-DILI external advisory committee.(Opar 2012)

    Kevin Mullane of Profectus Pharma Consulting and Michael Williams of the Department of Molecular Pharmacology and Biological Chemistry, Feinberg School of Medicine, Northwestern University have written an article published in Drug Discovery Today.(Mullane and Williams 2012) The article acknowledges that advances have been made by using reductionism to study human disease and develop drugs to treat those diseases, just as I acknowledge this. However the main theme of the article is that Pharma and society are facing crisis in terms of developing new drugs that are safe, effective, and inexpensive. They cite the decrease in number of new chemical entities entering the market and late failure of many drugs in development, for example a success rate of only 5% for drugs that enter clinical trials (B. H. Munos and Chin 2011) and an 82% failure of drugs in Phase II proof of concept trials (Arrowsmith 2011), to illustrate the problem.(B. Munos 2009; Pammolli et al. 2011) They note that this is ironic since the total investment in biomedical research in the US reached $150 billion in 2010 (B. H. Munos and Chin 2011) and the amount of knowledge regarding knowledge of life has also increased substantially in the recent past. Mullane and Williams state: “The difficulties in predicting drug efficacy from preclinical models have been of concern for more than two decades . . . Thus, novel findings apparently related to the systems and targets involved in disease causality; the delineation of the efficacy, selectivity and safety of NCEs; and the predictive relevance of biomarkers and animal model data to the human disease state, even when there is evidence for target engagement in humans, all frequently fail to enhance the success rate for new drug applications (NDAs).”

    They then question the notion that advances in biomedical science equate to potential advances in drug development. I too have discussed this notion that more knowledge of the material universe ipso facto means more knowledge that is useful for patients. They then discuss the very concepts I have been discussing in an attempt to understand why Pharma is in crisis:

    As scientists active in TM [translational medicine] focus on defining appropriate criteria to improve decision-making and success at the preclinical and/or clinical interface, many of the basic paradigms in biomedical science that are key to these activities are being compromised. There is a failure to acknowledge the complexity of biology (Horrobin 2003; Walker 2011) to avoid confusing the simplistic, reductionist linearity of current approaches to biomedical research (Hogenesch and Ueda 2011; Kohl and Noble 2009). Added to this are significant concerns that the US research enterprise is now in crisis mode [31,32], coupled with a perception that the quality of scientific research has become ‘low’, approaching mediocrity (http://pipeline.corante.com/archives/2010/06/24/all_those_worthless_papers.php) with ‘any paper, however bad, . . .[get-]. . .published’ owing to the pressures on peer review (http://www.guardian.co.uk/science/2011/sep/05/publish-perish-peerreview-science/print). The venture capitalist Bruce Booth has commented (http://lifescivc.com/2011/03/academic-biasbiotech-failures/) that at least 50% of published studies from academic laboratories could not be repeated in an industrial setting. The prestige of the investigator or the journal did not appear to impact these numbers. An analysis (Prinz et al. 2011) by Bayer of their internal efforts to replicate published new drug target data indicated that 65% could not be reproduced to such an extent that projects had to be abandoned. A similar analysis of company-driven research programs and their reproducibility by independent third parties has not been performed, but it may not differ substantially since concerns of translation and robustness of data highlight several broad issues related to data generation, relevance, quality and transparency. These include:
    (i) An over-reliance on animal models of diseases that are poorly validated in the manner they are applied. Such models are ‘validated’ either because they provide a phenotypic behavior in response to a ‘gold standard’ drug, or they represent some pathophysiological phenomenon thought to be associated with the human disease state. In the former situation, the models can only be relied upon with any assurance to identify NCEs with the same mechanism of action, whereas the latter often represents an oversimplification of the disease, where absolute belief in a mechanism often trumps any contrary data, however robust the latter. Examples of this include the T helper 2 (Th2)/eosinophil model of asthma [34], the Non-obese diabetic (NOD) mouse in diabetes [35] and the various animal models of stroke, that together, have led to over a 1000 failed compounds in the clinic [36]. Difficulties in interpreting results from animal models are far from new. However, they remain a key part of hypothesis testing provided that newer data are integrated hierarchically and taken in context with other datasets to inform broadly the validity of the hypothesis being tested [37,38].
    (ii) The intrinsic reductionism of molecular biology, where engineered cell lines bearing little resemblance to native systems (or the human species) are used to define disease pathophysiology . . . (Mullane and Williams 2012)

    Cook et al:

    The primary purpose of preclinical therapeutic efficacy testing is to predict whether a particular compound will be successful in the clinic. Despite encouraging preclinical results, unfortunately most drugs are found to be ineffective late in their development, with only a small percentage (5%) of patients in Phase I clinical trials responding (Roberts et al. 2004). Apart front using inaccurate tumour models, there are many other reasons why preclinical studies fail to predict clinical activity. Species-specific PK, its addition to differences in drug delivery, and tumour heterogeneity might all contribute to discordant results. Such failures are costly to scientists and drug companies and of great consequence to the patients that optimistically enrol in experimental clinical trials. (Cook et al. 2012)

    I can do this all day but I trust you get the point.
    The FDA still requires animal testing for safety and efficacy but the federal government also requires/funds NCCAM so I would not put much stock in what the government requires.

    # Harriet Hall on 13 Sep 2012 at 6:33 pm
    A lot of drugs have different effects in some animals, but a lot of them have the same effects in some animals as in humans. Seems to me the lesson is that we must choose our test animals carefully, with the guidance of veterinarians who understand the similarities and differences. Cooperation with zoologists was the whole point of Zoobiquity.

    The whole point here is that one cannot know which species will mimic humans until after the fact. There is some overlap when conserved processes are involved but even then, side effects vary and there are still clinically significant differences among species. See the conserved process paper. Cooperation with vets will not solve the problem. The problem is extrapolation between evolved complex systems.

    More later

    References for sections below tamoxifen
    Arrowsmith, J. (2011). Trial watch: Phase II failures: 2008-2010. [10.1038/nrd3439]. Nat Rev Drug Discov, 10(5), 328-329.
    Cook, N., Jodrell, D. I., & Tuveson, D. A. (2012). Predictive in vivo animal models and translation to clinical trials. Drug Discovery Today, 17(5/6), 253-260.
    Gura, T. (1997). Cancer Models: Systems for identifying new drugs are often faulty. Science, 278(5340), 1041-1042.
    Hogenesch, J. B., & Ueda, H. R. (2011). Understanding systems-level properties: timely stories from the study of clocks. [Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Review]. Nature Reviews. Genetics, 12(6), 407-416, doi:10.1038/nrg2972.
    Horrobin, D. F. (2003). Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat Rev Drug Discov, 2(2), 151-154, doi:10.1038/nrd1012
    nrd1012 [pii].
    Kohl, P., & Noble, D. (2009). Systems biology and the virtual physiological human. [Editorial
    Research Support, Non-U.S. Gov't]. Molecular systems biology, 5, 292, doi:10.1038/msb.2009.51.
    Littman, B. H., & Williams, S. A. (2005). The ultimate model organism: progress in experimental medicine. Nat Rev Drug Discov, 4(8), 631-638, doi:nrd1800 [pii]
    10.1038/nrd1800.
    Mullane, K., & Williams, M. (2012). Translational semantics and infrastructure: another search for the emperor’s new clothes? Drug Discovery Today, 17(9/10), 459-468.
    Munos, B. (2009). Lessons from 60 years of pharmaceutical innovation. [Historical Article]. Nature reviews. Drug discovery, 8(12), 959-968, doi:10.1038/nrd2961.
    Munos, B. H., & Chin, W. W. (2011). How to revive breakthrough innovation in the pharmaceutical industry. Science Translational Medicine, 3(89), 89cm16, doi:10.1126/scitranslmed.3002273.
    Opar, A. (2012). Overtaking the DILI Model-T. [10.1038/nrd3818]. Nat Rev Drug Discov, 11(8), 585-586.
    Pammolli, F., Magazzini, L., & Riccaboni, M. (2011). The productivity crisis in pharmaceutical R&D. [10.1038/nrd3405]. Nat Rev Drug Discov, 10(6), 428-438.
    Prinz, F., Schlange, T., & Asadullah, K. (2011). Believe it or not: how much can we rely on published data on potential drug targets? [Comment
    Letter]. Nature reviews. Drug discovery, 10(9), 712, doi:10.1038/nrd3439-c1.
    Reuters (2011). U.S. to develop chip that tests if a drug is toxic. http://www.msnbc.msn.com/id/44554007/ns/health-health_care/ – .To5AMnPaixF. Accessed October 6 2011.
    Roberts, T. G., Jr., Goulart, B. H., Squitieri, L., Stallings, S. C., Halpern, E. F., Chabner, B. A., et al. (2004). Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. [Meta-Analysis
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.]. JAMA : the journal of the American Medical Association, 292(17), 2130-2140, doi:10.1001/jama.292.17.2130.
    Sharp, P. A., & Langer, R. (2011). Promoting Convergence in Biomedical Science. Science, 333(6042), 527, doi:10.1126/science.1205008.
    Walker, M. J. (2011). The major impacts of James Black’s drug discoveries on medicine and pharmacology. [Biography
    Historical Article]. Trends in Pharmacological Sciences, 32(4), 183-188, doi:10.1016/j.tips.2011.02.001.

  60. lilady says:

    “More later” Yawn.

  61. weing says:

    “The problem is extrapolation between evolved complex systems.”
    Some people can extrapolate, some can’t.

  62. Harriet Hall says:

    The question was: “If a new drug came out that worked great in cell culture models, but 90% of the rats who it was given to developed tumors and died, would you recommend human clinical trials?”

    Dr. Greek answered “Tamoxifen,” which clearly doesn’t meet that description.

    And then said he would recommend human trials for a drug that killed 90% of the test animals.

    Nuff said.

  63. David Gorski says:

    More later

    Is that a promise or a threat? :-)

    My goodness. I think that I’ve figured out a new term for Dr. Greek’s “debate” style. It’s “argument by verbal tsunami.” And SBM readers occasionally criticize me for being too verbose! Talk about paragraph after paragraph after paragraph of tendentious, repetitive tsunamis of verbiage! Dr. Greek is clearly drowning out his opponents to the point where they throw up their hands and give up, concluding that countering every claim Dr. Greek tries to make—or even evaluating them to determine which are reasonable, which are not, and which are not supported by the references he cites and the arguments he makes—is just not worth the amount of work it would take. In blog discussions, it’s also a variant of threadjacking, given that Dr. Greek has, through sheer quantity of his verbiage, taken the thread in a direction that panders to his personal hobby horse. Unfortunately, Dr. Greek’s verbal waterfall (yes, I know I’m mixing metaphors) has worked with evilrobotxoxo (and probably others).

    Of course, what Dr. Greek is doing is a variant of what those of us in the skeptic biz are unfortunately all too familiar with when dealing with creationists; i.e., the Gish Gallop. Sure, it’s a more sophisticated form of the Gish gallop in that Dr. Greek doesn’t just make stuff up the way Dwayne Gish used to. Also, not being able to take advantage of time limits that exist for in-person debates, he has to step up the verbal torrent a bit. So what Dr. Greek does do (and here is where he shares commonality with Dwayne Gish) is to drown his opponents in a torrent of claims, factoids, and—shall we say?—questionable interpretations of history in order to control the agenda and force his opponents to spend so much time countering them that they don’t have the time (or the energy) to make positive points of their own. Where he is more sophisticated is that, unlike the case for Gish, most of his references are legitimate scientific papers. However, his citations and examples might or might not support his point. (When examined more closely, often they do not, as those who have pointed out for specific examples.) The problem countering such an assault is that it takes far more effort to go and check to see which of Dr. Greek’s examples and citations actually do support his arguments (not very many), which ones don’t (quite a few), and which ones are spun (probably the majority). The Tamoxifen example is a perfect one. Tamoxifen is a drug whose history is best summed up by the words of the Grateful Dead, “What a long strange trip it’s been,” and by Greek’s own references it isn’t an example that refutes the point behind the question asked, although Dr. Greek does labor mightily to convince you that it does.

    One also notes that Dr. Greek, when confronted with an example that he can’t counter (the development Blalock-Taussig shunt or transplantation surgery), retreats into the “let’s have a public debate” tactic so favored by those making his sorts of arguments:

    After our prediction debate lets publically debate what you said about the BT shunt. For a surgeon, you are leaving out a few somewhat important details. But thats the problem, David. You will never put yourself in a position where you can be held accountable for spouting nonsense or misrepresenting facts, history, and positions.

    Uh, no. Invitation declined. But thanks anyway.

    Like evilrobotxoxo, whose criticism of Dr. Greek’s lapses of logic, science, and argumentation are so spot on that I wish he or she would continue to deconstruct them but fully understand why the desire isn’t there, I “have evaluated his [Greek's] claims, and I find that they simply do not merit a commitment of my time beyond writing this post.” In fact, I’m not sure that they merit even the time I’ve already spent and am spending now. However, if there’s one shortcoming I have, it’s that I sometimes can’t resist wrestling with the proverbial metaphorical pig in mud even though I just get dirty and the pig likes it. If that weren’t the case, I wouldn’t have been such a persistent blogger for the last seven and a half years. There are, I note, limits even to my penchant for getting dirty in this fashion, limits that I’ve pretty much reached right now.

    In any case, I’ve written about my feelings with regard to debating people making such claims. I will paraphrase a historian whom I greatly admire: Debating people like Dr. Greek is “like trying to nail a blob of jelly to the wall.” The vast majority of the time, it’s a waste of time and effort. I trust that any science-based objective observer will see that this simile applies quite well to the prospect of debating Dr. Greek. If there’s one talent that he’s unequivocally demonstrated himself to have, it’s the talent to be the jelly that you can’t nail to the wall.

    In any case, I need to leave for work; so no more fun (if any fun) until this evening.

  64. mousethatroared says:

    I know this isn’t really on topic to the article, but I found this really exciting and I wanted to share.

    http://www.nature.com/news/human-embryonic-stem-cells-restore-gerbil-hearing-1.11402

  65. mousethatroared says:

    Also, Thanks for the article, Harriet Hall. This sounds like by kind of book. Since I am currently dealing with a teen-age dog, I’ll make sure to compare to my kids upcoming teen-age years. One difference, of course, is that humans are teen-agers for so much looooonger. :)

  66. DugganSC says:

    @Dr. Greek
    :) Well, I’ll freely admit to being somewhat ignorant on many details of the medical field. Somehow, they forgot to cover it in my Software Engineering courses. That said, I do feel like you can’t have it both ways. Either animal models have been helpful or they haven’t (I suppose that one could make a third argument that they’re helpful but at too high of a cost, but I don’t see the evidence yet for that). It looks like, so far, animal models are the best method we have. They’re not perfect, but there’s nothing else which approaches them for success.

    I always learn such interesting things on this blog.

  67. Ray Greek MD says:

    I will address a couple more points then summarize my view of this exchange and my position. People are missing the big points and asking what are essentially the same questions or committing the same fallacies over and over so I think we have reached the point of diminishing returns.

    Tamoxifen is an excellent example of the concept that tumors in animals do not translate to tumors in humans. Hence the question regarding 90% of rats was answered. Penicillin kills 100% of certain strains of guinea pigs and hamsters. Again, this illustrates that toxicities simply do not translate in a predictive fashion. I could provide volumes on drugs that were toxic to animals but not humans. The length of the list is not important nor is the percentage of animals affected: 70%, 90%, or even 100%. The concept asked about in the question was lack of translation and I established that concept as well as answering the question very directly. Mechanisms simply do not translate in a predictive fashion. The Pharma literature supports this. Denying this concept does not change its reality.

    The animal model community routinely uses the term “animal model” as a single class. When I say that animal models gave a PPV of such and such, that is what the articles says. Fault them for their terminology. I certainly do. Most papers actually commit the error of counting as a positive any animal exhibiting the toxicity in question but then do not count the negatives the same way. Few break the animal model into species or strains. But those that do, reveal PPVs in the same general area, which are far less than what is considered predictive in medical science. So when I say the animal model does not predict ADMET or efficacy or mechanisms or whatever, I mean the animal model as a paradigm and or individual species tested individually. There is no subterfuge here and as the literature conflates the term my use is actually more nuanced and hence more honest.

    I do not believe PPV etc should apply to “experiments.” I believe the binomial classification table can be used to assess any modality that claims to be predictive. It would be silly to use it in judging basic research or anything not claiming to be predictive, as I have stated many times. Wikipedia use an example of drug sniffing dogs to catch drug smugglers in how to calculate PPV etc. Any modality can be assessed with this method

    Water is incredibly toxic if given in high enough dose. Any physician should know this.

    On to some general themes.
    1. In order to understand our position a person needs to have a working knowledge of philosophy of science, the empirical evidence from many fields comparing animal and human results, the lab animal literature, complexity science, evolutionary biology with an emphasis on evo devo, the drug development literature, as well as general science principles including how to perform simple calculations from the binomial classification table. One also needs critical thinking skills and an awareness of Dunning-Kruger. One needs self-honesty.

    2. Massimo Pigliucci, writing in his book “Nonsense on Stilts:”

    A recurring theme of this book is that one cannot simply trust authority no matter how, well, authoritative it may appear to be. There is, unfortunately, no shortcut to using one’s brain and critical sense and doing some background research before taking a position. p90

    Most people that have studied this topic, including me, say it takes quite a bit of time and effort before understanding it. I often likened learning about this topic to taking a course in organic chemistry. There is no way anyone is going to learn organic via blogs. Neither is there anyway one is going to learn it without reams of material (the textbook). So criticizing the teacher/presenter for writing reams of material is irrational. Self-honesty via Dunning-Kruger demands that the readers of this exchange ask themselves if they are competent in everything listed in #1. If the reader is not, and based on the content comments, the commenters, at least, are not, then complaining about the amount of material presented is irrational. If you don’t want to learn organic chemistry, don’t take the course. But if you do, don’t go into the course assuming you know more than the teacher and then complain about how hard the course is or how much material you have to learn.

    Steven Novella wrote on 4-10-11 in his NeuroLogicaBlog the following regarding fringe beliefs:

    Proponents of theories and ideologies are always looking for that knockout punch – the smoking-gun evidence that proves their beliefs in a single stroke. Most theories are too complex to be established by a single piece of evidence, and require multiple independent lines of evidence to establish them. But there are often cases in which a single solid piece of evidence can push a theory over the line to general acceptance. (Emphasis added.)

    Available at http://theness.com/neurologicablog/?p=3089

    Shanks and I developed a theory that explains empirical evidence from a variety of fields. Our theory (not hypothesis) draws from diverse fields and accordingly requires quite a bit of attention if one wants to understand it. Looking for a knockout punch before you understand the theory is unlikely to be fruitful unless you have an agenda.

    3. Claiming someone is wrong is not the same as proving it. I stand by my offer to debate this topic under the conditions I listed in my blog. Videoing my presentation beforehand, vetting it with referees who are experts in the above-mentioned fields and having those same referees to rule on items of contention is about as fair as it gets, and would satisfy all of David’s supposed reservations about my debating techniques. The fact that he still refuses speaks volumes even if you do not have any clue what I have been writing about in this exchange.

    4. If someone really wants to understand this topic a good beginning would be the books and article listed at
    http://www.afma-curedisease.org/resources.html
    under the Recommended Reading sections. None of these are by me. But if you do not understand the concepts in these sources there is no way you will understand our position. You cannot understand partial differential equations before taking calculus I. The sources listed are obviously minimal. Many people (myself included), will need (needed) more in order to understand the concept if it is outside your area of education.

    After learning the very basics about the science, THEN read what I have written. I have not gone into the detail of say, evo devo and complexity science in those articles. They are articles that employ such concepts not articles meant to educate the reader on the concepts or fields.

    5. Finally, when I lecture to university classes on this topic I always state that the opposition I encounter is not primarily incompetence in general science but incompetence in critical thinking. Very few scientists have the background in the various areas of science to address our position. That having been said, they could study the areas, become competent and then dissect our position. That is fair! But that is not what happens. No, what happens is a series of fallacies and accusations. Classic example of what we as skeptics try to combat. In his book “Hopeful Monsters,” Nicholas Mosley discusses the way the scientific community responded to the Lamarkian ideas of the biologist Paul Kammerer: “But what is striking about the objections to Kammerer on the part of mainstream biologists . . . was that they did not point out rationally, as they might so easily have done, the flaws in his arguments and procedures; they seemed intent on impugning emotionally his honesty and even his sanity; they claimed that he was ‘cooking’ his results – even those that were so obviously tentative.”

    One thing is certain, if I am wrong, I am spectacularly wrong and deserve what I get. But if I am right, this exchange will be used in critical thinking courses.

    So, thanks to everyone for reading all this! If anyone wants to pursue a debate in any venue or wants a copy of one of the books, please contact me. “Animal Models in Light of Evolution” was written for people with doctorates in science that don’t mind getting in to a certain amount of depth in areas of science they might not be familiar with. It is not an easy read. “FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed” was written for people challenged by or uneducated in science or at least some areas of science. It is an easy read. I will probably send you one for free if you read this exchange.

    Thanks to the editors of this website for allowing the discussion!
    And! I promise to learn more about HTML before we do this again.

  68. Harriet Hall says:

    @Ray Greek,

    “if I am wrong”

    You are not entirely wrong. That’s the pity. You have some good points to make, but you undermine them by going too far. I would be more disposed to take you seriously if you didn’t say so categorically that animal models are “never” predictive of human responses. That is demonstrably not true.

  69. ConspicuousCarl says:

    Ray Greek MD said:
    Second, most people make this exact argument and what they mean is either that animal model A did not predict human response for outcome P but did predict outcome Q and therefore was predictive for one but not the other.

    I don’t think that is what they mean. You are looking at this as though everyone is just saying it happened to be right in this case, therefore it was predictive.

    I will have to let your fellow doctors argue the rest in detail, but the way I have heard animal research mentioned in the past is in regards to whether or not a particular animal with a particular disease, in general, has a history of responding in similar ways to humans, and based on that assigning more or less confidence that a new animal study might be transferable to humans. I have not heard any of them refer to animal predictability with the kind of random success credit you are describing.

  70. DugganSC says:

    On a side note, since drug-sniffing dogs were mentioned, the last I heard, their objective efficacy is under question. Basically, they found that whether the handler believed drugs to be present had a greater influence on whether the dog sounded an alarm than the actual presence of drugs.

    @Dr Greek:
    I appreciate that you’re willing to continue to expound upon the topic, and relatively objectively rather than take things personally. As someone who’s held extreme views, though, I’ll warn you that extremities are hard to defend (admittedly, a lesson I’ve also received in martial arts classes). If I understand the citations by others, you’re against animal usage in general. It’s something that you feel very strongly about, and it’s painful to not state that absolute in your arguments, even when you’re trying to find common ground with another person. You don’t want to compromise yourself even though you know that a minor level of compromise might help win people over to your point of you. I respect that. As someone who’s pro-life, I’ve been faced with that issue before. Frankly, there are rare cases where abortion is the right decision and there’s a minority of cases where it’s morally grey. If I take a hardline stance, I alienate the very people who’d agree with me in 95% of the cases and make them want to oppose me. I’ll admit that it’s still something I wrestle with, but as one principled person to another, take a good look at whether a change of approaches may do more good than harm.

  71. David Gorski says:

    One also needs critical thinking skills and an awareness of Dunning-Kruger. One needs self-honesty.

    My irony meter just exploded again.

    Finally, when I lecture to university classes on this topic I always state that the opposition I encounter is not primarily incompetence in general science but incompetence in critical thinking.

    Dang! My backup irony meter just exploded, too!

  72. David Gorski says:

    Most people that have studied this topic, including me, say it takes quite a bit of time and effort before understanding it. I often likened learning about this topic to taking a course in organic chemistry. There is no way anyone is going to learn organic via blogs.

    I wasn’t going to go there, but you decided to go there first, so now I feel justified in responding: Nor is anyone going to really learn about research, basic or translational, without actually doing basic or translational research. There is no way anyone is going to learn how to do research via blogs or just reading about it in textbooks or journals.

    Neither is there anyway one is going to learn it without reams of material (the textbook). So criticizing the teacher/presenter for writing reams of material is irrational.

    Nonsense. You are not being criticized for just “writing reams of material.” That is, of course, a straw man fallacy, and you’re too smart not to realize that that’s what it is. I write “reams of material” every week and only occasionally receive criticism for excessive length. No, you’re being criticized for writing reams of material of questionable relevance, much of which doesn’t actually support your arguments, and the interpretation of some of which is highly debatable. In other words, you’re being criticized for burying your “students” in material that obfuscates rather than enlightens.

    Self-honesty via Dunning-Kruger demands that the readers of this exchange ask themselves if they are competent in everything listed in #1. If the reader is not, and based on the content comments, the commenters, at least, are not, then complaining about the amount of material presented is irrational. If you don’t want to learn organic chemistry, don’t take the course. But if you do, don’t go into the course assuming you know more than the teacher and then complain about how hard the course is or how much material you have to learn.

    It is quite possible part way through a “course” (or from previous experience with the “teacher”) to realize that the teacher is himself a victim of the Dunning-Kruger effect and/or that he has an agenda to which he goes to great lengths to fit the material, rather than teaching the material reasonably objectively. Nobody expects complete objectivity. That is impossible in a human being. We do, however, expect that the other side will be represented accurately and fairly and that the strengths and weaknesses of one’s own argument will be recognized. You have failed at that.

  73. David Gorski says:

    You are not entirely wrong. That’s the pity. You have some good points to make, but you undermine them by going too far. I would be more disposed to take you seriously if you didn’t say so categorically that animal models are “never” predictive of human responses. That is demonstrably not true.

    Indeed. Dr. Greek boxes himself in with his steadfast refusal to admit to the existence of even one good predictive animal model, as if doing so would completely invalidate his overall argument. Here’s a hint: It wouldn’t, necessarily, unless his argument is that all animal models are utterly useless and that there has never been a useful animal model to predict human responses to treatment. Clearly, he doesn’t have sufficient confidence in his own position to admit even one exception, not even transplantation, insulin, or the Blalock-Taussig shunt, to name a few. That’s some serious black-and-white, all-or-nothing thinking going on there, all gussied up with “reams of material” to make it appear nuanced. It is not. When asked to name a single good predictive animal model, Dr. Greek just can’t bring himself to do so, implying that he thinks that every “predictive” animal model ever utilized was useless. And, no, this isn’t a straw man position; it’s an inference from Dr. Greek’s arguments and his reaction to such questions. When presented with an example of an animal model that was reasonably predictive of human physiology, Dr. Greek tries very hard to redefine it as either not being a “predictive” animal model or as being “basic research,” because, clearly, to him no animal model is ever predictive of human responses.

    The funny thing is, those of us sparring with Dr. Greek readily admit deficiencies and shortcomings in animal models and that some of them are actually not very good at all. However, we also point out the ones that do work. In this, we demonstrate considerably more nuanced thinking than Dr. Greek does in that he is unwilling or unable to admit even a single success from an animal model in predicting human responses. There’s the difference, and there’s the pity. In fact, I think I could, just by being a bit more flexible, argue Dr. Greek’s position better than he does and with 1/3 the verbiage.

  74. Calli Arcale says:

    Dr Greek,

    Okay, I can see that having a conversation with you is going to be difficult. You did not address my point about your curious dichotomy between “basic research” and some unspecified other form of research, where animal models are only predictive and useful in one of those and utterly useless in the other. Instead, you decided to blame me for misunderstanding your vague and meandering posts. It’s true — it did take three readings of your post for me to figure out that you were conceding that basic research can be done on animals, but attempting to draw a nebulous dichotomy between that and what one must conclude by context (since you did not specify it) is clinical research.

    If it takes people three readings of your very long posts to even get a glimmer of your point, that is not due to their lack of interest or skill. It is because you are either a very bad writer, not terribly interested in people actually knowing what your point is. I understand you probably will not regard this as constructive criticism of your writing style, since you clearly feel quite comfortable with your prose. You are also clearly quite comfortable of your position (however badly stated it may be) on animal testing. Comfortable enough, on both counts, to completely close your mind.

    Sadly, I think Dr Hall was correct. You were not coming into this thread with honest intentions. You were coming in to grind an axe. At least the axe is tangentially on topic, but it’s very unfortunate that the content of the original post in this thread has been largely lost now. The discussion on the ethics of veterinary medicine was fascinating. You stomped on it rather effectively. I will not humor you further.

  75. Calli Arcale says:

    Oh, and this might amuse:
    http://xkcd.com/169/

  76. Patrick says:

    Thank you Dr. Greek for steering this discussion into a direction it doesn’t belong; this is about the merits of evolutionary medicine, a topic that Dr. Hall has initially been very critical of. However, in this context, she embraces it. Find another thread to debate this topic.

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