As one might expect, AFMA’s position that using animals as predictive models is an invalid scientific paradigm often ignites an intense and highly emotional response from a misinformed public, who believes erroneously that eliminating animals from medical research will set back medical science, as well as from the research community, which has a vested interest in continuing the practice.
Rather than waste our time and resources responding to commentary that attempts to sidetrack the discussion from the science involved in the issue, it is AFMA’s policy to respond only to commentary in peer-reviewed journals or books.
To read recent comments to criticisms of AFMA and our position, click on the following:
4. AFMA and the October 2008 issue of Nature Medicine (October 2008)
3. Response (unprinted) to op-ed by Frankie Trull in LA Times. (August 2008)
2. Conn and Parker accuse of taking quotes out of context. (June 2008)
1. Response (indirect) to Skeptic article By Skeptic contributor Harriet Hall MD. (June 2008)
4. AFMA and the October 2008 issue of Nature Medicine. (October 2008)
The August 2008 issue of Nature Medicine (NM) featured an editorial about the use of nonhuman primates in research. NM is a very prestigious journal. According to their website: “The 2007 impact factor for Nature Medicine is 26.382, according to the Thomson Reuters Journal Citation Reports. This places Nature Medicine as the top primary research journal in Medicine (Research and Experimental).”
Shanks and Greek wrote a letter regarding the editorial that was published (the correspondence can be viewed at http://www.nature.com/nm/journal/v14/n10/full/nm1008-1012a.html if you have a subscription or are willing to pay to download). Two other letters were published regarding the use of nonhuman primates and the editors then responded to all three of the letters. AFMA would now like to address that response.
Before we examine the issues raised, AFMA would like to thank NM for printing the letter and for addressing the issue at all. Most journals are not as courageous and NM stands out as the leader they are for addressing the issue and allowing responses.
Shanks and Greek stated, with supporting references, that nonhuman primates, while viable for obtaining knowledge are not predictive models for humans. NM then stated, in part, the following which is very typical for the industry.
- Animal models while not being predictive are useful.
- Even if the model does not predict human response it can still be used, as it is the best research method we have. In vitro and in silico are not predictive.
- Even if the model does not predict human response it can still be used, as the more we understand about the model the more we can make the model mimic humans.
- They cite the “usefulness of experimental autoimmune encephalomyelitis as a model of multiple sclerosis . . . because successful therapies have emerged from their use.”
- Animal models should not be abandoned because it is very difficult to develop new drugs.
- It took 50 years to develop a polio vaccine so we should not expect great breakthroughs like an HIV vaccine to occur quickly.
We will address the above in order.
1. Animal models while not being predictive are useful.
In Shanks and Greek’s letter they acknowledged that animals could be used in science for many purposes. Their only point was that animals such as nonhuman primates are not predictive. The editors at NM are changing the subject when they justify using animals because they are useful. The issue here was prediction not usefulness. Further what do they mean by useful? Useful how? Useful for whom? Any research method can be useful in the most general sense of the word, but that does not mean it should be funded. To attempt to justify animal models because they are useful is to cloud the real issue of predictability which was the point Shanks and Greeks were making.
2. Even if the model does not predict human response it can still be used, as it is the best research method we have. In vitro and in silico are not predictive.
It is true that in silico and in vitro are not predictive for drug toxicity and other areas however neither are animal models and in vitro and in silico using human tissue does give us a true picture of what is happening in humans in disease research even its uses are limited. Using in vitro techniques to study HIV led to the 2008 Nobel Prize in Medicine or Physiology. Such research methods are underfunded compared to animal models. However, the relative merits of various research methods are immaterial to the issue of predictability.
If the purpose of the model is to predict human response and the model does not accomplish this, then the model has not fulfilled its purpose. Whether another technique can fulfill the purpose is irrelevant as the question remains, “Does the animal model predict human response?” Either it does or it does not. Astrology cannot predict the future therefore it is useless for that purpose. Just because no other modality can predict the future does not justify using astrology to see into the future.
The burden of proof for using animals as predictive models is on the animal modelers themselves. Animal models are sold to society on the basis of prediction. If they are not predictive then the scientific community should stop telling society that animal models will make their drugs safer (by predicting human response) and help us cure diseases (again by predicting how the disease affects humans).
3. Even if the model does not predict human response it can still be used, as the more we understand about the model the more we can make the model mimic humans.
This assumes we can make the model more accurately resemble humans. Genetically modified animals have shown this to be false. Davis Horrobin [D. F. Horrobin, Nat Rev Drug Discov 2, 151 (Feb, 2003)] wrote in 2003:
Does the use of animal models of disease take us any closer to understanding human disease? With rare exceptions, the answer to this question is likely to be negative. The reasoning is simple. An animal model of disease can be said to be congruent with the human disease only when three conditions have been met: we fully understand the animal model, we fully understand the human disease and we have examined the two cases and found them to be substantially congruent in all important respects...
Will genetically modified mice lead to better understanding of human disease? The only appropriate answer at this stage is perhaps or perhaps not. But the omens are not good and the confidence of so many in the Castalian establishment seems to me to be entirely misplaced. Why am I so sceptical?
First, most human disease is highly unlikely to be due to a single abnormal gene. It may well be that the consequences of catastrophic failure of a single gene can be partly understood with the assistance of appropriate genetically modified mouse models. But such diseases are for the most part rare and tend, in any case, to be reasonably well understood from direct human studies.
Second, consistent phenotypes are rarely obtained by modification of the same gene even in mice. The disruption of a gene in one strain of mice may be lethal, whereas disruption of exactly the same gene in another strain of mice may have no detectable phenotypic effect. If this is true of the impact on one gene of the rest of the mouse genome, how much more is it likely to be true of the impact of the rest of the genes in the human genome?
Third, the great majority of human diseases that affect large numbers of the population are likely to be the result of the interaction of several different genes. If one mouse gene is so difficult to understand in a mouse context, and if the genome of a different inbred strain of mouse has so much impact on the consequences of that single gene's expression, how unlikely is it that genetically modified mice are going to provide insights into complex gene interactions in the non-interbred human species? At the least one must conclude that most predictions of near term human benefit are not only overblown but are actually fraudulent.
Because animals are complex systems and as such small pertubations result in changes in the system as a whole in a nonlinear fashion, the only animal that will ever accurately resemble a human is the human in question.
4. They cite the “usefulness of experimental autoimmune encephalomyelitis as a model of multiple sclerosis... because successful therapies have emerged from their use.”
This is problematic for several reasons. 1) Just because a treatment followed temporally the use of an animal model does not mean the use of the animal model caused the treatment to be discovered. 2) If the animal model was successfully used was it necessary? The position of the animal model industry is that such models are necessary for science to discover cures and treatments. 3) A review of the literature casts doubt on whether the experimental autoimmune encephalomyelitis model of multiple sclerosis has been useful at all in explaining human multiple sclerosis. The burden of proof for claiming it has been useful in this fashion is on the person making the claim.
5. Animal models should not be abandoned because it is very difficult to develop new drugs.
It is difficult to develop new drugs, that is why society and shareholders should demand tax, charity, and company dollars be used only on scientifically viable research methods. Just because something is hard does mean we abandon science and the scientific method in search of answers.
6. It took 50 years to develop a polio vaccine so we should not expect great breakthroughs like an HIV vaccine to occur quickly.
Science is more advanced today than in the first half of the 20th century when the search for the polio vaccine was waged. It is not unreasonable to expect faster progress in light of more knowledge. Further, one reason it took so long to develop the polio vaccine was the use of animal models that reacted very differently than humans. Those who do not learn from history are doomed to repeat it.
These themes are explored more fully in Animal Models in Light of Evolution by Shanks and Greek, due out in 2009.
Again, AFMA thanks NM for addressing these issues and gratefully acknowledges their leadership in the field.
3. Response (unprinted) to op-ed by Frankie Trull in LA Times. (August 2008)
On August 18, 2008 an op-ed by Frankie Trull, president of the Foundation for Biomedical research appeared in the LA Times (http://www.latimes.com/news/opinion/commentary/la-oe-trull18-2008aug18,0,7681668.story). I wrote the below in response but it was rejected by the LA Times which is unfortunately not unusual. Despite their protestations otherwise, the media is rarely interested in both sides when it comes to challenging the animal experimentation industry.
The debate over the use of animals in research has escalated lately due in part to the acts of terrorism committed by those opposed to such use. Society has heard the philosophical arguments for and against using animals in biomedical research but the scientific arguments have not received as much attention.
There are many ways animals can be and are being used in science in general that are viable from a scientific perspective. Dissecting animals in high school teaches the student fundamental concepts about animals and life in general. Many patients are alive today because of tissue harvested from animals such as aortic valves, insulin, and lung surfactant. Animals can be used in research to search for fundamental truths; such as the fact that the cell is the building block of life and that genes are how heritable traits are transmitted from generation to generation.
Importantly however, there are ways in which the use of animals is not scientifically viable. Animals cannot predict the response of humans to drugs or disease. I am not saying animals and humans have nothing in common in terms of disease and drug response, merely that the commonalities are insufficient to be predictive. Testing a drug on a monkey or rat will not predict what the drug will do to you. Even humans cannot reliably predict drug and disease response for other humans. Vioxx and Rezulin are but two examples. Many patients responded well to those drugs but others died.
Physicians have noticed for decades that humans do not respond identically to drugs or disease. Even identical twins do not always react the same. Because of advances in science from research, such as the Human Genome Project, we now understand that very small differences in genetic make-up or environment can lead to a drug curing you but killing your sister. Today medicine is aiming for, and in some circumstances has achieved, the goal of personalized medicine. Personalized medicine is diagnosis and treatment based of your unique genetic make-up. We are already seeing this in treatments of cancer and other diseases.
If one human cannot predict disease and drug response for another it is silly to think another species will do better. Yet this is what society is told by many in the animal-based research community. “Your dog or your child” is a frequent refrain. The fact is that using dogs or mice in research is not going to make medications safer or more effective. Using animals is not going to inform us about HIV/AIDS in humans. In order to find a vaccine or cure for AIDS we must study human tissues and humans in general. Fortunately this is being done but animal studies continue to garner the lion’s share of grant money.
Those with a vested interest in using animals as predictive models for humans also list what they claim are the past successes of using animals. These claims have been questioned and in some cases refuted by those without a financial interest in using animals. Regardless, today we want medical treatment based on our genes not our dog’s.
I condemn unconditionally terrorism such as that perpetrated in Santa Cruz recently. I also condemn wasting taxpayer money on research methods that have been proven ineffective when patients need cures. These are two separate issues and society should carefully consider them as such. Opposition to violence does not imply support to an outmoded status quo.
Ray Greek MD
President, Americans For Medical Advancement
AFMA supports some uses of animals in research but condemns uses that are not viable.
2251 Refugio Rd
Goleta, CA 93117
2. Response to Conn and Parker’s accusation of taking quotes out of context.
In Drs Greek’s first book Sacred Cows and Golden Geese, we quoted an article in the September 21, 1997 Atlanta Journal Constitution in which Dr. Mark Feinberg, a leading AIDS researcher stated:
To make an AIDS vaccine, we really need to know more about the basic human immune system and how it works. They knew next to nothing about it when they made the polio vaccine, but that's not going to work here. We need to understand more about how the immune system recognizes and deals with HIV antigens. Clearly few, if any, people can deal with HIV once they're infected with it; nobody that we know of has ever cleared the virus from their bodies after infection. Somehow we have to demand that the vaccine be better than that. I think the way of doing that is doing studies on human beings at very early stages of the development of vaccines to test whether certain ideas work; then you go back to the laboratory to modify them and then back to human beings. What good does it do you to test something in a monkey? You find five or six years from now that it works in the monkey, and then you test it in humans and you realize that humans behave totally differently from monkeys, so you've wasted five years.
We went on to say:
Of course, because Dr. Feinberg has a vested interest in animal-models he went to say that animal models are ``incredibly important.'' He explained quite well why they are useless but did not go into detail as to why they are so ``incredibly important.''
Elsewhere in the book, we also said: “Monkeys do not die of AIDS and humans do” but that statement was not attributed to Dr Feinberg as it was ours.
Compare that with the below from The Animal Research War (Palgrave 2008).
When Dr. Feinberg had a chance to speak for himself, he said, “There are many instances where the use of animal model research is absolutely essential for evaluating the safety and efficacy of [AIDS] candidate vaccines. Moreover, the statement that "Monkeys do not get AIDS; humans do," is completely false. The SIV [simian immunodeficiency virus] infection model for AIDS has been extremely important for understanding critical aspects of AIDS pathogenesis that cannot be studied in humans. I do not wish to be held responsible for comments . . . that have been so removed from their context that they no longer convey the meaning I had intended.” (Personal email from Mark Feinberg, MD, PhD, to Charles Nicoll, PhD.
There are several things to note about what was written in The Animal Research War:
1. While our source was the Atlanta Journal Constitution Conn and Parker quoted an email from Feinberg to Charles Nicoll, a Berkeley professor who had contacted Feinberg in preparation for a debate with Ray Greek. If one member of the animal model community chastises another for a quote pointing out the flaws of animal-based studies, we do not find it surprising that the criticized member would respond as Feinberg did to Nicoll.
2. Feinberg’s email misquotes us when he said, referring to our book, that we say "Monkeys do not get AIDS; humans do." What we actually said was: “Monkeys do not die of AIDS and humans do.” That is not a subtle difference. However, in point of fact injecting HIV into monkeys does not result in human AIDS. Injecting SIV into monkeys results in simian AIDS; two different viruses and two different diseases.
3. Feinberg accuses us: “I do not wish to be held responsible for comments . . . that have been so removed from their context that they no longer convey the meaning I had intended.” In the very next sentence, after the Feinberg quote we again quote Feinberg as saying that animal models are “incredibly important.” The power of the Feinberg quote lies in the fact that he is a true believer in the animal model and yet said what he did about testing vaccines on monkeys. His vaccine statement was not put into a different context precisely because our point was based on the fact that he was a true believer.
4. Despite Conn and Parker’s accusation, Feinberg had a chance to speak for himself in the Atlanta Journal Constitution. During the interview that led to the article he was not surrounded by hostile animal rights people with guns forcing him to say what he did.
5. As Feinberg’s position that “… animal model research is absolutely essential for evaluating the safety and efficacy of [AIDS] candidate vaccines.” Compare that to an article by Jocelyn Kaiser in Science April 4, 2008:
NIAID called for a summit earlier this year following the suspension in September of an international trial of a Merck AIDS vaccine, which failed to protect against HIV infection and may even have made some people more susceptible (Science, 16 November 2007, p. 1048) . . . The summit also considered another problem: the need for a predictive animal model. Participants agreed that the rhesus macaque system now used to test potential vaccines isn't working well.
In point of fact, animals have not predicted human response to HIV vaccines. Over fifty vaccines have tested well in monkeys; none have been effective in humans.
If all accusations of us quoting out of context are examined as above you will find the above to be typical. Judge for yourself whether we quoted Feinberg out of context.
1. Our response to Skeptic contributor Harriet Hall, MD re: our Skeptic article
Harriet Hall MD, a contributor to Skeptic magazine posted the website science based medicine on 03 Mar 2008 at 2:16 pm (http://www.sciencebasedmedicine.org/?p=61).
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.
Her response was actually a response to a very long diatribe by David H. Gorski, MD, PhD who (according to the website) is a surgical oncologist specializing in breast cancer and an Associate Professor of Surgery at the Wayne State University School of Medicine based at the Barbara Ann Karmanos Cancer Institute as well as an NIH-funded investigator. To address Gorski’s entire rant would require a book (we refer the reader to Animal Models in Light of Evolution). But we will address Dr Hall’s brief comment here.
Dr Hall writes a column for Skeptic and AFMA applauds her efforts in educating readers to the differences between science and pseudoscience. Her columns provide nice illustrations and demonstrate the thinking process involved in real science and scientific evidence. She defends critical thinking and AFMA strongly defends all efforts at demonstrating and teaching critical thought.
However, in this case we must disagree with Dr Hall. Contrary to Dr Hall’s statement that pseudoscience seeks to demonstrate whereas real science questions, science teaching and the teaching of critical thought seek to demonstrate. AFMA’s computer dictionary on Microsoft Word (Encarta® World English Dictionary © 1999 Microsoft Corporation) defines demonstrate as:
1. to explain or describe how something works or how to do something
2. to show or prove something clearly and convincingly
AFMA is primarily an educational not for profit. Other educational not for profit organizations include the National Center for Science Education (http://www.natcenscied.org/default.asp), which provides educational material and lectures on evolution. On their website (as of 6-20-08) they state: “(NCSE) defends the teaching of evolution in public schools.” If Dr Hall objects to organizations involved with science that demonstrate principles or defend positions we respectfully suggest she rethink her position, as we seriously doubt she really thinks such organizations are pseudoscience groups.
Science or critical thought education do not perform the same function as scientists doing research. A physics textbook or class does not question the 2nd law of thermodynamics, it teaches or demonstrates (in the laboratory portion of the class) why it is true. Neither do organizations that defend evolution question it in the sense of the word Dr Hall is using it. AFMA does research and in that sense we do question. Indeed in the Skeptic article Dr Hall was indirectly commenting on we delineate what would falsify our position. That is consistent with true science.
As to our “try[ing] to substitute activism for the scientific process,” AFMA is not exactly a constant presence on the lecture or talk show circuit or radio and television waves. Neither are we marching and waving signs in front of laboratories. In reality it is very difficult for us to attract any media attention or fund raise as: 1. AFMA is not an animal protection group so we do not have a product (cuddly little animals) that tugs at the heartstrings; 2. Although our goal is patient driven as soon as one brings in the issue of animals in science one is mistakenly labeled pro-animal and thus anti-patient therefore fundraising as a patient advocate organization is challenging; 3. Because we focus solely on the science of using animals primarily as predictive models and secondarily in all the other ways animals are used in science our message is perceived as boring or esoteric. (We question using animals as predictive models and readily acknowledge the scientific viability of using animals in other ways.) Over the past year (6/2007-6/2008) we have written a couple of letters to the editor which were published in peer review and lay literature, the Skeptic article, participated in one debate, approximately 5 radio interviews, three newspaper or magazine interviews, and spoken publicly twice (to the best of our recollection). AFMA mainly performs research for books and articles that we hope to have published in peer reviewed journals. We fail to see how our activism is in contrast to the scientific process. We would like to be more active (however one defines that word), but our budget simply does not allow it.
As to how AFMA came to its current position, we refer Dr Hall to the resources on the website.
AFMA respects Dr Hall and appreciates her efforts on behalf of demonstrating the importance of critical thought and science and would be happy to dialogue with her should she desire.
