An in-depth study using GPS-sensors placed on northern bald ibises may finally explain why birds fly in V-formation.
Scientists found each ibis flew at a 45-degree angle positioned an average of four feet behind the bird in front of it. This position is precisely the place to catch the rising air, or “upwash,” from the flapping wings of the bird in front, according to the study published in Nature Thursday.
"Downwash is bad," explained lead researcher Dr. Steven Portugal. "Birds don't want to be in another bird's downwash as it's pushing them down."
"They're seemingly very aware of where the other birds are in the flock and they put themselves in the best possible position,” he tells the BBC.
Just as precise as their positioning, they also timed wing beats precisely so they continuously catch the upwash – their wingtips tracing the same path in the air as the bird in front.
"This can give a bit of a free ride for the bird that's following," he said. "So the other bird wants to put its own wingtip in the upwash from the bird in front."
These results "once again remind us that animals are much more complicated … than we often give them credit for," Kenny Breuer, a professor of engineering and ecology at Brown University who was not involved with the study, told USA Today. "They're reacting in very sophisticated ways to maintain these V formations."
“What these birds are able to do is amazing," Portugal said. "They're able to sense what's going on from the bird in front, where this good air is coming from and how to position themselves perfectly in it. So from a sensory point of view, it's really incredible."
Shocking figures for 2012 disclosed that British universities killed a staggering 1.3 million animals in the name of research, leaving animal welfare advocates expressing their “disgust” at the findings.
Almost 75 percent of those sacrificed were mice, but among the others who suffered in the name of creating better medicine were 124 monkeys, 10 dogs and six emus, reports the Daily Mail.
The figures were obtained in Freedom of Information Act requests by The Tab, a series of student newspapers. The FoI request was submitted to a total of 132 universities and research institutes. Among the 44 universities that replied, a total of 1,329,013 animals were killed between July of 2012 and July of 2013.
Michelle Thew, CEO of The British Union for the Abolition of Vivisection (BUAV) said: “The details of some [university] research will not only surprise but disgust. Some 226,000 fish, 50,000 frogs and 4,250 birds were put to death for vivisection.”
“Many members of the public are under the illusion that all animal experimentation is vital for human health benefits, whereas this couldn’t be further from the truth,” Thew said.
By comparison, 40,248 animals were slaughtered for research by the Institute for Cancer Research.
Andrew Tyler, the director of Animal Aid, said the experiments carried out on animals are unreliable for human medicines, the Daily Mail reports.
“Apart from causing a great deal of suffering to these animals the experiments of this type do not deliver the data that is reliable and productive for human medicine,” Tyler concluded. “It should not happen, especially not at universities.”
The follwing figures represent the number of animals slaughtered for research at universities, according to The Tab:
- Mice: 978,259
- Fish: 278,586
- Rats: 51,218
- Frogs: 5,552
- Birds: 4,246
- Chickens: 2,953
- Reptiles: 2,040
- Monkeys: 124
- Dogs: 10
- Cats: 2
- Emus: 6
“Much of the research of this sort in universities is funded by medical research charities,” said Andrew Taylor. “When we polled people, a huge 80 per cent said they didn’t want their money going into this type of research, so the British public is not happy with this either.”
“I don’t think they know this happens at universities.”
Edinburgh University had the highest death rate, with 226,341 animals being killed, followed by Oxford and Cambridge. Kings College London, Imperial College London and Stirling University in Scotland were the only other three institutions which killed more than 100,000 animals.
Newcastle University used 14 macaques, while Kings College London euthanized 39 marmosets, the Freedom of Information request revealed.
Mr. Tyler’s sentiments were echoed by Ben Williamson, of the People for the Ethical Treatment of Animals (PETA), who said: “These universities need to rethink their policies regarding animal use and align themselves with public opinion, social progress and 21st-century scientific pursuits if they are to stay ahead of the curve.”
“Studying any species other than humans while investigating human diseases is studying the wrong species. More than 90 per cent of drugs that pass animal tests fail in human trials.”
But the Association of Medical Research Charities claims the research being carried out was unnecessary.
“Charities fund projects using animals only when they are satisfied that there is no possible alternative,” said Chief Executive Sharmila Nebhrajani. “That the scientific benefit that will come from the project will outweigh the impact of the experiment on animals and that all animals in the lab are treated as respectfully and humanely as possible.”
One Green Planet writes, “Opinions may range on the issue of animal experimentation, yet it is becoming increasingly difficult to support the use of animals in research thanks to new technological advances like 3-D printers, adult stem-cell research and a technology that mimics standard human muscular functions.”
Public awareness is shaping a cosmetic industry in which an increasing number of countries do not manufacture or sell animal-tested products. This is occurring because enlightened purchasers around the world are using their pocketbooks to demand that companies rely on animal-free research.
Until all animal experimentation has ended, One Green Planet reminds us, we as consumers can increase the corporate world’s motivation to escalate progress by buying cruelty-free products, contributing to charities that refuse to support animal experimentation, and by urging universities and labs to switch to cruelty-free research tools and technologies.
Most people use the phrases animal research and animal experimentation interchangeably. Most people do not use the phrases human research and human experimentation interchangeably. The reason we differentiate research from experimentation on humans is self-evident—research implies consent while experimentation does not. In reality, humans are subject to medical experiments but only if they volunteer or are provided money in exchange. So there is more to the research vs experimentation dichotomy than just consent.
Research implies that the participant might benefit from the study being performed while experimentation implies the probability of the participant benefitting is very low. People volunteer to test new drugs in exchange for money: an oxymoron. While giving people cash in exchange for the use of their body is taboo in our society, hence the euphemism volunteer, some people have this as an occupation and their main source of income. The probability that these volunteers will benefit from testing the new drug is essentially zero.
People who are involved in invasive medical research usually have the disease being studied and seek to derive benefit either directly or indirectly. There are areas of overlap between research and experimentation but most of the time one can easily distinguish between the two. The same is true of animal research and animal experimentation. Consider Nemo.
Nemo is a 700+ pound pig who was recently diagnosed with lymphoma. He was treated for this with chemotherapy at Cornell University Hospital for Animals and is thought to be the first pig so treated. His story can be read at the above link. The Cornell oncologist Cheryl Balkman stated: “We adapted a treatment plan based on what we know is effective in dogs, cats and humans with lymphoma.” This is animal research just as treating a first-time case of a disease in humans would be human research. The purpose of treating Nemo was to cure Nemo or at least make him feel better. It was research because no one had any experience with this disease in pigs and because whatever was done would probably be reported in the veterinary literature so others could benefit from this new knowledge. It was not experimentation because Nemo and his humans wanted Nemo to get better and thus gave their consent just like parents consent for their children to undergo new therapies. Experimentation would have been inducing a disease in Nemo that he probably would not have otherwise contracted and giving him medications, regardless of the origin of his disease, merely to increase our knowledge about the disease or the medication. Nemo’s wellbeing would not be a consideration in experimentation.
Likewise, a new drug called PAC-1 has been shown effective in treating cancers in dogs. The drug is being developed for humans with brain cancer and was administered to dogs from the community who were already suffering from other cancers. Tim Fan of the University of Illinois Veterinary Teaching Hospital stated: “We know that mice will always be used as a traditional model for cancer research. But conventional preclinical models use mice with induced cancers, which fail to faithfully recapitulate the development of natural cancers. This means that novel therapeutics that may be effective in mice might fail in patients that develop cancer spontaneously, as observed in both dogs and people.”
Fan is correct in what he confirms but wrong in what he denies. Yes, drugs that are effective or ineffective in mice might be ineffective or effective in humans but so too might drugs that were tested in dogs. Humans are more closely related to chimpanzees than mice and dogs but chimpanzees are not of predictive value for human response to drugs and disease either.[1-5] Moreover, naturally occurring cancers have too little in common among species for animal models to be of predictive value for humans. Decades of cancer research in mice have proved this. If PAC-1 is effective in humans, and I hope it will be, this will be one instance of an animal—dogs—reacting the same as humans and that is insufficient to claim that dogs offer predictive value for humans. The mechanisms the drug uses for curing cancer may not even be the same in the two species.
Regardless, administering PAC-1 to dogs is an example of research not experimentation. Expecting the results to transfer across species lines is an example of wishful thinking.
The way these drugs were administered to Nemo and the dogs is essentially the way human research is conducted. Humans present to hospitals, usually teaching hospitals, with incurable illnesses and they are given new drugs that may or may not be effective. Even when patients have a non-lethal illness, when that illness crosses a line in terms of interfering with the activities of daily living or pain or disfigurement, such patients may want to try a new treatment despite the risks associated with new treatments. If animal experimentation stopped tomorrow, new treatments for animals would continue in the framework of the above. Experiments on animals such as are performed with NIH grants are rarely conducted on behalf of animals and when they are they should, for scientific reasons, be conducted like the above. We don’t need alternatives to animal experimentation conducted with the goal of benefiting animals; we already have them. We need to mandate that such studies be conducted like the above.
Scientifically, animal research works. Animal experimentation works if the goal is to add knowledge to the world or maybe get an idea for what to study in humans. But experiments on animals do not provide data that has predictive value for human response to drugs and disease. Society wants predictive value and vivisection activists have assured society that animal models provide predictive value. Conflating animal research with animal experimentation is part of this effort.
As long as vivisection activists can conflate experimentation with research they can convince the unknowing that what vivisectors really do with animal in labs is all touchy-feely and composed of warm blankets and chocolate cake. So why worry if that whole prediction thing is not working out? Words have meaning and implications. An industry as large as the animal model industry hires the same consultants political campaigns hire to make sure that when they use a word it conveys the meaning they want it to convey regardless of the validity of the dictionary definition of the word. Vivisection activists and politicians both lie.
1. Shanks, N. and R. Greek, Animal Models in Light of Evolution. 2009, Boca Raton: Brown Walker.
2. Greek, R. and N. Shanks, Complex systems, evolution, and animal models. Studies in history and philosophy of biological and biomedical sciences, 2011. 42(4): p. 542-4. http://www.ncbi.nlm.nih.gov/pubmed/22035727
3. Greek, R., N. Shanks, and M.J. Rice, The History and Implications of Testing Thalidomide on Animals. The Journal of Philosophy, Science & Law, 2011. 11(October 3). http://www6.miami.edu/ethics/jpsl/archives/all/TestingThalidomide.html
4. Greek, R., Animal Models and the Development of an HIV Vaccine. J AIDS Clinic Res, 2012: p. S8:001. http://www.omicsonline.org/2155-6113/2155-6113-S8-001.php?aid=5787
5. Jones, R.C. and R. Greek, A Review of the Institute of Medicine's Analysis of using Chimpanzees in Biomedical Research. Sci Eng Ethics, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23616243
6. Greek, R., Animal Models of Cancer in Light of Evolutionary Biology and Complexity Science, in The Research and Biology of Cancer. 2013, iConcept Press: Hong Kong. http://www.iconceptpress.com/www/site/papers.webView.php?publicationID=BK030A
7. Greek, R. and N. Shanks, FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. 2009, Lanham: University Press of America.
Because the use of animal models to predict human response to drugs and diseases has its foundations in a creationist view of origins [1-3], animal modelers tend to view humans and animals as simple systems. The fact that each is an evolved complex system that differs from other evolved complex systems complicates their mythical view of animal models. Nowhere is this more evident than when considering the role of regulatory genes in evolution.
Arbiza et al state, in Nature Genetics:
For decades, it has been hypothesized that gene regulation has had a central role in human evolution, yet much remains unknown about the genome-wide impact of regulatory mutations. Here we . . . demonstrate that natural selection has profoundly influenced human transcription factor binding sites since the divergence of humans from chimpanzees 4–6 million years ago. . . . We find that, on average, transcription factor binding sites have experienced somewhat weaker selection than protein-coding genes. However, the binding sites of several transcription factors show clear evidence of adaptation. Several measures of selection are strongly correlated with predicted binding affinity. Overall, regulatory elements seem to contribute substantially to both adaptive substitutions and deleterious polymorphisms with key implications for human evolution and disease. 
This means that the human-chimpanzee split was due largely to changes in regulatory genes as opposed to structural genes—the genes that actually build the body. This is consistent with the fact that humans and chimpanzees share ~99% of their genes. “The researchers showed that the number of evolutionary adaptations to the part of the machinery that regulates genes, called transcription factor binding sites, may be roughly equal to adaptations to the genes themselves.” Humans and chimpanzees share many structural genes, but when and for how long these structural genes are turned on varies. Think of the keys on a piano as the structural genes and the sheet music as the regulatory genes. The sheet music dictates when the keys are played and for how long. You can play very different music on the same set of piano keys. You cannot simply cite similarity of the keys and predict the next selection a pianist is going to play. “The regulatory machinery works when proteins called transcription factors bind to specific short sequences of DNA that flank the gene, called transcription factor binding sites, and by doing so, switch genes on and off.”
This again reveals that two species may share a vast majority of their structural genes but still demonstrate very different responses to perturbations like drugs and disease.
Another reason for differences in response is convergent evolution. Convergent evolution occurs when species in two different lineages acquire the same trait. Examples include vision in the form of a camera eye, wings for flight, and “antifreeze” in fish. The mechanism whereby the organism acquired the trait, the genes responsible for the trait, and the “wiring” of the trait may vary considerably. This means that the way the organism responds to perturbations involving the trait may differ dramatically.
Examples of convergent evolution were recently discussed by scientists in the UK. [5-7] Many species need more oxygen under specific circumstances. Elephant seals, for example, store oxygen in their muscle tissue and extract it when diving. Myoglobin in the muscles of whales and other sea mammals have a higher charge than the myoglobin of land mammals. This allows access to oxygen that they otherwise would not have access to. But this mechanism differs from that of ray-finned fish and that of deer mice, who also need more oxygen occasionally. [5-7] Just because an animal modeler discovers a mechanism for a trait in an animal does mean the mechanism for that same trait, or a similar trait in humans or other animals, will be the same. It is therefore ironic that animal modelers harp on mechanisms when asked to defend their profession.
All of the above is not to imply that differences in structural genes are unimportant. Scientists at the University of Chicago Medical Center discovered that African-American women are more likely to carry certain mutations that predispose them to triple negative breast cancer. It was already know that African-American women are at higher risk for triple negative breast cancer than Caucasian women. There are many more differences among humans; for example, the anatomy of the brains of patients with dyslexia may differ between the sexes. 
Considering the dramatic intra-human variation in response to drugs and disease, pretending that animal models have predictive value reveals a child-like view of reality. That, or a vested interest in the paradigm. Genetic composition is not the sole determining factor in how we think, act, and react to drugs and disease. Environment plays a big role as well. But just considering the complexity of genetic make-up, including regulatory genes, a strong case could be made that the predictive value of animal models for human response to drugs and disease should be minimal. And that is exactly what the empirical evidence shows.
When Galileo offered a representative of the pope the opportunity to view the four moons of Jupiter through his telescope, thus challenging the Ptolemaic view of the universe, the representative stated: “I refuse to look at something which my religion tells me cannot exist.” Vivisection activists manifest the same attitude regarding empirical evidence, complexity science, and genetic composition when discussing the predictive value of animal models.
Finally, just FYI.
Our Hen House has published an essay from me, which is available at http://www.ourhenhouse.org/2013/05/how-to-argue-against-vivisection-in-the-21st-century-by-ray-greek-m-d/
1. Bernard, C., An Introduction to the Study of Experimental Medicine. 1865. 1957, New York: Dover. 125.
2. Elliot, P., Vivisection and the Emergence of Experimental Medicine in Nineteenth Century France, in Vivisection in Historical Perspective, N. Rupke, Editor. 1987, Croom Helm: New York. p. 48-77.
3. LaFollette, H. and N. Shanks, Animal Experimentation: The Legacy of Claude Bernard. International Studies in the Philosophy of Science, 1994. 8(3): p. 195-210.
4. Arbiza, L., et al., Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet, 2013. advance online publication. http://dx.doi.org/10.1038/ng.2658
5. Natarajan, C., et al., Epistasis among adaptive mutations in deer mouse hemoglobin. Science, 2013. 340(6138): p. 1324-7. http://www.ncbi.nlm.nih.gov/pubmed/23766324
6. Rummer, J.L., et al., Root effect hemoglobin may have evolved to enhance general tissue oxygen delivery. Science, 2013. 340(6138): p. 1327-9. http://www.ncbi.nlm.nih.gov/pubmed/23766325
7. Mirceta, S., et al., Evolution of mammalian diving capacity traced by myoglobin net surface charge. Science, 2013. 340(6138): p. 1234192. http://www.ncbi.nlm.nih.gov/pubmed/23766330
8. Evans, T., et al., Sex-specific gray matter volume differences in females with developmental dyslexia. Brain Structure and Function, 2013: p. 1-14. http://dx.doi.org/10.1007/s00429-013-0552-4
A recently published report of the limitations of mouse models ("Genomic responses in mouse models poorly mimic human inflammatory diseases") has been used by the Humane Society of the United States (HSUS). to justify their drive to end all animal use in research. However, this report in PNAS was a further refinement of our knowledge concerning which animal models are useful for studying various diseases, and is not a blanket condemnation of animal research at all.
The notion that research animals are only useful when they mimic human complexity is simple-minded. Much modern research is done on other organisms because they possess a basic primitive trait and do not have a complexity that confounds experiments.
For instance, Tetrahymena thermophila is a primitive one-celled organism that allows us to study the ultrastructure, physiology, development, and biochemistry of a cell without the interference of our added-on complexity. This is based on "functional conservation"—the concept that a genetic solution to the chemical problems of living is usually solved only once in evolution, and remains operational in the lineage up to humans today.
Nobel Laureate Andre Lwoff grew Tetrahymena in pure culture in 1923; this led to the later Nobel-prize winning discovery of ribozymes, as well as other discoveries of lysosomes, telomeres, etc. It should not be surprising that the vast majority of Nobel Prizes in Physiology or Medicine have been based on animal research.
Researchers have no reason to use research animals that do not contribute to our understanding. Just as they have lists of animals that are useful for researching certain diseases, researchers have a longer list of animals that are not appropriate. The recent PNAS paper merely advances that knowledge. Indeed, the breakthroughs in the last two decades have spawned a resurgence in both basic and applied research, and expanded the frontiers for animal research. Critical roles of animals in research include:
-Sequencing the genome of a primitive sponge reveals genes for the first signaling pathways and structures of animals, including early genes implicated in cancer.
-Hydra and comb jellies allow researchers to understand body patterning, the origin of epithelia, and regulation of development.
-Flatworms help us understand regeneration of body parts, stem cells, and the beginning of complex behavior.
-The roundworm C. elegans continues to be an excellent model for understanding genetic control of development and physiology; it was the first multicellular organism to have its genome completely sequenced, and revealed that some cells must die on cue for normal development ("programmed cell death").
-Segmented worm larvae have the simplest eyes known; some species are bioindicators of pollution.
-Without the huge neurons of the squid, we could not understand the process of nerve signal transmission because human axons are several orders of magnitude smaller.
-The 20,000 neurons of the sea hare Aplysia allow us to associate nerve cell chemistry with behavior.
-Millions of fruit flies drive our understanding of genetics
-Transparent external sea urchin eggs help us understand fertilization.
-Lampreys are used in spinal cord research.
-African clawed frogs are critical in developmental biology because they have large embryos and a high tolerance for physical and drug manipulation.
-The chicken is used for developmental studies—an excellent model for micromanipulation in tissue grafting and research on the over-expression of gene products.
-The zebra finch is used to study birdsong and non-mammalian hearing systems.
-Ferrets made recent news in studies of mammal-to-mammal transfer of the bird flu virus.
-Downsizing of the chimpanzee research population still recognizes that there are some research applications for which these animals are the only option.
Another case of "no-animal-research, no-cure" is leprosy (now called Hansen Disease). We could not develop an effective drug to the mycobacterium that causes this disease because we did not have an animal model to test potentially risky candidate drugs. When the nine-banded armadillo was discovered to harbor the disease in the 1970s, effective drugs were developed and Western leprosariums closed.
Alexander Fleming tested penicillin in a Petri dish and decided it did not work as a clinically effective antibiotic. But Florey and Chain tested it against mice and found it was effective. The history of biological research contradicts any claims that we can set aside all animal research and just use simulations.
What makes science distinct from non-science is its constant referencing to the real world. No computer simulation, tissue culture, or other model begins to approach the complexity of whole living organisms.
Suppressing science research has consequences as well. Failure to have used animal models would mean nearly all vaccines, antibiotics and other pharmaceuticals could not have been developed. Are advocates of ending animal research willing to bear the responsibility for continuing polio, leprosy, etc.?
With the recent breakthrough in sequencing the genomes of organisms from protozoans to humans, whole new fields of study have opened up. We are in a new golden age of discovery connecting DNA to its physical expressions. New fields of proteomics, transcriptomics, metabolomics, and other "omics" require an expanded research effort to integrate the new molecular data with the biology of whole organisms. Our understanding of life processes forms a vast fabric, the threads of which tie together protists and sponges and worms and mice and chimpanzees and humans.
The H.S.U.S. no-animal-research position also ignores animal research that allows us to provide better care for our animals by advancing veterinary science. And ecotoxicity testing, based on the diversity and complexity of animal systems also serves animals by protecting our shared environment.
To end animal use in research makes no more sense than ending plant research or research in the physical sciences. And advocacy for doing so threatens your health and the health of future generations.
---John Richard Schrock is a Professor of Biology at Emporia State University and an NAIA Board member.
The New York Times headline summed up a recent PNAS article quite well: “Mice Fall Short as Test Subjects for Humans’ Deadly Ills.” Gina Kolata begins the NYT article by saying:
For decades, mice have been the species of choice in the study of human diseases. But now, researchers report evidence that the mouse model has been totally misleading for at least three major killers — sepsis, burns and trauma. As a result, years and billions of dollars have been wasted following false leads, they say.
The article in question is titled: “Genomic responses in mouse models poorly mimic human inflammatory diseases,” and is authored by more than 20 scientists. The abstract reads:
A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.
This is essentially what Niall Shanks and I have been saying for over a decade.
The paper, published Monday in Proceedings of the National Academy of Sciences, helps explain why every one of nearly 150 drugs tested at a huge expense in patients with sepsis has failed. The drug tests all were based on studies in mice. And mice, it turns out, can have something that looks like sepsis in humans, but is very different from the condition in humans. . . . “This is a game changer,” said Dr. Mitchell Fink, a sepsis expert at the University of California, Los Angeles, of the new study.
I assure you, this will not be a game changer. Why? Kolata:
The study’s investigators tried for more than a year to publish their paper, which showed that there was no relationship between the genetic responses of mice and those of humans. They submitted it to the publications Science and Nature, hoping to reach a wide audience. It was rejected from both.
More on why in a moment.
This is not the first study to conclude that animal models of human disease fail to mimic human response to drugs and disease. (See [1-4] to mention but a few. See this blog and Animal Models in Light of Evolution for more.) Nor will it be the last. What science is good at, or I should say, among the many things that science is good at, is looking at diverse examples and coming up with an explanation for why all the data exists. In the physical sciences, scientists can look at regularities in the material universe and discover laws. Newton’s laws of motion, the laws of thermodynamics and so forth are examples. But in biology, laws are difficult because of things like chaos and complexity, among other reasons. Because the biological sciences are more statistics-based, they rely on theories. But a theory in biology is more than just a hypothesis. The National Academy of Sciences (USA), explains theory as follows:
In everyday usage, “theory” often refers to a hunch or a speculation. When people say, “I have a theory about why that happened,” they are often drawing a conclusion based on fragmentary or inconclusive evidence. The formal scientific definition of theory is quite different from the everyday meaning of the word. It refers to a comprehensive explanation of some aspect of nature that is supported by a vast body of evidence. Many scientific theories are so well established that no new evidence is likely to alter them substantially. . . . One of the most useful properties of scientific theories is that they can be used to make predictions about natural events or phenomena that have not yet been observed [p11]. (Emphasis added.)
The Germ Theory of Disease is a case in point. Many humans were dying from seemingly very different things. But the 19th century scientists figured out that all of the deaths were related. They were all caused by germs. Scarlet fever, hepatitis, whooping cough, sepsis, tetanus, and rabies, although causing symptoms that varied, were all caused by a group of organisms referred to as germs.
What Shanks and I have tried to do is find an explanation that accounts for all the failings of animal models as well as the successes (see Animal models and conserved processes for how to predict what will and what will not work in terms of animal models.) This would be the vast body of evidence referred to by the National Academy of Sciences. We have sought, and proposed, a theory. Put succinctly, our theory states that animals and humans are examples of evolved complex systems that are differently complex. If you understand complex systems and you understand evolutionary biology, that one sentence is all that is needed to explain why the PNAS paper on mouse models is a fact of the material universe as well as the other papers that come to similar conclusions. It also explains why some animal models function well for things other than predicting human response to drugs and disease. (For a broader and deeper examination of the issue, see our published works.)
But it takes time for even non-threatening theories to be accepted by the scientific community. This is why the PNAS paper will not be game changer. Kolata on the rejection of the article by top journals:
Still, Dr. Davis said, reviewers did not point out scientific errors. Instead, he said, “the most common response was, ‘It has to be wrong. I don’t know why it is wrong, but it has to be wrong.’ ” . . . “When I read the paper, I was stunned by just how bad the mouse data are,” Dr. Fink said. “It’s really amazing — no correlation at all. These data are so persuasive and so robust that I think funding agencies are going to take note.” Until now, he said, “to get funding, you had to propose experiments using the mouse model.”
Research in biomedical science is not a sacred thing. It revolves around money and ego, and facts rarely affect the status quo very quickly. Scientific research, especially biomedical research where so much money is involved, is no different from selling widgets. It is all about the bottom line. Universities keep roughly 50% of every biomedical research grant dollar that animal-based research brings in. Considering the fact that some universities see hundred of millions of dollars in animal model-related grants each year, their cut is in the hundred million dollar range. That's motivation! [6-11]
Science and medicine are no different from any other human enterprise in that both are conducted by humans that have human nature. Graduating from medical school or a PhD program does not change basic human nature. Money is as important to doctors, scientists, and researchers as it is to plumbers, engineers, and day laborers. Honesty and altruism operate under the confines of human nature in all humans regardless of education and profession. It is naïve to think a white coat makes a person undefiled by normal human passions.
The strength of a scientific position or piece of information can be judged by consilience; how well it fits into the web of other knowledge. If you think of the sum total of scientific information as a network and with each factoid, law, and or theory as a node then the probability that any individual item is true can be judged by how many connections it has. For example the node representing the Theory of Evolution has millions of connections to other nodes while string theory node has far fewer and homeopathy has essentially none. The PNAS article points out the fact that mice are poor models for sepsis, trauma, and burns while other article have shown that animal models in general are not predictive for carcinogenesis or Alzheimer’s or heart disease. This raises the question: “Is there something that connects all this?” The answer is: evolved complex systems theory. An appreciation for the fact that animals and humans are differently complex systems secondary to evolution allows us to predict success and failure of animal models. One will most certainly find examples of humans and animals responding the same way to drugs and disease but such instances will be unpredictable and, even with the same symptoms, the mechanisms may differ. Animal models per se will never be predictive modalities for human response to drugs and disease.
A comment by James Watson is appropriate at this time:
“Oh sure, I knew it would cause trouble," says [James] Watson, eyes widening with unabashed glee. "I said most scientists are stupid.” He pauses, furrowing his brow in an effort to quote himself accurately. “The fact is most scientists act as though they are stupid because they are wedded to some approach they can't change, meaning they are moving sideways or backwards.” 
That is pretty much our position regarding the use of animal models to predict human response to drugs and disease. The researchers and universities that use animals will never support our position. Not because our position is false but because their bottom line depends on using animals. Scientists who do support our position will not actively campaign on the issue as they have friends, family, and maybe even members of their own department who use animals. Even if these conditions are not present, it takes quite a bit of courage to rock a multibillion-dollar boat. The repercussion will be great and most scientists, or most people for that matter, do not seek out controversy for themselves.
Kolata concludes her article wit theme we have also articulated:
“This is a very important paper,” said Dr. Richard Hotchkiss, a sepsis researcher at Washington University who was not involved in the study. “It argues strongly — go to the patients. Get their cells. Get their tissues whenever you can. Get cells from airways.” “To understand sepsis, you have to go to the patients,” he said.
If you want to understand human response to drugs and disease, you must study humans. Who’d have thunk it?
1. Morgan, P, PHVD Graaf, J Arrowsmith et al. (2012) Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discovery Today 17:419-424.
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An editorial in Nature in 2009, stated: “Animal-research policies need to be guided by a moral compass—a concensus of what people find acceptable and unacceptable” (1). Giles, also writing in Nature in 2006, stated:
In the contentious world of animal research, one question surfaces time and again: how useful are animal experiments as a way to prepare for trials of medical treatments in humans? The issue is crucial, as public opinion is behind animal research only if it helps develop better drugs. Consequently, scientists defending animal experiments insist they are essential for safe clinical trials, whereas animal-rights activists vehemently maintain that they are useless. (2)
So, does testing new drugs on animals result in safer and better drug? According to Kelly Rae Chi, writing in The Scientist, September 1, 2012, it does: “The most straightforward way to find out whether a drug or environmental chemical might harm an unborn baby is to test its effect on a pregnant lab animal.” (3) (For the reality of teratogenicity testing on animals, see The History and Implications of Testing Thalidomide on Animals.) Dr. Keith Cheng of Penn State's College of Medicine agrees, stating: “Animal tests are necessary for some research, such as testing drugs for toxicity. It would be, in my opinion, improper to release drugs for human use without animal testing.” (4) Former UK science minister Lord Drayson said that without animal-based research “it is not possible to develop new medicines.” He went on to state that animal-based research was “necessary and that people would ‘suffer and die’ without it.” Examples of similar sentiments could easily be multiplied.
But data supporting such statements is scarce to nonexistent while data to the contrary is ubiquitous.
For example, van Meer et al, writing in Regulatory Toxicology and Pharmacology, 2012, stated:
The value of animal studies to assess drug safety is unclear because many such studies are biased and have methodological shortcomings. (5)
I have pointed this many times, including our critique of the Olson study (6) in Animal Models in Light of Evolution. Van Meer et al also commented on the Olson study, stating:
Olson et al. defined a true positive non-clinical event as one in which ‘. . .the same target organ was involved in humans and in animals in the judgment of the company clinicians and the toxicologists’ (Olson et al., 2000). While identifying toxicity at the target organ level in animals may be useful for evaluating the safety of a drug from a development perspective, it is inadequate when attempting to establish the predictive value, because toxicity in the target organ may give rise to several specific side effects in humans.
Van Meer et al retrospectively studied whether serious adverse drug reactions (SARs) in humans could have been identified using animal models prior to the drug being released. They evaluated drugs currently on the market and discovered that only 19% of 93 SARs were seen in animals. Van Meer et al state: “Accordingly, the sensitivity of the animal studies for detecting SARs in humans was 19%.” Again referring to the Olson study, they state:
Because we think that a stricter definition of true positive results is needed, we distinguished between target organ involvement and non-clinical events that were either identical to the SAR or causal to it. For this reason, non-clinical events which were related to the target organ but which did not give rise a SAR by similar mechanisms were not considered true positive.
One could argue that non-clinical studies are not designed to identify rare adverse reactions that appear after market approval. Although the number of animals used in non-clinical studies is relatively small, the studies are designed to find important side effects that are likely to occur in humans. (5) (Emphasis added.)
For support of this statement, they cite: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 2009. Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals M3(R2), EMA, London.
It should also be noted that sensitivity does not equal positive predictive value (PPV). Therefore, a sensitivity of 19%, while inadequate in and of itself, would result in a PPV that is even less helpful.
This is why Pharma has statistics like the following:
- 5% of cancer drugs that have IND go to market. (7)
- Young 2008: “The success rate of this heuristic approach [to drug development] is very low. For example, the average probability that a candidate emerging from lead optimisation will not make it to be a drug is above 99.8% (8). . . .” (9)
- The FDA: “a new medicinal compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market. (10)
- 80% of drugs for which an IND has been filed, fail in development and approximately 50% fail in Phase III. (11)
- Kola and Landis wrote: “Analyses success rates from first-in-man to registration during a ten-year period (1991–2000) for ten big pharma companies in the United States and Europe. The data indicate that the average success rate for all therapeutic areas is approximately 11%; or, put another way, in aggregate only one in nine compounds makes it through development and gets approved by the European and/or the US regulatory authorities.” (12)
- Kola and Landis: “Even the rate of failures in Phase III trials — by which stage significant amounts of the costs of discovering and developing a drug would have been incurred— is far too high: approximately 45% of all compounds that enter this phase of full development undergo attrition.” (12)
This is, in part, why medications are so expensive. There are many misses before even one hit and Pharma has to pay for the development of all of them.
Vivisection activists will point out that there is a difference between drug testing and drug research using animals. Animals are frequently used in so-called basic research in an attempt to find druggable targets and this differs from testing drugs on animals in order to evaluate safety, efficacy, and so forth. But using animals in an effort to find druggable targets has not been very successful either.
An editorial in Nature titled “Must try harder,” addressed a major problem in the basic research community: the results are not replicable nor are they translating to human treatments. (13) The editorial was accompanied, in the same issue, by two articles on the same topic. According to Ledford, author of the first article: “Between 2008 and 2009, only 18% of drugs in phase II clinical trials succeeded. (14) And, as described in a Comment in this issue (see page 531), when the biotechnology company Amgen, based in Thousand Oaks, California, tried to reproduce data from 53 published preclinical studies of potential anticancer drugs, it failed in all but six cases.” (15) (For more see Is the use of sentient animals in basic research justifiable?)
A recent example of the failure of animal models to predict human response is the drug dexpramipexole. Dexpramipexole was supposed to slow the progression of ALS, also known as Lou Gehrig’s disease, based on animal studies. (16) It failed in human clinical trials.
Yet, animals continue to be used in research and testing despite a history of failure and despite a scientific theory that explains why they fail. (For more on evolved complex systems theory see Animal models and conserved processes, Systematic Reviews Of Animal Models: Methodology Versus Epistemology and Complex systems, evolution, and animal models, which is available here.) For example, a January 15, 2013 press release from the University of Missouri-Columbia describes: “A quantum leap in gene therapy of Duchenne muscular dystrophy,” which is based on gene transfer experiments on dogs. (FYI, beware of anything with the word quantum in it when the author is not a physicist discussing physics.)
Once again, all of the above must be placed in the context of the fact that human response to drugs and disease also varies. For example, a recent study (17) revealed that: “African American women coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are less likely to die from liver disease than Caucasian or Hispanic women.”
As the Nature editorial stated: “Animal-research policies need to be guided by a moral compass—a concensus of what people find acceptable and unacceptable." (1) Note that the editors did not say the consensus of what those with a vested interest find acceptable. But even if the entire scientific community were to state that animal testing was essential, if the basis for a consensus opinion is shown false, then you can no longer rely on or quote the consensus opinion in terms of supporting the position. Such would be unethical and immoral. The scientific consensus, though usually both valuable and reliable, has been shown incorrect more than once.
1. Editorial, A slippery slope. Nature 462, 699 (2009).
2. J. Giles, Animal experiments under fire for poor design. Nature 444, 981 (Dec 21, 2006).
3. K. R. Chi, Stemming the Toxic Tide. The Scientist 26, 55 (2012).
4. E. Gibson. (The Patriot-News, 2012), vol. 2012.
5. P. J. K. van Meer, M. Kooijman, C. C. Gispen-de Wied, E. H. M. Moors, H. Schellekens, The ability of animal studies to detect serious post marketing adverse events is limited. Regulatory Toxicology and Pharmacology 64, 345 (2012).
6. H. Olson et al., Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32, 56 (Aug, 2000).
7. S. Kummar et al., Compressing drug development timelines in oncology using phase '0' trials. Nature reviews. Cancer 7, 131 (Feb, 2007).
8. European Commission, “Innovative Medicines Initiative: better tools for better medicines” (Luxembourg, 2008).
9. M. Young, Prediction v Attrition Drug Discovery World, 9 (2008).
10. FDA. (2004).
11. L. J. Lesko, J. Woodcock, Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nat Rev Drug Discov 3, 763 (Sep, 2004).
12. I. Kola, J. Landis, Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3, 711 (Aug, 2004).
13. Editorial, Must try harder. Nature 483, 509 (2012).
14. J. Arrowsmith, Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Discov 10, 328 (2011).
15. H. Ledford, Drug candidates derailed in case of mistaken identity. Nature 483, 519 (2012).
16. P. Corcia, P. H. Gordon, Amyotrophic lateral sclerosis and the clinical potential of dexpramipexole. Ther Clin Risk Manag 8, 359 (2012).
17. M. Sarkar et al., Lower liver-related death in African-American women with human immunodeficiency virus/hepatitis C virus coinfection, compared to Caucasian and Hispanic women. Hepatology 56, 1699 (Nov, 2012).