The contention among the vested interest groups is that basic research using animals is the only way for biomedical science to advance (see previous essay). Before I go any further, let me again state that animals can be used in basic science to generate hypotheses, for their tissues in assays and so forth. All this is scientifically viable. But what is their value in advancing cures and treatments for humans? Clearly they are not predictive for humans in drugs and disease response (see book Animal Models in Light of Evolution) but do not other uses result in cures?
Ioannidis, writing in the Journal of Translational Research: “While basic sciences are conceived as having made amazing leaps forward, this progress has not resulted in many major cures” (1).
Helen Philips wrote in New Scientist:
There is increasing recognition that basic research doesn't just flow automatically into clinical treatments and that both basic researchers and clinicians have to change the way they work to make this happen more readily . . . These plans have been widely welcomed, but there are still some problems specific to neuroscience. "The biomedical model is failing," says Susan Fitzpatrick, vice-president of the James S. McDonnell Foundation in Saint Louis, Missouri. Basic biomedical research relies heavily on animal models, especially rats and mice, but she thinks it may be necessary to rethink this approach if treatments for brain diseases are going to reach the patients who need them. Even if we know all there is to know about the animal model we don't necessarily know about the disease, Fitzpatrick says. "The model becomes what we study, not the human disease." And while this is a problem in all areas of disease, nowhere is it more acute than in brain disease. Kidney, liver or heart function is basically the same in different animal models, but the human brain is different. "It is not a chimp brain or a monkey brain or a mouse brain. It is very, very different." Take brain cancer. The traditional model for studying brain cancer is to take human cancer cells, sometimes tissue-cultured into cell lines, and transplant them under the skin of an immunosuppressed mouse. This approach ignores the fact that cancer is a disease of context: as soon as you change the environment you will change those cells. "Any agent you test is probably unlikely to be effective when you have a tumour in context," Fitzpatrick says. "It's a fundamental flaw. We need a fundamentally new approach." (2) (Emphasis added.)
The above, at least in part, addresses the question of value raised by some with a vested interest in using monkeys to model human brains. There is value in such research if by value you mean discovering new things. But as the above states, human brains are not monkey brains.
Surely all the animal-based basic research is paying off in other ways. Tracy Hampton writing in JAMA in 2006:
While investment in basic research in the United States doubled from 1993 to 2003, the number of therapeutics entering the clinic has actually declined. New compounds entering phase 1 trials today have about an 8% chance of reaching the market compared with about a 14% chance 15 years ago . . . Many drug candidates that enter later phases of the drug development process are also falling by the wayside. "In the phase 3 trials, where a lot of money and a lot of hope, patient lives, and time have been invested, the failure rate is now reported to be about 50%," said Janet Woodcock, MD, of the US Food and Drug Administration (FDA), in Rockville, Md. The failure rate was approximately 20% a decade ago…. (3)
Sharon Begley science writer for Newsweek and the Wall Street Journal writing in the Wall Street Journal:
“Patients," says immunologist Ralph Steinman of Rockefeller University, New York, "have been too patient with basic research.“…Many of the brightest scientists have, therefore, plunged into the minutiae of roundworm genes and fruit-fly receptors, instead of human diseases. "Most of our best people work in lab animals, not people," says Dr. Steinman, who presents his case in a recent issue of the journal Cerebrum. "But this has not resulted in cures or even significantly helped most patients.” . . . “Human experiments are much more time-consuming and more difficult than animal studies," says Rockefeller's James Krueger, whose human research includes trying to correlate gene activity and changes in immune-system cells with the progression of psoriasis. "There are also funding issues. It's much easier to write a successful grant proposal for animal experiments. Animals are homogeneous, and let you say 'aha!' in a neat, clean experiment.” Humans, in contrast, are genetically and behaviorally diverse, making it hard to tell whether some aspect of their disease reflects the disease alone, their DNA, how they live -- or some messy permutation of all three. (Emphasis added.)
O’ Connell and Roblin in Drug Discovery Today 2006:
Current developments in basic discovery sciences have not been mirrored by the same level of progress in understanding the clinical basis of disease and ultimately the development of novel effective therapies . . . (4)
So, apparently many think basic research that uses animals is not working well in terms of finding cures. Why then does it continue? Sharon Begley wrote in 2008:
Most of the people who evaluate study proposals for the National Institutes of Health "are basic scientists," notes Daniel Sessler of the Cleveland Clinic. "In basic science, being cutting edge and innovative is what's valued. But in clinical research you'd never take something completely innovative and try it in people." . . . That's what clinical scientists, who feel like the stepchildren of biomedical research compared with the cool kids who study fruit flies, have long suspected, and last month brought quantitative proof. Analyzing 92,922 NIH grant applications from 2000 to 2004, scientists led by Theodore Kotchen of the Medical College of Wisconsin found that those for research with people got much lower scores, and thus were less likely to be funded, than those for research on cell cultures, animals and the like. "There is still the perception that clinical research doesn't have the cachet of discovering a gene," says Kotchen. (5) (Emphasis added.)
I have always claimed that animal-based research is funded more than human-based. This dates from 1986 when the National Academy Press (6) published a report containing a chart that showed over 50% of NIH grants went to research with animals. The fact that basic researchers judge the grant proposals speaks for itself. Nathan and Schechter in JAMA 2006:
In 1995, Harold Varmus, then director of the NIH, became concerned that the NIH was not providing sufficient support for clinical research. He formed a panel of experienced academic leaders who accomplished 3 important goals. First, the panel defined clinical research broadly and estimated that about one third of the NIH extramural budget was devoted to clinical research. That amount seemed reasonable to the panel, considering that much basic research would be expected to be required in such a scientific program because most basic research provides only a small piece of information that, by itself, cannot be used in the clinic without further information. But the panel cautioned the NIH not to let the ratio decrease further. (7)
One-third clinical means two-thirds basic and that means the ratio of basic to clinical is about 2:1. This is consistent with the 1986 report revealing that over 50% of grants went to animal-based research and what I said in the UCLA panel discussion in February. (Although not all basic research is animal-based, most is and all animal-based is basic research.) All this money going to animal-based research has consequences. So what has society seen for it’s money? Consider the following.
Butler in Nature:
“NIH stands for the National Institutes of Health, not the National Institutes of Biomedical Research, or the National Institutes of Basic Biomedical Research.” This jab, by molecular biologist Alan Schechter at the NIH, is a pointed one. The organization was formally established in the United States more than half a century ago to serve the nation's public health, and its mission now is to pursue fundamental knowledge and apply it “to reduce the burdens of illness and disability”. So when employees at the agency have to check their name tag, some soul searching must be taking place. There is no question that the NIH excels in basic research. What researchers such as Schechter are asking is whether it has neglected the mandate to apply that knowledge. Outside the agency too there is a growing perception that the enormous resources being put into biomedical research, and the huge strides made in understanding disease mechanisms, are not resulting in commensurate gains in new treatments, diagnostics and prevention. “We are not seeing the breakthrough therapies that people can rightly expect,” says Schechter, head of molecular biology and genetics at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland . . . The basic biomedical research enterprise has now evolved its own dynamic, with promotions and grants based largely on the papers scientists have published in top journals, not on how much they have advanced medicine. (8) (Emphasis added.)
Sharon Begley 2009:
The desire for academic advancement, perversely, can also impede bench-to-bedside research. "In order to get promoted, a scientist must publish in prestigious journals," notes Bruce Bloom, president of Partnership for Cures, a philanthropy that supports research. "The incentive is to publish and secure grants instead of to create better treatments and cures." And what do top journals want? "Fascinating new scientific knowledge, [not] mundane treatment discoveries," he says. (9)
Which would explain the following from Freeman and St Johnston in Disease Models and Mechanisms 2008:
Many scientists who work on model organisms, including both of us, have been known to contrive a connection to human disease to boost a grant or paper. It’s fair: after all, the parallels are genuine, but the connection is often rather indirect. DMM is about something quite different. This new journal is aimed at people who set out with an explicit goal to investigate human disease using model organisms. (10)
There are also risks (besides the funneling of money from more worthwhile projects) to using animals even in basic research. Alini et al.:
Clearly, animal models can be useful in studying some specific aspect of disc biology (with a clear scientific question). However, most of these animal models if used in the wrong way (to mimic human disc degeneration) do not serve to advance scientific knowledge. Rather they then just serve to spread incorrect information about the processes involved in disc degeneration and about the possibilities of repair. It is better not to do the experiment than to do it using the wrong model. A more fruitful exercise is to take the time instead to design better experiments. The FDA, and other regulatory bodies, should be concerned about the inappropriate use of animals and models which can lead to misinformation. While animal work can be useful to help with the development of techniques and provide baseline data, work should ideally be done on human tissue. If we want to improve understanding of pathology and treatment of human IVDs [intervertebral discs], legislation should change to allow us easier access to human tissues, e.g. from pathological, cadaveric and organ donor source. The fundamental question to be addressed is: is it more (un)ethical to use animal models, which we know do not represent any human disc pathological conditions, or to use human tissues with all the ethical issues? We collectively believe the answer is clear: human tissue needs to be made more available! (11)
Heidi Ledford in Nature points out that at least one Nobel laureate, who won the Prize for basic research, agrees with Alini et al.:
In April this year, Nobel laureate Sydney Brenner brought the crowd to its feet at the American Association for Cancer Research meeting in San Diego, California. Brenner pioneered the use of the nematode Caenorhabditis elegans as a simple model for studying growth and development. But in his talk, he championed experiments on a more complicated creature: Homo sapiens. “We don't have to look for model organisms anymore because we are the model organism,” he said. (12)
The animal model community is trying (and succeeding) to have it both ways. 1. Give us money for basic science research because our research is predictive for humans and there is no other way to do it. 2. When it turns that animal-based research is neither predictive nor yielding cures they say their research is only basic research and should not be held to the same standard as other research methods. Of course, some simply deny the facts and claim even more loudly that basic research using animals works really, really well (or that the emperor really does have clothes). Even those who admit that basic research is not predictive hide under the umbrella of animals are really predictive to increase their likelihood of obtaining grant money. For example, basic science research in the field of biology is primarily funded by the NIH, not the NSF (National Science Foundation). If basic research is not goal oriented why is the organization concerned with health funding it?
The entire atmosphere of using animals in research is permeated by the fallacy that one species can predict response for another. There is an underlying assumption that research with animals will lead to cures whether it is called animal research, applied research, basic research, translational research or any other of the myriad names animal experimentation goes by.
Funding animal-based researchers in the remote hope of curing human disease is nothing but white coat welfare. Patients are dieing so the white coat welfare can continue.
(If all this science talk is a little too much for you but you are nonetheless interested in the subject, please try reading FAQs About the Use of Animals in Science: A handbook for the scientifically perplexed. As the title suggests, it was written along the same lines as Animal Models in Light of Evolution but with less science speak.)
1. J. P. Ioannidis, J Transl Med 2, 5 (Jan 31, 2004).
2. H. Philips, New Scientist 184, 54 (October 16, 2004).
3. T. Hampton, JAMA 296, 1951 (Oct 25, 2006).
4. D. O'Connell, D. Roblin, Drug Discov Today 11, 833 (Sep, 2006).
5. S. Begley, “Coddling Human Guinea Pigs,” Newsweek, August 18 2008.
6. Committee on Models for Biomedical Research Board on Basic_Biology, Committee on Models for Biomedical Research. Board on Basic Biology. Commission on Life Science. National Research Council. Models for Biomedical Research: A New Perspective. (National Academy Press., Washington, DC, 1985).
7. D. G. Nathan, A. N. Schechter, JAMA 295, 2656 (Jun 14, 2006).
8. D. Butler, Nature 453, 840 (Jun 12, 2008).
9. S. Begley. (Newsweek, 2009), http://www.newsweek.com/id/200599.
10. M. Freeman, D. St Johnston, Disease Models & Mechanisms 1, 6 (July 2008).
11. M. Alini et al., Eur Spine J 17, 2 (Jan, 2008).
12. H. Ledford, Nature 453, 843 (Jun 12, 2008).