Easy but Futile or Difficult and Beneficial
The use of animals as human surrogates continues at an unparalleled pace. A press release from the Allen Institute for Brain Science announced that Paul Allen plans to donate $300 million to expand the Institute. It states the money will be used to map the mouse brain in detail never before attempted.(Koch and Reid 2012) Neuroscientist Christof Koch states: “Once neuroscientists know the basic mechanisms in the mouse, they may start to understand more-complex forms of perception in other animals, including humans. In short, we believe that this project has the potential to revolutionize our understanding of the mammalian brain.”(Koch and Reid 2012)
Koch is correct in saying science will understand more about the mammalian brain by studying mice. He went on to describe why studying the mouse brain is easier than studying the human brain and he is also correct in this. Among other differences, the brain of the mouse has less mass and fewer neurons than the human brain. Furthermore, scientists can do things to mice they cannot do to humans. There is no question that knowledge will be gained from studying the mouse. One must remember however that similar research—basic research using animals—has around a 0.004% likelihood of translating into human treatments.(Crowley 2003) This reminded me of the story about the intoxicated guy that was looking for his car keys under a street lamp. Another guy walked by and asked him what he was doing and the intoxicated guy replied that he lost his keys in the alley and was looking for them. The second guy asked why he was looking under the street lamp when he lost the keys in the alley. The intoxicated guy said it was easier looking under the light than in the dark alley. The intoxicated guy was also correct.
There is a difference between interesting, indeed in some cases fascinating, basic science research and medically relevant scientific research. To equate medical advances from basic research in the hard sciences of chemistry, physics and engineering with using animal models in basic science is an example of the fallacy of equivocation. Real medical advances have come from basic science research in the hard sciences. Animal-based research is a different story. (See Is the use of sentient animals in basic research justifiable? for more on this.)
This reality gives rise to the notion that all science needs in order to cure human disease and predict drug response is better mice. This is illustrated by Megan Scudellari in her article New Mice on the Block: “In the beginning, the mice were few and far between. In 2001, over beers at a conference, a group of geneticists dreamt up the ideal resource for systems genetics—a mouse population bursting with genetic diversity, far more than traditional inbred lab strains. Such a resource would better model human diversity and disease in the lab, they surmised.”
The Collaborative Cross (CC) mouse project, referred to by Scudellari, has yielded 450 strains of mice with great genetic diversity. Scudellari: “Each strain has been fully genotyped, and the resource is now ready, its creators say, to help scientists unravel the genetics behind complex traits like cancer, aging, fertility, and more. . . . ‘The complex trait problem is a hard one. How do you solve diabetes or figure out how heart disease works?’ said Lauren McIntyre, a geneticist at the University of Florida and senior editor of Genetics, who was not involved in the creation of the CC. ‘Having a resource that is more reflective of human complexity and gets us closer, faster, to some of the solutions is a great thing.’ ”
I would suggest that the answer to the above question regarding complex traits would be to study humans and human tissues. Extrapolating between complex systems is very difficult. Moreover, when the two complex systems are evolved, adaptive, living complex systems, extrapolation becomes essentially impossible, especially at the level of examination where disease and drug response occur. We are thus back to the drunk and his keys. Granted, scientists can find mechanisms in mice but that does mean the mechanisms in humans are the same. Usually they are not, hence the poor translation rate. Further, one does not need to know the mechanisms to find a treatment or cure. The mechanism(s) for general anesthesia are still unknown just as they were in the 1800s when general anesthetics were discovered. In reality, many treatments are based on clinical observation and or serendipity and scientists still do not known the mechanisms for the medical interventions.
An explanation for why animals are poor models for humans in terms of prediction comes from recent studies involving gorillas. The western lowland gorilla’s genome was studied and compared to humans. Scally et al report: “In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing.”(Scally et al. 2012) In other words, humans and gorillas are the same except for where they are different and these differences are what make us humans and them gorillas. These differences are also the reason why they respond differently to drugs and disease than we do.
Along similar lines, a press release from the Wellcome Trust announced that: “Scientists at the University of Oxford and the University of Chicago have constructed the world's first genetic map in chimpanzees of recombination – the exchange of genetic material within a chromosome that makes us all unique. The study . . . shows surprising differences compared to how the process occurs in the human genome. . . . in both chimpanzees and humans, recombination only occurs at specific locations of the genome, known as 'recombination hotspots'. . . . researchers found that there was no overlap in the location of recombination hotspots between humans and chimpanzees. This was an extraordinarily unexpected finding given the 98.5 per cent similarity between the human and chimpanzee genomes and extensive similarities at the cellular and organism level.” The study can be found here. Once again we see that the very small differences are what separate the species.
The above two studies again explain why the very small differences between species are more important than the vast similarities when studying response to drugs and disease. The primate studies above are examples of good scientific research. The research is comparative meaning that it illuminates the differences among species. I fully approve of comparative research from a scientific perspective and it can be performed ethically, regardless of your standards. (For example, DNA can be obtained from animal scat and tissues—Zebra carcass in the Serengeti—in the wild. Animals do not have to be in captivity.) Comparative research is interesting but it should not be conflated with finding cures or predicting human response to drugs and disease. Cancer will not be cured because of comparative research. There are simply too many important differences between species. In fact, what the above comparative studies, as well as others, reveal further validates the fact that important inter-species differences exist. This is why interesting scientific research that uses animals is not the same as medically relevant scientific research. But medically relevant science is where the grant money is, so basic researchers that use animals will continue to claim that their research will cure cancer or heart disease despite the massive empirical evidence and confirming support from theory that it will not.
As always, animal-based research needs to be contrasted with personalized medicine. Personalized medicine (PM) is real and currently happening despite what you may hear from vivisection activists. The reason some vivisection activists deny the reality of PM is that the same science that explains why personalized medicine is needed also explains why animal models are not predictive for human response to drugs and disease. But it is difficult to argue with success. A press release from Duke reports that: “Genetic variation in East Asians found to explain resistance to cancer drugs.” Tyrosine kinase inhibitor drugs (TKIs) are used to treat cancers such as chronic myelogenous leukemia (CML), however some patients do not respond as well as others. A variation in the BIM gene has been found responsible for this. The BIM gene variant occurs in about 15 percent of the typical East Asian population but has not been found in patients of European or African descent. The article was published in Nature Medicine.
The following vignette about PM is from the New England Journal of Medicine.
“Ms. H. is a 35-year-old woman from Japan who has had a cough for 3 weeks. Her physician sends her for an x-ray and CT scan that reveal an advanced lesion, which a biopsy confirms to be non–small-cell lung cancer. She has never smoked. Can anything be done for her? Had Ms. H.'s cancer been diagnosed before 2004, her oncologist might have offered her a treatment to which about 10% of patients have a response, with the remainder gaining a negligible survival benefit and experiencing clinically significant side effects. But her diagnosis was made in 2011, when her biopsy tissue could be analyzed for a panel of genetic variants that can reliably predict whether the disease will respond to treatment. Her tumor was shown to be responsive to a specific targeted agent, whose administration led to a remission lasting almost a year; her only side effect was a rash.”(Mirnezami, Nicholson, and Darzi 2012)
Contrast this with the following: “Non-human primates are vital to scientists’ understanding of disease, said Helen Burt, associate vice-president of research at the University of British Columbia, which uses macaques, or cynomolgus monkeys, for Parkinson’s-related tests. ‘At a certain point, one has to have a living animal with a complete blood system, a functioning nervous system,’ Burt said. ‘You need a living organism in order to move our understanding forward about disease states and potential therapies.’ ”
Burt might as well say that at some point you need an entity composed of stardust in order to predict the response of humans who are also composed of stardust. At one level of organization, humans and other stardust entities, say for example, meteorites, have much in humans. Each is composed of essentially the same elements. But this is meaningless as it is the differences in how those elements are used that separates us from meteorites. Granted, animals and humans have similarities, but at the level of examination where responses to drugs and disease occur, the differences are more important.
Finding your keys in a dark alley after a night of partying is hard. But finding them a block away, under the street lamp, will be impossible.
Crowley, W. F., Jr. 2003. Translation of basic research into useful treatments: how often does it occur? Am J Med 114 (6):503-5.
Koch, C., and R. C. Reid. 2012. Neuroscience: Observatories of the mind. Nature 483 (7390):397-8.
Mirnezami, Reza, Jeremy Nicholson, and Ara Darzi. 2012. Preparing for Precision Medicine. New England Journal of Medicine 366 (6):489-491.
Scally, Aylwyn, et al. 2012. Insights into hominid evolution from the gorilla genome sequence. Nature 483 (7388):169-175.