I had never really thought of the complications that could arise when studying a disease that we either don’t know the source or can’t directly translate the disease to an animal model. In an article from Nature Neuroscience, the authors describe how chronic exposure to rotenone, a pesticide, can be used as a more accurate model for Parkinson’s than the MPTP, the standard animal model. They note that MPTP produces symptoms that are almost identical to idiopathic Parkinson’s. It functions by inhibiting Complex I in the inner mitochondrial membrane, which shuts down the electron transport chain, leading to loss of ATP and formation of ROS. However, they also point out that MPTP tends to elicit a systemic response as well, targeting platelets and other tissues. The paper goes on to describe how rotenone, which also inhibits complex I, can be used to produce a better animal model. Both these methods induce a problem that mimics Parkinson’s. Yet the actual cause of Parkinson’s is unknown, so how applicable are studies that improve symptoms if the symptoms are induced by a different mechanism. I know Dr. Cohen talked about the difficulties of inducing diseases like diabetes in animal models, and I’m sure the same holds true for many diseases. I was wondering, for those of you who are involved in research, if not having an exact model of the disease makes switching to human trials more difficult than if the disease can be directly translated to animal models, even if the study seems to be producing successful results?
Article
www.nature.com/neuro/journal/v3/n12/full/nn1200_1301.html
I understand that if you can do something against the pain of Parkinson's, you just have to look to get it, I suffer from chronic pain for 4 years and I keep very well, then I read online in Findrxonline had medications as Hydrocodone, Lortab, Vicodin, among some that indicate there if prescription medications are prescribed by the doctor to relieve your pain symptoms.
ReplyDeleteIt is tough to induce reliable disease models in animals, mostly because so many animals don't suffer from so many diseases associated with aging like humans do. It's probably even harder when we don't know what the initial trigger is. The good news is that by trying to come up with a way to do, we might just stumble upon the initial cause of disease.
ReplyDeleteI'm not currently in research, but the step from mice/rats to something like dogs or cats to primates and eventually humans takes a long time. And if any primates react unfavorably you can bet that it's back to the drawing board.
Just curious, but how often do they perform testing on primate models? I know it used to be more common, but realistically, they are our closest evolutionary relative. It seems that they would almost be a target for testing after simple models such as rodents.
ReplyDeleteA couple of comments: the first one is about using animal models to study disease, and the second comment is about using primate models.
ReplyDelete1. WillM295, in answer to your question, I say that yes, not having an exact model of the disease makes switching to human trials more difficult.
a. As you alluded to in your post, we can sometimes come close to representing one aspect of the disease in animal models—in the case you described above, the symptoms of Parkinson’s can be more accurately represented with this new model—but any non-human disease model will never fully tell us what will happen in humans. Consider the major block in developing and testing therapies for AIDS and HIV, which are very specifically human diseases/infections that have no directly translatable animal model (SIV in chimpanzees comes close, but it still isn’t HIV).
b. Another point to consider when pondering extension of animal research to humans is that it is nearly impossible to explore all side effects in all species. As a case in point, thalidomide was a sedative given to pregnant women in the late 1950s and early 60s to treat morning sickness. When their babies were born with multiple birth defects, it came to light that using thalidomide in the first trimester caused the malformations. Interestingly, thalidomide was tested extensively in mice and rats before being approved for human consumption. Side effects weren't seen in these rodents, however, had the researchers used chicks or even zebrafish as their animal model, thalidomide’s teratogenic activity would have been discovered. These animals develop limbs using pathways similar to humans and so thalidomide interferes with development via similar mechanisms.
c. As a final note, I’d mention that fortunately, for some diseases, we can make transgenic mice that bear the exact gene(s) we are studying in humans. In this way, we can get closer to studying a more perfect semblance of the disease. However, even with these transgenic models, it’s important to bear in mind that animal studies are useful for GUIDING research, and the predictions we can make based on animal models are just that: predictions. They are not the end all, be all for human therapies. I think that pairing animal studies with human clinical trials to slowly test new therapies in a few people before launching large-scale studies is the best approach we have so far.
2. Quickly, I’ll share what I know about primate models. I agree with you that primates are probably the best non-human model we could have (especially chimpanzees), and they do seem like a logical next step to testing diseases and interventions after some lesser evolutionarily-related species is tested. But primates are not commonly used in research because they are very expensive to obtain, costly to house and care for (sometimes over $15,000 EACH/year!...and you would need several primates in order to get statistical significance between groups), facilities that can support primates are limited, primate use is surrounded by ethical debates and strict regulations that many researchers just don’t want to mess with, and sometimes, using primates actually isn’t practical. As with all research projects, it’s important to consider the aims of the research and then determine which animal model best meets those aims. Primates develop slowly, have long life spans relative to mice and flies, and genetic manipulation isn’t ideal, so if your goal is to make a transgenic animal and study Parkinson’s disease, your first choice wouldn’t be primates because it would take years to make a transgenic primate and then many more years for the disease to even manifest itself.