How to do animal experiments scientifically in the research and development of new drugs?

 

    Animal experiments play a very important role in the evaluation and screening of new drugs. The ancients said that “their position is in their position, and they seek their own politics”. It is precisely because of the key role of animal experiments in research and development. When the output of research and development is not ideal, we should first reflect on whether these key experiments that affect research and development decisions are used properly.

　　Although animals and humans are >97% genetically identical, there are huge differences in many ways, especially in terms of immune response and behavior. Scientists at Stanford University recently discovered that there is almost no correlation between the immune stress genes activated in humans and mice when injured. On the other hand, there is a huge difference between the disease itself and the disease model. We don't know the cause of most diseases, and the causes of disease models are very clear. Animals can't be a model without your help. From animals to humans, from disease models to the disease itself are two huge leaps, and many R&D projects have lost their way in this process. At present, the drug candidates that have passed animal experiments are <10%, which can be finally marketed. However, considering that many drugs go together (the same target), the success rate of the first drug that can truly predict the therapeutic effect of humans through animal models is much lower than 10. %, the first drugs that can be sufficiently distinguished from the existing drugs are rare.

If any experiment wants useful information, the most important thing is to ask the right question, followed by the strictness of the experimental design and the complexity of the research question, and the animal experiments of new drug development currently have a big gap between these two aspects .



　　 Animals are good human biological and physiological models, but not good pathological models. The effect is more complicated, because the effect depends on how to define it, that is, the end point of observation. Therefore, the most useful place for animal experiments is to observe the regulation of drugs on biological pathways, that is, the effects of drugs on the biological processes of interest under real-world conditions such as blood flow, nutrition, positive and negative feedback, and dynamic balance in life. The observation index is best to compare the changes of biomarkers with objective mechanism and function, such as the expression of downstream proteins. Pathological models are somewhat predictive, but many of the questions we ask now are too difficult for these poor mice. The lack of mental illness in mice is the natural nature of mice as they do not speak. The mouse model of schizophrenia, like the mouse model of stuttering, has little to do with human diseases. How can Alzheimer's disease take 60 to 70 years for humans to get in mice within tens of days? Although it is rare, mice can indeed develop cancer naturally, but I have not seen reports of mice naturally suffering from Alzheimer's disease. It is doubtful whether mice can suffer from such diseases.

　　 The second major problem is that since you ask these animals such a complex question (ie, efficacy), you should use an experimental procedure that matches this complex question. Phase III clinical trials must almost be double-blind, controlled, randomized, multi-center, multi-gene background patients, multiple lifestyle habits and complications, but none of these control factors exist in animal experiments. Mice are close relatives of the same genetic background that are bred in the laboratory. Their living habits and energy intake are exactly the same, and they are very different from ordinary mice, let alone patients. It was previously thought that limiting energy intake could extend the lifespan of mice, but it was later discovered that these experimental mice usually ate too much. Double-blind, controlled, random these control mechanisms are rarely used in animal experiments, which obviously increases the unreliability of animal experiment results. A large number of published animal experiment results cannot be repeated is one of the proofs. Although multi-center may be more common today in the globalization of research and development, once two different laboratories produce inconsistent results, most people’s solution is not to improve the animal model, but to concentrate the experiment on one of the laboratories. Consistency", cover your ears and steal bells.

　　 So the correct solution is to ask the questions that the model can answer and the questions that the animal can answer, instead of handing over all the problems you cannot solve to the animal model, and then torture the data to draw the desired conclusion. If you are asking complicated questions, look at your experiment design strictly for God's sake. Don't pick the most sensitive model and use the experiment design that is most likely to produce false positives. The future of new drug development depends on greater investment in clinical research by the entire society. Confirm the role of the target in the disease in humans, and investigate whether the drugs can regulate the biological function of this target in animals, rather than the so-called animal model's therapeutic effect. In many cases, this is not much different from fishing in the water.