Readers of this column should by now be aware that we neuroscientists are proud of what we have accomplished in terms of understanding the brain and applying this information to treating brain diseases. However, we have only scratched the surface. As we learn more, the implications of our ignorance only grow greater. As the great neuroscientist Max Cowan said, “Some day we will know the entire human genome, but we will still have to ask: How does the brain work?”
How do we make progress, both now and in the future? Our ability to directly study the human brain is limited. We can record functions at time of surgery, or as a prelude to surgery; put electrodes in deep as part of deep brain stimulation; analyze brain activities by various imaging techniques; and, of course, see the brain directly at time of autopsy.
But what’s really going on at the level of brain circuits? When we introduce a new drug to modify a disease? Or try to identify the function of a group of genes identified by genome-wide screening techniques? Answers to these questions require the use of brains we can directly access, namely animal brains. Animal brains serve as models of human brain functions and disease.
In an article that appeared in The San Diego Union-Tribune, Michael (“Mickey”) Goldberg, the immediate past president of the Society of Neuroscience, states the case for animal research. I would like to add some further specifics to his comments.
There are numerous examples of progress that depended on animal research, but I will emphasize two: Parkinson’s disease and Alzheimer’s disease.
The advances in Parkinson’s came about by accident. In 1982, seven people in California developed the symptoms of Parkinson’s, a disease of the elderly, after taking a street drug called MPTP (similar to Demerol). The thing is, the users were relatively young—at least two were in their 20s.
MPTP became a very valuable research tool for inducing the disease in various animals, particularly the monkey. Studies of these Parkinsonian monkeys led to our understanding of the abnormalities of the circuits involved in motor control and, most importantly, how modifications of these circuits could treat the disease. The result for humans is the development of deep brain stimulation to specific parts of these motor circuits, and relief of symptoms for hundreds, if not thousands, of people.
With Alzheimer’s disease, we've known from the beginning that there was a distinctive pathology involving two features: plaques and tangles. The plaques have been shown to contain a protein, “amyloid.” A small proportion of those with Alzheimer’s have a clear-cut heritable disease occurring in several generations of a family. When these families have been studied further, almost all have a genetic abnormality in either the production or breakdown of amyloid. Further, when the abnormal human gene is put in a mouse, a mouse-model of Alzheimer’s disease is created. All this has reinforced the “Amyloid Hypothesis” as a basis for Alzheimer’s disease, and led numerous pharmaceutical firms to “bet the farm” on developing an anti-amyloid drug. Many of the studies of these drugs are in progress, but results so far have not been encouraging.
Attention is now being directed at the “tangle,” involving another protein called “tau.” Current theories suggest that the process involves both tangles and plaques, and possibly some other factors as well. But these new theories can also be evaluated in the mouse, long before a theory-based drug is tried in a person.
The list of diseases currently without animal models is also long. Again, two examples: mental illness and brain tumors.
One of the hang-ups in understanding mental illnesses like depression or schizophrenia is that the pathology of the disease is not clear. There are no consistent abnormalities at autopsy. Also, there are no recognized animal models. Pharmaceutical companies use models based on how they think drugs might be working, not on the basis of the underlying disease mechanisms. Proper animal models would be most helpful.
There are models of human brain tumors, but not satisfactory ones. Our progress in treating the most severe form of brain tumor, glioblastoma, has been dismal. We desperately need new approaches. Such approaches can be evaluated in an animal model and then taken to the human.
Application of the advances in genetics have been somewhat disappointing in changing our approaches to human diseases. The latest genetics approach is “genome-wide association studies.” These studies involve large numbers of subjects comparing those with and without disease. They often identify a number of genes in the disease group, some of which make sense in terms of our current understanding about the disease, and other genes one would not expect. How to sort out what is real in terms of a disease will require putting combinations back into animals to try to reproduce the disease. Such studies are coming.
The use of animals in research is an emotional issue. No responsible investigator defends the indiscriminant or careless use of animals. However, to go to the other extreme and suggest that animals are not needed is equally irresponsible.