Good, bad, useful? Reflections on animal models for Parkinson’s disease research

Parkinson’s disease is a relentless, ruthless neurodegenerative disorder that often strikes in the early “golden years”, around 60 years of age, but sometimes much earlier.  It progressively robs its victims of every capability that makes life enjoyable, from their ability to move, talk, eat by mouth, and in the worst cases, decreasing their cognitive abilities.

In the sixties, pioneering work in animal models, primarily rats, led to the discovery of a “pill” that transformed the lives of many patients by restoring their ability to move and allowing them to perform daily tasks, often continuing to work, travel, and to enjoy sports and family time.  In research that earned him a Nobel prize many years later, Arvid Carlsson and colleagues reproduced in these rats the main chemical deficit that exists in patients, and found that administration of l-dopa (sinemet) could greatly improve the motor deficits of PD patients.

Subsequent work, always based on generating a “model” of the disease in animals by destroying the neuronal cells that also die in patients, have led to refinement of this treatment; additional advances have led to surgical methods (deep brain stimulation) that further improved quality of life for many patients.

Why should we continue to use animals to study this disorder?

First, as any patient will tell you, the available treatments do not work on all the symptoms they experience, such as depression, sleep disorders, and digestive problems that plague their lives often even more deeply than their motor disorders. Second, the current treatments do not cure the disease, and their benefits do not last forever. In time, the treatments progressively lead to side effects, for example uncontrolled movements or spasms that leave the patient to chose between not moving at all or moving too much. Today’s medications do not stop the progressive loss of nerve cells in the brain, which will ultimately lead to disability and death.

A real treatment for the disorder will have to address its root cause and stop its process, perhaps even reverse them. This is where a lot of confusion on the utility and value of the animal models arises. In the press and even the scientific literature there are statements expressing concern that there is “no good model” of Parkinson’s disease, and sometimes that existing models are useless because some drugs that work in animals fail in the clinic.  It is a complex issue that is a source of debate among scientists and lay people alike. However, one has to examine the roots of the problem.

Models are only as good as our understanding of a human disease at a given time. Science is an evolving process and so are our models of disease. There was a time when we did not understand why some people would die from blood transfusion and others did not, because blood types had not yet been discovered. In the case of Parkinson’s disease, we have known for about a century which cells die in the brain of patients but we still do not know why. The early models, those that led to the major breakthroughs in treating some of the symptoms of the disease, reproduce this loss of cells but do not address its mechanism. We now know more about this mechanism because of research on the causes of rare cases of the disease that have a genetic component and run in families. We also know that even though most cases of Parkinson’s disease do not have a clear genetic component, the mechanisms may be the same. New understanding has led to a new generation of models, in which defective genes are introduced in mice to reproduce the mechanisms thought to cause the disease in people.

GM mice help to uncover the processes of Parkinson's disease. Image courtesy of Understanding Animal Research.

Are those models perfect?

No model is perfect. No model can be expected to reproduce all the symptoms that occur in patients. Even if similar, the brain and nervous system of mice are not identical to those of a human, who walks on two legs, not four paws, and can live up to a hundred years rather than two. Yet, a lot of the general functions that are affected by the disorder in humans are present to some extent in the mouse model.

More importantly, only in an animal can one examine the very beginning of the disease process. Many studies in humans have now shown that diseases like Parkinson’s begin to affect a person’s body decades before they even know it. The disease causes subtle changes that are not even perceived as abnormal but have long-term consequences, just as a minute water leak can over years rot a wooden beam and lead to a roof collapse. As the disease progresses, it can manifest itself with minor troubles, so unremarkable that they are not recognized as related to Parkinson’s disease, for example problems with sleep and smell, that are very common and have many different causes.

Thus, in a human, we will never be able to understand the beginning of the disease, the water leak, because we do not know in which individuals they are occurring. This is where animal models are the most useful. By reproducing anomalies, such as the overexpression of the protein alpha-synuclein, that cause the disease in people, we can study the mechanisms from the beginning and find ways to stop the damage as early as possible.

Why then are people writing that animal models of Parkinson’s disease did not accurately predict whether a new treatment can be effective in patients? For one thing, those drawbacks were largely based on old models, which were – and still are – useful for some things (developing treatments for symptoms and evaluating new approaches to restoring lost function such as gene therapy) but were only minimally productive in developing treatments to halt the development of Parkinson’s disease because of our limited knowledge of mechanisms at the time.

Will the new models be better at predicting drug efficacy in the clinic? It is too early to tell because none of the new compounds developed and currently being tested in these models has yet been tested in patients. Should these animal models be replaced by computer modeling of the disease?  Probably, but this is years in the future. The science of modeling all the molecular interactions that take place within a cell, and of all the connections this cell establishes with other cells in a complex organism in a way that could illuminate a disease process and make sound predictions leading to effective treatments is in its infancy. In the meantime, patients are diagnosed, grow worse, and die every day.

We cannot wait. Just as previous models, although imperfect, led to transforming discoveries that bought years of functioning to patients who otherwise would have been locked in a chair and condemned to an early death, the new models continue to lead every day to discoveries that bring us closer to an effective treatment. Nothing can replace them at the moment.

Marie-Francoise Chesselet, M.D., Ph.D.
Charles H. Markham Professor of Neurology
University of California, Los Angeles

6 responses to “Good, bad, useful? Reflections on animal models for Parkinson’s disease research

  1. Thank you for providing insight into how scientists study this awful disease. My Mom got a diagnosis of Parkinson’s when she was in her 70s. Luckily, it turned out to be something else–a “Parkinson’s-like” syndrome–that did not progress.

    People with this disease suffer terribly. I am glad that you are are working to help us conquer it.

  2. What a great explanation of the need for animals in this work. Thank you.

  3. Thank you for giving such a great insight into current research using animals. I do make reference to speaking of research on my blog
    http://www.research4drugdiscovery.blogspot.ca/ hope you find it interesting.

  4. I find the research most interesting too. Hope you enjoy these as well.

    http://rebeccaskloot.com/faq/

  5. Silvermaven, I would be very careful about the suggestion that Autism is caused by Chronic lyme Disease, as the evidence that chroinic lime disease is due to persistant infection is pretty thin and unreliable.

    http://www.nejm.org/doi/full/10.1056/NEJMra072023
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250243/?tool=pubmed
    http://www.aldf.com/pdf/Halperin_Book_Chapter_17.pdf

    The topic of chronic lime disease has also been discussed on a few science blogs

    http://www.chicagotribune.com/health/ct-met-chronic-lyme-disease-20101207,0,5671843.story
    http://scienceblogs.com/insolence/2010/12/the_chicago_tribune_chronic_lyme_disease.php
    http://scientopia.org/blogs/whitecoatunderground/2010/05/13/bad-science-done-badly-its-bad/#more-629

    The American lyme Disease Foundation have a decent page on this controversy at http://www.aldf.com/Misinformation_about_Lyme_Disease.shtml