Are you like me, that you get irate about Big Pharma making money hand over fist and charging ridiculous amounts for drugs? Well, I still feel like Big Pharma makes too much money, but I’m starting to get why they charge so much. At the World Parkinson’s Congress I attended in October, Dr. Fabrizio Stocchi (Director of a PD research center in Rome) said the average drug development program took 15 years and cost $1.2 billion.
Yikes! How can drug development take this long and cost so much?! This blogpost will cover challenges with animal testing that add expense and time and impair meaningful test results; another post will cover challenges with human testing.
On animal testing, first, put aside any PETA squeamishness about chimps being inflicted with Parkinson’s. It’s just not ethical to try out new drugs on humans first. Also, basic research questions often can only be answered by an autopsy of the brain.
OK, if we have to do animal testing, what are the challenges?
—Animals don’t get Parkinson’s. No one really knows why PD is not observed in animals, although one theory is that PD is a type of accelerated aging, and most animals don’t live that long.
–So how do animals “get” Parkinson’s for the purpose of testing? There are (presently) two ways, both of which distort test results for humans:
–One approach is that animals (mice or primates are the usual subjects) are injected with MPTP. This is a toxin which creates Parkinsonian like symptoms. This way of emulating PD in animals was stumbled upon in the 1980s when heroin addicts showed up at hospitals literally frozen because they had injected heroin contaminated with this compound.
–Animals have a “catastrophic attack” of Parkinson’s; it’s not slow and subtle as it actually progresses in humans.
–Non-motor symptoms of PD are difficult to observe (how do you tell if a mouse is depressed or seeing hallucinations?) so it’s hard to assess the impact of a new drug on these symptoms.
— The MPTP approach shows inconsistent results compared to humans. One of the few things you can say about PD that’s always true is that you will always find Lewy bodies (knots of tangled proteins) in the brain after autopsy…. except …..animals are inconsistent: they can have dopamine neuron deaths without Lewy bodies or lots of Lewy bodies but no dopamine death.
— With the advances in genetic research, a second approach has more recently been developed: Animals are genetically modified, using a known mutant gene that has been associated with PD. The distortion here is that this genetic model only covers about 10% of the Parkinson’s population
–It is expensive and time-consuming to get animals set up with Parkinson’s, especially if part of the research is measuring the “before” condition of the animals (say, their time to run a maze).
–And of course, with any animal testing, there is the challenge that animals can’t talk. Mr. Test Mouse can’t report that the drug is helping his tremors but he is seeing blue space aliens. Researchers have to come up with non-verbal ways to measure, say, cognitive skills or dementia.
So, what are some remedies to mitigate limitations of animal models?
—Worms. That’s right, worms. John Sulston at the MRC Laboratory of Molecular Biology in Cambridge, England, thought a worm model for Parkinson’s would be cheaper, easier and faster. (Think about how fast worms reproduce!) So he set out to breed a worm with Parkinson’s. Sulston and his colleagues found these mutant C. elegans worms (Caenorhabditis elegans if you’re feeling exceptionally geeky) that couldn’t make dopamine. (Yes, incredibly, despite the biological distance from homo sapiens, these invertebrates use dopamine.) Although Sulston went on to be awarded a Nobel Prize for his work on C. elegans, the bad news was the worms didn’t seem to exhibit Parkinson’s symptoms (although it’s difficult to observe hand tremors in a worm!)
Illustrating the global teamwork necessary to move PD research forward, another scientist, Jon Pierce-Shimomura, assistant professor of neurobiology at University of Texas, found that yes, these worms did exhibit Parkinsonian symptoms. The worms had to be viewed under the right circumstances and with the right equipment. Having worms available as a Parkinsonian animal model means researchers can test a thousand drug compounds at the same time, not just a couple dozen, the practical limit with mice today. And they can have new groups of animals ready much quicker for the next round of testing.
—Humans. I have noticed as I read about different PD projects, that researchers are trying to think out of the box and skip the animal stage altogether. For instance, most research to find a biomarker for PD by its nature has to focus on humans. Follow the link to an example of using human skin tissue as a potential PD indicator.
However, it’s hard to design an ethical drug trial that skips the animal stage. And once you do get to the human stage of testing, it has its own distorted results. See a future blog post for challenges with human testing.