October 5, 2012 | 1
In a previous post I described the benefits and enduring value of Small Science. I emphasized the fact that in the current economy and funding environment, Small Science is likely to be consistent while Big Science happens in fits and starts. And I talked about how crowdsourcing and crowdfunding could bring great value to both Big and Small Science.
Now I want to describe a crowd funded Small Science project that could prove very valuable in understanding the root causes of one of the most pernicious scourges of our time – methamphetamine addiction. Ethan Perlstein at Princeton and David Sulzer at Columbia are interested in dissecting the different ways in which meth acts in and on the brain and they have taken the bold step of pitching this as a crowdfunding project. Their project and others like it could not only help us develop new treatments for meth addition but they could address a more general and key question; how do psychotropic drugs work?
It turns out that in spite of the legions of psychiatrists prescribing a record number of antidepressants and other medications every year, we still don’t have a good idea how these compounds work. The same lack of understanding permeates our efforts in tackling the addiction epidemic. From a chemical standpoint the simplicity of psychotropic drugs like meth and PCP is breathtaking. The fact that a few carbon, hydrogen, oxygen and nitrogen atoms arranged in and around a simple ring can cause such profound behavioral changes in human beings continues to beguile and fascinate us. Sadly, our knowledge of the mechanism of action of these molecules as well as legal psychotropic drugs has reached a kind of roadblock. Of course we have made significant advances during the last half decade and we now know that these drugs work their magic by mimicking the action of neurotransmitters and binding to specific proteins called receptors, just like many other medicinal drugs do. However in case of psychotropic drugs the workings are much more complex since they usually have multiple effects, binding to different flavors of receptors to varying extents in different parts of the brain and provoking a cocktail of biochemical activity. The complexity of the process combined with the complexity of the brain itself has challenged CNS researchers for decades.
This whole paradigm of understanding how drugs work by looking at their direct interaction with specific proteins has productively driven drug discovery since its reductionist origins. But Perlstein, Sulzer and the project’s chief experimentalist, Daniel Korostyshevsky, are taking a different tack in answering this question. In a very intriguing paper published earlier this year, Perlstein demonstrated that the antidepressant sertraline actually causes physical changes in the structure of cell membranes, affecting their curvature, fluidity and other properties and provoking autophagy, the degradation of a cell’s own machinery. This study fits into a larger perspective. If you think of the cell as a building with girders, beams and floors and the drug as a small but very powerful iron ball hitting this building, you would in fact expect the ball to cause structural reorganization. Thus it shouldn’t come as a surprise to find that small molecules like drugs affect physical changes in the structure of membranes and other organelles. But for some reason this morphological approach has been overlooked relative to the traditionally pursued protein-drug binding viewpoint. Now researchers like Perlstein and Sulzer are emphasizing the morphological paradigm and asking us to consider the physical, more global effects of drugs on the cell’s structural machinery along with their interaction with specific proteins.
Meth is as good a candidate as any for this kind of thinking. We don’t know the details of its mechanism of action, and any information gleaned from studying it could be potentially valuable in advancing treatments for meth addiction. It’s clearly a problem that is both ripe for scientific study and of great public interest. So Perlstein has taken the novel approach of pithing it as a $25,000 crowdfunded project. $25,000 is a modest amount, far less than many of the grants that get routinely rejected these days from funding agencies like the NIH. But it’s enough to start making inroads into the problem. Part of the money will support a master’s level technician for 2-3 months and the rest will contribute to overhead costs. To study how meth works, Perlstein and Sulzer will use a classic technique called autoradiography which essentially tracks the movement and fate of drugs inside tissues using radioactive tracers. Once the localization of a drug is revealed, other techniques including those used to study protein-drug interactions can then be used to further find out what the drug is doing at that particular location in finer detail.
Perlstein has all the details on his site, along with a really nice video explaining the project. True to the spirit of crowdfunding and open source science, the progress of the project will be regularly documented on a public website. In addition, depending on the level of contribution, contributors will have access to regular project reports, brainstorming meetings and perhaps even a relaxing cocktail in NYC. The biggest contributors can even participate in lab meetings and discuss the resulting manuscript. All contributors will be acknowledged on the website. From a scientific sense, the biggest value of the project is in taking an alternative approach to understanding psychotropic drug action by looking at large-scale morphological effects on cell structure and function.
I think this project and the general idea look very promising and I hope that the project gets funded. Citizen science should play an increasingly important role in solving our problems. In one sense the scientific research and peer review process with its dependence on large grants, exclusive cliques and anonymous peer review is still stuck in the pre-Internet age. This project and others like it are making sincere attempts to punch through the wall so we can all contribute to both scientific understanding and the fruits of such inquiry. I hope we can do our part in taking out a few bricks.
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