An open approach to Huntington’s disease research

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Guest post by Rachel Harding, postdoctoral fellow at the Structural Genomics Consortium, University of Toronto, Canada

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a mutation in the huntingtin gene1. The progressive break down of brain neuronal cells in HD patients leads to deteriorating mental and physical abilities over a 10-20 year period prior to death, the symptoms often described as having Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) simultaneously2. At the start of the huntingtin gene there is a CAG trinucleotide repeat region that encodes a stretch of poly-glutamine residues in the amino-terminus of the encoded protein. This repeat tract is expanded in HD patients. The repeat length of this region correlates with the age of symptom onset3. Affecting approximately 1 in 10,000 of the population4, rare juvenile forms of the disease exist in patients with the longest CAG expansions, although adult-onset HD patients typically have between 40-50 CAG repeats with symptom onset beginning between the ages of 35-50.

What interests many scientists most in the field, and would be imperative to developing targeted and effective therapeutics, is how the CAG repeat number seems to expand and reach a tipping point. As the repeat tract increases beyond 36 repeats the pathogenic threshold is bypassed, resulting in the severe and devastating neurodegenerative symptoms seen in patients. Despite the HD mutation being mapped to the huntingtingene over 30 years ago5, efforts to understand a precise and complete mechanism for this disease at the biochemical level remain elusive. My hypothesis is that this progress would be faster if all scientists shared their data, both positive and negative, more rapidly.

Traditional publishing methods in the biomedical sciences promote the publication of select successes; rarely are failed experiments or those that produce “negative” data reported. This situation results in an incomplete picture of the studies undertaken, needless repetition of failed experiments and slow progress towards answering the big scientific questions at hand, ultimately delaying the development of novel therapeutics. In HD the need for better understanding of the underlying molecular pathology, and most importantly patient therapies, is desperate, with limited therapeutic relief currently available for affected individuals6.

Using biochemistry and structural biology methodologies, I am studying how the causative mutation affects the huntingtin protein structure, potentially pointing towards a disease mechanism. This is not a novel premise for a project in this field, with many labs already attempting similar experimental strategies. However, the exact details of what experiments have been previously attempted by these groups and which have been fruitful, and perhaps more importantly which have not, are generally not publicly available.

In an effort to buck this trend and catalyze research to answer the challenging questions underlying the disease mechanism of HD, I decided to open up my lab notebook, making my methods, data and analyses freely available online. The Structural Genomics Consortium (SGC), University of Toronto, where I work as a postdoctoral fellow, and the CHDI Foundation, who fund my project, have agreed that all output from this project should be released freely into the public domain with no restriction. This approach does not only aim to present the end successes of the research project but also all of the incremental steps forward, failures and mistakes made along the way, providing an honest and transparent representation of all of the work completed in real-time. Even if my own project is not successful in answering these questions about HD, perhaps others can learn from my own mistakes, but more hopefully fellow scientists will share and contribute along the way to expedite scientific discovery.

Building on the pioneering efforts of other open notebook advocates I set up a blog, labscribbles.com, through which I describe my recent experiments and findings. LabScribbles posts links through to Zenodo, a data repository where I upload detailed methods, raw data and analysis, available freely through a Creative Commons Attribution license. The free Zenodo platform allows easy application of a variety of different licenses to uploaded files to suit the depositor’s needs as well as DOI and citation generation, authorship and funding acknowledgements along with a variety of other features suitable for scientific self-publication and data deposition.

Shortly after commencing this project, I found that daily updates and installments of a lab notebook impose a real time burden on myself, the writer, and are likely tedious for readers. Therefore I write up experiments after they have reached a reasonable conclusion, resulting in approximately one post per week. In each blog posting I write a brief summary describing the experiments and findings in that week’s Zenodo upload, along with some of my personal opinions of the data. By using fairly plain language in these broader explanations I also hope that this will provide insight into the scientific process to non-scientists, in particular the patient and HD family population.

The blog also allows anyone to email me or directly write comments on the blog posts which, together withTwitter using the handle @labscribbles and other online platforms, opens a dialogue with scientific peers, HD family members and interested persons alike to ask questions or discuss their own thoughts or ideas. So far the online response has exceeded any of my original expectations. I have received many touching messages from HD patients or affected family members detailing their personal experiences, for which I am very grateful. The HD family community is renowned for their engagement with both scientific advancements and the latest clinical trial data. I have found that particularly through Twitter as well as by publishing articles in various news outlets, including HDBuzz, the online notebook has been an effective channel to further publicize this rare disease with the support of the numerous HD advocacy organizations, in particularHuntington’s Disease Society of America and the Huntington Society of Canada.

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Source: blogs.nature.com/ 

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