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forward. As it operates mostly in the pre-clinical space, it does not hamper drug development, but as proponents say, it will enhance it. The Montreal Neuroscience Institute (a working hospital and research institute) and partners have spearheaded such an endeavour in neuroscience, an area which has seen few new drug approvals and a drastic fail- ure rate, but all areas of science could benefit from such an approach (Montreal institute going ‘open’ to accelerate science doi:10.1126/science. aae0265). Talking the talk is easy in this case, as everyone can say “we publish our results so we are open sci- ence”. However, walking the walk is a bit more challenging and will require new thoughts on how one really creates an open environment. Publication of results in a timely manner is one facet, but in reality, it happens only with ‘failed’ research pro- jects, or when the impact has fallen off the cliff. One of the biggest and perhaps most valuable aspects is also the inclusion and/or publication of negative results. Think about it. Each year, billions of dollars are provided to academic labs to pursue ideas, and each year a large number of research papers are published. It is, however, rare to see the research that did not work. Yet, the same experi- ments are often carried out by other researchers, who would have not travelled the path and wasted significant resources had they known. Negative data is good data to have, particularly as we move towards an era of employing artificial intelligence to enhance discovery and development. But how does one employ this in a world which only rewards positive results through publications and grants? One potential way would be to utilise a self- curated Wikipedia-like contribution which has some data entry standards employed to make the data easily searchable with respect to field, technol- ogy used and results portrayed.


Outsourcing To harness the best avenues possible in the most cost- effective way, pharmaceutical industry now actively pursues and outsources many of its activities, and academic partnerships have become a key element of early pipeline strategies3. When we outsource research, we risk losing serendipity and chance obser- vations/findings that quite often fuel innovation and pave the path towards unchartered territories. For this not to happen, outsourced research projects must be managed actively, with an eye towards ‘neg- ative’ results and unexpected findings.


Phenotypic and cell-based screening Along with phenotypic screening comes the chal- lenge of identifying genes/proteins/compounds that


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can alleviate a syndrome. Previously we have relied on si/shRNA knockdown to investigate which genes are necessary from an expression point of view with the hopes of uncovering potential targets for our compounds. Miniaturisation of the tech- nology, utilising reverse transfection technology has been able to provide the interrogation of thou- sands of genes, via siRNA or CRISPR (clustered regularly interspaced short palindromic repeats) technologies on a glass slide that can easily be viewed by high content instruments. Persomics, Inc (http://www.persomics.com/) has pursued this technology and, once it becomes validated in the community, one could envision larger arrays cover- ing the entire genome. If the phenotypic assay is run on one slide, one could quickly determine the effects of RNA expression on assay readouts and this would perhaps lead one to be able to identify pathways which would be appropriate to drug. With the advance of CRISPR technologies, this has become simpler and perhaps more practical in that genes are knocked out providing a clearer picture of protein involvement in a disease.


CRISPR CRISPR has revolutionised the way we do discov- ery biology. This exquisite technology comes from a bacterial defence mechanism used to destroy invading DNA. The small DNA repeats in the bac- terial genome producing short RNAs which recog- nise and bind to the invading DNA while bringing the DNA cleavage enzyme Cas9 to its location to cut the DNA so it becomes ineffective, while ensur- ing a copy of the short piece of invading DNA is reproduced and inserted into the bacterial genome to ensure ‘memory’ of this invading species. Since 2013 CRISPR technology has generally replaced other gene-editing/modifying systems due to its precise and efficient abilities. Examples include knocking out specific genes in cells and in animals, gene editing of human embryos to correct muta- tions, as well as extraction of HIV from a living organism thus preventing the progression of a latent infection. As we delve more and more into the disruption


of protein-protein complexes to create a newer generation of drugs, we need to be aware that a knock out (KO) of that protein may not provide compelling proof of target validation. Quite often, a KO is lethal, causing drug developers to drop the target – unless your field is oncology. But in other fields, it is not a KO that is required but more of an inhibition of an interaction with a neighbouring protein that is critical to prevent the disease or out- come. By modulating that interaction, one could


Drug Discovery World Spring 2018


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