Drug Discovery


disease, from the very rare to the more common and provides a powerful way to identify novel tar- gets for drug discovery21,22. Crucial to these studies is the availability of cell models which represent both healthy cells and disease cells – isogenic cancer cell lines, iPSC-derived physiolog- ical models and even primary cells can be paired up and evaluated for selective responses and to find synthetic lethal targets, genes which interfere with the disease cell survival but do not affect the healthy cells, for drug discovery. But what if the disease state of the cell model is


not marked by a difference in cell health? Pooled screening can also be adapted for more complex phenotypic readouts. The simplest example of this approach is the use of high-throughput fluores- cence-activated cell sorting (FACS) to determine cell phenotypes based on a biomarker signal (see Figure 2). Success with this approach is governed in part by the availability of suitable tools (anti- bodies, reporter cell lines) but the applications can


be highly diverse. A recent study exemplified the use of this approach to study ATP dynamics, revealing new targets and pathways which influ- ence the pathophysiology of energy deficiency in neurodegenerative disease and even ageing23. The approach can even be extended to monitor


secreted biomarkers or intracellular events by using permeabilisation and secretory pathway blocking reagents such as brefeldin A. In these experiments, the biomarker (ie a cytokine) is locked in the cell shortly before the sample collec- tion point24. The resulting accumulation of the biomarker in the cell is then read out directly, for example by antibody staining, and cells can be sorted by FACS. Barcodes corresponding to the sorting of populations differentially expressing the biomarker can be captured and sequenced. Recent advances have also seen the development


of novel platforms that massively increase the phe- notypic throughput of CRISPR screening. These new approaches combine CRISPR-based pooled


New Easi-CRISPR Technology


The latest evolution in the CRISPR revolution.


Taconic Biosciences’ new Easi-CRISPR capabilities let you perform rapid whole genomic insertions, rather than limiting your projects to point mutations and constitutive knockouts.


With Easi-CRISPR, our genetic engineers deliver more complex models, faster.


 Simplify large genetic insertions, such as conditional knockouts.  Produce viable models up to six months faster than traditional large insertion methods.


 Easily generate a genetically humanized mouse model expressing the human instead of the mouse protein.


Read Taconic’s White Paper, Application of CRISPR/Cas to the Generation of Genetically Engineered Mice at taconic.com/crispr-applications


US: 1-888-822-6642 | EU: +45 70 23 04 05 | info@taconic.com


Drug Discovery World Fall 2018


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