The next step towards more biomimetic in vitro models is the design of multi-organ devices, which allow for communication of different tissue types. Combining physiologically relevant organ models in perfusion systems bears technological challenges and often leads to complicated culturing setups. Complex systems require trained personnel, feature lower reproducibility and make integration into scalable routine processes difficult. The presented multi-tissue platform features microfluidic channels and chambers that were specifically engineered for culturing of microtissue spheroids under physiological flow conditions. The platform has a plate-format, is fabricated completely out of polystyrene and complies with SBS-standard dimensions. Each plate includes 8 parallel channels, each channel contains 10 microtissue compartments. The compartments have minimal dead volume (<2 uL) and the so-called ‘StandingDropPort’ render microtissues individually accessible, so that a robotic pipet tip can be used for parallelized microtissue loading and retrieval. Open media reservoirs are located at both ends of each channel. Perfusion flow is generated through tilting the device back and forth on an automated system inside an incubator. Multiple devices can be operated in parallel, which increases the number of conditions and statistical replicates that can be executed in parallel. The concept allows for on-demand interconnection of up to 10 identical or different microtissues per channel in a very flexible way. With the broad range of available spheroid-based organ-models, a variety of pre-clinical testing applications can be served using the very same platform.

I will discuss three novel technologies that our laboratory has developed in recent years. In the first part of the talk, I will describe our work on engineering variants of the RNA-guided endonuclease, Cas9, for the selective control of gene expression. I will then share our method for endowing Cas9 with single-nucleotide specificity and describe how it can be used to generate an in vivo mutation prevention system. Finally, I will outline a novel technology for the simultaneous generation of hundreds of mutant cells, each with a defined genetic alteration (point mutation, deletion or insertion), as well as methods for tracking the fitness of all generated mutants within a single experiment.

The pharmaceutical industry’s productivity crisis is well known with >90% of drug candidates failing in clinical testing, primarily due to unexpected toxicity or lack of efficacy.  Despite advances in high throughput ‘omics technologies and the large volume of information that is now amassed on new drug candidates, the probability of success for new molecules is not improving.  Scannel and Bosney (2016) have pointed to a lack of predictive preclinical models as one of the key factors.  New approaches using human-based in vitro cell systems are showing promise for replacing the use of animal models, particularly in cases where animal testing has failed to predict human effects. These new approaches will be described along with case studies that illustrate how these methods can generate mechanistic hypotheses for drug induced cardiovascular toxicity.  Also to be discussed is how phenotypic assay data may be incorporated into safety risk assessments through the adverse outcome pathway framework being developed for chemical safety testing.

NSD2 catalyzes the mono- and di-methylation of the e-amine of lysine 36 from histone H3, utilizing the methyl donor S-adenosyl-L-methionine. Increased catalytic activity of NSD2, either by overexpression or point mutations, is associated with multiple human cancers. To date, potent, selective and cell-active NSD2 inhibitors have not been described. A platform was established for the discovery of selective NSD2 inhibitors from quantitative high-throughput screening in a 1536-well format using a nucleosome substrate. Active compounds from the primary screen were triaged by a panel of assays and tested against two clinically relevant NSD2 mutants, E1099K and T1150A. Five confirmed inhibitors were further evaluated by a radiolabeled validation assay, surface plasmon resonance studies, methyltransferase profiling, and histone methylation in U-2 OS cells. Several inhibitors bound the NSD2 catalytic SET domain and demonstrated activity in cells, which validates the use of this workflow for the discovery and development of selective NSD2 inhibitors.

AstraZeneca has an ambition to create a porous organisation, seamlessly collaborating with external partners. This desire has led to the establishment of the AstraZeneca-MRC UK Centre for Lead Discovery, ultimately located in the future R&D centre in Cambridge, UK. 

This new global screening centre encompassing AstraZeneca, Medical Research Council, Cancer Research UK and additional scientific partners has created the unique opportunity to completely re-develop our screening infrastructure and its capabilities, resulting in the concept of our next generation of HTS automation to deliver the varied capacity and assays formats across this partnership. This presentation will describe the generation, use and support for this new generation of HTS screening. 

I will discuss three novel technologies that our laboratory has developed in recent years. In the first part of the talk, I will describe our work on engineering variants of the RNA-guided endonuclease, Cas9, for the selective control of gene expression. I will then share our method for endowing Cas9 with single-nucleotide specificity and describe how it can be used to generate an in vivo mutation prevention system. Finally, I will outline a novel technology for the simultaneous generation of hundreds of mutant cells, each with a defined genetic alteration (point mutation, deletion or insertion), as well as methods for tracking the fitness of all generated mutants within a single experiment.

In this webinar Automation Meets Cell Separation as we will discuss the benefits of automating cell isolation processes in laboratories of variable size and sample throughput, and go into detail about what aspects should be considered when selecting an automated solution for your laboratory. We will introduce new solutions, both instrument- as well as reagent-based, from Miltenyi Biotec to shorten sample processing time, automate more and more steps of the cell isolation process and Select the best for your cells to ensure the best results for your downstream assays. 

Synthetic biology is a new set of tools and techniques for engineering biology. Its earliest applications were in biotech-related fields like medicine and agriculture, but today it’s being used to make new textiles, foods, and other consumer goods. In this presentation, InnovationLab’s Mark Bünger will introduce the key ideas and accomplishments in synthetic biology to date, and describe how it is now entering these new industries.

The next step towards more biomimetic in vitro models is the design of multi-organ devices, which allow for communication of different tissue types. Combining physiologically relevant organ models in perfusion systems bears technological challenges and often leads to complicated culturing setups. Complex systems require trained personnel, feature lower reproducibility and make integration into scalable routine processes difficult. The presented multi-tissue platform features microfluidic channels and chambers that were specifically engineered for culturing of microtissue spheroids under physiological flow conditions. The platform has a plate-format, is fabricated completely out of polystyrene and complies with SBS-standard dimensions. Each plate includes 8 parallel channels, each channel contains 10 microtissue compartments. The compartments have minimal dead volume (<2 uL) and the so-called ‘StandingDropPort’ render microtissues individually accessible, so that a robotic pipet tip can be used for parallelized microtissue loading and retrieval. Open media reservoirs are located at both ends of each channel. Perfusion flow is generated through tilting the device back and forth on an automated system inside an incubator. Multiple devices can be operated in parallel, which increases the number of conditions and statistical replicates that can be executed in parallel. The concept allows for on-demand interconnection of up to 10 identical or different microtissues per channel in a very flexible way. With the broad range of available spheroid-based organ-models, a variety of pre-clinical testing applications can be served using the very same platform.