Open Targets
Open Targets is an innovative collaboration between EMBL-EBI, the Wellcome Sanger Institute, GSK and Biogen, which seeks to accelerate drug discovery using genome-scale experiments and analyses. Drug discovery is a highly challenging process and with a relatively low success rate. Traditionally, animal models have played a key role in the process of validating possible drug targets. The goal of the CTTV is to transform the drug discovery process by predicting whether a drug acting on a particular target is likely to provide therapeutic benefit, more effectively and much earlier in the drug discovery process than is currently possible.
The Open Targets have developed an open-access informatics platform (www.targetvalidation.org) that allows users to start from the standpoint of the disease or the target. Users can ask what might be likely targets for a certain disease, or what diseases might be associated with a particular target. The platform works by combining information from a range of biological data sources which are then scored to reflect the strength of an association between a target and a disease.
In order for drugs to be approved and licensed for use in humans, their safety and efficacy must still be tested in animals; however the Open Targets programme allows researchers to validate targets using information from existing biological data and human disease models thereby reducing the need for data from animal models in the earlier stages of drug development.
Organoids
Before any research is ever carried out in animals preliminary data must be gathered in order to provide evidence and justification for moving into animal models. For many researchers much of this evidence is gathered using cell-lines. Cell-lines are cultures of individual cell types such as white blood cells or liver cells, for example. They are cheap and easy to grow and use, however they often contain large genetic differences from cells found in the body and they also only grow in 2D layers. This means they are poor models of the three dimensional organs they are derived from.
The Sanger Institute has been heavily involved in the development of organoids – small clusters of cells that grow in 3D so they more accurately mimic the behaviour of human tissue than traditional cell-lines.
Many of the organoids created at the Sanger Institute have been created from tumours of patients with cancer. This means they carry all the genetic mutations which are unique to the individual tumour making them identical to the tumour. By building up a collection of organoids it will be possible to test a range of existing and new therapies on multiple tumours from the same cancer type and connect drug efficacy with the mutations present in the tumour, offering the potential for more tailored treatment in the future.
Although unable to replace the use of animals, organoids provide an additional screening step between cell-lines and animal models meaning fewer potential therapies and interventions will move on to testing in animal models and a higher rate of success in those animals.
This research was awarded a prestigous 3Rs Prize by the National Centre for 3Rs. The international NC3Rs Prize is awarded to highlight an outstanding original contribution to scientific and technological advances in the 3Rs in medical, biological or veterinary sciences published within the last three years. The prize is part of our commitment to recognise and reward high quality research which has an impact on the use of animals in the life sciences.
Genome Editing in induced Pluripotent Stem cells
Researchers at the Sanger Institute have traditionally used mouse models in order to understand which genes are required for development of the embryo into the adult. By “knocking out” different genes they have been able to determine which genes are required for the development of stem cells all the way into tissues in the adult mouse. This has helped researchers understand which genes in humans are vital for human development as mice and humans share many genes. However, the methods for deleting genes or turning them off in mice are difficult, expensive and each gene can take months, making such a project hugely expensive and time-consuming.The development of the CRISPR-Cas9 technology, which allows precisely targeted changes to be made easily and cheaply to genomes of many species, has allowed our researchers to make genetic changes to human induced Pluripotent Stem (iPS) cells grown in culture. When grown in the right conditions iPS cells can develop into different human tissues. CRISPR-Cas9 allows researchers to switch off specific genes, in a way that previously wasn’t possible at the scale we work at. The development of a large-scale, high-throughput approach means some research programs no longer use animals.