A phenotype is one or more observable features that report changes in the genotype, epigenotype or environmental response of a single cell, a group of cells, organ or of a whole organism. Phenotypic changes are the causes of disease, whether this is a cancer cell undergoing uncontrolled cell division, a motor neuron which fails to connect to muscle tissue in motor neuron disease, or the complex defects seen in the brain of a patient with schizophrenia or bipolar disease. Screening for agents that alter a phenotype is an effective route to finding new therapies.
Why use phenotypic screening rather than other approaches?
Target-based discovery has limitations
A number of factors could explain this situation, including undue emphasis on a “one gene, one protein, one target, one drug” philosophy that can be far removed from the complex reality of human biology. This simplistic approach is compounded by poor understanding of the biology of diseases and their often complex causative mechanisms.
Industry needs phenotypic screening to innovate
Low rates of success in drug discovery, expensive late stage failures in phase II/III clinical trials, and imminent patent expiries have challenged the financial viability of the pharmaceutical industry.
Industry is searching for novel ways to discover medicines and products of value to the economy and society.
Phenotypic screening is historically successful
Phenotypic screening has been a more successful at finding “first-in-class” drugs (Swinney & Anthony, 2011). The technique makes only limited assumptions about mechanism of action and none about the target. Phenotypic screening starts from a more complex position that is closer to the disease mechanism, making it a better platform for translation.
New technologies mean the time is right for phenotypic screening
Technological advances allow the study of phenotypes and target deconvolution at a useful scale:
Novel stem cell and genome engineering technologies
Increasingly dense annotation of small-molecule libraries
Big-data analysis yields results from more complex phenotypes
Novel chemoinformatics and AI approaches allow ‘informed’ iterative screening strategies
Real-world diseases can be acurately modelled with phenotypic screens
Disease relevant assays can be developed thanks to the complementary power of novel stem-cell and genome engineering technologies, such as zinc finger nucleases, TALENs and CRISPR.
Phenotypic screening can also be carried out on co-cultures, 3D cell models, human biopsies, human tissues, and organoid cell cultures. This means that pathophysiologically relevant assays can be developed to achieve the best in vivo representation of the disease to be affected.
Phenotypic screening at NPSC is an opportunity for scientists to translate novel biology
Phenotypic screening moves hit discovery away from the narrow emphasis on the isolated target and involves screening for chemical matter that quantitatively perturbs a cellular, organotypic or even organismal phenotype.
NPSC offers an ideal opportunity for biologists to validate their phenotypic assays, translate their biological innovations, and create impact from their research.
Who benefits from the use of Phenotypic Screening at NPSC?
Collaborating with NPSC has the following key advantages:
- Access to validated novel phenotypic assays
- Ability to generate validated hit lists and high quality chemical starting points
- Capacity to take molecules further and discover new pathways
- Use target deconvolution strategies to dissect mechanisms of action and ultimately identify target(s) that can be exploited for rational design of lead compounds and beyond
- Benefit from a platform that is applicable to human, animal and plant health.
Academic scientists and clinical researchers with novel phenotypic assay ideas can benefit from the expertise of our scientists, the high-quality data for the equipment in our cutting-edge facility, and the access to the annotated compound-sets in our in-house chemical libraries.
We will work closely with you, host your postdocs or PhD students during the assay development and screening phases to deliver a high quality data package including an SOP, and (hopefully!) a hit list.
Working to industry standards means that the results can also be used as a springboard for further funding and industrial collaboration or commercial exploitation.
Supporting the NPSC allows you to invest in a world-leading research centre dedicated to advancing phenotypic discovery sciences across a spectrum of important areas impacting human health and wellbeing.
You will also contribute to an exciting team leading the development of next-generation disruptive technologies.
Taken together this investment will deliver positive impacts for patients, the knowledge economy and wider society.
Phenotypic Screening References
Arrowsmith, J. and Millar, P. (2013)Trial watch: phase II and phase III attrition rates 2011-2012.
–Nat. Rev. Drug Disc., 12, 569
Feng Y, Mitchison TJ, Bender A, Young DW, Tallarico JA. (2009)Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds.
–Nat Rev Drug Discov. 8(7), 567-78
Lee, J.A. and Berg, E. (2013)Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches.
J. Biomol. Screen. 18(10):1143-55
Macarron, R. et al. (2011)
Impact of high-throughput screening in biomedical research.
Nat. Rev. Drug. Discov. 10, 188-195.
Munos, B. (2009)
Lessons from 60 years of pharmaceutical innovation.
Nat Rev Drug Discov. 8, 959-968.
Prinz F, Schlange T, Asadullah K. (2011)Believe it or not: how much can we rely on published data on potential drug targets?
Nat Rev Drug Discov. Aug 31;10(9):712
Swinney, D.C. and Anthony, J. (2011)How were new medicines discovered?
Nat Rev Drug Discov. 10(7), 507-19.
Swinney, D.C. (2013)The contribution of mechanistic understanding to phenotypic screening for first-in-class medicines.
J Biomol Screen.18(10), 1186-92