From Phenotype to Phenotypic Screening – Going with the Flow
Author: Linda Trinkle; Published: Sep 14, 2011; Category: Drug Discovery, Flow Cytometry, Phenotypic Screening; Tags: multiparameter phenotypic profiling, Phenotype, Suspension Cells; No Comments
A friend sent me a link to a blog a couple of days ago: Phenotype Reigns Supreme by Derek Lowe. I am familiar with phenotyping, as it has been a mainstay application for flow cytometry for decades and so I definitely wanted to know what exactly it was reigning over. First, I googled “phenotype”(results=14 million) just to make sure that I hadn’t missed the formation of a new political party this week.
OK, now I was ready to delve into Derek’s blog about the phenotype. Derek reviewed an article entitled: How were new medicines discovered?. The paper’s authors, David Swinney and Jason Anthony, looked back at 259 drugs approved between 1999 and 2008, and noted of the 75 first-in-class drugs, 28 were assigned to phenotypic assays and only 17 to target-based approaches. Now, I am having a little problem with the math. What’s the story with the other 30 first- in-class drugs? So I googled the original article (results=1) and found out that of the 75 first-in-class drugs, 50 were small molecules and 25 were biologics. Interesting, and the math works. The article compares efficiency with effectiveness of the two approaches and provides some great insights into the high attrition rates and low productivity in pharmaceutical research.
However, I am still intrigued about the evolution of the phenotype. I googled flow cytometry phenotype. (Results = 3,790,000) Flow cytometry excels at phenotyping. In my personal experience in the lab, we routinely performed phenotypic analysis of peripheral blood using monoclonal antibodies to identify subpopulations of cells in patient samples to identify or quantify disease states back in the 80’s. So why has it taken so long for flow cytometry to move from phenotyping to phenotypic screening in drug discovery? I googled flow cytometry phenotypic screening (Results = 270,000), then googled phenotypic screening (Results= 2,770.000)
Now, I had to know more and found a review article that provides some great insights. In Multiparameter phenotypic profiling: using cellular effects to characterize small molecule compounds, published in 2009, the authors state that…”cell based screens tend to have higher hit rates than biochemical screens, presumably reflecting the existence of many potential targets” and propose multiparameter phenotypic profiling as a promising solution for evaluating cellular efficacy and to pinpoint side effects earlier in the drug discovery pipeline. The authors compare several profiling technologies and listed the advantages and disadvantages of each. For flow cytometry, the advantages were: 1) Allows single cell response to be measured, 2) High signal to noise ratio and 3) Can be multiplexed. The disadvantages listed were: Requires many cells and low throughput. However, they go on to say, “Technology improvements-such as the continuous-flow autosampler” (referencing the paper Flow cytometry for high-throughput, high content screening by Bruce Edwards et. al. describing the HyperCyt)…has enabled high-throughput flow cytometry experiments for profiling purposes.”
I googled HyperCyt (Results = 41,900) So, after emerging from this rabbit hole, I can see why phenotypic screening by flow hasn’t been more widely used in the past, but now with tools like the HyperCyt or HTFC Screening System, phenotypic screening by flow cytometry is a valid and practical option for researchers in drug discovery and elsewhere to perform multiplexed, suspension cell screening in order to create better drugs faster to treat and cure disease. Just go with the flow.
