Stem Cells Induced Pluripotent Stem Cells – A New Wave of Tools for Drug Discovery Chris Parker Chief Commercial Officer, Cellular Dynamics International, Inc.


Abstract


Historically, embryonic cells have been required for the formation of stem cell lines, but this has proved controversial and led to the technology being largely avoided because of the potential commercial consequences. However, since pluripotent stem cells were first isolated from mouse embryos in 1981, the wide-ranging potential of stem cells has been recognised, and in recent years the advent of induced pluripotent stem cells – derived from terminally differentiated human adult cells – has opened the floodgates for stem cell research, removing many of the ethical and moral obstacles to exploration of this powerful technology. This article looks at the past, present and future of stem cell technologies for drug discovery applications.


Keywords Cardiomyocytes, induced pluripotent stem (iPS) cells, in vitro models, drug discovery, pre-clinical testing, automation


Disclosure: Chris Parker is an employee of Cellular Dynamics International. Received: 23 May 2010 Accepted: 7 June 2010 Citation: Drug Discovery, 2010;7:42–3 Correspondence: Chris Parker, Cellular Dynamics International, 525 Science Drive, Madison, WI 53711, US. E: cparker@cellulardynamics.com


Support: The publication of this article was funded by Tecan.


The pharmaceutical industry has traditionally had a difficult relationship with stem cells. The potential applications and benefits of stem cells within the industry – for both drug development and therapeutic use – are numerous, yet the ethical issues and political sensitivity surrounding their use have often meant that such technologies have been employed only sporadically, or avoided altogether. The historical requirement of embryonic cells for formation of stem cell lines divided opinion among both regulators and the general public, with potentially disastrous commercial consequences for any company choosing to use this technology.


reported the creation of induced pluripotent stem (iPS) cells from terminally differentiated mouse fibroblast cells. One year later, Thomson2


However, all this changed in August 2006, when Takahashi and Yamanaka1


and Yamanaka3 concurrently published on the


creation of iPS cells from human adult tissue. These breakthroughs side-stepped the controversy surrounding embryonic stem cell use, re-opening the door to commercial application of stem cells. Since this original publication, the rate of technological advances has been staggering, with a whole industry now based around ways of harnessing and controlling stem cell proliferation and differentiation.


Big News for Pharma


The pharmaceutical industry, and therefore the advancement of our medical understanding, stands to gain significantly from the use of iPS and iPS-derived cells, arguably more than any other area of biological science. The use of cell-based assays and in vitro models is widespread throughout the industry – from drug discovery activities to pre-clinical testing – and the nature of the cells used in each assay


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varies significantly in terms of both cell type and origin. As large quantities of homogeneous cells are required for each assay, a majority of these tests employ immortal cell lines. These are generally transformed cell lines derived from cancerous tumours, such as HepG2; however, these cellular models have only limited functionality compared with native cells in vivo. An alternative strategy is to use extracted cells from cadavers. While the biological function of these cells obviously more accurately reflects in vivo behaviour, the limited availability of material, combined with high batch-to-batch variability, significantly impedes their widespread application.


By contrast, iPS cells can be used to provide a virtually limitless supply of homogeneous cells. Through carefully controlled differentiation, these cell lines are able to yield terminally differentiated cells from all three germ layers, with very little batch-to-batch variation. These cells accurately represent the biological activity of primary cells, improving cell-based testing by ensuring appropriate drug selectivity and sensitivity and by allowing direct comparison between assays. Stringent quality control and reliable differentiation processes are crucial to the reliability of these assays, requiring high-quality iPS cells as a starting material. Having a large quantity of homogeneous iPS cells is also very important, as a majority of differentiation pathways are very inefficient in terms of fully differentiated cell yield.


A Question of Numbers


To minimise batch-to-batch variation, and to generate the large quantity of cells required for candidate drug screening trials, automation of cell handling is essential. This removes human error and stabilises the culturing process, improving the yield and


© TOUCH BRIEFINGS 2010


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