Stem cells in predictive toxicology - benefits to pharma

Drug discovery is a complex process and is highly regulated across the globe. It takes over a decade for any new medicine to pass through several stages of research, development and regulatory approvals before it becomes available for clinicians to treat patients. The mission of any pharmaceutical research and those associated with it is to understand a disease and to develop an effective and safe drug for treatment. It includes and aims at connecting together the basic causes of a disease at the level of genes, proteins and cells.

Researchers work to validate these targets using high throughput and bioinformatics tools/screening and thereby discover the right molecule. The tests on the new compound is through in vitro and in vivo assays to predict the related toxicity and efficacy of these leads in pre-clinical models paving way to clinical stage trials for safety, and ultimately approval to get the new drug into the hands of doctors for treatment.

Reports indicate that on an average, it costs $800 million to $1 billion to research and develop a successful drug and the primary reason for such high research related costs is thousands of failures in identifying the right molecule. Estimates show that the success rates are very low. Only  one out of 5,000 -10,000 compounds that enter the research and development pipeline ultimately gets approval as a candidate drug for clinical trials.

Research scientists carry out in vitro and in vivo tests during the preclinical stage. In vitro tests are experiments conducted in the lab, usually carried out on artificial cell models and in vivo studies are those in living cell cultures and animal models. Testing the toxicity of pharmaceutical candidates in lab rats before the compounds are judged safe enough for human clinical trials is extremely undependable. Often compounds that appear safe in the rodents or small animals prove to be toxic in humans. Availability of validated human cell-based in vitro toxicity screens may facilitate earlier attrition of compounds with unacceptable safety profiles, and therefore, also reduce the use of animals. The predictability of in vitro screens is largely dependent on the appropriateness of biological modelling, which is limited otherwise.

Stem cells are master cells that have the self-renewing and differentiation capabilities with battery of genes (both stage and stemness specific) expressed that are identified. Human originated harvested stem cells can be expanded sometimes indefinite, while retaining the stem cell specific characteristics. Stem cells are broadly classified based on their origin as Embryonic, Fetal and Adult.  Embryonic stem cells based assays in toxicity testing seem to be the immediate answer to reduce the time taken for drug discovery, though Fetal and Adult stem cells sources are being explored as alternatives.

Embryonic stem cells (ES cells) are totipotent stem cells derived from the inner cell mass of the blastocysts, an early-stage embryo. Human embryos reach the Blastocysts stage 4–5 days post fertilization, at which time they consist of 50–150 cells. The embryonic stem cell tests are typically tests designed to predict developmental toxicity based upon compound-induced inhibition of embryonic stem cell (ESC) differentiation. The end point scoring, the test duration and the definition of the predictivity and the applicability domain require improvements to facilitate implementation of the EST into regulatory testing strategies. Several groups are working on genes regulated both during the ESC differentiation, and by exposure to each of the developmentally toxic compounds tested, to come up with the assays in predicting toxicity.

The embryonic stem cell test is an example in vitro embryo toxicity test using two permanent mouse cell lines that is currently the most promising in vitro assay to predict the embryotoxic potential of compounds. In this assay the disturbance of the differentiation of embryonic stem (ES) cells into contracting cardiomyocytes by test compounds as well as the direct cytotoxicity of the test compounds on ES cells and 3T3 fibroblasts is analysed. On the basis of these results and by applying a biostatistical prediction model, the compounds are screened. Mouse Embryo Assay and ZebraFish Embryo Toxicity Assay are the other examples of efficient stem cell based assays for drug screening and chemical toxicity assessment.

So, in essence significant potential value-add is promising from stem cell technology to the pharmaceutical industry which is multi-fold, reliable, consistent and an unlimited source of cells for screening, thus avoiding sporadic and limited availability of human tissue and enabling a closer phenotypic match than any animal material.

However, stem cell technology is evolving and the laws relating to research and use of such technology is varied and is subjected to several controversies in different parts of the world. This domain is regulated and laws relating to policy governance concerning not just the treatment using stem cells in humans, but also the sources and related research are not clearly established.

Among the European countries there is a divide on research on stem cells using the human embryo. It is permitted in Sweden, Finland, Belgium, Greece, Britain, Denmark and the Netherlands. However, it is illegal in Germany, Austria, Ireland, Italy and Portugal. Similarly the embryonic stem cell research has acceptance in some states of the United States, while some others enforcing a complete ban; interestingly a few states also give financial support for research. Among others, Australia, Japan, India, Iran, Israel, South Korea, China are supportive. However, New Zealand, most of Africa (except South Africa) and most of South America (except Brazil) are restrictive.

The global in vitro toxicity (predictive toxicity) testing market is valued at more than $1.3 billion in 2010. With heightened awareness of animal welfare in laboratory research testing, the in vitro toxicity testing market has an anticipated value of $2.7 billion in 2015, a compound annual growth rate (CAGR) of 15 per cent between 2010 and 2015.

The key in developing stem cell based predictive toxicity assays is the large scale production of human stem cells and maintenance of the cell lines generated, which requires tremendous skill set and resources pool. The cost involved in developing assays with dedicated sites and personnel trained and co-ordinated is also colossal. Pharmaceutical companies are engaging in passive partnerships with stem cell research organisations or setting up stem cell based research laboratories as extension of their research and development portfolio.

In general though it is quite evident that toxicity testing using stem cells will be the future, the regulatory requirements coupled with diverse opinions on using human embryonic stem cells still remain largely unanswered and will see a push back unless there is a strong lobbying on use of these by established pharmaceutical companies to regulatory bodies.  

Countries that favour stem cell research will see significant demand for toxicity testing from those nations where there is resistance paving way for passive partnerships and low cost drug discoveries. These economies will also see a surge for scientists and research professionals in stem cell technology. Globalisation has given a meaningful shape to move work across the globe where labour arbitrage is an effective tool to reduce costs.

GE Healthcare Life sciences and Promega are some of the global companies developing in pipeline offering cell based predictive toxicity assays. Companies like Astrazeneca, BMS, Pfizer, Amgen are pondering a consortium to develop assays for predicting the toxicity of the new compounds towards developing safer medicines.