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European Biopharmaceutical Review

iPS Power

The obstacles that currently face the drug discovery and development process can be overcome by using disease models that use in vitro differentiated cells. This has the ability to transform patient therapeutics

Although it was only announced three months ago, it is now ‘old news’ that Professor Shinya Yamanaka was co-awarded the Nobel Prize in Medicine for his contributions in discovering that mature cells can be reprogrammed, or induced, to become pluripotent (1). Although the innovation of in vitro differentiated cells has been known for several years, this endorsement of the technology has become a slingshot for greater acceptance of in vitro differentiated cells, specifically those derived from induced pluripotent stem (iPS) cells, in biomedical research and drug discovery (2).

The research community has generally been slow to accept the use of stem cells in general: embryonic stem cells (ESCs), mainly due to ethical controversy; and iPS cells, due to initial uncertainty of their application in developing therapeutics and treating disease. However, as the future rapidly becomes the present and in vitro differentiated cells become more common in drug safety/toxicology, tissue engineering and disease modelling, for example, the biopharmaceutical industry still needs convincing to change its current drug development model, which is greatly inefficient and unproductive (3-6).

This article briefly looks at the ineffectiveness of today’s drug discovery and development (DDD) process and how disease modelling can help improve results. It also discusses limitations in existing animal disease models and outlines how in vitro differentiated cells, including those derived from human iPS cells, have already demonstrated value in revolutionising disease models and, thus, drug development.

Why Current DDD is Ineffective

Traditional DDD has always started with the disease. During the last 20 years, however, this process has shifted from disease-based to target-based discovery, centred on using the present knowledge of molecular pathways and then selecting a target (7). DDD now often starts with the theory that if you modulate the action or expression of a certain target with a chemical agent, you will achieve the desired effect of treating a disease.

To accomplish this feat, vast libraries of small molecules are screened with hopes of identifying a set that bind to the target. The set is narrowed by selecting the substances that not only bind, but also show a functional effect on the target in further assays. This is usually done in vitro by over-expressing the target in a cell line and measuring a surrogate parameter for functionality. The compound set is further selected for the molecules that demonstrate this functional effect in vivo in an animal model, if such a model is available.

Although this process allows for the screening of millions of compounds, it is not highly effective. The DDD process is still very inefficient, as most know, typically requiring investment of several years and tens of millions of euros. Despite the enormous investment, many candidate substances are abandoned for safety or a lack of efficacy at late stages, either because the substance did not achieve the desired effect in vivo, or because the preclinical findings did not translate to the clinic.

Applying In Vitro Disease Models

The concept of a disease model is appealingly simple and well established (8). You take a model organism (for example, a rat) that displays the phenotype of the disease you are investigating, and then you test various compounds to see which one has the desired effect.

In contrast to the traditional animal disease model, the in vitro disease model takes the cell as a starting point. Screened compounds are advanced in development only if they produce the desired change in phenotype. This improves efficiency in drug development because the effort to elucidate the mechanism of action is only done on the efficacious compounds. This is the case as the target, or the theory of the mechanism of action, is not the starting point.

Use of Animal Disease Models in DDD?

As elegant as these animal models seem, it is not possible to apply it to a large compound set. Even assuming that a suitable animal disease model is available, the cost is prohibitive to perform these screens for a large number of substances, and especially for a whole chemical library. This approach also introduces ethical concerns of animal testing, especially in Europe, and, perhaps the greatest limitation, it attempts to translate results in a non-human species to predict a human response (9).

A Great Concept Meets Better Tools

Despite the limitations of existing (animal) disease models, the concept itself holds great value, especially given new tools such as human in vitro differentiated cells, namely those from human iPS cells. Companies have licensed the Yamanaka protocols and are producing pure, standardised iPSC-derived human cells in theoretically unlimited quantities (10). With the increased possibilities of iPS cells, there exists ready access to many different genomes as in vitro differentiated stem cells. In its simplest form, an in vitro disease model is generated by inducing the disease phenotype in the somatic cell through chemical or physical stimuli (11).

The iPSC technology enables researchers to not only use iPS derived somatic cells in a disease model through changing of the environmental conditions (chemical or physical induction), but it can also be applied to the selection of cells with a genetic background portraying prevalence or disposition to develop the diseased phenotype (12). This can be further applied to the selection of individuals with polygenetic or monogenetic diseases where the genetic factors have not been identified, or by the introduction of a specific genetic mutation to induce the disease.

The tissue specific cell is then derived from the iPS cells, in which the patient’s genome remains, thereby providing a derived cell line that portrays the disease phenotype. Compared to a native (wild-type) cell, the in vitro differentiated cells produced in large quantities can then be used to screen for substances reducing or reverting the diseased phenotype (12).

Real-World Example

Researchers are making new breakthroughs everyday to replicate human physiology in stem cell cultures, and the use of in vitro differentiated cells in human disease models is being studied for multiple conditions, one example being HCM (hypertrophic cardiomyopathy), or cardiac hypertrophy (5,13).

Cardiac hypertrophy is a potentially fatal disease that can develop in at least two in 1,000 people worldwide (14). To date, there is no effective therapy or predictive in vitro disease model suitable for screening for HCM drug candidates.

Scientists have developed a HCM disease model using iPS cell-derived cardiomyocytes and have validated it in-house on a number of known compounds. In in vitro differentiated cells, HCM is induced via chemical stimulation (endothelin-1 or phenylephrine), creating the same molecular picture as the disease in vivo. After compound treatment, the cells are analysed by RT-PCR or high content analysis (HCA), depending on the desired phenotype measurement (for example, RNA, cell size) (see Figure 1) (15).

Another advantage of in vitro disease models is that they ultimately reveal novel targets and new mechanisms of action. Many new drugs brought to market act on well-established targets. A particularly effective and direct method to use the disease model approach to identify novel targets is to employ a si-RNA screen. The newly identified targets, upon showing that inhibition does influence the phenotype in the desired way, can then enter the established small molecule DDD pipeline.

The value of disease models using in vitro differentiated cells is gaining such attention that, recently, patents for the HCM disease model were issued in the world’s major markets including the European Union, US and Japan (5,16).

Why Not Use Primary Human Cells?

Philosophers might say that the beauty of being human is that we are all different. In drug development, testing cells from different human beings results in high variability and poor experimental results. Especially in high throughput screening (HTS), consistency and purity of cells is of utmost importance. Given that human beings are very fond of their own cells and generally unwilling to part with them, the limited supply of primary cells is another challenge and a constraint for most researchers.

These limitations of primary human cells help to highlight the benefit of using pure, readily available, in vitro differentiated cells. And with demand increasing, the cost of these cells continues to become even more reasonable.


Disease models will improve today’s inefficient drug discovery and development process by placing central focus on the disease again, specifically by starting with effects on cell phenotype rather than target binding. In vitro differentiated cells, derived from iPS cells, have the ability to offer large cost savings and translational power, relative to existing animal models of disease.

The intent of this article has been to portray specific challenges in traditional drug discovery and development, and to offer an argument as to why disease models employing in vitro differentiated cells, such as those derived from human iPS cells, have the potential to positively and profoundly change the way therapeutics are developed for patients.


  1. The Nobel Prize in Physiology or Medicine, visit: nobel_prizes/medicine/laureates/2012/ yamanaka.html
  2. Takahashi K, Yamanaka S, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors, Cell 126(4): pp663- 676, 2006
  3. GSK taps stem cell discovery to spot heart threats early, visit: cell-discovery-spot-heart-threats- early/2012-10-23
  4. Roche, Pfizer, Sanofi plan $72.7 million stem-cell bank, visit: com/news/2012-12-05/roche-pfizer-sanofi-plan-72-7-million-stem-cell-bank. html
  5. Axiogenesis press release, visit: home/20121204005099/en
  6. The Wall Street Journal, stem cell trial without embryo destruction, visit: 0001424127887324296604578177420241 514666.html
  7. The truly staggering cost of inventing new drugs, visit: sites/matthewherper/2012/02/10/ the-truly-staggering-cost-of-inventing-new- drugs
  8. The Op-Ed: how to lower attrition rates in labs, visit: rates-in-labs
  9. European Union Reference Laboratory on Alternatives to Animal Testing, visit:
  10. Axiogenesis in-licenses Yamanaka patent portfolio from iPS academia Japan covering induced pluripotent stem cell technology, visit: yamanaka-patent-portfolio-from- iPS-academia-japan-covering-induced-pluripotent-stem-cell-technology- 837665
  11. de Jonge HW, Dekkers DH, Houtsmuller AB, Sharma HS, Lamers JM, Differential signaling and hypertrophic responses in cyclically stretched vs endothelin-1 stimulated neonatal rat cardiomyocytes, Cell Biochem Biophys 47(1): pp21-32, 2007
  12. Kawaguchi N, Hayama E, Furutani Y, Nakanishi T, Prospective in vitro models of channelopathies and cardiomyopathies, Stem Cells Int, Epub 2012
  13. Soldner F, Jaenisch R, iPSC disease modeling, Science 338: pp1,155, 2012
  14. Maron BJ, McKenna WJ, Danielson GK, et al, A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines, Eur Heart J 24(21): pp1,965- 1,991, 2003
  15. McKinsey T, Kass D, Small-molecule therapies for cardiac hypertrophy: moving beneath the cell surface, Nature Reviews Drug Discovery 6 (8): pp617-635, 2007
  16. Axiogenesis press release, visit: 20111010005072/en/cardiomyopathy-disease- model-axiogenesis-grantedfar- reaching-patent

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Felix von Haniel is responsible for intellectual property and commercial aspects for Axiogenesis AG, a pioneer in the field of stem cell biology with the aim of developing and commercialising highly translational models of human disease and pharmacology. Felix graduated with an MBA from the University of Cambridge and a BSc and GDipSc Molecular Biology and Biotechnology from the University of Melbourne. He has worked in the biotechnology industry since 1998.
Felix von Haniel
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