Disease-In-A-Dish: Leveraging in vitro Human Models to Advance Drug Discovery

Paul R. August

Treatment of diseases, especially rare diseases, is very complex due to specific changes in the genetic makeup of the individual patient. As such, a more personalized approach to the generation of therapeutics is gaining greater traction not only with medical personnel, but also with the patient.

The term “personalized medicine” relates to the dedication of therapeutics to the individual patient but does not tell the full story of just how individualized the new wave of pharmaceutical therapies could soon become. Diseases that share the same set of symptoms are often reclassified into different subtypes based on their genetic variants. Specifically targeting these subtypes has transformed drug discovery into a highly segmented pursuit driven by the fact that every individual is genetically unique. 

Considering the inherent biological differences between humans and other mammals, animal models for studying human disease remain inadequate and overwhelmingly untranslatable. Although animal models can be useful to study drug safety and distribution, more and more researchers are avoiding animal models to assess the efficacy of therapeutic candidates. Instead many groups are now developing “disease-in-a-dish” drug screening programs that harness the promise and power of human inducible pluripotent stem cells (iPS). iPS cells derived from an individual patient can be differentiated into a variety of cell types (i.e., skeletal muscle, neurons, cardiomyocytes, etc.) that can be used to evaluate the effects of potential therapeutics on cells from the target organ of the disease. This is beneficial because it demonstrates the direct effect of a potential therapeutic on the organ of interest versus using an animal model to evaluate target engagement. 

Additionally, iPS cells from multiple patients with similar genetic changes can be differentiated at the same time, in the same assay dish, providing a means to potentially stratify populations of patients that may respond to a potential therapeutic (completing a “clinical-trial-in-a-dish”). Furthermore, having the ability to differentiate the same iPS cell from a patient into multiple lineages provides an immediate means to assess off-target/cytotoxic effects.

The Case For Human Models

Despite attempts to improve animal models, the majority of drugs that pass preclinical research and include “pivotal” animal tests fail in human trials. This figure has increased from the FDA’s 2004 estimate of 92%.1 The inherent difference in the biological makeup between humans and other mammals leads to models that produce untranslatable results. Furthermore, it is unclear “whether variability within human populations, due to either genetic or environmental factors, can be captured sufficiently within laboratory animal models.”2 For many rare genetic diseases, there simply isn’t an animal model on which to test the efficacy of lead candidates. For example, recently the FDA approved Vertex’s Orkambi® to treat ΔF508 homozygote cystic fibrosis patients; it was never evaluated for efficacy in an animal model.3

Studies have even shown that compounds that produce promising results in animal models sometimes exhibit the opposite effect in humans. Besides issues with efficacy, if you ask any professional in pharmaceutics, they will likely tell you that animal testing for safety, both for toxicology and pharmacokinetics, is not going anywhere anytime soon. But the argument can be made that this statement isn’t as true as it once seemed. “Retrospective analysis indicates that toxicity evaluation in healthy rodent and non-rodent species results in prediction of human risk in approximately 71% of instances.”4 To some this may seem an acceptable number, until faced with the percentage of times when effectiveness of animal testing shows its shortcomings in clinical stages. A recent example of this is the devastating case in January 2016 when a man was declared brain dead after receiving an experimental drug in a first-in-human trial.5 Human cells that are difficult to isolate and expand in vitro are rapidly being employed in pharmaceutical laboratories to enhance drug safety evaluations to prevent these types of adverse events.

In addition to animal models, researchers have developed and relied on specialized
cell lines to screen compounds. This can be relatively easy for many cell types. A researcher can obtain some types of cells from a donor, expand the cells in a petri dish, test the compound of interest on the cultivated cell lines and even introduce specific mutations. But finding volunteers to donate affected cells for a specific disease adds a level of difficulty. Further, some cells, such as cardiomyocytes and neurons, cannot be isolated from living humans, making research in diseases that affect these biological systems even more complex. Due to these facts, a combination of iPS cell derived cells and animal models — in some form or another — will be required to complete modern drug discovery going forward. Importantly, however, this marriage between the disease-in-a-dish and the animal model is being employed by many biotech/biopharma companies and academic groups in an effort to create personalized, centered approaches for drug discovery. In fact, a number of compounds have recently entered the drug development pipeline without an animal model for efficacy.

Icagen is positioned to be at the forefront of phasing out obsolete and inadequate animal models.

Disease-In-A-Dish Breakthrough

When Shinya Yamanaka discovered inducible pluripotent stem cells in 2006, the most obvious trajectory for their use was in regenerative medicine. Derived from adult skin cells, pluripotent stem cells can be differentiated into a variety of different cell types and composite tissues. Therefore, they can in principle be employed to replace damaged or diseased patient cells through cellular therapy approaches. To date, however, only one therapeutic treatment has been developed (and subsequently halted) for human trials using the cells.6 Importantly, other efforts are continuing and it is not unreasonable to expect that in the next 10 years we will see iPS cell–derived cellular therapy (allogenic — coming from a single patient) approved in some rare, life-threatening diseases like Duchenne Muscular Dystrophy.7 However, many concerns still exist with regards to the safety of employing these cells and their potential to undergo unlimited cellular expansion if not appropriately addressed. 

Although regenerative therapies employing iPS cells have been heralded as the future of medicine, iPS cells have made a quieter revolution in drug discovery. Plagued with the lack of translatability of human diseases in animal models, researchers understand the possibility of iPS cells to create specialized cell lines that previously couldn’t be harvested (such as neurons). With the introduction of CRISPR-cas9 gene-editing technology, the iPS cell field has again been transformed. Researchers can now use iPS cells to build cell lines of previously difficult-to-harvest cell types, and then modify these cells to exhibit a disease. In many ways, for specialized organizations such as Icagen, this alignment proved pivotal. 


Icagen has been able to successfully harness 20-plus years of experience in employ­ing primary human and animal stem cells for drug discovery. Historically, Icagen also has experience in developing cell lines that express ion channels — considered challenging therapeutic targets. Combining this expertise, Icagen is leveraging iPS cell–based approaches to generate neurons and muscle cells that can be phar­macologically evaluated by therapeutics that modulate channel function. In order to transform capabilities to the next level of human biology, Icagen is laboring to create complex tissue systems of co-intercommunicating human cells. For example, Icagen is advancing efforts to combine contractile skeletal muscle cells with motor neurons derived from diseased and normal iPS cells to essentially create a functional motor unit. Leveraging this entire human tissue model, disease mechanisms can be studied at the neuromuscular junction at a molecular level never before possible. In addition, therapeutic molecules for neurodegenerative diseases can be evaluated.8,9 

These types of in vitro–engineered “Tissues” are capable of producing some of the greatest breakthroughs in science and could someday lead to the evaluation of drug candidates in complete in vitro human systems. For rare diseases like amyotrophic lateral sclerosis (ALS) with historically inadequate animal models that lack predictivity, there is a strong case for Icagen to work with partners to create unique human cell models that will outperform the animal model alternative, leading to the identification and development of new therapeutics.

Icagen collaborates with key leaders in the ALS field such as Dr. Justin Ichida at USC, who uses complex “disease-in-a-dish” ALS models to examine a small number of high-quality leads or pathway probes. “For the past three years,” states Dr. Ichida, “my lab has been collaborating with Icagen on two projects using patient-specific iPS cells to identify therapeutics for ALS. Icagen’s advanced iPS cell disease modeling capabilities, along with its leading expertise in small molecule screening and hit-to-lead development have made them invaluable partners for these innovative Department of Defense– and Muscular Dystrophy Association–funded projects.” The relevance of the human “disease-in-a-dish” model — and the throughput it enables — is guaranteed to outpace what is possible in any of the leading animal models. 

New Frontiers

New technologies transform the pharmaceutical industry daily, but again, what truly sets Icagen apart is experience — especially experience working in partnership with industrial and academic partners interested in tackling complex biology in in vitro models to discover new therapeutics to treat rare diseases with a great unmet medical need. A quarter of a century operating with the same team has allowed us to seamlessly adopt and implement revolutionary technologies. Our “disease-in-a-dish” human model for drug discovery is the culmination of this hard work and dedication. 

We are positioned to be at the forefront of phasing out obsolete and inadequate animal models, in hopes of contributing to the advancement of new methods that will improve safety and efficacy, and shorten the discovery time for new drugs. Icagen is capable of producing a human model for drug discovery that may one day replace the most viable animal models. Our integrated biology and chemistry, top-of-the-industry in silico approaches for compound screening, and downstream safety toxicology and pharmacokinetics all contribute to our unique positioning as a CDMO. With these capabilities combined with a diversified compound collection coupled to ultra-high-throughput screening, we are considered the first organization to be fully focused on advancing early drug discovery.  


  1. Akhtar, Aysha. The Flaws and Human Harms of Animal Experimentation.” Cambridge Quarterly of Healthcare Ethics 24.4 (2015): 407-419. Web.
  2. Burden, Natalie, Fiona Sewell, Kathryn Chapman. “Testing Chemical Safety: What Is Needed to Ensure the Widespread Application of Non-animal Approaches?” PLoS Biology 13.5 (2015). Web.
  3. Lavelle, Gillian M., Michelle M. White, Niall Browne, Noel G. McElvaney, Emer P. Reeves. “Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences.” BioMed Research International (2016). Web.
  4. Morgan, Sherry J., Chandikumar S. Elangbam, Shawn Berens, Evan Janovitz, Allison Vitsky, et al. “Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Novel Pharmaceuticals.” Toxicologic Pathology 41 (2013): 508-518. Web.
  5. Kimmelman, Jonathan, Carole Federico. “Consider Drug Efficacy Before First-in-Human Trials.” Nature 542 (2017): 25-27. Web.
  6. Scudellari, Megan. “How iPS Cells Changed the World.” Nature 534 (2016): 310-312. Web.
  7. Filareto A, Parker S, Darabi R, Borges L, Iacovino M, Schaaf T, Mayerhofer T, Chamberlain JS,Ervasti JM, McIvor RS, Kyba M, Perlingeiro RCR, (2013) “An Ex Vivo Gene Therapy Approach to Treat Muscular Dystrophy Using Inducible Pluripotent Stem Cells” Nat Communication, Mar 5;4:1549. PMID: 23462992. Company, 21 Sep. 2016. Web.
  8. Park, Hyun Sung, Su Liu, John McDonald, N.v. Thakor, Hong Yang. Neuromuscular Junction in a Microfluidic Device. IEEE Engineering in Medicine and Biology Society, Japan. July 2013. Print.
  9. Nesmith, Alexander P., Matthew A. Wagner, Francesco S. Pasqualini, Blakely B. O’Connor, Mark J. Pincus, et al. A Human in vitro Model of Duchenne Muscular Dystrophy Muscle Formation and Contractility. Rep. The Journal of Cell Biology. 3 Oct. 2016. Web.

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