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Stem Cells Create “Disease in a Dish” for Drug Development

Scientist on January 24, 2013

Last week we talked about Stem cell research getting the “green light” and this week we continue with our stem cell blog series. Biology has long relied on animal models and immortalized cell lines to gain insight into human diseases and to test drug candidates. While these approaches have proven useful, they don’t always accurately recapitulate the human condition. Induced pluripotent stem cells (iPS) offer an alternative to traditional models.

IPS cells come from terminally differentiated cells, such as skin, fat, or blood. After harvesting, these cells can be turned back into stem cells if they are forced to express transcription factors present in stem cells. This is accomplished through viral transduction or small molecule transfection.

Because iPS cells are obtained directly from patients, they are representative of the human disease, at least more so than mouse models or immortalized cell lines. They also enable study of previously inaccessible tissues. For example, it’s hard to collect neurons from people with autism or Alzheimer’s, but it’s possible to take a skin biopsy, make iPS cells, and differentiate the stem cells into neurons. This concept of making iPS cells from people with specific diseases for study in the laboratory is known as creating “disease in a dish,” and it could be a game changer in the drug discovery process.

Skin fibroblasts can be converted into iPS cells and then differentiated into cardiomyocytes for study in vitro. A single such cardiomyocyte is shown here, immunostained with cardiac markers alpha-actinin (green) and MLC-2v (red). DAPI (blue) labels nuclei. Image source: Mayurika Desai and Michael Xavier Doss, Masonic Medical Research Laboratory, Utica, NY.

For example, a recently published paper used iPS cells to study the leading cause of sudden cardiac death in young athletes, hypertrophic cardiomyopathy.1 Researchers made iPS cells from skin biopsies of 10 members of a family with inherited mutations in the MYH7 gene, which has been linked to hypertrophic cardiomyopathy. The stem cells were differentiated into cardiomyocytes, and those with the mutation recapitulated aspects of the disease including irregular contractions and hypertrophy. Studying the cardiomyocytes, the researchers found that abnormal calcium processing led to the arrhythmia. Drugs approved for hypertrophic cardiomyopathy or arrhythmia were screened against the cells. One, verapamil, was able to both modulate calcium activity and prevent cellular hypertrophy. This study is an example of iPS cells modeling disease in a dish, revealing both the molecular basis of disease and the best candidate drug.

Scientist recently blogged about the high, and highly debated, cost of drug development. One major factor that up drives costs is the large number of drugs that are brought to clinical trials, only to fail. If iPS cells are developed as a resource for drug development and screening, the process of drug discovery could be made more efficient, with fewer failures. Screening large numbers of differentiated stem cells from patients could lead to a better understanding of diseases and drug targets. Issues with toxicity to the specific cells being targeted could be revealed earlier in the drug lifecycle. While there is no magic bullet to improving the drug discovery process, using iPS cells to model disease could help reverse the trend of escalating costs, long development cycles, and numerous failures.

More resources are being developed to enable non-specialists to use this stem cell technology. In our next post, we’ll discuss the outsourcing options currently available.

  1. Lan et al. Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells. Cell Stem Cell, Jan 3, 2013, Vol 12(1), 101-113.