A major impediment to developing effective drugs is the heavy reliance on animal models to derive estimates of human efficacy, toxicity, tolerability and metabolism. Their use has been driven by tradition and regulatory guidelines as well as a technical limitation: the lack of suitable human tissues that mimic disease states.
This situation is about to improve considerably. Cellular reprogramming, the conversion of adult cells to induced pluripotent stem cells (iPSCs), has become embedded in the scientist’s toolkit and the likelihood of developing human disease models of high predictive utility has dramatically increased. As we enter an “Era of Reprogramming,” cell repositories are beginning to collect large numbers of patient-derived iPSC lines. While this is welcome news to drug hunters and basic researchers, the usefulness of these collections will depend on their quality.
Animal models are a frustratingly imperfect method for studying complex human disorders and relying excessively on these models can lead to costly failures in the clinic. Human genetic studies have been highly successful in identifying genomic regions or genes that are statistically likely to contribute to disease. But translating those genetic findings into worthwhile drug targets has often proved elusive due to a lack of human tissue for study. Most human cells types are only available as transformed cell lines or from cadavers- sources that are far from ideal. Transformed cell lines have the advantage of immortality, but continuous passage introduces chromosomal abnormalities and changes in gene expression. Cadaveric tissues represent “one-off” samples that vary between donors due to various differences.
An exciting solution to this dilemma arrived a decade ago in the form of cellular reprogramming. Reprogramming allows for the conversion of adult somatic cells to pluripotent stem cells by the forced expression of a small number of genes. Developed by Dr. Shinya Yamanaka in 2006 using mouse fibroblasts and extended to human cells by Yamanaka and Dr. James Thomson in 2007, cellular reprogramming allows for the creation of stem cell lines, called induced pluripotent stem cells (iPSCs), from individuals with defined diseases or genetic background. iPSCs share many properties with embryonic stem cells, most importantly the ability to be differentiated into a variety of somatic cell types important for drug discovery.
Scientists immediately seized on reprogramming’s potential to develop in vitro models that could be used to understand disease biology and to test new drugs for efficacy or toxicity. Several funding agencies, such as the US National Institutes of Health, the California Institute for Regenerative Medicine, the Innovative Medicines Initiative and the New York Stem Cell Foundation, have begun to establish banks of iPSC lines with the goal of making them available to researchers.
This effort on the part of funding agencies does not come without challenges. In particular, it is important to remember that if these lines are to increase our understanding of disease or accelerate the development of new drugs the quantity of available cell lines is less important than the quality of available cell lines. Several challenges still remain in the development of high quality iPSC banks.
For iPSC lines to be most useful, they must be annotated with comprehensive medical data to allow selection of appropriate samples for study. Due to the costs of data collection, most clinical information will represent only a snapshot in time. In these cases, the clinical information should be as comprehensive as possible. However, where possible, funding agencies should strive to enable longitudinal data collection from donors. For example, knowing whether a donor’s disease stabilized or progressed, or whether it responded to drug treatment, is valuable data for interpreting results from iPSC-based models. Some researchers who recruit, evaluate and treat potential donors may have a vested interest in releasing as little clinical data as possible until after they’ve been published. This is an unfortunate reality of the present-day practice of science and cell banks may need to compromise on what information they request from depositors.
Genetic & Demographic Diversity
Banks should strive to capture a broad swath of the population, including both patient cases and controls. Specific genetic information is crucial, especially for genes involved in drug metabolism, known toxicology sensitizers, and disease-causing/protective alleles. The cost in time and money to purchasing, differentiating and studying iPSC lines makes careful selection critical. In some cases, disease-specific lines, with no knowledge of genetic differences, will be acceptable. However, many researchers are focused on specific genes or pathways. They will want to know which lines have allelic differences in their genes of interest before choosing ones for study. Genetic information also provides the basis for developing companion diagnostics. As the cost of sequencing drops, the number of fully sequenced lines will increase, enhancing the value of such collections.
In order to extract the most value from banks of patient-derived iPSC lines, informed consent should allow for their broadest possible use, including those that do not yet exist, so long as they conform to the spirit of the consent, and contribute to the understanding of disease and advancement of medicine. This includes allowing lines to be used by commercial entities for use in drug screening or commercial development. Care must be taken to ensure that consents conform to local legal requirements as regards patient confidentialtyconfidentiality, payment, and withdrawal. Nothing else discussed in this article will matter if customers refuse to purchase lines because donors were improperly consented.
Infectious Disease Testing
It is a good practice to screen donors for common infectious diseases, especially those caused by viruses that integrate into the genome. Even if retention of these infectious agents may not affect reprogramming and differentiation, disqualifying infected donors reduces one potential source of variability in iPSC function.
Quality Control (QC)
It will be impossible for any single bank to control all iPSC lines. Therefore, banks should strive to develop a set of agreed-upon quality control assays for identity, pluripotency, sterility and chromosomal integrity. In addition, they should develop and validate methods that are faster and cheaper than G-banding for chromosomal integrity.
As these issues with cell banks designed for research applications are addressed, immense potential will be unlocked for drug development. Additional issues, including production of cell lines under Good Manufacturing Practices, are required for cell banks designed for therapeutic applications.