There have been a handful of experiments in the history of medicine that have shaped modern health. Pasteur discovered the germ theory of disease, Fleming pioneered the first antibiotic and Jenner spearheaded the first vaccine. Similarly, thirteen years ago, Dr. Shinya Yamanaka made a groundbreaking discovery that forever altered the future of genetic therapy and regenerative medicine. I can only imagine Dr. Yamanaka’s face as he stared down into his microscope in his lab at Kyoto University and found his petri dish, primed with agar, teeming with undifferentiated, pluripotent cells.
In 2006, Dr. Yamanaka engineered the first induced pluripotent stem cells (iPSCs) from fibroblast cells — differentiated cells that form collagen and other structural features of the extracellular matrix (1). What makes an iPSC newsworthy is the fact that it is both pluripotent, meaning it has the ability to differentiate into any cell in the body, and it is a stem cell, meaning that the cell has indefinite self-renewing capability. A major limitation to the field of regenerative medicine is the threat of rejection from foreign stem cells. But, if one were to use his own differentiated cell and convert it into an iPSC, there would be no threat of rejection — the cells would be derived from the person’s own body. iPSCs’ capacity for autogeneic transplantation also eliminates the ethical qualms associated with the acquisition of embryonic stem cells, another source of pluripotent stem cells which requires the abortion of embryos (2).
The process of discovery was as ingenious as the end result. Dr. Yamanaka started with twenty-four genes he deemed necessary for pluripotency in embryonic stem cells and engineered mice fibroblast cells with Fbx15, a protein that would fluoresce when the cell became pluripotent. Next, by a process of trial-and-error, he narrowed the list of genes to four necessary for pluripotency: c-Myc, Sox2, Oct4, and Kilf4 (1). In 2007, just a year later, Dr. Yamanaka found the same monumental results in human fibroblast cells. The buzz of the discovery of iPSCs reached the United States, and Dr. Rudolf Jaenisch, a professor at the Massachusetts Institute of Technology, coupled CRISPR/Cas9 — a genetic engineering method to splice or alter genes — with iPSCs to successfully cure sickle cell anemia in mice (3).
Since then, CRISPR/Cas9 and iPSCs have been used against a variety of diseases, such as recessive dystrophic epidermolysis bullosa, a genetic condition in which human patients do not make type seven collagen and form painful blisters between their epidermis and dermis. By correcting the mutation and differentiating iPSCs into fibroblasts onto skin grafts, researchers have created a clinical platform to potentially treat the condition with minimal off-target effects (4).
Recently, a branch of the National Institute of Health, the National Eye Institute (NEI), created the first iPSC-based therapy for age-related macular degeneration (AMD) — the leading cause of irreversible blindness or visual impairment in the world due to the loss of the retinal pigment epithelium (5). Within ten weeks, the NEI used iPSCs to successfully cure AMD-related blindness in rat and pig models by differentiating iPSCs into the retinal pigment cells and implanting them directly into the subjects’ eyes. As of January, 2019, the FDA approved the NEI’s Investigative New Drug application and the therapy is now in the first phase of human clinical trials — the first clinical trial to test an iPSC therapy for treating a disease (6).
Dr. Yamanaka’s work is truly revolutionary. The approval of the iPSC therapy will not only potentially cure millions of patients (pending the price point), but it may also set a precedent for pharmaceutical industries to funnel resources into iPSC research and development. This is necessary as iPSC derivation is currently slow and inefficient; it takes 1-2 weeks to derive iPSCs from mouse cells and 3-4 weeks from human cell lines. Moreover, derivation is successful to a precision of .01 to .1% (7). Additionally, a major limitation of iPSC treatments is the threat of tumorigenesis, as an inherent property of stem cells is the ability to self-renew indefinitely. Lastly, more research will help cast a wider net of iPSC applications to treat a greater array of conditions.
Edited by: Arko Dhar
Illustrated by: Lily Xu