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Howard Green and the Accidental Birth of the Stem Cell Era.

Dr Howard Green was a professor of cell biology at Massachusetts Institute of Technology from 1970 to 1980 before continuing at Harvard Medical School until 2013. He died on October 31, 2015. It was his accidental laboratory finding that led to the first therapeutic use of a cellbased therapy for skin regeneration, giving birth to an era of stem cell therapies in wound and disease healing. While studying cultivated murine teratomas to better understand embryogenesis, Green and a graduate student noted that teratoma cells gave rise to cell colonies with an epithelial appearance. Green hypothesized that these cells were fibroblasts and attempted to isolate them, adding lethally irradiated cells of the fibroblast line 3T3 to support their growth. Once isolated, examination through electron microscopy revealed the presence of stratified squamous epithelia, including desmosomes and keratohyalin granules. Using 3T3 support, Green boldly attempted to culture human keratinocytes, a feat that had previously not been successfully accomplished. His experiment proved successful: using human keratinocytes obtained from a small biopsy, it was possible to generate enough epidermal cells to cover the human body. Although a full-time scientist, Green had been clinically trained in medical school, and he saw his experiment’s human therapeutic implications in third-degree burn healing. Green took time to develop a skin graft from a confluent sheet of cultured keratinocytes using a neutral protease enzyme. After successfully testing the graft in an animal model, Green moved to examining its efficacy in humans. Perhaps the most famous example of this was its application in the treatment of 2 siblings, 5-year-old Jamie Selby and 6-year-old Glen Selby. Both brothers had sustained thermal burns over 97% and 98% of their bodies, most of which were third-degree in nature. As a result, they had no chance of survival with traditional skin grafting. Green and his team successfully grafted both boys with cultures of autologous epidermis; the boys survived for over 20 years, eventually dying of complications unrelated to their burns. Further study revealed that the presence of holoclone, or stem cell colonies, in the culture graft was vital for the epidermal keratinocytes’ proliferative capacity. As a direct result of Green’s work, limbal stem cells were cultivated and grafted in the eye to help restore vision and relieve inflammation following a chemical burn. Green’s work was even applied in gene therapy to treat junctional epidermolysis bullosa. Cultivated epidermal cells were transduced with a retroviral vector and grafted into areas of affected skin, curing the disease. As we remember the life of Howard Green, we should note that his accidental discovery had an enormous impact not only on burn healing but also on the burgeoning field of stem cell therapy and regenerative medicine as a whole.