Biological similarities that extend from amphibians to mammals demonstrate the value of model organisms in disease-related discovery, which is highlighted by one of this year’s most prestigious awards. This year’s Lasker Award for Basic Medical Research went to two scientists whose work in model organisms, frogs and mice, led to the molecular definition of stem cells and the factors that allow cells to specialize into any cell type, including those as unique as a fat cell, a muscle cell or a neuron. The nuclear reprogramming discoveries of the winners, John Gurdon and Shinya Yamanaka, demonstrate that it is possible to reprogram mature adult cells. Cells reprogrammed in this way might someday promote regeneration of diseased or dysfunctional tissue in human patients.
John Gurdon’s work was once hotly debated. At the time, it was generally believed that cells undergo permanent nuclear changes as they specialize, and that they lose the programming information that tells them how to become a different cell type during maturation. However, after inserting nuclei from fully differentiated cells from the skin or intestine of the frog Xenopus laevis into eggs that lacked a functional nucleus of their own, Gurdon was able to generate fully developed tadpoles. This technology of nuclear transfer was later used to clone a sheep, resulting in Dolly, and provides evidence that the entire array of developmental programs that a cell needs to differentiate are always present in its nucleus. How the cell activates the appropriate program, and how it might be reprogrammed to become a different cell type, remained a mystery in the early days of this work.
Shinya Yamanaka and his colleagues tackled the question of cell programming and discovered how to restore the pluripotent capacity to previously specialized cells. Yamanaka’s lab generated a list of the genes that are activated in mouse embryonic stem cells and determined exactly which ones were necessary to make cells pluripotent. They showed that expression of just four genes (Oct3/4, Sox2, c-Myc and Kif4) together could turn a differentiated adult mouse fibroblast into a cell with the potential to become any cell type. They called these cells induced pluripotent stem cells or iPS cells, which are now known to be capable of generating whole fertile mice. This technology may lead to the ability to take mature cells from a patient and reprogram them into cells to replace dead tissue resulting from a heart attack, brain injury, cancer or a host of other diseases.
The work of Gurdon and Yamanaka is honored by the foundation for its amazing potential, while the Lasker Foundation recognizes scientists whose discoveries have already changed patient care with its Lasker-DeBakey Clinical Medical Research Award. This year, Brian Druker, Nicholas Lydon and Charles Sawyers were honored for creating Gleevec (imatinib), a drug that can be taken as a pill by patients with chronic myelogenous leukemia (CML). Before Gleevec, patients with CML often died within 5 years of diagnosis, but the drug has now boosted their 5-year survival rate to almost 90%.
The emergence of Gleevec onto formularies is testament to the resolve of the awardees and their colleagues. Many believed that the therapeutic strategy, to specifically target the aberrant Abl (BCR-Abl) enzyme that is characteristic to CML patients, would not offer the necessary specificity and would create significant side effects. They believed that the novel approach had fundamental flaws. Some executives at Novartis also worried about the cost recovery of pursuing a potential drug that might only affect a very small subset of cancer patients. The creators worked diligently to keep Gleevec moving forward.
As soon as the clinical trials began, however, the potential for Gleevec, the first molecular-based chemotherapeutic agent, was clear. The specific inhibition of BCR-Abl in cancer cells immediately improved survival and quality of life, with fewer side effects than the previously available treatments. In pursuit of more targeted and more effective cancer treatments, other scientists now copy the same strategy that was used to create Gleevec. The use of Gleevec now extends beyond CML and includes patients with gastrointestinal stromal tumors (GIST) and hypereosinophilic syndrome (HES). The story of Gleevec shows the translational power that can be achieved when creative minds bring clinical and laboratory experience together with strong determination.
