“Success” in biomedical research is difficult to define. However, surrogate markers can give some insight into how well a particular organization is doing. For example, research is published in papers in scientific journals. In its 27 years of existence, Gladstone has published more than 1700 papers in respected, peer-reviewed journals. In addition, Gladstone has an excellent record for obtaining research support from the National Institutes of Health through their highly competitive grant review process. Rigorous outside review of grant applications is critical to Gladstone. The award of a grant carries with it a validation of the careful planning and execution of science at Gladstone. In addition, the work of Gladstone investigators has been recognized by many prestigious awards. For example, Dr. Robert W. Mahley was elected to the National Academy of Sciences and the Institute of Medicine. Dr. Warner C. Greene was elected to the Institute of Medicine. Dr. Lennart Mucke was named the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF and received an NIH MERIT award. Dr. Deepak Srivastava was named the Wilma and Adeline Pirag Distinguished Professor in Pediatric Developmental Cardiology at UCSF. And finally, the steady growth of the Institutes from six faculty-level scientists in 1979 to 22 in 2006 vouches for the long-term success of the research program. During the same period, the research staff grew from 25 to 325 today. Scientific progress builds incrementally on previous findings, and predicting which area will bear fruit is difficult. The best way to illustrate future work is to describe some recent breakthroughs. Dr. Steven Finkbeiner developed an automated microscope and used it to resolve a major long-standing controversy in Huntington's disease. The microscope enables scientists to follow intracellular events in thousands of individual cells over time and to use powerful statistical techniques of survival analysis. This innovative approach has wide applications for resolving questions of cause and effect, for example in Alzheimer's, Parkinson's, and other diseases, that were impossible to address with previous methods. Dr. Finkbeiner will continue to refine and expand the microscope's capabilities and to simplify its use. His ultimate goal is to make this revolutionary technology widely available to the scientific community. Dr. Warner Greene discovered how an HIV protein defeats a powerful antiviral factor commonly found in our cells. By explaining the interaction of these two components, his team has laid the groundwork for a potential new class of anti-HIV drugs that are desperately needed to combat the global AIDS pandemic. Dr. Greene will continue his cutting-edge studies of these factors. Dr. Deepak Srivastava has elucidated a cascade of transcriptional and signaling events that control the early steps of cardiomyocyte differentiation and expansion into ventricular chambers. In addition, he discovered a developmental gene, thymosin 4, that protects heart muscle during heart attacks. He is also a leader in exploring the role of microRNAs in regulating development and the uses of cardiac progenitor cells and stem cells to repair damaged hearts. For years, Drs. Robert W. Mahley, Karl H. Weisgraber, and Yadong Huang studied the role of apolipoprotein (apo) E in cholesterol metabolism and heart disease only to find out that a form of apoE, called apoE4, plays a key role in Alzheimer's disease. For example, they showed that apoE4, which is the major genetic risk factor for Alzheimer's disease and other neurological diseases, is much less effective than apoE3 in maintaining and repairing damage of nerve cells in the brain. Modulating the structure and function of apoE represents a potential therapeutic target for Alzheimer’s disease.