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This month, Francis Collins will step down as director of the US National Institutes of Health (NIH) after more than 12 years leading the agency, the world’s biggest public funder of biomedical research. A former head of the Human Genome Project, he championed similar bold, big-budget science efforts, such as the All of Us Project, which aims to study health data from one million people. He led the NIH under three US presidents, steered it through a roiling pandemic, and faced myriad clashes over politics and biomedical science. Collins will stay on at the NIH to continue research in his lab. He spoke to Nature about some highlights of his time at the helm, and issues facing the agency in the future.