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Biology, initially known as Natural Sciences, has a long history at the Ecole Normale Supérieure (ENS). Louis Pasteur played an important role at the Ens, of which he was appointed administrator and director of studies at the age of 35. There, in an attic, he installed at his personal expense the laboratory in which over the next 30 years he and his collaborators worked on the bulk of his major contributions: fermentation, biogenesis, germ theory, silk worm diseases, pasteurisation, vaccines. It was in that same laboratory that the young Joseph Meister received the first successful rabies vaccination.

Historically, biology at the Ens was subdivided into the disciplines of zoology, botany, and geology. However, in modern times it became steadily more apparent that this represented an artificial organisation, especially after the advent of molecular biology.

The Natural Sciences division was radically overhauled in the 1980s when the mathematician Geogres Poitou was appointed as director of the Ens. After overcoming significant internal resistance, the restructuring led to the creation of the Department of Biology. During the same period, the buildings of the department were completely renovated.