Set in downtown New York in 1900, The Knick is centered on the Knickerbocker Hospital and the groundbreaking surgeons, nurses and staff who work there, pushing the bounds of medicine in a time of astonishingly high mortality rates and zero antibiotics. John Thackery is a brilliant surgeon pioneering new methods in the field, despite his secret addiction to cocaine. He leads a team of doctors including his protégé Dr. Everett Gallinger; the young Dr. Bertie Chickering Jr. and Dr. Algernon Edwards, a promising surgeon whos been recently thrust upon him. The lively cast of characters at the hospital also includes Cornelia Robertson, the daughter of its benefactor, Captain August Robertson; surly ambulance driver Tom Cleary; Lucy Elkins; a fresh-faced nurse from the country; the crooked hospital administrator Herman Barrow; and Sister Harriet, a nun who isnt afraid to speak her mind.

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