My sense so far is that the charm and unease of the Doctor lies in the extent to which he's able to pass for human. He can be charming, compassionate, perceptive, and then turn down Rose's offer of dinner with her mother, who has only just been convinced that the Doctor might be decent, with a blunt and confused "tough, I've got better things to do." Christopher Eccleston's version of the Doctor, at least, is every bad boyfriend a girl has ever had--undependable, often inconsiderate, consistently winning--with the excuse that he's genuinely alien, and genuinely unaware he's causing trouble or hurt.
Depp's uniquely good at playing aliens in human skin. Sometimes, his lack of humanity is physical, he's the sweet young man with blades for fingers. Sometimes, he looks normal even though he's actually psychotically high, the kind of person who will abandon all responsibility and allow an associate to keep a young woman in virtual sexual slavery without really being aware what's going on. Sometimes, he's almost entirely human, but radically displaced from the only element where he's remotely functional. Sometimes, he's violent, clever, and deeply uninterested in functioning in polite society, except to the extent that it lets him take pretty girls to the movies.
True he did flub one of the roles that I think would have best let him prepare to play the Doctor, that of Lucas Corso, a man out of place and time and caught up in two byzantine plots, in The Ninth Gate, a dreadful Roman Polanski adaptation of Arturo Perez-Reverte's The Club Dumas. But I cite that failure more in Polanski's butchery of the plot and characters than in Depp's performance. So as long as Polanski, and even more importantly, Tim Burton, architect of the worst excesses of Depp's career, are kept far, far away from this project, I'm willing to give it a shot. Though maybe I'll change my mind, once I get further into the show.
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