Set in 2030–2031, ten years after the events of Software, Wetware focuses on the attempt of an Edgar Allan Poe-obsessed bopper named Berenice to populate Earth with a robot/human hybrid called a meatbop. Toward this end, she implants an embryo in a human woman living on the Moon (Della Taze, Cobb Anderson's niece) and then frames her for murder to force her to return to Earth. After only a few days, she gives birth to a boy named Manchile, who has been genetically programmed to carry bopper software in his brain (and in his sperm), and to grow to maturity in a matter of weeks.
Berenice's plan is for Manchile to announce the formation of a new religion unifying boppers and humans, and then arrange to have himself assassinated. (Rucker makes several allusions to the Christ story; Taze's abbreviated pregnancy is discovered on Christmas Eve, for instance.) Before the assassination, Manchile impregnates several women, the idea being that his similarly accelerated offspring will create a race of meatbops at an exponential rate.
The plot goes disastrously awry, and a human corporation called ISDN retaliates against the boppers by infecting them with a genetically modified organism called chipmold. The artificial disease succeeds in killing off the boppers, but when it infects the boppers' outer coating, a kind of smart plastic known as flickercladding, it creates a new race of intelligent symbiotes known as moldies — thus fulfilling Berenice's dream of an organic/synthetic hybrid.
Both of the two main human characters of Software play prominent roles in Wetware: Cobb Anderson, whose robot body was destroyed at the end of the last novel, has his software implanted in a new body so he can help raise Manchile; while Sta-Hi Mooney—now known as Stahn Mooney—is now working as a private detective on the Moon after accidentally killing his wife, and is used as a pawn in various bopper and anti-bopper schemes.
The Belle of Louisville, a steamboat of historic significance located in Louisville, Kentucky (the setting for the earthbound portions of the book), occurs as a character in the book, in which it is revealed that the steamer has been imbued with an onboard artificial intelligence.
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