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Rapture couldn't keep its secrets forever. The First Biological Warfare Command, alias "Blackwatch", is established in 1962 by DARPA and the Department of the Army. The program's mandate is to secure America against biological attack, but its leadership goes further: they want to create new viral agents as weapons of war.

Dr. Tenenbaum was one of Andrew Ryan's Operation Paperclip recruits, under the alias "Anna Zimmerman". Blackwatch's agents track her down after her escape from Rapture, and manage to wrest some of the secrets of ADAM from her. She refuses to work with them, and is killed by government assassins. Blackwatch begins tracking down Jack and the escaped Little Sisters, whose bodies have been significantly altered by their exposure to ADAM.

In 1963, Blackwatch begins "Carnival I": the introduction of a new "Redlight" virus into chimpanzees. Redlight is derived from the "Lot 111" treatment obtained from Tenenbaum, adapted into viral form. The effects are immediate and positive: enhanced intelligence, strength, and other physical features.

By 1964, Blackwatch is ready to test the effects of the Redlight virus on humans. The create an artificial town in Idaho, called "Hope", and round up a genetically diverse population to inhabit the place. The official story is that Hope is meant to test self-sufficient towns in the event of a nuclear war. On June 11, 461 subjects are infected with Redlight, told only that they are receiving routine immunization shots. Unlike chimpanzee subjects, no immediate mutations or physical changes were observed. 27 children, dubbed "Hope Children", were born to the infectees in 1965. Their life expectancy was typically 3 years or less.

Blackwatch also sponsors the creation of a facility for studying Redlight. This facility is buried underground near Flatrock, NV, and dubbed "Wildfire". A series of protocols are put in place to keep Wildfire safe, and if necessary to sterilize it with an atomic bomb. The laboratory is equipped with every conceivable scientific tool for studying microbial and viral lifeforms.

Frank Fontaine's investment in ADAM was richly rewarded. His Umbrella Corporation has become independently wealthy thanks to pharmaceuticals and medical supplies, bioweapons, and genetic engineering. Lord Oswald E. Spencer, one of the virologists and independently wealthy to begin with, publicly becomes president of Umbrella. In 1966, he, Dr. James Marcus, and Brandon Bailey make a breakthrough in unlocking the double-stranded RNA virus they called "Progenitor".

Lord Spencer has a mansion in the Arklay Mountains designed and built in 1967 as a place where research can take place away from official scrutiny and Blackwatch's prying eyes. Spencer also leads an expedition to the city of Ndipaya people, during which his colleague Sir Edward Ashford dies due to viral exposure. To cover their tracks in Africa, the Umbrella team releases an artificial and rapidly-spreading virus into the ancient Ndipaya ruins. Blackwatch officers General Ford and Major General McClintock use a fuel bomb to destroy the infected area, assigning the name "Motaba" to the viral agent they found.

Spencer's real reason for creating the mansion is to get access to George Trevor's daughter Lisa, and her unique "Little Sister" physiology. Spencer does away with George, then forcibly administers the Progenitor virus to Lisa and her mother Jessica on November 10, 1967. When Jessica shows no interesting effects, Umbrella kills her. Lisa, however, survives the process and is horribly altered. Umbrella extracts a modified virus, the "G-virus", from Lisa's body.

In 1968, Dr. Marcus are officially brought on board by Umbrella to push Progenitor research forward. Spencer hope to use Progenitor's unique infective and mutative properties as a substitute for ADAM, and as a tool to achieve godhood.

By 1968, almost all the "Hope Children" were dead. The exception was a child of a former Little Sister, now going by the name Elizabeth Greene. Redlight turned Greene's body into a virus factory, and their infections turned the other residents of Hope into a hive mind with one purpose: defend and obey Greene.

Alexander Ashford, son of deceased Lord Edward, begins construction of a secret base in Antarctica to perform further viral research. This work is completed in 1968.

In 1969, Blackwatch initiates "Operation Altruistic": the forced purification of the Carnival II experiment site in Hope, ID. They capture or destroy all of the infected citizens, take possession of the bodies of the Hope Children, and recover Elizabeth Greene and her child (dubbed "Pariah").

The Hope infectees controlled by Greene come in several varieties. One, of a highly mobile and intelligent type dubbed a "Runner" by Blackwatch, escapes the Hope military cordon. It flees, crossing 1400 miles to reach Piedmont, AZ (mistakenly labeled "Two Bluff" in Blackwatch records). Robert Cross, then a captain in Blackwatch, tracks the creature there, thankfully with minimal casualties along the way. He is able to destroy it, but not able to prevent the resulting infection of Piedmont's residents. Everyone except two people - the town drunk and an infant child - subsequently dies. Blackwatch sterilizes the town with a thermobaric weapon.

Blackwatch takes its Carnival II samples and dispatches government scientists to Wildfire to study mutated microbes that survived the Hope experiment, under the code name "Andromeda". After several tense days, including the near obliteration of the facility by its inbuilt nuclear weapon, the researchers discover that Andromeda itself has mutated into a benign form. To maintain operational security, none of the researchers are told the true origin of the microbe: instead, they are informed that it came down as part of a crashed military satellite.

In 1970, Anna Hart is born. In reality, she is a clone of Brigid Tenenbaum, alias "Anna Zimmerman". Blackwatch has produced several other clones, and fostered them into families identical to Tenenbaum's. Over the next several years, the clones receive trace amounts of ADAM harvested from Tenenbaum herself. Blackwatch hopes that ADAM's memory-transferring properties will awaken Tenenbaum's memories and genius in the clones.

Blackwatch creates a front company, the Rossum Corporation, to invest in medical technologies and research that will validate the presence of emergent memories in their Anna clones. To that end, Rossum purchases the rights to magnetic resonance imaging, or MRI, after it's invented by Paul C. Lauterbur in September 1971. The corporation gradually dissociates itself from Blackwatch to pursue the ambitions of one of its executives, Clyde Randolph.

In 1970, Andy McGee and Vicky Tomlinson meet in college. The next year, the two are married and expecting their first child, Charlene. They met as test subjects for a hallucinogen called "Lot 6". Like Ephemerol, Lot 6 is derived from Rapture "Plasmid" biotechnology and the mutated Little Sister physiology, but processed and concentrated. The drug in their systems endows both of them with psychic abilities, and finds its way into the brain of their unborn child Charlie. Charlie herself is born in 1973.

The National Institute of Mental Health receives samples of Redlight for further experimentation. They apply the virus to a collection of rats and mice. Unbeknownst to the researchers, the rodents acquire enhanced intelligence (and perhaps other special abilities), and engineer their own escape from the NIMH facility in 1971.

Blackwatch manages to extract a sample of the viral infection Elizabeth Greene used to control her fellow citizens in Hope. Although the infection doesn't create a hive mind, it does induce gradual insanity. This virus, code named "Trixie", is transported by airplane in 1973. The plane crashes near Evans City, PA, and pollutes the local water supply. The townsfolk are quickly driven insane by the infection, while Blackwatch soldiers under the command of Colonel Peckem move in to clean up, contain, or sterilize the city.