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Though during the 1940's the existence of mutants was unknown to the general public, a few individuals were aware of the coming of Homo Superior, and that they had the potential to replace baseline humans as the dominant species of Earth. Thus Weapon Plus was created to address the so-called mutant problem. What was ignored by everyone involved in Weapon Plus is that its mastermind, John Sublime, was actually the host body for a sentient bacteria present on every living creature on the planet, save for mutants, who were genetically immune to the Sublime infection.

The first nine installments of Weapon Plus were partially successful. Weapon X produced a number of agents, though it branched off and even became opposed to Weapon Plus's interests. To prevent subsidiary programs from going rogue, Weapon Plus directly oversaw the creation of the last living weapons operating in the clandestine facilities of The World, employing Bolivar Trask's Sentinel technology.

Throughout the decades, Weapon Plus has used increasingly more extreme methods to create its supersoldiers. Captain America was enhanced to peak human levels. Weapon X employed genetic alteration, brainwashing and memory implants. The latest creations were bred specifically to become mutant-hunting weapons much deadlier than Sentinels.

Project: Rebirth, headed by Professor Abraham Erskine (given Reinstein's name as a cover identity) managed to produce Captain America (Steve Rogers). However Erskine was murdered moments after Rogers was successfully empowered, the refinements he introduced which made the process successful lost with his death. With his demise, Josef Reinstein took over the American program.

Two other subjects, Clinton McIntyre, a.k.a. Protocide, a failed experiment who was placed in suspended animation and was revived in the modern era by AIM, and the first mutant experiment designated Queen seem to have occurred prior to the serum being tested on Steve Rogers.

Reinstein's early attempts to refine the formula resulted in African American super soldiers (most prominently Isaiah Bradley). Three hundred African-American soldiers were taken from Camp Cathcart and subjected to potentially fatal experiments at an undisclosed location, as seen in Truth: Red, White and Black in an attempt to recreate the Super Soldier formula. Only five men survived the original trials; hundreds of test subjects left behind at Camp Cathcart and the camp's commander were executed by US soldiers in the name of secrecy, the families of the three hundred were told that they had died in battle. Isaiah Bradley was the lone survivor.

Although there were many later attempts to recreate or reverse-engineer Project: Rebirth's Super-Soldier Serum, none are known to have been involved with Weapon Plus except for the attempt that resulted in the creation of Isaiah Bradley's son Josiah X. Weapon Plus considers Captain America as its most successful creation, despite the fact that Rogers has been at odds with the United States government a number of times. It should be noted that Project: Rebirth was retroactively made a part of the Weapon Plus after WWII when Weapon Plus was actually formed.

Weapons II-IV experimented on animals. It is unknown if the experiments succeeded in creating a living weapon. Grant Morrison only touched lightly on this element of the Weapon Plus project during his tenure on New X-Men, but later explored the theme of animal-based weapon development in other projects such as the DC Comics publication We3.

Weapons V and VI employed various ethnic minorities as test subjects.

Weapon VII, aka Project: Homegrown, experimented on human soldiers during the Vietnam War. Some of the known participants who died in Project: Homegrown included Andrew Perlmutter, Michael Labash, John Walsh, James MacPherson and fourteen other unknown recruits. The only known successful subject of Project: Homegrown was Nuke, who had armored implants under his epidermis and was addicted to powerful steroids. Logan, who would later become one of Weapon Plus' victims, kidnapped Nuke as a child, and oversaw his conditioning.

The United Kingdom also had its own version of Project: Homegrown, aka the Black Budget, which managed to create the team known as the Super Soldiers: Dauntless, Gog, Dreadnaught, Revenge, Victory, Invincible, Challenger, and some other unnamed super-soldiers.

The Mercy Corporation, an off-shoot of S.H.I.E.L.D. that worked on super-soldiers and eventually broke off, also had its own unit of super-soldiers, using a serum similar to previous derivatives of the Super-Soldier Serum from Weapon I. Their agents included Jack Reno, Keel, Kyle, Agent Villarosa, Agent Davis and Agent Milo.

Weapons VIII & IX experimented on criminals and psychopaths.

In Wolverine: The End, by Paul Jenkins, it was revealed that Weapon IX was, in fact, Wolverine's older brother John Howlett (first introduced in Origin), long thought deceased. However, due to the inherent instability in the possible futures depicted in Marvel comics, it is unknown if this is regarded as canon.

Weapon X, tenth in the series, is the X-Man Wolverine, and this project would spin off into its own series of subjects.

No individual with the 'Weapon XI' moniker has been seen, but John Sublime has mentioned it. A likely candidate for Weapon XI's true identity is the Hound (a mutant with the power to hunt and kill other mutants), who was transformed by the Hound Program of the US government into a techno-organic killing machine. He battled the government-sponsored incarnation of X-Factor after massacring scientists at a US government research facility, nearly killing Sabretooth in the process, but was stopped by Polaris, who was forced to use her power at its full limit. He was later after Shard, but was destroyed in an explosion after being defeated by her and Bishop.

Weapon Plus created Weapon XII (aka Huntsman, real name Zona Cluster 6) at the England-based facilities of The World. He was the first living weapon created employing artificial evolution and nanosentinel technology. Weapon XII was "accidentally" unleashed on the Channel Tunnel and fought X-Corporation members Cannonball, M, Darkstar, Rictor, Siryn and Multiple Man. Weapon XII was eliminated by Fantomex with the aid of Jean Grey and Professor X, but at the cost of Darkstar's life. Huntsman was created to be part of the Super-Sentinels, a mutant-hunting team of superheroes with a base in a Weapon Plus space station. This team, a brainchild of John Sublime, was intended to be a publicity stunt to make the genocide of mutants much more acceptable to the public.

Weapon Plus created Weapon XIII Fantomex, whose real name is Charlie Cluster 7, also at The World. However, Fantomex rebelled against his creators. Like in the case of Weapon XII, Fantomex's powers derive from Nanosentinel technology.

In New X-Men #154 (May 2004), Grant Morrison's last issue of New X-Men, the telepathic quintuplets called the Stepford Cuckoos were identified as Weapon XIV. The Stepford Cuckoos link to Weapon Plus has finally been addressed in the Phoenix: Warsong miniseries, written by Greg Pak, which explores unresolved storylines from Morrison's New X-Men and Pak's Phoenix: Endsong.

So far, the last creation of Weapon Plus is Weapon XV, aka Ultimaton, designed to be the Super-Sentinels' grand powerhouse. He dies when Wolverine destroys the Weapon Plus space station that was designed as the Super-Sentinels HQ's.