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The Super-Soldier program was developed as an advanced infantry program, trying to produce a 'superior' soldier from recruits who would be otherwise physically inadequate. The program was first started in earnest by Nazi Germany under the direct supervision of the Harbingers.

The chief architect of the Super-Soldier program was Abraham Erskine and the mutant known as Nathaniel Essex. Essex's earlier efforts were derived from the Terrigen Mists, ancient Kree bioweapons developed to accelerate the mutation of the human genome. They had stumbled upon this secret after capturing and torturing the Atillan woman known as Jiaying and extracting from her the location of a small sample of Terrigen Mists.

The leader of the Harbingers, Vandal Savage, selected Johann Schmidt as the first test subject for their experimental serum. The artificial metagene crisis vastly improved Schmidt's physical capability, but profoundly changed his appearance and drove him deeper into madness and egomania.

Erskine discovered Essex was performing his experiments upon detainees and captured soldiers. He was horrified to learn that Essex and Schmidt served a higher purpose than even the intolerable cruelty of the Third Reich.

Erskine fled to America and offered his knowledge to the Strategic Scientific Reserve. One more effort was made to repeat the project, called Project: Rebirth. Steve Rogers was selected as the test subject. The results were a resounding success. Erskine was assassinated moments later, taking the necessary detailed knowledge of the project to the grave. The remaining research materials were taken by Howard Stark and Thomas Wayne Sr., and split between them in trust so no one could steal the data and duplicate the results. An attempt was made to replicate the Super-Soldier Serum, but all attempts ended in disaster. The best nearest success for many years was Isaiah Bradley, 'Black Cap', a soldier from the Tuskeegee Company who led a special commando unit of Super Soldiers in the Pacific Theater.

Spin-off projects would be attempted intermittently over the following decades. The Department of Extranormal Operations established multiple sub-directorates and programs, including CADMUS, Weapon Plus, and Weapon X. Other research would periodically dip into the well of knowledge, producing The Hulk as Bruce Banner studied gamma-ray energies, and Luke Cage in an effort to produce medical research.

Unfortunately, the failure rate for the various super-soldier programs was staggeringly high. Many died. Others went insane or berserk with power. Only a handful could be remotely approximated as successes.