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From 1953 to 1959, Major Simons was Chief of Space Biology at the Air Force Missile Development Center at Holloman Air Force Base, New Mexico. During that time, he was Project Officer on Project 7851, "Human Factors of Space Flight." This program included 60 high altitude balloon flight experiments studying cosmic radiation effects, weightlessness and space equivalent conditions. In 1957, Simons would take part in the Manhigh project, a series of balloon flights to record altitudes to study the effects of a near-space environment on human physiology. On August 19 and 20, 1957, Dr. Simons piloted a 32-hour balloon flight to a then-record altitude of 101,516 feet during the Manhigh II mission. Just before dawn on August 19, 1957, Major Simons, wearing a pressure suit, sat in enclosed gondola beneath the Manhigh II balloon as it rose above Crosby, Minnesota. The balloon ascended rapidly and after two hours and eighteen minutes, it reached almost 100,000 feet. The balloon was expected to drift westward into Montana, but it was slower than anticipated and never got beyond the eastern part of the Dakotas. The flight was also supposed to last just 24 hours but dragged on almost a half day longer, as Simons in his balloon capsule and tracking parties on the ground looked for a suitable opening in the cloud cover through which to descend. In the afternoon of August 20, Dr. Simons was able to begin a steady rate of descent and finally landed near Frederick, South Dakota. The Manhigh II flight had lasted thirty-two hours and ten minutes, but Simons had actually been forty-four hours in the cramped capsule, including the time spent before launch. The delay in ending the flight had led to several problems in capsule environment. The effectiveness of chemicals in the air regeneration system began to decline, carbon dioxide was not absorbed fast enough, and at regular intervals Major Simons had to use a facemask for breathing. With power supply also running low, it was necessary to cut off the capsule cooling system, and temperature rose to eighty-four degrees, a situation extremely uncomfortable due to the pressure suit. Despite these problems, Major Simons emerged from the ordeal in good shape and the mission was a great success. In words of Colonel John Stapp "Human performance in an environment equivalent to space is now known to be possible."
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