Prior to starting the Linus Pauling Institute, Pauling had worked at Stanford University where he met Dr. Paul L. Wolf, Associate Professor of Pathology and Director of the Clinical Laboratories at Stanford's medical center. In 1971 Pauling and Wolf discussed starting clinical trials on sickle cell anemia sufferers by way of orthomolecular methods using vitamin C, urea, and nicotinic acid (also called niacin). Pauling had heard promising things about niacin from Hoffer; thus, he was confident that "n. [nicotinic] acid would be much more effective than either ascorbic acid [vitamin C] or urea." About one year later, Wolf responded that niacin did not block or reverse sickling and that research on niacin no longer interested him.

Pauling and Wolf drafted a proposal for trials to search for an anti-sickling agent through dietary control. They believed that there was a relationship between metabolism and diet, which could aid prevention and treatment of sickle cell anemia. They proposed to analyze the urine of sickle cell patients in hopes that the urine test might "throw light on the mechanism of sickling and the reasons for the occurrence of crises of the disease."

Wolf suggested to Pauling that they submit a funding proposal to the National Heart and Lung Institute for research on sickle cell anemia. As a result of the 1972 National Sickle Cell Anemia Control Act, the United States government allocated large amounts of money to research on sickle cell diseases, including $92,000 to Pauling and Wolf. Using a portion of these funds Wolf and his colleagues found that prostaglandins, fatty acids manufactured by bodily tissues that act on other parts of the body, can induce sickle cell crises. Sickle cell crises are painful episodes, lasting for days or weeks, experienced during periods when the blood flow slows because of distorted blood cells. Wolf and his co-workers then searched for drugs to treat the crises. Pauling, Robinson, and other researchers at the Linus Pauling Institute used the funds to analyze urine in hopes of determining chemical changes between periods of crises and relative health among sickle cell disease sufferers. Pauling and Wolf devised another clinical trial in the summer of 1972 using vitamins C and E for sickle cell patients. The concept for this trial arose from Pauling's desire to prove the efficacy of vitamin C.

In the early 1970s, Pauling unsuccessfully solicited for funding to conduct research on sickle cell patients using nutritional therapies by means of orthomolecular medicine from the International Sickle Cell Anemia Foundation and San Francisco's Sickle Cell Anemia Research and Education, Inc.