Historically, drug developments have frequently been made by a trial-and-error methodology. As a consequence, the element of chance has been an essential one in the development of new pharmaceuticals. George Hitchings and Gertrude Elion diverged from this traditional path in their own research, utilizing what today is termed 'rational drug design'. They methodically investigated areas where they could see cellular and molecular targets for the development of useful drugs. During their long collaboration, Hitchings and Elion produced a number of effective drugs to treat a variety of illnesses—including leukemia, malaria, herpes, and gout.

George Hitchings was born in 1905 in Hoquiam, Washington, the son of a shipbuilder. His family moved around often along the west coast during Hitching's early years. When Hitchings was only twelve, his father died, an event that led Hitchings, ultimately, to pursue a career in medicine.

Hitchings demonstrated his early interest in science through his selection of courses at Franklin High School in Seattle. When he graduated from high school, his salutatorian address centered on the life and work of Louis Pasteur, whom Hitchings greatly admired for his commitment to basic research for practical developments.

Hitchings enrolled at the University of Washington in 1923, choosing to major in chemistry, primarily due to the enthusiasm of the chemistry department for their subject. He received his bachelor's degree in 1927, and stayed on at the University of Washington to earn a master's degree in 1928. Hitchings then attended Harvard University, where he received his Ph.D. in biochemistry in 1933. His work at Harvard centered on analytical methods used in physiological studies of purines, which are a class of compounds, including caffeine and adenine, composed of a two-ringed structure containing carbon and nitrogen.

For the next decade, Hitchings held a variety of temporary appointments at institutions like Western Reserve University [now Case Western Reserve] and the Harvard School of Public Health. In 1942, however, he joined the Wellcome Research Laboratories, then located in Tuckahoe, New York, as a biochemist. The company, now known as GlaxoSmithKline, was British. Two years later, Hitchings hired Gertrude Elion as a laboratory assistant, thereby beginning a life-long collaboration on drug development.

Gertrude Elion, known to her friends as “Trudy”, was born in 1918 in New York City, the daughter of a successful dentist. A shy young woman, Elion was an excellent student, and her parents encouraged her to attend college. The death of her grandfather from stomach cancer shortly before she began her studies at Hunter College prompted Elion to devote her life to medicine. This dedication was renewed when, soon after her graduation in 1937 with a degree in chemistry, her fiancé died of subacute bacterial endocarditis, an inflammation of the heart lining.

Elion knew that she needed to have a Ph.D. to do laboratory research. However, despite her excellent academic record, she was unable to get either a graduate fellowship or assistantship, and so began to look for a job. There, too, she had a great deal of difficulty, mostly due to gender discrimination. At one point, she enrolled in secretarial school to get some practical skills. After a series of temporary jobs, Elion decided to volunteer her time in a chemistry laboratory; six months after she started, she was put on the payroll. Having saved enough money after a year and a half, Elion enrolled at New York University as a master's student in chemistry, working part-time as a doctor's receptionist, and later as a substitute teacher, to help pay the expenses. Nights and weekends were spent in the laboratory at NYU, doing research.

With the ongoing war, jobs in chemistry were beginning to open up for women. After graduation, Elion took a job testing food products for A&P grocery stores. She learned a lot about instrumentation, but left when the position became too routine. She was then hired by Johnson & Johnson to synthesize sulfonamides, but the lab closed after six months. In 1944, she joined Wellcome Research Laboratories, intending to stay only as long as she continued to learn new things. Elion stayed there for the remainder of her career.

Rather than the traditional trial-and-error method of drug discovery, Hitchings believed in the necessity for a more rational method of research. The recent development of sulfa drugs led him to think that other substances that interfered with the metabolism of microbes—as sulfa drugs had been shown to do—could also be developed as drugs. As a result, Hitchings began examining the nucleic acids—now known as DNA and RNA—and assigned Elion to investigate purines, including adenine and guanine, two of DNA's building blocks. They soon discovered that bacterial cells could not produce nucleic acids—a material that determines the genetic makeup of a cell and directs the process of protein synthesis—without the presence of certain purines, and set to work on antimetabolite compounds—compounds which locked up enzymes necessary for the incorporation of these purines into nucleic acids.

By 1950, this line of research had paid off. Elion and Hitchings synthesized two substances—diaminopurine and thioguanine, which the enzymes apparently latched onto instead of adenine and guanine. These new substances proved to be effective treatments for leukemia. Leukemia is a form of cancer characterized by a great increase in the number of white blood cells in the body due to the activity of oncogenes, genetic material that has the ability to cause cancer. Elion later substituted an oxygen atom with a sulfur atom on a purine molecule, thereby creating 6-mercaptopurine (also known as 6-MP), a molecule closely related to thioguanine. The new material, 6-MP, was also used to treat leukemia. But with all of these new treatments, the cancer was not cured; patients went into remission, but then relapsed and died. Elion decided to examine everything about 6-MP, devoting six years of her life to this research. As a result of her research, childhood leukemia today is treated with a combination of 6-MP and one of a dozen other drugs. During remission, drug therapy continues. This method of treatment cures the majority of cases.

After this success, Elion and Hitchings developed a number of additional drugs using the same principle that had led them to 6-MP. Another form of leukemia could be treated with 6-thioguanine. Later, these related drugs were found to not only interfere with the multiplication of white blood cells, but also suppress the immune system. This latter discovery led to a new drug, Imuran (azathioprine), and a new application—organ transplants. Imuran suppressed the immune system that would otherwise reject newly transplanted organs. For the first time, patients could receive organ transplants without their bodies rejecting the new organs. The team also developed allopurinol, a drug successful in reducing the body's production of uric acid, thereby treating gout, a condition caused by the buildup of uric acid in the joints.

In the 1960s, Elion and Hitchings shifted their research to nucleic acid formation in lower animals, and the differences between these processes in animals and in people. They determined that infectious diseases could be fought if drugs could be targeted to attack bacterial and viral DNA. This work resulted in pyramethamine, used to treat malaria, and trimethoprim (Septra), used to treat meningitis, septicemia, and bacterial infections of the urinary and respiratory tracts.

As a result of these overwhelming successes, Hitchings was promoted in 1967 to Vice President of Research; this promotion ended his active participation in research. Elion, too, was promoted—to head of the Department of Experimental Therapy. Despite her new responsibilities, Elion continued her research and was essential in the development of acyclovir, an antiviral drug effective against herpes. Although the drug was originally synthesized by Dr. Howard Schaeffer, Elion determined exactly how and why it worked. Acyclovir, marketed as Zovirax, interferes with the replication process of the herpes virus—and only the herpes virus—proving that drugs can be selective. This principle led to the eventual development of AZT (azidothymidine) by Elion's colleagues. AZT is used to treat AIDS.

In 1970, the Wellcome Laboratory moved to Research Triangle Park, North Carolina; both Elion and Hitchings moved along with it. Elion retired in 1983, eight years after Hitchings. With James Whyte Black, they received the 1988 Nobel Prize in Medicine.

(Reproduced from Bowden, Mary Ellen. Pharmaceutical Achievers. Philadelphia: Chemical Heritage Foundation, 2002.)

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