Gertrude B. Elion

Gertrude Belle Elion was born on January 23, 1918 in New York City the daughter of immigrant parents. She grew up in New York City and the Bronx, which at that time was a still a suburb of New York with many open lots for children to play in. By her own account she was a child with an insatiable thirst for knowledge and she did well in all her classes. Her interest in science was sparked by the death of her grandfather, who died of cancer when she was 15. When she went to Hunter College in 1933, she chose to study science and in particular chemistry.

After graduating from Hunter College she had trouble finding work, but was eventually able to able to find work teaching and as a laboratory assistant. In 1939 she entered graduate school at New York University. The only woman in her class, she continued her studies, taking work as a substitute secondary teacher, graduating with a masters in chemistry in 1941. After finishing her masters she took a job working in the quality department of a food company. She soon bored of this work and looked for a job doing research. The most interesting position she found was working in George H. Hitchings' laboratory at Burroughs Wellcome. Hitchings was working on antagonists to nucleic acid analogs and she worked for him as an organic chemist, synthesizing new compounds.

Nucleotide and nucleoside analogs are compounds that resemble nucleic acids. These compounds can be used to treat patients with viral diseases, cancer and can also be used as immunosuppresent drugs used for organ transplants. Viruses, replicating cancer and immune cells can be inhibited if their ability to reproduce DNA is inhibited. These compounds inhibit the synthesis of new DNA, by substituting a compound that resembles a nucleic acid or nucleoside but which blocks further synthesis. For their work in developing these compounds Elion and Hitchings were awarded the 1988 Nobel Prize in Physiology and Medicine.

Shortly after taking the position in Hitchings laboratory, Elion began taking classes to earn her Ph.D. After a year of taking classes she was told that she would have to work on her Ph.D. full time. Given the choice she continued her work for Hitchings. She worked for Burroughs Wellome until 1983 when she retired and assumed the status of scientist emeritus. Other awards won by Elion include honorary doctorates from the Polytechnic University of New York and Harvard University, The National Medal of Science, and induction into the Inventors Hall of Fame, of which she was the first woman to be inducted. She was elected into the National Academy of Science in 1990 and to the National Institute of Medicine in 1991.

While on her daily walk on February 21, 1999 she collapsed. She was admited to the hospital and passed away at midnight at the age of 81.

References:

Avery, Mary Ellen; "Gertrude B. Elion" in Biographical Memiors; National Academy Press; 2000

Gertrude B. Elion Nobel Autobiography

Gertrute B. Elion Wikipedia Entry

George Herbert Hitchings

George Herbert Hitchings was born on April 18, 1905 in Hoquiam, Washington, the son of George Herbert Hitchings, shipbuilder and Lilian Matthews Hitchings. Although not well educated, his parents were avid readers and their thirst for knowledge was passed on to him. Hitching's father died when he was only twelve. Due to his family's wanderings Hitchings attended grade school Berkeley and San Diego, California and Bellingham, Washington. He completed his secondary education in Seattle, Washington, where he was class salutatorian.

In 1923 he entered the University of Washington and initially intending to be a pre-medical student, however the enthusiasm of the students and faculty of the chemistry department shifted his course to become a chemistry student. He finished his B.S. in 1927 and is M.S. in 1928. He then went to Harvard University, where he was assigned to work with Cyrus Fiske, whose group was studying analytical methods for studying purines and had detected and isolated adenosine triphosphate (for a brief review of purine chemistry see here). Hitchings finished his Ph.D. in 1933 and for the next nine years served in a variety of temporary positions including doing cancer research at the C. P. Huntington Laboratories at Harvard, doing nutrition research at the Harvard School of Public Health, and doing electrolyte research at Western Reserve University Medical School.

In 1942 Hitchings joined Burroughs Wellcome Research Laboratories (now GlaxoSmithKline), in Tuckahoe, New York as the head and sole member of the biochemistry department. At first his resources were limited and this allowed him to be free to develop his own methods of inquiry. In 1944 he hired Gertrude Elion as a laboratory assistant, beginning a life-long collaboration in drug research. They began investigating the way that purines and pyrimidines are synthesized and metabolized by human cells, bacteria and viruses. Inspired by the recent development of sulfa drugs, they began investigating other substances that could inhibit microbial growth by mimicking these nitrogen containing bases. Their research indicated that bacteria could not synthesize nucleic acids without the presence of certain purines in their growth media and this led them to investigate substances that would inhibit the incorporation of purines into their DNA.

DNA (and RNA) is made up of three components: nitrogen containing bases, deoxyribose (a five carbon sugar missing an oxygen on carbon 2, that in RNA is replaced by ribose) and phosphate. There are two different types of nitrogen containing bases which make up the part of the DNA that carries the information used to synthesize proteins: purines, which have a bicyclic structure composed of a six membered ring fused to a five membered ring, and pyrimidines which contain a six membered ring. adenine and guanine are the purines, and cytosine and thiamine are the pyrimidines that are found in DNA. The focus of Hitchings' research was to find a chemical analog of one of these bases which would inhibit the microbial enzymes which were responsible for synthesizing it's DNA. These nitrogen containing base analogs can also be used to inhibit the growth of cancer cells, which require them for their rapid growth.

In 1947 Hitchings began to receive financial assistance from the Sloan-Kettering Institute in exchange for providing compounds to be used in cancer treatment. Among the compounds that they developed for the treatment of cancer are diaminopurine, thioguanine and 6-mercaptopurine, which have all been used in the treatment of leukemia due to their ability to block the synthesis of DNA in white blood cells. They also developed azathioprine, a less toxic form of 6-mercaptopurine, which can be used to block the immune reaction after organ transplants and allopurinol, a drug used to treat gout by blocking the synthesis of uric acid, an end product of purine metabolism. Hitchings and Elion also developed zidovudine, which led directly to the development of AZT, one of the first drugs used to treat A.I.D.S.

In 1967 Hitchings became the vice president of research for Burroughs Wellcome and he retired and became a scientist emeritus in 1976. In 1968 he became director and in 1971 president of the Burroughs Wellcome Fund, a charitable foundation dedicated to funding medical research. He also served as director and vice president of The United Way and director and chairman of the American Red Cross. In 1988 he and Gertrude Elion (along with Sir James Black) were awarded the Nobel Prize for Physiology or Medicine. Other honors he received include the Gregor Mendel Medal from the Czechoslovakian Academy of Science in 1968 and the Albert Schweitzer International Prize for Medicine in 1989. He was awarded 11 honorary degrees and was made a member of the National Academy of Science.

Hitchings died on February 27, 1998.

References:

Harvey, Robert C.; "Hitchings, George H." in American National Biography: Supplement 2 (American National Biography Supplement)
; Mark C. Carnes, Editor; Oxford University Press, 2005

Hitchings, George H., Nobel Prize Autobiography at nobelprize.org

Kresge, Nicole, Simoni, Robert D., and Hill, Robert L.; "The Rational Design of Nucleic Acid Inhibitors to Treat Leukemia: The Work of George H. Hitchings"; The Journal of Biological Chemistry (2008) 283: e10

Norman George Heatley

Norman Heatley was born on January, 10 1911 in Woodbridge, Suffolk, his parents' only surviving child. His father, Thomas, was a veterinarian and he would often travel with his father to the surrounding farms. From his father he inherited the ability to work on a small scale. In an era of train travel, when everybody traveling carried with them a basket with things for tea and breakage was unavoidable, the ability to repair broken crockery was a useful skill.

At age seven he was sent to boarding school at St. Felix School, near Ipswitch, which he later called, "The nearest thing to Lord of the Flies I had ever heard of." The next year he was enrolled at Westbourne House, a boarding school in Folkstone. It was there that each week an elderly man came to the school and gave Heatley and the other students a lesson on practical science. It was these "re-letter lessons of the week" which sparked Heatley's interest in science.

In 1929 he entered St. John's College, Cambridge graduating in 1933 with a degree in natural science. He stayed on at Cambridge to earn a Ph.D. in biochemistry at the Dunn Institute of Biochemistry, completing his dissertation on "The Application of Microchemical Methods to Biological Problems". After graduating Heatley intended to set up an analytical service but after interviewing with Howard Florey he got a temporary job doing microchemical analysis at Oxford.

Florey's group was investigating antimicrobial substances and Ernst Chain, one of Florey's workers, had found paper by Alexander Fleming about the antibacterial properties of a mold called Penicillium Notatum. Chain's role was to find the structure of the antibacterial compound while Florey would determine its effects. While it soon became clear that this new substance was more effective in killing bacteria than anything currently available, the group was hindered by the fact that there was no test to determine the activity of the new compound and the currently used methods of extracting interesting compounds from the growth medium did not work on it. Heatley was able to solve both of these problems, devising a new unit for activity, called "Oxford units", and a two step extraction process.

By May 1940 the group was convinced that they had an important new antibacterial drug on their hands, with Heatley playing a key role in the experiment that had proved its worth. Heatley had injected 8 mice with virulent bacteria, four of which also received an injection of penicillin a hour later. Overnight he watched as the four mice without the penicillin injection die and while the other four, with penicillin injections, survived. Now the problem was to be able to produce enough penicillin for the much larger human system.

Due to the war British Pharmaceutical companies were unwilling to expend effort on a project involving an unproven drug and Florey and his team were forced to carry the project out on their own. The first thought to scale up their production using glass cultureware. It was quickly discovered that this would be prohibitively expensive and the group was forced to use cheaper ceramic cultureware designed by Heatley. The process, developed by Heatley, produced a white powder that was only about 1% penicillin, but was effective in fighting bacterial infections in humans.

Because it was war time and the threat of a German invasion was real, the group had to be prepared to destroy all its work, lest it fall into enemy hands. To ensure that all would not be lost Florey and his group seeded their lab coats with Penicillium spores, which were stable for years and could be used to regenerate their work.

On June 26, 1941 Florey and Heatley, took a blacked out Pan-Am Clipper seaplane bound for New York. The Rockefeller Foundation, which had funded Florey's group, urged Florey to come to America in order to find firms that would be interested in production of the new antibacterial drug. Unable to get any drug companies to continue his research Florey soon returned to England. Heatley stayed on, working at the Northern Regional Research Laboratory in Peoria, Illinois were he was assigned to work with A.J. Moyer. Heatley soon found that Moyer was carrying out his own research, not telling him what he was doing. Later Moyer used his solo research to apply for a patent on the new drug. The English would be forced to pay royalties for the use of penicillin, which they had discovered.

Heatley returned to Britain in July 1942. He went back to Oxford where he continued his work on penicillin until 1943. In 1945 Fleming, Florey and Chain were awarded the Nobel Prize for Medicine for the discovery of Penicillin. Heatley was awarded an Honorary Doctorate in Medicine from Oxford in 1990, the first given in its 800 year history. The Heatley Medal and Prize, given by the Biochemical Society, is awarded "for exceptional work that makes biochemistry widely accessible and usable, and for achievements that enable widespread progress and understanding."

Norman Heatley died on January 5, 2004.

References:

"Making Penicillin Possible: Norman Heatley Remembers" at sciencewatch.org

Evans, Ruth; "Norman Heatley"; The Guardian; Jan, 8 2004

Lax, Eric; The Mold in Dr. Florey's Coat: The Story of the Penicillin Miracle; Holt Paperbacks; 2004

O'Conner, Anahad; "Dr. Norman Heatley, Pioneer of Penicillin Supply, Dies"; New York Times; January 17, 2004

Nobel Prize in Medicine 1945 at nobelprize.org

The Heatley Prize at biochemistry.org