George Herbert Hitchings (1905–1998)

George Herbert Hitchings researched and developed medications that targeted specific parts of DNA replication processes to treat cancers and various illnesses in the US during the twentieth century. By studying DNA analogs, or manmade substances that resemble the structure of naturally occurring DNA components and are capable of inhibiting DNA replication, Hitchings promoted a novel approach to pharmaceutical research and drug development, known as rational drug design. Using that novel approach, Hitchings and his research team created acyclovir, one of the first medications to effectively treat herpes, a condition that can be sexually transmitted but can also be passed from mother to child, causing life-threatening illness in infants. Hitchings also contributed to the development of cancer treatments, immunosuppressant medications, anti-viral medications, and anti-malarial medications. Hitchings’s research on DNA analogs established rational drug design as a method to create new pharmaceutical drugs, some of which treat sexually transmitted illnesses.

1. Early Life and Education
2. Early Professional Career
3. Later Professional Career
4. Legacy and Impact

Early Life and Education

Hitchings was born on 18 April 1905 in Hoquiam, Washington, to parents Lillian Matthews and George Herbert Hitchings Sr., and he had two older sisters. In a Nobel Prize autobiographical feature, Hitchings explains that his father died after a prolonged illness when Hitchings was twelve years old, and that event left a deep impression on him, leading to his interest in medicine. Hitchings graduated from Franklin High School in Seattle, Washington, in 1923. As salutatorian of his high school class, Hitchings delivered a speech about the life of Louis Pasteur, who studied microbiology and invented the pasteurization process, a method of milk and food preservation, as well as the rabies vaccine. In his Nobel Prize autobiographical feature, Hitchings explained that he aspired to achieve practical results through basic research methods, just as Pasteur did.

After high school, Hitchings continued his education, earning bachelor’s and master’s degrees from the University of Washington in Seattle, Washington. Hitchings began attending the University of Washington in 1923 as a pre-medical student, then he switched his major to chemistry at the end of his first year of college. In 1927, Hitchings graduated cum laude, meaning he graduated with honorific distinction for good grades, with his bachelor’s degree in chemistry. In 1928, he earned a master’s degree in chemistry also from the University of Washington.

After completing his bachelor’s and master’s degrees, Hitchings began a doctoral program in 1929 at Harvard Medical School in Boston, Massachusetts, in the Department of Biological Chemistry. During his time in the Department, Hitchings studied under the guidance of Cyrus H. Fiske, who researched the metabolic products of a type of nucleic acid called adenosine triphosphate, or ATP. ATP is a molecule that living organisms use to store the energy that fuels cellular functions, and metabolic products are the compounds that result when a biochemical reaction takes place in the body. Under the tutelage of Fiske, Hitchings studied various analytical methods that researchers could use to study the metabolic products of ATP. In his Nobel Laureate lecture, Hitchings noted that the research he did during his doctoral candidacy on the nucleotide ATP piqued a lifelong interest in nucleic acids such as DNA and RNA, which are composed of nucleotides. Nucleic acids serve as the genetic material that exists in all organisms including human beings and other animals, as well as viruses and bacteria. One fundamental component of nucleic acids is a nitrogenous base. Nitrogenous bases have two subcategories based on their molecular structure, purines, which are two ring structures, and pyrimidines, which are one ring structures.

In 1933, Hitchings earned a doctoral degree in biochemistry and married Beverly Reimer, with whom he would later have two children, Lamarie Ruth and Thomas Eldridge Hitchings. After earning his doctoral degree, Hitchings did not receive any permanent employment positions. In his Nobel Prize biography, Hitchings described the period of time after he earned his doctoral degree as a period of impermanence. During that time, the US fell into the Great Depression, a period of severe global economic downturn, and Hitchings held a variety of temporary academic positions until he entered the pharmaceutical industry.

Early Professional Career

In 1942, Hitchings began working at the Burroughs Wellcome and Co. branch called Wellcome Research Laboratories, in Tuckahoe, New York, where he continued to study nucleic acids as he had done during his doctoral program. Wellcome Research Laboratories was a pharmaceutical company that researched, manufactured, and sold medications in the late 1800s and 1900s. As of 2024, the company is called GlaxoSmithKline, or GSK. In the 1940s, Wellcome Research Laboratories employed researchers to create the novel pharmaceuticals the company eventually manufactured and sold. When Hitchings joined the laboratory, he was the head of the Biochemistry Department, a new department in the company, and he was the department’s only member. In that position, Hitchings’s research focused on developing medications containing nucleic acid analogs capable of inhibiting cancer growth, the replication of viruses, growth of bacteria, and other causes of disease.

By the early 1940s, other researchers in the field of biochemistry had only recently discovered nucleic acid analogs and their ability to inhibit growth and replication, and Hitchings used their findings to develop his own work. In 1940, Donald Devereux Woods and Paul Fildes, researchers who studied biochemistry in the UK, both published academic articles on the antimetabolite principle. The antimetabolite principle refers to the idea that some substances can prevent the normal functioning and replication of a cell, virus, bacteria, or even cancer by interfering with the metabolites necessary for their normal functions and replication. The antimetabolite substances can do that by competing with, replacing, or altogether stopping the required metabolite from initiating the metabolic process for replication in pathogens. Woods and Fildes identified that the chemical substances sulfanilamide and mercury interfered with the reproduction of bacteria. After investigating the mechanisms that allowed for that antibacterial behavior, they both suggested that researchers could create drugs to interfere with the specific substances essential to replication. When he began his career at Wellcome Research Laboratories, Hitchings set out to develop a drug that could inhibit the replication and growth of pathogens and cancer using the interference method that Woods and Fildes proposed.

In 1945, Hitchings and two of his colleagues published a paper in the academic journal Science on their findings regarding pyrimidines and the effect they had on the growth of the bacteria L. casei. In that paper, titled “The Effects of Pyrimidines on the Growth of Lactobacillus Casei,” Hitchings and colleagues explain that they conducted experiments to determine how L. casei grew when they replaced one of the bacteria’s necessary metabolites, folic acid, with analogs of either uracil or thymine, which are two pyrimidine nucleic acid bases. They found that replacing folic acid with certain analogs of thymine and uracil inhibited bacterial growth, while others had no effect. In their paper, Hitchings and his colleagues discuss the growth inhibiting properties of nucleic acid analogs, and they point out that researchers could use them in medications to halt pathogen replication and treat disease.

After the 1945 publication, Hitchings established new collaborations with institutes outside of Wellcome Research Laboratories, and he published numerous other papers on nucleic acid analogs and their replication-inhibiting properties. In 1947, as the head of the Biochemistry Department, Hitchings expanded the department by hiring new employees. That same year, Hitchings collaborated with the Sloan Kettering Institute, a cancer research institute in New York City, New York, to investigate various chemical compounds with anti-tumor properties. The Sloan Kettering Institute provided Hitchings with funding to support his lab’s research on possible cancer treatments. In conjunction with the Sloan Kettering Institute, Hitchings and his colleagues discovered two noteworthy compounds with anti-tumor properties, and they found that they could treat specific forms of cancer by using nucleic acid analogs to target the mechanism by which cancer spreads and causes illness. In 1948, Hitchings and his colleagues focused their research on another pyrimidine and its ability to inhibit the growth of L. casei, publishing a paper about their findings in the Journal of Biological Chemistry that same year. Hitchings went on to publish two more papers in 1950 and 1951 about that analog, which he and his team demonstrated has antimalarial properties.

In the 1950s, Hitchings and the researchers in his laboratory discovered a nucleic acid analog with anticancer properties and developed a drug, 6-MP, that doctors could use as a treatment for leukemia, which is a cancer of white blood cells. Cancer is the result of normal human cells becoming mutated and beginning to divide uncontrollably, invading and damaging other internal body structures. Thus, Hitchings and his colleagues developed a cancer treatment using nucleic acid analogs to interfere with the cancer cell division cycle. By the beginning of the decade, Hitchings and his research team had studied over 100 various nucleic acid analogs to search for growth and replication inhibiting properties that they could turn into medicine. In 1951, a member of Hitching’s lab, Gertrude Elion, who studied biochemistry and pharmacology, synthesized 6-MP, a purine analog that was found to be capable of inhibiting tumor growth, shrinking tumors, and extending the lives of rodents with leukemia. In clinical trials, one of Hitching’s colleagues from the Sloan Kettering Institute treated children with leukemia with 6-MP and found that a significant number of the children went into remission, and even for those whose cancer did not entirely go away, the treatment increased their survival time. In 1953, the FDA approved 6-MP as a treatment for leukemia in children.

In 1957, Hitchings and the members of his laboratory assisted other researchers in the development of an immunosuppressant medication for kidney transplants called azathioprine. When a person undergoes organ transplant surgery and receives an organ from another individual, the recipient’s body does not recognize the new organ as a part of its system. The differences in the makeup of the new organs alert the immune system. So, the recipient’s body perceives the donor organ as a foreign object and the immune system then attacks the donor organ. Such a reaction is called an immune response, during which the immune system generates antibodies, or proteins, that damage the new organ. Hitchings and colleagues developed azathioprine from 6-MP after recognizing its immunosuppressant properties during research studies in the late 1950s. In 1962, doctors began using azathioprine to prevent organ rejection in kidney transplant patients. Azathioprine works to prevent kidney transplant rejection by inhibiting the immune system’s ability to produce antibodies during an immune response. In 1969, Hitchings and Elion published a paper titled “The Role of Antimetabolites in Immunosuppression and Transplantation,” in which they explained azathioprine’s mechanism.

Later Professional Career

In the late 1960s and 1970s, Hitchings accepted various leadership roles within the Burroughs Wellcome Co. prior to retirement. Hitchings became Vice President in Charge of Research of Burroughs Wellcome Co. in 1967, and he held that position until retirement in 1976. In 1970, the company moved to Research Triangle Park, North Carolina. Shortly thereafter, in 1971, Hitchings became the President of the Burroughs Wellcome Fund, a non-profit organization that receives funding from Burroughs Wellcome Co. to advance underserved areas of biomedical research, including drug development and clinical pharmacology. In 1976, Hitchings retired from his vice president position, taking on the title Scientist Emeritus, an honorific bestowed on accomplished scientists who retire from their position in academia or industry.

Even after his official retirement, Hitchings continued giving lectures, conducting research, and publishing papers about nucleic acid analogs, and in 1977, he and his colleagues used the technology to develop acyclovir, which inhibits the replication of herpes viruses. Herpes simplex virus type 1 and herpes simplex virus type 2, or HSV-1 and HSV-2, are viruses that cause fluid-filled lesions on the mouth and genitals, respectively. Such lesions can be painful, especially those that erupt on the genitals. Both viruses can be transmitted through sexual activity or from mother to child during birth, and HSV-1 is commonly spread via casual contact such as sharing eating utensils or kissing. Prior to Hitchings and his colleagues’ creation of acyclovir, the scientific and medical community did not have effective treatments for oral and genital lesions caused by HSV-1 and HSV-2.

In 1977 and 1978, Elion and other researchers who remained at Wellcome Research Laboratory after Hitchings’s retirement published two additional papers on acyclovir. In 1977, Elion and colleagues published a paper in in the academic journal Proceedings of the National Academy of Sciences explaining the herpes-inhibiting behavior of acyclovir. In that paper, the researchers explain that the compound had the ability to stop HSV-1 from replicating with a high degree of specificity, which means that acyclovir stopped HSV-1 from replication without damaging the host cells. Just one year later, in 1978, the same group of researchers published a paper in the academic journal Nature detailing the results of their experiments they conducted on guinea pigs, in which they infected a group of guinea pigs with HSV-1 and then treated them with acyclovir. They found that when treated with a topical ointment formulation of acyclovir, the guinea pigs’ lesions healed quicker, and the drug was non-toxic at doses much higher than what was needed to treat lesions. After successful clinical trials in 1982, the FDA approved acyclovir for public use to treat lesions caused by HSV-1 and HSV-2. Hitchings’s theory about nucleic acid analogs provided the framework needed to create a highly effective medication capable of treating a viral disease without harming the person taking the medicine.

After the development and release of acyclovir, Hitchings pursued multiple philanthropic endeavors. In 1983, Hitchings founded the Greater Triangle Community Foundation, a charity dedicated to serving the needs of three cities in North Carolina, Raleigh, Durham, and Chapel Hill, which form a triangle on a map and, thus, are often referred to as the Triangle. As of 2024, according to the Greater Triangle Community Foundation website, the organization coordinates with private donors and nonprofit organizations to improve youth literacy, capacity building, environmental conservation, and art in the Triangle area community. Hitchings also continued to serve as a part of the Burroughs Wellcome Fund, explaining in his Nobel Prize biography that he focused the organization’s resources on assisting underfunded areas of medical research, pharmacology research, and innovative drug development. Hitchings’s wife died in 1985 of collagen disease, a general term that refers to an autoimmune condition in which the immune system attacks and damages the connective tissue. In February 1989, Hitchings got remarried to physician Joyce Shaver Hitchings.

Legacy and Impact

Hitchings was one of the first researchers to develop medications using rational drug design, meaning he designed entirely new molecules with specific molecular structures. The previously accepted form of drug development was trial and error, in which researchers sought out medicinal properties in substances that already existed and experimented with the naturally derived materials. Hitchings’s method of drug development allowed researchers to create medications with a high degree of specificity, making them incredibly effective and not as harmful to human cells, something that was not true of previous drugs. 6-MP provided evidence that Hitchings’s theory that nucleic acid analogs could specifically target and inhibit cancer was correct, which allowed researchers to use them to create effective medications.

As of 2024, physicians continue to use Hitchings’s method of rational drug design and his drug acyclovir. For example, physicians continue to use acyclovir as of 2024 to treat HSV-1 and HSV-2, which has helped prevent the spread of herpes from person to person, reduce the length of time that a herpes outbreak lasts, and prevent outbreaks from occurring in people who have contracted the virus. The drug is also included on the World Health Organization, or WHO, Model List of Essential Medicines. In 2016, WHO estimated that 3.7 billion people globally had HSV-1 and 491.5 million had HSV-2, and as of 2024, acyclovir is still one of few medications that can effectively treat herpes, providing relief to the many people experiencing outbreaks and preventing further transmission of the virus.

In 1988, Hitchings and Elion won the Nobel Prize in Physiology or Medicine for the creation of acyclovir. The two shared the Nobel Prize with Sir James Black, a pharmacology researcher and physician who developed propranolol, a medication that treats irregular heartbeats. In the years after receiving the Nobel Prize, in 1991 and 1992, Hitchings published two additional accounts of his career and research with nucleic acids. As of 2024, Hitchings published over 200 research papers, which have over 10,000 citations.

George Hitchings died on 27 February 1998 of Alzheimer’s disease in Chapel Hill, North Carolina.