Writer’s Digest 93rd Annual Competition Nonfiction Essay or Article First Place Winner: “Rational Drug Design”

Congratulations to Leonardo Chung, first-place winner in the Nonfiction Essay or Article category of the 93^rd Annual Writer's Digest Writing Competition. Here's his winning article, "Rational Drug Design: Gertrude Elion and Her Medicines That Changed the World."

by Leonardo Chung

“It's amazing how much you can accomplish when you don't care who gets the credit.”¹

- Gertrude Elion

Faced with financial hardships, gender discrimination, and difficulties many first-generation immigrant families experienced in the early 20th century, one persevering scientist overcame these obstacles and co-created a pioneering method of inventing new medicines, better known as rational drug design. This method of creating the next generation of medications would go on to save millions of lives. This scientist is the Nobel Prize-winning Gertrude B. Elion, who, despite all of the challenges she faced, advanced the pharmaceutical industry and pioneered a new medical frontier. After receiving her Masters in Science, Elion tried many times to pursue a Ph.D. To her surprise, she was rejected from 15 schools due to her financial situation and gender. However, because of the severe labor shortages caused by World War II and the lack of males to fill scientific job openings, Elion gratefully accepted a position as a laboratory assistant in New York. With the help of her mentor and fellow scientist George Hitchings, Elion would become one of the most influential women in science of her generation. This is the story of her critical role in establishing the frontier of rational drug design.

Elion’s Early Life

Gertrude Elion was born to immigrant parents Bertha Cohen (from Poland) and Robert Elion (from Lithuania) in the bustling metropolis of New York City on the 23rd of January, 1918. Elion’s brilliance was clearly visible in her early childhood as she devoured book after book and earned outstanding grades in school.² As Elion entered her teens, the Wall Street Crash of 1929 struck the US, essentially erasing her family’s life savings.³ Adding to the family’s misery, Elion’s grandfather was diagnosed with and eventually succumbed to stomach cancer in 1933.⁴ Despite the emotional pains of her grandfather’s death, she graduated early from Walton High School at age 15. Her grandfather's death guided her toward a career in the study of medicines and their biological responses within the human body.^{5, 6}

Elion stated in 1997:

“I watched him go over a period of months in a very painful way, and it suddenly occurred to me that what I really needed to do was to become a scientist, and particularly a chemist, so that I would go out there and make a cure for cancer.”⁷

Gendered Educational Inequalities of the Twentieth Century

Through an educational bursary, Elion was able to subsequently attend and graduate summa cum laude from Hunter College in New York City, earning a Bachelor of Science in Chemistry in 1937. After completing her degree, however, Elion became aware that it was unusual for women to pursue a scientific education at that time⁸ and, as a result, her job prospects were poor.⁹

“I thought there was no reason that someone wouldn’t let me try… but wherever I went, there weren’t many jobs to begin with, and what they were, they couldn’t see any reason to take a woman. They would interview me for long periods of time, but then they would say, ‘Well, we think you’d be a distracting influence in the laboratory.’”¹⁰

Frustrated by the lack of options available to her, Elion enrolled in a secretarial school, one of the few career paths that was open to young women in the 1940s,¹¹ while she searched for a Ph.D. program that would accept her.¹² However, after completing six weeks of secretarial classes, Elion dropped out because the classes did not align with her interests and were unrelated to her particular academic expertise. She instead decided to teach biochemistry to nurses at the New York Hospital School of Nursing.¹³

After working as a teacher for three months, Elion was able to secure a job as an unpaid scientific assistant with chemist Alexander Galat, eventually being hired on as a full-time employee.¹⁴ Earning a comfortable weekly salary of 20 dollars, Elion saved up enough money to pursue a Master’s degree at New York University (NYU).¹⁵ While attending NYU, she taught chemistry and physics to high school students to finance her studies. At the university, Elion met Leonard Carter, who became her fiancé. Tragically, Carter passed away from bacterial endocarditis shortly before Elion's graduation, causing her immense grief. In the aftermath of his death, Elion reaffirmed her commitment to her life's goal in medicine.

“It reinforced in my mind the importance of scientific discovery, that it really was a matter of life and death to find treatments for diseases that hadn't been cured before.”¹⁶

In 1941, Elion received her Master of Science degree from NYU. Eager to continue her studies and pursue a doctoral degree, she applied to 15 graduate schools but was rejected by all of them. During this time, women in the scientific field were often discouraged and discriminated against, and Elion believed that this was the reason for her rejection from all of the institutions she applied to.¹⁷

“I almost fell apart. That was the first time that I thought being a woman was a real disadvantage. It surprises me to this day that I didn’t get angry."¹⁸

During World War II, many men were drafted into military service, which created numerous job openings in the United States—particularly in the field of science. Elion took on a role as a food analyst for The Great Atlantic & Pacific Tea Company, where she was responsible for analyzing the acidity of pickles and the color of mayonnaise for the company's grocery stores.¹⁹ Although the job was unconventional, Elion gained valuable instrumentation skills while working at the food research facility.²⁰ She later secured a research position at a new laboratory in Johnson & Johnson, which was focused on developing a new method of drug manufacturing. However, after a change in administration, this project was abandoned, and Elion left the company as she did not see any further opportunities for growth within her areas of interest.²¹

In 1944, Elion was contacted by a job agency desperately seeking chemists, inquiring if she was interested in conducting medical research:

“Interested? Of course I was still interested! It was all I ever wanted to do. It wasn’t until men went to war though, that they finally found they needed me! War changed everything. Whatever reservations there were about employing women in laboratories simply evaporated."²²

Shortly thereafter, she was recruited by pharmaceutical giant Burroughs-Wellcome to work as a laboratory assistant to George Hitchings.²³

Realizing a Dream

When Elion joined the Burroughs-Wellcome laboratory in Tuckahoe, New York, her work centered on the synthesis of new drugs.²⁴ At this laboratory, Elion became the pioneer of a process later labeled as rational drug design, which is the creation of new drugs designed by targeting specific molecules by understanding their chemical properties and interactions.²⁵

Meanwhile, inspired by her new career and recent discoveries, Elion reaffirmed her desire to pursue a Ph. D. degree. However, she realized that she would have to earn the degree while working at Burroughs-Wellcome to financially support her studies.²⁶ For two years, she commuted to Brooklyn Polytechnic Institute at night to take classes. However, she was informed by the dean that she would need to leave her job and study full-time in order to earn her degree. Elion decided that she could not leave her laboratory position and sadly stopped taking classes at the institute.²⁷

At Burroughs-Wellcome, Dr. Hitchings was studying nucleic acids, compounds that were not yet fully understood. Hitchings assigned the newly hired Elion the task of analyzing purines, which are the building blocks of DNA. Elion’s work focused on synthesizing imitation purines and manipulating them in order to affect the synthesis of amino acids, proteins, and ultimately a disease process.²⁸

People at the time, including some of Elion's peers, were skeptical of her work and considered it to be of little value. However, Elion persisted and focused on understanding the properties and pathways of purines.²⁹ She began designing chemotherapeutic drugs that interfered with the synthesis of DNA, known as antimetabolites. Elion also studied the role of nucleic acids in the proliferation of cancer cells, recognizing that these molecules were vulnerable to disruption.³⁰ Elion's approach was to create synthetic versions of purines that were similar enough to combine with natural purines, but that would inhibit the replication of cancer cells.³¹ Elion believed that “letting the drug lead [her] to the answer nature was trying to hide"³² was key to her success.

She discovered that the bacterium Lactobacillus casei, which grows on purines, also grew on her synthetic purines.³³ This enabled her to test purine, pyrimidine, and folic acid analogs for their ability to interfere with the growth of L. casei. Through this method, she realized that she could now control how and when this bacteria could be produced.^{34, 35} In 1948, Elion’s first cancer drugs were tested—unsuccessfully, as human bodies did not tolerate this false purine very well.³⁶ In particular, one patient, pseudonymized “JB,” appeared to be improving from the drug. Observing this, Elion considered it an early success. “JB” married and had a child, but passed away as the cancer relapsed.³⁷ Elion was deeply saddened by this, as she often developed personal relationships with her patients. Yet, Elion did not allow this experience to impede her research.

“Research is very hard work. There’s no other way, but how you handle setbacks can make a difference…you must never feel that you have failed. You can always come back to something later, when you have more knowledge or better equipment and try again."³⁸

A Pharmaceutical Frontier

In the early 1950s, Elion achieved her first breakthrough. She found that substituting an element in the amino acid guanine, also a purine, created a substance that prevented cancer cells from replicating.^{39, 40, 41} Elion’s new drug, named 6-mercaptopurine (6-MP), was tested on children with acute lymphoblastic leukemia (ALL), and astoundingly, 15 of 45 children were cured of the disease or showed significant improvement.⁴² In another study of 6-MP, of 67 children with leukemia, 30 had complete remission, and 16 others showed significant improvement.⁴³ In 1953, the Food and Drug Administration approved her new drug, branding it Puri-Nethol.⁴⁴ It became the first-ever drug to treat leukemia and continues to be an integral drug in the treatment of this disease. Presently, 6-MP is used to treat Crohn’s disease and ulcerative colitis, and also plays a pivotal role in organ transplantation.

The first human organ transplant was successfully completed in 1954.⁴⁵ However, at this time, organ transplants could only be conducted between related donors, as unrelated donors’ immune systems would act as though the organ’s antigens were different from theirs. Therefore, their bodies would reject the organ. During their investigative work with 6-MP, it was also found to lower the immune system’s responses in very particular ways. Elion and her colleagues gave the drug to Dr. Roy Calne, a young British transplant surgeon.⁴⁶ Utilizing this medication, he was successful in transplanting an allograft kidney in dogs. The initial success was tempered due to the side effects of 6-MP. Undaunted, Elion investigated azathioprine, an altered version of 6-MP that had less toxicity, and in 1959, once again collaborated with Dr. Calne.⁴⁷ He administered the drug to a dog that had received a kidney transplant from an unrelated dog—to find that the recipient did not reject the kidney. This was a monumental advancement in the field of transplantation, as this indicated that organ transplants could be conducted on unrelated persons.

In 1962, the first kidney transplant in humans between unrelated donors was performed.⁴⁸ This was successful only because of the immunosuppressive effects of azathioprine. Her investigative work with azathioprine revolutionized transplant surgery. Allograft organ transplantation has helped save thousands of lives, and azathioprine continues to be an indispensable drug in organ immunosuppression. Elion’s drug would also go on to be the drug required for patients who undergo liver, heart, and lung transplantations.⁴⁹

Tackling the Impossible

In the early to mid-1900s, it was thought that a virus never left its host after infection. There were no treatments for viral infections, and very little ongoing research. Antiviral medicines were considered impossible to create.⁵⁰

Elion made it her next objective to embrace this seemingly futile task. In 1974, Elion derived acyclovir from guanosine—a nucleoside related to guanine—that inhibited viral growth and acted as an antimetabolite.^{51, 52} She noticed that acyclovir mainly targeted cells that were infected with the herpes virus and did not attack healthy or uninfected cells. Four years later, Elion’s research team officially revealed the new drug to other scientists—as they had concealed this drug discovery for years to analyze it properly and publish findings in the esteemed journal, Proceedings of the National Academy of Sciences of the United States of America.⁵³ Acyclovir, the first-ever antiviral drug, is now widely used for treating oral herpes, genital herpes, shingles, and herpes simplex infections.⁵⁴

“[Acyclovir was] my final jewel. That such a thing was possible wasn’t even imagined up until then."⁵⁵

Her other major contributions using rational drug design include designing drugs to treat gout and parasitic and bacterial infections. Several examples include allopurinol, the main

therapy used worldwide for the treatment of gout; trimethoprim, a drug that interferes with bacterial DNA and is a critical antibiotic to treat various infections; and pyrimethamine, an antiparasitic used to treat parasitic infections such as malaria, toxoplasmosis, and pneumonia.

The Legacy of Rational Drug Design

The significance of Elion’s drug discoveries and method of drug design is monumental. They have influenced lives worldwide and have given life back to patients with previously terminal diseases.^{56, 57} Rational drug design continues to be the gold standard for drug discovery, as exemplified by the discovery of the landmark drug azidothymidine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS).⁵⁸ Other well known drugs recently discovered using this approach include sildenafil (Viagra), omeprazole (Prilosec), fluoxetine (Prozac), varenicline tartrate (Chantix), and celecoxib (Celebrex) just to mention a few. Elion’s drugs: 6-MP (leukemia), acyclovir (herpes), trimethoprim (bacterial infections), pyrimethamine (parasitic infections), and allopurinol (kidney stones and gout) are on the World Health Organization list of essential medicines.⁵⁹ For her lasting and distinguished contributions, she was awarded the Nobel Prize for Medicine in 1988.^{60, 61} She was the fifth woman bestowed this prestigious award and one of only a few without a Ph.D.⁶² Elion has been the recipient of many other lifetime achievement awards in science, most notably the US National Medal of Science and many honorary doctoral degrees.⁶³

Conclusion

Gertrude Elion made her mark on the world of medical science by pioneering the novel technique of rational drug design. This pharmacological frontier meant, for the first time ever, biochemists could design medicines based on the known biological properties of a substance rather than through trial and error. The process made it possible to design new drugs that targeted very specific diseases. From her immensely disadvantaged beginnings, as a woman of a low-income immigrant family seeking work at the highest levels of scientific research, she overcame financial obstacles and gender discrimination. Her steadfast scientific contributions, from curing widespread diseases to organ transplantation, will always be remembered.

¹ “Gertrude Elion.” Jewish Women’s Archive, jwa.org/womenofvalor/elion. Accessed 5 Feb. 2023.

² Creston Junior High School. “Report of Elion, Gertrude.” Department of Education - the City of New York, Jewish Women’s Archive, 1930, jwa.org/media/gertrude-elions-junior-high-report-card. Accessed 29 Dec. 2022.

³ Gertrude B. Elion – Biographical. NobelPrize.org. Nobel Prize Outreach AB 2022. Thu. 29 Dec 2022. https://www.nobelprize.org/prizes/medicine/1988/elion/biographical/

⁴ “Gertrude Elion (1918–1999).” American Chemical Society, www.acs.org/education/whatischemistry/women-scientists/gertrude-elion.html. Accessed 29 Dec. 2022.

⁵ “Gertrude Elion.” Lemelson-MIT, lemelson.mit.edu/award-winners/gertrude-elion. Accessed 29 Dec. 2022.

⁶ Elion, Gertrude. Letter to Rani Shankar. 21 Sept. 1989. Nobel Prize.

⁷ Avery, Mary Ellen. Biographical Memoirs. Washington, D.C., National Academies Press, 13 Nov. 2000, www.nap.edu/read/9977/chapter/14. Accessed 25 Feb. 2023

⁸ "Women, Impact of the Great Depression On". Encyclopedia of the Great Depression. Encyclopedia.com. 20 Dec. 2022. www.encyclopedia.com. https://www.encyclopedia.com/economics/encyclopedias-almanacs-transcripts-and-maps/women-impact-great-depression

⁹ American Chemical Society.

¹⁰ Elion, Gertrude. Interview. Conducted by Academy of Achievement. https://www.youtube.com/watch?v=kamweFBx0iU. 18 Nov 2016.

¹¹ Lewis, Jone Johnson. “The 1930s: Women’s Shifting Rights and Roles in United States.” ThoughtCo, 29 Jan. 2020, www.thoughtco.com/womens-rights-1930s-4141164. Accessed 29 Dec. 2022.

¹² Ibid.

¹³ Elion, Gertrude B. “The Quest for a Cure.” Annual Review of Pharmacology and Toxicology.

¹⁴ Ibid.

¹⁵ Koenig, Rick. “The Legacy of Great Science: The Work of Nobel Laureate Gertrude Elion Lives On.” The Oncologist, vol. 11, no. 9, 1 Oct. 2006, pp. 961–965, https://doi.org/10.1634/theoncologist.11-9-961.

¹⁶ “Gertrude Elion.” Jewish Women’s Archive.

¹⁷ Wasserman, Elga Ruth. The Door in the Dream: Conversations With Eminent Women in Science. Joseph Henry Press, 2000.

¹⁸ McGrayne, Sharon Bertsch. Nobel Prize Women in Science: Their Lives, Struggles, and Momentous Discoveries: Second Edition. Subsequent, Joseph Henry Press, 2001.

¹⁹ “Gertrude B. Elion.” Biography, 2 Apr. 2014, www.biography.com/scientist/gertrude-b-elion. Accessed 29 Dec. 2022.

²⁰ Elion, Gertrude. Interview. Conducted by Academy of Achievement.

²¹ Ibid.

²² Macbain-Stephens, Jennifer. Gertrude Elion: Nobel Prize Winner in Physiology and Medicine (Women Hall of Famers in Mathematics and Science). 1st ed., Rosen Pub Group, 2003.

²³ “Gertrude B. Elion, M.Sc.” Academy of Achievement, 16 Feb. 2022, achievement.org/achiever/gertrude-elion.

²⁴ “How Gertrude Elion Became a Pioneer of Modern Medicine.” PBS, www.pbs.org/video/how-gertrude-elion-became-pioneer-modern-medicine-uaapru. Accessed 29 Dec. 2022.

²⁵ Elion, Gertruade. Interview. Conducted by Charlie Rose. https://charlierose.com/videos/30741. 10 May 2020.

²⁶ Hitchings, George. Letter to Milan Logan. 17 Dec. 1951. Jewish Women’s Archive.

²⁷ Elion, Gertrude B. “The Quest for a Cure.”

²⁸ Hajdu, Steven I. “Pathfinders in Oncology from the First Clinical Use of Single Agent Chemotherapy to the Introduction of Mammography.” Cancer, vol. 127, no. 1, 23 Oct. 2020, pp. 12–26, https://doi.org/10.1002/cncr.33223. Accessed 14 Oct. 2021.

²⁹ Shader, Richard I. “A Tribute to Gertrude Belle Elion on the 100th Anniversary of Her Birth.” Clinical Therapeutics, vol. 40, no. 2, Feb. 2018, pp. 181–185, https://doi.org/10.1016/j.clinthera.2018.01.008. Accessed 26 Oct. 2021.

³⁰ Elion, Gertrude. Interview. Conducted by Lou Massa. https://www.youtube.com/watch?v=UMXxk7cx66k. 10 May 2020.

³¹ Nicholls, Mark. “George H. Hitchings and Gertrude B. Elion.” European Heart Journal, vol. 41, no. 47, 2020, pp. 4453–4455., https://doi.org/10.1093/eurheartj/ehaa124.

³² McGrayne, Sharon Bertsch.

³³ Kent, Richard, and Brian Huber. “Gertrude Belle Elion (1918-99).” Nature, vol. 398, no. 6726, Apr. 1999, pp. 380–380, https://doi.org/10.1038/18790. Accessed 12 May 2020.

³⁴ Balis, M. Earl et al. “On the interconversion of purines by Lactobacillus casei.” The Journal of Biological Chemistry vol. 188, 1 (1951): 217-9.

³⁵ Elion, Gertrude B., and George H. Hitchings. “Antagonist of nucleic acid derivatives. III. The specificity of the purine requirement of Lactobacillus casei.” The Journal of Biological Chemistry vol. 185,2 (1950): 651-5.

³⁶ Whitlock, Catherine, and Rhodri Evans. Ten Women Who Changed Science and the World: Marie Curie, Rita Levi-Montalcini, Chien-Shiung Wu, Virginia Apgar, and More (Trailblazers, Pioneers, and Revolutionaries). Diversion Books, 2021.

³⁷ Ibid.

³⁸ Elion, Gertrude. Interview. Conducted by Academy of Achievement.

³⁹ Elion, Gertrude B. et al. “The purine metabolism of a 6-mercaptopurine-resistant Lactobacillus casei.” The Journal of Biological Chemistry vol. 204, 1 (1953): 35-41.

⁴⁰ Balis, M. Earl et al. “The effects of 6-mercaptopurine on Lactobacillus casei.” Archives of Biochemistry and Biophysics vol. 71,2 (1957): 358-66. doi:10.1016/0003-9861(57)90046-2

⁴¹ Skipper, Howard E et al. “Observations on the anticancer activity of 6-mercaptopurine.” Cancer Research vol. 14,4 (1954): 294-8.

⁴² Burchenal, J. H., et al. “Clinical Evaluation of a New Antimetabolite, 6-Mercaptopurine, in the Treatment of Leukemia and Allied Diseases.” Blood, vol. 8, no. 11, American Society of Hematology, Nov. 1953, pp. 965–99. https://doi.org/10.1182/blood.v8.11.965.965.

⁴³ Heyn, Ruth M., et al. “The Comparison of 6-Mercaptopurine With the Combination of 6-Mercaptopurine and Azaserine in the Treatment of Acute Leukemia in Children: Results of a Cooperative Study.” Blood, vol. 15, no. 3, American Society of Hematology, Mar. 1960, pp. 350–59. https://doi.org/10.1182/blood.v15.3.350.350.

⁴⁴ Elion, Gertrude B. “The Quest for a Cure.”

⁴⁵ Barker, Clyde F., and James F. Markmann. Historical overview of transplantation. Cold Spring Harb Perspect Med. 2013 Apr 1;3(4):a014977. doi: 10.1101/cshperspect.a014977. PMID: 23545575; PMCID: PMC3684003.

⁴⁶ Ibid.

⁴⁷ Elion, Gertrude B. Significance of azathioprine metabolites. Proceedings of the Royal Society of Medicine. 1972 Mar; 65(3):257-60. PMID: 5083313; PMCID: PMC1644003.

⁴⁸ Hatzinger, Martin, et al. “Die Geschichte der Nierentransplantation” [The history of kidney transplantation]. Der Urologe. Ausg. A vol. 55,10 7(2016): 1353-1359. doi:10.1007/s00120-016-0205-3

⁴⁹ Cohn, Sharyn. Letter to Gertrude Elion. 3 Mar. 1998. Jewish Women's Archive.

⁵⁰ “The Legacy of Gertrude Elion: Inventor of Medicines.” YouTube, uploaded by Burroughs Wellcome Fund, 10 Aug. 2020, www.youtube.com/watch?v=qqza99M1b3s.

⁵¹ “How Gertrude Elion Became a Pioneer of Modern Medicine.” PBS.

⁵² Elion, Gertrude B. “An overview of the role of nucleosides in chemotherapy.” Advances in Enzyme Regulation vol. 24 (1985): 323-34. doi:10.1016/0065-2571(85)90084-6

⁵³ Elion, Gertrude. Interview. Conducted by Academy of Achievement.

⁵⁴ Adams, Patrick. “Meet the Woman Who Gave the World Antiviral Drugs.” National Geographic, 4 May 2021, www.nationalgeographic.com/science/article/gertrude-elion-antivirals-coronavirus-remdesivir.

⁵⁵ Whitlock, Catherine, and Rhodri Evans.

⁵⁶ Pack, Ted. Letter to Gertrude Elion. 11 Aug. 1996. Jewish Women’s Archive.

⁵⁷ Elion, Gertrude. Letter to Ted Pack. 20 Aug. 1996. Jewish Women’s Archive.

⁵⁸ Crouwel, Femke, et al. “The Thiopurine Tale: An Unexpected Journey.” Journal of Crohn’s and Colitis, vol. 16, no. 7, 12 Jan. 2022, pp. 1177–1183, https://doi.org/10.1093/ecco-jcc/jjac004. Accessed 10 Feb. 2023.

⁵⁹ Ibid.

⁶⁰ Scanpix Scandinavia. “Gertrude Elion and Other Recipients at the Nobel Prize Ceremony, 1988.” Jewish Women’s Archive, 1988, jwa.org/media/gertrude-elion-with-other-recipients-at-nobel-prize-awards-ceremony.

⁶¹ Gertrude B. Elion – Biographical. NobelPrize.org.

⁶² “Gertrude B. Elion, M.Sc.” Academy of Achievement.

⁶³ Larsen, Kristine. “Gertrude Elion.” Jewish Women’s Archive - Shalvi/Hyman Encyclopedia of Jewish Women, 31 Dec. 1999, jwa.org/encyclopedia/article/elion-gertrude-belle. Accessed 29 Dec. 2022.

Scanpix Scandinavia. “Gertrude Elion and Other Recipients at the Nobel Prize Ceremony, 1988.” Jewish Women’s Archive, 1988, jwa.org/media/gertrude-elion-with-other-recipients-at-nobel-prize-awards-ceremony.

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