1988 Nobel Prize in Physiology or Medicine: Black, Elion, and Hitchings, Pioneers of Rational Drug Design

What You Will Learn in This Article

You will understand how the shift occurred from the era of discovering drugs by chance to the era of precisely designing drugs by targeting specific mechanisms. James Black, born in a Scottish mining village, developed beta-blockers (propranolol) and H2-receptor antagonists (cimetidine). Gertrude Elion, born into a New York immigrant family, and George Hitchings, a Harvard doctoral graduate, developed 6-MP, acyclovir, allopurinol, and azathioprine at the Wellcome Research Laboratories. Together, we will explore how these individuals created standard treatments for today's conditions such as hypertension, angina, peptic ulcers, leukemia, herpes, gout, and organ transplantation, and how a young girl, who witnessed her grandfather's death from cancer at the age of 15, dedicated her life to developing new drugs.

A Different Perspective: Drugs Should Be Designed, Not Discovered by Chance

Until the mid-20th century, the standard method for developing new drugs was chance and mass screening. Penicillin was discovered by chance (1928), and various antibiotics were randomly screened from fungi and soil microorganisms. Most sedatives, anesthetics, and antihistamines were used by observing their effects without knowing the specific targets.

The limitations of this approach were clear: significant side effects, unclear mechanisms of action, and difficulty in improving the drugs due to a lack of knowledge about the targets. Finding new drugs required testing thousands or even tens of thousands of compounds.

The three Nobel laureates in 1988 pioneered a completely different approach. They focused on first defining the target and then designing compounds that act precisely on that target – rational drug design. The following three examples are representative:

Black's Beta-Blockers: Beta-adrenergic receptors in heart muscle cells increase heart rate and myocardial contractility when epinephrine and norepinephrine bind. This is a problem in angina patients, where the heart's oxygen demand becomes excessively high. Black designed compounds that block these receptors – the result is propranolol (1964). This reduces the heart's oxygen demand and alleviates angina.

Black's H2-Receptor Antagonists: Histamine H2 receptors in parietal cells of the stomach are stimulated, which causes the secretion of gastric acid. This is a problem for patients with peptic ulcers who have excessive gastric acid. Black designed compounds that specifically block H2 receptors – cimetidine (1976). This revolutionized the treatment of peptic ulcers.

Elion and Hitchings' Metabolic Analogue Approach: They targeted the nucleotide metabolic pathways necessary for DNA synthesis in pathogens such as cancer cells, viruses, and parasites. They created compounds that are similar to normal metabolites but slightly different, deceiving the pathogen's metabolic enzymes. 6-mercaptopurine (6-MP, 1953), azathioprine (1961), allopurinol (1966), and acyclovir (1978) are all the results of this metabolic analogue approach.

In the language of computer science, this is a precise application of API target interception. Cells have various receptors and enzymes as API endpoints, and each endpoint only recognizes specific ligands (parameters). Rational drug design is about understanding the recognition specifications of the target endpoint and then designing an adapter function (drug molecule) that fits those specifications. Some adapters activate the endpoint (agonists), while others block it (antagonists).

The power of this approach lies in its potential for improvement. After propranolol, atenolol (1976) and metoprolol (1975), which have stronger beta-1 selectivity, were sequentially developed. Following cimetidine, more potent H2 antagonists such as ranitidine (1981) and famotidine (1985) were developed. Knowing the target allows for refactoring.

The Zeitgeist: The Seoul Olympics and the Prelude to the End of the Cold War

1988 was a year of redefining Korea's national status in modern Korean history.

The Seoul Olympics were held from September 17 to October 2, with participation from both the Eastern and Western blocs for the first time in 12 years. Korea ranked 4th overall, establishing itself as a successful developing country on the international stage. The image of the boy carrying the Olympic torch at the opening ceremony and the scene of people holding hands at the closing ceremony remain iconic images of the era. The successful operation of the Games was a decisive event that marked Korea's entry into the international community as a mature nation.

On February 25, Roh Tae-woo was inaugurated as president, elected through direct elections, which was the result of the June 1987 uprising. On September 1, the Constitutional Court was established, a new pillar of the rule of law. In December, a decision was made to revive local autonomy, and local councils were revived after 30 years.

In international politics, the Iran-Iraq War ended on August 20, ending an 8-year war that claimed over one million lives. The Soviet Union began withdrawing from Afghanistan in May, a prelude to the end of the Cold War. In November, George H.W. Bush was elected President of the United States, succeeding the Reagan era. On December 21, Pan Am Flight 103 was bombed over Lockerbie, killing 270 passengers, crew, and people on the ground. This marked a new phase of international terrorism.

Culturally, Stephen Hawking's "A Brief History of Time" became a worldwide bestseller, and Michael Jackson's Bad World Tour continued. Apple released the Macintosh IIx, and the landscape of personal computing continued to expand.

In this year of Korea's rapid rise in national status, the Nobel Committee recognized the three individuals who pioneered the era of rational drug design. In the year that Korea entered the world stage as a mature nation, the turning point that allowed humanity to design drugs instead of discovering them by chance was recognized.

Sir James Black: The Scottish Boy and His Beta-Blockers

Sir James W. Black (1924-2010) was a British pharmacologist. Born in 1924 in a Scottish mining village, he grew up surrounded by nature. In middle school, he dreamed of becoming a musician, and in high school, he was passionate about mathematics. He later recalled that the harsh life in the mining village gave him a strong will, and music nurtured his creativity.

He received his Ph.D. in Medicine from the University of St Andrews in 1946 and accumulated experience as a lecturer and researcher. In 1958, he joined the pharmaceutical company Imperial Chemical Industries (ICI). Here, he achieved his first success with pronethalol (1962), the first beta-blocker. Subsequently, propranolol (1964) became the standard treatment for angina, arrhythmias, and hypertension and was added to the world's prescription list.

In 1963, he moved to Smith Kline & French and challenged the problem of peptic ulcers. He targeted histamine H2 receptors, which regulate gastric acid secretion, and developed cimetidine (first marketed in 1976, brand name Tagamet). This was once the world's best-selling drug and marked a turning point in the treatment of peptic ulcers, shifting it from surgery to medication.

He was Professor of Pharmacology at University College London from 1973 to 1977 and Head of the Therapeutic Research Department at the Wellcome Research Institute from 1977 to 1984, and Professor of Medicine at King's College London from 1984 to 1993. He continued his research in both academia and industry. He was knighted in 1981.

Black's approach was clear: first define the physiological target (receptor), understand the chemical recognition pattern of that target, and then design compounds that bind to the target but do not transmit a signal. This approach became the standard for developing many new drugs.

Gertrude Elion: A Female Researcher Who Received the Nobel Prize Without a Degree

Gertrude B. Elion (1918-1999) was an American biochemist. Her life story is particularly impressive.

Born in New York in 1918 to a dentist father and a music-loving mother, she graduated from Hunter College in 1937 and received a master's degree from New York University in 1941. However, she does not have a regular Ph.D. In an era when it was extremely difficult for women to enter science graduate schools, her family went bankrupt in 1929 after her father's stock market investment failed, and she earned tuition money by working as a middle school teacher and studying at the State University of New York at night. It was almost impossible for a woman to get a job in a pharmaceutical company in that era.

She decided to dedicate her life to developing new drugs when she witnessed her grandfather die of cancer at the age of 15. This experience became her lifelong driving force.

From 1944 to 1984, she worked as a researcher at Burroughs Wellcome Research Institute in Tuckahoe, New York. She spent 40 years as a researcher in one institution. In 1983, she became a research professor at Duke University, but most of her academic achievements were made at the Wellcome Research Institute. She lived a lifelong single life, never marrying.

George Hitchings: Harvard Doctorate, Elion's Mentor and Colleague

George H. Hitchings (1905-1998) was an American pharmacologist. He received his Ph.D. from Harvard University in 1933 and worked as a lecturer at Harvard University (1933-1939). In 1942, he joined the Burroughs Wellcome Research Institute, where he continued his research until 1975.

Hitchings was 13 years older than Elion, and the two met at the Wellcome Research Institute, where they collaborated for over 40 years. Their relationship began with Hitchings hiring and mentoring Elion, but they eventually developed into equal partners.

Their approach was unique. At the time, mass screening was the mainstream method for drug development, but Hitchings and Elion adopted the approach of defining the target based on biochemical understanding and designing compounds that act on that target. They targeted enzymes in nucleic acid metabolic pathways and developed a strategy to attack pathogens (bacteria, viruses, cancer cells, and parasites) while sparing normal cells.

Decisive Discoveries: 40 New Drugs in 40 Years

The drugs that Black, Elion, and Hitchings created before receiving this award are now widely used in today's prescriptions.

Black's cardiovascular and gastrointestinal drugs:

• Propranolol (1964): The first successful beta-blocker. Used for angina, hypertension, arrhythmias, and migraine prevention. A standard in prescriptions for the elderly today.
• Cimetidine (1976): H2-receptor antagonist. Used for peptic ulcers and gastroesophageal reflux disease. Subsequently, proton pump inhibitors such as omeprazole were developed.

Elion and Hitchings' anti-cancer, anti-viral, and immunosuppressant drugs:

• 6-Mercaptopurine (6-MP, 1953): The first treatment for childhood acute leukemia. Inhibits purine metabolism, which is necessary for DNA synthesis. Dramatically improved survival rates for childhood leukemia.
• Azathioprine (1961): A 6-MP derivative, an immunosuppressant. Enabled the first successful non-twin kidney transplant in 1962. This marked the beginning of the era of organ transplantation.
• Allopurinol (1966): The standard treatment for gout. Inhibits uric acid production.
• Trimethoprim (1962): An antibacterial drug used to prevent bacterial infections in lung cancer.
• Acyclovir (1977): The first safe and effective antiviral drug. The standard treatment for herpes infections. This became the conceptual basis for the development of HIV drugs.
• AZT (zidovudine, 1987): Developed from the acyclovir lineage, the first treatment for HIV/AIDS. Although Elion had retired, this was the result of her legacy.

The impact of this list is overwhelming. A significant portion of the drugs frequently prescribed today are the result of the work of these three individuals.

CS Framework — Precision Adapter Functions and Metabolic Analogue Injection

Reconstructing rational drug design in the language of CS results in the following diagram:

Receptor = API Endpoint: Cell surface receptors are API endpoints that recognize only specific ligands. β1 receptors recognize epinephrine, and H2 receptors recognize histamine. Each endpoint has a defined recognition spec (three-dimensional binding site).

Agonist = Resource Activation Adapter: When a natural ligand binds, the receptor switches to an active state, triggering downstream signaling. When epinephrine binds to the β1 receptor, heart rate increases.

Antagonist = Resource Blocking Adapter: Beta-blockers bind to β1 receptors but do not transmit activation signals. They only bind and provide no signal. They occupy the binding site that a natural ligand would occupy, effectively blocking the signal.

H2 Blocker = Similar Blocking of Another API: Cimetidine blocks the H2 receptors in the parietal cells of the stomach, blocking the signal for gastric acid secretion.

Metabolic Analogue = Parameter Spoofing: 6-MP is a compound that is very similar to normal purine nucleotides but differs subtly. When a cell's DNA synthesis enzymes mistake 6-MP for a normal purine, they process it, causing DNA synthesis to fail and the cell to die. This is like an attack pattern that involves passing a forged parameter to an API to cause a function to fail.

Acyclovir = Targeting Only Specific Cells: Acyclovir is inactive in its original form but is activated when phosphorylated by the thymidine kinase (TK) enzyme of the herpes virus. Normal cells' TK does not recognize acyclovir. Only virus-infected cells generate active drugs, which then block viral DNA synthesis within those cells. This is the pinnacle of target precision.

Refactoring = Next-Generation Drugs: Propranolol → Atenolol, Metoprolol, Bisoprolol (increased β1 selectivity), Cimetidine → Ranitidine, Famotidine (enhanced efficacy), Acyclovir → Valacyclovir, Famciclovir (improved oral absorption). This is like iterative improvements, similar to v2 and v3 releases of an API client.

This analogy is not perfect. The actual action of drugs involves complex factors, including activity at multiple targets, metabolism, and tissue distribution. There are also common, specific side effects that cannot be explained by simple target blocking.

Academic Impact — The Standard for Target-Oriented New Drug Development

After the discoveries of these three individuals, the paradigm of new drug development has been completely changed.

Since the 1990s, a target-oriented approach has become the standard. New drug development projects generally follow a pipeline of target definition → target validation → compound screening → lead optimization → clinical trials. The method that was an exception in the era of Ellian and Black has become the standard today.

The Era of Targeted Anticancer Drugs: In 1998, trastuzumab (targets HER2), and in 2001, imatinib (targets BCR-ABL) — both are the pinnacle of a target-oriented approach. Ellian and Hitchings' metabolic analogue approach is the conceptual ancestor.

The Era of Antiviral Drugs: Acyclovir (1977) was the beginning, followed by HIV/AIDS drugs AZT (1987), lamivudine (1995), anti-hepatitis B drug entecavir (2005), anti-hepatitis C drug sofosbuvir (2013), and anti-COVID drugs molnupiravir (2021) and Paxlovid (2021) — all of which are in this lineage.

The Era of Organ Transplantation: After azathioprine (1961) enabled the first kidney transplant through immunosuppression, cyclosporine (1983) and tacrolimus (1994) were developed sequentially, and today, kidney, liver, heart, and lung transplants are standard treatments.

Computational Chemistry and Crystal Structure-Based Design: Since the 1990s, the approach of designing compounds using the crystal structure of a target protein has developed. Today, it is an essential tool in the early stages of new drug development.

The Legacy in Korea and Today

In Korea, the impact of this lineage is also evident. Since the 1990s, domestic pharmaceutical companies (Hanmi, Yuhan, Green Cross, Jonggeundang, etc.) have entered the field of target-oriented new drug development. Today, Korea is one of the world's top 8 pharmaceutical markets, and one of the reasons for this is the establishment of this standard in this era.

In clinical practice, acyclovir is a standard treatment for shingles and herpes, and its use is very active in Korea. Beta-blockers and H2-blockers are standard treatments for chronic cardiovascular and gastrointestinal diseases. 6-MP and azathioprine are the foundation of treatment for pediatric leukemia, autoimmune diseases, and inflammatory bowel diseases in Korea.

The background for the development of Hanmi Pharmaceutical's proprietary new drugs (Esomezol, Rosuvastatin, Rolontis, etc.) is the target-oriented approach established in this era. Domestic chemical and bio companies such as Amorepacific and LG Chem also follow this standard pipeline for new drug development.

Why is it Important?

What these three people left behind is the establishment that "drugs are designed based on an understanding of the target, not by chance."

This change in the methodology of drug development has determined the landscape of new drug development over the past 30 years. These three individuals are at the conceptual root of the world's pharmaceutical industry, which has grown to a market size of $1.5 trillion in annual sales today.

Ellian's life is a special symbol of women in science. She worked at the Wellcome Research Institute for 40 years without a formal doctorate and received the Nobel Prize. She is a case of someone who overcame the barriers of academic gender and received the highest recognition solely based on her achievements. After receiving the Nobel Prize, she often said in several interviews that "she was a 15-year-old girl who witnessed her grandfather die of cancer, and that experience led her to pursue new drug development." This is an archetypal narrative of personal loss transforming into an academic mission.

Black's narrative of a Scottish mining village is in the same vein. It is an achievement accomplished solely through hard work and talent, without resources or background. The fact that two of his inventions (propranolol and cimetidine) became the world's best-selling drugs is evidence of how powerful a methodology target-oriented new drug development is.

The flow of new drug development after this award continues as follows:

• 1990, Murad, Ignarro, and Furchgott (1998 Award) — Nitric oxide signaling, background for sildenafil (Viagra) development
• 1994, Gilman and Rodbell — G protein-coupled receptor signaling (more than 30% of all new drugs target GPCRs)
• 2001, Imatinib (Gleevec) — First successful targeted anticancer drug, chronic myeloid leukemia
• 2020, mRNA COVID vaccines — Pinnacle of target (spike protein) definition → design → deployment

The clinical establishment of these discoveries:

• Standard cardiovascular drugs: Propranolol, atenolol, bisoprolol, etc. (beta-blockers)
• Standard gastric acid regulators: Cimetidine, ranitidine, famotidine (H2-blockers), omeprazole, esomeprazole (PPIs)
• Standard for pediatric leukemia: 6-MP + methotrexate + vincristine + doxorubicin
• Standard for organ transplantation: Azathioprine, cyclosporine, tacrolimus
• Standard for viral infections: Acyclovir, valacyclovir (herpes), lamivudine, entecavir (hepatitis B)

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