2015 Nobel Prize in Physiology or Medicine – Campbell, Omura, and Tu Youyou: Saving Humanity from Parasitic Diseases and Malaria with Natural Compounds

What You'll Learn in This Article

The 2015 Nobel Prize in Physiology or Medicine was divided between two discoveries of novel drugs derived from natural sources that dramatically reduced the burden of infectious diseases in developing countries. Half of the prize was awarded to William Campbell, an Irish-born American researcher, and Satoshi Ōmura, a Japanese microbiologist, for their discovery of ivermectin, an effective treatment for river blindness and lymphatic filariasis, from soil bacteria. The other half was awarded to Tu Youyou of China, for her isolation of artemisinin, an active ingredient from sweet wormwood (Artemisia annua) found in traditional Chinese medicine literature, which revolutionized the treatment of malaria. Although these two discoveries originated in different national, cultural, and historical contexts, they share a common thread: novel drugs identified through screening of natural product libraries have reduced the burden of infectious diseases in developing countries and transformed the lives of hundreds of millions of people.

A Different Perspective on Common Knowledge: Nature Remains a Vast Chemical Library That Humanity Has Yet to Fully Explore

The common perception that "modern drugs are synthesized chemically" is a snapshot from the mid-20th century. In reality, a significant number of approved drugs in the early 21st century are derived from natural products or their derivatives. Most antibiotics come from compounds found in fungi or bacteria, and many anticancer drugs are derived from plants or marine organisms.

If we frame this in terms of computer science, nature is a code library compiled over billions of years of evolution. Each organism has evolved compounds to regulate other organisms for its own survival, and these compounds are often exquisitely tailored to specific targets. While it is difficult for humans to design new compounds synthetically, it is relatively easier to find useful codes in the library that nature has already compiled.

Ōmura's approach was a systematic pipeline for screening this library. He collected and cultured microorganisms from soil samples on a large scale, and then examined the biological activity of the metabolites produced by each microorganism. This is similar to performing a brute-force search on a curated dataset. Tu Youyou's approach started with a different database: thousands of years of traditional Chinese medical literature – a list of active candidates that humans have already accumulated through trial and error. She identified sweet wormwood as a candidate from this legacy document and isolated its active ingredient using modern methods.

The fact that both approaches, starting from different datasets, yielded the same result is the story of this award. Humanity has access to various sources of chemical knowledge, and each source is valid in its own way.

The Landscape of the Time: MERS and the Paris Attacks, a Difficult Year for Humanitarianism

In 2015, South Korea was shaken by the MERS (Middle East Respiratory Syndrome) outbreak from May to July. After the first confirmed case, hospital-acquired infections spread in large hospitals such as Samsung Seoul Hospital, resulting in 186 infections and 38 deaths. This event revealed several vulnerabilities in hospital infection control, information disclosure, and the national quarantine system, and subsequent efforts were made to fundamentally reform the infectious disease response system. The decision to raise the Sewol ferry in April was announced, and preparations were made for the salvage operation in time for the first anniversary of the disaster.

The world continued to be turbulent. In January, a terrorist attack on the Charlie Hebdo magazine office in Paris killed 12 people, sparking a major debate in Europe about Islamic extremism and freedom of expression. In November, simultaneous terrorist attacks in Paris, including at the Bataclan theater, killed 130 people, fundamentally reshaping the security landscape of Europe. In September, the photograph of Alan Kurdi, a Syrian refugee child, drowning in the Mediterranean Sea, shocked the world and intensified the debate over refugee policy in Europe.

On July 14, the Iran nuclear deal (JCPOA) was concluded, marking a new phase in relations between Iran and the international community. On December 12, the Paris Agreement (COP21) was adopted, with 195 countries agreeing to address climate change. This was one of the iconic moments of international cooperation in the 21st century.

In the world of technology, the Volkswagen diesel emissions scandal was revealed in September, shaking the credibility of the automotive industry. In the field of artificial intelligence, DeepMind's AlphaGo was preparing for its match against Lee Sedol, a top Go player, and the match was announced to take place in March 2016. This was the prelude to a period when public awareness of deep learning would soon explode.

The first successful clinical trial of a recombinant Ebola vaccine was announced in 2015. This vaccine, developed through international cooperation after the 2014 West African epidemic, would play a crucial role in preventing future infections.

In the scientific community, this award had several layers of symbolism. It was the first Nobel Prize in the natural sciences for a scientist from mainland China (Mo Yan won the Nobel Prize in Literature in 2012), and the fact that her research was conducted as part of a national project during the Cultural Revolution was re-examined. It was also a record as a case of two non-Western natural drugs being recognized together.

The Human Story: Three Continents, Three Trajectories, Two Effective Drugs

Satoshi Ōmura (1935–) was born in Nirazaki, Yamanashi Prefecture, Japan. He received his bachelor's degree from Yamanashi University and his Ph.D. in Pharmaceutical Sciences from the University of Tokyo. He then joined the Kitazato Institute in Tokyo (named after Kitazato Shibasaburo, the same scientist who was nominated for the Nobel Prize in 1901).

Ōmura's methodology was systematic and large-scale. He collected soil samples from all over Japan and isolated and cultured the microorganisms within them on a large scale. He established a pipeline to examine the metabolites produced by each microorganism and their biological activity. In particular, the Streptomyces genus of actinomycetes was known as a rich source of antibiotics, antifungal agents, and antiparasitic agents, and Ōmura's laboratory came to possess one of the world's largest collections of Streptomyces.

Around 1974, Ōmura's team isolated a unique Streptomyces strain from a soil sample collected near a golf course in Ito, Shizuoka Prefecture. This was Streptomyces avermitilis – the strain that would later become the source of ivermectin. Ōmura shared this strain and its metabolites with the research team at the American pharmaceutical company Merck, and the next chapter begins there.

William Campbell (1930–) was born in Derry, Ireland. He received his bachelor's degree from Trinity College Dublin and his Ph.D. from the University of Wisconsin before joining the Merck Research Laboratories in the United States. Merck tested the antiparasitic activity of the metabolites produced by Ōmura's strain, and Campbell's team confirmed the critical activity. This compound was avermectin, a potent insecticide that acts specifically on the nervous system of insects and parasites.

Campbell's team chemically modified avermectin to create ivermectin, a semi-synthetic derivative. Ivermectin was safer than the original avermectin and was first commercialized as an anthelmintic for animals. It proved to be remarkably effective in treating parasitic infections in cattle, sheep, and dogs, and became a standard drug in veterinary medicine.

However, the real impact came in human infectious diseases. River blindness (caused by infection with Onchocerca volvulus) is a parasitic disease that is endemic in river regions of West Africa, Central Africa, and South America, and the larvae that invade the eye can cause blindness. By the late 20th century, it was the leading cause of blindness in adult men in West Africa. Campbell's team found that ivermectin strongly killed the river blindness larvae, and they subsequently found that it was also effective against other parasites that cause lymphatic filariasis (elephantiasis).

Merck made a crucial humanitarian decision in 1987. The company decided to provide ivermectin free of charge indefinitely to all developing countries that needed it. The Mectizan Donation Program – often cited as a case of humanitarian decision-making by the pharmaceutical industry in the late 20th century – has since distributed billions of doses of ivermectin, and river blindness has been brought to the point of complete eradication in several African countries.

Tu Youyou (1930–2024) was born in Ningbo, Zhejiang Province, China. She graduated from the Department of Pharmacy at Peking University and began her research at the Chinese Academy of Traditional Chinese Medicine (now the China Academy of Chinese Medical Sciences). Her life was changed by the "523 Project," ordered by Mao Zedong in 1967. During the Vietnam War, the North Vietnamese army, which China was supporting, was suffering heavy losses from malaria, and there was an urgent need for a new treatment because of the spread of malaria parasites resistant to existing drugs (chloroquine).

Tu Youyou's team, which participated in the 523 project, adopted an approach of screening a large number of traditional Chinese medical texts. They created a list of candidate herbs for treating fever and malaria from thousands of years of Chinese medical literature and tested more than 200 of them in the laboratory. Most of them had little effect, but sweet wormwood (Artemisia annua, qinghao) showed some activity in initial tests. However, the results were not reproducible, and the results were inconsistent.

The crucial insight came from the literature. Tu Youyou reread "Handbook of Prescriptions for Emergencies," written by Ge Hong in the 4th century, and noticed a passage that said that when using sweet wormwood, it should be extracted with cold water. This means low-temperature extraction, which was not the standard method in the laboratory, which used heat extraction. It turned out that heat was destroying the artemisinin.

When Tu Youyou changed the method to low-temperature extraction with ether, the activity increased dramatically. In 1972, her team purified the active ingredient from sweet wormwood and named it artemisinin (qinghaosu). Initial clinical trials in humans showed remarkable results, and several derivatives (dihydroartemisinin, artemether, artesunate) have since been developed.

Artemisinin-based combination therapy (ACT) is now the standard treatment for acute malaria recommended by the WHO. In malaria-endemic countries in Africa, Southeast Asia, and South America, this drug has saved hundreds of millions of lives and has made a significant contribution to the dramatic reduction in malaria deaths since the early 21st century.

The three individuals' different trajectories converged in this award. Systematic screening of soil microorganisms in Japan, development of semi-synthetic derivatives by an American pharmaceutical company, and reinterpretation of traditional Chinese medicine literature. The Nobel Committee recognized that these three ways of finding effective drugs from natural products are each a valid path.

Core Achievements: Understanding the Mechanisms of Two Natural Products Through a CS Framework

The mechanism of action of Ivermectin can be visualized as a pipeline:

• Target Specificity: Ivermectin binds to the glutamate-gated chloride channel (GluCl) in invertebrates. This channel is present in the muscles and nerves of insects and parasites but is absent in vertebrates. This difference explains why Ivermectin is lethal to parasites but relatively safe for humans.
• Channel Activation: When Ivermectin binds to GluCl, the channel opens, and chloride ions continuously flow into the cell.
• Nerve Paralysis: This continuous ion influx maintains the nerve and muscle cells of the parasite in a hyperpolarized state, paralyzing its activity. The parasite is unable to move, feed, or reproduce, leading to its death.
• Blood-Brain Barrier: In humans, the blood-brain barrier protects the brain from Ivermectin. Certain dog breeds (collie lineage) have a defective blood-brain barrier, making them susceptible to Ivermectin side effects, but most vertebrates are safe.

The mechanism of action of Artemisinin is fundamentally different.

• Chemical Structure: Artemisinin is a sesquiterpenoid with a unique structure called an endoperoxide (O-O bond). This O-O bond is the key to its reactivity.
• Iron-Catalyzed Reaction: Malaria parasites digest hemoglobin in infected red blood cells, generating a large amount of free iron. This iron cleaves the O-O bond of Artemisinin, producing reactive oxygen species (ROS).
• Parasite Damage: These reactive oxygen species oxidize the proteins and lipids of the malaria parasite, rapidly killing it.
• Selectivity: Normal human cells have less free iron than infected red blood cells, resulting in relatively low Artemisinin activation and limited damage to normal tissues.

The CS analogy of these two natural products is interestingly different. Ivermectin employs a target-specific activation script – it activates specific hardware resources present only in invertebrates, shutting down the system. Artemisinin is an environment-responsive bomb – it activates in a specific environment (free iron) within infected cells, causing damage. Both approaches exploit biochemical differences between the pathogen and the host, but in fundamentally different ways.

It is also important to acknowledge the limitations of this analogy. Drug resistance is emerging in both drugs. In particular, Artemisinin-resistant malaria parasites have been observed in the Mekong region of Southeast Asia, and their spread to Africa is a concern. Ivermectin resistance is also emerging in some parasite species. Even natural product "wonder drugs" have a time limit in the face of evolving pathogens, and continuous development of new-generation drugs is necessary.

Why It Matters: Infectious Diseases in Developing Countries, Natural Product New Drugs, and the Weight of Recognition

First, it drastically reduced the burden of infectious diseases in developing countries. In the late 20th century, onchocerciasis was a leading cause of adult blindness in West Africa, but it has been eliminated in several countries due to mass distribution of Ivermectin. Lymphatic filariasis has also been significantly reduced. Malaria deaths have decreased significantly since the early 21st century, and Artemisinin combination therapy has been a key factor in this reduction. These two infectious diseases were a major burden on the health of developing countries in the late 20th century, but these two drugs have substantially alleviated that burden.

Second, it revitalized the development of new drugs from natural products. After the late 20th century, with the rise of synthetic chemistry and computer-aided drug design, screening of natural products declined in relative interest. The Ivermectin and Artemisinin cases confirmed that natural products are still a powerful source of new drugs, and since then, various natural product new drug programs have been activated, including marine microbial screening, screening of tropical plants, and AI-based analysis of natural product libraries.

Third, it is a meeting of traditional medicine and modern science. Tu Youyou's approach was a hybrid methodology that utilized traditional Chinese medicine literature as a list of active candidates and extracted effective ingredients using modern isolation, purification, and structural analysis techniques. This was a new approach that neither dismissed traditional knowledge as superstition nor accepted it uncritically, and similar traditional medicine screening programs have been activated in various countries.

Fourth, it is a model of humanitarian pharmaceutical industry. Merck's decision to donate Mectizan free of charge set a benchmark for how the pharmaceutical industry can participate in the fight against infectious diseases in developing countries, and it led to similar programs by other companies (e.g., GSK's free supply of Albendazole). It is the foundation of the pharmaceutical industry's voluntary humanitarian participation, which has become one of the pillars of the international health cooperation system in the 21st century.

Fifth, it is international recognition of Chinese science. Tu Youyou's Nobel Prize was the first Nobel Prize in natural sciences awarded to a scientist working in mainland China. The fact that her research was carried out during the Cultural Revolution as part of a national project, and that it was a collective effort by a team of people, were all discussed extensively after the award. The Nobel Committee's principle of awarding the prize to three individuals clashed with China's collectivist research practices, but the award nevertheless symbolically confirmed the international status of Chinese science in the early 21st century.

Sixth, it is the Ivermectin controversy after COVID-19. After 2020, Ivermectin was incorrectly promoted as a potential treatment for COVID-19, leading to a major controversy. Ivermectin showed activity against SARS-CoV-2 in vitro, but this was at concentrations that were dozens of times higher than what could be safely reached in the human body. Actual clinical trials did not confirm its efficacy in treating COVID-19, and the WHO does not recommend its clinical use for COVID-19. This case emphasizes that natural product drugs are not always a panacea and that evidence-based use for each indication is essential.

One person started in the soil of a golf course, another in the 4th-century literature, and the third in a purification laboratory, each following their own path to alleviate humanity from the burden of infectious diseases. The fifteenth Nobel Prize in Physiology or Medicine of the new century recognized these three paths together and reaffirmed that the old source of natural product libraries is still open in the 21st century.

The story of the new century's Nobel Prizes, which began with the first part of the cell cycle in 2001, reaches its first series of fifteen in this edition of 2015. Cell cycle, apoptosis, MRI, olfactory combinatorial code, Helicobacter, RNAi, knockout mouse, HPV/HIV, telomeres, IVF, innate immunity, iPS cells, vesicular transport, brain GPS, parasite-specific drugs - fifteen discoveries have expanded the horizon of human understanding in the first fifteen years of the new century. The story of the next ten years (2016-2025) will continue in the next batch.

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