1989 Nobel Prize in Physiology or Medicine: Bishop and Varmus Discover Cancer-Causing Genes Within Us

What You Will Learn in This Article

You will understand how the fact that cancer originates not from external invasion, but from our own genes was revealed. J. Michael Bishop and Harold Varmus made the surprising discovery at UCSF that the cancer-causing gene src of the Rous sarcoma virus actually exists in normal cells. In other words, cancer is not caused by external genes entering and manipulating cells, but by the malfunction of genes originally present within us. This discovery, which laid the foundation for today's targeted cancer drugs (Gleevec, Herceptin, Osimertinib), genetic testing, and personalized cancer treatments, will be explored along with its historical context.

A Story Different from Common Sense: Cancer-Causing Genes Were Already at Work Within Us

In 1966, Peyton Rous received a Nobel Prize for his discovery that certain viruses (Rous Sarcoma Virus, RSV) induce tumors in chickens, opening a major question in 20th-century oncology. How do viruses transform normal cells into cancer cells? Later, in 1975, Baltimore, Dulbecco, and Temin discovered reverse transcriptase, revealing that retroviruses insert their RNA into the host genome as DNA. However, the exact mechanism of cancer development remained a mystery.

In 1976, Bishop and Varmus provided an answer that shook the academic world. The cancer-causing gene src (sarcoma) present in RSV – a gene that causes cells to become cancerous when introduced – was found to be present in the DNA of normal chickens. This was an unexpected result, initially suspected to be an experimental error. Subsequently, similar genes were found in quail, ducks, cows, mice, and salmon. The virus's cancer-causing gene was originally a normal gene in animal cells. It is believed that the virus stole this gene during a past infection and incorporated it into its own genome.

This discovery had three major implications:

First, a new understanding of cancer. Cancer is not caused by external genes, but by the mutation of proto-oncogenes into oncogenes, leading to their activation. Factors such as radiation, chemicals, ultraviolet rays, and errors in replication can trigger these mutations.

Second, understanding the normal function of proto-oncogenes. Most of these genes play a role in regulating growth, division, and differentiation in normal cells. src is a tyrosine kinase, myc is a transcription factor, and ras is a GTPase signaling molecule – all crucial components in the regulation of normal cell growth. When these components mutate, they become "always on," causing cells to proliferate uncontrollably.

Third, a multi-step, multi-gene model of cancer development. Cancer does not result from a single mutation in a proto-oncogene, but from the accumulation of multiple mutations in multiple genes before normal cells become cancerous. This view was later established as the Vogelstein multi-step model of colon cancer development (1988-1990).

In terms of CS, this can be described as a bug in a normal function. Proto-oncogenes are normal functions in the cell growth regulation API. These functions have a normal lifecycle: they are activated when a signal is received and deactivated when the signal is absent. When a mutation occurs, the function becomes permanently activated, the normal termination logic is ignored, or the signal is amplified in the wrong direction. As a result, the cells become zombie processes that ignore kill signals.

From this perspective, cancer treatment is a precise intervention that targets and inhibits the bugged function. This is the conceptual root of today's era of targeted cancer therapies.

The Era: The Decisive Year of the End of the Cold War and the Dawn of the Internet

1989 was one of the most decisive years of the late 20th century.

In world history, the Berlin Wall fell on November 9th – the concrete wall that had divided West and East Germany for 28 years collapsed in the hands of the citizens, and the images were broadcast around the world. This became a symbolic image of the end of the Cold War. On June 4th, the Tiananmen Square Incident occurred – the pro-democracy demands of Chinese students and citizens were suppressed by force. These two events demonstrate the two different paths taken by the socialist camp. On February 15th, the Soviet Union completed its withdrawal from Afghanistan – the end of a 10-year war and a decisive step in the trajectory of the Soviet Union's collapse. In June, free elections were held in Poland as a result of the Round Table Talks – marking the beginning of the practical collapse of communist regimes in Eastern Europe.

In the history of technology, a crucial event occurred on March 12th when Tim Berners-Lee submitted a proposal for the World Wide Web (WWW) to CERN – this is the fundamental document for today's web. The first web server was launched in 1990. On July 31st, the Nintendo Game Boy was released in Japan – marking the beginning of the era of portable games. Super Mario and Tetris conquered the world on this handheld device. On August 25th, Voyager 2 passed Neptune – marking the moment when humanity completed the close observation of the outer planets of the solar system.

In South Korean history, on March 25th, Reverend Moon Ik-hwan visited North Korea – followed by Im Soo-kyung's participation in the Pyongyang World Youth and Student Festival (July). The issue of reunification became the focus of domestic politics. The Roh Tae-woo administration's Northern Policy led to the establishment of diplomatic relations with Hungary (February) and Poland (November), taking advantage of the trend towards the end of the Cold War. Lee Byung-chul, chairman of Samsung, visited the Soviet Union to discuss the development of Siberia. Domestically, the distribution of color TVs was completed, and professional sports became more widespread.

In this year, which marked the end of the Cold War, the Nobel Committee recognized the two scientists who elucidated the fundamental causes of cancer. In the year that the old walls of international politics were crumbling, the discovery of the two scientists, who found the causes of cancer not in the outside but within, was recognized.

J. Michael Bishop and Harold E. Varmus: The Son of a Rural Pastor and the Son of Scholar Parents

J. Michael Bishop (1936–) is an American molecular biologist. He received his Ph.D. in medicine from Harvard University in 1962, and after serving as a researcher at NIH from 1964 to 1967, he became a professor at UCSF (University of California, San Francisco) in 1968. After receiving the Nobel Prize, he served as Chancellor of UCSF.

Harold E. Varmus (1939–) is an American molecular biologist. He received his Ph.D. in medicine from Columbia University in 1966 and was a professor at UCSF from 1970 to 1993, where he and Bishop made their Nobel Prize-winning discoveries. His career path is unusual. He served as Director of the NIH from 1993 to 1999 – in charge of the US National Institute of Health. He then served as Director of the Sloan-Kettering Cancer Center from 1999 onwards – leading one of the world's leading clinical oncology institutions. He is one of the few people who has continued to play a central role in US science policy after receiving the Nobel Prize.

The two men's backgrounds are strikingly different. Bishop had lived in a city for only a short time before the age of 21. He grew up in a peaceful environment, the son of a Lutheran pastor and a housewife, and his elementary school had only two classrooms. His high school graduating class had only 80 students.

Varmus is the opposite. He was born to parents who were both professors at Harvard University and Wesleyan University and attended a prestigious high school in a city known for its good educational facilities and outdoor activities.

Despite their contrasting backgrounds, the two men met at UCSF and became very close friends, and they discovered that they had something in common: they had both entered academia relatively late in life. Their collaboration lasted for more than 15 years.

The Decisive Experiment: Discovery of the src in Normal Cells through DNA Hybridization

The question Bishop and Varmus asked was clear: Where did the src gene of RSV come from? Was it a gene that the virus had from the beginning, or did it acquire it from somewhere else?

The methodological tool was DNA hybridization. If two DNA fragments have similar sequences, they will bind to each other (hybridize). Using this principle, they could test whether there was a sequence in normal chicken DNA that was similar to the src gene of RSV.

The two men used reverse transcriptase to convert the virus's RNA (including the src region) into DNA, and labeled this DNA as a radioactive probe. Then, they attached this probe to DNA isolated from normal chickens.

The result was surprising. A region in the chicken DNA was found where the src probe bound. There was already a gene in the normal chicken DNA that was very similar to src. This was published in a paper in 1976.

This observation led to the next question: what about other animals? As the experiment continued, similar genes to src were found in other birds, such as quail and ducks, and then in 1978, in various vertebrates, including cows, mice, and salmon. The concept of proto-oncogenes was established.

RSV had originally stolen src from the chicken and incorporated it into its own genome, and this stolen src caused cancer by being under strong expression control and being always active. In other words, the virus's cancer-causing gene was a distorted copy of what was originally ours.

Once this discovery was established, several other proto-oncogenes were subsequently discovered. myc, ras, erbB, sis, jun, fos, etc. Today, about 100 proto-oncogenes have been identified, and it has been found that each of them regulates a specific axis of growth, division, differentiation, and death in normal cells.

CS Framework: Bug in Normal Function and Zombie Process

The concept of proto-oncogenes can be reconstructed in the language of CS as follows:

Normal Function = Proto-Oncogene: src is a normal function in normal cells that transmits growth signals through tyrosine phosphorylation. myc is a transcription factor that regulates the expression of cell division genes. ras is a GTP-binding switch that turns growth signaling on and off.

Normal Function Lifecycle: Normal proto-oncogenes are activated only when a signal is received, automatically deactivated after activation, and degraded when no longer needed – a normal function's acquire/execute/release lifecycle.

Mutation = Function Bug:

• Point mutation: The function signature changes slightly and malfunctions (ras G12V mutation)
• Gene amplification: The number of function instances is excessive and continues to execute (myc amplification)
• Chromosomal translocation: The function is placed under different regulation and is always active (BCR-ABL, Philadelphia chromosome in CML)
• Promoter mutation: The function call condition is incorrectly activated (Burkitt lymphoma with c-myc translocation)

Zombie Process: Normal cells stop growing when they do not receive growth signals, and they undergo apoptosis (programmed cell death) when they are severely damaged. However, cells in which oncogenes are activated ignore these commands and proliferate indefinitely. In Linux terms, this is a zombie process that ignores SIGKILL.

Multi-Step Cancer = Accumulation of Multiple Bugs: A single function bug is not enough for a cell to become a full-fledged cancer cell. Several components, such as a growth-promoting function, a tumor suppressor function, and a cell death evasion function, must accumulate to transform a normal cell into a cancer cell. This is a pattern of defense in depth failure, where the system must pass through several safety measures in sequence.

Targeted Cancer Therapy = Precise Patch: Drugs that target specific oncogenes are today's targeted cancer therapies. Imatinib (Gleevec) inhibits the tyrosine kinase of BCR-ABL, trastuzumab (Herceptin) blocks the HER2/neu receptor, and osimertinib (Tagrisso) targets the EGFR T790M mutation. This is about knowing the exact location of the bug and applying a precise patch.

This analogy is not perfect. Cells have multiple signaling pathways that operate in parallel and compensate for each other, making them a robust system. Even if a specific function is targeted, bypass pathways may be activated, leading to resistance. This is the problem of resistance in the actual clinical use of targeted cancer therapies.

Scholarly Impact: The Dawn of Targeted Cancer Therapies

Following this discovery, the field of oncology underwent a fundamental shift towards a molecularly-oriented approach.

Restructuring of Research and Infrastructure: The U.S. National Cancer Institute (NCI) made large-scale investments in research on proto-oncogenes and tumor suppressor genes. The University of Southern California, MIT, NIH, and UCSF became centers for tumor genetics research. In Korea, genetics oncology research laboratories were also established at Seoul National University, Yonsei University, and Seoul Asan Hospital during this era.

Discovery of Tumor Suppressor Genes: The concept of tumor suppressor genes (growth-inhibiting function) was established, contrasting with proto-oncogenes (growth-promoting function). RB (discovered in 1986) → p53 (detailed elucidation in the 1990s) → BRCA1/BRCA2 (1994 and 1995). p53 is known as the "guardian of the genome," and mutations are observed in more than 50% of human cancers.

The Era of Targeted Cancer Therapies:

• 1997: Rituximab - CD20-targeted antibody
• 1998: Trastuzumab (Herceptin) - HER2-targeted, changing the landscape of breast cancer treatment
• 2001: Imatinib (Gleevec) - BCR-ABL-targeted, increasing 5-year survival rate for chronic myeloid leukemia from 30% to 90%
• 2003: Gefitinib - EGFR-targeted, for lung cancer
• 2011: Ipilimumab - The first immune checkpoint inhibitor (CTLA-4)
• 2014: Pembrolizumab and Nivolumab - PD-1 inhibiting immune checkpoint inhibitors
• 2015: Osimertinib - Targets EGFR T790M resistance mutation

Personalized Cancer Treatment: Sequencing the tumor genes of patients and selecting drugs that match the identified mutations is now the standard in precision oncology. Tests for HER2 status and estrogen receptor status in breast cancer, and EGFR, ALK, ROS1, and BRAF status in lung cancer, and KRAS, NRAS, and BRAF status in colon cancer are now standard for determining treatment.

Advances in Genetic Diagnostics: PCR, DNA sequencing, microarrays, and next-generation sequencing (NGS) have advanced, allowing for clinical testing of mutations in proto-oncogenes and tumor suppressor genes. Today, genetic testing is included in the diagnosis of most cancers, including lung, breast, colon, prostate, and leukemia.

Cancer Genome Project: TCGA (The Cancer Genome Atlas, 2005-2018) and ICGC (International Cancer Genome Consortium) sequenced the genomes of tumor cells from tens of thousands of patients, creating a comprehensive map of cancer genetics. Today's targeted cancer therapy strategies are built on this map.

Korea's Continuity and Today

The impact of this lineage is also widespread in Korea. From the 1990s, genetics oncology research laboratories have been actively operated at Seoul National University, Yonsei University, Samsung Seoul Hospital, Seoul Asan Hospital, and St. Mary's Hospital. The fact that the frequency of EGFR-activating mutations in Korean lung cancer patients is higher than in Western populations (30-40%) has led to the widespread use of gefitinib and osimertinib in Korea.

Hanmi Pharmaceutical's Olastatin (2015) - The first domestically developed novel anticancer drug. A domestic example of a target-oriented approach, belonging to the HDAC inhibitor family.

Korean Breast and Colon Cancer Genetic Testing: BRCA1/2 gene testing, HER2 testing, and K-RAS/EGFR testing have expanded to university hospitals and regional hospitals, standardizing personalized cancer treatment. Domestic diagnostic companies (MacroGen, EONE Testing, SeeGene, etc.) are responsible for this testing market.

Korean-Specific Genes: Research on Korean-specific gene profiles, such as the K-RAS G12V mutation in colon cancer and specific BRCA1 mutations in breast cancer, is being conducted at Seoul National University, Samsung Seoul Hospital, and Asan Hospital. This is an example of ethnically specific precision oncology.

Why is it Important?

What Bishop and Varmus left behind is the established concept that "cancer is caused by the malfunction of normal genes within us."

The concept of cancer itself has changed. Previously, cancer was imagined as something that invades from the outside, but after this discovery, it is understood as the result of mutations that accumulate in our own genes. This conceptual shift is the root of today's targeted cancer therapy era.

The concept of "cancer-causing genes within us" has changed people's psychological perception of the disease. The recognition that the cause of the disease is not external but within us dramatically highlights the importance of prevention, screening, and early diagnosis. This is the conceptual background for the establishment of today's national cancer screening programs.

Different backgrounds, same goals: The collaboration between Bishop, the son of a rural pastor, and Varmus, the son of scholar parents, is an example that academic dedication leads to the greatest achievements regardless of background. The trajectory of the two collaborating at UCSF for more than 15 years is itself a representative success story of American science in the late 20th century.

After this award, the flow of oncology continued as follows:

• 1990s: Detailed elucidation of p53 - Guardian of the genome
• 1994 and 1995: BRCA1 and BRCA2 - Hereditary breast and ovarian cancer
• 2001: Imatinib (Gleevec) - The first successful targeted anticancer drug
• 2005-2018: TCGA - Human cancer genome map

Clinical establishment of this discovery:

• HER2 targeting: Trastuzumab, Pertuzumab, Lapatinib (breast cancer)
• EGFR targeting: Gefitinib, Erlotinib, Osimertinib (lung cancer)
• BCR-ABL targeting: Imatinib, Dasatinib, Nilotinib (leukemia)
• BRAF targeting: Vemurafenib (melanoma)
• PD-1 immune checkpoint: Pembrolizumab, Nivolumab (various cancers)
• Standardization of genetic testing: BRCA, K-RAS, EGFR, ALK, etc.

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