1992 Nobel Prize in Physiology or Medicine – Fischer and Krebs: A Single Phosphate Group Turns Cellular Switches On and Off

What You Will Learn in This Article

This article will help you understand the amazing fact that almost all regulatory reactions within a cell are carried out by the attachment and detachment of a single phosphate group. Edmund Fischer and Edwin Krebs, starting in the mid-1950s at the University of Washington, elucidated reversible protein phosphorylation – this reaction is the fundamental language of widespread regulation, encompassing muscle contraction, gene regulation, cell signaling, growth, cancer development, and immune responses. We will explore the lineage of many of today's prescribed targeted anticancer drugs (Gleevec, Herceptin, Osimertinib, etc.), which target this phosphorylation reaction.

A Story Different from Common Knowledge – Cellular Switches are Phosphate Groups

Numerous regulatory reactions occur in real-time within cells. Muscles contract, nerves are excited, hormones transmit signals, genes are expressed, and cells divide. Each of these reactions must be precisely regulated by on/off mechanisms.

Fischer and Krebs discovered that a significant portion of this vast regulation is carried out using a common language. The activity of a protein is turned on or off by the attachment or detachment of a single phosphate group (-PO3^2-) to a specific amino acid (serine, threonine, or tyrosine) within the protein.

Phosphorylation: The reaction of attaching a phosphate group; the enzyme is a kinase. Dephosphorylation: The reaction of removing a phosphate group; the enzyme is a phosphatase.

This reaction is reversible. It can be turned on when needed and turned off when no longer necessary. It is also very fast – regulation is possible at the millisecond level. And it is energy efficient – only a single phosphate group needs to be transferred, allowing for activity regulation without major structural changes.

First Example: Glycogen Phosphorylase. Fischer and Krebs showed that the glycogen (energy storage form) breakdown enzyme in muscle exists in two forms: one form is an active, phosphorylated form, and the other is an inactive, dephosphorylated form. When the muscle needs energy, this enzyme is phosphorylated and activated, breaking down glycogen into glucose. This was the fundamental language of muscle contraction regulation.

Following this initial discovery, over the next several decades, the picture emerged that phosphorylation regulation is involved in almost all regulatory reactions within the cell. Today, we know that there are approximately 500 kinase genes (kinome) in the human genome, and that these regulate the majority of cellular activities. Approximately 1% of the genome is dedicated to this regulatory reaction.

In terms of CS (Computer Science), this is a perfect example of a function active flag toggle. Each protein within the cell is an object with an active flag, the kinase is setState(active=true), and the phosphatase is setState(active=false). A single signal can sequentially activate multiple kinases, creating a cascade, and at the end of the cascade, gene expression or cell state changes.

Signature Cascade = Callback Chain. Example: EGF binds to EGFR → EGFR autophosphorylation → Grb2·SOS adapter activation → Ras activation → Raf phosphorylation → MEK phosphorylation → ERK phosphorylation → translocation to the nucleus, phosphorylation of transcription factors → expression of specific genes. This is surprisingly similar to the pipeline of event broker → listener → handler → action that we are now familiar with in microservices architecture.

The Zeitgeist – The Birth of the EU and the Inauguration of the Korean Civilian Government

1992 was a decisive turning point in both international and Korean politics.

In world history, the Treaty of Maastricht was signed on February 7th, transforming the European Economic Community (EEC) into the European Union (EU). This became the foundational document for 20 years of European integration. The Rio Earth Summit was held in June, the largest international environmental conference ever held, with the participation of 172 countries. It laid the groundwork for the Climate Change Convention and the Biodiversity Convention. From April 29th to May 4th, the Los Angeles Riots occurred, resulting in 55 deaths and marking a symbolic explosion of racial tensions in the United States, sparked by the Rodney King verdict. The first SMS message was sent on December 3rd, with British engineer Neil Papworth sending "Merry Christmas," marking the beginning of SMS and the roots of KakaoTalk, Line, and WhatsApp.

In Korean history, the South-North Basic Agreement went into effect in February, a result of the Roh Tae-woo government's Northern Policy. On December 18th, Kim Young-sam was elected president, marking the inauguration of the first civilian government in 30 years. This effectively ended the military regime. It marked the first transition to a purely civilian leader, breaking the line of military or former military figures that included Syngman Rhee, Park Chung-hee, Chun Doo-hwan, and Roh Tae-woo.

In technological history, Microsoft Windows 3.1 was released (April), the Intel 486DX2 66MHz processor was introduced, early IRC chat became widespread, and the development of the first web browser, Mosaic, began.

In this year of transition, the Nobel Committee recognized the two individuals who had elucidated the language of cellular regulation. In the year that politics was transitioning to a new system, the fundamental language of biological system regulation was recognized.

Edmund Fischer and Edwin Krebs – A 40-Year Partnership in Seattle

Edmund H. Fischer (1920-2021) was an American biochemist. He received his PhD from the University of Geneva, Switzerland, in 1947, and served as a professor at the University of Washington (Seattle) from 1953 until his retirement in 1990, becoming a professor emeritus. He was born in Switzerland and completed his academic career in the United States.

Edwin G. Krebs (1918-2009) was an American biochemist. He received his MD from the University of Washington (Seattle) in 1943 and served as a professor at the University of California, Davis, and the University of Washington from 1968 to 1991, retiring as a professor emeritus in 1991.

The two met at the University of Washington (Seattle) and engaged in joint research that lasted for over 40 years. Their discovery of the phosphorylation regulation of glycogen phosphorylase in the mid-1950s marked the beginning of their collaboration. They subsequently conducted research together on various kinases and phosphatases.

Note: He is a different person than Sir Hans Krebs (discoverer of the TCA cycle), who won the Nobel Prize in 1953. It was a coincidence that they had the same last name.

The Decisive Discovery – The Two Forms of Glycogen Phosphorylase

When Fischer and Krebs met, it was already known that the glycogen breakdown enzyme in muscle existed in two forms (a and b), but it was unknown what the difference between the two forms was. a was the active form, and b was the inactive form. What distinguished a from b?

From 1955 to 1956, the two tackled this problem. They discovered that glycogen phosphorylase a was the phosphorylated form, and b was the dephosphorylated form. They then isolated and characterized the enzymes that convert a to b (phosphorylase phosphatase) and b to a (phosphorylase kinase). This was the first empirical demonstration of a kinase-phosphatase dual system.

In the following decades, this principle was widely expanded. Protein kinase A (PKA), protein kinase C (PKC), CDK kinases (cell cycle), MAP kinases (cell growth), tyrosine kinases (growth factor receptors), JAK-STAT (cytokine signaling) – most of the signal transduction pathways we know today were revealed to be phosphorylation cascades.

CS Framework – Function Active Flag and Cascade

If we reconstruct reversible phosphorylation in terms of CS, we get the following picture:

Protein = Function Object with Active Flag: Each protein has a flag (phosphorylation state) that represents its active state. In the active state, it performs its normal function; in the inactive state, it waits.

Kinase = Active Setter: Attaches a phosphate group to a specific amino acid (serine, threonine, or tyrosine) in a specific protein, turning the active flag to true. Each kinase has its own target specificity.

Phosphatase = Active Resetter: Removes the phosphate group, turning the active flag to false. Kinases are approximately 5:1 more abundant than phosphatases.

Signal Cascade = Callback Chain: Extracellular signal (growth factor, hormone, etc.) → receptor activation → adapter activation → sequential activation of several kinases → activation of terminal transcription factor → change in gene expression. This is similar to a Promise chain.

Parallel Signal Integration = Context Switching: A single cell receives and integrates signals from multiple signal cascades simultaneously. Each cascade operates differently depending on specific conditions and cell states. This is the same as multiple event sources adjusting the system state in parallel.

Targeted Anticancer Drugs = Specific Kinase Inhibitors: The uncontrolled proliferation of cancer cells is often caused by a specific kinase in the growth signal cascade being constantly fixed in the active state. Drugs that target this are kinase inhibitors.

• Imatinib (Gleevec, 2001) – inhibits BCR-ABL tyrosine kinase, chronic myelogenous leukemia.
• Gefitinib (2003) and Erlotinib (2004) – inhibit EGFR tyrosine kinase, lung cancer.
• Sunitinib (2005) and Sorafenib (2006) – multi-kinase inhibitors, kidney cancer and liver cancer.
• Palbociclib (2015) – inhibits CDK4/6, breast cancer.
• Osimertinib (2015) – targets EGFR T790M resistance mutation, lung cancer.

Immune Regulation = Phosphate Manipulation: T cell activation is also regulated by multiple phosphorylation reactions. Cyclosporine inhibits the CN (calcineurin) phosphatase in T cells, blocking the immune response.

This analogy is not perfect. Cell signaling is probabilistic, and the various regulatory layers are intertwined, providing robust robustness. It is a much more complex network than a simple cascade.

Academic Impact – The Kinome Era and Targeted Drugs

Following this discovery, cell signaling, oncology, and immunology were fundamentally reorganized.

The Kinome Era: It was discovered in the 2000s that there are approximately 500 kinase genes in the human genome. The concept of the kinome was established. The targets and functions of each kinase are mapped in detail.

Targeted Anticancer Drugs: Since Imatinib was approved in 2001, nearly 100 kinase inhibitors have been approved by the FDA in the following 20 years. A significant portion of the anticancer drugs prescribed today belong to this lineage. The first approved drug, Imatinib, dramatically improved the 5-year survival rate of chronic myelogenous leukemia from 30% to 90%.

Treatment of Autoimmune Diseases: JAK inhibitors (Tofacitinib, Baricitinib, etc.) are used to treat rheumatoid arthritis, atopic dermatitis, and ulcerative colitis. They inhibit the JAK-STAT phosphorylation pathway.

Medical Diagnostics: Kinase activity assays have become standard for tumor diagnosis, prognosis prediction, and prediction of treatment response. Testing the HER2 status of breast cancer, the EGFR status of lung cancer, and the BCR-ABL status of leukemia are the basis for prescribing decisions.

Applications in Neuroscience: Nerve signaling, synaptic plasticity, and memory formation are regulated by phosphorylation reactions. CaMKII is essential for long-term potentiation (LTP).

The Korean Legacy and Today

The impact of this lineage in Korea has also been widespread. Since the late 1990s, research on phosphorylation reactions has been actively conducted in the biochemistry and cell biology laboratories of Seoul National University, Yonsei University, KAIST, and POSTECH.

Clinical Use of Kinase Inhibitors: At Seoul National University Hospital, Asan Medical Center, Samsung Medical Center, and Severance Hospital, targeted anticancer drugs such as Imatinib, Osimertinib, Palbociclib, and Nilotinib are prescribed as standard. Prescriptions are tailored to the specific profiles of Korean patients (e.g., EGFR activating mutations in 30-40%).

Development of Domestic Kinase Inhibitors, such as Hanmi Pharmaceutical's Orastatin: This is a cornerstone of domestic drug development.

Why is it important?

What the two researchers established is that "the regulatory language of cells is phosphate toggle."

This is a discovery that revealed the fundamental grammar of cell regulation. Without understanding this language, today's advanced oncology, immunology, and neuroscience would not be possible. It is a required chapter in undergraduate biology textbooks.

A model of 40 years of collaboration. Fischer and Krebs met at the University of Washington (Seattle) and collaborated on research for over 40 years. This demonstrates the power of a partnership where each person complements the other's weaknesses.

The concept that a small switch regulates a large system. Within cells, reactions regulated by the addition and removal of a single phosphate range from muscle contraction to gene expression. This is the beauty of system design – controlling maximum complexity with the minimum unit of a switch.

Following this award, the flow of cellular signaling continued as follows:

• 1994, Gilman & Rodbell: G-protein signaling
• 2000, Carlsson, Greengard & Kandel: Signaling in the nervous system
• 2004, Hartmut Michel et al. (actually the 1988 Chemistry Prize): GPCR structure
• 2013, Südhof, Rothman & Scheman: Regulation of intracellular transport

Clinical and industrial applications of this discovery:

• Kinase inhibitor-targeted anticancer drugs: Gleevec, Gefitinib, Osimertinib, Palbociclib, etc.
• JAK inhibitors: Tofacitinib, Baricitinib (for autoimmune diseases)
• Immunosuppressants: Cyclosporine, Tacrolimus (phosphate regulation)
• Kinase activity diagnostics: Standard for tumor gene testing
• Neuroscience tools: LTP, memory formation research

→ Previous: 1991 — Neher & Sakmann → Next: [1993 — Batch 8 in progress]