1960 Nobel Prize in Physiology or Medicine — Burnet and Medawar, the Immune System Learns Itself

What You Will Learn in This Article

You will understand how Burnet of Melbourne, Australia, developed the theory that “the immune system learns what is self and what is non-self during its development,” how Medawar of the UK demonstrated this theory through mouse fetal experiments, and how these two discoveries became the theoretical foundation of modern organ transplantation.

A Story Different from Common Sense — Immunity is Not Complete from the Beginning

We often imagine the immune system as a “system that recognizes its own body from birth and attacks external invaders.” This is a natural conclusion when we only look at the function of a fully developed immune system, but it avoids the fundamental question: how can the immune system accurately distinguish between self and non-self from the beginning?

Burnet’s insight provided an answer to this question. The immune system does not know what is self and what is non-self at birth. Instead, during its development, it “learns” the various tissues of its own body by encountering them, and acquires the ability to classify anything other than what it has learned as non-self. In other words, the immune system’s ability to distinguish between self and non-self is not innate but learned.

Why is this theory so important? If this theory is correct, then it is theoretically possible to teach the immune system to recognize a particular foreign substance as self during the learning period. And if this is possible, then there theoretically exists a way to avoid immune rejection in organ transplantation. This implication is what determines the clinical significance of the award.

Medawar’s demonstration of this theory through mouse experiments was crucial. He clearly showed that mice that received injections of cells from a particular strain during the fetal period did not reject skin grafts from that strain as adults — a phenomenon called acquired immune tolerance. The combination of Burnet’s theoretical insight and Medawar’s experimental demonstration completed the theoretical framework for transplantation medicine over the following half-century.

In the language of Computer Science, this theory can be expressed as a “system where a whitelist is learned.” The system starts with nothing on the whitelist, and the things it encounters during the initial learning period (development) are registered on the whitelist. Subsequently, anything not on the whitelist is automatically classified as an intruder.

The Landscape of the Time — A Year When the Terrain Was Redrawn

1960 was a year in which the political landscape of several regions of the world was fundamentally redrawn.

In Korean history, the April 19 Revolution took place. This event, which began with student protests against the Lee Syngman regime’s March 15 rigged election and eventually led to Lee’s resignation, decisively changed the political trajectory of South Korea. Although the short-lived Second Republic of the Chang Myun administration was overthrown by the May 16 coup the following year, the spirit of April 19 remained the starting point for Korean democratization movements for the following half-century.

Globally, 17 African countries gained independence this year. This year, known as the “Year of Africa,” marked the beginning of a new political landscape on the African continent. In May, a U.S. U-2 spy plane was shot down over Soviet airspace, escalating Cold War tensions. In November, Kennedy narrowly defeated Nixon in the U.S. presidential election. The beginning of the Kennedy era.

It is symbolic that the Nobel Committee chose Burnet and Medawar in this year, recognizing the theme of “self-non-self learning” at a time when new countries in Asia, Africa, and Latin America were emerging on the world stage. At a time when new political entities are establishing their identities, the discovery of how the human immune system establishes its own identity has coincided.

Burnet — Insights from Melbourne, Australia

Frank Macfarlane Burnet was born in Victoria, Australia. He trained at the University of Melbourne and spent most of the rest of his life at the Walter and Eliza Hall Institute of Medical Research (WEHI). He led this institute from 1944 to 1965, decisively elevating the international standing of Australian medical research.

His early career involved research on various viruses, including influenza, yellow fever, and Q fever. In the mid-1940s, his interest shifted to immunology. At that time, immunology had accumulated various experimental observations, but lacked an integrative theoretical framework. Burnet was one of the key figures who created this framework.

His crucial theory can be summarized in two parts:

Acquired Immunological Tolerance (1949): The ability of the immune system to distinguish between self and non-self is not complete at birth, but is acquired by “learning” the antigens encountered during development. Why is this theory crucial? If the theory is correct, then injecting cells from a different strain into a mouse during its developmental stage will cause it to “learn” those cells as self, and when it becomes an adult, it should not reject tissues from that strain. This was a testable prediction, and Medawar demonstrated it experimentally.

Clonal Selection Theory (1957): The immune system already has various lymphocyte clones with different antigen specificities, and when a specific antigen invades, only the clone specific to that antigen is selected and proliferates. This theory became the theoretical basis for the discovery of the genetic mechanism of antibody diversity (Susumu Tonegawa, 1987 Nobel Prize).

Medawar — Demonstration of Tolerance During Development

Peter Brian Medawar was born in Rio de Janeiro, Brazil, to a Lebanese father and a British mother (1915). He moved to Britain in his youth and trained at Oxford, and then worked at Oxford, Birmingham, and University College London.

The root of his interest in immunology lies in World War II burn patients. In the management of burn injuries in Battle of Britain fighter pilots (see 1941 special), there were attempts to transplant skin from various donors to patients, and it was observed that these transplants were always rejected. This led Medawar to become interested in elucidating the precise mechanism of this rejection reaction.

His crucial experiment in 1953 was conducted as follows. He injected cells from a particular strain (B) into the uterus of mice of a different strain (A) during the fetal stage. After these mice grew up, he transplanted skin from strain B. Surprisingly, these mice did not reject the skin from strain B. They had learned the B cells as self during the fetal period.

In the control group (mice of strain A that did not receive cell injections during the fetal period), the skin from strain B was normally rejected. The contrast between the two experimental groups clearly demonstrated the existence of acquired immunological tolerance.

Medawar was also known as a scientific essayist. In several popular books, such as The Uniqueness of the Individual and The Art of the Soluble, he conveyed deep insights into the nature of science and the life of a scientist, and remains one of the leading figures in 20th-century scientific writing.

CS Framework for Whitelist Learning

Now, let’s summarize the theories of the two men in the language of Computer Science.

Whitelist of a security system: A pre-defined list of which users or requests a system trusts. If on the whitelist, allowed; if not, blocked. The strength of this approach is that it can defend against new types of threats by default denying anything not known.

The immune system’s self-non-self recognition is exactly this type of whitelist system. Various characteristics of self tissues (mainly self-peptides presented on MHC molecules) are on the whitelist, and anything not on the whitelist is classified as non-self and attacked. This approach allows the immune system to attack even new pathogens that it has never encountered, simply because they are not recognized as self.

The crucial question is how to learn the whitelist. It is difficult for an evolutionary programmer to explicitly list all the self proteins in each individual’s body. Each person’s genes are slightly different, and the proteins expressed also change with age. Explicit listing is not sufficient; learning is needed.

Burnet’s theory is that this learning is achieved through negative selection. During development, T cells are produced in the thymus, and each T cell has a randomly generated T cell receptor. During this process, T cells that strongly react with self-antigens are killed, and only those that do not react with self-antigens survive. As a result, the T cells in an adult are trained not to react with self-antigens.

The CS counterpart of this learning model is contrastive learning in machine learning. The system learns to distinguish what is not self by seeing many examples of “this is self.” This self-learning is much more flexible and robust than explicit programming.

The Legacy That Continues Today

There are several ways in which the theories of Burnet and Medawar live on in clinical medicine today.

Organ Transplantation: With the understanding that immune rejection is a result of self-non-self recognition, various approaches have been developed to suppress this reaction. HLA matching (optimizing the MHC combination of the donor and recipient), immunosuppressants (see cortisone in 1950), cyclosporine (developed in 1972), etc. Today, hundreds of thousands of organ transplants are performed worldwide each year, and all of these procedures are based on the theoretical foundation of this award.

Understanding Autoimmune Diseases: What happens when acquired immunological tolerance fails? The immune system attacks its own tissues. This is the theoretical framework for autoimmune diseases (type 1 diabetes, rheumatoid arthritis, multiple sclerosis, lupus, etc.). The understanding that specific failures in tolerance learning are involved in the pathogenesis of these diseases is the theoretical root of treatment today.

Immune Checkpoint Inhibitor Cancer Immunotherapy (James Allison and Tasuku Honjo, 2018 Nobel Prize): An approach to block the mechanisms by which tumor cells evade normal self-non-self recognition, allowing the immune system to attack the tumor. The theoretical basis for this approach also comes from the understanding of self-non-self recognition.

Why It Matters

What Burnet and Medawar left behind is a fundamental example of the principle that “the function of a complex system is constructed through learning.”

Until then, how the immune system recognized self was a mystery. Burnet and Medawar clearly answered this mystery with “learning.” The reason this answer was so powerful was that it provided a mechanism for flexibly recognizing self, which is different for each individual. Evolution cannot explicitly specify the self of each individual in advance, but the ability to learn allows each individual to learn its self during development.

This principle is repeated in various fields of CS and biology. Deep learning is exactly a human-made re-creation of this approach. Instead of explicit programming, it learns from example data to acquire complex pattern recognition abilities. The history of deep learning is the history of humans rediscovering the learning approach that evolution discovered over 3 billion years in 60 years (1960-2020).

Another implication is the concept of a “critical period of development.” The fact that the immune system learns self only during the developmental period means that this learning is difficult in adulthood. This characteristic is a major challenge in transplantation medicine, but conversely, it provides the principle that “intervention during the developmental period is much more powerful than intervention in adulthood.” Developmental biology and gene editing are now developing in directions that utilize this principle.

Nobel Batch 6 concludes with this. What Burnet and Medawar discovered in 1960 opened a major door in 20th-century immunology, and the entire trajectory of transplantation, autoimmune, and cancer immunotherapy for the following half-century stemmed from this award. This is a prime example of a single discovery that changed the landscape of clinical medicine for half a century.

1960 Burnet and Medawar Summary: Burnet established the theories of acquired immunological tolerance and clonal selection theory. Medawar demonstrated the tolerance theory through mouse fetal experiments. These two discoveries are the theoretical roots of modern organ transplantation, understanding autoimmune diseases, and cancer immunotherapy.

→ Previous: 1959 — Ochoa and Kornberg → Next: 1961 — von Békésy and the Physics of Hearing