1935 Nobel Prize in Physiology or Medicine — Hans Spemann

What You'll Learn in This Article

You will understand the story of Spemann and his student, Hilde Mangold, who elucidated how a single fertilized egg develops into a complete organism, and how a small number of cells within this developmental process determine the fate of the entire organism.

The Mystery of One Egg Becoming One Person

A fertilized egg is a single cell. This cell divides into two, then four, and eventually becomes a complete organism composed of trillions of cells. Brain, heart, liver, bones, skin — all these diverse tissues originate from that single initial cell.

This naturally leads to the question: How do cells with the same genetic information differentiate into different tissues? Who decides which cell will become which tissue?

Until the early 20th century, the prevailing answer was largely "It's already predetermined." The idea was that each part of the embryo already knows its fate, and development is simply the unfolding of this pre-existing information. This was called the "mosaic theory of development."

However, Spemann's laboratory in Freiburg overturned this theory. The key to his discovery was this: A small region of the embryo instructs the rest of the embryo "what it should become." If this region is absent, development proceeds entirely differently. If this region is transplanted to another location, another embryo will form there. He called this region the "organizer" — the structure that directs the formation of other tissues.

The Historical Context — The Nuremberg Laws and the Darkness of Academia

The year 1935 was the year in which Nazi Germany’s anti-Semitism was codified into law. On September 15th, the Nuremberg Laws were enacted, depriving Jews of their citizenship and prohibiting marriage between Jews and non-Jews. These laws served as the legal foundation for the Holocaust.

During this period, Spemann was a professor of embryology at the University of Freiburg. His relationship with the Nazi regime is a subject of debate. While he did not become an explicit member of the Nazi Party, he did not offer any clear resistance to the Nazi activities within the university at that time. Johannes Holtfreter, one of his Jewish students, left Germany and sought refuge in the United States for political reasons during this period.

In Italy, the invasion of Ethiopia began in October. Mussolini's fascist regime implemented its ambitions for African colonies. The world responded to this invasion with League of Nations sanctions, but these proved ineffective, and this failure led to the appeasement policy that would culminate in the Munich Agreement three years later and the attack on Pearl Harbor six years later.

In the Soviet Union, after Stalin's Holodomor (Ukrainian famine), the period of recovery and preparation for the Great Purge was underway. In a few years, a significant number of intellectuals and scientists would be executed or sent to the Gulag.

When compared with Korean history, 1935 was the year when the Korean Language Society began the serious work of compiling a standard Korean dictionary. This work, aimed at defining the precise meaning and form of Korean vocabulary, was forcibly halted seven years later with the Korean Language Society incident. In Europe, while the organizer, which determined "which cell of an embryo will become what," was being discovered, in Korea, the work of organizing the knowledge of "what each word should mean" was underway.

The Story of the Individuals — The Master of Precision Surgery and His Student Facing Death

Spemann — Master of Micro-Surgery

Hans Spemann was born in Stuttgart, Germany, in 1869. His key strength was his extremely precise micro-surgical technique. Cutting out a small piece of a newt embryo and transplanting it to another embryo — he accomplished this using an eyelash-thin loop that he made himself. In an era without micro-tools, a baby's delicate hair was his crucial instrument.

This precision enabled his discovery. The act of precisely cutting out just a few cells from a specific point of the embryo and attaching them to another location. Today, we perform such experiments with microscopy and micro-manipulators, but he repeated this precise experiment for decades with his hands, eyes, and eyelash loops.

He was a person who had the attitude of "where the hand is, there the mind is." He was an experimentalist who understood that the success or failure of an experiment depended on the sense of touch in his fingertips, rather than on theory.

Hilde Mangold — A Young Woman Who Made a Discovery with Her Doctoral Thesis and Died in an Accident

Hilde Mangold (née Pröscholdt) was born in 1898. She was Spemann's doctoral student. Her doctoral thesis experiment was the basis for the organizer experiment that we know today.

Mangold's experiment was as follows: She used two types of newt embryos. One type had pigment, and the other type did not. She took a small piece of the dorsal blastopore lip — a specific region on the dorsal side of the embryo — from a pigment-free embryo and transplanted it to the ventral side of a pigmented embryo.

The results were remarkable. The transplanted pigment-free tissue developed normally in its new location, but it also caused the surrounding pigmented tissues to gather and form a second embryo. As a result, a second complete embryo was created within the pigmented embryo, with the pigment-free transplanted tissue at its center. This second body had a notochord, muscles, spinal cord, and even a nervous system.

This was the decisive experiment. It clearly showed that the transplanted piece instructed the surrounding tissues to "become dorsal tissue." The transplanted piece not only determined its own fate but also determined the fate of the surrounding cells.

Mangold completed this experiment between 1921 and 1923 and published her paper in 1923. A few months later, she died at the age of 26 in an accident involving an explosion of a gasoline heater in the kitchen. The true significance of her discovery became known to the world only after her death. If she had lived, this Nobel Prize should rightfully have been a joint award for Spemann and Mangold. However, because the Nobel Prize is not awarded posthumously, Spemann was the sole recipient.

In his Nobel Prize lecture, Spemann explicitly acknowledged Mangold's contribution. "The decisive experiment for this discovery was performed by my student, Hilde Mangold." This is why, in the history of developmental biology, the organizer is referred to as the "Spemann-Mangold organizer."

Key Achievement — Development as a Bootstrapping Process

The Decisive Organizer

Mangold's experiment demonstrated the principle that a small region initiates the entire developmental program of the rest of the embryo.

The CS analogy fits naturally here. This is similar to the computer's bootstrapping process.

When you turn on a computer, the first few milliseconds involve initializing the hardware, loading the BIOS, and running the bootloader. This short initial sequence determines the environment in which the rest of the operating system and all applications will run. If the boot sequence proceeds differently, everything that follows will be different.

Embryonic development follows the same principle. The few cells in the early embryo establish the coordinates: "This is the dorsal side, this is the ventral side, this is the anterior." After these coordinates are established, the remaining cells refer to these coordinates to determine their identity. Mangold's transplantation experiment clearly demonstrated this: when the organizer is transplanted to another location, a new coordinate system is created there, and a new embryo grows.

The amazing implication of this discovery is that the information of the early cells is not only in the genes. If all cells have the same genes, then the genes alone cannot determine which cell will become what. The spatial location of the cell and its interactions with its neighbors determine its identity. Mangold's transplanted tissue, in its new location, maintained its own identity and sent signals to the surrounding area to create a new embryo, clearly demonstrating this principle.

However, this analogy breaks down here. The bootstrapping process is a sequence that we explicitly designed, and the code for each step exists. However, for a long time, it remained a mystery how the "organizer substance" directs the surrounding cells with specific signals (molecules). Attempts to identify the "organizer substance" were followed by numerous failures for 60 years. Finally, in the 1990s, it was discovered that several proteins (Chordin, Noggin, Wnt signaling, etc.) together are responsible for this role. It is not a single magic substance, but rather a coordinated combination of several signals that creates organizer activity.

The Timing of Fate Determination

Another important question raised by the Spemann-Mangold experiment was: "When is the fate of a cell determined?" Their subsequent experiments showed that this occurs very early.

In the early embryo, if certain cells are cut out and transplanted to another location, the transplanted cells will receive information from their new location and acquire a new identity (the identity is still fluid). However, if the same transplantation is performed after development has progressed a bit further, the transplanted cells will develop into the tissue they were originally destined to become (after the identity has been determined). Identity determination occurs at a specific time in response to specific signals, and after that point, it cannot be reversed.

This concept is the basis for what we know today as the distinction between stem cells and differentiated cells. Stem cells remain in a state where their identity has not yet been determined, while differentiated cells are in a state where their identity has been determined in a specific direction.

Why It's Important

Spemann's Nobel Prize remains valid today on three levels.

Developmental Biology Level: All of today's developmental biology is built on the concept of the organizer. To understand the developmental program of any embryo, you must start by finding its organizer(s). Humans, fruit flies, worms, fish — this principle is valid in all multicellular organisms.

Regenerative Medicine Level: Stem cell research, induced pluripotent stem cells (iPS), organoid culture — all of these modern regenerative medicine concepts have their conceptual roots in Spemann's organizer concept. Under what conditions do cells maintain their identity, and under what conditions do they acquire a new identity? This question is at the heart of today's regenerative medicine.

Evolutionary Developmental Biology Level: It was discovered that the genes that create the organizer in humans, fruit flies, and worms were established very early in evolution and are largely conserved in most organisms. This is called evolutionary developmental biology (evo-devo), and it is a thriving field today.

There is a lesson for us. "To understand the final form of a complex system, you must look at the initial conditions and the initial coordination rules." Whether it is an organization, a project, or a system, its final form is largely determined by the initial decisions. This principle is valid today in software architecture, organizational culture, and even urban planning. Small differences at the initial point create large differences in the later stages.

Even as you read this sentence, organizers are active in the bodies of pregnant women around the world, creating new people. The principles of this coordination were revealed 100 years ago in the newt embryo transplantation experiments in Freiburg.

A Brief Remembrance of Hilde Mangold

The decisive experiment for this prize was performed by a 26-year-old female graduate student, and she did not live to see her discovery win the Nobel Prize. Her paper, "Über Induktion von Embryonalanlagen durch Implantation artfremder Organisatoren" (On the Induction of Embryonic Anlagen by the Transplantation of Heterologous Organizers), remains one of the most cited papers in the history of developmental biology.

This is why, in the standard description of developmental biology, this organizer is called the "Spemann-Mangold organizer."

Summary of the Organizer Discovery: Spemann and Mangold demonstrated, through newt embryo transplantation experiments, that a specific region of the embryo (the dorsal blastopore lip) determines the coordinates and fate of the rest of the embryo. This organizer concept became the foundation of 20th-century developmental biology and has become the root of modern regenerative medicine and evolutionary developmental biology.

→ Experience it with code: DevBench — Initial Conditions and Bootstrapping Sequence → Learn about CS concepts: DryBench — Initialization Functions and System Identity