The Physicist Who Gave Us 'Molecular Biology'

Few scientific papers can match the enormity of James Watson and Francis Crick’s paper on the DNA double helix model, published in the journal Nature on 25 April 1953. This paper described the structural properties of DNA without dwelling much on its functional implications. They provided evidence for these ideas in their second paper, which appeared in the same journal just a month later, on 30 May 1953. This time, they moved beyond describing DNA’s structure to proposing how it copies, mutates, and stores information, laying the conceptual foundation for molecular genetics. The two papers complemented each other so well, almost like a glove fitting a hand. The only thing remaining was for the world to grasp the ideas presented in these two articles, and the scientific community surely did and went gaga over them.

But when I say the world, I mean almost the whole world except for one person. He had an issue with this model, and his name was Max Delbrück.

Max Delbruck (1906-1981)

Delbrück was neither a competitor nor a hardcore critic of Watson and Crick’s work; in fact, he was one of Watson’s mentors. Along with Salvador Luria, Delbrück started the famous Phage Group in the mid-1940s. Watson became an integral part of this group after joining Luria for his PhD. It was here that Watson was deeply influenced by Delbrück’s ideas about genes and mutations.

When the Korean War began in the early 1950s, many young men faced the possibility of being drafted into military service. Watson was one of them, and he was summoned for a pre-induction physical examination on March 19, 1951. At the time, he had just completed a year as a postdoctoral fellow in Copenhagen. Sensing the possibility that Watson might be drafted to serve in the war, Delbrück wrote a strong recommendation letter arguing that it was in the national interest to allow Watson to continue his studies and research. This intervention helped Watson defer military service and continue his scientific career, which eventually led him to the University of Cambridge and to Crick. Such interventions were not uncommon for promising young scientists, but Delbrück’s influence proved especially significant in shaping Watson’s career.

Watson always saw Delbrück as a mentor-level authority and frequently sought his opinion. This is evident from Watson’s regular correspondence with Delbrück, including his request for comments on the first paper he wrote with Crick. Watson wrote to him on March 12, 1953, just a few days before submitting the paper to Nature, describing the DNA structure and explaining how they had arrived at it. However, what is particularly interesting is the way Watson phrased one of the paragraphs in that letter.

“In the next day or so Crick and I shall send a note to Nature proposing our structure as a possible model, at the same time emphasizing its provisional nature and the lack of proof in its favor. Even if wrong I believe it to be interesting since it promises a concrete example of a structure composed of complementary chains. If by chance, it is right then I suspect we may be making a slight dent into the manner in which DNA can reproduce itself. For these reasons (in addition to many others) I prefer this type of model over Pauling's which if true would tell us next to nothing about the manner of DNA reproduction.”

James Watson letter to Max Delbruck on March 12, 1953

In this letter, Watson was not celebrating the discovery of the DNA structure; instead, he was almost confessing that he could still be wrong. He was being very cautious, fully aware that he did not yet have the kind of direct evidence that Delbrück might demand. Watson was intellectually hedging here. He was essentially saying that although they may not yet have complete proof for the DNA structure, they might finally have a model that explains how genes copy themselves. Watson knew that if anyone could truly grasp the relationship between DNA structure and function, it was Delbrück. Unfortunately, we do not know Delbrück’s reply to this correspondence, or at least it is not publicly available online. It would be fascinating to know what Delbrück’s initial reaction was to the structure of DNA.

But what is truly amazing is Delbrück’s reaction to the second manuscript. Just as before, Watson sent him a copy of the manuscript before submission. We do not know the exact date Watson wrote to him, but it is clear that Delbrück had seen the paper before it appeared in the journal. In a correspondence dated May 12, 1953, Delbrück wrote one of the most famous lines in biology:

“I am willing to bet that the plectonemic coiling of the chains in your structure is radically wrong.”

MaxDelbrück letter to James Watson on May 12, 1953

This single line, written in a simple letter to Watson, is in many ways responsible for the birth of a new field in biology that we now call DNA topology. In fact, this exact sentence serves as the opening line of the book Untangling the Double Helix: DNA Entanglement and the Action of the DNA Topoisomerases written by James D. Wang, who first discovered DNA topoisomerase activity. It took several decades for the scientific community to fully appreciate the depth and impact of Delbrück’s statement.

According to the Watson and Crick DNA model, the two DNA strands are twisted around each other in such a way that they cannot be separated without uncoiling. In short, if DNA needs to be replicated, it first needs to be unwound. So how do the two strands get uncoiled during replication? This was the question Delbrück posed to Watson in his correspondence. I am not sure Watson or Crick had an answer to this question at the time. Also, we do not know what Watson’s reply to Delbrück’s letter was.

The world began to understand the true significance of this question when Delbrück published a theoretical paper in the journal of PNAS in 1954 titled 'On the Replication of Desoxyribonucleic Acid (DNA)'. In this paper, he clearly described the topological problem of DNA replication and proposed possible solutions. First, he suggested that the two strands could simply be pulled apart in opposite directions, but he ruled out this idea because of the enormous length of DNA molecules. Second, he proposed that one strand could be broken, another strand passed through the gap, and the break subsequently rejoined. According to Delbrück, breaking and rejoining were the only realistic ways to remove the coiling generated when DNA is opened.

A figure from the MaxDelbrück 1954 paper illustrating how DNA strands can be separated

What is remarkable is that he proposed this at a time when we had almost no understanding of how DNA replication actually occurred. The concepts of DNA polymerases, DNA helicases, and many of the proteins involved in separating DNA strands were still unknown. Today, we know that specialized enzymes called DNA topoisomerase perform precisely the function Delbrück envisioned in 1954, although it took more than two decades to identify, purify, and experimentally demonstrate this activity. What a genius!

What Delbrück’s paper did was open the door for alternative models proposing different ways in which the two strands of DNA could be separated during replication. Some of these models were outrageous, while others are still waiting to be fully tested experimentally. But most importantly, Delbrück’s work initiated a serious discussion on how DNA replicates when its two strands are tightly coiled around each other.

But Delbrück’s importance to biology went far beyond DNA topology. Long before questioning the double helix, he had already helped reshape how biologists think about mutations themselves. Before proposing how DNA could replicate and unknowingly laying the foundation for DNA topology, Delbrück was already well known for helping settle the debate between Lamarckism and Darwinism. In the early twentieth century, biology was still heavily influenced by Lamarckian thinking derived from Jean-Baptiste Lamarck. Lamarckism suggested that variations (or mutations) are directed by an organism’s needs and environment, whereas Darwinism proposed that variations arise randomly and that the environment merely selects the fittest among them. By the 1930s and 1940s, Darwinian evolution through natural selection was widely accepted in principle, but the origin of variation (aka mutations) was still under debate.

In 1943, Salvador Luria and Delbrück devised an elegant experiment in which they grew many separate bacterial cultures, exposed each culture to bacteriophages, and then counted the number of resistant colonies. The logic behind the experiment was simple but powerful. If the Lamarckian idea of adaptive mutation were correct, resistance should arise only after exposure to the phage, and similar numbers of resistant colonies should appear across all cultures, resulting in low variation. On the other hand, if the Darwinian idea were correct, mutations would occur randomly before exposure during bacterial growth, leading to large fluctuations in the number of resistant colonies between cultures.

What they observed were dramatic “fluctuations” in resistant colony numbers across cultures. Some cultures contained very high numbers of resistant colonies, whereas others had very few or none at all. Their observations strongly suggested that mutations are random and spontaneous, and that selection (in this case resistance to phage infection) does not cause mutations but merely reveals them. In many ways, one could argue that this experiment was among the earliest and most influential experiments leading to molecular biology. First, it was designed with remarkable elegance to address fundamental biological questions, including evolution itself. Second, they used rigorous statistical methods to estimate mutation rates, something almost unprecedented in microbiology at the time. In fact, what they called “fluctuation analysis” is still used today to calculate mutation rates. Their work showed that evolution does not anticipate the future; instead, it operates on random variation and selects what survives.

Delbrück and Luria later shared the 1969 Nobel Prize in Physiology or Medicine with Alfred Hershey for their pioneering work on bacteriophages and viral genetics.

What is particularly fascinating is that Delbrück was never formally trained as a biologist; in fact, he initially trained as a physicist. Born into an elite intellectual family, he studied astronomy, astrophysics, and later quantum mechanics in Germany. During the late 1920s and early 1930s, he worked with leading physicists across Europe, including John Lennard-Jones in Bristol, Niels Bohr in Copenhagen, and Wolfgang Pauli in Zurich. It is difficult to pinpoint exactly when his interest shifted toward biology, but one gets the sense that it happened sometime in the early 1930s. In particular, Bohr’s famous “Light and Life” lecture had a profound influence on him and helped redirect his career from theoretical physics toward biology.

In the early 1930s, genetics was still largely descriptive. Scientists knew that genes existed because of Mendelian inheritance, but nobody knew what genes physically were. DNA itself had not yet been recognized as the hereditary material, and many biologists still believed proteins carried heredity. At the same time, physics was undergoing a revolution through quantum mechanics, and physicists began wondering whether biological phenomena could also be explained in physical and molecular terms. Around this time, three scientists from very different backgrounds came together for a remarkable and unique study. A geneticist, Nikolai Timofeeff-Ressovsky, a radiation physicist, Karl Günther Zimmer, and Delbrück, a theoretical physicist, published a paper in 1935 titled On the Nature of Gene Mutation and Gene Structure (German: Über die Natur der Genmutation und der Genstruktur). The paper soon became known as the “Three-Man Paper” (Dreimännerarbeit).

The cover of the Green Pamphlet

Strangely, the authors published it in the journal 'Nachrichten von der Gesellschaft der Wissenschaften zu Göttingen', which ceased publication after only a few issues. Delbrück later joked in a 1978 oral interview that publishing there was like giving the paper “a funeral first class.” Because it appeared in a specialized German academy journal, the paper initially received very little international attention. Yet the paper survived through its many reprints, which were enclosed in a green cover and eventually became famous as the “Green Pamphlet.”

Today, this paper is widely regarded as one of the foundational texts of modern molecular biology. The authors argued that genes are not abstract hereditary “factors,” but actual physical entities composed of atoms. For the first time, they proposed that mutations are physical alterations in these atomic structures, suggesting that mutations could arise through the “rearrangement of atoms or dissociation of bonds.” Using X-ray mutation experiments in Drosophila, they showed that mutation frequency increases approximately linearly with radiation dose. This led to the application of target theory, where genes were treated as tiny physical targets struck by radiation. The logic behind this idea was simple yet revolutionary: if radiation hits a gene, it alters its atomic structure, and the altered structure becomes a mutation. In this way, they directly connected genetics with atomic physics. It was perhaps the clearest early statement that heredity could be understood molecularly.

Delbrück, in particular, introduced the idea that genes behave like unusually stable molecular systems. He argued that genes must possess stable structures while also retaining the ability to switch into alternative states, aka mutations. These ideas emerged from quantum mechanics and chemical bond theory, concepts largely unfamiliar to biologists at the time. Overall, the paper suggested that mutation is a molecular event rather than an unexplainable biological phenomenon. What makes this even more remarkable is that they proposed all of this in an era when DNA was not yet known to be the genetic material.

We might have lost this little gem in history if not for the preprints. Since these preprints were enclosed in a green cover and  they were labelled as green pamphlet. These preprints began circulating widely around the time World War II started. The war caused one of the largest scientific migrations in modern history and reshaped global science, especially in the United States and the United Kingdom. One could even argue that the scientific dominance of the United States over the past decades would not have been possible without this migration.

The movement of scientists also transformed biology, as many displaced physicists began exploring biological problems during and after the war. Biology became, in some sense, a safer intellectual refuge for physicists who had previously been pushed toward work on radar systems and nuclear weapons. The reprint became almost symbolic for physicists caught in the middle of the war because it suggested that biology could be understood using thermodynamics and quantum theory.

One such green pamphlet reached the hands of Erwin Schrödinger in 1942. Like many scientists of that period, Schrödinger was also a refugee of war. He had moved to Ireland at the invitation of then Irish Prime Minister Éamon de Valera to join the newly established Institute for Advanced Studies in Dublin.

In February 1943, Schrödinger began a lecture series at Trinity College Dublin titled What Is Life? The Physical Aspect of the Living Cell. These lectures were deeply influenced by the 1935 green pamphlet. Schrödinger spoke about genes as structures that he famously termed “aperiodic crystals.” Unlike ordinary crystals with repeating patterns, he argued, genes must contain highly ordered yet non-repetitive structures capable of encoding information. The lectures became enormously popular, attracting cabinet ministers, diplomats, scholars, and socialites alike. Encouraged by the overwhelming response, Schrödinger later compiled the lectures into a small book titled 'What Is Life?.'

This tiny 194-page book changed biology forever. It inspired many scientists to enter biology, including James Watson, Francis Crick, Maurice Wilkins, and Seymour Benzer, all of whom openly acknowledged its influence on their careers.

Without Schrödinger’s lectures and his little book, we might well have lost the Three-Man Paper (the Green Pamphlet) to history. There are certainly important differences between Schrödinger’s ideas and Delbrück’s theories from the original paper, but few would deny that Delbrück’s work formed the intellectual foundation for Schrödinger’s book. It is therefore fair to say that the Three-Man Paper represents one of the intellectual starting points of molecular biology.

Even though Delbrück did not coin the term “molecular biology”  (the term first appeared in a 1938 report to the Rockefeller Foundation by Warren Weaver), one could still argue that if anyone deserves to be called the founder of molecular biology, it would be Max Delbrück.

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Disclaimer: I do not own the copyright or claim ownership of any material shown in this article. The images were sourced from internet archives and are used here purely for educational purposes.