Genes Before DNA

How geneticists around the world struggled to bring the foundation of life's building blocks to light.

By Matthew Cobb|Thursday, July 23, 2015
Austrian physicist Erwin Schrödinger in 1929.
Ullstein Bild/Getty Images; background: Kenneth Eward/BioGrafx/Science Source

Trinity College sits in the heart of Dublin, its gray, three-story, neoclassical buildings positioned around lawns and playing fields. At the eastern end of the campus is another gray building, built in 1905 in a rather different style. This is the Fitzgerald Building, or the Physical Laboratory as it is called in deeply engraved letters on the stone lintel. On the top floor is a lecture theater, and in the late afternoon of the first Friday of February 1943, around 400 people crowded onto the varnished wooden benches.

Top: Schrödinger gave his “What Is Life?” lectures at the Fitzgerald Building at Trinity College in Dublin. Above: Seated second from the right, Schrödinger poses with peers and Irish Prime Minister Éamon de Valera, far left.
The Board of Trinity College Dublin; Irish Press Plc

According to Time magazine, among those lucky enough to get a seat were “Cabinet ministers, diplomats, scholars and socialites,” as well as the Irish prime minister, Éamon de Valera. They were there to hear the Nobel Prize-winning physicist Erwin Schrödinger give a lecture with the intriguing title “What Is Life?” The interest was so great that scores of people were turned away, and the lecture had to be repeated the following Monday.

Schrödinger arrived in Dublin after fleeing the Nazis — he had been working at Graz University in Austria when the Germans took over in 1938. Although he had a reputation as an opponent of Hitler, Schrödinger published an accommodating letter about the Nazi takeover, with the hope of being left alone. This tactic failed, and he had to flee the country in a hurry, leaving his gold Nobel medal behind. De Valera, who was interested in physics, offered Schrödinger a post in Dublin’s new Institute for Advanced Studies. And so the master of quantum mechanics found himself in Ireland.

On three consecutive Fridays, 56-year-old Schrödinger walked into the Fitzgerald Building lecture theater to give his talks, in which he explored the relationship between quantum physics and recent discoveries in biology.

Heredity vs. Physics

One of the topics he tackled was the nature of heredity. Like others before him, Schrödinger was struck by the fact that chromosomes are accurately duplicated during ordinary cell division (mitosis, the way in which an organism grows) and during the creation of the sex cells (meiosis). For your body to reach its current size, there have been trillions of mitotic cell divisions. And through all that copying and duplicating, the code has apparently been reliably duplicated. Furthermore, genes are reliably passed from one generation to another: Schrödinger explained to his audience that a well-known characteristic such as the Hapsburg, or Habsburg, lip — the protruding lower jaw shown by members of the House of Hapsburg — can be tracked over hundreds of years, without apparently changing.

An original copy of Schrödinger's book What Is Life? based on the popular, compelling lectures he gave in Dublin.
Agströmer Medico-Historical Library
For biologists, this apparently unchanging characteristic of genes was simply a fact. However, as Schrödinger explained to his Dublin audience, it posed a problem for physicists.

Schrödinger calculated that each gene might be composed of only 1,000 atoms. In that case, genes should be continuously shimmering and altering because the fundamental laws of physics and chemistry are statistical; although atoms overall tend to behave consistently, an individual atom can behave in a way that contradicts these laws. For most objects that we encounter, this doesn’t matter. Things such as tables or rocks or cows are made of so many gazillions of atoms that they don’t behave in unpredictable ways. A table remains a table; it does not spontaneously start to turn into a rock or a cow.

But if genes are made of only a few hundred atoms, they should display exactly that kind of uncertain behavior, and they shouldn’t remain constant over the generations, argued Schrödinger. And yet experiments showed that mutations occurred quite rarely, and when they did happen, they were accurately inherited.

Left to right: Charles V, Rudolf II and Charles II have protruding lower jaws, called the Hapsburg lip.
Form left: Yorck Project via Wikimedia; Web gallery of Art via Wikimedia; Granger NYC

Schrödinger outlined the problem in the following terms: 

“Incredibly small groups of atoms, much too small to display exact statistical laws … play a dominating role in the very orderly and lawful events within a living organism. They have control of the observable large-scale features which the organism acquires in the course of its development; they determine important characteristics of its functioning; and in all this, very sharp and very strict biological laws are displayed.”

The challenge was to explain how genes act lawfully, and cause organisms to behave lawfully, while being composed of a very small number of atoms, a significant proportion of which may be behaving unlawfully. To resolve this apparent contradiction between the principles of physics and the reality of biology, Schrödinger turned to the most sophisticated genetic theory that existed at the time, proposed by Nikolai Timoféef-Ressovsky, Karl Zimmer and Max Delbrück.

The Three-Man Paper

In 1926, Timoféef-Ressovsky, a Russian geneticist, collaborated with American geneticist Hermann Muller and showed that exposure to X-rays could induce mutations in genes. Shortly afterward, Timoféef-Ressovsky began a project with Zimmer, a radiation physicist, and Delbrück, a young German quantum physicist.

The trio decided to apply “target theory” — a central concept in the study of the effects of radiation — to genes. They bombarded a cell with X-rays to see how often different mutations appeared as a function of the radiation’s frequency and intensity. By doing so, they thought it should be possible to deduce the physical size of the gene (the “target”) and that measuring its sensitivity to radiation might reveal something about its composition.

The outcome of their collaboration was a joint German-language publication that appeared in 1935, called On the Nature of Gene Mutation and Gene Structure, more generally known as the Three-Man Paper.

The trio concluded that the gene was an indivisible physicochemical unit of molecular size, and they proposed that a mutation involved the alteration of a chemical bond in that molecule. Despite their best efforts, however, the nature of the gene, and its exact size, remained unknown.

Imagno/Getty Images
In Dublin, as Schrödinger explored the nature of heredity for his audience, he was forced to come up with an explanation of what exactly a gene contained. But even the Three-Man Paper, the most advanced theory at the time, couldn’t answer that question. And so, with nothing more than logic to support his hypothesis, Schrödinger argued that chromosomes “contain, in some kind of code-script, the entire pattern of the individual’s future development and of its functioning in the mature state.” This was the first time anyone clearly suggested genes might contain, or even simply could be, a code.

Taking his idea to its logical conclusion, Schrödinger argued that it should be possible to read the “code-script” of an egg and know “whether the egg would develop, under suitable conditions, into a black cock or into a speckled hen, into a fly or a maize plant, a rhododendron, a beetle, a mouse or a woman.”

Although this was partly an echo of the earliest ideas about how organisms develop and the old suggestion that the future organism was preformed in the egg, Schrödinger’s idea was very different. He was addressing the question of how the future organism was represented in the egg and the means by which that representation became biological reality. He was suggesting these were one and the same: The chromosome structures are instrumental in bringing about the development they foreshadow. They are law-code and executive power — or, to use another simile, they are like an architect’s plan and a builder’s craft — in one.

Speaking in Code

To explain how his hypothetical code-script might work — it had to be extremely complicated because it involved “all the future development of the organism” — Schrödinger resorted to some simple mathematics to show how the variety of different molecules found in an organism could be encoded.

Schrödinger calculated that if each biological molecule was determined by a word of between one and 25 letters and the word was composed of five different letters, there would be 372,529,029,846,191,405 different possible combinations — far greater than the number of known types of molecule found in any organism. Having shown the potential power of even a simple code, Schrödinger concluded that “it is no longer inconceivable that the miniature code should precisely correspond with a highly complicated and specified plan of development and should somehow contain the means to put it into operation.”

Although this was the first public suggestion that a gene contained something like a code, in 1892 a scientist named Fritz Miescher came up with something vaguely similar. In a private letter, Miescher argued that the various forms of organic molecules were sufficient for “all the wealth and variety of hereditary transmission [to] find expression just as all the words and concepts of all languages can find expression in 24 to 30 alphabetic letters.” Miescher’s view can appear far-seeing, especially given that he was also the discoverer of DNA, or nuclein, as it was known at the time. But Miescher never argued that nuclein was the material making up these letters, and his suggestion was not made public for nearly 80 years. Above all, the vague letter-and-word metaphor was nowhere near as precise as Schrödinger’s code-script concept.

Schrödinger then explored what the gene molecule might be made of and suggested that it was what he called a one-dimensional aperiodic crystal — a non-repetitive solid, with the lack of repetition being related to the existence of the code-script. The non-repetition provided the variety necessary to specify so many different molecules in an organism. Although Muller, American physicist Leonard Troland and Russian geneticist Nikolai Koltsov had all suggested two decades earlier that genes might grow like crystals, Schrödinger’s idea was far more precise. His vision of gene structure was focused on the non-repetitive nature of the code-script, rather than on the relatively simple parallel between the copying of chromosomes and the ability of crystals to replicate their structure.

Big Idea, Little Attention

Schrödinger’s words would have had little influence had they simply hovered in the Dublin air and briefly resonated in the minds of the more attentive listeners. The sole international report to describe the lectures, which appeared in Time magazine in April, did not refer in detail to anything that Schrödinger said, and there are no indications that any of his ideas escaped to the outside world. The only detailed account appeared in The Irish Press, which managed to condense his main arguments and included both the code-script and aperiodic crystal ideas. Other newspapers found it difficult to give the story the attention it deserved; when Schrödinger gave a version of his lectures in Cork in January 1944, the local newspaper, The Kerryman, gave his talk equal coverage to the Listowel Pig Fair. (There was good demand for the 126 pigs on sale, they reported.)

Schrödinger felt the public would be interested in his views, and as soon as he finished the lectures, he began to turn them into a book, which was eventually published by Cambridge University Press in December 1944. The combination of Schrödinger’s name, the intriguing title and a prestigious publisher with a global reach, coupled with the imminent end of the war, meant that the book was widely read and has remained in print ever since. Despite the commercial success of What is Life?, that was the end of Schrödinger’s excursion into biology. He never wrote publicly on the topic again, even after the discovery of the existence of the genetic code in 1953.

After Schrödinger founded wave mechanics and developed Schrödinger's equation, he fled to Ireland where he lectured on the possible roots of heredity.
SSPL/Getty Images
The book’s immediate impact can be seen from the enthusiastic reviews it received in both the popular press and in scientific journals. There were over 60 reviews in the four years after publication, although few writers noticed what now seem to be far-seeing ideas — the aperiodic crystal and the code-script — and it was translated into German, French, Russian, Spanish and Japanese.

There were two extended reviews in the leading scientific weekly Nature, one by geneticist J.B.S. Haldane, the other by the plant cytologist Irene Manton. Haldane got straight to the heart of the matter, picking up on the aperiodic crystal and the code-script innovations and making a link with the work of Koltsov. Manton also noted Schrödinger’s use of the term code-script, but she took it to mean “the sum of hereditary material” rather than a particular hypothesis about gene structure and function. The New York Times reviewer put his finger on the central point:

“The genes and chromosomes contain what Schrödinger calls a ‘code script,’ that gives orders which are carried out. And because we can’t read the script as yet, we know virtually nothing of growth, nothing of life.”

In contrast, some scientists later recalled they’d been unimpressed by the book. In the 1980s the Nobel Prize-winning chemist Linus Pauling claimed that he was “disappointed” on reading What Is Life? and stated, “It was, and still is, my opinion that Schrödinger made no contribution to our understanding of life.”

Also in the 1980s, another Nobel laureate, biochemist Max Perutz, wrote of Schrödinger: “What was true in his book was not original, and most of what was original was known not to be true even when the book was written.” In 1969, geneticist C.H. Waddington criticized Schrödinger’s aperiodic crystal concept as an “exceedingly paradoxical phrase.”

As well as these retrospective criticisms, some dissenting views were voiced when the book first came out. In a review, Delbrück was critical even though he received a publicity boost from Schrödinger’s espousal of his work in the Three-Man Paper. He claimed Schrödinger’s term aperiodic crystal hid more than it revealed:

“Genes are given this startling name rather than the current name ‘complicated molecule.’ … There is nothing new in this exposition, to which the larger part of the book is devoted, and biological readers will be inclined to skip it.”

This was distinctly ungenerous, as Schrödinger’s hypothesis was, in fact, quite precise and did not simply involve coining a new name. Delbrück concluded by grudgingly accepting that the book “will have an inspiring influence by acting as a focus of attention for both physicists and biologists.”

In another review, Muller said that he, too, expected the book would act as a catalyst for “an increasingly useful rapprochement between physics, chemistry and the genetic basis of biology.” Muller clearly felt aggrieved that Schrödinger had not cited his work, and he pointed out that he had suggested the parallel between gene duplication and crystal growth in 1921 (though Muller decided not to mention that he took this concept from Troland). He also dismissed the idea that there was anything novel in Schrödinger’s discussion of order and negative entropy, as these were both “quite familiar to general biologists.” Neither Delbrück nor Muller made any comment about the code-script idea.

Inspiring Nonetheless

Despite their overall skepticism, Delbrück and Muller were absolutely right: Schrödinger’s book did indeed inspire a generation of young scientists. The three men who won the Nobel Prize for their work on the structure of DNA — James Watson, Francis Crick and Maurice Wilkins — all claimed that What is Life? played an important part in their personal journeys toward the double helix.

In 1945 Wilkins was handed a copy of What is Life? by a friend when he was working on the atomic bomb in California. Shaken by the horror of Hiroshima and Nagasaki, Wilkins was seduced by Schrödinger’s writing and decided to abandon physics and become a biophysicist. Crick recalled that his 1946 reading of Schrödinger “made it seem as if great things were just around the corner.” Watson was an undergraduate when he read What is Life? and as a result, he shifted his attention from bird biology to genetics.

Even though some of the ideas developed in What is Life? were visionary and the book undoubtedly inspired some individuals who played a central role in 20th-century science, there are no direct links between Schrödinger’s lectures and the experiments and theories that were part of the decades-long attempt to crack the genetic code, and historians and participants differ about the significance of Schrödinger’s contribution.

The view of mutation put forward in the Three-Man Paper, which Schrödinger espoused so vigorously, had no effect on subsequent events, and his suggestion that new laws of physics would be discovered through the study of the material basis of heredity was completely mistaken. Even the code-script idea, which looks so prescient today, had no direct effect on how biologists looked at what was in a gene. None of the articles that later formed part of the discovery of the genetic code cited What is Life?, even though the scientists involved had read the book.

In fact, the meaning of Schrödinger’s “code-script” did not have the same richness as our “genetic code.” Schrödinger didn’t think there was a correspondence between each part of the gene and precise biochemical processes, which is what a code implies. Nor did he address the issue of what exactly the code-script contained, beyond the vague suggestion of a plan.

Ask any biologist today what the genetic code contains, and they will give you a one-word answer: information. Schrödinger did not use that powerful metaphor. It was completely absent from his vocabulary and his thinking, for the simple reason that it had not yet acquired the abstract, wide-ranging meaning we now give it.

“Information” was about to enter science, but had not done so when Schrödinger gave his lectures. Without that conception of the content of the code, Schrödinger’s insight was merely part of the zeitgeist, a hint of what was to come rather than a breakthrough that shaped all subsequent thinking.

Excerpted from Life's Greatest Secret: The Race to Crack the Genetic Code by Matthew Cobb. Available from Basic Books, a member of The Perseus Books Group. Copyright 2015.
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