Life's Greatest Secret (2 page)

Sutton’s insight – which Boveri soon claimed he had at the same time – was not immediately accepted.
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First there was a long tussle over whether Mendel’s theory applied to all patterns of heredity, and then people argued over whether there truly was a link with the behaviour of chromosomes.
¹⁰
In 1909, Wilhelm Johannsen coined the term ‘gene’ to refer to a factor that determines hereditary characters, but he explicitly rejected the idea that the gene was some kind of physical structure or particle. Instead he argued that some characters were determined by an organised predisposition (writing in German, he used the nearly untranslatable word
Anlagen
) contained in the egg and sperm, and that these
Anlagen
were what he called genes.
¹¹

One scientist who was initially hostile to the new science of what was soon known as ‘genetics’ was Thomas Hunt Morgan, who also worked at Columbia (by this time Sutton had returned to medical school; he never completed his PhD).
¹²
Morgan had obtained his PhD in marine biology, investigating the development of pycnogonids or sea spiders, but he had recently begun studying evolution, using the tiny red-eyed vinegar fly,
Drosophila
.
¹³
Morgan subjected his hapless insects to various environmental stresses – extreme temperatures, centrifugal force, altered lighting conditions – in the vain hope of causing a change that could be the basis of future evolution. Some minor mutations did appear in his fly stocks, but they were all difficult to observe. In 1910, Morgan was on the point of giving up when he found a white-eyed fly in his laboratory stocks. Within weeks, new mutants followed and by the summer there were six clearly defined mutations to study, a number of which, like the white-eyed mutant, seemed to be expressed more often in males than in females. Morgan’s early doubts about genetics were swept away by the excitement of discovery.

By 1912, Morgan had shown that the white-eyed character was controlled by a genetic factor on the ‘X’ sex chromosome, thereby providing an experimental proof of the chromosomal theory of heredity. Equally importantly, he had shown that the shifting patterns of inheritance of groups of genes was related to the frequency with which pairs of chromosomes exchanged their parts (‘crossing over’) during the formation of egg and sperm.
¹⁴
Characters that tended to be inherited together were interpreted as being produced by genes that were physically close together on the chromosome – they were less likely to be separated during crossing over. Conversely, characters that could easily be separated when they were crossed were interpreted as being produced by genes that were further apart on the chromosome. This method enabled Morgan and his students – principally Alfred Sturtevant, Calvin Bridges and Hermann Muller – to create maps of the locations of genes on the fly’s four pairs of chromosomes. These maps showed that genes are arranged linearly in a one-dimensional structure along the length of the chromosome.
¹⁵
By the 1930s, Morgan’s maps had become extremely detailed, as new staining techniques revealed the presence of hundreds of bands on each chromosome. As Sutton had predicted, the patterns of these bands could be linked to the patterns with which mutations were inherited, so particular genes could be localised to minute fragments of the chromosome.

As to what genes were made of, that remained a complete mystery. In 1919, Morgan discussed two alternatives, neither of which satisfied him. A gene might be a ‘chemical molecule’, he wrote, in which case ‘it is not evident how it could change except by altering its chemical constitution’. The other possibility was that a gene was ‘a fluctuating amount of something’ that differed between individuals and could change over time. Although this second model provided an explanation of both individual differences and the way in which organisms develop, the few results that were available suggested that it was not correct. Morgan’s conclusion was to shrug his shoulders: ‘I see at present no way of deciding’, he told his readers.
¹⁶

Even fourteen years later, in 1933, when Morgan was celebrating receiving the Nobel Prize for his work, there had been little progress. As he put it starkly in his Nobel Prize lecture: ‘There is no consensus of opinion amongst geneticists as to what the genes are – whether they are real or purely fictitious.’ The reason for this lack of agreement, he argued, was because ‘at the level at which the genetic experiments lie, it does not make the slightest difference whether the gene is a hypothetical unit, or whether the gene is a material particle. In either case the unit is associated with a specific chromosome, and can be localized there by purely genetic analysis.’
¹⁷
It may seem strange, but for many geneticists in the 1930s, what genes were made of – if, indeed, they were made of anything at all – did not matter.

In 1926, Hermann Muller made a step towards proving that genes were indeed physical objects when he showed that X-rays could induce mutations. Although not many people believed his discovery – among the doubters was his one-time PhD supervisor Morgan, with whom he had a very prickly relationship – within a year his finding was confirmed. In 1932, Muller moved briefly to Berlin, where he worked with a Russian geneticist, Nikolai Timoféef-Ressovsky, pursuing his study of the effects of X-rays. Shortly afterwards, Timoféef-Ressovsky began a project with the radiation physicist Karl Zimmer and Max Delbrück, a young German quantum physicist who had been working with the Danish physicist Nils Bohr. The trio decided to apply ‘target theory’ – a central concept in the study of the effects of radiation – to genes.
¹⁸
By bombarding a cell with X-rays and seeing how often different mutations appeared as a function of the frequency and intensity of the radiation, they thought that it should be possible to deduce the physical size of the gene (the ‘target’), and that measuring its sensitivity to radiation might reveal something of its composition.

The outcome of this 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.
¹⁹
The article summarised nearly forty studies of the genetic effects of radiation and included a long theoretical section by Delbrück. The trio concluded that the gene was an indivisible physicochemical unit of molecular size, and 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. As Delbrück explained in the paper, things were no further on from the alternatives posed by Morgan in 1919:

We will thus leave unresolved the question of whether the individual gene has a polymeric form that arises through the repetition of identical structures of atoms, or whether it exhibits no such periodicity.

The Russian geneticist Nikolai Koltsov was bolder than Delbrück or Morgan. In a discussion of the nature of ‘hereditary molecules’ published in 1927, Koltsov, like Delbrück, argued that the fundamental feature of genes (and therefore of chromosomes) was their ability to replicate themselves perfectly during cell division.
²¹
To explain this phenomenon, Koltsov proposed that each chromosome consisted of a pair of protein molecules that formed two identical strands; during cell division, each strand could be used as a template to produce another, identical, strand. Furthermore, he suggested that because these molecules were so long, the amino acid sequences along the proteins could provide massive variation that might explain the many functions of genes.
²²
However perceptive this idea might look in the light of what we now know – the double helix structure of DNA and the fact that genes are composed of molecular sequences – Koltsov’s argument was purely theoretical. Furthermore, it was not unique – in a lecture given in 1921, Hermann Muller picked up on a suggestion by Leonard Troland from 1917 and drew a parallel between the replication of chromosomes and the way in which crystals grow:

each different portion of the gene structure must – like a crystal – attract to itself from the protoplasm materials of a similar kind, thus moulding next to the original gene another structure with similar parts, identically arranged, which then become bound together to form another gene, a replica of the first.

In 1937, the British geneticist J. B. S. Haldane came up with a similar idea, suggesting that replication of genetic material might involve the copying of a molecule to form a ‘negative’ copy of the original.
²⁴
Koltsov’s views were initially published in Russian and then translated into French, but like Haldane’s speculation they had no direct influence on subsequent developments.
²⁵
Koltsov died in 1940, aged 68, having been accused of fascism because of his opposition to Stalin’s favoured scientist, Trofim Lysenko, who denied the reality of genetics.
²⁶

Koltsov’s assumption that genes were made of proteins was widely shared by scientists around the world. Proteins come in all sorts of varieties that could thereby account for the myriad ways in which genes act. Chromosomes are composed partly of proteins but mainly of a molecule that was then called nuclein – what we now call deoxyribonucleic acid, or DNA. The composition of this substance showed little variability – the leading expert on nucleic acids was the biochemist Phoebus Levene, who for over two decades explained that nucleic acids were composed of long chains of repeated blocks of four kinds of base (in DNA these were adenine, cytosine, guanine and thymine – subsequently known by their initials – A, C, G and T) which were present in equal proportions.
²⁷
This idea, which was called the tetranucleotide hypothesis (‘tetra’ is from the Greek for four) dominated thinking about DNA; it suggested that these long and highly repetitive molecules probably had some structural function, unlike the minority component of chromosomes, proteins, which were good candidates for the material basis of genes simply because they were so variable. As Swedish scientist Torbjörn Caspersson put it in 1935:

If one assumes that the genes consist of known substances, there are only the proteins to be considered, because they are the only known substances which are specific for the individual.

This protein-centred view of genes was reinforced that same year when 31-year-old Wendell Stanley reported that he had crystallised a virus, and that it was a protein.
²⁹
Stanley studied tobacco mosaic disease – a viral disease that infects the tobacco plant. Stanley took an infected plant, extracted its juice and was able to crystallise what looked like a pure protein that had the power to infect healthy plants. Although viruses were mysterious objects, in 1921 Muller had suggested that they might be genes, and that studying them could provide a route to understanding the nature of the gene.
³⁰
Viruses, it appeared, were proteins, so presumably genes were, too. During the 1930s, many researchers, including Max Delbrück, began studying viruses, which were considered to be the simplest forms of life. Whether viruses are alive continues to divide scientists; whatever the case, this approach of studying the simplest form of biological organisation was extremely powerful. Delbrück, along with his colleague Salvador Luria, focused on bacteriophages (or ‘phage’) – viruses that infected bacteria, and in the 1940s an informal network of researchers called the phage group grew up around the pair as they tried to make fundamental discoveries that would also apply to complex organisms.
³¹

Stanley’s discovery caused great excitement in the press – for the
New York Times
it meant that ‘the old distinction between life and death loses some of its validity’. Although within a few years valid doubts were expressed about Stanley’s claim that he had isolated a pure protein – water and other contaminants were present and, as he admitted, it was nearly impossible to prove that a protein was pure – the overwhelming view among scientists was that genes, and viruses, were proteins.
³²

The most sophisticated attempt to link this assumption with speculation about the structure of genes was made in 1935 by the Oxford crystallographer Dorothy Wrinch. In a talk given at the University of Manchester, she suggested that the specificity of genes – their ability to carry out such a wide variety of functions – was determined by the sequence of protein molecules that were bound perpendicularly to a scaffold of nucleic acids, a bit like a piece of weaving. As she emphasised, however, ‘there is an almost complete dearth of experimental and observational facts upon which the testing and further development of the hypothesis now put forward must necessarily depend.’ Nevertheless, her conclusion was optimistic, as she encouraged her colleagues to explore the nature of the chromosome and of the gene:

The chromosome is not a phenomenon belonging to a closed field. Rather it should take its place among the objects worthy of being treated with all possible subtleties and refinement of concept and technique belonging to all the sciences. A concerted attack in which the full resources of the world state of science are exploited can hardly fail.

*

In the 1930s, most geneticists were not particularly concerned with finding out what genes are made of; they were more interested in discovering what genes actually do. There was a potential link between these two approaches. As the
Drosophila
geneticist Jack Schultz put it in 1935, by studying the effects of genes it should be possible ‘to find out something about the nature of the gene’.
³⁴
One of the scientists who took Schultz’s suggestion very seriously was George Beadle, who had studied the genetics of eye colour in
Drosophila
in Morgan’s laboratory, alongside the Franco-Russian geneticist Boris Ephrussi. When Ephrussi returned to Paris, Beadle followed him to continue their work. Their objective was to establish the biochemical basis of the mutations that changed the eye-colour of
Drosophila
flies. Beadle and Ephrussi’s experiments failed: the biochemistry of their system was too complicated, and they were unable to extract the relevant chemicals from the fly’s tiny eyes. They knew the genes that were involved, and they knew the effect they had on eye colour, but they did not know why.