Brilliant Blunders: From Darwin to Einstein - Colossal Mistakes by Great Scientists That Changed Our Understanding of Life and the Universe (18 page)

Pauling started to turn his attention to DNA only in the summer of 1951. Until the early 1950s, most life scientists subscribed to the protein paradigm: the view that proteins, rather than nucleic acids, formed the foundation for life and were the crucial players in reproduction, growth, and regulation. The roots of this view could be traced to biologist Thomas H. Huxley (“Darwin’s Bulldog”), who believed that the protoplasm—the living part of the cell—was the source
of all of life’s attributes. Proteins, which are built up of amino acids in a long chain, make up a large fraction of all living cells, while nucleic acids, as their name implies, were found first in the nuclei of cells.

The early work on the structure and constitution of the nucleic acids by biochemist Phoebus Levene did not help to spark interest in these molecules. If anything, his studies achieved precisely the opposite effect.
Levene managed to distinguish the deoxyribonucleic acid (DNA) from ribonucleic acid (RNA), and to find some of their properties. But his results generated the impression that these were rather simple and dull substances unsuited for the complex tasks of governing growth and replication. In the words of cytologist Edmund Beecher Wilson (in 1925):
“The nucleic acids of the nucleus are on the whole remarkably uniform . . . In this respect they show a remarkable contrast to the proteins, which, whether simple or compound, seem to be of inexhaustible variety.” This impression persisted throughout the 1940s. By then, DNA was known to be composed of unbranched chains of units called
nucleotides.
The nucleotides themselves also appeared to be fairly uncomplicated, with each one containing three subunits: a
phosphate
group (a phosphorus atom bonded to four oxygen atoms), a five-carbon
sugar,
and one of four nitrogen-containing
bases.
The four bases were:
cytosine
and
thymine,
which were single ringed; and
adenine
and
guanine,
which were both double ringed (see figure 13). What was still not known, even in 1951, was the actual structure: how exactly the subunits connected to each other to form nucleotides, and the nature of the links between the nucleotides themselves. However, while all of this seemed to be fairly interesting from a chemical perspective, at the end of 1951
most geneticists still believed that DNA’s only role was structural, acting perhaps as a scaffold for the more sophisticated proteins rather than being directly related to heredity.

This fact in itself was somewhat surprising, given that in a paper published back in 1944, biologists Oswald Avery, Colin MacLeod, and Maclyn McCarty provided strong experimental evidence that the genetic material of living cells was composed of
DNA.
Avery and his colleagues grew large quantities of virulent bacteria, and after managing to separate them into their biochemical constituents, they concluded that DNA molecules—and not proteins or fats—were the components responsible for converting nonvirulent bacteria into virulent ones. In a May 1943 letter describing the results to his bacteriologist brother, Roy, Avery concluded,
“So there’s the story, Roy—right or wrong it’s been good fun and lots of work.” The reason that Avery’s findings
did not get the attention they deserved may have had to do with the fact that since none of the three scientists was a geneticist, their conclusions were formulated with such caution that many of the life scientists failed to appreciate their full import. The statement in the paper read: “If it is ultimately proved beyond reasonable doubt that the transforming activity of the material described is actually an inherent property of the nucleic acid, one must still account on a chemical basis for the biological specificity of its action.” Still, careful readers should
have taken notice of the paper’s summary: “The data obtained . . . indicate that, within the limits of the methods, the active fraction contains no demonstrable protein . . . and consists principally, if not solely, of a highly polymerized, viscous form of desoxyribonucleic acid [DNA].”

Figure 13

Pauling was familiar with Avery’s work, but even he admitted in a later interview that at the time he did not believe that DNA had much to do with heredity: “I knew the contention that DNA was the hereditary material. But I didn’t accept it; I was so pleased with proteins, you know, that I thought that proteins probably are the hereditary material, rather than nucleic acid.” Chemist Peter Pauling, Linus’s son, also affirmed that this had indeed been his father’s attitude. In a short article written in 1973, Peter reported,
“To my father, nucleic acids were interesting chemicals, just as sodium chloride [ordinary table salt] is an interesting chemical, and both presented interesting structural problems.”

Nevertheless, toward the end of 1951,
an unusual paper by biochemist Edward Ronwin, then at the University of California at Berkeley, intrigued Pauling sufficiently to prod him into action. The paper, entitled “A Phospho-tri-anhydride Formula for the Nucleic Acids,” appeared in November 1951. In it, Ronwin proposed a new “design” for DNA, in which each phosphorus atom connected to five oxygen atoms, while Pauling—the consummate structural chemist—was absolutely convinced that it had to link only to four. Annoyed, Pauling fired a quick communication to the editor of the
Journal of the American Chemical Society
(together with chemist Verner Schomaker) in which they first noted that
“in formulating a hypothetical structure for a substance, one must take care that the structural elements of which use is made are reasonable ones.” Their conclusion was even more dismissive: “The ligation of five oxygen atoms about each phosphorus atom is such an unlikely structural feature,” they said, that the proposed formula for DNA “deserves no serious consideration.”
Ronwin retorted by pointing out that other substances in which phosphorus was bonded to five oxygen atoms did exist.
Pauling and Schomaker had to withdraw their
disparaging statement, but they still insisted correctly on the fact that structures of this type were extremely sensitive to moisture, which made them unlikely candidates for DNA. This exchange would have been insignificant except that it did get Pauling thinking about how DNA might be constructed. To make progress, however, he needed high-quality X-ray diffraction photographs of DNA, since the ones available in print were old photos taken by William Astbury and Florence Bell in 1938 and 1939. Unfortunately, good X-ray photos were not easy to come by. Caltech did produce new photographs in the early 1950s, but, surprisingly, those turned out to be of inferior quality to those of Astbury and Bell. While weighing his options,
Pauling heard that Maurice Wilkins of King’s College, London, had generated what were described as “good fibre pictures of nucleic acid.” Deciding that he had nothing to lose, Pauling wrote to Wilkins to inquire whether the latter was prepared to share those photos. Unbeknown to Pauling, however, the activity around DNA in England was rapidly approaching frenzy.

Three separate events, all happening in 1951, proved to be fateful for the “race” to uncover the structure of DNA. In that year, Francis Crick, at age thirty-five, was working at Cambridge toward a PhD degree in biology after having been bored with physics. (He later described his work on the viscosity of water as “the dullest problem imaginable.”) His mathematical background would be crucial for the discoveries to come. In the same year, James Watson, then twenty-three, arrived at Cambridge to learn about X-ray diffraction from Max Perutz. Watson had completed his PhD at the University of Indiana on the effects of X-rays on viruses and later had some training in nucleic acid chemistry at the University of Copenhagen. Also in 1951, Rosalind Franklin, then thirty-one, came to King’s College, after having completed three years of research in Paris, where she became proficient in X-ray diffraction techniques.

Franklin, who came from an erudite banking family, had earned
her PhD from Cambridge in 1945. When she arrived at King’s College, physicist Maurice Wilkins was hoping that by virtue of her being an accomplished crystallographer, she would help him in his studies of molecular structure. That Wilkins would expect that of Franklin was not at all surprising, since at the time, according to Watson’s account,
“molecular work on DNA in England was, for all practical purposes, the personal property of Maurice Wilkins.” This was not at all, however, what Franklin had in mind when she signed up to come to King’s, and she had good reasons for her different presumption. Sir John Randall, director of the college’s Biophysics Research Unit, had written her a letter in which he described her job as follows:
“This means that as far as the experimental X-ray effort is concerned there will be at the moment only yourself and Gosling [Raymond Gosling, who was a graduate student at the time], together with the temporary assistance of a graduate from Syracuse, Mrs. Heller.” Franklin was therefore under the logical impression that she was going to be her own boss as far as the DNA work was concerned—an attitude that clearly conflicted with Wilkins’s assumptions. Consequently, Franklin and Wilkins were bound to clash, and they did. Later, they ended up working separately, even though they shared the same laboratory quarters.

By contrast, Watson and Crick, who were sharing an office at Cambridge, hit it off right away. Watson described Crick as
“no doubt the brightest person I have ever worked with and the nearest approach to Pauling I have ever seen.” The two men brought together rather different but complementary expertise, traits, and temperaments. As Crick noted in an interview,
“The interest was that his [Watson’s] background was in phage work which I had only read about and did not know first hand and my background was in crystallography which he had only read about and did not know first hand.” It is amusing to read how they described each other’s personality. Referring to Crick’s assuredness, puckish wit, and habit to speak his mind, Watson wrote about him,
“I have never seen Francis Crick in a modest mood.” He also added that Crick “talked louder and faster than anyone else.” On the other hand, Crick wrote about
Watson,
“Jim was distinctly more outspoken than I was.” Despite the different backgrounds, something clicked immediately between the two. Crick suspected that this was “because a certain youthful arrogance, a ruthlessness, and an impatience with sloppy thinking” came naturally to both of them. Their thought processes were also fairly similar. In Crick’s words, “He was the first person I had met who thought the same way about biology as I did . . . I decided that genetics was the really essential part, what the genes were and what they did.”

There was something else that made the Watson-Crick collaboration truly powerful. Because neither of them was professionally senior to the other, they could afford to be brutally honest in criticizing each other’s ideas. This type of intellectual honesty is sometimes missing in relationships burdened by formal politeness, bowing to one’s superiority, or by one or the other pulling rank. This is how Crick himself described his interaction with Watson:
“If either of us suggested a new idea, the other, while taking it seriously, would attempt to demolish it in a candid but nonhostile manner.” According to Crick, Watson
“was determined to discover what genes were and hoped that solving the structure of DNA might help.” This turned out to be absolutely true.

One may still wonder what it was that convinced Watson and Crick that the DNA structure was at all solvable rather than being an irregular mess. Conceivably, it was a talk Maurice Wilkins had given at a meeting in Naples, Italy, in the spring of 1951—a meeting that Watson attended. Wilkins succeeded in pulling extremely thin fibers of the sodium salt of DNA, and in producing X-ray photographs that were significantly superior to the ones by Astbury and Bell. The pictures showed a crystalline form of DNA, which indicated to Watson that the structure was regular. These were the same pictures that Pauling had requested from Wilkins.

Upon receiving Pauling’s letter, Wilkins, who was fully aware of Pauling’s abilities when it came to molecular structure, did not quite know what to do about the request. Eventually, he replied politely that his pictures were not ready to share until he had the opportunity
to carry out some additional investigations. Pauling did not give up, and he decided to try his luck with Randall, only to be refused again on the grounds that
“it would not be fair to them [Wilkins and his collaborators], or to the efforts of our laboratory as a whole, to hand these over to you.” So by the end of 1951, Pauling was still unable to see any X-ray diffraction images of reasonable quality.

Meanwhile, Watson and Crick were becoming increasingly obsessed with the desire to beat Pauling at deciphering the structure of DNA. The Austrian-American biochemist Erwin Chargaff, who met Watson and Crick in May 1952, gave a humorous description of the dynamic duo:
“One, thirty-five years old; the looks of a fading racing tout, something out of Hogarth . . . The other, quite undeveloped at twenty-three, a grin, more sly than sheepish; saying little, nothing of consequence.” Even funnier was Chargaff’s depiction of the burning ambition of the two scientists:
“So far as I could make out, they wanted, unencumbered by any knowledge of the chemistry involved, to fit DNA into a helix. The main reason seemed to be Pauling’s alpha-helix model of a protein.” Indeed, even though Pauling was unaware of it, Watson (in particular) and Crick (to some extent) saw themselves as participating in a race against him.