The Molecule Of Life

Until the early 1950s, most scientists, including Linus Pauling, believed that protein—not nucleic acid—was the stuff that genes were made of. It took a kitchen blender to convince them otherwise.

Researchers knew that genes were hidden in the chromosomes, which themselves were composed of nucleoprotein, a tangled mixture of proteins and nucleic acids. But most thought that only the protein parts of the chromosomes were important. Only protein was thought to have the complexity necessary for determining the growth of an organism. Proteins, after all, were made of 20 or more different amino acids. The nucleic acids, made of just four building blocks called nucleotides, probably existed only to support the proteins.

Opinions did not change even when Oswald Avery, an American medical researcher, discovered in 1944 that DNA could by itself transfer genetic traits from one Pneumococcus bacterium to another. Pauling knew Avery and his work, but he did not accept the evidence. "I was so pleased with proteins, you know, that I thought that proteins probably are the hereditary material rather than nucleic acids—but that of course nucleic acids played a part," he said. "In whatever I wrote about nucleic acids, I mentioned nucleoproteins, and I was thinking more of the protein than of the nucleic acids."

It took another, more dramatic, set of experiments to kill the idea that genes were made of protein. In 1952, the American microbiologist Alfred Hershey and his colleague Martha Chase labeled bacterial viruses using different radioactive tags for their protein coats and nucleic acid cores. They then allowed the "hot" viruses to infect and replicate inside bacteria, stopping the process at specific stages and separating the viruses from the bacteria by whipping everything in a kitchen blender. By tracking the radioactive tags, they discovered that the viral protein remained outside the bacteria, doing nothing. The DNA from the viruses, on the other hand, was injected into the bacteria and showed up in viral offspring. Therefore, DNA alone was involved in replication.

As soon as he learned about the Hershey-Chase experiments at a scientific meeting in France in the summer of 1952, Pauling realized that the protein gene was a myth. He immediately switched his attention to DNA and started a new, and very fast, attack on its structure.

text continued from page 93

protein at all. After a decisive set of experiments by the American microbiologists Alfred Hershey and Martha Chase, completed in early 1952, it became clear that genes were made of a long-chain molecule called deoxyribonucleic acid, or DNA.

Pauling was still refining his protein models, altering the alpha helix to allow for turns, and proposing that the 510-picometer repeat in natural keratin resulted from a supercoiling of the long alpha helix molecule itself, like a piece of yarn wound around a finger. But he also became interested in DNA. Compared to proteins, he thought it would be a relatively simple problem. Instead of the 20 amino acids that went into proteins, DNA was made up of only four subunits, called nucleotides, each consisting of a sugar attached to a phosphate group and a large, flat carbon-and-nitrogen ring structure called a base. There had not been any very good X-ray studies of DNA published, but the fuzzy few that there were seemed to indicate that the DNA molecule was probably a helix.

With this in mind, in the fall of 1952 Pauling made a fast attack on the structure of DNA. He started by looking first at what little was known of the structure of the sub-units (unfortunately, no one had completed a good analysis of the size and shape of any nucleotide), then considering which rules of chemistry applied to this type of molecule. Again unfortunately, there was no peptide bond-like clue here either. And he got off on the wrong foot by overestimating DNA's density, leading him to think it might be made of three chains wrapped tightly around one another.

With poor basic information, and operating with the wrong density for DNA, Pauling next thought about the simplest way to make a regularly repeating structure. Just as he had pointed the amino acid side chains away from the center of the alpha helix, thus simplifying the problem of how to fit things into the middle of the molecule, he now pointed the flat DNA bases to the outside of his proposed structures, where they too would be out of the way. Having the bases pointed out meant that the phosphates would be packed tightly together at the DNA core, in the middle of the three intertwined chains. After a few days' work with pencil, ruler, and paper, Pauling had sketched a rough structure that seemed to match the available data. It was very tightly wrapped, but that was good in a way, because nature preferred a tight fit at the biomolecular level, so that fewer small molecules or ions could get inside and throw things off.

Pauling now felt he was on the verge of another great discovery. The only problem came at the core, where the phosphates were packed together so tightly that they were jostling one another. When Corey checked out Pauling's calculations in more detail, he reported back the disappointing news that there was no way the phosphates could fit as Pauling was proposing. For weeks, Pauling stretched and twisted and distorted his model as much as he felt he reasonably could. Finally he made the phosphates fit.

And he decided to publish. Only a month had passed since he had first sat down to take a serious look at the structure of DNA. There were still many questions to answer, such as why the phosphates, which would probably carry a negative charge, wouldn't repel each other and blow the structure apart. Pauling decided to ignore this question for the moment, as he had ignored the 510 picometer repeat with the alpha helix.

He had been right with the alpha helix, and he felt confident enough in himself to ignore the niggling problems about DNA as well. If his proposed DNA structure were right, the reasons for the odd phosphate behavior could be found later. Perhaps there were positive ions in the center of the molecule. Or there might be something unique to the physiology of chromosomes that altered phosphate chemistry. Pauling was willing to ignore the smaller questions as long as his major structure looked right.

And there was an additional reason to hurry. Pauling's second son, Peter, now a graduate student in the Cavendish Laboratory, was working with a couple of men who were also trying to crack the structure of DNA. Peter wrote his father about them: Jim Watson, a tall, thin, American postdoctoral fellow, and Francis Crick, an older British graduate student with a quick mind and a love of chatter. They were all part of Sir William Bragg's group, the ones Pauling had beaten twice, most recently to the structure of the alpha helix. Pauling did not think a postdoc and a grad student represented serious competition, but the structure of DNA was a great prize. He did not want to be the second to discover it.

So, at the end of December 1952, he and Corey sent in their article on DNA structure for publication in the Proceedings of the National Academy of Sciences. It would prove the greatest blunder Linus Pauling would ever make.

When Peter Pauling showed Watson and Crick a pre-publication draft of his father's DNA paper, they could not believe what they saw. As fans of Linus Pauling's, they had carefully imitated his techniques of model building and chemical rule making in their own attack on DNA. They, too, had considered a three-stranded structure a few months earlier, but had been lucky enough to show it to Rosalind Franklin, an x-ray crystallographer at nearby King's College, who had recently taken the world's best X-ray pictures of DNA. She tore it apart.

Not only have you got all those negatively charged phosphates in the middle, she said, but your molecule is too dense. Her own studies had shown that in the body, DNA soaked up a great deal of water, too much to be accounted for by the three-stranded model. She was convinced that DNA existed in two forms, one "dry" and more dense, the other "wet" and fully extended. The phosphates need to be on the outside, she said, where they could be encased in water. She eventually showed Watson and Crick her X-ray photos of the pure "wet" form of DNA, which put them on the right track.

Now, looking at Pauling's paper, Watson and Crick were ecstatic. The master of structural chemistry had made an elementary mistake by putting his phosphates at the core. The density was wrong, and the negative phosphates would repel each other. There was still a chance for them to interpret the structure first. Crick wrote Pauling a short, acidic note in response to his paper, noting dryly, "We were very struck by the ingenuity of the structure. The only doubt I have is that I do not see what holds it together."

Then he and Watson went back to work. Within a few months, the two of them pulled off the scientific coup of the century, coming up with a new DNA structure made of two complementary chains wound around each other to form a spiral—they called it a double helix—each of which, when separated, could form another, identical chain. This was exactly what Pauling had described as a likely feature of the genetic material four years earlier.

Within a few weeks of reading Watson and Crick's description of their model, Pauling graciously agreed that it looked as if they had gotten it right. He continued thinking about DNA—correcting the Watson and Crick structure on one point involving a hydrogen bond—and encouraged workers in his laboratories to do DNA research. Throughout, he maintained his sense of humor. When Alex Rich, one of the researchers in Pauling's group, was later making progress in his own DNA studies, Pauling stuck his head into the office and said, "You work hard on that problem, Alex. I like most of the important discoveries to be made in Pasadena."

Getting DNA wrong—very publicly—was, however, a blow to Pauling's pride, and an error he would regret for the rest of his life. Watson and Crick would go on to win the Nobel Prize for their discovery, and work on DNA and its biological function would dominate the life sciences for the next fifty years. Pauling would never play a significant role in it.

And rarely would a year go by after that without some journalist asking Pauling where he had gone wrong. Sometimes he said it was the incorrect density data. Sometimes he suggested that it was muddy X-ray photos. Ava Helen finally tired of hearing the excuses and cut through them all with a simple question: "If that was such an important problem," she asked, "why didn't you work harder on it?"

Pauling, surrounded by molecular models, in his Caltech office around 1957.

Was this article helpful?

0 0

Post a comment