November 7, 2019
When it was first discovered by complete accident in the late 1860s by Friedrich Miescher, DNA was nothing more than a new substance that was found in an attempt to study the proteins of a white blood cell. He, nor anybody else in the scientific community, fully understood the importance or the potential of this unknown substance. Many years later, after little research was done on DNA, a Russian biochemist by the name of Phoebus Levene attempted to decipher the structure of the substance. He was a recognized researcher, who had published more than 700 papers on the chemistry of biological molecules over the course of his career. He found the three major components of a nucleotide and he was able to identify the carbohydrates that distinguished RNA and DNA, which laid the foundation for future discoveries about DNA. But by far, the biggest contribution to solving the mystery was identifying the way RNA and DNA molecules are put together. Though this was essential to solving the mystery, he and many other scientists were still baffled by the way that individual nucleotides of DNA were arranged. In continuation of Levene’s work, Austrian biochemist Erwin Chargaff was able to define specific rules of nucleotides. He determined that the same nucleotides do not repeat in the same order, as was originally proposed by Levene. In other words, he found that DNA has fundamental properties. In particular, the amount of adenine (A) is usually similar to the amount of thymine (T), and the amount of guanine (G) usually approximates the amount of cytosine (C).1 It took countless hours and a little bit of luck to finally put all the evidence together to discover the structure of DNA. It took two close friends to eventually solve the mystery, and their names were James Watson and Francis Crick.
Francis Crick was always interested in finding the structure of proteins, and eventually saw that discovering the structure of DNA would not be the Rosetta Stone for unraveling the true secret of life. Rather, he realized it would instead provide the key to enable us to find out how genes determined, among other characteristics, the color of our hair, our eyes, most likely our comparative intelligence, and maybe even our potential to amuse others. Though Crick was willing, none of his colleagues were nearly as interested, and the enormous amount of time and money that would have to be put into the project frightened them. As if it were destiny, Crick knew of two scientists already interested in DNA who had been working on it for several years already. He knew of King’s College’s Maurice Wilkins and Rosalind (Rosy) Franklin, who were doing excellent research using X-ray diffraction to look at DNA’s structure. Though Wilkins and Franklin did not always get along well, they both shared the common goal of solving the structure. They were competing against Linus Pauling, an American who had partly solved the structure of proteins, his structure known as the α-helix, and who was almost certainly set on solving a model for DNA. Watson was actually already involved with DNA, since he was in Europe working on a postdoctoral fellowship to learn DNA’s biochemistry. He wanted to know what a gene was even though he never truly pursued chemistry. In fact, he even went out of his way to avoid chemistry and physics courses while pursuing his undergraduate degree. After going to a scientific meeting in Naples, and listening to a talk by Wilkin, Watson was inspired and got excited about chemistry. Watson figured that if genes could, they must have a regular structure that could theoretically be solved in a straightforward fashion.2 In other words, he knew that if he worked hard enough, he could solve the structure of DNA.
With Watson’s interest peaked, he applied to work alongside Max Perutz, who was interested in the structure of large biological molecules. He planned to learn how to solve X-ray diffraction pictures (a major component in solving the structure) from Max at the Cavendish Laboratory of Cambridge University, where he would eventually meet a young Francis Crick working on his PhD. Watson found a lot of enjoyment in talking to Crick and shared a similar perspective on the importance of DNA, in that it was more significant than proteins. Pauling made the model simply from “common sense” rather than complicated mathematical reasoning, so Francis and Crick saw no reason why they couldn’t do the same. They eventually determined the best course of action would be to regard the sugar phosphate backbone as regular (meaning that the structure was a given, based on previous known work) and they should search for a helical three-dimensional configuration. After working with various formations for their structure, eventually they decided that a three-chain helical model could be supported by Wilkins and Rosalind’s pictures. This model had the nucleotides on the outside rather than the inside. The model certainly fit with the general locations of the X-ray reflections provided, so they called Wilkins and Rosalind to show their potential success. They were sternly and quickly proven wrong, however, when Franklin provided evidence against their argument. After her corrections and criticisms the number of potential DNA models alarmingly increased. The news of their failure quickly spread throughout the laboratory and eventually it was determined by their superiors that Watson and Crick were inept at making models, and they were advised to abandon the project. Crick was advised to continue his thesis, and was told that, with any luck, a year to eighteen months of steady work could help him earn his PhD, allowing him to seek employment elsewhere. Watson on the other hand, studied RNA of tobacco mosaic virus (TMV).3 Though they were discouraged, the two friends did not give up as they worked on the model in secrecy.
Pauling eventually started working on DNA, and Watson was later given Pauling’s manuscript for his paper on the structure of DNA. To Watson’s and the Chemistry department’s delight, Pauling had also proposed a three-stranded structure. Pauling was wrong! It was only a matter of time before Pauling’s colleagues corrected him, so Watson and Crick had to work even harder. Watson rushed immediately to Wilkins and Rosalind to tell them the great news. Watson pointed out to Rosalind the superficial resemblance between Pauling’s three-chain helix and the model that he and Crick had provided fifteen months earlier. She reacted in the same way she did fifteen months prior, as she angrily told him that the true structure would be obvious if he would stop blubbering and look at her X-ray evidence. After suggesting that Rosalind was misinterpreting her data, Watson left an angry Rosalind ready to strike him, and spoke to Wilkins about Pauling’s flaw. Wilkins then revealed that he had been quietly duplicating some of Rosalind’s X-ray work. One picture, Rosalind’s Photo 51, provided indisputable evidence that DNA had a helical structure. Watson told his superiors all that he had learned and was actually encouraged to start building models. Watson had originally paired the bases of nucleotides with each other in a “like-to-like” pattern (Adenine paired with Adenine, Guanine with Guanine, etc.), as he believed that this would explain how DNA is replicated and how exact copies are made. He was quickly proven wrong, however, when another colleague, crystallographer Jerry Donohue, informed him that the forms of the molecules he had been using were false. Although Watson did not want to believe it, he knew that Donohue was right. Even if Watson was right about the base pairings, Crick did not like the fact that the proposed structure gave no explanation for Chargaff’s rules (adenine equals thymine, guanine equals cytosine). Watson continued to work on the base pairings, randomly shifting the model of bases in and out of various pairing possibilities when he suddenly he noticed something. He noticed that an adenine-thymine pair had an identical shape to that of a guanine-cytosine pair. Suddenly, Chargaff’s rules made sense, and he realized that this double helix and this base pairing (Adenine with Thymine and Cytosine with Guanine), supported what was known about DNA replication. Later, Watson would show Crick his grand discovery. Even though they still had to prove that the pairings fit in their backbone configuration, Crick was not hesitant to tell everyone within hearing distance, including members of a local pub, that they had found the secret to life.4
As it turns out, Crick was right, and the discovery of the structure of DNA has allowed scientists to do things that many were once considered science fiction. With the structure of DNA unlocked, scientists have been able to better understand life and its complexities. In 1990, researchers from twenty research centers and universities in six countries were able to come together to work on an ambitious project, the Human Genome Project. The goal of the project was to determine all 3 billion bases in the entire human genome, as well as how many genes we actually have in our genome, which in turn, helped scientists determine which mistakes in someone’s DNA sequence could increase or decrease the risk of getting a disease.5 Eventually this would lead to obtaining the ability to detect and diagnose diseases faster and more effectively, as well as identify the most vital genes that are critical for life. That is only what we were able to do with the human genome. Researchers have developed the capability to make crops more resistant to droughts and they have developed ways to correctly predict a baby’s potential to inherit a genetic disorder before it is even born. This simple structure has helped us advance beyond what we originally thought was possible and has helped us continue to advance in our pursuit of knowledge.
I find it amazing that DNA was discovered by a complete accident. In the time of its discovery no one knew how important the discovery was to human biology and science as a whole. Once other scientist started looking deeper into DNA and what is was that we started to open up so many other discoveries. This was a very well written article that taught me a lot.