By Carli King

Seventy years ago, the discovery of the deoxyribonucleic acid (DNA) double helix rocked the scientific world and is still, to this day, considered one of history’s greatest scientific achievements. Twenty years ago, The Human Genome Project was completed, marking the first generation of the human genome sequence, further propelling scientific research. These scientific anniversaries and the scientists behind the discoveries continue to inspire scientists and drive biomedical research. In celebration, let’s reflect on the discovery of the double helix and the story of the scientists Rosalind Franklin, Francis Crick, and James Watson (Figure 1).

The Discovery of DNA

The discovery of DNA is credited to Friedrich Miescher, a Swiss physiological chemist, who first isolated DNA from the nuclei of human white blood cells in 1869^{1, 2}. This discovery was actually incidental; at the time, Miescher was focused on extracting proteins from white blood cells (isolated from pus-coated bandages) when he noticed an unknown component of the cell nuclei that differed from proteins in its chemical makeup². Miescher noted that this unknown component, which he originally termed “nuclein,” had higher phosphorous content than proteins and could not be degraded by traditional protein degradation techniques². At the time, scientists believed that proteins held hereditary information, so the importance of Miescher’s discovery was overlooked for many years³. 

Advancements in Understanding DNA

Several scientific breakthroughs laid the groundwork that later allowed for the discovery of the structure of DNA. In the late 1800s, Albrecht Kossel discovered the nitrogenous “bases” of DNA, which he named thymine (T), adenine (A), cytosine (C), and guanine (G)⁴. Later, in 1929 at the Rockefeller Institute, Phoebus Levene identified the components that define DNA, coined nucleotides, including the four bases (A, T, G, C), sugar (deoxyribose), and phosphate (Figure 2)⁵. Oswald Avery, Colin Macleod, and Maclyn McCarty determined DNA carried genetic information in 1944, which directly contradicted the idea that proteins held genetic material⁶. A few years later, Erwin Chargaff discovered two rules that later supported DNA had a double helix: (1) DNA had equal percentages of A to T and G to C and (2) A and T were always paired, while C and G were always paired⁷. Together, these advancements helped scientists begin to understand the structure of DNA.

The DNA Double Helix

The credit for discovering the DNA double helix is often solely attributed to James Watson and Francis Crick. However, there were actually four scientists that had significant contributions towards the scientific discovery: James Watson, Francis Crick, Rosalind Franklin, and Maurice Wilkins.

In the early 1950s, Wilkins, a physicist at King’s College London, began applying X-ray crystallography techniques in an attempt to uncover the structure of DNA⁸. X-ray crystallography works by sending X-rays at a crystalline sample, which bounce off atoms in the sample and produce a characteristic pattern, which is captured on film⁴. Franklin joined faculty at King’s College London in 1951, also with the goal of studying DNA’s structure⁸. The overlap in Franklin and Wilkins’ research goals is thought to have added a competitive nature that negatively influenced their professional relationship⁸. It was at King’s College London in 1952 that Franklin took “Photograph 51” using X-ray crystallography (Figure 3)³. This image, among others, led Franklin to note the crystallized DNA fibers showed DNA strands in a helical shape with phosphates located on the outside of the structure (Figure 3)³.

Meanwhile, Watson began working at the Cavendish Laboratory in Cambridge in 1951 at the age of 23⁸. He was working under the same principal investigator as Crick, and the duo became interested in designing molecular models of DNA⁸. Watson and Crick’s effort was sped up significantly when Wilkins shared Franklin’s unpublished experimental evidence with them, including Franklin’s Photograph 51. Wilkins did this without Franklin’s knowledge or consent⁹. It wasn’t long before Watson and Crick announced they had figured out the double helix structure of DNA, on February 28, 1953, in a London pub⁶. A few months later, Watson and Crick published their data describing the double helix structure in a mere 900-word, one-page manuscript, “A Structure for Deoxyribose Nucleic Acid” published in Nature on April 25, 1953^{6, 10, 11}.

Watson, Crick, and Wilkins were awarded the 1962 Nobel prize in Physiology or Medicine for discovering the double helix structure of DNA⁸. Franklin, despite her significant contributions to the discovery, was excluded from receiving the Nobel Prize. To this day, the reason for her exclusion remains unclear. However, it is speculated that she was omitted due to a rule barring the Nobel Prize from being divided amongst more than three individuals or because she died prior to the prize being awarded⁸. While there is a rule against posthumous Nobel awards, it was not put in place until 1974⁸. The controversary surrounding the discovery does not end there. Watson detailed his account of the discovery in his book The Double Helix (1968); but Crick believed this portrayal to be a direct betrayal of friendship and privacy, resulting in a falling out between the infamous duo¹⁰.

Breakthroughs Beyond the Double Helix

After the discovery of the double helix structure of DNA, researchers aimed to further understand the relationship between DNA’s structure and function. One of many noteworthy discoveries occurred in 1961, when Marshall Nirenberg and colleagues at the National Institutes of Health “cracked the genetic code” directing protein synthesis³. Their experiments used a strand of synthetic messenger RNA (mRNA) containing only uracil (U), and they found this mRNA directed synthesis of a protein that contained only phenylalanine, leading to the discovery that UUU was the “code” (codon) for phenylalanine³. Before long, Nirenberg and colleagues identified60 mRNA codons for all twenty amino acids, and they were awarded the 1968 Nobel Prize in Physiology or Medicine for significant contributions to understanding protein synthesis. This discovery, among many others, prompted the first discussion of sequencing the human genome.

The Next Step: The Human Genome Project

Discussions of studying the human genome began in 1984, and the United States National Research Council officially recommended starting a program to map the human genome in 1988³. In 1990, the United States Department of Energy and the National Institute of Health published official documents outlining the first five years of the anticipated 15-year project³. In 1996, Leaders of the Human Genome Project ultimately agreed that the data generated from the Human Genome Project, including all human genomic sequencing information, should be made free and publicly available within 24 hours of project completion³. Other goals of the project included sequencing the genomes of select model organisms, such as the bacterium E. coli, baker’s yeast, fruit fly, nematode, and mouse for use in scientific research projects¹².

The Human Genome Project recruited volunteers with informed consent, and the multiple individuals who provided blood samples were kept anonymous¹². Chromosome 22 was the first of the 23 human chromosomes to be completely decoded in 1999 through international collaboration between scientists in six countries³. It was chosen first due to its small size and known association with diseases³. A mere two years after chromosome 22 was decoded, the first draft of the human genome was released in 2001³. This first draft accounted for approximately 90% of the human genome, despite containing more than 150,000 gaps of unknown DNA sequences (gaps can be the result of complex or highly repetitive DNA regions)¹².

The completion of the Human Genome Project was announced in April 2003. The final version covered roughly 92% of the human genome with less than 400 gaps, and was more accurate than previous drafts ^{3, 12}. Surprisingly for projects of this scale, the project was finished 2.5 years ahead of schedule and under the project’s budget of $3 billion ^{3, 12}. It was recently announced (2022) that the remaining gaps have been filled by the Telomere-to-Telomere (T2T) consortium, resulting in the first complete human genome sequence¹².

TL:DR

• 2023 marks 70 years since the discovery of the DNA double helix by James Watson, Francis Crick, Rosalind Franklin, and Maurice Wilkins.
• Despite Rosalind Franklin’s major contribution to the discovery, most credit is attributed to Watson and Crick. In fact, only Watson, Crick, and Wilkins received a Nobel Prize for the discovery.
• 2023 also marks 20 years since the completion of The Human Genome Project, a project sequenced the human genome with a coverage of over 92%.
• The first complete human genome was completed in 2022.

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References

1. Nightingale, Kath. “DNA: a timeline of discoveries.” BBC Science Focus. April 10, 2020. https://www.sciencefocus.com/the-human-body/dna-a-timeline-of-discoveries/
2. Pray, Leslie A. “Discovery of DNA Structure and Function: Watson and Crick.” Nature Education. 2008. https://www.nature.com/scitable/topicpage/discovery-of-dna-structure-and-function-watson-397/
3. Genome: Unlocking Life’s Code. “A Brief History from Mendel to the Human Genome Project.” https://www.unlockinglifescode.org/timeline
4. Nightingale, Kath. “How we unravelled the structure of DNA.” BBC Science Focus. April 10, 2020. https://www.sciencefocus.com/the-human-body/how-we-unravelled-the-structure-of-dna/
5. Aliouche, Hidaya. “History of DNA Research: Scientific Pioneers & Their Discoveries.” News-Medical. https://www.news-medical.net/life-sciences/History-of-DNA-Research-Scientific-Pioneers-Their-Discoveries.aspx
6. Markel, Howard.  “February 28: The Day Scientists Discovered the Double Helix.” Scientific American. February 28, 2013. https://www.scientificamerican.com/article/february-28-the-day-scientists-discovered-double-helix/
7. Preceden. “History of DNA.” https://www.preceden.com/timelines/317130-history-of-dna.
8. Science History Institute. “Francis Crick, Rosalind Franklin, James Watson, and Maurice Wilkins.” July 28, 2022. https://www.sciencehistory.org/historical-profile/james-watson-francis-crick-maurice-wilkins-and-rosalind-franklin. 
9. Maddox, Brenda. “The double helix and the the ‘wronged heroine.” Nature. January 23, 2003. https://www.nature.com/articles/nature01399#:~:text=In%201962%2C%20James%20Watson%2C%20Francis,of%20the%20structure%20of%20DNA.
10. National Library of Medicine. “The Discovery of the Double Helix, 1951-1953.” https://profiles.nlm.nih.gov/spotlight/sc/feature/doublehelix
11. National Human Genome Research Institute. “1953: DNA Double Helix.” https://www.genome.gov/25520255/online-education-kit-1953-dna-double-helix
12. National Human Genome Research Institute. “Human Genome Project.” https://www.genome.gov/about-genomics/educational-resources/fact-sheets/human-genome-project