The double helix and the Human Genome Project: DNA Day 2023

DNA Day is an annual celebration of the discovery of the DNA double helix. This year the celebration is even bigger. The 25^th April 2023 commemorates both the 70^th anniversary of the discovery of the DNA double helix and the 20^th anniversary of the completion of the Human Genome Project.

In this feature we will cover the history of genomics, including the developments that led to the discovery of the double helix and the Human Genome Project. We will look at the significance of these achievements in the field of genomics and the impact they continue to have on research, healthcare and the wider world.

Finally, we will also explore how DNA Day is being commemorated in 2023, with the National Human Genome Research Institute (NHGRI) hosting an event celebrating these two momentous anniversaries.

The foundations of genomics

Genomics can be defined as the study of the complete set of DNA (including all of its genes) in a human or another organism. This definition brings together multiple elements of complex molecular biology, but the ability to study all of the genes in a particular organism did not happen overnight.

Early discoveries

Just four years after Gregor Mendel showcased the hereditary characteristics of peas in 1865, DNA was isolated for the first time by Swiss scientist Friedrich Miescher. In 1869, Miescher used white blood cells to isolate a phosphorus-rich material he named nuclein. Other early discoveries included the identification of chromosome patterns and the detection of the nucleotide bases (adenine, cytosine, guanine, thymine and uracil). Next, the concentrations of adenine and thymine, and cytosine and guanine, were found to always be in equal amounts in DNA. This led to the hypothesis that A always binds to T and C always binds to G.

Moving into the 1940s, William Astbury obtained the first X-ray diffraction pattern of DNA, revealing its structure with atomic precision. This showed that DNA must have a periodic structure, that Astbury described as being “like a pile of pennies”. After this, the Hershey-Chase experiments demonstrated that DNA, rather than protein, was the molecule responsible for carrying genetic information.

Discovering the DNA double helix

In the middle of the 20^th century, the discovery of the double helix structure of DNA signified the beginning of modern molecular biology. Unfortunately, this ground-breaking achievement has been marred with some controversy. However, today four scientists – Francis Crick, Rosalind Franklin, James Watson and Maurice Wilkins – are credited with the co-discovery of the DNA double-helix.

X-ray crystallography

Maurice Wilkins was the first to study DNA using X-ray crystallography techniques at King’s College London in the early 1950s. During this time, Rosalind Franklin was also becoming a respected authority in the field of X-ray crystallography. In 1951 she joined Wilkins at King’s College, tasked with upgrading the X-ray crystallography laboratory to tackle the ongoing DNA work.

What followed was the production of high-resolution X-ray images of DNA fibres that suggested a helical, corkscrew-like shape (see Figure 4). Franklin had already concluded that DNA had its phosphate groups on the outside of the molecule and that it existed in two forms. In February 1953, she also noted that the structure of DNA had two chains. Together, this body of research revealed the great symmetry and consistency in the structure of DNA molecules, as well as giving important clues about its dimensions.

The double helix model

James Watson and Francis Crick were both inspired by, and in competition with, Linus Pauling, who had previously discovered the alpha-helical structure of some proteins and published a paper suggesting a triple-helical structure of DNA. Racing to crack the DNA structure, Watson and Crick used paper cut-outs for bases and metal scraps to construct their own DNA models.

Instrumental to the development of Watson and Crick’s model was Rosalind Franklin’s crystallographic evidence, which was shown to the pair without Franklin’s knowledge. The findings were published in Nature on the 25^th of April 1953, in a short paper titled “A Structure for Deoxyribose Nucleic Acid”.

Watson and Crick’s model revealed the following properties of DNA:

• DNA is a double helix, with the sugar and phosphate parts of nucleotides forming the two strands of the helix and the nucleotide bases pointing into the helix and stacking on top of each other.
• The nucleotide bases use hydrogen bonds to pair specifically, with an A always binding to a T and a C always binding to a G.
• The two strands of the DNA double helix run in opposite directions.

In 1962, James Watson, Francis Crick and Maurice Wilkins were awarded the Nobel prize for the discovery of the structure of DNA. Absent from this award was Rosalind Franklin, who had died in 1958 from ovarian cancer.

The legacy of the double helix

The discovery of the DNA double helix marked a major milestone in the history of science and led to many ground-breaking insights into genetics and genomics. In the 1970s and 1980s, new and powerful scientific techniques were developed off the back of the DNA double helix, eventually leading to multi-billion-dollar biotechnology industry seen today. These include recombinant DNA research, genetic engineering, rapid gene sequencing and monoclonal antibodies.

Sequencing and genomic medicine

In 1977, a major breakthrough from Frederick Sanger and team came in the form of the “chain-termination” technique for DNA sequencing. This technique involves the use of di-deoxynucleotides (ddNTPS) – analogues of deoxynucleotides (dNTPs) – with a mixture of radio-labelled ddNTPs and dNTPs used in a DNA extension reaction.  

As ddNTPs are randomly incorporated during extension using Sanger sequencing, DNA strands of every possible length are produced (see Figure 6). Other technical advances included the polymerase chain reaction (PCR), a technique that can be used to amplify DNA, and DNA profiling.

The Human Genome Project

In 1990, the Human Genome Project (HGP) was launched, aiming to sequence the complete 3 billion base-pairs of the human genome in 15 years. The launch of the project marked a change of focus from researching individual genes to a genomics-based approach.

Leading up to the project

A number of human genes had been sequenced prior to the beginning of the HGP. However, the overwhelming majority of the human genome remained unexplored. Researchers recognised the necessity and scientific value of having a full human genomic sequence and were beginning to implement ways to determine this quicker. It was known that the HGP would take billions of dollars to complete and likely detract from traditional biomedical research that was ongoing. This led to debates surrounding the benefits, risks and the costs of sequencing the entire human genome in one project.

Despite the concerns, the HGP began in 1990 under the leadership of Francis Collins, supported by the US Department of Energy and the National Institutes of Health (NIH). An initial five-year plan was drafted and the project was soon joined by scientists from around the world.

Early achievements

In the early-to-mid 1990s, the HGP published a number of early achievements. These include a detailed genetic linkage map of the human genome, published in 1994. This was followed by a physical map of the human genome in 1995. In 1998, the HGP updated its five-year goals and in 1999 the pilot phase of sequencing the human genome was completed.

Technological advances and rapid progress

A series of technical advances in sequencing processes and the hardware and software used to analyse the data resulted in a rapid progression of the HGP. As well as this, in 1998 a private-sector organisation, Celera Genomics, further increased the pace of discovery.

Headed by former NIH scientist J. Craig Venter, Celera Genomics began to compete with and undermine the publicly funded HGP. This conflict was fuelled by the potential to gain control over patents on the human genome sequence, considered to have very high financial value pharmaceutically.

Joining forces to complete the sequence

Eventually, the rivalry between Celera Genomics and the NIH ended (although the legal and financial reasons remain unclear) and they joined forces to accelerate the completion of the HGP. In 2000, Collins and Venter (as part of The International Human Genome Sequencing Consortium) announced the completion of the rough draft of the human genome.

For the following three years, the draft sequence was further refined, extended and analysed. The HGP was declared complete in April 2003, coinciding with the 50^th anniversary of the publication of the discovery of the DNA double helix. This meant that the HGP was completed two years ahead of schedule and confirmed that the human genome has 20,000-25,000 genes.

DNA Day 2023

Here, Rosann Wise, M.A., Education Outreach Specialist at the NHGRI, takes us through the significance of DNA Day 2023 and what the NHGRI has planned for the occasion.

FLG: Could you explain the significance of DNA Day to the NHGRI and the wider community?

Rosann Wise: The 108th Congress passed a resolution designating April 25th as National DNA Day. The late Rep. Louise M. Slaughter (D-NY) spearheaded the resolution to celebrate the completion of the first draft of the human genome sequence, one of the greatest feats in the history of science! National DNA Day is an annual event to empower educators, our next generation of scientists – students, and communities, to learn more about genomics and how it impacts our everyday lives.

FLG: What is the most significant application so far of the Human Genome Project, and where do you think we would be without that work?

Rosann: The Human Genome Project is important specifically because it has had, and will continue to have, an impact in so many areas. Speeding up biomedical research was a primary goal of the project. This is evidenced by the vast number of researchers who have made genetics and genomics an element of their research.  DNA-based diagnoses and genome guided treatment are on their way to becoming standard clinical tools. The project has had an impact on other fields as well. Many of the technologies created as part of the Human Genome Project are now mainstays of agricultural science, they have been used to solve crimes and allow individuals to learn more about their ancestors. 

FLG: The human genome was “truly” completed in 2022 – how will this new information shape the future of genomics?

Rosann: These newest achievements have filled in the pieces of the genome that we knew we were missing when the original version project was completed in 2003. Technological improvements allowed NHGRI-funded scientists to tackle these really difficult areas of the genome. The 2022 version of the human genome will enable us to ask questions about these areas previously shrouded in darkness. Now in the light, these regions can be probed by researchers for new biological functions and connections to health and disease. This new and improved version of the human genome will also serve as an excellent reference to which we can compare all of the genome sequences being generated throughout the world.

FLG: What do you hope people will take away from the day?

Rosann: DNA Day is an international celebration of genomics! We can all appreciate how genomics is expanding our understanding of human biology, transforming approaches to healthcare, and creating career opportunities for the next generation of scientists.

FLG: How would you suggest people celebrate DNA Day – activities in schools, for example?

Rosann: Educators can participate by introducing topics in genomics to their students and engaging in discussions about current topics that go beyond the science and explore ethical, legal and social issues as well. Educators may also explore the opportunity to invite someone in the field of genomics to speak to their students using video conferencing software.  Students can celebrate by participating in these discussions, or by leading a hands-on activity with their fellow students, or possibly as part of a science club at their school.

Communities in general have opportunities such as doing one of the hands-on activities, such as DNA extraction from a strawberry, that are available using common household items. Finally, all can celebrate by joining NHGRI for the National DNA Day Symposium, which will explore the evolution and future of genomics research, learn about the greater impacts of genomics on society, and discover the wide array of careers in genetics and genomics.

References

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