The Revolution in DNA Sequencing Through the Ages 

Scientists first cracked the code of DNA sequencing in 1968.¹ They gradually refined these methods through the 1970s until Frederick Sanger’s “chain-terminating” sequencing approach that used radiolabeled dideoxy nucleotides emerged as the hallmark for nucleic acid decoding in 1977.^2-5 Advancements over the next two decades swapped out these radiolabels for luminescent molecules, eventually giving rise to next-generation sequencing.^6-8

As sequencing technology entered more labs, researchers set their goals to greater heights. One of the largest projects at the end of the 20^th century, the Human Genome Project, launched in 1990 with the intention to completely decode the human blueprint. This effort ushered in even more technological advances in sequencing. Take a look at some of our most popular stories on DNA sequencing over the years as we celebrate The Scientist’s 40^th anniversary!

1995: Major Scientific Projects Lead to Leaps in Technology

In 1995, with the Human Genome Project underway, sequencing was all the rage. Scientists working on the project cloned short fragments of the whole genome and used Sanger sequencing to determine the order of nucleotides, using multiple overlapping clones to create a consensus sequence. This approach was limited in the length of base pairs researchers could sequence at a single time and the technology available to run the polyacrylamide gels and analyze them.

Researchers wanted to be able to decode longer sequences faster and more reliably, so companies stepped up to meet those demands. They introduced new formulations for gel polymers and electrophoresis equipment to improve casting and temperature control. At the same time, companies continued to improve their sequencers to read longer fragments and automate many of the experimental steps.

2007: A Celebrity Hard Launch for DNA Sequencing

In 2005, a group of researchers decided to promote their new sequencing company, 454 Life Sciences, by decoding the DNA of none other than famed geneticist James Watson. Watson agreed enthusiastically, but when he announced the project to the public, the researchers found themselves straining to meet the tall task as their sequencer struggled to produce sufficiently long and accurate reads. The team finally achieved their desired read length, 250 base pairs, with above 99 percent accuracy. They handed a DVD to Watson with his complete genome in 2007. Check out how he reacted to this gift.

2007: Different DNA Sequencing Methods Offer Deeper Insights Into Genomes

The boom in sequencing technology, from reagents to instruments, made their way to laboratories. By 2007, two biotechnology companies—454 Life Sciences and Illumina—were helping scientists probe the genome for questions about function and disease. While 454 Life Sciences’ long-read approach was useful for de novo sequencing, Illumina’s technology allowed researchers to run multiple, short-read samples. These platforms provided insights in the fields of epigenetics, metagenomics, cancer genes, and small RNAs.

2014: The (Sequencing) Price is Right

As sequencing technology continued to advance, the cost to decode DNA steadily decreased. However, even in the 2010s, no company had achieved whole genome sequencing for under $1,000. That changed in 2014 when Illumina introduced the HiSeq X that promised genomes for the coveted price tag of $1,000 that included the cost of reagents, equipment, and staff overhead. While many institutions were eager to place their orders—which Illumina was only selling as a minimum of 10 machines for $10 million—some scientists, like Watson, were quick to point out that aspects like the cost of clinical interpretation still weren’t included. Nonetheless, this marked another milestone in sequencing becoming a more accessible tool for researchers.

2017: Sequencing Goes to Space

Space has long been called the final frontier. While Sanger and his colleagues may have never fathomed doing science in microgravity, in 2016, microbiologist Kate Rubins took sequencing to the stars, or at least the International Space Station. After mastering the challenges of culturing cells and pipetting liquid in orbit, Rubins used a portable, handheld sequencer to complete the first DNA sequence off world.

2018: Miniaturized Sequencer Provides Full Scale Readouts

In 2018, Oxford Nanopore Technologies debuted their pocket-sized sequencer, the MinION, that could assemble a human genome. The tiny-but-mighty technology helped fill some gaps in the sequenced human genome by achieving sequencing reads of almost one million bases. Some scientists said that this was the most impressive feat; others found the small size was an important advancement to making the technology more accessible.

2023: Long-Read Sequencing Comes to Single Cells

Scientific technologies grow up in parallel with one another. Sometimes, though, they combine to push the boundaries of research further. As single-cell technology became more common, helping researchers find rare cell variations and study cell lineage, long-read sequencing also continued to improve. However, these two technologies were mutually exclusive, since the amount of DNA for long-read sequencing exceeded what researchers could extract from single cells. But, by suspending single-cell DNA fragments in droplets with a limited amount of reagents, scientists could amplify the DNA for long-read sequencing without having overrepresentation in some regions. Researchers shared how this collision of science technique worlds could further help them identify rare mutations in cancers and other disorders.

2025: Speeding Up DNA Sequencing to Get Clinical Results Stat

In the neonatal intensive care unit, genetic testing helps guide clinical decisions, but current rapid sequencing methods often don’t keep up with hospital timelines, sometimes taking days to return results. Biochemist Mark Kokoris at the biotechnology company Roche saw that the biggest challenge to improve sequencing time was overcoming the signal-to-noise ratio. Kokoris tackled this problem by reimagining sequencing: He converted the DNA into a surrogate molecule that could be lengthened and then used a metal oxide semiconductor sensor that allowed him and his team to rapidly sequence human genomes.

Partnering with Broad Clinical Labs and Boston Children’s Hospital, the scientists applied this approach to 15 neonatal samples. The results aligned with standard clinical diagnostic tests, but in contrast to traditional genetic testing, returned these findings in less than four hours. The findings showed how sequencing can become even more helpful in clinical care.