Beautiful Science: High-speed Human Genome Sequencing

Genomics is the study of all of a person’s genes (the genome), including interactions of those genes with each other and with the person’s environment. The UK has led the world in genomics over a long period in both fundamental discovery and applications. Ii was British molecular biologist, Francis Crick (1916 – 2004) who started the ball rolling by discovering the structure of the DNA with his American counterpart, James Watson. For their epochal discovery, Crick and Watson were awarded the Nobel Prize in Physiology or Medicine in 1962.

British scientists, too, played important roles in the Human Genome Project that began in the 1990s. The principle that genomic data should be universally shared without commercial involvement owes its widespread acceptance largely to John Sulston, a British geneticist who was the director of the Wellcome Trust Sanger Institude in the UK at the time, as well as principal leader of the UK side of the project. In 2002, Sulston shared the Nobel Prize in Physiology or Medicine for his contribution to understanding how genes control the fate of cells in the developing roundworm Caenorhabditis elegans

American scientist James Watson (left) and British scientist Francis Crick with their #D DNA model in 1953.

The Tricky Business of Genome Sequencing

Fast forward into the 21st century, British scientists again led the way in the application of technology to genome sequencing. Full genome sequencing is always the ultimate goal; it is the process of determining the entire DNA sequence of an organism’s genome at a single time. Of particular interest is the full or nearly full sequencing of the human genome, as this would open the door to potentially life-saving diagnostic and treatment applications. A major challenge to this effort is the sheer complexity of the human genome. Consider the fact that the human genome includes the coding regions of DNA, which encode all the genes (between 20,000 and 25,000 in a human), plus the noncoding regions of DNA, which do not encode any genes, and furthermore, in each and every cell, there are about 3 billion base pairs of DNA residing in the 23 pairs of chromosomes within the cell’s nucleus, and you get some idea of this complexity. This explains why initial efforts in sequencing the human genome was both slow and expensive.

Fortunately, human ingenuity has led to significant advances in the technology of genome sequencing, so much so that it now can be done much faster and cheaper. In 2000, sequencing of one human genome took over 10 years and cost more than a billion dollars. Today, the human genome can be sequenced in one day at a cost of $1,000, and more than a million human genomes are sequenced at scale each year. All this is thanks to a technology known as Next-Generation Sequencing (NGS) co-invented by two biochemist researchers, Professors Shankar Balasubramanian and David Klenerman, both at Cambridge University.

David Klenerman and Shankar Balasubramanian, Cambridge, UK

Eureka Moment

Their discovery began in Cambridge on 26 August 1997. Shankar Balasubramanian’s diary records the date as the day of “The Solexa Idea!” (Solexa was the company he co-founded with David Klenerman and which was acquired by American company Illumina in 2007).

Sitting in the beer garden of Cambridge’s Panton Arms, he and David Klenerman sketched out their plans to watch DNA polymerase (a DNA synthesizing enzyme) as it assembled the building blocks of life. Their ideas were progressing fast – and with them, something even more exciting. Later, he would describe the evening as when “the pieces of the jigsaw came together”. They realised that if they could watch the enzyme copying a genome then they were inadvertently also reading the genome. They had discovered a radically new way to sequence DNA. But it was when they calculated their possible ‘reading speed’ that it occurred to them they could be looking at something revolutionary: genome sequencing that would be fast, accurate, low-cost and scalable. Within a year, they had co-founded the company Solexa to make the technology more widely available to the world.

Shankar looks back at his diary for 1997, where he later wrote ‘the Solexa idea!’ next to ‘meeting Klenerman & Co’ in the Panton Arms, Cambridge.

Far-Reaching Applications

NGS is now being widely adopted in healthcare and diagnostics, such as cancer, rare diseases, infectious medicine, and sequencing-based non-invasive prenatal testing. It is currently also providing an effective way to study and identify new corona-virus strains and other pathogens with the hope of developing “future-proof” vaccines against these viruses before they wreak untold misery that we are now seeing in the current Covid-19 pandemic. In addition to medical applications, NGS has also had a major impact on all of biology as it allows the clear identification of thousands of organisms in almost any kind of sample. This is now critically important for Agriculture, Ecology and Biodiversity studies.

“It really hit home when I heard someone had used our technology to sequence and treat a baby born with a rare disease. I realised, wow, it’s not just a technology for scientists, it’s actually a technology that can make a difference.”

~ David Klenerman

For their pathbreaking work, Professors Balasubramanian and Klenerman were awarded the 2020 Millennium Technology Prize, the equivalent of a “Tech Nobel Prize” on 18 May 2021.


Journey of Discovery: Rapid Genome Sequence

For an introduction to NGS, see this video (technical), see this next video.

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