Frederick Sanger, developer of the chain-termination method of DNA sequencing.
Frederick Sanger, developer of the chain-termination method of DNA sequencing.

The $1000 genome is here.

Illumina announced last week that its latest DNA sequencing system, the HiSeqX Ten, can sequence an entire human genome for $1000.

And this doesn’t just take into account the costs of the reagents, a figure used by many to calculate the goal, but also amortization of the $10 million price tag for the ten-machine system.

Since its birth as a catchphrase over ten years ago, the $1000 genome has been an important psychological milestone for the scientific community and the public.  It represents an easy-to-digest number that brings a technological and scientific platform, upon which true personalized medicine can be developed, that much closer to everyday reality.

I’ve been casually following the advances of whole-genome sequencing since 2009, when only a relatively small group of people had undergone the process and the $10,000 barrier was about to be broken.  The fact that we’ve come so far so fast spurred me to learn more about the history and advances that led up to this breakthrough.

Leaving the history of the discovery of DNA for another article (you can read about Rosalind Franklin in this article on our blog), I decided to start with the launch of the first international project to sequence an entire human genome:  The Human Genome Project.

(Read more about Illumina’s HiSeqX Ten announcement on the BioSurplus blog.)

Advances Of The 1970s and ‘80s

First, let’s backtrack.  Major advances in DNA sequencing were made in the 1970s and ‘80s, namely the invention of the chain-termination sequencing method by British biochemist Frederick Sanger in 1977, and the launch of automated sequencing machines based on this method.

Frederick Sanger, who won the Nobel Prize twice for his work in chemistry, developed a technique to rapidly sequence long pieces of DNA.  His method was developed into what is known as shotgun sequencing.

In shotgun sequencing DNA is broken randomly into numerous small fragments and then sequenced to obtain “reads.”  Multiple reads are taken and the overlapping ends are then reassembled into a continuous sequence.

Applied Biosystems launched the first automated DNA sequencing machine in 1986.  The Model 370A DNA Sequencing System utilized fluorescent dyes, and was the first machine to digitize sequencing data, allowing for analysis and the development of databases.

These two breakthroughs were key to the creation of the Human Genome Project in 1990.


The Human Genome Project And Celera


J. Craig Venter, founder of Celera Genomics.
J. Craig Venter, founder of Celera Genomics.

The Human Genome Project was created in 1990 by the U.S. National Institutes of Health and the Department of Energy. In partnership with international research organizations and geneticists, the project’s goal was to sequence all three billion letters in the human genome – the complete set of DNA in the human body.

The $3 billion project was expected to be completed in 15 years.  Due to rapid advances in sequence analysis and computing speed the project was finished ahead of time and a rough draft, assembled by the Genome Bioinformatics Group at the University of California, Santa Cruz, was announced in 2000.  The complete genome was finished in 2003 and the results published in the journal Nature.

Biologist J. Craig Venter, former NIH investigator and founder of The Institute for Genomic Research, believed he could sequence the human genome much more quickly and cost-effectively than the Human Genome Project.  In 1998, with $300 million in private funding, Venter launched Celera Genomics and announced that his company would produce results within three years.

Celera had one major advantage.  Results to date of the Human Genome Project’s research were publically available, and Celera utilized this data to begin their work.  The company was also criticized for its attempt to turn what many thought should be public domain knowledge into a for-profit database.

Celera published its results in the journal Science one day after the Human Genome Project’s publication in Nature.  In spite of the criticism leveled at Celera, its efforts, and the sense of competition they engendered, are generally perceived to have been a positive influence on the process as a whole.

Illumina's HiSeqX Ten DNA sequencing system.
Illumina’s HiSeqX Ten DNA sequencing system.


High-Throughput Sequencing

The next step in the race to the $1000 genome came with the development of new, much faster techniques for sequencing DNA.  These methods, also known as next-generation sequencing, enable the sequencing process to run in parallel and produce thousands or millions of sequences at the same time.

Competing platforms have been launched over the last few years by companies such as 454 Life Sciences, Agencourt and Solexa.  454 was later acquired by Roche in 2007, Agencourt by Applied Biosystems in 2005 (later becoming part of Life Technologies in 2008), while Illumina acquired Solexa in 2006.  Solexa’s internally developed sequencing technology now forms the basis of Illumina’s DNA sequencing systems.

Life Technologies nearly beat Illumina to the mark with its announcement in 2012 of a new machine capable of sequencing an entire human genome in a single day at a cost of $1000.  Their calculations, however, only took into account the cost of reagents, not the cost of the machine itself, which is not yet available for sale.

As with the Human Genome Project and Celera, competition can be a good thing when it comes to technology development, serving as a catalyst for efficiency.  In the meantime, Illumina continues to be the dominant player in this emerging market, and their launch of the HiSeqX 10 is a major breakthrough in the move toward personalized medicine.

And we still have far to go.  The more affordable the cost of whole-genome sequencing, the quicker we will be able to develop a comprehensive database of disease-causing genetic variations, leading to further breakthroughs in drug discovery and treatments.

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