A decade of the human genome

A couple of weeks ago I attended a Cambridge Network event 'Personalised medicine - the challenges and opportunities of the $500 genome' at which David Bentley (Chief Scientist of Illumina) and Paul Flicek (Head of Vertebrate Genomics, European Bioinformatics Institute) gave presentations (http://www.cambridgenetwork.co.uk/events/article/default.aspx?objid=67434). The fascinating talks prompted a lively debate on the pace of technological change, the likely impact of personal genomes on medicine and the technical and ethical issues that are being raised by the availability of huge quantities of data from large-scale genome sequencing studies (e.g. the 1000 Genomes project http://www.1000genomes.org).

It is of course ten years since the announcement on June 26th, 2000 that sequencing of the human genome had been completed; although it is worth recalling that the announcement relied on a generous definition of ‘complete’ (a truly complete sequence was not published until 2003). The announcement generated huge excitement and, let’s be honest, loads of hype; there was speculation that a cornucopia of new drugs for previously unknown genetic targets would be unleashed, an era of personalised medicine would be ushered in, and a biotech boom would result.

But then it all went terribly quiet. So, what happened? Well, perhaps not surprisingly in hindsight, genome biology turned out to be more complicated than anybody anticipated. The way in which genes are switched on and off is at least as important as the composition of genes; the process by which the genome regulates itself is vastly more complicated and sophisticated than anybody expected. The methods for linking genetic variation to disease available at the time were found to be inadequate. And, most importantly, each human genome was found to be different; individual genetic variations are where the excitement lies when it comes to the causes and progression of disease. In turn, this highlights the importance of personal genomes and underscores the significance of the $500 genome.

When we talk about the possibility of a $500 genome it is worth remembering that the original human genome sequence (actually a composite from several individuals) took 13 years and cost $3 billion to complete. Eric Lander, the head of the Broad Institute (http://www.broadinstitute.org), which is America’s largest DNA sequencing centre, calculates that the cost of DNA sequencing at the institute has fallen to a hundred thousandth of what it was a decade ago. Now, using the latest sequencers from Illumina (http://www.illumina.com), a human genome can be read in eight days at a cost of about $10,000. Nor is that the end of the story. Pacific Biosciences (http://www.pacificbiosciences.com) has a technology that can read genomes from single DNA molecules. It thinks that in three years’ time this will be able to map a human genome in 15 minutes for less than $1,000. And a rival technology being developed by Oxford Nanopore Technologies (http://www.nanoporetech.com) aspires to similar speeds and cost.

There is another factor complicating the application of advances in our understanding of the human genome. Did you know that humans have two genomes? Some 1.5 kilograms of bacteria colonise the human gut, with others inhabiting the external and internal surfaces of the body. In fact, only 10% of the total number of cells in the human body consists of human cells, with the rest coming from symbiotic bacterial cells. The collective genetic information encoded in all the microorganisms that generally live harmoniously with us, which are collectively known as the microbiome, constitutes a second genome.

The International Human Microbiome Consortium (http://www.human-microbiome.org) recently released an initial reference-genome sequencing of 178 bacterial species from the human microbiome. It is estimated that the human gut microbiome contains around 1,000 bacterial species, which can have a significant impact on health and disease. Molecules produced by the gut bacteria can enter the bloodstream via either a normal anatomical route called the enterohepatic circulation or through a partially damaged gut barrier. Beneficial gut bacteria can produce anti-inflammatory factors, pain-relieving compounds, antioxidants and vitamins to protect and nurture the body. Conversely, harmful bacteria may deregulate genes mediating energy metabolism, and can produce toxins that mutate DNA, affecting the nervous and immune systems. The outcome is various forms of chronic disease, including obesity, diabetes and even cancers. This close and specific contact with human cells, exchanging nutrients and metabolic wastes, makes symbiotic bacteria essentially a human organ and their collective genomes our second genome.

As more strains of gut bacteria are sequenced, researchers can more accurately determine the effect of various factors on the composition of the gut microbiome, and thus on health and disease. For example, diet – the main factor behind the increased incidence of disorders such as obesity, diabetes and colon cancer - could override the effects of host genetics by changing the gut-microbiome composition. Sequencing and characterizing the human microbiome, therefore, although a dauntingly complex task, could be vitally important for understanding how an unhealthy diet might lead to chronic disease.

In conclusion, the next wave of the genomics revolution is just beginning to build and its potential impact on society is at best poorly understood. Whilst the biotech industry tends to focus on technology and its commercial exploitation, the ethical and societal issues raised by genomics need to be addressed if society at large is going to benefit from the amazing technological advances.