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We stand on the shoulders of the genome giant

Posted on 06 April, 2013 by Joe Dunckley

This week, Sir Mark Walport took up the position of the UK's Chief Scientific Advisor, having stepped down after 10 years at the controls of the Wellcome Trust -- the world's largest medical research charity, and a major funder of projects here at the Institute of Cancer Research. The BBC's Fergus Walsh asked Sir Mark to reflect on that decade, and the results of the £5.6 billion worth of research funded during his time in the Director's chair. The dominant scientific advance of the decade was, he said, without a doubt, genomics.

Sir Mark took the top job at the Trust in 2003, at the same time as the International Human Genome Sequencing Consortium — including the Wellcome Trust's Sanger Centre — was publishing the final sequences of its first full human genome. The importance of sequencing the human genome, 13 years in the making, was highlighted by its almost unique distinction for a scientific project of being announced to the world by a president and a prime-minister. But inevitably, such unprecedented publicity prompted accusations of hype: how could a genome sequence, little more than a very long and still poorly understood series of As, Cs, Gs and Ts, justify the prestige of a presidential press conference?

Well Sir Mark Walport thinks that all the hype was justified, and more. And at the ICR, we're inclined to agree. Wondering where all the medical breakthroughs promised in 2003 are? They're all around us.

Sir Mark cites the example of BRAF, a gene which when mutated can cause cancers such as melanoma. In the 10 years since the discovery of BRAF's role was made — by scientists here at the ICR, in a collaboration with the Sanger Centre — drugs like Zelboraf have been designed to attack cells with BRAF faults, enabling us to fight the disease in a far more targeted and effective way than traditional chemotherapeutics. Zelboraf was recently recommended for use on the NHS, a very visible sign of the genomic revolution — in the form of personalised medicine — reaching patients.

But the human genome has revolutionised cancer research far more fundamentally than a few individual new drugs. In this era of targeted treatments, the human genome project underpins in some way almost everything that we are doing at the ICR. As Isaac Newton was able to see further in 1676 by standing on the shoulders of giants, today's cancer researchers are raised up and carried high by the human genome project. Our medical breakthroughs are the medical breakthroughs promised by the human genome project.

Because, although the announcement of the complete sequence in 2003 did come with some of its own scientific results (discoveries about the structure of the genome, such as the number and distribution of genes within it), the main value of the project was to provide an essential reference work for researchers in medicine and biology. The sequences from the human genome project — and now many other genome projects, representing different species, varieties, and diseases — are available for free from a database called GenBank. At the ICR, we tap into this database, and others like it, all the time as part of our research.

When we find genes that appear to be acting up in cancer cells, we identify them with a quick search of the database. When we want to figure out how exactly the molecular machines and signals in our cells interact with each other, one of the things that we do is check what happens when we turn a gene up or down — using methods likeRNA interference, which depend on the sequences from the database. And for lots of our projects, we need to be able to casually check when and whether a particular gene is switched on or off  -- for example, in response to an experimental drug treatment -- for which we use methods like real-time PCR and microarrays, methods which wouldn't be available to us without the sequences from the database.

But there are also bigger projects working to translate the publicly available genome project data into real scientific knowledge and patient benefit. Dr Rachael Natrajan's functional genomics team at the ICR, for example, are working their way through the mountain of data that has been piling up as sequencing has become faster and cheaper, and since the dedicated sequencing centres once busy with the human genome project have turned their efforts to sequencing the damaged genomes within tumour cells. "We've taken the set of mutations that are commonly found in those sequenced genomes of breast cancer cells, and are assessing each one in the lab to see exactly what effect they actually have," Rachael says. "We want to know which are the oncogenic mutations, driving the cancer, and which are harmless passengers picked up along the way. Those driver mutations should be the focus of future targeted treatment development."

I put the idea that genome projects are all hype to Rachael. "We couldn't do any of this without that genome data," she says. "Sequencing such a large number of samples would be too large and expensive a job for any individual lab. That’s why dedicated sequencing centres and large consortia like The Cancer Genome Atlas and the International Cancer Genome Consortium are a fabulous resource. By coordinating sequencing efforts of different tumour types worldwide, and making their data easily available to other researchers, they provide a vital service enabling projects like this."

The human genome project deserved the hype, not because that day in 2003 saw an instant great leap forward, but because it paved the way for a mass march of small, and not so small, steps.


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