Thursday, 1 September 2016

Celebrating 10 years at the CRUK-Cambridge Institute today

Today I have been working for Cancer Research UK for ten years! September 1st 2006 seems like such a short time ago but a huge amount has changed in that time in the world of Genomics. NGS has changed the way we do biology, and is changing the way we do medicine. The original Solexa SBS has been pushed hard by Illumina to give us the $1000 genome, and perhaps just as exciting are the results coming out of Oxford Nanopore's MAP community - this maybe the technology to displace Illumina? What the next ten years will hold is difficult to predict, but today I wanted to focus on the highlights of the last ten years at CRK for me.

CRUK-Cambridge Institue circa early 2006
I was employed to build a brand new genomics facility and was hired for my expertise in gene expression microarrays - previously I'd set up an Affymetrix facility at the John Innes Centre in what is now the Earlham InstitutePerhaps the one thing I remember from my interview is the answer to a question I'd posed at the end "Will the CRUK institute be using the new next-generation sequencing technologies?" NGS was still in its infancy then, in late 2005 the first 454 paper made a big splash, and a Solexa sequencer has been installed at the Sainsbury lab in Norwich and I'd heard interesting things about the technology.

The answer was something like "we want this facility to focus on microarrays, we'll see if the NGS comes to anything useful". Well everyone reading Core-Genomics knows how disruptive NGS was, microarrays are dead (for gene expression anyway) and virtually all the data we generate in my lab comes off an Illumina HiSeq sequencer.

When I arrived the site had only just been handed over by the builders. In January of 2007 we had the first instruments installed and were processing Sanger sequencing and Illumina arrays by the Spring. But we'd decided to get our first sequencer and our initial discussions with the Solexa rep ended up with the purchase of an Illumina GAI. The rest as they say is history.

Highlights from the last ten years: The Institute celebrates its 10th anniversary in February of 2017 so I'll not go into too much detail about the top ten projects the Genomics core has been involved with. But I did want to pick upon three projects that I was personally involved with and that I think were major advances.
  1. Understanding gene regulation: In a wonderful paper: Species-specific transcription in mice carrying human chromosome 21, Mike Wilson, in Duncan Odom's group, demonstrated that sequence differences in regulatory regions are the dominant force in governing when and where genes are expressed. Mike designed an incredibly elegant experiment using a Mouse model of Down's syndrome, the TC1 mouse carries an extra copy of chromosome 21, but it is a Human copy. That Human chromosome is in a mouse nuclear environment and this allowed the authors to show that the Mouse transcription factors bound to Human DNA in a Human specific context i.e. the DNA sequence was the dominant force driving gene expression. Mike and Duncan were instrumental in the development of NGS at the Institute. Mike was great to work with, and hosted probably the best "crash pad" in Cambridge; and Duncan has kept up an amazing pace of research over the whole of the last ten years.
  2. Molecular subtyping of Breast cancer: The METABRIC project was a major reason I took the job at CRUK. It was the largest array project I ever worked on and had a huge impact on our understanding of Breast cancer, revealing novel subtypes of breast cancer with distinct clinical outcomes and subtype- specific driver genes. It was truly a landmark study. The Genomics core processed all of the UK-based samples extracting DNA and RNA, quality controlling and normalising them for analysis. I managed the Affymetrix genotyping on SNP6.0 arrays, carried out as a service by Aros in Denmark. And my lab processed all of the 2500 Illumina HT12 arrays used in the study in just 6-8 weeks. Christina Curtis now runs her own lab at Stanford. And the Caldas group continues to lead on Breast cancer genomics, most recently we've been working with them most recently on a PDX project where we introduced low-coverage WGS of pre-capture exome libraries to significantly improve CNV calling.
  3. Liquid biopsy: probably the biggest advance I've been involved with, NGS analysis of ctDNA as a liquid biopsy, is changing the way we do cancer medicine. Tim Forshew in Nitzan Roselfeld's group was the first person to use NGS to non-invasively identify mutations by sequencing the DNA from a patients tumour circulating in their blood. In a hugely impactful Science Translational Medicine paper Tim and colleagues showed that this could be used to detect and quantify mutations seen in the tumour, that de novo mutations could be identified, and that a liquid biopsy could be used to monitor tumour progression in patients. Mohammad Murtaza (now Assistant Prof at TGEN) pushed the technology even further by showing that it was possible to perform whole exome analysis of ctDNA, and that this could be used to monitor tumour evolution. This was a groundbreaking study published in Nature, but when I presented it at AGBT the following year the audience was still highly skeptical of how widely ctDNA might be used - that has changed and now there are dozens of companies pursuing liquid biopsy including Nitzan and Tims Inivata.
I've worked with some amazing people over the last decade many of whom have gone on to start their own labs. My team has been great; people have come and gone, marriages have happened and babies have been born. The CRUK Cambridge Institute continues to be an excellent place to work, and is still a world leader in Genomics, and I've played my part in helping that to happen. Here's to the next ten years.

2 comments:

  1. Wonderful post James. Congrats on your ten year "anniversary" at CRUK! It was great to work with you for almost a tenth of that time!

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