Gene sequencer the size of an apple

06 February 2018

Interview with

Matt Loose, University of Nottingham

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The human genome project, which was completed in 2003, was an international collaboration to read the entire genetic code - or sequence - of the human genome - the DNA recipe that makes you you. It ultimately took over 13 years, cost billions of Pounds and involved warehouse-scale buildings full of car-sized sequencing machines to do it. A third of the work was completed down the road from where we are at the Sanger Institute near Cambridge. Since those days, sequencing technology has come on leaps and bounds, and this week scientists announced that they’ve achieved the same feat - sequencing a whole human genome - but this time with a machine smaller than a chocolate bar. It took weeks, rather than years, and cost only about a thousand pounds. Lewis Thomson has been hearing how…

Lewis - Inside each of your cells a huge amount of DNA is tightly wrapped up. In fact, if all of the DNA from just one cell was stretched out, it would be about two metres long even though it fits inside a space just a hundreth of a millimetre across.

This DNA in its entirety is called your genome and it’s made up of lots of smaller subunits called bases - As, Ts, Cs, and Gs. The human genome is three billion bases long and the sequence of these bases is what determines the function of each gene - a bit like a computer code.

Being able to sequence a genome quickly and at low cost could affect how disease is diagnosed and treated, and this possibility is now one step closer. Matt Loose from the University of Nottingham told me more…

Matt - The goal of this project was to really try and push the boundaries of DNA sequencing on a new technology which is the Oxford Nanopore minION Sequencer. This sequencer was introduced about four years ago now, and it became clear around a year ago that it would be possible to sequence a human genome one a minION sequencer. The thing that’s remarkable about that is that the sequencer itself is about the size of a chocolate bar or a small mobile phone. It’s an extremely portable device and you just plug it into a laptop and you can sequence DNA anywhere that you want to.

Lewis - Most genome sequences used today by scientists are extremely large expensive machines which require specialist training. The minION sequencer is much smaller and cheaper. But how does it work?

Matt - Essentially, it’s a rectangular metal box. It has a cartridge that slips inside it and that cartridge or flow cell, as we call it, contains a membrane and in that membrane are lots of nanopores, and nanopores are essentially small holes. The way the sequencer works is it applies a voltage across the surface of the membrane, that allows a current to flow through those small holes. Also, DNA can pass through those holes and as the DNA passes through the hole it of course blocks, and changes, and alters the current flow. It turns out that the changes in current flow are proportional to the sequence that’s present in the nanopore at that moment in time. So, effectively what you get is a current trace, or we call it a squiggle, which reflects the underlying As, Ts, Gs, and Cs.

Lewis - For several years, the minION sequencer was much less accurate than the large sequencing machines used by most scientists. However, the technology has now improved to the point of being almost as accurate and, in addition to its size and cost, it has other benefits. Many current methods involve cutting the DNA sample up into tiny fragments of just a few hundred bases to be sequenced. A computer then has to the assemble these short sequences together to make the full genome sequence. This takes a great deal of time and can also lead to inaccuracies. The minION sequencer has a much higher read length - in other words it can sequence much longer fragments of DNA - fragments which are hundreds of thousands of bases long.

Matt - The advantage of this technology over other competing technologies essentially is the read length that you can generate, plus the real time nature that you can look at the sequence. So with respect to the read length, we can see parts of the genome that we haven’t been able to see before. Things like telomeres: the ends of chromosomes which can be absolutely critical in understanding particular tumour types.

I think the other issue is in nanopore sequencing, in principle, you can start looking at the sequences the moment they appear from the sequencer. So if you were looking for a particular bacteria or detecting a virus, you can see that the moment that it appears in the sequencer. There are lots of examples of people taking nanopore sequencers into the field; some of my co-authors were involved in sequencing Ebola during the outbreak. They went on to sequence Zika virus during the recent outbreak in Brazil and others are applying this technology in similar situations around the world to get real time, rapid information about the pathogens in the environment and about their sequences.

Lewis - So maybe in the future doctors could use this handheld sequencing technology to diagnose illnesses, whether that’s identifying the genome of a particular virus or bacterium or even sequencing a cancer tumour to work out which treatment would be the most effective. Thirty years ago, this would have been impossible. Now, it’s looking more and more likely.

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