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18 highlights from 2018 (and a New Year quiz)

Mon 31st December 2018

Last week, as the year was coming to a close, we were discussing some of our highlights of 2018.  It made us realise how much breakthrough science has come out of the nanopore community this year.  2018 was a huge year for us, and we have so much more to do in 2019.  We hope you enjoy the list, and taking the quiz at the bottom of the page

Wishing you a happy New Year for 2019. 

Gordon

Gordon Sanghera, CEO

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1. Landmark Nature Methods paper showed direct RNA sequencing

In January, the front cover of Nature Methods featured a landmark paper on the first direct sequencing of RNA, without the need for reverse transcription or amplification, allowing for generation of full-length, strand-specific RNA sequences with modification information intact.  Direct RNA is being explored in many labs, even on a MinION on the International Space Station.

2. The first publication of a human genome using nanopore showed most complete genome ever using a single sequencing technology

January: Nature Biotechnology published a human genome assembly using nanopore technology – the most complete human genome assembly to date using a single technology. The consortium of researchers, from nine different institutions, added ultra-long reads to their assembly to double their contiguity, estimate telomere lengths, and resolve complex regions including the 4Mb major histocompatibility complex.  This first published nanopore human genome used MinION, and plenty of flow cells, to do the work in 2017.  Today, the same 91.2Gb could be sequenced using a fraction of MinION flow cells or indeed just one PromethION flow cell.

3. MinION used in real-time surveillance of Lassa fever, and other outbreaks

In March, MinION was used to perform real time genomic surveillance of an unexpected surge in the number of Lassa fever infections in Nigeria.  The team used genomic insights to ascertain that the surge was of an existing strain rather than a new one, informing the public health response. This added to experience that has this year seen the technology deployed by public health teams looking at Rabies, Lassa fever, Yellow Fever, Flu, Dengue, Malaria, E. coli, MRSA and more.  We are proud of the impact that the portable MinION is starting to make in this area, where transporting samples is logistically undesirable and costs time.  And, we’re excited to see how this might impact more lives in the future, for example the ARTIC network has been working with collaborators in many countries, developing practical and effective methods of using real-time, portable DNA/RNA sequencing to understand outbreaks and improve outcomes for people affected by them.

4. MinION is used to sequence a single fragment of DNA 2.3Mb in length

In May, Matt Loose from Nottingham took the crown for the longest ever fragment of DNA to be continuously sequenced – 2.3Mb in length.  The BBC wrote that this was not only a scientific feat, but also an engrossing story of friendly scientific rivalry: “This research has kick-started an Ashes-style competition to sequence an entire chromosome in a single read".

5. PromethION launched: long-read, direct sequencing can now address large genomes and projects

May: Since the end of 2017, the performance of PromethION in our own labs and in early access had been accelerating.  By May, PromethION performance had evolved and we were getting as much as 100Gb of DNA sequencing data from a single flow cell, promising Tb outputs if using 48 flow cells. So, we decided to make it commercially available.   As you know we want to disrupt the availability of sequencing technology, and we have made PromethION highly accessible – you don’t need to pay capital for the device itself and flow cells can cost as little as $625, making low-cost large nanopore genomes both possible and accessible. 

As we reach the end of 2018, PromethION has moved on even more.  148Gb has been achieved from a single flow cell in the community, and 220Gb internally. These continual improvements have come with no increase in cost per flow cell and no upgrade fee for the PromethION itself.   During the year, PromethION was increasingly used for high impact projects including population scale genomics, the analysis of human and plant genomes.  In October, Amgen noted that DeCode had used nanopore technology for several hundred human genomes, and during the annual ASHG conference, the team at VIB issued the first publication of a full human genome using PromethION, demonstrating that large-scale, affordable, long read sequencing is now here.

6. New 'RevD' flow cell starts to deliver as much as 30Gb of sequence data per MinION / GridION flow cell

June:  The modular form of nanopore sequencing allows us to continually improve the system by upgrading various elements including the nanopore, the algorithms, the kit chemistry, etc.  We believe that continually getting more, better data helps researchers explore new areas of biology as well as improving the cost per Gb.  In June, we released some 'RevD' flow cells, which extend the life of MinION/GridION flow cells so they can deliver as much as 30Gb of data.  In October these became the de facto MinION and GridION flow cell.

7. Nanopore based assembly of human Y chromosome

In June Kuderna et al. published a paper in pre-print, now in Nature, demonstrating a highly continuous and complete assembly of the first human Y chromosome of African origin. By developing a novel strategy to sequence native, unamplified, flow-sorted DNA on the MinION, the team made significant improvement over comparable previous methods, increasing continuity by more than 800%. Crucially, this approach is generalisable to any species, simplifying the assembly of extremely large and repetitive genomes.

Also of relevance to the Y chromosome, in March, research led by Dr. Karen Miga at the University of California, Santa Cruz that focused on the centromere of the Y chromosome had been published in Nature Biotechnology.  The work demonstrated the use of nanopore technology to deliver the first complete and accurate sequence of a human centromere. Human centromeres are composed of long tracts of near identical tandem repeats making them intractable to assembly using short-read sequencing technology. Using the long reads generated by nanopore technology, the team sequenced eight BAC clones that together spanned the Y chromosome centromere.

Read more about nanopore research on the Y chromosome here.

8. Single cell:  nanopore is used to understand the transcriptional landscape of lymphocytes

As single cell analysis becomes of greater interest to researchers, September saw the publication of a method that combined targeted long-read nanopore sequencing with short-read based transcriptome profiling of barcoded single cell libraries generated by droplet-based partitioning. The results demonstrated an accessible and cost-effective method for high-throughput deep single cell profiling, applicable to a wide range of biological challenges.

9. Flu virus sequenced in its native form for the first time

In September, for the first time, a complete genome of an RNA virus was sequenced in its original form. The team behind the research designed an adapter to short highly conserved termi of the influenza virus genome to target the (-) sense RNA into a protein nanopore on the MinION. The team were able to use this method to demonstrate successful sequencing of the complete influenza virus genome with 100% nucleotide coverage, 99% consensus identity, and 99% of reads mapped to influenza. The authors noted that this method has the potential to identify and quantify splice variants and base modifications, which are not practically measurable with current methods.

10. MinIT released, making its debut in a force 8 storm at sea, and on a remote East African farm

In October, MinIT was released - a small but powerful computing accessory to accompany MinION/Flongle.  MinIT contributes towards our goals of breaking down barriers in DNA sequencing - towards bringing it to anyone, anywere.

As MinION performance has evolved to produce sequence data more quickly, we released a small supercomputer that arrives with preconfigured software and basecalls as much as 150,000 bases per second. Based on powerful GPU technology, the MinIT was tested in challenging conditions.  Researchers used MinIT to analyse marine microbiome on an Alaskan marine research vessel, in a force 8 storm.  And the Cassava Virus Action Project characterised the viral content of cassava stems on an East African farm, going from sample to answer in under three hours.

11. China’s first plant genome using nanopore sequencing: the chrysanthemum; a source of potential interest in the genomics of traditional medicine

China has more than 30,000 types of plants, ranking the third most abundant plant resource in the world.  Among these, the ~11,000 medicinal species represent a source of potential investigation into the genomics of traditional medicines.  In October, the whole genome sequencing of Chrysanthemum was completed for the first time. In this paper, nanopore sequencing was used to perform de novo sequencing and assembly of the genome of C. nankingense, an out-crossing perennial plant with large commercial value as an ornamental.  It has a highly complex genome of approximately 3.07 Gb that features high heterozygosity and long, highly similar repeats; reflecting the fact that nanopore sequencing can now provide long read, direct sequencing data at large volumes.  The research also included the investigation of full-length transcriptome genetic information of an important medicinal chrysanthemum variety.

Elsewhere the feature of generating high throughput long reads with nanopore is continuing to generate new science from the plant genomics community; you might also be interested in watching “100 [tomato] genomes in 100 days”, presented by Michael Schatz at NCM 2018:

12. Using real-time sequencing to understanding serious lung infections more quickly

In November, an important method paper was published by Justin O’Grady’s team at the University of East Anglia, showing that nanopore sequencing could be used for rapid characterisation of lung infections, including drug resistance characteristics.  The WHO notes that lower respiratory tract infections (LRTI) are the deadliest communicable disease globally, causing 3.2 million deaths annually. If clinicians can respond rapidly and precisely to an infection then there is a greater chance of improved outcomes for these patients, many of whom are being cared for in critical care facilities.

The team showed that a typical response of >48 hours with culture-based methods – which have their own limitations – could be reduced to under 6 hours with nanopore sequencing. 

Elsewhere, scientists from the Madagascar National TB Program, Institute Pasteur Madagascar, University of Oxford, European Bioinformatics Institute (EMBL-EBI) and Stony Brook University collaborated to train Malagasy scientists to rapidly detect TB and drug-resistance using the MinION. The goal of the project was to improve diagnosis and treatment whilst providing insights on disease transmission. This is vital work as drug resistant TB continues to be a major threat around the world, and presents a public health threat to the people of Madagascar.

13. Flongle released into early access, promising rapid, small tests in any environment

In November, we started releasing Flongle to early access users.  Flongle is an adapter for the MinION, enabling low-cost, rapid, real-time sequencing tests to be performed easily and in any location.  We believe that it will open up new applications for nanopore sequencing, such as rapid infectious disease analysis or on-demand cancer panels, food testing or other types of supply chain surveillance.  In early release, a single Flongle flow cell generated as much as 1.8Gb of sequencing data.  More than 1,000 scientists have told us about the novel applications they would like to use Flongle for; we look forward to much more in 2019.

14. New R10 nanopore and other improvements drive accuracy towards Q50 and beyond

In November we hosted the Nanopore Community Meeting in San Francisco.  As part of Clive’s update, he talked about the work that we are doing to drive accuracy of nanopore sequencing. 

The signal that we measure as DNA or RNA passes through a nanopore is rich in data. Our high-performance, compact electronics are capable of exquisite measurements of picoamp currents, so as we continue to embrace cutting-edge machine learning algorithms, we can extract better information from the existing signal.  To accompany improved algorithms and methods, we’re also releasing a new nanopore, R10.  It’s a different shape to the current R9, reading longer-range DNA information which  has allowed us to produce consensus Q42/43 accuracy and Q50 identity data. In 2019 we are targeting, by a variety of methods, Q50 then Q60 highly accurate, highly contiguous, complete finished genomes.

15. Closing in on rapid diagnostics for patients with leukemia

In December, Will Jeck, from the Nardini group at Massachusetts  General Hospital published a method using nanopore for rapid analysis of samples from patients with acute leukemia (AML).  Categorised as an ‘oncological emergency’, fast turnaround is critical for these patients who need the right treatment.  It is particularly exciting, and motivational for us to see more methods being developed that could take advantage of nanopore’s real-time data streaming in a way that could help improve lives.  Here, the authors noted that they “confidently identified BCR-ABL1 fusion transcripts, with >100 reads within 15 minutes of sequencing”. 

We also saw exciting work from Adam Burns, from the Schuh group at Oxford University Hospitals showing how nanopore sequencing could accurately detect the point mutations, deletions and complex rearrangements that inform diagnosis, prognosis and treatment of chronic lymphocytic leukaemia. His work points the way to a future where the traditional complex diagnostic pathways for leukaemia could be streamlined into a single assay, performed on a single nanopore flow cell

As we continue to prepare our regulatory and manufacturing processes for future clinical applications, we hope to share more news on this subject throughout 2019.

16. Accurate and fast base calling:  Release of GPU-accelerated base callers and algorithm improvements

Software improvements are one of our most powerful tools for driving performance improvements.  In December, we started to push a profound upgrade to our basecalling software by releasing the community stand-alone version of “Guppy,” our GPU accelerated base caller. We also included a major upgrade to our primary base calling algorithm, which we call “Flip-flop”. These upgrades deliver ~95 % per-read (ie the accuracy of raw data, rather than consensus which is higher) base call accuracy. They also deliver a user-interpretable single-base output (meaning that the user can understand the probability of a single base call, and therefore judge it in context if using a reference genome), and visualisation of alternative calls.  All these features are GPU accelerated and compatible with our existing sequencing chemistry.   

As we always think about rapid and easy ‘sample to answer’, Guppy is also packaged with MinIT (for MinION/Flongle), GridION and PromethION.

17. More than 150 nanopore publications in myriad areas of science

As 2018 draws to a close, more than 150 manuscripts have been published by scientists in the nanopore community -- you can browse in the publications area of our resource centre.

18. Accessible sequencing for the next generation of scientists

In 2019, as VolTRAX, Flongle and more EPI2ME applications come online, and with the arrival of MinIT, we believe that nanopore will become more accessible as an education tool. We are looking at ways of making that happen – and always welcome your feedback on that. 

In the meantime, we were thrilled to see Arwyn Edwards participate in this year’s Royal Institution Christmas Lecture, where he talked to a young audience about sequencing and microbiomes.  Featuring alongside dogs, cows, twins, an ethicist, fingerprint specialist and children, and of course Professor Alice Roberts and Professor Aoife McLysaght, we were reminded that genomics is a subject that can reach us all.

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What did we miss?!

Thanks to everyone in the nanopore community for your support in 2018, and we look forward to a busy year in 2019.  Wishing you and your families a very Happy New Year.

 

Why not kick start 2019 with our New Year quiz

New Year quiz

Credit to Richard Manning for making this quiz, inspired by terliz.blogspot.com/2012/03/lego-quiz.html.

Quiz answers

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