Podcast: Long-read sequencing, episode 2

The method of the year according to Nature Methods is: long read-sequencing. Here's a podcast with Gordon Sanghera, CEO of Oxford Nanopore Technologies.
Podcast: Long-read sequencing, episode 2

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Long-read sequencing is the method of the year 2022 according to Nature Methods .

And here is a Focus on this subject with comments, perspectives and my news feature for which I chatted with scientists at companies and in academia about long-read sequencing and did some podcasts, too. 

In my podcast series on long-read sequencing, this one is with Dr. Gordon Sanghera, CEO of Oxford Nanopore Technologies, which is one of the companies that offers instruments that can do long-read sequencing. 

Gordon Sanghera, CEO of Oxford Nanopore Technologies (Oxford Nanopore Technologies)

You can listen to the podcast here or on streaming services. Links to the podcast on streaming services such as Spotify, Apple podcasts and Google podcasts are here

A transcript is here 

Transcript of the podcast

Note: These podcasts are produced to be heard. If you can, please tune in. Transcripts are generated using speech recognition software and there’s a human editor. But a transcript may contain errors. Please check the corresponding audio before quoting.

When labs want to dig into genomes, they tend to use use instruments called sequencers. These instruments deliver a read-out and tell researchers what units, what nucleotides, make up the stretch of DNA they are looking at. And the read-out might be for one stretch of DNA or entire genomes or many genomes. 

One issue has been that existing instruments delivered--short reads—short readouts of sequence. Then scientists have to computationally stitch together short reads into contiguous sequence. 

But genomes have a lot of gnarly bits that make assembly from short reads hard and sometimes even impossible. 

To address this, a few companies developed instruments that can perform long-read sequencing, one of which is Oxford Nanopore Technologies. There are others such as Pacific Biosciences. There are newer offerings from other companies such as MGI, Ultima Genomics and Element Biosciences. Illumina, one of the more well-known sequencer makers also has started to offer long-read technology. 

As part of a story for one of the Nature journals, Nature Methods, I spoke with researchers in academia and with scientists at companies about long-read sequencing. This is an episode  in a series about long-read sequencing. Nature Methods calls long-read sequencing the method of the year for 2022. 

This episode is with and about Dr. Gordon Sanghera, the CEO of Oxford Nanopore Technologies.

Gordon Sanghera [1:35]
I did a PhD in coupling biology to electronics. And I was involved. I came to Oxford, to to work for a prof who had a company in the 80s, who transformed the lives of Type-1 diabetics, if you know anybody who injects insulin, if you remember those little credit card sized, glucose meters with a finger stick. They were invented here in Oxford. That was transformative and disruptive, but I didn't really know any of that back then. You know, I was just in this role, really, I was doing a job that, you know, I was able to get, which is specialist in my PhD, which is coupling biology electronics. So that was a 14 year, I didn't realize that at the time training for Oxford Nanopore. 

Because the company, I joined when they were 20, or 30, people as an R&D  bench scientist, worked my way up, became head of r&d. And then I moved to our head offices in Boston, Mass, mass. And in mid-flight, we got acquired by Abbott Laboratories. So by the time I landed, we were part of a big Abbott diagnostics division. So I did seven years at Abbott. And, you know, which really allowed us to accelerate and change so many lives of Type-1 diabetics. 

The most memorable moment from that was I was in Atlanta, at an American Diabetes Association Conference. And this beautiful health care worker came over and gave me a big hug. And I thought, boy, it must be my lucky day. And she looked after juvenile diabetics, and she said:  You have no idea how, how transformative this has been, because of very small amount of blood, very easy to use, and very low cost. 

So it really could get at those low and middle income groups where, you know, there was a fear, there was a lack of education. You know, it was so it was wonderful. 

By 14 years, seven years in as Abbott, I became very frustrated working for a large company. Too much of a straitjacket. And that was in my early 40s and Abbott offer a wonderful final salary pension schemes. So I thought I've got to get out of here before that, you know, stops me leaving forever. And also, you know, like a good band, I wanted to break up the band and start again and see if I could go in a different direction. And that's where Oxford Nanopore came about.

The idea of melding biology and electronics might not sound too off-beat these days perhaps, but when he was a PhD student it was quite unusual. 

Gordon Sanghera [4:25]
It was an obscure field even back when I did my PhD, which was nuanced to what Nanopore were doing. But when I looked in 2004, when I, you know, really wanted to get out of Abbott. You know, I was looking at what Oxford were doing. 

And, and I came across Nanopore, and and it is basically a very sophisticated method of coupling biology to electronics. And there are only five academic groups. So that is something really unusual for a company to almost be incepted at the same point as the field starts. So you end up with this like. We were spun out of Oxford, but we immediately did a deal with Harvard. Specifically Dan Branton who is in his 90s and still going strong. I mean, he's, he's amazing. He had his 90th Birthday during lockdown a couple of years ago, I think, you know, we all had a Zoom call. It was wonderful. 

But Santa Cruz, California, Massachusetts, Harvard, Oxford, we partnered with all of them. And we went to see them all and said, Look, this is such a nascent technology. It requires a huge leap of faith and a lot of money to convert an academic curiosity into something that could be broadly adopted and used. And let me show you my CV because I helped do that with glucose testing. And I think some of the things that we did over there, we can bring over here because the underlying underpinning innovation in manufacturing can be developed. And that's kind of, you know, leap forward 15 years of hard work, blood, sweat, and tears, and we launched our first products. 

Oxford Nanopore started in 2005 and grew out of ideas from scientists such as David Deamer who was then at the University of California Davis, Hagan Bayley at University of Oxford and Dan Branton at Harvard University. Oxford Nanopore introduced its first device, the MinION. There was an early access program. This was in 2014. 

Gordon [6:35] 
We put out a call, I can't remember, oh, you know, like 200 words, it was like a Twitter thing. In less than 200 words, tell us what you'd like to do. And you pay us $1,000 deposit, and we'll send you a benign and some flow cells, it was 200 words. And we thought we might get 20,30 applications. I think we got 3000. So we sifted through all these up. Like it was a really fun. We set aside Friday afternoons. And we'd go through these different things we wanted to really, we wanted to show the breadth, depth and diversity. And this was in 15, when you know that it was rudimentary in terms of performance, but we got some amazing applications. And that's the first time you start to think, Okay, we might have something quite significant here.

I wondered what domains these 3,000 people were active in. These were people keen on trying out a new sequencing technology. As it turns out these were not exclusively people already heavily involved in sequencing. 

Gordon Sanghera [7:40]
The first thing was a lot of these people didn't do sequencing. So you know, the way sequencing is, is it's IBM mainframe, it's like the computer superpowers, right? You know, the Broad Institute, WashU. you know these people. Wellcome Trust Sanger Center you know, that's where the money is, right? It's like a G20 correlation is very strong. You have multimillion dollar CapEx, multimillion dollar infrastructures, and government or non-for-profit funding to pull this off. What we found was a very broad church from my favorite being a 16 year old Guatemalan schoolgirl, right through to some pretty powerful profs. But mostly not in sequencing more interested in, I can get some information from this at my desk in real time that I cannot do with any other technology. 

So primarily, the focus was initially on infectious disease, which is a no-brainer, because that's the one where time to result is really, really important. But actually, we always, when we when I think about that list, the breadth, depth and diversity in that. It was plant. It was human health, it was infectious disease in humans, infectious disease in plants, environmental I mean, the church was very broad. And when you do offer somebody the capability of interrogating source  codes of of yourself, the things around you, the environment, the food we eat, it's a very seductive value proposition,  at a price point that is, you know, $1,000 for a starter pack targeted to ensure that an undergraduate, you know, DPhil, a PhD student, postgrad doing a PhD, could just go off and sign off and do it. And that's really an ethos of this company, you know, create these, these real, you know, innovators at a price point that they can really go and rip the rulebook up. 

And so, so when we do our London conference every year, and so he can fill you in on that. It, you know, it started as a little bit of fun. The first one we did was 2015, in London, and I said, Well, you know, let's just do something slightly different to a normal science conference, let's play the opening bars of 'London calling by The Clash, really loud at nine o'clock in the morning. Let's set the tone. And, and that became really

Really works from the for the people who have come in from California and who are seriously sleep deprived.

Gordon Sanghera [12:30]
Right, exactly, wake them all up. But not only that, it. So then we kind of extended that to the plenary speakers, why don't you tell us what the opening bars, so we've created this whole cool vibe around this tech. And it's got nothing to do with our choice of music or anything like that. It's the tech, the tech is cool. And the people who use it, our ethos and gold has been, like a computer to create this innovation platform for our customers, they will absolutely produce the innovation. 

There is no way we could potentially think of some of the amazing things they've done in the seven years since we launched the product. So the answer, of course, in a very long way it's  the coolest thing in the world when I get up and open that conference, and then sit there for two and a half, three days. 

And you know, I don't understand all of the biology, but you know, you get the sense of the gasps. And because what we can do now, in an affordable, accessible way, in real time, I gave a talk last week at a Web Summit in Portugal, and just did a bit of background reading. 

If the Industrial Revolution was about industries being built by atoms, the Information Age was built by bytes. And now we're about to hit the Genomic Information Age. And that all came about from the real time accessible nature. So this   idea, this value proposition of affordable, accessible data at your fingertips, we think is transformative. And we're on the cusp of the genomic era. And you know, we believe we believe our platform has the potential to really help to catalyze that revolution.

As I spoke with researchers who included fans and users of Oxford Nanopore devices, they described the projects they worked on with these instruments and also what they wish for from the company for the future. Among the things I heard was an ability to work with lower sample amounts and to deal with fewer software updates from the company. 

Gordon Sanghera  [15:00]
As a disruptor, the rulebook says, you know, release software, hardware fast, release it regularly, but seven years in, there is a new customer base emerging, right. And they are very much focused on applied markets, the technology is good enough now. And you know, in the features and benefits that can provide. They  cannot, they do not want to, and they cannot cope with the continual change. So there's, you know, we're now seeing this emergent new group. And they're really important because, you know, the first genome was mapped 20 years ago now and cost 3 billion and took 10 years and all of that. 

We've not really crossed the chasm into applied market. So that group are really important to us. And we're going to be launching a set of product lines called the Q-Line, q for quality, where we don't change things as regularly, We mustn't lose sight of the innovators. They're the goose that lays the golden egg They want regular rapid changes. So we just have to, you know, as we become a more mature business, there are the early adopters, they just want the newest stuff. But then there are the middle who just want to use it do tests, to do apply market applications. So we're starting to build that. But you know, it is a work in progress. I wouldn't want to say that it's perfect and we've solved it or we are, you know, we will work out how to do both. And so that's coming.

Indeed Oxford Nanopore  is no longer an upstart but it's also true the company is not alone in the market. And there has been litigation between for example Pacific Biosciences, another sequencing company, and Oxford Nanopore. 

Researchers told me they are sad that things like litigation happen but of course in the business world they just do. But some of the litigation was about how to make sequencing with Oxford Nanopore devices more accurate. And indeed accuracy has increased dramatically over time. 

What has changed accuracy and does not involve litigation is an approach At Oxford Nanopore called the Duplex pipeline.  It's a way to sequence one DNA strand and its complement. It's a way to capture reads from both DNA strands of the same double-stranded DNA molecule. 

Gordon Sanghera [16:05]
Accuracy is a continuum. So if you've got drug resistant MRSA, you just need to know it's drug resistant, you don't need to know highly, accurately, you know what it is. But if you've got a really rare mutation in cancer, one in 10,000 or 100,000, then you need that sort of different accuracy. Now, we've always wanted to have the second strand follow the first one. It has many, many advantages beyond just accuracy. And we noted that naturally one strand will follow the other without any chemical coupling, and it was a chemical coupling that was killing us. The strand naturally goes through, but it's not connected in any way. And that is something that we've launched. And it's called duplex. 

This approach for example is useful if someone wants to look at maternal and paternal contributions, the alleles on both chromosomes. 

Gordon Sanghera [16:05]
Also, just because of long reads, you can look at alleles and phasing anyway. You can see it here. And then you can see over there, you know, think about it, you got 500 mini sequencers, right? And you can just say, oh, you know, channel number 256 has got my partner. You know, I'm here in channel 27, 256 is there. So you can informatically bring it together, but it always helps if they're all together. Because you can see one after the other and we know from the time domain, because the strand goes through the, enzyme singulates a double strand, one goes down the hole to be read. 

The other one drifts off into the ether, captured later, goes down a different channel. But when one follows the other, the time between the two is such that we know  it's the partner. And then when they follow each other, we can look at them and say it's definitely the partner because you can't have you know, CTGAT. They can't match perfectly if they're not the partner. So it's so nice trick and it will you're right. It helps in many, many ways. And particularly for those who really want that high level accuracy. One stick we've been beaten with continually, oh, we'll never be as accurate. And we're about to show that it surpasses the existing tech in exactly the same way. And this is the disruptor' s playbook versus the incumbents defense, that everybody said digital photography would never be as good as Kodak color. The rest is history. Right?

In the Oxford Nanopore London Calling event of 2022, Clive Brown, the chief technology officer of Oxford Naopore talked about a bonkers idea. When I did this interview with Gordon Sanghera, Clive brown was unwell so let me just play you a bit from the London Calling event. 

Clive Brown [18:05]
There's one other point I wanted to make, oh yes the toothbrush. This is why they think I'm complete bonkers at Oxford Nanopore. What does the ideal device look like? If you wanted to decentralize liquid biopsy, how would you do that. And there are some great examples, if you think about blood glucose. 
Early blood glucose you would; trot along to a cline, give 20mls of blood, they'd do a huge extraction and tehn you'd get your blood glucose measurement. Gordon worked on this, then it moved on to lateral flow strip tests. And now you can put a device on your arm with a needle in it that continuously measures your blood glucose using tiny amounts of blood. Think about the evolution of that, it's quite remarkable. I don't see why measuring DNA or RNA from blood should be any different  

An ideal device would be a toothbrush, I thin. In the mouth you have 50,000 white blood cells per ml. Why you scrape your teeth you release around 100 mls of serum or blood, doing that twice a day if you sum over the stuff you are measuring, you're looking at 10, 20 mls of blood, in tiny steps. We can select molecules, filter molecules, if we see a molecule that looks suspicious we can sequence it again and again and be certain that we're seeing a pathogenic mutation. That all sounds completely bonkers but that's where I want to take this technology over the next 2,3 years. 

And here's Gordon Sanghera commenting on this toothbrush idea and generally on the future prospects. 

Gordon Sanghera [20:05]
When I talk about when I mentioned, we're on the cusp of the genomic era, we know very little about the source code of any living thing at all right. And if you take a simple example, as Clive was your oral microbiome, it could be a phenomenal way of, you know, there's no reason why we can't have a small integrated sequencer that would fit inside a toothbrush, you know, there was, there's a real, you know, idea there. 

And when you clean your teeth, if you clean them, well, there should be a little bit of blood. So you're basically opening up cells, you're releasing the DNA, and plus your your microbiome is all the bugs that live in your mouth. So for example, if you're having open heart surgery, they will swab the inside of your mouth and make sure they're no no infections in the saliva, that can infect the heart. So the vision is, you change the healthcare paradigm, from diagnosis, when you don't feel well, to continuously monitoring to pick up early warning signs. And that doesn't necessarily have to be a disease. 

When your immune system starts to react to something, your RNA expression levels change. So it could be something very simple, that you can see just like temperature, or blood pressure shifting, it's very generic, but it's very broad. And that doesn't just, you know, you can expand that to your gut microbiome where there are trillions of organisms and, and the gut microbiome, you know, you're starting to see some associations. 

People say, you know, if you change the flora and fauna in your gut, you can change, you know, you can lose weight, you can impact things like Crohn's disease, these are all really, really, we're really in the foothills of this journey. But the future we envisage, is this capability. So with the oral, but the gut microbiome, there's no reason why a smart toilet can't just check everything this is this is what the world will look like. 

We never imagined a world where you could look up the weather in Singapore, you know, in the next three days, while I'm gonna be there at the at my fingertips. That wasn't possible. Before the information age it does. So, yeah, there's real rationale in there. 

And one of the most exciting ones is cancer. What will happen with cancer? Is this whole Are you familiar with liquid biopsies? Yes. So the idea that signatures of cancerous free floating DNA before you see any biopsies, you really what you're saying there is I'm going to pick cancers up at stage one, stage two. And so we envisage a future where you might like the glucose thing, do a monthly blood test, and it checks to see if there's any signatures there. 

Where it goes first people in remission. They are paranoid that you know, they have this six monthly appointment the day after cancer occurs, and he's got six months to take rip. So this idea again, that pushing back and these are smart systems, the patient, the consumer, doesn't need to be an oncologist. The data will go to a specialist and they'll come back red amber green. It's amber, pop in let's take a look at you. And that's how we are going to save our healthcare systems by shifting everything and all of us taking responsibility for these tests. 

And the big frontier that is unmapped in diagnosis is genetics. And you can port that to environmental monitoring, to food monitoring, you know, food protection, pathogen attack. I mean, it really is quite a broad canvas. And we have ideas and brainstorms about the kinds of products that we could bring to bear. And the toothbrush was a visionary, you know, embodiment of what we think will come

As we were wrapping up the conversation we returned to the question of what historic figures would say about this technology, if they came around. 

Gordon Sanghera [24:50]

So Rosalind Franklin would really be able to see like Curie, how her stuff really is, is transforming. We're gene editing now, there's going to be a huge transformation, both in in human health, animal health, but also crops, and food security. And there's so many exciting things happening.

The conversation then turned to access to this technology. 

Gordon Sanghera [25:10]
 One of the things that we're really passionate about is enabling the access of DNA, RNA information, affordable access, so low and middle income countries. So in the context of the pandemic, we sequenced over a million genomes in 85 countries, and a lot of those countries have public health laboratories who are new to sequencing. We provided them the kit that made it as simple as a PCR workflow, to be able to at home, in real time, look at what the mutations were and whether it was Omicron or other. And that really has opened the eyes of those lower middle income countries to the power of decentralized, low cost affordable, accessible real time, DNA RNA sequencing and I think that is is like that alone. so he can tell you many other use cases is something that, you know, kind of, we're very proud of.

This also brought us to the topic of cost. Sequencing isn't free of course. And sometimes it's quite costly. 

Gordon Sanghera [26:10]
The way our system works, we actually give the devices away for free anyway, you only buy consumables. So the minION, it's the size of a Hershey bar and sits in the palm of your hand. So we can make them at such low cost, we can bundle them, so that peopl e don't have to pay.

That was Conversations with scientists. Today's guest was Dr. Gordon Sanghera, CEO of Oxford Nanopore Technologies. And here's a shoutout and thank you to Zoe McDougall who helped make this podcast happen. And I just wanted to say because there's confusion about these things  sometimes.  Nobody paid for this podcast and nobody paid to be in this podcast. This is independent journalism that I produce in my living room. 
And the music used for this media project is Winnie The Moog Funky Energetic Intro and Acid Trumpet by Kevin MacLeod, downloaded and licensed from filmmusic.io. I'm Vivien  Marx, thanks for listening.

(Getty Images/Science Photo Library/ A. Wojcicki/Science Photo Library)

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