The future of next-generation sequencing: Interview with Shawn Levy of Element Biosciences

Insights from VIB's Revolutionizing Next Generation Sequencing conference

April 13, 2023

This blog post is part of the VIB Technologies campaign.

At the VIB Conference RNGS23: a glimpse into the future of next-generation sequencing technology. Toon Swings (VIB Technologies and member of the RNGS23 organizing committee) talked to Shawn Levy, SVP of Applications and Scientific Affairs for Element Biosciences about the future of, and challenges for, next-generation sequencing.

Toon Swings – Welcome and thanks for taking the interview. Next-generation sequencing has seen a boom in the past couple of years, especially now with all the startups coming, of which Element Bio is a prime example. Let's start with a brief introduction.

Shawn Levy - Sure, and thanks for inviting us. I spent a little over 20 years in academic research, first at Vanderbilt University in the US and then at the HudsonAlpha Institute. After some interesting transitions in my laboratory there and working with Discovery Life Sciences, there was an excellent opportunity for change. I was very impressed with the flexibility of Element's chemistry, and it was a great opportunity to do something different. I joined Element right before their virtual launch, which was about a year ago, and now in early 2023, we're starting commercialization of the platform in Europe.

Toon Swings - We also have a platform at VIB and are very enthusiastic about it. In sequencing, you balance quality, throughput, and cost. How do you see that evolving?

Shawn Levy - If we rewind to the early days of next-generation sequencing, it was common knowledge that when you added up all of the issues in the systems from sample isolation through library prep, sequencing, and data analysis, you end up with errors. It doesn't take a high percentage of errors to end up with many inaccuracies when you sequence 3 billion genome bases. Our goal is to improve the efficiency of sequencing, but we have to look at the big picture; we have to look at the whole process. You can't just look at just sequencing quality and isolation. It makes for an easy marketing pitch but doesn't give you a result.

Looking ahead, a key goal is the de novo assembly of anybody's personal genome. But short-read genomes, from a single nucleotide variant perspective, still have exceptional value in personalized medicine. The take-home message is that genomics has opened many doors regarding resolution over the last ten years. Now we're figuring out how to apply that resolution to a biological perspective, which is just revealing new challenges. Sequencing is certainly evolving. Now sequencing is both a discovery tool for the long read/short read personalized medicine and a detector.

Shawn Levy: "To steal a quote from David Bentley, the grandfather of sequencing: 'The ultimate sequencer is where the DNA information you get out matches perfectly the DNA information you put in,' and no technology is there yet, which illustrates that we have many opportunities to continue improving and evolving."

Element Biosciences' Aviti Benchtop Sequencer at the "Revolutionizing Next Generation Sequencing" conference last March.

Navigating a challenging environment

Toon Swings - What would be the main challenges still to be overcome for sequencing technologies?

Shawn Levy - Oh, I think that segments very quickly into application areas; you have the commercial aspect of sequencing, the scientific aspect, and the commercial aspect. The reality of all of these companies is that they have to build a viable business in the long term. If you look at the unique applications, things like ChIP-seq, RNAseq, etc., they came out of academic labs, and I think the real challenge for sequencing is embracing that diversity. So I hope the field starts to recognize that, from a core facility perspective, most cores should probably aim to have a diversity of technologies.

Toon Swings - What challenges did you face? And how did you work around those?

Shawn Levy - The challenge Element has faced is being a new company entering a commercial market, where you have to figure out how to compete commercially and scientifically and strike a balance between those two. Element has taken a very scientific approach. We've tried to be as transparent with our technology and platform as possible and to try to set reasonable expectations. At the same time, we know that we have to have a solid commercial organization to not only inform people of what the platform can do but when someone is a customer that we can support them.

Toon Swings - Maybe a more personal question for you. What was the most exciting discovery or breakthrough in genomics leveraging sequencing technologies from the last few years?

Shawn Levy - Gosh, my answer is not going to be one single one. I would say one of the most rewarding aspects of working in and developing a core facility has been a diversity of projects. We've had the privilege of being directly involved in the sequencing of a child in the NICU, where the speed with which we did the sequencing and the interpretation led to saving that child's life, or working in forensic sciences where we've used genomic technologies to solve several cases of either unidentified remains or even contributing to the investigation process. And then, on top of that, there's also the overall personalized medicine aspect. But if I had to pick a technology aspect, I'd say I was fortunate to be funded by the All Of Us Program, which was focused on long-read sequencing. And I think for me, if I purely wear a scientific hat, and not necessarily my Element hat, the ability to start deciphering some of the complexities of the genome has been very humbling in the sense of really now appreciating just how much complexity is there.

Toon Swings - This reminds me of the tagline we always use at Tech Watch to justify our actions. 'You can only see what your technology allows you to see.' And now, you can see all the different layers of complexity; I would say it keeps getting more exciting.

Shawn Levy - Yes, it's like you solve one kind of mystery of biology or one interaction, then you realize that biology is simpler or less simple in some ways. And I think the one thing in personalized medicine that may surprise someone who's not in the field is that, from a genomics perspective, their genome was probably somewhat uninteresting from a single gene disorder perspective, because they would have known they had those. Again, there are many exceptions, and there are certainly some age-related conditions for which that's not true. Still, for the most part, I think that means we'll enter a phase of personalized genomics where it's more about the interaction of your past choices, your environment, your genetic potential, and how to modulate that. If you could tell somebody, based on their genetics, that they have a much higher risk for phenotype x, y, or z or certain choices, our interventions may be much more effective.

Staying ahead of the curve

Toon Swings - How do you ensure from a company point of view that you stay ahead of the curve?

Shawn Levy - It's something we debate all the time internally. And I think some of it's how we've structured the groups. I oversee the applications group, which sits between R&D and commercial. And then there's a very large R&D part of the organization which Mike Previte, one of the co-founders, oversees. And then Matt Kellinger, the third co-founder, with Molly He being the CEO. She keeps everybody focused in the right direction. There are a lot of collaborations with both academic and commercial laboratories. And I think you'll see that we're certainly not unique in that fashion; we have to embrace the creativity and the brainpower that's out there in the field and try lots of stuff. We can't be afraid to fail.

Toon Swings - One thing that was said in the presentation is that "we will solve this by using the Early Access program." As a regular participant in Early Access programs, I could not agree more. Maybe people also want to know how you incorporate user feedback because it comes from having so many devices in the field. Can you take them all in? Can you do something about them?

Shawn Levy - Yeah, that's a great question. What we know is that we want to have both an in-person user group meeting. But we also want to have more of a virtual opportunity. Although travel has largely gotten back to normal, we won't be able to have everyone come to one location effectively as a global company. We want to strike a balance between doing in-person events and capture input and feedback transparently through some virtual events.

About ethics

Toon Swings - Maybe to close off one final question related to ethics, which is always involved in DNA sequencing. How do you balance commercial interests with the ethics around genetic sequencing, especially from human material? Is there a strategy behind it?

Shawn Levy - The integrity of the data and the ethical use of that data are critical to everyone in the genomic space. To give you a simple answer: the ethics of this and ensuring we're protecting the most vulnerable populations must come first. We cannot have long-term success if we don't do that upfront. We also must recognize that we will probably not get it 100% right initially. We're never going to understand biology if we don't have diverse participation, and we're never going to have diverse participation if we don't have appropriate protections.

Toon Swings - It's a two-way street. Also, there are many developments in the informatics space: data protection, data security, etc. Some startups from e.g. George Church's lab, are leveraging blockchain technology in data security.

Shawn Levy - Yes, and I think those efforts are essential because you should be able to own your data and decide who gets access to it and for what. If we can solve that and people can make sure that their data is only used in conditions that they feel are appropriate, there's going to be an iterative process to manage risk with as much good information as possible and ensure that everybody is proceeding with positive intent.