Q&A with Dr. Gary Schroth, Distinguished Scientist, Illumina
Less than a decade since the first next-gen sequencers hit the market, the technology has transformed nearly every field of biological science. The pace of scientific discovery during this period has been unprecedented, largely driven by innovative applications and an astonishing rapid evolution of the technology.
So what lies ahead for the technology? How will the next wave of advancements impact the next-generation sequencing (NGS) lab?
We sat down with Illumina distinguished scientist, Dr. Gary Schroth, to get his perspective, vision, and insight on the next frontier of NGS. In this conversation, Dr. Schroth focuses on advancements in library preparation technology that will alter the future of NGS.
Where do you believe that innovation is needed most to further the promise of NGS?
Over the years, sequencing has become much simpler, much more straight forward, and a lot faster, such that we don’t hear about the actual process of sequencing as a limiting factor today. When people talk about doing NGS, it’s generally more about feeding the sequencer with samples and then also downstream analysis of the data. If you look at a typical sequencing workflow, the time spent and the cost involved suggest quite an efficient process. So the bottlenecks from a user’s point of view are both upstream and downstream of the sequencer. Illumina has already done a great deal to address the downstream data analysis with the introduction of cloud-based informatics tools. Upstream library preparation remains an opportunity for innovation.
How will innovations in library preparation impact the NGS laboratory?
Let’s think about it: preparing libraries for sequencing, when done manually, can take anywhere from 4 hours to 3–4 days, depending on the prep method. Some commonly used protocols for preparing both DNA and RNA are up to 3 days long. You’re not necessarily doing something all the time, but hands-on time for some of those preps can add up to 24 hours over the course of 3 days. Meaning that someone has to be at their bench pipetting or running a centrifuge or performing some other intermediary step in the process. This is a big opportunity for innovation, and it will likely come in the form of advances in automation.
Let’s say you’re used to doing a protocol that takes 3 days with 16 hours of hands-on time. What if across those 3 days, all you have to do is spend 30 minutes or less setting up an instrument, press go, and go back to your desk or over to another part of the lab to do whatever you want over the course of those three days? The potential labor and resource savings could just be enormous for some of these labs if these protocols were more automated.
Why is hands-on time so important? Does library preparation really consume that much of a lab’s budget?
For most labs, the greatest amount of time involved in doingnext generation sequencing is spent prepping samples. More of their dollars, in terms of headcount and what people that work in the lab actually do, is spent on preparing samples for sequencing than actually doing the sequencing. Innovation in automation to enable very minimal hands-on time to do these complicated library prep protocols is on the horizon, and this will allow labs to be more productive with their headcount. Labs with very high throughput already enjoy the benefits of automation through liquid handling robots, but there is still a breakthrough needed to make these benefits accessible to labs that don’t have the resources to obtain or support a robot.
How will innovation in library preparation technology improve data quality?
Well there definitely is a certain amount of art to doing sequencing library prep by hand, and certain people are really good at it and other people are okay at it. For labs that have a dedicated library prep expert to feed their sequencers, they may not have a big challenge in terms of reproducibility. For labs that either don’t prepare their own libraries, or that need library prep to be consistent across different locations and/or operators, there is a big need and benefit for an innovative automation solution. For instance in academic settings, this would allow incoming grad students to produce libraries as well as the most experienced post docs. Essentially, the right instrument would take the art out of the process, enabling a range of staff members within a lab to consistently generate high-quality libraries over time. As with time requirements, the complexity of protocols vary quite a bit between different type of preps. More complex protocols, such as exome and RNA-Seq, only amplify the reproducibility challenges and provide extra motivation to make it an automated process.
What impact will automation have on the standard sequencing workflow?
My dream is that, over the course of the next year or so, more and more labs will have a workflow where they’ll start with their purified DNA or RNA, they’ll spend 20 minutes setting up a library prep run and loading their samples, press go and come back the next day to put them on the sequencer. They’ll spend another 20 minutes or so setting up the sequencer, press go and then go back to their desk and wait for an email to tell you when your results are ready. That’s how much simpler the whole NGS process could be. That kind of automation, and streamlining the workflow that much, is vastly different from what people think of today as a typical next-generation sequencing workflow. The introduction of NextSeq and the BaseSpace Apps made NGS vastly more accessible to every lab, and the next innovation in library prep automation will allow every lab to do sequencing as well as the largest genome centers in the world.
Who do you think has the greatest need or will benefit most from this next evolution in library prep innovation?
I think the early users will be core sequencing labs. Basically every university, most large biotech companies, and pharmaceutical companies have their own core lab. Many core labs provide sequencing services as a business. All these high-throughput users have gotten to the point where the library prep process is a real bottleneck. If they’re big enough, they may have already implemented the larger liquid handling robots, but many of them work on projects that are closer to one or two dozen samples or less. Library prep innovation will really help with cost savings on their part. You'd be freeing up technicians in those groups that used to spend all their time making libraries for sequencing so they can just start up a few automated runs each day and then be on to doing other things instead of just preparing libraries. Whether you prep your own libraries or a technician does it for you, this next generation in library prep could really shift the way we approach library prep and NGS in labs of all types and sizes, and bring a whole new level of productivity to genomics.
To see how Illumina is driving innovation in library prep, visit www.illumina.com/neoprep.