DNA sequencing has been crucial in deepening our comprehension of organisms' genetic composition, enabling the diagnosis of genetic disorders, and setting the stage for customized therapies. In a recent conversation with Nava Whiteford, currently working as consultant at Whiteford Research Limited, we covered key subjects such as the progress of DNA sequencing, its role in personalized medicine, the anticipated advancements in DNA sequencing technology, and the obstacles and strategies for overcoming them.

#LBS: How has the landscape of DNA sequencing evolved from its inception to the present day? Could you delve into the pivotal technological milestones that have shaped this journey?

Nava Whiteford: I entered the industry just after 454s launch and just as Solexa was acquired by Illumina and the Genome Analyzer was starting to take off. As such, I missed most of the fun associated with Sanger sequencing, the initial growth of genome centers and the completion of the human genome project.

The upside is I got to see the rise of “Next-Generation Sequencing” (NGS). At launch the Illumina Genome Analyzer generated 25bp reads. But could generate gigabases of data. This enabled ambitious projects like the “1000 Genomes” project. I got involved in this first by writing a paper which in a small way help justify the utility of these short reads [link]. And then by working in a small group at the Sanger institute supporting what I believe was the largest Next-Generation sequencing facility in the world at the time.

So, the ability to sequencing individual genomes on mass was a huge milestone. This was enabled by a number of technological developments (bridge amplification by Pascal Mayer and co. at Manteia Predictive Medicine) and reversible terminators by the folks at Solexa.

Beyond this, after the Illumina acquires Solexa, there were a number of important incremental developments which helped push the ever increasing throughput of Illumina instruments in particular:

  • The introduction of TDI imaging with the HiSeq.
  • The introduction of patterned flow cells with the HiSeq X (including ExAmp).
  • The introduction of 2 color sequencing.
  • The introduction of super-resolution imaging on the NextSeq 2000.

Compared to the initial development of the technology these are all relatively small improvements. But they have insured that Illumina has been able to launch instruments with higher throughput and lower cost.

Outside of Illumina, the other major milestones have been in the development of single molecule DNA sequencing at Pacific Biosciences and Oxford Nanopore Technologies.

After my stint at the Sanger Institute, I worked at Oxford Nanopore for several years. It really is amazing that we can now sequence a single molecule of RNA and DNA on tiny instruments. This feels like a major milestone, but one which is yet to find a strong product-market fit. This is mostly because Oxford’s quality seems to lag behind Illumina’s significantly.

I’m hopeful that Pacific Biosciences will be able to find a solid product-market fit. Their new instruments (the Revio) provides high quality long read DNA at relatively low cost ($1000 per genome). For me, this feels like the sweet spot. A number of people have suggested that this should be the “new clinical whole genome standard” and I would tend to agree.

#LBS: Could you provide some illuminating examples showcasing how personalized medicine benefits from DNA sequencing, particularly in tailoring treatments based on individual genetic makeup?

Nava Whiteford: This is a personally difficult question. My son is intellectually disabled and I’ve been struggling to find someone to perform whole genome sequencing for him. To be frank it was a struggle to even have relatively basic tests performed (Karyotype, CMA. Metabolic testing). Part of the reason for this is because except for some specific cases (e.g. PKU) there are no treatments for intellectual disability.

So there’s some inherent bias in the question. Yes, of course treatment is desirable. But it’s not the only reason for more clearly understanding the etiology of a disease. An understanding of the genetic (or otherwise) basis of a condition impacts siblings and parents. It can provide a better understanding of the nature of a condition of a disability and how it can be best supported.

And as a parent the knowledge has value to me in and of itself.

#LBS: How do you anticipate DNA sequencing technology progressing in the near future? What transformative impacts might these advancements have across diverse fields such as personalized medicine, agriculture, and evolutionary biology?

Nava Whiteford: There are now a number of new players entering the market (Element, Ultima, Singular, PacBio Onso). These companies are shipping instruments substantially similar in data quality to Illumina. That’s going to put downward pressure on the cost of DNA sequencing. This should be great for users as they won’t be tied to a single vendor.

What’s less clear is what new applications this lower cost might enable. It’s possible that many of the barriers to adoption now lie elsewhere…

#LBS: What obstacles stand in the way of seamlessly integrating DNA sequencing into standard clinical practices? From data interpretation challenges to regulatory hurdles and reimbursement issues, what strategies can be implemented to address these complexities effectively?

Nava Whiteford: It depends on the application. For whole genome sequencing, I think there are cultural barriers. My personal experience is that clinicians are used to generating a hypothesis (or more prosaically going with the most common cause) testing for that, and if that comes back negative testing for something else… or if it’s not a serious condition “waiting to see what happens”. Sequencing enables a hypothesis-free approach. Where you look across the genome, or across meta-genomic samples (in the case of infection) to determine a cause.

This way of working requires a significant cultural shift.

In some cases it may require a new regulatory framework. Current regulations can’t really cope with a diagnostic test which is updated “in software”. For example, I’ve previously proposed “sample-to-answer” meta-genomic sequencing for infectious disease testing. I believe it would be possible to get this down to the cost of current respiratory panels, or even lower. The goal would be to create tests which detect all known respiratory viruses but could also detect currently unknown pathogens… that is detecting a new pandemic causing virus. Or at least allowing existing diagnostic kits to be updated in software to detect a new pathogen in circulation.

But how do you get regulatory approval for a diagnostic kit that can be updated in software? That’s less clear to me.

On the technological side, the current generation of sequencers have mostly been designed with research applications in mind. There’s really nothing that has been designed to be embedded in the clinic. Nothing like a Cepheid GeneXpert where a sample can be loaded by a technician with limited training and a report pops out.

Technically a GeneXpert-like sequencer is possible [link]. But I believe this will only come if there’s a clear market for clinical sequencing instrumentation. Something of a Catch-22 perhaps.

#LBS: What is your view about the London Biotechnology Show 2024, which aims to convene relevant stakeholders from the industry under one single roof to discuss and display biotech solutions?

Nava Whiteford: Looks like a lot of fun!