Whole Genome Sequencing - Decoding rare diseases....

Lately, there has been some buzz around Whole Genome Sequencing (WSG) as corporate heavyweights (from Healthcare and related industries) move to leverage it more rigorously for the greater good.

Begs the question, what is WGS anyway?

For starters, Whole Genome Sequencing (WGS) is a cutting-edge technology!

As the name probably suggests, it is used (by scientists and clinicians, mainly) to analyze the complete DNA sequence of an individual.

Pretty straightforward, right?

However, what that line above does not highlight is the monumental task represented by the three simple words “complete DNA sequence” …… simple words that cover comprehensive ground spanning 3 billion base pairs of the genome, including both coding regions (the true essence of “genes”) and non-coding regions (the sensitive areas that regulate gene function).

This span (of 3 billion base pairs) also distinguishes WGS from another “Whole” (Whole Exome Sequencing or WES) approach that is limited to the protein-coding parts of the genome (i.e. ~1-2% of the genome).

How WGS Works

Mostly a sequential play, WGS begins by extracting (and purifying) DNA from a biological sample (say, blood or saliva).

Then, the above DNA is quantified and DNA libraries are prepared (fragmented into smaller pieces, ligated and amplified).

After that, the libraries are sequenced (using Next Gen Sequencing) and the base pairs are read to determine the exact order of the nucleotides (A, T, C, and G) in the DNA fragments.

Thereafter, the sequenced reads are aligned to a reference genome (a species-specific, standard genome sequence) and queried using specialized software to detect genetic variants (differences between the reads and the reference genome). These variants can be about change of single i.e. just one base (Single Nucleotide Polymorphism or SNP), the addition/removal (Insertion/Deletion or Indels) of a sequence of bases or segment-level deletion/duplication (Copy Number Variations or CNV) besides others (structural variants). ??

In other words, WGS is crucial because it covers comprehensive depth to deliver robust results.

Utility areas

Below, I have tried to summarize focus areas where WGS can be useful (with high/medium/low utility per my personal evaluation):

1.?????? Rare Diseases (High Utility): WGS is particularly valuable in diagnosing rare diseases; many are caused by genetic mutations which can reside in non-coding regions (or be structural variants) that are missed by WES.

In contrast, WGS could provide a high-resolution map of the entire genome, making it easier to identify these mutations, potentially facilitating accurate diagnoses and treatments.

2.?????? Cancer Research (High Utility): WGS can lend a (very) helpful hand by providing a detailed picture of the mutations which play crucial roles in how cancer develops and evolves.

WGS can make comprehensive contributions (with synergistic potential) for detecting complex disruptors (like chromosomal rearrangements, gene fusions, etc.), further informing prognostics, drug response, and personalized treatments – factors crucial for determining patient responsiveness to prominent interventions (immunotherapies or targeted therapies).

3.?????? Pharmacogenomics (Medium Utility): Fundamentally, pharmacogenomics explores how genetic variations can affect patient response to drugs/medications – here, WGS can synergize to point out specific genetic variants (like those that influence drug metabolism and efficacy), facilitating personalized medicine.

Contributions made by WGS would see an uptick as the underlying data volume (on gene-drug relationships) becomes more robust!

4.?????? Infectious Diseases (Medium Utility): While infectious diseases have always posed challenges, their position (and visibility) was conclusively cemented ever since covid-2019 landed!

I would have indicated High Utility because WGS is already leveraged to track outbreaks, viral variants (of covid 2019), identify drug resistant mutations, and explore pathogen evolution.

However, WGS is NOT a routine diagnostic tool, so I’ve currently labelled it as Medium Utility!

5.?????? Neurology & Psychiatry (Medium Utility): WGS, IMO, can potentially unravel the genetic basis of complex conditions like autism, epilepsy, and schizophrenia. Early studies (mostly research phase) have shown promise regarding WGS’ potential to help identify rare variants often missed by other querying approaches.

Why are companies turning to WGS (now)?

Companies are increasingly turning to Whole Genome Sequencing (WGS) for diagnosing rare diseases. One particularly disturbing observation that stayed with me ever since I read it is descriptive of the challenge that rare diseases represent: For rare disease patients, a diagnosis, even one with a poor outcome, is often a luxury—long sought after, hard won, and, in a worst-case scenario, forever elusive. The average time to diagnosis, if one can be found: eight years.

That description clearly shows WGS’ immense potential to fill a critical gap in healthcare, providing patients with literally life-changing answers. Of course, the ensuing trust with patients (and clinicians) can position the successful company as a leader in high-value, cutting-edge diagnostics!

From a commercial perspective, the high cost of WGS — historically, a barrier — has decreased in recent years, enhancing access. However, WGS is still a premium priced offering!

From a perceptual perspective, companies that offer WGS may be perceived to be frontliners of precision medicine – which could potentially allow them to capture a lucrative market (made up of commercially viable patients who are desperate for answers)!

Of course, patient-side underpinnings include the fact that patients of rare diseases often have complex (and costly) diagnostic journeys, which fuels patients' willingness to invest in WGS as a viable source of hope (if not a definitive solution).

From a “sustained revenue” perspective, companies offering WGS also see the potential to create medium – long term revenue (Follow-up? Genetic counselling? Ongoing patient monitoring?).

Finally, the generated data can be repurposed for pharmaceutical companies seeking genetic insights into rare conditions, offering a secondary market opportunity for the data. While many contend that “there are no low-hanging fruits anymore,” using the same “low branches” as stepping points for more complex goals and targets can deliver favorably on Cost, Development, Efficiency and Time – factors that are somehow always seen as pressure points whenever R&D tells its story!

Essentially, while WGS provides invaluable benefits for diagnosing rare diseases, companies using this technology are also motivated by clear commercial interests, particularly in terms of Premium Pricing and potential for medium – long term revenue (profit?) generation through related services and data utilization.

Incidentally, Orphan Drug development and Whole Genome Sequencing can operate synergistically in rare diseases - niche, high-need areas that are amenable to premium pricing and continued revenue generation. While the former can develop innovative therapies, the latter can synergize because of diagnostic prowess!

In summary, Whole Genome Sequencing offers a highly detailed view of an individual’s genetic landscape which is a growing necessity in multiple areas including clinical research and personalized medicine.