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DNA sequence with each colour representing one of the four base pairs: A, T, C, G (Credit: Gerald Barber, Virginia Tech on the National Institute of Standards and Technology (NIST) webpage)

Whole Genome Sequencing (WGS) and Chronic Inflammatory Diseases: A Potential Area of Opportunity?

The convergence of whole genome sequencing, gene editing as well as AI and machine learning technologies has led to an explosion in our understanding with regards to our genes and illnesses. However, have we currently overlooked an entire class of diseases?

In recent years, novel ‘multi-omics’-based approaches have shed new light on the complexities of our own biology. Approaches such as genomics, transcriptomics and proteomics have provided tons of data previously unavailable to us, revealing insights into our genome and the building blocks that make each individual. Critically, the simultaneous development of AI and machine learning algorithms with the ability to process and analyze these vast swathes of data has allowed us to push these boundaries even further. Thanks to the simultaneous growth of these technological platforms, the field of genetics has been catapulted to the forefront of our consciousness. This was best encapsulated by the awarding of the 2020 Nobel Prize in Chemistry to Dr. Jennifer Doudna and Dr. Emmanuelle Charpentier “for the discovery of a method of gene editing”, a mere 8 years after their seminal paper on CRISPR-Cas9¹.

The convergence of various technologies at this point in time has led to an explosion in the fields of genomics, personalized medicine and biotechnology. Modern next-generation sequencing (NGS) platforms, such as Illumina’s NovaSeq 6000 and Pacific Biosciences’ Sequel IIe, can now generate whole genome sequences within a few hours or days. Contrast this to the Human Genome Project, which spanned 13 years (!) in total, yet provided only a fraction of the data obtainable today. The ability to process, visualize and analyze such data is only possible due to improvements in processing power available for analytics; AI, as well as machine learning tools and algorithms. Simultaneously, the discovery of CRISPR as a tool for gene editing has led a renewed push to identify the links between our genes and various disorders in order to leverage its therapeutic potential. The synergies between these converging technological platforms have ultimately pushed the genomics space to new highs. The global market for genomics and its related applications has grown rapidly with greater investment and demand. For example, the SoftBank Group recently announced investments of USD 900 million and USD 1.2 billion in Pacific Biosciences of California² and Invitae Corporation³ respectively, while Invitae has increased its annual billable volume by 41% year-over-year in 2020, representing a startling compound annual growth rate (CAGR) of 103% since 2015⁵.

In particular, gene sequencing and editing has zoomed in on diseases with established genetic causes such as cancer and sickle cell disease. However, chronic inflammation and chronic inflammatory diseases in general appear to have been largely overlooked by gene sequencing and its related applications. At first glance, this seems like a logical choice. Chronic inflammatory diseases such as rheumatoid arthritis (RA), chronic obstructive pulmonary disease (COPD), steatohepatitis and inflammatory bowel disease (IBD) are believed to have multifactorial modes of development — they require multiple causative factors. While genome-wide association studies (GWAS) have revealed genes associated with chronic inflammation and its related conditions, there has never been an established genetic factor demonstrated to be the main driver behind their development. For chronic inflammatory diseases, genetics are usually considered to be a risk, rather than a cause.

Nonetheless, chronic inflammatory diseases currently pose a severe burden to society due to their lack of a definitive cure. The prevalence of chronic inflammatory diseases in Western society is estimated to be around 5–7%. In the United States, patients with such conditions spend an estimated USD 38,000 more on related expenditures each year. In Europe, the direct healthcare costs incurred by patients afflicted with IBD have been estimated to be between 4.6–5.6 billion Euros per year. Meanwhile, COPD has risen to become the third highest cause of mortality worldwide. The chronic nature of these diseases also results in a significantly lower quality of life over extended periods, disproportionately leading to other conditions such as cancer and depression. The complexity of these conditions with regards to their pathogenesis and aetiology has hampered efforts to develop viable cures. With the causes of chronic inflammatory diseases remaining unknown, current therapeutics are only aimed at their symptoms. However, what if the genetic aspect underlying the development of chronic inflammatory conditions is much greater than we think? Two things spring to mind in such a scenario. First, modern NGS approaches could allow better identification of such genetic ‘markers’, if they exist. Second, the presence of such markers would immediately open up new market opportunities for screening technologies to capitalize on, focusing on the development of tests to robustly detect and identify these genetic variants.

Indeed, a recent finding questions this notion that genetics alone are insufficient as a driver of chronic inflammatory diseases . An original research article in the journal Proceedings of the National Academy of Sciences (PNAS), describes how a mutated protein was sufficient to cause hepatic macrovesicular lipidosis in mice, that is, fat buildup within the liver. When the mutant protein was removed, the accumulated fat disappeared after some time. In conventional studies of non-alcoholic fatty liver diseases (NAFLD), the condition is usually induced via the provision of a high calorie diet over a few months. This approach ties in with the conventional ‘multiple hits’ model, as the high calorie diet triggers a complex network of signals eventually culminating in disease. However, the study in this article describes a situation where a single mutated protein, with no additional inducements, was sufficient to cause the beginnings of NAFLD in mice. Although it is important to remember that these findings were only demonstrated in laboratory mice, the underlying logic does merit further consideration. Could there be something similar in humans, where like oncogenes in cancer, a mutant protein is capable of driving development and progression of a chronic inflammatory condition?

While these findings are admittedly in the early stages, they highlight the potential for genetics as a key cause (as opposed to a mere risk factor) in chronic inflammatory diseases. The mutated protein used was just one variant from a library of mutants, each possessing varying levels of heightened activity as the result of 1–2 point mutations. Critically, the increased activity of these mutants arose from a natural phenomenon, and were also tested to ensure they retained their normal properties. Could it be possible that similar mutations and polymorphisms exist in humans, perhaps in other proteins as well which possess similar capacities for initiating chronic inflammatory diseases? At this point in time, it remains unknown if such mutations exist. As mentioned earlier, genetics has never been seen as a key causative factor behind the development of such diseases, only a risk. Genome sequencing and testing for individuals with diseases such as NAFLD is not common, resulting in a lack of data with regards to possible genetic drivers. Should the concept demonstrated in this study be applicable in humans, it suggests that gene sequencing could possibly reveal genetic causes behind chronic inflammatory diseases, potentially even opening them up to be treated at the source with gene editing-based therapeutics in the future.

Gene sequencing and its applications for personalized medicine has seen exponential growth in recent years due to the convergence of various technological platforms. If genetics are revealed to be a major cause of chronic inflammatory diseases as well, it should feed into this rapidly expanding sector, resulting in new market opportunities becoming available. The potential identification of genetic causes behind such diseases could lead to a paradigm shift — targeting genetic ‘root causes’ unlike current symptom-directed approaches. As more resources are dedicated towards the R&D of the aforementioned technologies, we are likely to see greater adoption driven by cost declines associated with Wright’s Law. If genomic analyses reveal a stronger link between our genes and chronic inflammatory diseases, it will only strengthen the case for further investment in the sector. Hopefully, this search for effective therapeutics will continue to drive research and innovation in the field in order to improve the lives of those suffering from such conditions.

“The more we know, the more we realize there is to know.”

Dr. Jennifer Doudna, joint winner of the Nobel Prize in Chemistry 2020 “for the development of a method of gene editing”.

Gene sequencing approaches during studies of chronic inflammatory diseases such as non-alcoholic fatty liver disease are uncommon, as their causes were always believed to be multifactorial in nature. However, a new finding raises the possibility that genetics could be a major causative factor, and not just a risk, for such conditions. If this is true, it opens up many new market opportunities for genomic testing, diagnostics and therapeutics, areas already seeing exponential growth due to the simultaneous development of NGS as well as AI and machine learning platforms.

Disclaimer: The author is one of the writers in the paper titled ‘Active p38α causes macrovesicular fatty liver in mice’ which was cited in this article.

  1. Jinek et al., A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity, Science, 2012. https://science.sciencemag.org/content/337/6096/816
  2. SoftBank to make $900 million investment in Pacific Biosciences, The Wall Street Journal, 2021. https://www.wsj.com/articles/softbank-to-make-900-million-investment-in-pacific-biosciences-11612921031
  3. SoftBank to lead $1.2 billion investment in genetic-testing company Invitae, The Wall Street Journal, 2021. https://www.wsj.com/articles/softbank-to-lead-1-2-billion-investment-in-genetic-testing-company-invitae-11617597250
  4. Press release: Invitae reports $279.6 million in annual revenue driven by 659,000 in billable volume in 2020, Invitae Corp., 2021. https://ir.invitae.com/news-and-events/press-releases/press-release-details/2021/Invitae-Reports-279.6-Million-in-Annual-Revenue-Driven-by-659000-in-Billable-Volume-in-2020/default.aspx
  5. CAGR calculated using billable volume reported by Invitae of 19,000 tests delivered in 2015 and 659,000 tests in 2020.
  6. Chronic inflammation and inflammatory disease, Pfizer Inc. https://www.pfizer.com/news/featured_stories/featured_stories_detail/chronic_inflammation_and_inflammatory_disease
  7. The top 10 causes of death, World Health Organization, 2020. https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
  8. Darlyuk-Saadon et al., Active p38α causes macrovesicular fatty liver in mice, Proceedings of the National Academy of Sciences, 2021. https://www.pnas.org/content/118/14/e2018069118
  9. Diskin et al., Active mutants of the human p38α mitogen-activated protein kinase, Journal of Biological Chemistry, 2004. https://www.jbc.org/article/S0021-9258(20)69925-2/fulltext

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