Deep Sequencing

Throughout their training and practice,…

What if, one day, we find that all autoimmune diseases are due to infections by microbes yet undiscovered or yet undetectable by current means?

Rheumatologists will be jobless, that’s what!

Or maybe, just maybe, we may still get to treat Gout, Osteoarthritis and Fibromyalgia (which most of us either frown on or suck at, or both).

Image result for genetic deep sequencing

Ankylosing spondylitis (AS), a chronic inflammatory disorder, has a notable association with HLA–B27. One hypothesis suggests that a common antigen that binds to HLA–B27 is important for AS disease pathogenesis….
Welcome to the era of supercomputers, big data analytics and brute force metagenomic (environmental) and genomic deep sequencing, whereby coverage (reads, copies of nucleotides) by the thousands and millions enables us to detect rare microbes, tumour clones or single-nucleotide polymorphisms (SNP) in disease samples.
In this study, deep sequencing (to ensure that nucleotide differences were genuine SNPs and not sequencing errors) was confined to the T-cell receptor ß-motif of HLA-B27 carriers, with or without active disease (Ankylosing Spondylitis). Hopefully, the unique disease-associated motifs discovered will help to elucidate the pathogenesis of AS.

If we apply deep sequencing indiscriminately to entire human population genomes in the hope of discovering some random clone/microbe/SNP which may be causing the various diseases in order to save the world, it has been estimated that the big data storage we can currently muster is not big enough: ever heard of an exabyte? That’s 10 to the power of 18, far outstripping YouTube’s and Twitter’s annual storage needs.


Alarmist, maybe. Fools’ Day joke, no.
My over-a-week’s posts on Ultrasound in Rheumatology is coming to a much nearer end, but I interrupt regular programming to bring you this report on Metagenomic Deep Sequencing (MDS).

Reading it, I was at once intrigued and perturbed: intrigued that possibly most of the autoimmune diseases I treat may be due to some obscure but curable infection; perturbed that I may consequentially be out of a job before I could provide adequately for my retirement, and family.

“Metagenomic” refers to the genomes of microbes in our tissue that are patently not ours. “Deep sequencing” refers to making numerous copies of the genomes (human and otherwise) to eliminate copying errors. The genomic sequences are then run through genetic data banks in the public domain to check if anything “non-human” lurks within. If so, perhaps that is the cause of the disease.

I hear through the grapevine that SGH is on the verge of acquiring such a system. Apart from hastening the planning for my exit plan or early retirement, I’m thinking what autoimmune disease specimens to offer at the altar of this new deity. Granulomas and germinal centres top my list.

Granulomas are our immune cells trying to wall off “illegal immigrants” and potential threats they could not get rid of, like TB, foreign body or uric acid. So, what lies at the heart of a Crohn’s, Sarcoid or Rheumatoid nodule? Or take germinal centres in salivary glands and the draining lymph nodes of Sjogren patients. Perhaps some bugs tracked up the secretory ducts of exocrine glands to start the whole circus! Yes, these specimens shall be what I propose to put first through the MDS juicer.