Advances in Microbiology and Autoimmune Disease - 2018

Encountering patients with an array of disabling autoimmune diseases in general practice, Stephen E. Fry, M.S., M.D. began investigating the causative agents of autoimmunity in order to provide targeted, effective treatments. Today, now-retired from medical practice and deeply missed by his patients, he remains invested in furthering the scientific understanding of autoimmunity with cutting-edge research as Founder, Director, and Principal Investigator of Fry Laboratories.

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Advances in Microbiology and Autoimmune Disease – 2018

Stephen E. Fry, M.S., M.D.

My first article for the Road Back Foundation was in the ‘Intercessor’, Winter 2003, ’Treating the Infectious Soup of Connective Tissue Disease’. Here, I discussed the possibility of Autoimmune disease being microbial with the added support of the efficacy of Tetracyclines. It mentioned the pioneering work of Dr. Thomas McPherson Brown and the potential role of Mycoplasma. I was impressed early on with my discussions with Henry Scammell and visiting Dr. Browns lab, whose legacy was operated by Dr. Coker Vann in Maryland. Since 1992, I have embraced the concept that autoimmune disease; Rheumatoid Arthritis (RA), Lupus, Multiple Sclerosis (MS), and other chronic inflammatory disorders, are caused by microbes. In 2000, I set up my own laboratory to investigate this. I incorporated, in 2007, and expanded and became one of the first non-academic laboratories to offer NGS-ID (Next Generation Sequencing for Infectious Disease) services. We have an added interest and capability of detecting unique complex organisms such as fungi, protozoa, and algae. We were recently acknowledged as having one of the best labs internationally by an industry leader, Qiagen, and now have 5 patents and 5 peer-reviewed articles using this technology. I feel that NGS-ID will come to prove that most chronic inflammatory infections are microbial in origin, as Dr. Brown and many clinicians have suspected, and we have demonstrated this finite possibility in our publications. I retired from clinical practice last year but am still as busy as ever in the Laboratory.

Next-Gen Sequencing for Infectious Disease

Next generation sequencing for infectious diseases (NGS-ID) promises a paradigm shift in how we diagnose microbial infections and will provide better insight and probable etiology of chronic disease. Past technologies: microscopy, culture, serologies, and newer molecular techniques, such as targeted PCR, are useful and will still have value going forward. As price points, speed, portability, bioinformatics, drug resistance mapping, and improvement in sensitivity and specificity occurs, NGS-ID will become adopted. The important studies using NGS-ID in variable disease states, chronic inflammatory disease, and in Lyme disease are ongoing, planned or anticipated. My direct clinical experience, combined with full laboratory access next to the clinic, have enabled a greater understanding of disease processes.

In microbiology, we have relied upon microscopy, cultures and serologies for identification. In the last years, PCR or simple molecular probes have advanced the field. Legacy medicine requires culture confirmation for positive identification. This can be a major drawback, as we now know that we can only cultivate or readily grow less than 2% of bacteria, and less so for eukaryotes, such as, fungi, protozoans and algae. Traditional Medicine has a bias against new microbes or etiologies and has favored a viral, bacterial or human genomic error for the etiology of inflammatory disease. The mainstream medical establishment needs to recognize that there are millions of different fungi, protozoans, algae, and bacteria in the environment, some of these yet unrecognized and are most likely causing disease in humans. In the last 6 years, powerful platforms and informatics systems have evolved to allow us to rapidly and effectively map the human genome. These platforms have been adapted to infectious disease and our laboratory is one of the first.

In concept, this is how it works:

1. 1. The sample is received; then viral, bacterial, protozoal, fungal or algal DNA/RNA is extracted and isolated. (The sample can be from blood, joint fluid, urine, stool, bone, CSF or tissue).
2. 2. After the DNA/RNA is extracted, specific ‘Domain’ or all-inclusive probes or tags are used, and the microbial DNA is amplified many times to produce enough DNA for analysis. This is called PCR or Polymerase Chain Reaction.
3. 3. Once the DNA is produced, the large amount is then ‘sequenced’ through several different technology platforms to uncover the DNA map of the organism, which is unique and identifying.
4. 4. The DNA sequence is then compared to a database; the optimal database we feel is the National Center for Biotechnology Information (NCBI) database with over 53, 000, 000 entries and ever growing. The comparison is made and a ‘closest or best match’ is derived. If there is a new or novel organism the system will pick it up! This allows an unbiased and restriction-free survey of the microbial landscape and the identification of variant, new or novel pathogens. Instead of tunnel vision, we obtain a panoramic and comprehensive view of the microbiome, enabling a global view of disease by identification of multiple organisms in the same sample.

These new tools, added to my combined 15 years of clinical experience, have modified my model of autoimmune disease. I now believe that autoimmune disease is caused by an inherent gene defect that is multifocal, making one more susceptible to fungal, protozoan and algal infections. Our published work (see references below), show a complex of organisms most closely matching Funneliformis spp. (a universal soil fungus), variant Toxoplasmosis gondi, aquatic algae, and Saccharomyces cerevisiae, as being implicated in chronic inflammatory disease. These wild type eukaryotes may look like human cells on histology slides, will have associated inflammatory cells around them, and possess a complex polysaccharide biofilm. Our publications in the peer review literature demarcate this NGS approach. We have published work on arterial plaque, Chronic Fatigue Syndrome (CFS), Fibromyalgia, RA, Lupus, MS, and surveyed levels of these eukaryotes in normal controls. We have pending manuscripts and research on MS, Lou Gehrig’s Disease (ALS) and Prostate disease. The need for larger studies in RA, Lupus, MS, and others, is fully warranted. Technologies to grow these uncultivable organisms must be developed so that we can determine drug sensitivity and to provide a model for appropriate new drug development. Our work has also implicated complex microbial communities, not just “one pathogen-one disease” as having a role in causation.

The realization of this, and application of this technology, changed my approach to the treatment of autoimmune disorders in my last 2 years of clinical practice, which I believe produced significantly better clinical outcomes. The use of antifungals and dietary intervention provided the best results to date. Most of my patients had failed traditional therapeutic approaches or had found them to be toxic. I also found a preference for Doxycycline within the Tetracyclines. Interestingly, it turns out that Doxycycline is a crude fungal biofilm inhibitor.

New technologies, such as NGS-ID, will lead the assault on chronic disease with better information and identification of pathogens. Armed with this knowledge, we will be able to appreciate the true disease landscape and arrive at better therapies and even cures.

Stephen E. Fry, M.D.
Scottsdale August 1, 2018

Peer Review publications from our laboratory utilizing NGS-ID.

1. 1. Putative Biofilm-Forming Organisms in the Human Vasculature: Expanded Case Reports and Review of the Literature.
   2. Rapid Infectious Disease Identification by Next Generation Sequencing.
   3. Evidence for polymicrobial communities in explanted vascular filters and atheroma debris.
   4. Applied Use of Next Generation Sequencing for Infectious Disease.
   5. Microbial Community Profiling of Peripheral Blood in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Pending Publications: Microbiome in MS, ALS and adenocarcinoma of the prostate.