The Quest for a Genetic Profile for Urogenital Degradation and Nutritional Solutions
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Approximately 8 million Americans suffer yearly from interstitial cystitis, a chronic bladder inflammatory condition; 80% of these sufferers are women (ICA 2017). About 12.2 women in the United States experience vaginal and bladder infections yearly (NIDDKD 2011). And 65% of the 35.2 million who endure irritable bowel syndrome are also women (Canaban+, 2014).
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The Quest for a Genetic Profile for Urogenital Degradation and Nutritional Solutions
- 1. Treat Yourself Well for Life.
- 2. Epithelial Mucosa: Our Inside Skin The Very Top Layer of Tissue that Lines our Tracts and Vessels, and Surrounds our Organs. Millions of People Suffer from Conditions Caused by Dysfunctional Mucosa or are Made Worse by this Dysfunction.
- 3. For Me These Aren’t Just Statistics. I Was One of Those Women
- 4. No One Could Definitively Help Me Conventional and Alternative Methods for Addressing My Interstitial Cystitis Did Not Relieve My Symptoms on a Continuing Basis.
- 5. I Decided to Figure It Out Myself.
- 6. What Medical Science Knows Now There is still lack of clarity regarding the definition of the condition(s). Akiyama+ (2020) proposes this categorization: * Bladder Centric: Hunner’s ulcers, epithelial denudation, inflammation, possible infection. IC *Bladder Beyond: Epithelial malfunction, nervous system dysfunction (bladder area pain but also pain in other locations), no inflammation, somatic effects and/or psychological impacts. PBS
- 7. The Map is Not the Territory This… Not this…
- 8. Mucosa Degradation Eventually Outpaces Production and Chronic Illness Sets In.
- 11. It Takes a Team to Bring Better Health to Millions of People Thanks to: Our Volunteers David Alli, Co-founder, Canopus BioPharma Adina Mangubat, CEO, Spiral Genetics Alan Leong, Ph.D., BioWatch News Jay Goth, Murrieta Genomics John Powers, Murrieta Genomics Brandon Young, Murrieta Genomics Rudy, Julia, Delaina, Golden Helix Patricia Alexander, Chief Cheerleader Helen C. Harrison, M.A. Robert L. Backstrand, M.A. 951-438-5531, txgenetic@gmail.com
Editor's Notes
- My thanks to you, Delaina, and to Golden Helix, for this opportunity to share my story. When we think about our genetic-related health research, sometimes we can get caught up in the details and the process and the schedule and forget that at the other end of the investigation there are real people who suffer horribly. They wonder why? But everywhere they turn they face a mass of mysteries which offers little comfort. This research is my mission to help find solutions to some of the many uncertainties surrounding interstitial cystitis/bladder pain syndrome.
- Epithelial Mucosa: Our Inside Skin The very top layer of tissue that lines our gastrointestinal, urogenital and respiratory tracts, lines our blood, lymph and brain fluid vessels, surrounds our organs, and is a component of our skin and eyes. It’s easiest to call it our inside skin. It forms a protective barrier between our body cavities and our blood vessels and our tissue, and it provides strength and flexibility for our organs. Millions of people in the United States suffer from conditions caused by dysfunctional mucosa or are made worse by this dysfunction. There are mechanisms of mucosa failure we know about. Failures in cell adhesion are well known to cause leaky GI mucosa, such as the stress polarity pathway elaborated recently by researchers at UC San Diego (Ghosh, 2017). Metabolic diseases with high blood sugar levels result in intestinal barrier dysfunction also through disruption of cellular adhesion (Thaiss+ 2018). And we have mechanisms of mucosa failure we know less about. 3. In women: i. Interstitial Cystitis/Bladder Pain Syndrome: 1-6M (ICA, 2018) Urogenital Infections: 12.2M (NIDDKD, 2011) 4. In men: Bacterial Prostatitis: 2M (NIDDKD, 2014) Chronic Prostatitis/Chronic Pelvic Pain Syndrome (non-overgrowth, non-bacterial): 2M (NIDDKD, 2014)
- For Me These Aren’t Just Statistics. I Was One of These Women. * Worsening food and environmental sensitivities starting in my mid-20s, which eventually included gluten intolerance * Chronic bladder, uterine or vaginal infections starting in my mid-20s * Uterine fibroids requiring a hysterectomy in my early 40s * Fibromyalgia in my early 40s after the hysterectomy * Ulcerative Interstitial Cystitis in my early 40s after the hysterectomy. In 2003 the first manifestation was urinary urgency and frequency only. The photographic bladder distension evidenced Hunner’s ulcers and had the benefit of relieving my urgency and frequency symptoms for a period before they returned. Immediately after the procedure I experienced a severe headache, facial flushing and rash for several days. Nine years later in 2012 the manifestation switched to a burning, searing, heat-radiating pain that I associate with inflammation along with the urgency and frequency. * Increase in joint pain, extended bleeding, lax skin, sluggish elastic recoil, slow healing wounds and growing numbers and size of cherry angiomas in my mid-40s and thereafter. * Increase in fatigue, “brain fog”, abdominal pain, insomnia, headaches, nausea, dizziness, night sweats, daytime hot flashes, pale complexion with purple eye rings and regular pimple outbreaks in my mid-40s and thereafter.
- The interstitial cystitis started as periodic in 2003 but slowly worsened until it became chronic in 2012 and reached such a severe level of pain and dysfunction that I felt the only sane solution was to have my bladder removed. It felt like an unrelenting chemical burn on the inside of my body. At the recommendation of a conventional urologist, I tried bladder instillations, which were so profoundly pain-causing I could not tolerate them. I used the expected drugs: pentosan polysulfate sodium, progesterone, an antidepressant, antihistamines, azos, gabapentin. I was sent to a psychiatrist by the medical clinic to investigate my alleged anxiety. After reading the medical notes and conversing for 30 minutes, he concluded with a bit of exasperation, “You don’t have a psychiatric issue. I don’t know why you’re here.” Holistic medical or naturopathic doctors and online IC forums reported benefit from alternatives such as mannose (aloe vera) and natural steroids (gotu kola, copaiba oil) along with sodium bicarbonate to sooth the bladder. Most of these approaches had a positive benefit temporarily but they did not create consistent improvement. After a period of time their advantage decreased and the pain and dysfunction returned. Some never worked at all. Like most women with IC, I knew to avoid highly acidic fruits and vegetables to prevent increased pain. This merry-go-round of dysfunction and eventually pain, broken by periods of relief, was my life for 13 years. No one could definitely help me.
- Like many people who have health problems whose causes are at first a mystery, I decided in 2014 to investigate the issue directly. I understand this is an unusual choice for a non-specialist to make. Most people do not have the academic background or personal resources to engage in literature review or execute studies. Fortunately my graduate work in the history of science, and specifically in evolutionary theory, enabled the task of apprehending biochemical and genetic information achievable. And I am still learning. It is also a benefit to be a patient-researcher, as I can directly apprehend the phenotypic manifestations associated with specific variants and diseases and assess the probability of their involvement in IC from a personal standpoint. So while I defer to the detailed research of others, I can construct a big picture of relevant variables from the view of an experiencer. I know what questions to ask. I have been at this research for 6 years, part-time for the first two years while a full-time faculty member at a state university and full-time since 2016 as a poorly self-funded citizen-scientist. I spent the first two years reading about nutrition, genetics and biochemistry, epithelial mucosa, interstitial cystitis. When I found a clue that answered one of my questions, if I could institute a change in diet or nutrition based on that information, I did. And slowly, slowly, slowly the dysfunction ceased and the pain receded. My interstitial cystitis symptoms diminished with a diet and nutrition program that my genetic profile indicated was necessary for me. These benefits remain as long as I follow this nutrition and diet program.
- Here’s what medical science knows now. Interstitial cystitis or Bladder Pain Syndrome is characterized by persistent lower abdominal pain in the area of the bladder in conjunction with urinary frequency and/or urgency. Akiyama+ (2020) expertly summarizes in “Interstitial cystitis/bladder pain syndrome: The evolving landscape, animal models and future perspectives” current perceptions: There is the recognition there is a variety of phenotypic manifestations, each with different possible origins. In line with recent research, Akiyama+ summarizes the distinction between “Bladder centric” or “Bladder beyond” phenotypes. The phrase “interstitial cystitis” should be limited to the presence of Hunner’s ulcers and considered a distinct bladder-centric inflammatory disease. It evidences epithelial denudation and enhanced subepithelial immune response (infiltrating mast and B cells, stromal tissue fibrosis, swelling) with possible infection. This summary suggests the primary form appears to be an autoimmune disorder, but this conclusion is still uncertain. The secondary form involves an inflammatory reaction to tissue injury from physical insult, metabolic failure or infection. IC manifests with an older age at diagnosis, has fewer co-morbidities and more favorable outcomes from endoscopic surgery. The gene expression pattern for IC shows clear upregulation of immune and infection related pathways. For the non-Hunner’s lesion form, the suggested label is “bladder pain syndrome” and is associated with urothelium malfunction and neurophysiological dysfunction but does not evidence inflammation. It may present with somatic and/or psychological symptoms associated with anxiety (abdominal pain, indigestion, chest pain, fatigue, dizziness, insomnia, headaches) with systemic pain apparently due to central nervous system sensitization. This tends to occur in younger individuals who have equal or less severe bladder symptoms, a larger bladder capacity and more co-morbid conditions. Endoscopic surgery is less effective and the bladder pathology is uncertain. The report suggests that common co-morbidities include fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, Sjorgren’s syndrome, migraines, vulvodynia, depression and anxiety, and are primarily associated with Bladder Pain Syndrome. Finally, Akiyama+ (2020) indicates that there are other diagnostic circumstances that do not easily fit into this categorization: an IC/BPS somatoform disorder related to the pelvis and a few documented instances where patients converted between the two forms of IC/BPS
- Such fully organized perceptions had not yet evolved in 2014. The evidence up to that time suggested glycosaminoglycan degradation, bacterial sterility, Hunner’s ulcers, apoptotic activity, mast cell activation. The puzzle pieces were scattered across biochemical disciplines. My approach was to familiarize myself with as many of those disciplines as possible so that I could understand how those categories could be contributing overall to the condition. I wasn’t then, and am not now, interested in conceptually consolidating data but in uncovering the variables within the different metabolic and functional pathways that enact enzyme outcomes. As clarifying as the schema might be, distinguishing as it does between bladder-centric and bladder-beyond , it could also create an artificial cognitive map of the phenotypic data. The report recounts, as in my case, that there are uncategorizable versions of IC/PBS that don’t fit neatly into the suggested schema. My phenotype, at different times in my life, according to this report, would be both IC and PBS. I have some thought about this. First, how much clarity does a schema provide if an exception is ruled out as a meaningful representation rather than regarded as a demonstration of many relevant contributing factors, perhaps more than expected? It may be a contracted way of thinking about the value of my lived experience as a resource for understanding what is happening. Second, this theoretical approach may also obscure the fluid nature of phenotype. Phenotype evolves from a combination of individual and shifting variant impacts within intersecting metabolic pathways that are up or down regulated to a greater or lesser extent according to a person’s stage of life, physical and emotional stressors, lifestyle choices and environmental exposures. Third, the accuracy of the schema is dependent upon the assignment of the meaning of the symptoms. I am thinking here specifically of the tendency to regard a set of symptoms as psychosomatic, as having an origin in anxiety, rather than having an origin in another metabolic process. This would be the abdominal pain, indigestion, chest pain, fatigue, dizziness, insomnia, headaches. As a woman I am sensitive to the historic tendency of the medical establishment to interpret women’s health through the lens of hystericism. While for some women an anxiety-related disorder may be an aspect of their total health constellation, that is not the only source of these types of symptoms.
- After 2 years of genetic and biochemical study, I developed an initial model, which has been refined since, to depict one way how our mucosa becomes disjunctive. My research has focused on the influence of nutrients, allergens, infections and xenobiotics, on the creation and degradation of connective tissue, on innate immune function and on the production of pain. Investigation of transcription signaling, acquired immunity and regulatory pathways is left to others. First contribution: there is a decrease in tissue production. Nutrient insufficiency combines with limitations in specific tissue protein biosynthesis to result in the decrease of certain mucosa proteins. Second contribution: there is tissue damage from multiple sources (allergens, toxins and/or pathogens) because of failures in innate immunity and/or xenobiotic processing and/or stress events. These evoke inflammation and switch on neural pain. Sources of damage eventually outpace production capability. Third contribution: this process is self-reinforcing. Once our inside skin becomes permanently disjunctive, it allows even more allergens, toxins and pathogens into the body, causing further damage to our mucosa, evoking more inflammation and pain. Lifestyle choices and life stage changes exacerbate this progression. Fourth contribution: because of the widespread presence of mucosa tissue throughout many portions of the body, some of the negative affects will be systemic because multiple types of interior tissue are being affected. The degree and severity of affect will vary between tissue locations depending upon the activity of an individual’s particular suite of pathogenic variants.
- In late 2016 and early 2107, I obtained a consumer saliva whole exome sequencing test. I understood, then as now, the limitations of using this form of testing for variant analysis, but it was what I could personally do to help solve the mystery of my condition. Following the theoretical clues, I found known pathogenic variants in the relevant categories and have been since then developing a list of elite and profile gene candidates. I was surprised to discover how prevalent some of these variants were and understood potentially millions of people could be experiencing disjunctive mucosa. By mid-2017 I starting approaching business leaders in the life sciences industry and explaining my research. I was uniformly encouraged to extend my research to other individuals to verify that my initial assessment applied to others besides myself. Through the end of 2017 and throughout 2018, I self-funded the purchases of saliva whole exome sequencing tests, and received permission to confidentially review these and other self-provided 23andme or Ancestry.com reports, for 16 people. These 16 individuals reported multiple food or environmental sensitivity issues or who had symptoms or conditions associated with mucosa disfunction. To reiterate, I understand the limits of these tests. I also developed a nutritional supplement for 12 participants to overcome the theorized nutrient insufficiency. Four individuals did not receive the nutrient supplementation and so had no change in their food or environmental sensitivities or other health symptoms. I also provided participants with a diet to follow during the study to minimize food chemical exposure. By the end of the four-month study, nine participants reported improvements in their sensitivities or symptomology. This allowed me to extend my understanding of the possible pathogenic variants involved in disjunctive mucosa to other people. A number of them also described less depression or anxiety. I reviewed variant inheritance patterns through text versions of the vcf files by individual RS number, which as you can imagine was a very time consuming process.
- In early 2019 I brought my story to Murrieta Genomics, which has a biotech incubator program in Murrieta, CA. The principals accepted my application as an incubatee and throughout 2019 I created marketing materials and business plans for Tx Genetic Research. Late in the year, a seed investor stepped up with a modest contribution. This allowed me in January 2020 to open an office and purchase the necessary equipment and programs to continue this research. Central to my ability to move ahead was the discovery of Golden Helix. I had trialed or researched other genetic variant analysis software but found either their user features or information reporting and management design unsuitable for this purpose. Once I read about Golden Helix’ VarSeq capabilities with the ACMG plug-in, spoke with Rudy and trialed the software, I knew this was the right program for this purpose. And it has proven to be as effective and helpful as I anticipated. My goal is to contribute to the construction of genetic profiles for disjunctive mucosa and interstitial cystitis/painful bladder syndrome, and to provide practical solutions in the area of nutrition and diet based on those genetic profiles. Elite genes are not currently known for either the broader category of disjunctive mucosa nor for the bladder manifestation of disjunctive mucosa, IC/PBS. Therefore, having as much information as possible heading into the variant analysis process, and having an effective way to create powerful filters, has enabled me to complete in 3 months of research what previously took me 6 months. And during this time I have assessed thousands more variants than what I could working with individual RS numbers. Having broad access to the type of variant, population frequencies, predictions, ClinVar classifications and ACMG guidelines gives me a quicker impression of the likelihood of a variant’s relevance. I am also deeply grateful for the assistance of Julia, who has with good humor and patience endured my technical naivetes as I’ve learned the logic and meanings of the user interface.
- I am currently comparing whole exome sequencing reports from 5 individuals who specifically have either interstitial cystitis/painful bladder syndrome and/or some type of urogenital hyperplasia and/or other connective tissue symptoms to further identify elite and profile genes. I am about 4/5 through the process of primary verification of these candidate genes and expect to complete secondary verification in the near future. I am extremely grateful to the volunteers who have allowed me to investigate their genetic profiles, to the friends and industry professionals who have encouraged me, and to Golden Helix for making VarSeq with the ACMG plus-in available. It takes a team to bring better health to millions of people. If you’re interested in how Tx Genetic is changing the landscape of nutritional genomics for epithelial mucosa-related conditions, I welcome your collaboration.