Preface

In 1993, I finished my 4 years of residency training in pediatrics. The last year of residency was an exceptional turning point in my life, during which I attended a one-year diploma in general pediatrics. Since then, I became interested in teaching junior residents. Not many people were involved in teaching during this period; thus, I had to educate myself about all specialties. My excitement and passion for teaching continued after my return from a one-year pediatric gastroenterology program in McMaster University in Canada; eventually becoming the pediatric board program director in my hometown for few years.

In November 1998, an enthusiastic transplant surgeon and myself started a living-related liver transplantation program in Prince Sultan Military Medical City, collaborating with a group of colleagues from Hamburg University in Germany. Our first case was a girl with progressive familial intrahepatic cholestasis type 2 (PFIC2), who continues to do very well until this time.

Since then, we were surprised by the number of PFIC patients in our community, among which was the unusual disease PFIC1. Nothing was logical about this disease. The mechanism of PFIC1 disease is similar to that of PFIC2, but the outcome in the liver is different; one is inflammatory and the other is not. Primary loss of BSEP in PFIC2 leads to severe inflammatory disease of the liver because of primary retention of bile acids. On the other hand, permanent loss of membrane asymmetry caused by primary loss of ATP8B1 (FIC1) in PFIC1 leads to secondary
loss or dysfunction of BSEP; however, hepatocytes lack inflammation despite secondary retention of bile acids.

From that point onward, I started my journey in search for answers. I noticed a relation between loss of membrane asymmetry and raft disruption. At the same time, an additional relation between exposure of phosphatidylserine (PS) and shedding of microvesicles was also noticed. I had to educate myself about lipid rafts and shedding of microvesicles while trying to connect both to the pathogenesis of PFIC1. In the early days, I thought that every exposure of PS is associated with disruption of lipid rafts. However, I realized later that exposure of PS is mostly followed by intact (or increased) building (or re-building) of lipid rafts. I then indulged myself with all causes of PS exposure and loss of membrane asymmetry, while relating them to physiological and pathological forms of membrane microdomain phenotypes.

Over the next few years, my theory went through many iterations. I had to read, think and re-think about every aspect of medicine. At the end, I settled on the final theory (and formula) which states that there are only two pathogenic membrane microdomain phenotypes: one with too little building of lipid rafts and the other with too much building of lipid rafts. To prove my theory, I had to read and learn about basic felids of physiology related to various modulations of membrane microdomain phenotypes during (or related to) cytokinesis, exocytosis, acidosis, shedding and blebbing, albumin loss, shedding of transmembrane proteins, apoptosis, eryptosis, autophagy, stress response, oxidative stress, cell size, inner leaflet, membrane defects, caveolae, unconventional secretion, cholesterol and sphingolipid homeostasis, chloride secretion, magnesium loss, vitamin K and E, cell pathways such as AMPK and EGFR, transcriptional factors including FXR and LXR, T regulatory cells, primary cilia, inflammation, and proliferation. I ended up by applying my theory to these aspects while writing a book about each of the above mentioned subjects. I applied this theory on most specialties of medicine and ended up with writing various related books in disease pathogenesis based on abnormal membrane microdomain phenotype of red blood cell (RBC) disorders, platelet disorders, renal diseases, deafness, eye disorders, primary cilia disorders, diabetes, pancreatitis, Crohn’s disease, alcohol, aging, Alzheimer’s disease, memory loss, and the effect of cell phone on membrane microdomain organization.

Being a pediatric gastroenterologist and hepatologist, I wrote a few books about membrane microdomain organization/disorganization of biliary secretion, cholestasis, cystic fibrosis, primary biliary cholangitis, cholangiopathies, PFIC1, PFIC3, FXR, gallstones, bile acids, inflammatory bowel disease, chloride loosing diarrhea, and hereditary fructose intolerance. In the presence of 2019-2020 coronavirus pandemic, I also discussed the role of membrane microdomains in entry, replication, and exit of viruses and their treatment options. This included discussion about hepatitis C virus (HCV), human immunodeficiency virus (HIV), and SARS-Cov-2. Lastly, I reached to the conclusion that most, if not all, drugs are modulators of membrane microdomains. I wrote four books about the mechanism of action of drugs based on modulation of membrane microdomains, then followed by two more books about the membrane microdomain phenotype of MDR1 and ABC transporters overexpression and their relation to drug resistance. At the same time, new ideas about various treatment options based on modulation of membrane microdomains were included within most books. Two more books were added about the mechanism of action of curcumin and polyunsaturated fatty acids (PUFAs) based on their effect on membrane microdomains. Predicting the life expectancy based on the results of simple serum tests that can be translated into the patency of a person’s membrane microdomain phenotype was proposed in a separate book. The help of Whole Exome Sequencing (WES) in interpreting the person’s own membrane microdomain phenotype was also added to the same book.

By the end of the last 14 years, I wrote more than 11500 pages within 83 books. These books encapsulate hundreds of discoveries on disease mechanism and various therapeutic options based on modulations of membrane microdomain organization, across all aspects in medicine. Most importantly, I propose a unified membrane microdomain phenotype as the cause of chronic inflammation (regardless of the cause, age, or affected organ), autoimmune disorders, cancer, drug resistance, neurodegeneration and aging. I have also discovered an approach that can be performed, by doing four simple tests, to envision one’s membrane microdomain phenotype and foresee the possible presence or absence of primary susceptibility to disease development and/or accelerated aging. I am hoping that these discoveries will bloom into great advancement in the medical field.

Achieving this was not an easy journey; I had to work extremely hard, reading thousands of papers while learning basic physiology and disease mechanism based on abnormal membrane microdomain organization in all aspects of medicine, and tweaking my theory countless times through continuous and nonstop reading, thinking, and writing. This was done while continuing my career as a pediatric hepatologist and transplant hepatologist, in addition to my role as a pediatric gastroenterologist. Above all, I had to take care of my beloved family.

“Mission Impossible”; was the title of my journey. Freedom of thinking, passion, and a lot of extreme hard work were the key factors that kept me going through the most fruitful years of my life. It was not without essential losses and sacrifices, especially in terms of social and family commitments.

I am glad to reach the final stages, where this knowledge can be shared and put to use. The objective of this book series is to change the history of medicine. I may not live to the time to see this objective achieved; I hope my wife and children can forgive me (for the so many moments that I could not share with them), when and if it comes to be true.