Exploring chronic disease
22 Aug 2007
All images of bacteria in this post are taken, with author’s permission fromClinical Microbiological Reviews, published in 1997, 10(2), 320-344.
Gerald Domingue is a medical researcher and academic who served as Professor of Urology, Microbiology and Immunology in the Tulane University School of Medicine and Graduate School for thirty years and also as Director of Research in Urology. He is currently retired and resides in Zurich, Switzerland where he is engaged in painting and creative writing. At retirement he was honored with the title of Professor Emeritus at Tulane. Prior to Tulane, he served on the faculty of St. Louis University, was a lecturer at Washington University and director of clinical microbiology in St. Louis City Hospital, St. Louis, MO.
Over the course of his thirty-nine year career, Domingue received funding from the National Institutes of Health, Veterans Administration, and a variety of national and international research foundations. He enjoys international recognition as an authority on the basic biology and medical significance of atypical bacterial organisms and is considered an expert on the role of these bacteria in the persistence and expression of kidney and urological infectious diseases.
He first became interested in the role of atypical bacterial forms after noting that a large number of patients with urinary tract infections suffer from continual relapsing illness. Using a direct phase microscope, he examined the urine specimens of several patients with urinary tract infections and found L-form bacteria in his sample.
He began to investigate L-form bacteria, striving to better understand their biology and the role they play in causing disease. Over the course of the next 30 years, he was able to explain much of the mystery behind how the bacteria are able to persist in the body, and published a wide array of clinical and experimental studies on the subject.
Domingue worked with a team that included pre and post doctoral students and fellows along with faculty colleagues and laboratory assistants. Together they discovered that L-form bacteria are able to form tiny dense bodies within parent cells that already lack cell walls. They noted that the forms, which they called electron dense bodies were so small that they could pass through bacterial filters that normally withheld ordinary bacteria with cell walls.
The electron dense bodies could persist inside tissue culture cells in the laboratory. After applying this data to the human condition, Domingue reasoned that in some patients who suffer from chronic bacterial infections, the disease process could be related to the fact that bacteria are able to differentiate into the resistant electron dense bodies that he observed in tissue cultures.
In 1974, he and his graduate student, Mary Green, along with Paul Heidger, a faculty collaborator, published two landmark companion papers in the prestigious journal Infection and Immunity. The papers detail how L-form bacteria inside an experimental human embryonic kidney tissue culture system are able to persist in cells and explains how they are able to revert into the cell wall-containing parent bacterial form. They also proposed a detailed reproductive cycle for L-form bacteria, followed by electron microscopy of the microorganisms.
These papers set the stage for Domingue and his team to delve even further into the role that cryptic atypical bacteria play in causing persistent and recurrent infections.
In 1997, he and a colleague, the late Hannah Woody published an invited extensive review article on chronic bacterial infection in Clinical Microbiological Reviews. Among their conclusions was the claim that “difficult to culture and dormant bacteria are involved in the latency of infection and that these persistent bacteria may be pathogenic.”
He implicated L-form bacteria in several kidney-related diseases including pyelonephritis, glomerulonephritis, idiopathic hematuria, and interstitial cystitis. He also speculated about their role in other diseases such as rheumatic fever, tuberculosis, syphilis, and rheumatoid arthritis.
In the review Domingue stated, “Clearly, any patient with a history of recurrent infection and persistent disability is sending the signal that the phenomenon (infection with L-form bacteria) could be occurring. The so-called autoimmune diseases in which no organism can be identified by routine testing techniques are particularly suspect.”
He went on to conclude, “Bacteriologic advances, which include special culture media and stains, electron microscopy and molecular techniques such as PCR (polymerase chain reaction), have revealed an increasing number of previously unidentifiable organisms in a variety of pathologic conditions. It is unwise to dismiss the pathogenic capacities of any microbe in a patient with a mysterious disease.”
Over the course of his thirty-nine year career Domingue published 160 papers, monographs, and book chapters; 65 devoted to L-form research. He was invited to deliver over fifty international and national lectures about L-form bacteria and wrote a book on the subject, Cell Wall-Deficient Bacteria: Basic Principles and Clinical Significance. His papers are filled with photos of cultures of L-form bacteria taken with an electron microscope. They show the microbes inside human and animal cells.
Although Domingue’s primary research focused on bacterial L-forms, he also published extensively on the relationship between a molecule that stimulates the immune response called the Entobacterial Common Antigen (CA) and certain types of bacteria. He detailed the structure of the antigen and explained how it is able to elicit antibodies in humans and in animal models. He also detailed how the antigen could serve as a possible vaccine against urinary tract infections. He also studied the effects that a vasectomy might have on the immune system and performed studies on the relationship between the host and various species of bacteria in the disease pyelonephritis.
He delved into the effects of antibiotic therapy and chemotherapy on patients with urinary tract infections, and performed several studies on bacteria that produce a substance called chorionic gonadotropin-like hormone, detailing the way the bacteria might be involved in an experimental tumor model. He was even the co-author of a publication that characterized the oral microbial flora of alligators in order to develop better therapy for alligator bites.
When asked recently about his work Domingue replied, “I worked in a controversial research area for decades, and I found that sticking to the facts and hard data are the best ways to make progress in a field. Meaningful experimental designs and careful interpretation and discussion of the results are of prime importance in science. The ultimate aim was always to seek the truth about the problem at hand. Unfortunately, in the area of L-form or cell wall-defective bacteriology, too often there have been conclusions (anecdotal) drawn without supporting scientific data. In my opinion, many of these studies have hampered progress in the field and especially the role of these cryptic organisms in bacterial persistence and expression of disease. Sometimes the controversial issues have become political, which is unfortunate.
As far as I am concerned, modern technological tools are presently at hand to support all of the above microbiological and immunological findings at the molecular level… which is really what present day medical scientists, clinicians, pathologists are willing to accept as proof (maybe) of the role of such aberrant bacteria in disease.”
Indeed, molecular modeling has revealed how L-form bacteria are able to persist in the body and disable the immune system. Over the past few years, L-form bacteria have been linked to a wide array of chronic diseases, many of them previously considered to be autoimmune in nature. In 2002, biomedical researcher Trevor Marshall created a medical treatment that effectively kills L-form bacteria.
Now that L-form bacteria are known to cause a wide array of chronic inflammatory diseases, Domingue’s work is of utmost importance in allowing researchers to correctly demonstrate and understand their behavior.
Domingue, G., Lloyd, K., & Schlegel, J. U. (1974). In vitro phagocytosis of transitional phase bacterial variants utilizing autoradiography. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 146(2), 635-42.
Domingue, G. J. (1980). Filterable cell-associated cryptic bacterial forms in immunologic renal diseases. Urological survey, 30(1), 1-4.
Domingue, G. J., Ghoniem, G. M., Bost, K. L., Fermin, C., & Human, L. G. (1995). Dormant microbes in interstitial cystitis. The Journal of urology, 153(4), 1321-6.
Domingue, G. J., & Schlegel, J. U. (1970). The possible role of microbial L-forms in pyelonephritis. The Journal of urology, 104(6), 790-8.
Domingue, G. J., & Schlegel, J. U. (1977). Novel bacterial structures in human blood: cultural isolation. Infection and immunity, 15(2), 621-7.
Domingue, G. J., & Schlegel, J. U. (1978). Novel bacterial structures in human blood. II. Bacterial variants as etiologic agents in idiopathic hematuria. The Journal of urology, 120(6), 708-11.
Domingue, G. J., Thomas, R., Walters, F., Serrano, A., & Heidger, P. M. (1993).Cell wall deficient bacteria as a cause of idiopathic hematuria. The Journal of urology, 150(2 Pt 1), 483-5.
Domingue, G. J., Woody, H. B., Farris, K. B., & Schlegel, J. U. (1979). Bacterial variants in urinary casts and renal epithelial cells. Archives of internal medicine, 139(12), 1355-60.
Domingue, G., & Woody, H. (1997). Bacterial persistence and expression of disease. Clin Microbiol Rev, 10(2), 320-344.
Domingue, G. J. (1982). Cell-wall Deficient Bacteria: Basic Principles and Clinical Significance. Reading, MA: Addison-Wesley Publishing Co.
Green, M. T., Heidger, P. M., & Domingue, G. (1974a). Demonstration of the phenomena of microbial persistence and reversion with bacterial L-forms in human embryonic kidney cells. Infection and immunity, 10(4), 889-914.
Green, M. T., Heidger, P. M., & Domingue, G. (1974b). Proposed reproductive cycle for a relatively stable L-phase variant of Streptococcus faecalis. Infection and immunity, 10(4), 915-27.
Ponig, B., Domingue, G., & Schlegel, J. (1972). The role of in vitro induced microbial L-forms in experimental hematogenous pyelonephritis. Investigative urology, 9(4), 282-5.
Amy Proal graduated from Georgetown University in 2005 with a degree in biology. While at Georgetown, she wrote her senior thesis on Chronic Fatigue Syndrome and the Marshall Protocol.