William Parker, PhD
Division of Surgical Sciences
Department of Surgery
Duke University Medical Center
487 Med Sci Res Bldg
Box 2605 DUMC
Durham, NC 27710
Work in the Parker lab focuses on the immune system and its role in biology and disease. We are currently involved in three primary areas of investigation related to medicine, as well as basic work in protein folding. Some references are provided here, and a greatly expanded list can be found on Dr. Parker's faculty profile.
Our laboratory is interested in the support of bacterial growth in the lumen of the gut by the mammalian immune system. Current work in our laboratory suggests that the model of “immune inclusion,” outlined in the figure below, is ubiquitous in mammals and is also important in non-mammalian species (e.g., amphibians).
In this model, secretory IgA and mucin, the major component of mucus, facilitate adherence of bacteria to the proximal part of the large bowel. Thus, the immune system supports biofilm growth by commensal (beneficial) bacteria.
Use of this model of gut immunity has enabled our laboratory to achieve the first growth of bacterial biofilms on live, cultured gut epithelial cells. Further, this model provides an apparent function of the human vermiform appendix, an issue that has been in question since Leonardo da Vinci first described the appendix in 1506 A.D.
The figure above shows a model of the apparent function of the human vermiform appendix as depicted by the New York Times Magazine. In this model, the appendix, which is relatively protected from infection by pathogens due to its narrow lumen and its location away from the fecal flow, sheds mutualistic (beneficial) bacteria on a regular basis. These bacteria would be useful in re-booting the bowel following dysentery, which is one of the leading causes of death in developing countries.
Uncovering the function of the human vermiform appendix has led to the discovery that the absence of an appendix is associated with increased risk for recurrent C. difficile colitis, apparently due to an inability of the normal microbiome to recover without an appendix. In addition, studies in evolutionary biology indicate that the vermiform appendix (a) is a “recurrent trait” that has appeared in evolutionary history more times than it has been lost, and (b) is generally associated with an increasing cecum size during evolution. These findings disprove Darwin’s thinking regarding the vestigial nature of the appendix and added further evidence supporting the function of the appendix.
Work on the immunological aspects of this project were conducted in collaboration with R. Randal Bollinger in the Department of Surgery. Work on the evolutionary aspects of this project have been conducted with evolutionary biologists, including Heather Smith in Arizona and Michel Laurin in Paris.
Everett, ML, Palestrant, D., Miller, SE, Bollinger, RR and Parker, W. Immune Exclusion and Immune Inclusion: a New Model of Host-Bacterial Interactions in the Gut. Clinical and Applied Immunology Reviews. 2004; 5: 321-332. Full text (PDF, 264 KB).
Bollinger, RR, Barbas, AS, Bush, EL, Lin, SS and Parker. W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J. Theoretical Biology. 2007; 249: 826-831. Full text (PDF, 177MB).
Smith, HF, Fisher, RE, Thomas, AD, Everett, ML, Bollinger, RR, and Parker, W. (2009) Comparative Anatomy and Phylogenetic Distribution of the Mammalian Cecal Appendix, Journal of Evolutionary Biology, 22:1984 - 1999. (Highlighted by Science magazine in the October 23rd, 2009 issue)
Laurin, M, Everett, ML, and Parker, W. The Cecal Appendix: One More Immune Component With a Funtion Disturbed By Post-Industrial Culture. The Anatomical Record 2011 DOI: 10.1002/ar.21357
Smith, H.F., Parker, W., Kotze, S.H., Laurin, M. (2013) Multiple independent appearances of the cecal appendix in mammalian evolution and an investigation of related ecological and anatomical factors. Comptes Rendus Palevol. doi:10.1016/j.crpv.2012.12.001.
Sanders, N.L., Bollinger, R.R., Lee, R., Thomas, S. & Parker, W. (2013) Clinical observations and predicted function of the appendix explain the relationship between appendectomy and C. difficile colitis. World Journal of Gastroenterology, 19:5607-5614.
Our laboratory is interested in the effects of chronic aspiration of gastric fluid on lung transplant recipients.
In pursuit of this goal, we have developed the first experimental model of chronic aspiration. Studies have demonstrated clearly, as shown in the figure below, that chronic aspiration in pulmonary allograft recipients can lead to obliterative broncheolitis, which is the hallmark of graft failure in the majority of lung transplant patients.
This provides the first re-capitulation of obliterative broncheolitis in an experimental model, providing a means by which potential treatment of this condition can be studied.
Our most recent studies indicate that cromolyn, a mast cell inhibitor with few side effects used in patients with asthma, greatly reduces the development of OB in our rat lung transplant model. We are currently working with Soman Abraham, an expert in mast cell function at Duke University, to address the mechanisms underlying this effect. Work on these projects is conducted in collaboration with R. Duane Davis and Shu S. Lin, both in the Department of Surgery.
Barbas, A.S., Downing, T.E., Balsara, K.R., Tan, H.-E., Rubinstein, G.J., Parker, W., Davis, R.D. & Lin, S.S. (2008) Chronic Aspiration shifts the Immune Response from Th-1 to Th-2 in a Murine Model of Asthma. European Journal of Clinical Investigation 38:596-602.
Chang, J.-C., Leung, J.H., Tang, T., Hartwig, M.G., Holzknecht, Z.E., Parker, W., Davis, R.D. & Lin, S.S. (2012) In the face of chronic aspiration, prolonged ischemic time exacerbates OB in rat pulmonary allografts. American Journal of Transplantation, 11:2930-2937.
Chang, J.-C., Leung, J., Tang, T., Holzknecht, Z.E., Hartwig, M.G., Davis, R.D., Parker, W., Abraham, S.N. & Lin, S.S. (2014) Cromolyn Ameliorates Acute and Chronic Injury in a Rat Lung Transplant Model. Journal of Heart and Lung Transplantation, 33:749-757.
It is now widely acknowledged that decreased biodiversity in the ecosystem of the human body has led to pandemics of allergic and autoimmune problems. More recent studies suggest that cognitive problems (depression, anxiety disorders, migraine headaches, autism) as well as many cancers are also associated with this decreased biodiversity.
For decades this decreased biodiversity was attributed to the “Hygiene Hypothesis”, although that term is both outdated and misleading. Rather, “Biome Depletion Theory” is more appropriate. In short, biome depletion is an “evolutionary mismatch”, a factor in our current environment that leads to disease because it is incompatible with our evolved genetic makeup. This model of disease can account for the high burden of disease in modern society despite the herculean efforts of the modern healthcare system.
Biome depletion operates in conjunction with other evolutionary mismatches (e.g., vitamin D deficiency, inflammatory diets, chronic psychological stress, sedentary lifestyles) to cause immune dysfunction. We view the issue of biome depletion in the same way that the other mismatches are viewed: prevention rather than a cure is far, far more desirable.
In this model (figure above), certain highly desirable advances in modern society have led to consequences which can be easily avoided. If these consequences are not proactively avoided, a cascade of immune related disease can result.
Our first studies in this field dealt with the immune function in wild rats, comparing the immunity found in wild rats with that of laboratory rats. These studies represented the first modern studies on immunity in wild rodents and were extremely informative. Although these studies are still ongoing, we have subsequently begun work “transforming’ laboratory rats into a more wild-like condition. This work has revealed that biome enrichment actually improves immune function, and that biome enrichment can protect the brain from inflammation. (Work in collaboration with Cindy Pi and Staci Bilbo, respectively.)
Our work on the biome has focused on both bacteria and eukaryotic organisms (“germs and worms”). Work from the lab with bacterial communities has been very informative, with two major studies describing how bacterial communities evolve in nature. Although most investigators in the field of biome enrichment focus on microbes, eukaryotic organisms have a much more profound impact on countering the consequences of evolutionary mismatch and restoring health. With this in mind, our current work related to the biome and human disease is focused on the use of “helminthic therapy” to avert disease in humans.
Bilbo, S.D., Wray, G., Perkins, S.E. & Parker, W. (2011) Reconstitution of the human biome as the most reasonable solution for epidemics of allergic and autoimmune diseases. Medical Hypotheses,77:494-504.
Parker, W. Perkins, S.E., Harker, M., & Muehlenbein, M.P. (2012) A prescription for clinical immunology: The pills are available and ready for testing. Current Medical Research and Opinion, 28:1193-1202.
Lin, S.S., Holzknecht, Z.E., Trama, A.M., Everett, M.L., Thomas, A.D., Su, K.-Y., Lee, S.M., Perkins, S.E., Whitesides, J.F., McDermott, P. & Parker, W. (2012) Immune characterization of wild-caught Rattus norvegicus suggests diversity of immune activity in biome-normal environments. Journal of Evolutionary Medicine, 1:Q120503.
Parker, W. & Ollerton, J. (2013) Evolutionary Biology and Anthropology Suggest Biome Reconstitution as a Necessary Approach toward Dealing with Immune Disorders. Evolution, Medicine, and Public Health, 2013:89-103.
Parker, W. (2014) The “hygiene hypothesis” for allergic disease is a misnomer. British Medical Journal, 349:g5267
Pi, C., Allott, E.H., Ren, D., Poulton, S., Lee, S.Y.R., Perkins, S., Everett, M.L., Holzknecht, Z.E., Lin, S.S., & Parker, W. (2015) Increased biodiversity in the environment improves the humoral response of rats. PLoS One, In Press.
In addition to the above projects related to medicine, Dr. Parker also continues some longstanding work in basic science in the field of protein folding. The main thrust of the work in this area involves testing the hypothesis that the formation of helical bundles is a primary event occurring in a general mechanism of protein folding, regardless of the native structure of the protein. Details regarding this model and the work associated with it can be found in the following references.
Parker W, and Stezowski JJ. Occurrences of Sequences with Amphiphilic a-helical Potential in b-sheet Proteins May Reveal Structural Features Important for Protein Folding. Proteins 1996; 25: 253-260.
Parker W, Sood A, and Song A. Organization of Regions with Amphiphilic a-helical potential Within the 3-dimensional Structure of b-sheet Proteins. Protein Engineering 2001; 14: 315-319. Full text (PDF, 574 KB).
Chen, E, Evetett, ML, Holzknecht, ZE, Holzknecht, RA, Lin, SS, Bowles, DE, and Parker, W (2010), Short-Lived alpha-helical Intermediates in the Folding of beta-sheet Proteins, Boichemistry 49:5609-5619.