A Disease Nexus
In this context, we have worked to identify points of convergence in pathological pathways that stem from different genetic and/or environmental origins. We refer to theses points as a “disease nexus”. We hypothesize that blocking pathological progression at a nexus will prevent or slow the course of multiple disease states, regardless of their exact genetic and/or environmental causes.
The vitamin A dimer disease nexus -– A striking chemical signature of diseases featuring retinal degeneration is the accumulation of dimers of vitamin A, such as N-retinylidene-N-retinylethanolamine (A2E), in the retinal pigment epithelium and Bruch’s membrane. This characteristic can be detected in diseases such as age-related macular degeneration (AMD), Stargardt disease, Best vitelliform macular degeneration (VMD), Sorsby’s fundus dystrophy, and malattia leventinese (also known as Doyne honeycomb or dominant radial drusen). The above conditions all seem to converge pathologically either in the overproduction of vitamin A dimers or in the malfunction of vitamin A dimer detoxification.
In the retina, a large percentage of proteins are involved in processing vitamin A to enable vision. Thus, a variety of different defects can lead to dysregulated vitamin A homeostasis and its subsequent dimerization. If vitamin A dimers are responsible for the major pathology observed during retinal degeneration, then correcting the flux of dimerized vitamin A should help to address several forms of blindness. We have been testing our hypothesis of a vitamin A dimer disease nexus by developing clinically amiable methods to curb the rate of vitamin A dimerization in the retina.
The superoxide radical anion disease nexus – Many human diseases, particularly those affecting the brain and retina, are characterized by the overproduction of superoxide radical anions. Although often not the underlying genetic or environmental cause, the aberrant generation of superoxides is thought to be a major factor in the development of many pathological phenotypes. This is because a large proportion of cellular machinery and biological pathways are dedicated to energy homeostasis. Thus the pathological pathways of a variety of genetic mutations and environmental pressures can converge to dysregulate metabolism, leading to the overproduction of superoxides. Manifestation of several disease states might be a result of genetic and environmental stimuli that both determine the rate at which superoxide is generated and the response to its overproduction.
We hypothesize that reducing the generation of superoxide radical anions in such cases will decrease disease-related morbidity and mortality. We have been testing this hypothesis by designing small molecules that decrease the generation of superoxides and using them to determine the consequences of reducing superoxide generation in models of human disease marked by an overproduction of superoxides.
Increasing Cellular Function – In other research, we have been attempting to increase the complexity and/or function of human cells by creating stable polygenetic systems. Nature expands biological function through the creation of polygenetic unions. Endosymbiosis, as exemplified by modern day mitochondria and chloroplasts, is a prime example and has been a major driving force of evolutionary change. In such systems, symbiotic guests can be considered as molecular machines that impart an advantage to their host. By extension, we hypothesize that the identification of distinct genetic systems that can cohabit within mammalian cells and be programmed to accomplish a specific task will expedite the development of microscale intracellular machines that can dictate cellular fate. In theory, such machines can be programmed through current genetic engineering practices to synthesize molecular instructions (DNA, RNA, small molecules, carbohydrates, proteins, and so forth) that would prevent or cure disease or extend the life span or the capabilities of a cell or tissue type.