Objective

We design and develop approaches to modulate how the body responds to ubiquitous environmental cues to modify the course of serious diseases. Interactions with environmental stimuli, such as light, gravity, the earth’s magnetic field, food, microbes, and our atmosphere are for all practical purposes inescapable. By providing the context for genetic variation, such cues have dictated evolution. The body’s composition of small molecules, gene expression patterns and biochemical, physiological, and morphological changes can be viewed as a culmination of its adaptation to long-term universal environmental influences. Common diseases such as cancer, metabolic, cardiovascular, neurological and degenerative disorders, and aging might be associated with environmental pressures, both preventable and inescapable, rather than the result of a single genetic event.

 

Thus, we aim to quantify the body’s precise response to select environmental stimuli, use this information to define who we are as a species and as individuals, and then modulate these interactions to redefine the individual and change the course of disease. We focus on unavoidable environment-organism interactions that have innately shaped organisms through evolution.

 

 

Research Overview

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.

Publications

  1. Washington, I, Houk, K.N. Transition States and Origins of Stereoselectivity of Epoxidations by Oxaziridinium Salts. J. Am. Chem. Soc., 122:2948-2949, 2000.
  2. Armstrong, A., Washington, I., Houk, K.N. Transition State Stereoelectronics in Alkene Epoxidations by Fluorinated Dioxiranes. J. Am. Chem. Soc., 122:6297-6298, 2000.
  3. Gree, D., Vallerie, L., Gree, R., Toupet, L., Washington, I., Pelicier, JP., Villacampa, M., Perez, J.M., Houk, K.N. Conformations of Allylic Fluorides and Stereoselectivities of Their Diels-Alder Cycloadditions. J. Org. Chem., 66:2374-2381, 2001.
  4. Washington, I., Houk, K.N. CH—O hydrogen bonding influences pie–facial stereoselective epoxidations.  Angew. Chem. Int. Ed., 40:4485-4488, 2001.
  5. Washington, I., Houk, K.N. Epoxidations by Peracid Anions in Water: Ambiphilic Oxenoid Reactivity and Stereoselectivity. Org. Lett., 4:2661-2664,2002.
  6. Washington, I., Houk, K.N., Armstrong, A. Strategies for the Design of Organic Aziridination Reagents and Catalysts: Transition Structures for Alkene Aziridinations by NH Transfer. J. Org. Chem., 68:6497-6501, 2003.
  7. Poon, T., Turro, N.J., Chapman, J., Lakshminarasimhan, P., Lei, X., Jockusch, S., Franz, R., Washington, I., Adam, W., Bosio, S.G. Stereochemical Features of the Physical and Chemical Interactions of Singlet Oxygen With Enecarbamates. Org. Lett., 5:4951-4953, 2003.
  8. Prakesch, M., Gree, D., Gree, R., Carter, J., Washington, I., Houk, K.N. Stereoselectivity of Nitrile Oxide Cycloadditions to Chiral Allylic Fluorides: Experiment and Theory. Chem. Eur. J., 9:5664-5672, 2003.
  9. Washington, I., Brooks, C., Turro, N.J., Nakanishi, K. Porphyrins As Photosensitizers To Enhance Night Vision. J. Am. Chem. Soc., 126:9892-9893, 2004.
  10. Poon, T., Sivaguru, J., Franz, R., Jockusch, S., Martinez, C., Washington, I., Adam, W., Inoue, Y., Turro, N.J. Temperature and Solvent Control of the Stereoselectivity in the Reactions of Singlet Oxygen with Oxazolidinone-Substituted Enecarbamates. J. Am. Chem. Soc.,126:10498-10499, 2004.
  11. Washington, I., Jockusch, S., Itagaki, Y., Turro, N.J., Nakanishi, K. Superoxidation of Bisretinoids. Angew. Chem. Int. Ed.,117: 7259-7262, 2005.
  12. Washington, I., Turro, N.J., Nakanishi, K. Superoxidation of Retinoic Acid. Photchemistry and Photobiology, 82:1394–1397, 2006.
  13. Isayama, T., Alexeev, D., Clint, M., Washington, I., Nakanishi, K., Turro, N.J. An Accessory Chromophore in Red Vision. Nature, 443:649, 2006.
  14. Lebedeva, I.V., Washington, I., Sarkar, D., Clark, J.A., Fine, R.L., Dent, P., Curiel, D.T., Turro, N.J., Fisher, P.B. Strategy for Reversing Resistance to a Single Anti-Cancer Agent in Human Prostate and Pancreatic Carcinomas. Proc. Natl. Acad. Sci. U. S. A.,104:3484-3489, 2007.
  15. Washington, I., Zhou, J., Jockusch, S., Turro, N.J., Nakanishi,K., Sparrow, J.R. Chlorophyll Derivatives as Visual Pigments for Super Vision in the Red. Photochem. Photobiol. Sci., 6:775-779, 2007.
  16. Qu, J., Kaufman, Y., Washington, I. Coenzyme Q10 in the Human Retina. Invest Ophthalmol Vis Sci., 50:1814-1818, 2009.
  17. Ma, L., Kaufman, Y., Zhang, J., Washington, I. C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological retinal degeneration in a mouse model of Stargardt’s disease. J. Biol. Chem., 286(10):7966-7974.
  18. Kaufman, Y., Ma, L., Washington, I. Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin a dimers in wild-type rodents. J. Biol. Chem., 286(10):7958-7965, 2011.
  19. Qu, J., Ma, L., Washington, I.  Retinal coenzyme Q in the bovine eye. Biofactors, 37(5):393-398, 2011.
  20. Qu, J., Ma, L., Zhang, J., Jockusch, S., Washington, I. Dietary chlorophyll metabolites catalyze the photo reduction of plasma ubiquinone, Photochemistry and Photobiology, 89(2):310 – 303, 2013.
  21. Mihai, D., Hongfeng, J., Blaner, W., Romanov, A., Washington, I. The retina rapidly incorporates ingested C20-D3-vitamin A in a swine model, Molecular Vision, 19:1677-1683, 2013.
  22. Xu, C., Zhang, J., Mihai, D., Washington, I. Light-harvesting chlorophyll pigments enable mammalian mitochondria to capture photonic energy and produce ATP, J. Cell Sci. doi:10.1242/jcs.134262, 2013.
  23. Black, CK., Mihai, DM., Washington, I. The Photosynthetic Eukaryote Nannochloris eukaryotum as an Intracellular Machine To Control and Expand Functionality of Human Cells, Nano Letters, 2014.
  24. Mihai, M. D., Washington, I., Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells, Cell Death and Disease, 2014, in press.

Dr. Washington was born in NYC and is an Assistant Professor at Columbia Medical Center in the Department of Ophthalmology. He received a BA in Chemistry from Bard College and a PhD in Computational Chemistry under Ken Houk from University of California Los Angeles. Dr. Washington was postdoctoral fellow at Columbia University where he worked in the fields of Natural Products and Photochemistry jointly under the mentorship of Koji Nakanishi and Nick Turro. Dr. Washington is a co-founder of Alkeus pharmaceuticals a specialty ophthalmology pharmaceutical company developed from technology originating in his lab.

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