20.109(F11): Light based therapeutics

Light Based Therapeutics

Team

• Jonathan Chien
• Michael Hwang

Introduction

In an effort to combine elements of the three different Modules we pursued in 20.109, we wish to explore light based therapeutics as a method to address significant unmet medical or research needs. Light is very non-invasive compared to other common inputs, which may involve flooding a cell with protein or chemical, which does not translate well to in vivo tests within an actual living system. Recently, a lot of work has been done within the field of optigenetics, which combines optical methods and genetic regulation to achieve control within living organisms.

Research Goal

Our goal is to construct useful novel circuits, which would sense light as an input, and modularly release a product or response (eg. apoptosis protein). We're exploring different methods of delivery, but the idea of gold nanoparticles that target a specific cell type (eg. tumor) look promising. Gold nanoparticles infused with a synthetic genetic circuit could be introduced into the human body, whereby it will become incorporated and localized to a patient's tumor. Upon delivery of the gold nanoparticles' cargo, herein the novel circuit, we could light activate the circuit by shining light, thus producing highly localized cytotoxicity to the tumor. Such a process could be engineered to combat other medical needs, such as aging, tissue regeneration, neurodegenerative diseases, etc or be used to allow easier non-invasive studying of cellular response in large-scale systems.

References

• Chow, B. Y., & Boyden, E. S. (2011). Synthetic Physiology. Science, 332(6037), 1508-1509. http://www.sciencemag.org/content/332/6037/1508.summary.

This is a nice perspective on the potential applications of optigenetics, especially in relation to physiological applications. They examine how the delivery of a payload could be regulated through a light-sensitive melanopsin-NFAT signaling cascade, which is one of the potential approaches we could take in our genetic circuit.

• Kleinlogel, S., Feldbauer, K., Dempski, R. E., Fotis, H., Wood, P. G., Bamann, C., & Bamberg, E. (2011). Ultra light-sensitive and fast neuronal activation with the Ca2+-permeable channelrhodopsin CatCh. Nature neuroscience, 14(4), 513-8. http://www.nature.com/neuro/journal/v14/n4/full/nn.2776.html.

In this paper, they develop a variant of the traditional rhodopsin protein, which is activated by light, that is over 70 times more sensitive to light than the wild-type protein. This is of particular interest to our circuit, which needs a way to quickly respond to light. They characterize their optimized rhodopsin protein in the paper, which gives an idea of the different assays we could use to test our system to see if it actually responds to light.

• Poon Z, Lee JB, Morton SW, Hammond PT. (2011). Controlling in vivo stability and biodistribution in electrostatically assembled nanoparticles for systemic delivery. Nano Letters, 11(5), 2096-103. http://pubs.acs.org/doi/pdf/10.1021/nl200636r.

• von Maltzahn G, Park JH, Lin KY, Singh N, Schwöppe C, Mesters R, Berdel WE, Ruoslahti E, Sailor MJ, Bhatia SN. (2011). Nanoparticles that communicate in vivo to amplify tumour targeting. Nat Materials, 10(7), 545-52. http://www.nature.com/nmat/journal/v10/n7/pdf/nmat3049.pdf.

• Ye, H., Daoud-El Baba, M., Peng, R.-W., & Fussenegger, M. (2011). A synthetic optogenetic transcription device enhances blood-glucose homeostasis in mice. Science, 332(6037), 1565-8. http://www.ncbi.nlm.nih.gov/pubmed/21700876.

In this paper, they expressed a genetic circuit in diabetic mice that expressed a glucagon-like peptide in response to blue light. This is especially interesting as they tested their construct both in vitro and in vivo, showing the potential robustness of such a genetic circuit in an actual application. In addition, their circuit is a new approach to combating diabetes, showing the power of light-based clinical applications.