Saving Sight Using Geometrical Isomerization and Channel Rhodopsin

Professor Sheila Nirenberg of Weill Medical College in Cornell University has been breaking new ground in the field of merging neural coding with mathematical equations in order to develop a prosthetic device that improves by leaps and bounds the severely impaired vision of people who have been diagnosed with retinitis pigmentosa or macular degeneration.

"Fundus of patient with retinitis pigmentosa, mid stage" by Christian Hamel - Retinitis pigmentosa by Christian Hamel. Licensed under CC BY 2.0 via Wikimedia Commons

Retinitis pigmentosa is an inherited condition that appears as darker pigmentation found in the epithelium of the retina, causing tunnel vision initially and eventually leading to blindness. The degeneration of light-sensitive photo-receptor cells is irreversible in both retinitis pigmentosa and macular degeneration.

The remarkable research that Dr. Nirenberg and her colleague Dr. Chethan Pandarinath (an electrical engineer now at the Neural Prosthetics Laboratory at Stanford University) have done is to view the process of vision this way:

 (Image from TEDMED talk by Dr. Nirenberg; http://www.ted.com/talks/sheila_nirenberg_a_prosthetic_eye_to_treat_blindness?language=en#t-135375)

The highlighted front end cells or photoreceptors of the retina respond to the image that we see in the form of a code. Then the output cells (orange balls) interpret the code and create numerous signals or action potentials that eventually travel to the brain which processes them into the image we see.

In a degenerative eye disease like retinitis pigmentosa, the front end cells are lost. So no visual encoding occurs. The solution proposed by Nirenberg and Pandarinath is to create a microchip that can mathematically encode the image ("encoder"):

(Image from TEDMED talk by Dr. Nirenberg; http://www.ted.com/talks/sheila_nirenberg_a_prosthetic_eye_to_treat_blindness?language=en#t-135375)

The transducer is a light-sensitive protein that fires the action potential signals. Currently, there is no prosthetic device superior to the visual enablement of this technology, and Dr. Nirenberg has plans to submit her research by the end of this year to the FDA for approval. If all goes well, a small clinical trial will begin in early 2016, implementing a prosthetic device (glasses) that requires little invasive surgery:

(Image from TEDMED talk by Dr. Nirenberg; http://www.ted.com/talks/sheila_nirenberg_a_prosthetic_eye_to_treat_blindness?language=en#t-135375)

  
Here, the glasses contain the microchip encoder that will mathematically interpret the images and send the code to the light-sensitive transducer cells or channel rhodopsin.

The transducer is known as channel rhodopsin, a protein that can form a channel when activated by light:

 (Image from https://justinpamute.files.wordpress.com/2010/06/rhodopsin1.gif)

Rhodopsin itself is composed of 2 components: opsin and retinal. Let's take a look at this latter molecule which has some interesting structural characteristics.

I highlighted the purple double bond to point out that retinal exhibits geometrical isomerism, a feature many alkene molecules have where they show differences in spatial arrangement around a carbon-carbon double bond. Upon exposure to visible light (the part of the electromagnetic spectrum we can see), the molecule changes from the trans to cis isomer. This reaction is important in the function of channel rhodopsin as it allows the protein to create a larger opening (by ~6 angstroms) and enables ions to travel through the channel and generate an action potential.

(Image from http://www.biophys.mpg.de/de/bamberg.html)

The YFP stands for yellow fluorescent protein which is found in green algae.

Fortunately for people with macular degeneration or retinitis pigmentosa, vision remains a possibility as long as trans- to cis-retinal isomerization can occur in this light-activated channel opening of rhodopsin.

For this innovative work, Dr. Nirenberg was awarded the MacArthur "Genius" Award. 

Resources

*Nirenberg Lab, Department of Physiology and Biophysics, Weill Medical College of Cornell University
*Retinal prosthetic strategy with the capacity to restore normal vision; S. Nirenberg and C. Pandarinath; Proceedings of the National Academy of Sciences (PNAS); vol. 109, no. 37, pp 15012-15017.
*"A Prosthetic Eye to Treat Blindness" (TEDMED 2011 talk by Dr. Nirenberg; October 2011)
*MacArthur Fellows/Meet the Class of 2013/Sheila Nirenberg
*Method of the Year 2010: Optogenetics - by Nature

Department of Physiology and Biophysics and a member of the Institute for Computational Biomedicine at Weill Medical College of Cornell University - See more at: http://www.macfound.org/fellows/899/#sthash.fXVHrHd7.dpuf

Astressin B: The Accidentally Discovered Cure for Stress-Induced Baldness in Mice

In researching compounds that may alleviate the effects of Cushing's Syndrome (symptoms from prolonged exposure to the stress hormone cortisol), the team of L. Wang, M. Million et al. made a significant discovery in using synthesized astressin-B on balding young mice that were genetically engineered to produce more cortisol. Baldness or alopecia has been linked to extreme stress, and the biochemical pathway involves several compounds.

(image from http://journal.frontiersin.org/article/10.3389/fneur.2013.00021/full)

When we perceive stress, the hypothalamus in our brain produces corticotropin-releasing hormone (CRH) which signals the nearby anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). This travels through the bloodstream to the adrenal cortex (the outside part of the adrenal gland that sits above the kidneys) and stimulates it to produce cortisol, a steroid molecule:

  Cortisol (By Calvero. [Public domain], via Wikimedia Commons

Steroids are easily identified by this 4-ring system - three of them have 6 carbons, and one has 5 carbons.

 Since CRH is the chemical key that starts this process, we should take a look at the complexity of its structure which has been designed by evolution:

 (image from chemBlink, http://www.chemblink.com/products/86784-80-7.htm)

A rather long strand of 41 peptides

So how does astressin B work in all of this and help prevent baldness in mice? The above mentioned authors (from the David Geffen School of Medicine and the Salk Institute for Biological Studies, respectively) collaborated with their team to see how this molecule can act as an agonist to CRH and thereby alleviate the symptoms of elevated stress in mice genetically engineered to overexpress CRH. What they discovered was a noticeable increase in hair growth after only 5 days of treatment with astressin B (5 micrograms intraperitoneal injection/day/mouse).

 

(image from http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016377)

Row A mice were injected with a saline solution; row B mice were injected with astressin B and are shown 3 days later; row C mice are the same mice from row B, 4 weeks later)

So what does astressin look like? As you can imagine, it is similar to CRH in that it is also a rather long polypeptide:

Resources:

*Wang L, Million M, Rivier J, Rivier C, Craft N, et al. (2011) CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-ExpressingMice. PLoS ONE 6(2): e16377. doi:10.1371/journal.pone.0016377

 

Survival of the Fittest! Chemistry Boot Camp at MIT

Have you been stressed by your chemistry lab experience? You're not alone - every January, groups of freshmen at MIT take a class called 5.301 Chemistry Lab Techniques, also known as "Chemistry Boot Camp". Noted for its intensity and very short period (4 weeks), students learn techniques and equipment that are commonly used in a chemistry research lab - NMR, organic synthesis, crystallization, gravity filtration, rotovap, thin-layer and column chromatography. In the process of learning, they spill chemicals, break glassware, generate toxic gases, and share some of their anxieties of meeting the challenges this course entails. During the course, each student has a transformative moment that helps them decide if they are meant for research.

The videos document the journey of these freshmen from nervous newbie to savvy lab assistant, all of whom survive the ordeal and emerge with newfound love for research and chemistry.

Being in chemistry lab is a human experience. There is laughter, crying, and cursing. But in the end, there is bonding and friendship from sharing a sometimes difficult experience together.

Episodes of Chemistry Boot Camp at MIT

Same or Different? How a Simple Carbon Atom Leads to Complex Natural Compounds

A deceptively simple atom like carbon exhibits diverse styles of bonding that can lead to a plethora of complex organic molecules:

Carbon's flexibility in bonding makes it possible for molecules to have structural complexity, such as nonsuperimposable mirror images known as enantiomers:

In this example, these are not the same molecule even though the way the individual atoms are connected is the same. Because the 3-dimensional spatial arrangement around the central carbon atom is different, these are also known as chiral molecules or enantiomers, and carbon is called a chiral center.

There is a nice video created by Lydia Flynn where she demonstrates how molecules can be chiral using molecular models.

Chirality/Basic Concept Explained

Chiral molecules can be found in nature, and sometimes we need an extra few seconds to check if we are seeing the same molecule or two different molecules. One example is a compound produced female gypsy moths known as disparlure. It turns out that only one form of this molecule (in purple) is attractive to male moths.

 

Female Gypsy Moth

"Lymantria dispar 8-8-2006 19-20-14" by Opuntia. 

Licensed under CC BY-SA 3.0 via Wikimedia Commons

Molecular models show these are enantiomers and not the same molecule of disparlure.

Brown tube sponge from the National Museum of Natural History (image by Rachel Cooper)

Sceptrin is a compound made by the brown tube sponge. It is currently researched for its antibiotic potential.

 

These are enantiomers of sceptrin, a compound whose structure was first synthesized in 2004 by scientists in The Scripps Research Institute.

Molecular models again illustrate the nonsuperimposability of these mirror image isomers.

The Most Astounding Fact-by Neil deGrasse Tyson

He was asked by a Time reader, "What is the most astounding fact you can share about the universe?" This beautifully edited video by Max Schlickenmeyer highlights Dr. Tyson's answer. Essentially the chemistry that created the atoms and elements of the universe is the same chemistry made us. That is how we are connected to the universe.

His eloquent response is here.

Image credit: NASA/CXC/SAO: X-ray; NASA/JPL-Caltech: Infrared

Inspiration from Worms and Mussels - A Sutureless Way to Do Surgery

Healing from surgery can be complicated by using sutures in particular parts of our bodies. Depending on the type of material (silk or polymer-based), the immune system can have a reaction, prolonging healing times to as long as 4 months! 

So what is a possible alternative that can be easily applied to sensitive tissue and maintain structural integrity long enough for healing? One clever organism that bioengineers are currently studying is the sandcastle worm or Phragmatopoma californica.


 

By Fred Hayes for the University of Utah [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Scott Creek, Santa Cruz Co., CA; 17 Mar 2008

Sandworms are typically shy creatures, coming out only to catch microorganisms and grain particles. Their tubules can be found along Baja California and Mexico.

Professor of Bioengineering Russell Stewart from the University of California Santa Barbara is currently studying waterproof adhesives that sandcastle worms (and caddisflies) use to create their elaborate constructions. In his research, he has determined that the forces of attraction are electrostatic (oppositely charged ions attracting each other) with some cross-linking between catechol and DOPA polymers.

Inspired by the worm's ability to create an adhesive that works in water, medical doctor Nora Lang and bioengineers Maria Pereira and Jeffrey Karp at Harvard Medical School teamed up with other scientists to create an adhesive that works in vivo in repairing tiny defects in sensitive tissue.

 Exposure of hydrophobic light-activated adhesive polymer (HLAA) to UV light creates crosslinking

(image from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157752/)

Using a polymer of glycerol and sebacic acid, they exposed the molecules to UV light and created crosslinks. This resulted in a highly flexible material that could be gently applied to very small tears in a carotid artery:

In this carotid artery, a hole was created and then sealed with HLAA polymer. After 24 hours, the seal remained intact. 

(from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157752/)

With its recently tested potential, light-activated liquid polymers may have a place on the surgeon's tray in place of sutures.

Articles and Resources of Interest:

*A Blood-Resistant Surgical Glue for Minimally Invasive Repair of Vessels and Heart Defects; by N. Lang, M.J. Pereira, Y. Lee, I. Friehs, N.V. Vasilyev, E.N. Feins, K. Ablasser, E.D. O'Cearbhaill, C. Xu, A. Fabozzo, R. Padera, S. Wasserman, F. Freudenthal, L.S. Ferreira, R. Langer, J.M. Karp, and P.J. del Nido

*Letting Bio-Inspired Solutions Evolve : Q &A with Jeff Karp

Amazing Uses of Bubble Wrap

The next time you toss that bubble wrap from your next package, think of the possible applications for it. What else can you do with air bubbles encased in plastic?

Interestingly, when it was created in 1957 by engineers Alfred Fielding and Marc Chavannes, the original plan was to cover walls with a 3-dimensional textured pattern:

Image from Mental Floss, bubble wrap was considered a distinctive wall covering.

Only three years later it was discovered to be a superb packing material. Bubble wrap itself is made of low-density polyethylene (LDPE), a polymer of ethylene monomers that has some branching.

"Bubble Wrap" by User Consequencefree on en.wikipedia. Licensed under CC BY-SA 3.0 via Wikipedia Commons

Branching around polyethylene reduces strands of it to pack closely, and this decreases its density.

Images from http://faculty.uscupstate.edu/llever/Polymer%20Resources/Topology.htm by David Whisnant

More recently,  other amazing uses for bubble wrap have emerged. One example is from Bradley Hart, an artist in New York who injects different colors of paint into the bubbles to create portraits and landscapes:

Image from http://www.visualnews.com/test/2013/03/paintings-made-by-injecting-paint-in-bubble-wrap/

Is there a place for bubble wrap in a chemistry lab? Most definitely! Professor George Whitesides and colleagues from Harvard University came up with some clever applications. Because the material is so cheap (about 60 cents per square meter) and the same area can have up to 5000 bubbles, the team discovered that the bubbles can safely hold liquid samples. This lead to a number of experiments testing the reliability of these plastic bubble holders:

Bubbles of Allura Red and rhodamine B dye - a test to see if liquid reagents can be stored and tested for absorbance measurements.

Image from dx.doi.org/10.1021/ac501206m; Anal. Chem. 2014, 86, 7478-7485.

Samples of E. coli grown in yeast and tryptone medium. Bubbles can be used to grow colonies of bacteria and microorganisms.

Image from dx.doi.org/10.1021/ac501206m; Anal. Chem. 2014, 86, 7478-7485.

A bubble can act as an electrochemical cell! Here 2 carbon electrodes are used to measure the current from different concentrations of ferrocyanide.

According to Professor Whitesides, bubble wrap can be repurposed to carry out a few chemistry and biology experiments in labs that normally cannot afford conventional test tubes and petri dishes.

Can you think of other unusual applications for bubble wrap? Test it out!

For further reading:

Adaptive Use of Bubble Wrap for Storing Liquid Samples and Performing Analytical Assays; David K. Bwambok, Dionysios C. Christodouleas, Stephen A. Morin, Heiko Lange, Scott T. Phillips, and George M. Whitesides; dx.doi.ord/10.1021/ac501206m; Anal. Chem. 2014, 86, 7478-7485.