As for many biomedical, basic-science research labs, my research flows and changes over time as we make new discoveries that lead us to new questions we form even as we uncover the answers to previous questions. That is the nature of basic science, and it is the way science investigation has always brought the most benefits to people and medicine in particular. While many organizations and countries have attempted to focus research support (funding) into specific diseases, it turns out that the overwhelming majority of high-impact medical discoveries have come from “serendipity”. That is, great useful ideas and tools were discovered to treat diseases simply by exploring how things work.
For example, drugs for controlling high cholesterol were not discovered by deciding to start making drugs for treating high cholesterol. In the course of biochemists investigating how our cells make cholesterol in the first place, chemicals were used to block enzymes to help figure out how cholesterol was made. Some of these chemicals were obviously the idea to become new drugs that could block cholesterol made in the body. Latanoprost, one of the later generation of drugs developed in the ’80s for reducing high intraocular pressure (IOP), was based on the discovery that prostaglandins made by some cells in the eye could increase the aqueous outflow in the eye, and reduce pressure. The basic science was elucidated in animal models. Again, a basic science discovery in the laboratory of physiologist Laszlo Bito at Columbia University was adopted by a Pharma company as the way to make drugs that mimic natural prostaglandins to produce this new class of drugs. As a result, thousands of people around the world have another class of drugs to reduce their intraocular pressure and reduce their risk of vision loss from Glaucoma.
So, you never really know where benefits will arise for biomedicine. That is why many research funding agencies, such as the NIH (USA) and the MRC (UK), understand the importance of funding physiologists and biochemists to explore how things work. In our case, how things work in the eye, and the retina of the eye.
Norrin treatment improves ganglion cell survival in an oxygen-induced retinopathy model of retinal ischemia. In Experimental Eye Research (2017), accepted, in press.
• Norrin treatment accelerates recovery of the mouse OIR model from ischemic insult.
• SD-OCT can compare NFL/GCL (nerve fiber layer/ganglion cell layer) thickness in vivo.
• Norrin treatment counters thinning of the NFL/GCL in the mouse OIR model.
• Norrin treatment increases the surviving population density of RGCs in OIR retinas.
This paper is one of the first to use the in vivo imaging methods of intrinsic fluorescence with a transgenic mouse strain to see individual ganglion cells in the living mouse eye, and to even follow their morphology over a period of many days in the mouse model of oxygen-induced retinopathy. This was done with a Phoenix Research Labs‘ system, in this case the Micron-III version of their imaging system. We used a light filter set recommended by Phoenix to image yellow-fluorescent protein (YFP). Axons and dentrites could be seen on single cells in anesthetized mice. Amazing!
We also employed SD-OCT (Spectral Domain – Optical Coherence Tomography) to capture 3D structural records of the mouse retina and then to measure the changes in thickness of the very thin Nerve Fiber Layer / Ganglion Cell Layer (NFL/GCL).
The ability to use these imaging systems in vivo, which are also used in clinical analysis of the Human retina, enables us to see disease processes as they progress and to use far fewer mice to get the answers to research questions. In this case we were testing the ability of Norrin (Norrie’s Disease Protein) to be used to help avascular regions of retina recover their vasculature more quickly and improve the survival of RGCs (retinal ganglion cells) from the stress of low oxygen. RGCs are the cells that form our optic nerves. Millions of RGCs per eye have axons that extend all the way into connections with our brain. This bundle of a million “wires”, or axons, is the optic nerve.
Our research here and that of other laboratories suggest that Norrin and other agents might have use to maintain a better vasculature in diseases where the blood vessels and capillaries are damaged, such as ROP, Diabetic Retinopathy and AMD.
#ARVO2015 World largest vision research meeting. Representing Oakland ERI.
Association for Research in Vision and Ophthalmology.
The 2015 meeting was held in the Colorado Convention Center, Denver CO
Panorama pictures captured using my Android phone (LG).
Our poster on VEGFA-165 b-isoform biochemistry got lots of attention in there.
The Poster hall at #ARVO2015 meeting. About 800 posters each day from Sunday to Thursday, May 3-7, 2015.
@VRRF_org @ARVO @Oakland_U Look at the size of this Grizz!
Ken Mitton, PhD, FARVO
Epigenetic regulation is an additional layer of control on top of our actual raw genomic DNA sequence. Basically, this means that without actually changing or mutating the DNA sequence of a gene, it is possible for that gene to be expressed differently. This extra later of control is often through changing how the DNA is packaged away in chromatin. Chromatin refers to how our chromosomal DNA is really organized. That is, DNA wrapped around cores of nucleosome core proteins, called histone proteins. The cytosines in our DNA can be methylated (addition of methyl groups), and histone proteins can be acetylated (addition of acetyl groups), and these chemical modifications control how our chromatin is packed away in our cells. Tightly packed away, genes are dormant, off, away in the closet like winter clothes you are not using in summer time. Active genes, are out of storage, unpacked and ready to work. In this review paper Alex Cvekl, from the Albert Einstein College of Medicine (Bronx, NY) and I put together a detailed review on what we know so far about the roles of epigenetic regulation in vertebrate eye development and disease. Continue reading