Working at IU's Biocomplexity Institute, postdoctoral researcher Abbas Shirinifard had hit a brick wall trying to develop detailed computer simulations of the behaviors and interactions of the cells and membranes composing the rear of the retina and its supporting vasculature. In choroidal neovascularization (CNV), blood vessels that supply the eye with oxygen and nutrients and originate in the choroid just behind the eye abruptly break into the retina and disrupt it. Blindness can follow in a matter of months.
Two current treatments for CNV either kill the invading blood vessels with drugs injected into the eye (also damaging the retina and killing needed blood vessels as well) or laser-heat the blood vessels, which can cause damaging retinal scars. Yet with 9,000 research papers published on CNV over the past 10 years, neither treatment still addresses the underlying problems that cause the blood vessels to invade, so relapses are common and many patients still lose vision within a year or two.
A serendipitous accident in which a donated human retina from an eye bank was severely shaken during shipping inspired Shirinifard to try again with a series of new simulations. Upon examination of the eye, Shirinifard and Biocomplexity Institute senior microscopist Sherry Clendenon found that regions of the retina with invading blood vessels had separated from their underlying membrane, while regions that had stayed attached showed much less invasion, suggesting that adhesion might be an essential but overlooked mechanism in maintaining the retina's structure.
Using an open-source modeling software program called CompuCell3D developed by the Biocomplexity Institute in collaboration with the University of Washington and the University of Wisconsin under National Institutes of Health funding, the team quickly began extending existing simulations to study the effects of adhesion defects.
"The simulations showed that reduced adhesion in the retina could indeed lead to its invasion by blood vessels," Shirinifard said. "But the complex structure of the retina meant that many types of adhesion could be important -- the three most prominent being between the pigmented retinal cells (the black lining of the eye) and Bruch's membrane (the substrate that supports the retina), between adjacent pigmented retinal cells, and between pigmented retinal cells and the overlying photoreceptors."
Those variables, the team realized, could be independent of one another or interact in complex ways, and knowing that the rate and type of progression of the disease varies greatly from patient to patient, they needed to examine many examples of each adhesion combination.
"We were able to model the interactions of different degrees of impairment of each type of adhesion and the variation from case to case," Shirinifard said. "Amazingly, these simulations were able to replicate the complex spectrum of CNV seen in the clinic."Simulations of adhesion defects caused by reduced adhesion between pigmented retinal cells and Bruch's membrane -- the type of CNV typical of aging -- produced a pattern and frequency of invasion agreeing with that in the clinic. Similarly, reduced adhesion between neighboring pigmented retinal cells, typical of inflammation due to severe infection, produced a pattern of invasion agreeing with that seen in young adults.
The full results of one of the most complex tissue evolution models ever deployed were published today in PLoS Computational Biology, and while the team has yet to move toward developing new CNV therapies, the work should have great significance in the search for better therapies, according to Biocomplexity Institute Director James Alexander Glazier, a co-author on the paper and professor in the IU Bloomington College of Arts and Sciences' Department of Physics.
"Hundreds of millions of dollars are spent annually to develop drugs and treatment approaches based on the two commonly hypothesized CNV initiation and progression mechanisms," he said. "Because the current work shows that neither hypothesized mechanism is an important cause of CNV, that money and effort are extremely unlikely to improve outcomes for patients. Scientists have been barking up the wrong tree. Instead, a search for therapies which restore normal adhesion in the eye is much more likely to produce effective treatments. In addition, the detailed agreement between simulation and clinical observations suggests that new approaches to measuring adhesion in patients would allow much more accurate predictions of the prognosis for individual patients."
The researchers believe these results will also have a much broader impact, as they apply to any tissue -- like the gut and the lung -- in which a basement membrane separates a capillary network from a nearby epithelium.
"The relationships between specific classes of adhesion failures and the types and dynamics of CNV in the eye simulations should carry over to the neovascularization-dependent pathologies of those tissues and to invasion of those tissues in cancer progression," Shirinifard said.
Co-authors on the paper, "Adhesion Failures Determine the Pattern of Choroidal Neovascularization in the Eye: A Computer Simulation Study," with Shirinifard and Glazier were associate scientists Maciej Swat and J. Scott Gens, both of the Biocomplexity Institute and the Department of Physics; Fereydoon Family and Hans E. Grossniklaus, M.D., of Emory University; and Yi Jiang of Georgia State University and Los Alamos National Laboratory.
| Newswise Science News
Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University
Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
24.02.2017 | Life Sciences
24.02.2017 | Life Sciences
24.02.2017 | Trade Fair News