Eye color genes are critical for retinal health

Metabolic pathways consist of a series of biochemical reactions in cells that convert a starting component into other products. There is growing evidence that metabolic pathways coupled with external stress factors influence the health of cells and tissues. Many human diseases, including retinal or neurodegenerative diseases, are associated with imbalances in metabolic pathways.

Elisabeth Knust leads a team of researchers from the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, who describe an essential role for one such metabolic pathway in maintaining retinal health under conditions of stress. They studied the classic Drosophila genes cinnabar, cardinal, white, and scarlet, originally characterized decades ago and named due to their role in eye color pigmentation, in particular the formation of the brown pigment of the fly eye. These genes encode components of the kynurenine pathway, whose activity converts the amino acid tryptophan by various steps into other products. In this study, the authors have highlighted the function of this metabolic pathway in retinal health, independent of its role in pigment formation.

The Kynurenine pathway is an evolutionary conserved metabolic pathway that regulates a variety of biological processes. Its disruption can result in the buildup of either toxic or protective biomolecules or metabolites, which can worsen or improve, respectively, the health of the brain, including the retina. Knowledge on this important metabolic pathway was recently extended by the research team, led by Elisabeth Knust, Director Emerita at the MPI-CBG, in their publication in the journal Plos Genetics. Being aware of the remarkable conservation of this metabolic pathway and the genes that regulate it, they used flies as a model system to unravel the role of individual metabolites in retinal health. The researchers looked at four genes -- cinnabar, cardinal, white, and scarlet - named after abnormal eye colors following their loss in flies. "Since the Kynurenine pathway is conserved from flies to humans, we asked whether these genes regulate retinal health independent of their role in pigment formation," says Sarita Hebbar, one of the lead authors of the study.

To find this out, the scientists used a combination of genetics, dietary changes, and biochemical analysis of metabolites to study different mutations of the fruit fly, Drosophila melanogaster. Sofia Traikov, a co-author, developed a method for the biochemical analysis of the metabolites of the Kynurenine pathway. This allowed the researchers to link different metabolite levels to the health state of the retina. They found that one metabolite, 3-hydroxykynurenine (3OH-K), is damaging to the retina. More importantly, they could show that the degree of degeneration is influenced by the balance between toxic 3OH-K and protective metabolites, such as Kynurenic Acid (KYNA), and not just by their absolute amounts. Sarita continues: "We also fed two of these metabolites to normal (non-mutant) flies and found that 3OH-K enhanced stress-induced retinal damage, whereas KYNA protected the retina from stress-related damage." This means that retinal health in certain conditions can be improved by altering the ratio of metabolites of the Kynurenine pathway.

Furthermore, by targeting these four genes and therefore four distinct steps within the pathway, the researchers were able to demonstrate that not only the accumulation of 3OH-K as such, but also its location in the cell and hence its availability in further reactions, is important for retinal health.

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'We're not all that different': Study IDs bacterial weapons that could be harnessed to treat human disease

When it comes to fighting off invaders, bacteria operate in a remarkably similar way to human cells, possessing the same core machinery required to switch immune pathways on and off, according to new University of Colorado Boulder research.

The study, published Feb. 8 in the journal Nature, also sheds light on how that shared, ancient machinery -- a cluster of enzymes known as ubiquitin transferases -- works.

Better understanding, and potentially reprogramming this machine, could ultimately pave the way to novel approaches for treating a host of human diseases, from autoimmune disorders like Rheumatoid arthritis and Crohn's disease to neurodegenerative diseases like Parkinson's disease, the authors said.

"This study demonstrates that we're not all that different from bacteria," said senior author Aaron Whiteley, an assistant professor in the Department of Biochemistry. "We can learn a lot about how the human body works by studying these bacterial processes."

The next CRISPR?

The study is not the first to showcase the lessons bacteria can teach humans.

Mounting evidence suggests that portions of the human immune system may have originated in bacteria, with evolution yielding more complex iterations of bacterial virus-fighting tools across plant and animal kingdoms.

In 2020, University of California Berkeley biochemist Jennifer Doudna won the Nobel Prize for CRISPR, a gene-editing tool that repurposes another obscure system bacteria use to fight off their own viruses, known as phages.

The buzz around CRISPR ignited renewed scientific interest in the role proteins and enzymes play in anti-phage immune response.

"Over the past three to five years people have realized it doesn't end with CRISPR. The potential is so much bigger," said Whiteley.

Missing link in evolutionary history

For the study, Whiteley and co-first author Hannah Ledvina, a Jane Coffin Childs Postdoctoral Fellow in the department, collaborated with University of California San Diego biochemists to learn more about a protein called cGAS (cyclic GMP-AMP synthase), previously shown to be present in both humans and, in a simpler form, bacteria.

In bacteria and in humans, cGAS is critical for mounting a downstream defense when the cell senses a viral invader. But what regulates this process in bacteria was previously unknown.

Using an ultra-high-resolution technique called cryo-electron microscopy alongside other genetic and biochemical experiments, Whiteley's team took an up-close look at the structure of cGAS's evolutionary predecessor in bacteria and discovered additional proteins that bacteria use to help cGAS defend the cell from viral attack.

Specifically, they discovered that bacteria modify their cGAS using a streamlined "all-in-one version" of ubiquitin transferase, a complex collection of enzymes that in humans control immune signaling and other critical cellular processes.

Because bacteria are easier to genetically manipulate and study than human cells, this discovery opens a new world of opportunity for research, said Ledvina.

"The ubiquitin transferases in bacteria are a missing link in our understanding of the evolutionary history of these proteins."

Editing proteins

The study also revealed just how this machine works, identifying two key components -- proteins called Cap2 and Cap3 (CD-NTase-associated protein 2 and 3) -- which serve, respectively, as on and off switches for the cGAS response.

Whiteley explained that in addition to playing a key role in immune response, ubiquitin in humans can serve as a sort of marker for cellular garbage, directing excess or old proteins to be broken down and destroyed. When that system misfires due to mutations in the machine, proteins can build up and diseases, such as Parkinson's, can occur.

The authors stress that far more research is needed but the discovery opens exciting scientific doors. Just as scientists adapted the ancient bacterial defense system CRISPR into scissor-like biotechnology that can snip mutations out of DNA, Whiteley believes pieces of the bacterial ubiquitin transferase machine -- namely Cap3, the "off switch" -- could ultimately be programmed to edit out problem proteins and treat disease in humans.

He and his team, with the help of Venture Partners at CU Boulder, have already filed for intellectual property protection, and they're moving forward with more research.

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Impact of climate change on human pathogenic diseases subject of new study by UH researchers

A comprehensive assessment of scientific literature has uncovered empirical evidence that more than 58% of human diseases caused by pathogens, such as dengue, hepatitis, pneumonia, malaria, Zika and more, have been -- at some point -- aggravated by climatic hazards. That eye-opening and startling finding is the topic of a research paper published on August 8 in Nature Climate Change by a team of researchers from the University of Hawaii at Manoa.

The researchers carried out a systemic search for empirical examples about the impacts of 10 climatic hazards sensitive to greenhouse gas (GHG) emissions on each known human pathogenic disease. These hazards included warming, drought, heatwaves, wildfires, extreme precipitation, floods, storms, sea level rise, ocean biogeochemical change, and land cover change.

Combining two authoritative lists of all known infections and pathogenic diseases that have affected humanity in recorded history, researchers then reviewed more than 70,000 scientific papers for empirical examples about each possible combination of a climatic hazard impacting each of the known diseases.

The research revealed that warming, precipitation, floods, drought, storm, land cover change, ocean climate change, fires, heatwaves and sea level changes were all found to influence diseases triggered by viruses, bacteria, animals, fungi, protozoans, plants and chromists. Pathogenic diseases were primarily transmitted by vectors, although case examples were also found for waterborne, airborne, direct contact and foodborne transmission pathways. Ultimately, the research found that more than 58%, or 218 out of 375, of known human pathogenic diseases had been affected at some point, by at least one climatic hazard, via 1,006 unique pathways.

"Given the extensive and pervasive consequences of the COVID 19 pandemic, it was truly scary to discover the massive health vulnerability resulting as a consequence of greenhouse gas emissions," said Camilo Mora, geography professor in the College of Social Sciences (CSS) and lead author of the study. "There are just too many diseases, and pathways of transmission, for us to think that we can truly adapt to climate change. It highlights the urgent need to reduce greenhouse gas emissions globally."

An interactive web-page showing each connection between a climatic hazard and a disease case was developed by the research team. The tool allows users to query specific hazards, pathways and disease groups, and see the available evidence.

The UH Manoa research team included experts from CSS, Department of Earth Sciences in the School of Ocean and Earth Science and Technology, Marine Biology Graduate Program in the School of Life Sciences, Department of Natural Resources and Environmental Management in the College of Tropical Agriculture and Human Resources, and Hawaii Institute of Marine Biology in SOEST.

Other key findings include:

•     Climatic hazards are bringing pathogens closer to people. Numerous climatic hazards are increasing the area and duration of environmental suitability facilitating the spatial and temporal expansion of vectors and pathogens. Warming and precipitation changes, for instance, were associated with range expansion of vectors such as mosquitoes, ticks, fleas, birds and several mammals implicated in outbreaks by viruses, bacteria, animals and protozoans, including dengue, chikungunya, plague, Lyme disease, West Nile virus, Zika, trypanosomiasis, echinococcosis and malaria to name a few.
•     Climatic hazards are bringing people closer to pathogens. Climatic hazards were also implicated with the forced displacement and migration of people causing or increasing new contacts with pathogens. Heatwaves, for instance, have been associated with rising cases of several waterborne diseases such as Vibrio (a kind of bacteria)-associated infections, primary amoebic meningoencephalitis and gastroenteritis. Storms, floods and sea level rise caused human displacements implicated in cases of leptospirosis, cryptosporidiosis, Lassa fever, giardiasis, gastroenteritis, Legionnaires' diseases, cholera, salmonellosis, shigellosis, pneumonia, typhoid, hepatitis, respiratory disease and skin diseases among others.
•     Climatic hazards have enhanced specific aspects of pathogens, including improved climate suitability for reproduction, acceleration of the life cycle, increasing seasons/length of likely exposure, enhancing pathogen vector interactions (for example, by shortening incubations) and increased virulence. For instance, storms, heavy rainfall and floods created stagnant water, increasing breeding and growing grounds for mosquitoes and the array of pathogens that they transmit (for example, leishmaniasis, malaria, Rift Valley fever, yellow fever, St. Louis encephalitis, dengue and West Nile fever). Climatic hazards were also implicated in the increasing capacity of pathogens to cause more severe illness. For example, heatwaves were suggested as a natural selective pressure toward "heat resistant" viruses, whose spillover into human populations results in increased virulence as viruses can better cope with the human body's main defense, which is fever.
•     Climatic hazards have also diminished human capacity to cope with pathogens by altering body condition; adding stress from exposure to hazardous conditions; forcing people into unsafe conditions; and damaging infrastructure, forcing exposure to pathogens and/or reducing access to medical care. Drought, for instance, was conducive to poor sanitation responsible for cases of trachoma, chlamydia, cholera, conjunctivitis, Cryptosporidium, diarrheal diseases, dysentery, Escherichia coli, Giardia, Salmonella, scabies and typhoid fever.

Researchers also found that, while the great majority of diseases were aggravated by climatic hazards, some were diminished (63 out of 286 diseases). Warming, for example, appears to have reduced the spread of viral diseases probably related to unsuitable conditions for the virus or because of a stronger immune system in warmer conditions. However, most diseases that were diminished by at least one hazard were at times aggravated by another and sometimes even the same hazard.

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