The paper describes current preclinical successes and clinical genome editing approaches for treating inherited retinal degenerative disease and stresses there is hope that in vivo gene editing will be the future treatment paradigm for IRDs. Currently, there are no effective treatments for these devastating diseases, which commonly result in blindness.

“Genome editing technologies are an excellent approach for targeting the root causes of genetic disorders,” explained Krzysztof Palczewski, PhD, Donald Bren Professor of Ophthalmology at the UCI School of Medicine and corresponding author. “Technologies in genome editing have continuously evolved to enable precise genome editing with fewer side effects and risks, making precision genome editing possible.”

The paper describes progress toward using genome editing for treating IRDs and important considerations for robust clinical translation.

“More and more CRISPR-based treatment approaches are being tested in clinical trials,” said Palczewski. “We believe that there will be an increasing number of clinical trials for targeting IRDs and that any mutation that causes them will be amenable to treatment with this approach.”

Programmable CRISPR-Cas nucleases are effective tools for gene disruption, but they are poorly suited for precisely correcting pathogenic mutations in most therapeutic settings. Improvements are needed for clinical translation.

Inherited retinal diseases (IRDs) are a genetically heterogeneous group of blinding disorders characterized by a progressive degeneration of the photoreceptors as well as the retinal pigment epithelium (RPE). These disorders affect ?1 in 3,000 individuals worldwide and profoundly impact patients’ quality of life. IRDs are caused by mutations in genes that are critical for development and/or function of the retina or RPE, and more than 270 causative genes have been identified.

Over the past two decades, major advances in gene therapy have engendered new hopes for successful treatment of these IRDs. Most recently, precision genome editing agents, including base editors (BEs) and prime editors (PEs), developed by The Liu Lab, have enabled efficient and precise target gene correction, rather than gene disruption, in various therapeutic settings, including mouse models of IRDs. Precise target gene correction greatly expands the potential therapeutic applications of genome editing technologies, since most genetic disorders cannot be treated by gene disruption.

“Precision medicine for IRDs has a promising outlook, as basic science has consistently led to the development of therapeutic tools to target patient-specific genetic mutations,” said Palczewski. “The results of initial clinical trials, that use in vivo gene editing to treat IRDs, will be essential for informing the design and translation of future precision genome editing therapies.”

This work was done in collaboration with David R. Liu, and supported in part by the National Institutes of Health, National Science Foundation, Howard Hughes Medical Institute and Research to Prevent Blindness.

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Materials provided by University of California – Irvine. Note: Content may be edited for style and length.

Led by The University of Texas at Austin and the University of California San Diego, the study, which was published Sept. 23 in Science Advances, is the first to simulate how aerosol pollution affects both climate and air quality for locations around the globe.

Aerosols are tiny solid particles and liquid droplets that contribute to smog and are emitted from industrial factories, power plants and vehicle tailpipes. They impact human health, agricultural and economic productivity in unique global patterns when compared with carbon dioxide (CO₂) emissions, which are the focus of efforts to mitigate climate change.

Although CO₂ and aerosols are often emitted at the same time during the combustion of fuel, the two substances behave differently in Earth’s atmosphere, said co-lead author Geeta Persad, an assistant professor at the UT Austin Jackson School of Geosciences.

“Carbon dioxide has the same impact on climate no matter who emits it,” said Persad. “But for these aerosol pollutants, they tend to stay concentrated near where they’re emitted, so the effect that they have on the climate system is very patchy and very dependent on where they’re coming from.”

The researchers found that, depending on where they are emitted, aerosols can worsen the social costs of carbon — an estimate of the economic costs greenhouse gasses have on society — by as much as 66%. The scientists looked at eight key regions: Brazil, China, East Africa, Western Europe, India, Indonesia, United States and South Africa.

“This research highlights how the harmful effects of our emissions are generally underestimated,” said Jennifer Burney, co-lead author and the Marshall Saunders Chancellor’s Endowed Chair in Global Climate Policy and Research at the UC San Diego School of Global Policy and Strategy. “CO₂ is making the planet warmer, but it also gets emitted with a bunch of other compounds that impact people and plants directly and cause climate changes in their own right.”

The work, which was supported by the National Science Foundation, represents a collaboration between Persad and Burney, who are physical scientists, and a group of economists and public health experts. Co-authors include Marshall Burke, Eran Bendavid, and Sam Heft-Neal at Stanford University and Jonathan Proctor at Harvard University.

Aerosols can directly affect human health and the climate independently of CO₂. They are associated with negative health impacts when inhaled, and can affect the climate by influencing temperature, precipitation patterns and how much sunlight reaches the Earth’s surface.

To study aerosols’ influence in comparison to CO₂, the team created a set of climate simulations using the Community Earth System Model version 1 developed by the National Center for Atmospheric Research. They ran simulations in which each of the eight regions produced identical aerosol emissions and mapped how temperature, precipitation, and surface air quality were affected across the globe. Then they connected this data with known relationships between climate and air quality and infant mortality, crop productivity, and gross domestic product across the eight regions. In a final step, they compared the total societal costs of these aerosol-driven impacts against the societal costs of co-emitted CO₂ in each of the eight regions, and produced global maps of the combined effects of aerosols and CO₂. The researchers said the study is a big step forward from previous work, which either only estimated the air quality impacts of aerosols or didn’t consider their diverse global climate effects.

The outcome paints a varied and complicated picture. Emissions from some regions produce climate and air quality effects that range from two to more than 10 times as strong as others and social costs that sometimes affect neighboring regions more than the region that produced the aerosol emissions. For example, in Europe local emissions result in four times as many infant deaths outside Europe as within.

But the researchers note that aerosol emissions are always bad for both the emitter and the planet overall.

“While we might think about aerosols, which cool the climate, as having the silver lining of counteracting CO₂-driven warming, when we look at all these effects in combination, we find that no region experiences overall local benefits or generates overall global benefits by emitting aerosols,” said Persad.

Researchers also said the findings create potentially new motivations for countries to cut emissions — and to care about other countries cutting emissions. For example, the study found that adding aerosol costs to CO₂ costs could double China’s incentive to mitigate emissions. And it switches the impact of local emissions in Europe from a net local benefit to a net cost. The study also shows that some emerging economies, like East African nations and India, might be motivated to collaborate on emission cuts since they are strongly impacted by each other’s emissions.

The framework developed in this study can also be applied to maximize societal benefits from current mitigation strategies being considered by policy makers. For example, the researchers applied it to the “fair-share” approach laid out in the Paris Climate Agreement in which all countries target the same per-capita CO₂ emissions. They found the approach, while beneficial for climate stability, does not improve the mortality and crop impacts from combined aerosol and CO₂ emissions because it focuses mitigation in regions that already have fairly low aerosol impacts, like the U.S. and Europe.

“By expanding societal cost calculations to include the geographically-resolved societal impacts of co-emitted aerosols, we’re showing that the incentive for individual countries to mitigate and collaborate on mitigation is much higher than if we only think about greenhouse gases,” Burney said.

Depending on the initial conditions used, such as nutrient levels and space constraints, bacteria tend to grow in specific ways. The researchers created a virtual bacterial colony and then controlled growth conditions and the numbers and sizes of simulated bacterial dots to create an entire alphabet based on how the colonies would look after they fill a virtual Petri dish. They call this encoding scheme emorfi.

The encoding is not one-to-one, as the final simulated pattern corresponding to each letter is not exactly the same every time. However, the researchers discovered that a machine learning program could learn to distinguish between them to recognize the letter intended.

“A friend may see many images of me over the course of time, but none of them will be exactly the same,” explained Lingchong You, professor of biomedical engineering at Duke. “But if the images are all consistently reinforcing what I generally look like, the friend will be able to recognize me even if they’re shown a picture of me they’ve never seen before.”

To encrypt real messages, the encoder ends up creating a movie of a series of patterns, each correlating to a different letter. While they may look similar to the untrained eye, the computer algorithm can distinguish between them. So long as the receiver knows the set of initial conditions that led to their creation, an interloper should not be able to crack the code without a powerful AI of their own.

Give the cypher a try yourself. You can type in anything from your name to the Gettysburg Address, or even the Christmas classic, “Be sure to drink your Ovaltine”:

https://www.patternencoder.com/

This research was supported by the National Science Foundation (MCB-1937259), the Office of Naval Research (N00014-20-1-2121), the David and Lucile Packard Foundation and the Google Cloud Research Credits program.

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Materials provided by Duke University. Original written by Ken Kingery. Note: Content may be edited for style and length.

At the same time, development of organs such as the intestine is anything but haphazard. In healthy embryos, rotation of the gut during development always occurs in a counterclockwise direction and is perfectly timed. It’s a complicated process that scientists have long worked to understand.

Now, a study published Sept. 23 in the journal Science finds that gut rotation during development is orchestrated by two waves of expression of a transcription factor called Pitx2. The second wave, it turns out, is triggered by mechanical cues within an elastic tissue that anchors the gut tube, and later becomes a conduit for blood and lymphatic vessels that supply the gut tube.

The findings have important implications for understanding the basic mechanisms of how organs form, which could aid efforts to diagnose and prevent birth defects, such as intestinal malrotation and volvulus, where developing intestines become twisted and strangle themselves.

“The entire gastrointestinal tract is one tube that absorbs all of our nutrients, and it’s giant, so it has to loop to fit inside our body,” said Natasza Kurpios, associate professor of molecular medicine in the College of Veterinary Medicine and senior author of the study. Bhargav D. Sanketi, a doctoral student in Kurpios lab, is the paper’s first author.

“What we found years ago is that looping is highly conserved and it’s very, very regulated,” Kurpios said.

It turns out that organs such as the heart, liver, lungs and gut (intestines) are all asymmetrically situated — found on one side of the body, or spanning the left and right, but not centered. Understanding how the gut forms with left-right asymmetry could reveal patterns of development found in other organs, such as the heart.

Previous work has shown that a gene called Nodal induces the first wave of Pitx2 to establish the early body plan. But Nodal’s presence is short-lived, and once it stimulates Pitx2 expression, it disappears before gut rotation occurs. So, for a long time it has been unknown how Pitx2 stays active to direct gut rotation when Nodal is gone. “Our first surprise was that Pitx2 expression actually goes away and then it comes back as the gut tube is ready to loop,” Kurpios said. “And so the question was, what wakes Pitx2 up?”

The researchers found that a sensor, TGF-beta, lies latent until it gets activated by mechanical forces. In the case of the gut, this is dictated by the dorsal mesentery which attaches to and holds the gut tube in place. To direct rotation, the dorsal mesentery tissue dramatically expands on the right side and compacts on the left. When it does so, TGF-beta senses these changing forces and activates expression of a second wave of Pitx2, which stimulates gut tube looping. In other words, the wave of Pitx2 that establishes body asymmetry is different from the wave that rotates the gut.

In the study, the researchers used engineered mice and chicken embryos, which allow Kurpios and colleagues to open a little window in the egg shell so they can view development and manipulate gene expression.

The lab of co-author Jan Lammerding, professor in the Meinig School of Biomedical Engineering, used a probe in live embryos to measure stiffness and elasticity in the dorsal mesentery. The measurements revealed expansion on the right side and TGF-beta-Pitx2 induced braking of that expansion on the left side, which created the perfect amount of tilt in the tissue for proper gut tube looping.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases; the March of Dimes; the National Heart, Lung and Blood Institute; the Volkswagen Foundation; and the Cornell Center for Vertebrate Genomics.

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Materials provided by Cornell University. Original written by Krishna Ramanujan, Cornell Chronicle. Note: Content may be edited for style and length.

Professor Jonghun Kam (Environmental Science and Engineering) at POSTECH and Chang-Kyun Park, researcher at the Institute of Environment and Energy Technology, have developed a self-calibrating effective drought index (scEDI) through joint research. This new index enabled them to explore 250 years of drought data, starting from late Joseon dynasty to date, comparing and analyzing precipitation records.

The EDI, a typical tool to determine the severity of droughts, is designed to monitor and characterize drought conditions on a daily scale. The index uses the last 30 years of daily precipitation records. In other words, the reference period determines EDI values, making it difficult to compare values over a long record period.

Professor Kam’s research team is the first to propose a self-calibrating EDI and use it to analyze the daily precipitation observed in Seoul from year 1777 through 2020. The scEDI that automatically calibrates the index behavior over time can maintain consistency in comparison by evaluating droughts of the same intensity and frequency.

Notably, this research employed the historical records of the Annals of the Joseon Dynasty (Joseon Wangjo Sillok) and daily precipitation data measured with Joseon’s rain gauge (chukwookee). The study demonstrated the value of unprecedentedly meticulous records left by the Koreans from that period.

The comparison between the records from Joseon era and the online search results of today implies that our predecessors were more sensitive to drought. Most drought damage records and spikes of public interest in droughts coincide with when droughts are moderate (-1.4 of scEDI) and severe (-2.0), respectively.

The findings infer that socioeconomic drought impacts hinge on the socioeconomic structure. As a valuable tool to quantitatively assess drought impacts, the scEDI has the potential to identify droughts with social consequences in advance.

Professor Kam explained, “The scEDI proposed in this study features automatic calibration corresponding to the climate of the reference period, enabling temporal detection and comparison of droughts (in terms of severity, duration, and intensity). This suggests a new research methodology for social droughts, which have been difficult to study in comparison with other drought-related categories: meteorological, agricultural, and hydrological.” He added, “Understanding both the social impacts of droughts and how they have been addressed will provide the Korean public with action plans to be prepared for future droughts in advance.”

Recently published in the Journal of Hydrology, the study was supported by the National Research Foundation of Korea (Sejong Science Fellowship Program and Mid-career Researcher Program) and the National Disaster Management Research Institute (Cooperative Research Method and Safety Management Technology in National Disaster).

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Materials provided by Pohang University of Science & Technology (POSTECH). Note: Content may be edited for style and length.

Potential applications range from monitoring exercise, sleep, and stress to diagnosing and monitoring disease through breath and vital signs.

Spun from a new Imperial-developed cotton-based conductive thread called PECOTEX, the sensors cost little to manufacture. Just $0.15 produces a metre of thread to seamlessly integrate more than ten sensors into clothing, and PECOTEX is compatible with industry-standard computerised embroidery machines.

First author of the research Fahad Alshabouna, PhD candidate at Imperial’s Department of Bioengineering, said: “The flexible medium of clothing means our sensors have a wide range of applications. They’re also relatively easy to produce which means we could scale up manufacturing and usher in a new generation of wearables in clothing.”

The research team embroidered the sensors into a face mask to monitor breathing, a t-shirt to monitor heart activity, and textiles to monitor gases like ammonia, a component of the breath that can be used to track liver and kidney function. The ammonia sensors were developed to test whether gas sensors could also be manufactured using embroidery.

Fahad added: “We demonstrated applications in monitoring cardiac activity and breathing, and sensing gases. Future potential applications include diagnosing and monitoring disease and treatment, monitoring the body during exercise, sleep, and stress, and use in batteries, heaters, anti-static clothing.”

The research is published today in Materials Today.

Seamless sensors

Wearable sensors, like those on smartwatches, let us continuously monitor our health and wellbeing non-invasively. Until now, however, there has been a lack of suitable conductive threads, which explains why wearable sensors seamlessly integrated into in clothing aren’t yet widely available.

Enter PECOTEX. Developed and spun into sensors by Imperial researchers, the material is machine washable, and is less breakable and more electrically conductive than commercially available silver-based conductive threads, meaning more layers can be added for to create complex types of sensor.

Lead author Dr Firat Guder, also of the Department of Bioengineering, said: “PECOTEX is high-performing, strong, and adaptable to different needs. It’s readily scalable, meaning we can produce large volumes inexpensively using both domestic and industrial computerised embroidery machines.

“Our research opens up exciting possibilities for wearable sensors in everyday clothing. By monitoring breathing, heart rate, and gases, they can already be seamlessly integrated, and might even be able to help diagnose and monitor treatments of disease in the future.”

Next, the researchers will explore new application areas like energy storage, energy harvesting and biochemical sensing, as well as finding partners for commercialisation.

This study was funded by the Saudi Ministry of Education, Engineering and Physical Sciences Research Council (EPSRC, part of the UKRI), Cytiva, Imperial’s Department of Bioengineering, Bill and Melinda Gates Foundation, and the US Army.

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Materials provided by Imperial College London. Original written by Caroline Brogan. Note: Content may be edited for style and length.

Understanding what causes the superior auditory ability in WBS patients may provide a target for treating the disease in addition to helping advance research on the ability to discriminate between sounds. WBS offers insight into the mechanisms that underlie enhanced auditory abilities. For instance, some people with WBS have perfect pitch, which is the ability to differentiate between notes or frequencies without a reference guide.

“WBS stands out among neurodevelopmental disorders because children with the disorder, despite profound learning disabilities, can have a higher prevalence of superior musical and linguistic abilities than children in the general population,” said corresponding author Stanislav Zakharenko, M.D., Ph.D., St. Jude Department of Developmental Neurobiology. “We were fascinated by that and wanted to know more about how a disorder that is caused by a loss of 27 genes could help individuals gain a better than normal ability for auditory processing.”

Excited neurons in the auditory cortex

Mouse models of WBS have an enhanced ability to discriminate between sound frequencies. These mice also have improved frequency coding in the auditory cortex, the part of the brain that processes sound. The researchers showed that the enhanced ability to discriminate between frequencies is caused by hyperexcitable interneurons in the auditory cortex.

To understand the cellular biology that underlies enhanced auditory abilities in WBS patients, the researchers conducted an RNAseq experiment. The data led the researchers to a neuropeptide receptor called VIPR1, which is reduced in the auditory cortex of individuals with WBS. The reduction in VIPR1 was also found in cerebral organoids, advanced models made in the laboratory using human induced pluripotent stem cells.

The scientists found that the transcription factor Gtf2ird1, encoded by one of the 27 genes lost in those with WBS, regulates VIPR1. Deleting or overexpressing VIPR1 in the auditory cortex can mimic or reverse the auditory effects seen in WBS. Thus, it is Gtf2ird1 downregulating VIPR1 that is responsible for the impact of WBS on auditory ability.

“I didn’t know a lot about VIPR1 before it popped up in our data because the role of this family of receptors in the brain is under-appreciated compared to other neuromodulator or neurotransmitter receptors,” said first-author Christopher Davenport, St. Jude Department of Developmental Neurobiology. “Our findings show that they can strongly impact information processing and behavior and are likely relevant for other behaviors and diseases as well.”

“This work suggests that reducing neuronal hyperexcitability might be a general mechanism for treating WBS through targeting VIPR1,” Zakharenko said. “It also opens up new directions to learn about musicality and how our brain differentiates sounds based on these findings in models of WBS.”

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Materials provided by St. Jude Children’s Research Hospital. Note: Content may be edited for style and length.