Konzo is a severe, irreversible neurologic disease that results in paralysis. It occurs after consuming poorly processed cassava — a manioc root and essential crop for DRC and other low-income nations. Poorly processed cassava contains linamarin, a cyanogenic compound. While enzymes with glucosidase activity convert starch to simple sugars, they also break down linamarin, which then releases cyanide into the body.

“Knowing who is more at risk could result in targeted interventions to process cassava better or try to diversify the diet,” said Eric Vilain, M.D., Ph.D., director of the Center for Genetic Medicine Research at Children’s National. “An alternative intervention is to modify the microbiome to increase the level of protection. This is, however, a difficult task which may have unintended consequences and other side effects.”

The exact biological mechanisms underlying konzo disease susceptibility and severity remained poorly understood until now. This is the first study to shed light on the gut microbiome of populations that rely on toxic cassava as their primary food source.

“While the gut microbiome is not the sole cause of disease given that environment and malnourishment play a role, it is a required modulator,” said Matthew S. Bramble, Ph.D., staff scientist at Children’s National. “Simply stated, without gut microbes, linamarin and other cyanogenic glucosides would pose little to no risk to humans.”

To understand the influence of a detrimental subsistence on the gut flora and its relationship to this debilitating multifactorial neurological disease, the researchers compared the gut microbiome profiles in 180 children from the DRC using shotgun metagenomic sequencing. This approach evaluates bacterial diversity and detects the abundance of microbes and microbial genes in various environments.

The samples were collected in Kinshasa, an urban area with diversified diet and without konzo; Masi-Manimba, a rural area with predominant cassava diet and low prevalence of konzo; and Kahemba, a region with predominant cassava diet and high prevalence of konzo.

“This study overcame many challenges of doing research in low-resource settings,” said Desire Tshala-Katumbay, M.D., M.P.H., Ph.D., FANA, co-senior author and expert scientist at Institut National de Recherche Biomédicale in Kinshasa, DRC, and professor of neurology at Oregon Health & Science University. “It will open novel avenues to prevent konzo, a devastating disease for many children in Sub-Saharan Africa.”

For next steps, the researchers will study sibling pairs from konzo-prone regions of Kahemba where only one sibling is affected with the disease.

“Studying siblings will help us control for factors that cannot be controlled otherwise, such as the cassava preparation in the household,” said Neerja Vashist, Ph.D. candidate and research trainee at Children’s National. “In this work, each sample had approximately 5 million DNA reads each, so for our follow-up, we plan to increase that to greater than 40 million reads per sample and the overall study cohort size. This study design will allow us to confirm that the trends we observed hold on a larger scale, while enhancing our ability to comprehensively characterize the gut microbiome.”

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

The new precision-guided sterile insect technique, or pgSIT, alters genes linked to male fertility — creating sterile offspring — and female flight in Aedes aegypti, the mosquito species responsible for spreading wide-ranging diseases including dengue fever, chikungunya and Zika.

“pgSIT is a new scalable genetic control system that uses a CRISPR-based approach to engineer deployable mosquitoes that can suppress populations,” said UC San Diego Biological Sciences Professor Omar Akbari. “Males don’t transmit diseases so the idea is that as you release more and more sterile males, you can suppress the population without relying on harmful chemicals and insecticides.”

Details of the new pgSIT are described September 10, 2021, in the journal Nature Communications.

pgSIT differs from “gene drive” systems that could suppress disease vectors by passing desired genetic alterations indefinitely from one generation to the next. Instead, pgSIT uses CRISPR to sterilize male mosquitoes and render female mosquitoes, which spread disease, as flightless. The system is self-limiting and is not predicted to persist or spread in the environment, two important safety features that should enable acceptance for this technology.

Akbari says the envisioned pgSIT system could be implemented by deploying eggs of sterile males and flightless females at target locations where mosquito-borne disease spread is occurring.

“Supported by mathematical models, we empirically demonstrate that released pgSIT males can compete, and suppress and even eliminate mosquito populations,” the researchers note in the Nature Communications paper. “This platform technology could be used in the field, and adapted to many vectors, for controlling wild populations to curtail disease in a safe, confinable and reversible manner.”

Although molecular genetic engineering tools are new, farmers have been sterilizing male insects to protect their crops since at least the 1930s. United States growers in the 1950s began using radiation to sterilize pest species such as the New World Screwworm fly, which is known to destroy livestock. Similar radiation-based methods continue today, along with the use of insecticides. pgSIT is designed as a much more precise and scalable technology since it uses CRISPR — not radiation or chemicals — to alter key mosquito genes. The system is based on a method that was announced by UC San Diego in 2019 by Akbari and his colleagues in the fruit fly Drosophila.

As envisioned, Akbari says pgSIT eggs can be shipped to a location threatened by mosquito-borne disease or developed at an on-site facility that could produce the eggs for nearby deployment. Once the pgSIT eggs are released in the wild, typically at a peak rate of 100-200 pgSIT eggs per Aedes aegypti adult, sterile pgSIT males will emerge and eventually mate with females, driving down the wild population as needed.

Beyond Aedes aegypti, the researchers believe the pgSIT technology could be directed to other species that spread disease.

“… This study suggests pgSIT may be an efficient technology for mosquito population control and the first example of one suited for real-world release,” the researchers say. “Going forward, pgSIT may provide an efficient, safe, scalable, and environmentally friendly alternative next-generation technology for wild population control of mosquitoes resulting in wide-scale prevention of human disease transmission.”

The complete list of paper co-authors: Ming Li, Ting Yang, Michelle Bui, Stephanie Gamez, Tyler Wise, Nikolay Kandul, Junru Liu, Lenissa Alcantara, Haena Lee, Jyotheeswara Edula, Robyn Raban, Yinpeng Zhan, Yijin Wang, Nick DeBeaubien, Jieyan Chen, Hector Sanchez C., Jared Bennett, Igor Antoshechkin, Craig Montell, John Marshall and Omar Akbari.

Funding for the research was provided by a DARPA Safe Genes Program Grant (HR0011-17-2-0047); the National Institutes of Health (R01AI151004 and R56-AI153334); the U.S. Army Research Office (cooperative agreement W911NF-19-2-0026 for the Institute for Collaborative Biotechnologies); and the Innovative Genomics Institute.

The brachiopod Discinisca tenuis lives on the west coast of Africa.I It has a mineral-rich shell that protects it from harmful environmental influences. Bathing the shell in water leads to a structural change in the material: The flat, hard shell becomes so flexible that it can even be folded up without breaking. With the help of the Swiss Light Source SLS, the researchers have deciphered exactly how this transformation takes place.

The phenomenon was discovered by chance a few years ago by Fabio Nudelman, a materials chemist currently at the School of Chemistry, University of Edinburgh in Scotland. Maggie Cusack, who was recently appointed president of Munster Technological University in Ireland, had provided Nudelman with shells of the brachiopod Discinisca tenuis, which originally came from Namibia. When he wanted to wash the hard object, it suddenly became soft and flexible in contact with water. The shell had absorbed liquid and thereby changed its structure. The process was reversible: When the shell dried, it became hard and brittle again.

Together with colleagues from six countries, Nudelman set out to discover what exactly takes place during this unexpected transformation. “In its composition, the shell resembles bone,” he explains. “But bone doesn’t change its structure when it gets wet.” The same goes for clams: If the animals need to adapt the properties of their shell to different environmental conditions, they normally have to rework the material in a lengthy and energetically costly process, by resorbing and redistributing minerals. It doesn’t work simply through the absorption of water.

Hybrid material with a special trick

It was so-called cryo-tomography, performed at the Swiss Light Source SLS, that “opened the door to reveal the secret,” says Johannes Ihli, a PSI researcher at SLS. With this technique, the researchers examined the material as if under a very high-resolution microscope, and in fact at extremely low temperatures. “At room temperature it would not have been possible, since the high-energy X-ray light would immediately alter the sensitive shell structure,” Ihli explains.

The brachiopod’s shell, which is no more than half a millimetre thick, consists of a hybrid material: mainly inorganic mineral in which organic polymers made from proteins and sugars are embedded. Bones, clam shells, and teeth are structured in a similar way out of a mixture of organic and inorganic material. The mineral that constitutes the main component of the shell is a type of fluoroapatite — similar to the material that makes up the enamel of our teeth.

Tiny nanocrystals of this material are arranged in layers. Nudelman compares it to brick walls: “In this analogy, the bricks are the nanocrystals, and the mortar between the bricks consists of organic molecules such as chitin and proteins.” As the researchers observed, this “mortar” can absorb large amounts of water, causing it to swell up. Through the storage of water, it changes its structure: It becomes soft, and the bricks become movable with respect to each other. “Then water acts like a lubricant between the individual nanocrystals,” Ihli explains. “The crystals can then slip against each other.” Through this movement, the shell becomes flexible. The researchers found a network of pores in the shell that was especially effective in guiding water inside and rapidly distributing it throughout the material.

Evolutionary advantage

Discinisca tenuis lives in large clusters in tidal zones on the coast where, depending on the tide, the animals are exposed to strong waves or calm waters. The researchers speculate that it is probably advantageous if the animals can quickly adapt the softness or hardness of their shell to the respective situation: “This could prevent damage to the shell and thus be a key to the animals’ survival,” they write in the study. The phenomenon may even be more widespread than suspected: “We don’t know how many other animal species there might be that have this kind of property,” says Nudelman.

Aside from biology and evolution, the newly gained insights are also of interest for materials science: The development of a hard, brittle material whose stiffness can be controlled could hold promise for many applications. Sports clothing or helmets, for example, might be able to flexibly adapt to movements and always offer the protection required depending on the impact. Harnessing this phenomenon could also prove useful in developing bone-replacement materials.

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Materials provided by Paul Scherrer Institute. Original written by Brigitte Osterath. Note: Content may be edited for style and length.