GN/ A novel COVID-19 vaccine using modified bacterial DNA
Genetics biweekly vol.33, 13th July — 27th July
TL;DR
- Researchers describe a different way to build a COVID-19 vaccine, one that would, in theory, remain effective against new and emerging variants and could be taken as a pill, by inhalation or other delivery methods.
- Evolution has long been viewed as a rather random process, with the traits of species shaped by chance mutations and environmental events — and therefore largely unpredictable. But an international team of scientists has found that a particular plant lineage independently evolved three similar leaf types over and over again in mountainous regions scattered throughout the neotropics.
- Bat cells have specific molecular barriers to deal with SARS-CoV-2 replication, according to a new study.
- For the first time, researchers have characterized the genome arrangement of tree ferns, which sheds new insight into how ferns evolved.
- A new study suggests that stem cells are able to integrate cues from their surroundings and coordinate their behavior across tissue through networks of vasculature in their close vicinity.
- A set of genes that promote sweet taste sensation is also crucial for protein management during fly development, according to a new study. The finding expands the understanding of a key process in successful development, and suggests a connection between taste-related genes and disorders of protein aggregation.
- A research team has succeeded for the first time in producing a molecular electric motor using the DNA origami method. The tiny machine made of genetic material self-assembles and converts electrical energy into kinetic energy. The new nanomotors can be switched on and off, and the researchers can control the rotation speed and rotational direction.
- Genetic mutations could be predicted before they occur using a new law of physics, according to a new study.
- SARS-CoV-2 is covered in spike proteins, which allow the virus to enter host cells once in the body. Researchers have developed a membrane that includes proteolytic enzymes that attach to the protein spikes and deactivate them.
- Researchers have developed a work-flow method, called Fanflow4Insects, that annotates gene functions in insects. In functional annotation, scientists collect information about a gene’s biological identity. The team’s new method uses transcribed sequence information as well as genome and protein sequence databases. With Fanflow4Insects, the team has annotated the functional information of the Japanese stick insect and the silkworm, including gene expression as well as sequence analysis. The functional annotation information that their workflow provides will greatly expand the possibilities of entomological research using genome editing.
- And more!
Overview
Genetic technology is defined as the term which includes a range of activities concerned with the understanding of gene expression, advantages of natural genetic variation, modifying genes and transferring genes to new hosts. Genes are found in all living organisms and are transferred from one generation to the next. Gene technology encompasses several techniques including marker-assisted breeding, RNAi and genetic modification. Only some gene technologies produce genetically modified organisms.
Modern genetic technologies like genome editing would not be possible without all the previous generations of genetic technologies that have enabled scientists to discover what genes are, what they do and how DNA can be modified to add, remove or replace genes. You can find major genetic technologies development milestones via the link.
Gene Technology Market
- The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.
- Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).
- North America holds the largest share in the global genetic engineering market, followed by Europe and the Asia Pacific, respectively.
- Another research provider, MarketsandMarkets, forecasts the genome editing, genome engineering market to grow from USD 3.19 billion in 2017 to USD 6.28 billion by 2022, at a compounded annual growth rate (CAGR) of 14.5% during the forecast period. The key factors propelling market growth are rising government funding and growth in the number of genomics projects, high prevalence of infectious diseases (like COVID-19) and cancer, technological advancements, increasing production of genetically modified (GM) crops, and growing application areas of genomics.
Latest News & Research
Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern
by Gonzalo Almanza, Alex E. Clark, Valentina Kouznetsova, Eduardo Olmedillas, Andrea Castro, Igor F. Tsigelny, Yan Wu, George F. Gao, Sandra L. Leibel, William Bray, Erica Ollmann Saphire, Aaron F. Carlin, Maurizio Zanetti in PLOS Pathogens
Researchers at University of California San Diego School of Medicine, with colleagues elsewhere, describe a different way to build a COVID-19 vaccine, one that would, in theory, remain effective against new and emerging variants and could be taken as a pill, by inhalation or other delivery methods.
The research involved building plasmids genetically altered to contain bits of genetic material specifically intended to target a vulnerability in the SARS-CoV-2 virus’s spike protein, a portion of the virus critical to binding and infecting cells. Plasmids are small, circular DNA molecules from bacteria that are physically separate from chromosomal DNA and can replicate independently. They can be used by scientists to transfer genetic material from one cell to another, after which the introduced genetic material can replicate in the receiving cell.
The approach, said senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and head of the Laboratory of Immunology at UC San Diego Moores Cancer Center, points to the possibility of a more durable, and more broadly effective, COVID-19 vaccine.
“The details are complicated, but the fundamentals are simple,” said Zanetti. “They are based on well-known and proven principles and methods.”
COVID-19 mRNA vaccines, such as those by Pfizer and Moderna, are the result of decades of previous research and development. The pandemic added new urgency, focus and resources. These vaccines promised a faster way to people, though not without significant challenges, such as the need of an ultralow temperature cold chain. The resulting mRNA vaccines have fundamentally altered the course of the pandemic, dramatically mitigating the severity of disease, hospitalizations and deaths. But notably, said Zanetti, they do little at blocking transmission of the virus. Case rates still rise and fall with the emergence of viral variants.
“The goal at the beginning wasn’t to stop the disease,” said Zanetti. “It was to mitigate the consequences, to reduce COVID’s severity and outcomes. The vaccines have done that. Vaccinated persons tend not to get as sick. They don’t require hospitalization as often. Death rates are down. All of this has greatly reduced pressures on health systems and society, which is a good thing.”
But the ever-evolving nature of the SARS-CoV-2 virus has revealed that the vaccines’ efficacy varies, depending upon variant, often diminishing. The Alpha variant, for example, proved more contagious than the “wild-type” strain that originated in Wuhan, China. The Delta variant was more transmissible than Alpha and Omicron more than Delta. Though the vaccines continue to provide substantial protection against severe disease, the antibodies they induce are consistently less powerful at neutralizing the virus, thus the increased transmission. SARS-CoV-2 continues to be an unrelenting global public health threat.
Zanetti said the newest work emphasizes “quality over quantity,” seeking the induction of antibodies preferentially blocking virus binding to its cell receptor and transmission. This results in a more focused antibody response with the vaccine.
“In the early days of COVID vaccine development, it was about generating a broad, robust immune response,” Zanetti said. “But it was a scattered approach. The vaccines response targeted many epitopes (parts of the virus that the host’s immune system recognizes) and it resulted in an immune response that was largely noise. Most of the resulting antibodies produced didn’t affect the virus’s ability to infect.”
“The new research narrows the focus to a part of the viral spike specifically involved in the virus’s ability to infect that appears to be evolutionarily conserved,” said co-senior author Aaron F. Carlin, MD, PhD, assistant professor in the Division of Infectious Diseases and Global Public Health at UC San Diego Health. In other words, the site doesn’t change with new variants, and represents a persisting site of vulnerability and a reliable vaccine target.
Zanetti and colleagues built plasmids containing immunogens — molecules that cause B lymphocytes to create antibodies — that were specifically designed to display a knob of the spike protein that is part of the receptor binding motif or RBM. Specifically, these were amino acid residues that act like keys to unlock the cell door. The keys and lock don’t change.
B lymphocytes are part of the immune system. They are prodigious producers of antibodies created to respond and protect against specific antigens or unwanted substances in the body, such as viruses. The average B lymphocyte can spit out 1,000 antibody molecules per second, an incredibly robust production if it is the right antibody for the job. Zanetti and colleagues cloned the selected spike protein amino acids into a plasmid DNA so that, when injected into the spleen of mice, the introduced immunogen molecules would provoke the production of neutralizing antibodies specifically tuned to the targeted nob on the RBM of the virus protein spike. The researchers then tested their approach on mice with variants of the original SARS-CoV-2 strain (Beta, Delta and Omicron) and found that the immune response was similar across all variants.
“We were a bit lucky in picking our target on the spike,” said Zanetti, “though it was also the result of experience and intuition. I’ve been doing this for 30 years. Earlier experiments by others had suggested this might be a ‘supersite.’ I followed my instincts.”
Zanetti said translating these findings into a vaccine suitable for clinical trials will be “an uphill battle.” There is much invested in current approaches, and it’s a considerable leap from mouse studies to human clinical trials. But the promise of a consistently effective and easy to administer vaccine is irresistible.
“DNA is very stable. The new ideas for delivery include a pill that survives the digestive system and releases the plasmid DNA to be picked up by B lymphocytes that seem to possess an ancestral property for taking up plasmid DNA. Alternatively, the DNA can be formulated for delivery to the upper airways by suitable formulation for inhalation. Many other researchers and I have investigated and pursued this basic idea before in other ways. It’s time to try it with COVID.”
Replicated radiation of a plant clade along a cloud forest archipelago
by Michael J. Donoghue, Deren A. R. Eaton, Carlos A. Maya-Lastra, Michael J. Landis, Patrick W. Sweeney, Mark E. Olson, N. Ivalú Cacho, Morgan K. Moeglein, Jordan R. Gardner, Nora M. Heaphy, Matiss Castorena, Alí Segovia Rivas, Wendy L. Clement, Erika J. Edwards in Nature Ecology & Evolution
Evolution has long been viewed as a rather random process, with the traits of species shaped by chance mutations and environmental events — and therefore largely unpredictable.
But an international team of scientists led by researchers from Yale University and Columbia University has found that a particular plant lineage independently evolved three similar leaf types over and over again in mountainous regions scattered throughout the neotropics. The findings provided the first examples in plants of a phenomenon known as “replicated radiation,” in which similar forms evolve repeatedly within different regions, suggesting that evolution is not always such a random process but can be predicted.
“The findings demonstrate how predictable evolution can actually be, with organismal development and natural selection combining to produce the same forms again and again under certain circumstances,” said Yale’s Michael Donoghue, Sterling Professor Emeritus of Ecology & Evolutionary Biology and co-corresponding author. “Maybe evolutionary biology can become much more of a predictive science than we ever imagined in the past.”
For the study, the research team studied the genetics and morphology of the plant lineage Viburnum, a genus of flowering plants that began to spread south from Mexico into Central and South America some 10 million years ago. Donoghue studied this same plant group for his Ph.D. dissertation at Harvard 40 years ago. At the time, he argued in favor of an alternative theory in which large, hair-covered leaves and small smooth leaves evolved early in the evolution of the group and then both forms migrated separately, being dispersed by birds, through the various mountain ranges. The new genetic analyses reported in the paper, however, show that the two different leaf types evolved independently, in parallel, in each of a number of mountain regions.
“I came to the wrong conclusion because I lacked the relevant genomic data back in the 1970s,” Donoghue said.
The team found that a very similar set of leaf types evolved in nine of 11 regions studied. However, the full array of leaf types may have yet to evolve in places where Viburnum has only more recently migrated. For instance, the mountains of Bolivia lack the large hairy leaf types found in other wetter areas with little sunshine in the cloud forest in Mexico, Central America, and northern South America.
“These plants arrived in Bolivia less than a million years ago, so we predict that the large, hairy leaf form will eventually evolve in Bolivia as well,” Donoghue said.
Several examples of replicated radiation have been found in animals, such as Anolis lizards in the Caribbean. In that case, the same set of body forms, or “ectomorphs,” evolved independently on several different islands. With a plant example now in hand, evolutionary biologists will try to discover the general circumstances under which solid predictions can be made about evolutionary trajectories.
“This collaborative work, spanning decades, has revealed a wonderful new system to study evolutionary adaptation,” said Ericka Edwards, professor of ecology and evolutionary biology at Yale and co-corresponding author of the paper. “Now that we have established the pattern, our next challenges are to better understand the functional significance of these leaf types and the underlying genetic architecture that enables their repeated emergence.”
Species-Specific Molecular Barriers to SARS-CoV-2 Replication in Bat Cells
by Sophie-Marie Aicher, Felix Streicher, Maxime Chazal, Delphine Planas, Dongsheng Luo, Julian Buchrieser, Monika Nemcova, Veronika Seidlova, Jan Zukal, Jordi Serra-Cobo, Dominique Pontier, Bertrand Pain, Gert Zimmer, Olivier Schwartz, Philippe Roingeard, Jiri Pikula, Laurent Dacheux, Nolwenn Jouvenet in Journal of Virology
Bat cells have specific molecular barriers to deal with SARS-CoV-2 replication, according to a publication of the American Society of Microbiology — which includes the participation of Jordi Serra-Cobo, lecturer of the Faculty of Biology and the Biodiversity Research Institute (IRBio) of the University of Barcelona and expert on ecoepidemiological studies.
The study was carried out on primary cells of bat species which had been little studied and which circulate around Europe and Asia (specifically, Rhinolopuhs ferrumequinum, Myotis myotis, Eptesicus serotinus, Tadarida brasiliensis and Nyctalus noctula). These cellular lines were obtained through small biopsies carried out on the wings of the bats — for instance, in bat colonies of Myotis myotis in Majorca and other cell lines brought by some research teams that took part in the study. As stated in the conclusions, these cellular models defined in chiropterans are shaped as tools of scientific interest to study the evolutionary relationship between bats and coronaviruses. The study, led by the experts Nolwenn Jouvenet and Laurent Dacheux, from the Institute Pasteur in Paris, includes the collaboration of experts from research institutions in France, the Czech Republic and Switzerland.
Coronaviruses are present in many animal species worldwide, such as bats (chiropteans). In this context, the scientific literature has described for years the great resistance of some chiropteran species towards the viral infection. In these flying mammals, the immune system is on a pre-alert stage, a condition that allows a faster response to viral infections. For most mammals, having an immune system on a constant pre-alert state would involve inflammation problems but this is not the case for bats, which is why they are the focus of many international epidemiological and immunological studies.
As part of the study, the team analysed the ability of primary cells from different bat species to support SARS-CoV-2 replication. “The results reveal that none of these cells was permissive to the infection, not even those expressing detectable levels of angiotensin-converting enzyme 2 (ACE2), a metallopeptidase that serves as a viral receptor in many mammal species,” says Jordi Serra-Cobo, member of the Department of Evolutionary Biology, Ecology and Environmental Sciences of the UB and the only expert in Spain to take part in this study.
“The cells did not allow the infection in the species Rhinolophus ferrumequinum, a chiropteran from the same genus as the Asian bat in which the BANAL-52 virus was found, a potential ancestor of SARS-CoV-2. Specifically, the genetic sequences of the BANAL-52 virus is 96.8% similar to that of SARS-CoV-2,” says Serra-Cobo, distinguished expert in studies with bats as natural reservoirs of infectious agents like coronaviruses.
Regarding the human species, it is known that the SARS-CoV-2 spike protein binds to the cell membrane receptor ACE2 and then the virus infects the cell. “In the case of the chiropteran cells, either the amount of ACE2 enzyme is small and it no longer enters the cell or, if the virus binds to ACE2, it cannot infect the cell,” highlights Serra-Cobo.
From a global perspective, this study contributes to a better understanding of the fighting mechanisms against viral infections. This is a line of research that has been carried out for years by the team led by Serra-Cobo at the UB and IRBio and which is now gaining strength within the framework of the EvoDevo-Cat research group at the Faculty of Biology of the UB.
“Specifically, our team is working to understand the adaptations of the chiropterans regarding viral infections. An important number of zoonotic viruses circulate in chiropter populations without causing symptoms of the disease in the carriers,” notes the researcher.
“Over the course of the evolutionary history of chiropterans — about 64 million years — , there have been processes of coevolution between bats and viruses. One example of these processes is in the adaptation to coronaviruses. The study of the evolutionary adaptations of living beings to deal with viral infections is of great interest, since they provide information that can have medical applications,” concludes Jordi Serra-Cobo.
The flying spider-monkey tree fern genome provides insights into fern evolution and arborescence
by Xiong Huang, Wenling Wang, Ting Gong, David Wickell, et al in Nature Plants
Land plants evolved 470 million years ago from algae and have since reshaped our world. Throughout their evolution, ferns have undergone a series of changes that have helped them survive on land. For the first time, researchers have characterized the genome arrangement of tree ferns, which sheds new insight into how ferns evolved.
A major event in the evolution of land plants was the invention of their vascular systems, which help them conduct water, nutrients, and food throughout their bodies. These systems consist of two tissues: xylem and phloem. While the xylem enables the transport of water to the stems and leaves, the phloem helps transport sugars, made from photosynthesis, to the rest of the plant. Additionally, only xylem cells are lined with lignin — supportive structural materials that provide rigidity to wood and bark. The researchers wanted to understand how these vascular systems evolved in ferns and how lignin is made.
“Ferns are the earliest vascular plants, and lignified cell walls were a key innovation during the evolution of these plants,” said Ray Ming (GEGC), a professor of plant biology. “This study has improved our understanding of how vascular tissues developed in ferns and other land plant species.”
For this study, the researchers sequenced the genome of flying spider-monkey tree fern Alsophila spinulosa and investigated how its vascular tissues are constructed. They found that two Vascular-related Mac-Domain genes were highly expressed in xylem compared to other tissues, indicating that these might be key regulators in the formation of xylem-specific cells.
Using microscopy and biochemical methods, the researchers also measured the levels of lignin and secondary metabolites — compounds that are not required for growth or reproduction, but confer certain benefits — in ferns. They found that lignin made up 40% of the stem cell wall. In comparison, wood generally contains 25%. They also discovered a new secondary metabolite primarily made in the xylem, which they named “alsophilin.”
“This new compound is abundant in the xylem, likely as one of the compounds filling up the cavity of non-functional tracheid cells. We also identified the genes involved in the biosynthesis of alsophilin in the genome,” Ming said.
To understand how ferns evolved, the researchers compared the genomic sequence of A. spinulosa to other members of the same species across nine locations in China. To their surprise, they discovered that there were six distinct populations, differing in their genomic sequences. Based on their sequencing results, the researchers reconstructed the history of the fern population and saw that there were two times that these species underwent a drastic decrease in population numbers. The first one occurred 35.6–34.5 million years ago and the second occurred 2.5–0.7 million years ago.
“This analysis of genomes and lignin composition from a broader collection of ferns will help us understand the role of lignin in the early lineage of vascular plants,” Ming said. “In our future studies, we hope to increase the number of locations and the sample sizes for the genomic analysis.”
Lymphatics act as a signaling hub to regulate intestinal stem cell activity
by Rachel E. Niec, Tinyi Chu, Marina Schernthanner, Shiri Gur-Cohen, Lynette Hidalgo, Hilda Amalia Pasolli, Kathleen A. Luckett, Zhong Wang, Sohni R. Bhalla, Francesco Cambuli, Raghu P. Kataru, Karuna Ganesh, Babak J. Mehrara, Dana Pe’er, Elaine Fuchs in Cell Stem Cell
To act as a robust barrier against pathogens while also absorbing needed nutrients, the lining of the intestines must regenerate on a daily basis to remain equal to the task. The intestine’s resident stem cells are responsible for meeting this need for constant repair and replenishment, but each stem cell faces decisions that depend on the overall conditions of the intestine and the needs of the moment. Bad decisions and poor coordination could result in intestinal diseases or cancer.
A new study suggests that stem cells are able to integrate cues from their surroundings and coordinate their behavior across the tissue through networks of vasculature in their close vicinity. Rockefeller scientists found that lymphatic capillaries — fine vessels that transport immune cells and drain fluids from tissues — represent a signaling hub that communicates with stem cells to regulate their activity. With molecular guidance from the lymphatics, the stem cells produce daughter cells to repopulate the intestinal lining or self-renew to restock the stem cell reserve.
The finding provide new insights about primary intestinal components whose disrupted communication may contribute to intestinal disorders, such as inflammatory bowel disease. “The key to treating these diseases will be to figure out who talks to whom in this ecosystem and how we can reset the communication networks,” says Rachel Niec, a clinical scholar in the laboratory of Elaine Fuchs.
The intestinal stem cells reside in so-called crypts, found at the base of densely packed indentations in the intestinal lining. The stem cells may renew and stay in the crypt, or differentiate into specialized cells, which then migrate out of the crypt to replenish the gut lining. “To understand how stem cells balance self-renewal with differentiation, we needed a more complete picture of crypt niches,” says Marina Schernthanner, a graduate student in the Fuchs lab.
To zoom in on the crypt, the team used a suite of techniques, including single-cell and spatial transcriptomics, which allowed them to identify cell types at specific locations and study their signaling molecules. The results showed that lymphatic capillaries, which form an intimate connection with the stem cells in the crypt, produce a number of proteins known to be important for stem cell functioning.
One previously underappreciated protein, REELIN, emerged as a top candidate for mediating communications between lymphatics and stem cells. By manipulating the amount of REELIN in lab-grown intestinal organoid cultures in some experiments and genetically suppressing it in mice in others, the researchers found that REELIN directly governs the regenerative behavior of intestinal stem cells.
The involvement of the lymphatic system in stem cell functioning is a relatively new concept. A previous study by the Fuchs team revealed that lymphatics are also closely involved with stem cells of the skin and play a key role in hair regeneration. There, however, it is the hair follicle stem cells that signal to lymphatic capillaries. By controlling their interactions with lymphatics, the stem cells synchronize hair regeneration across the tissue. “This suggests that lymphatics may be a conserved feature of stem cell niches, but their relationship to stem cells are likely tailored around the needs of each tissue,” Niec says.
Systematic Functional Annotation Workflow for Insects
by Hidemasa Bono, Takuma Sakamoto, Takeya Kasukawa, Hiroko Tabunoki in Insects
Genome sequencing, where scientists use laboratory methods to determine a specific organism’s genetic makeup, is becoming a common practice in insect research. A greater understanding of insect biology helps scientists better manage insects, both those that are beneficial to the ecosystem and those that damage the food supply and threaten human health by carrying diseases.
Researchers have developed a work-flow method, called Fanflow4Insects, that annotates gene functions in insects. In functional annotation, scientists collect information about a gene’s biological identity. The team’s new method uses transcribed sequence information as well as genome and protein sequence databases. With Fanflow4Insects, the team has annotated the functional information of the Japanese stick insect and the silkworm, including gene expression as well as sequence analysis. The functional annotation information that their workflow provides will greatly expand the possibilities of entomological research using genome editing. The team, with scientists from Hiroshima University, Tokyo University of Agriculture and Technology, and RIKEN Center for Integrative Medical Sciences, has published their Fanflow4Insects method.
Insects are so diverse and abundant that scientists need a way of studying them on a large scale. This is what led scientists to begin work on sequencing the genome of insects. As of May 2022, scientists had decoded and registered the genomes of around 3000 insect species. They are also using long-read sequencing technology to further accelerate the pace of insect genome sequencing.
Next-generation sequencing has made it easier for researchers to decode the genomes of numerous insects along with their transcript sequences. However, the biological interpretation of these sequences remains a primary bottleneck of transcriptome analysis. The transcriptome is the sum of an organism’s RNA molecules. Transcriptome analysis is an important first step in functional annotation, which serves as an important clue for selecting genome editing targets.
Because some insects have genomes larger than the human genome, the difficult process of whole-genome sequencing is even more complicated. So scientists are using transcriptome sequencing with next-generation sequencing technology, also called RNA sequencing, as a tool for evaluating large genome-size insects. With this powerful tool, scientists can efficiently identify tens of thousands of possible genes in a specific tissue by assembling tens of millions of reads. They then assemble the gene sequences into transcriptional units for identification. But this type of analyses is dependent upon the scientists having access to comprehensive datasets and their functional annotation. Databases do exist, but they are unable to keep pace with the increase in insect genome sequencing.
As transcriptome analysis becomes more popular, many research groups are running their own pipelines, with the information regarding the transcription units from various studies being reported on a study-by-study basis. These pipelines are sets of algorithms used to processes the genome sequencing data. But scientists need a way to integrate the functional annotation from all the different groups doing this type of research into public databases.
In this current study, the research team used their newly developed Fanflow4Insects to create a functional annotation pipeline for the silkworm. Then the researchers also tested Fanflow4Insects for the transcriptomes of the Japanese stick insect. “Functional annotation is one of the most important processes to accelerate the selection of target genes once genome or transcriptome of the target organism is decoded. The functional annotation information obtained by the workflow Fanflow4Insects will greatly expand the possibilities of entomological research using genome editing,” said Hidemasa Bono, a professor with the Graduate School of Integrated Sciences for Life at Hiroshima University, and the first and corresponding author on the paper.
The Fanflow4Insects workflow for insects has been openly developed on GitHub, and is freely accessible. In conjunction with the functional annotation derived from expression, the data from Fanflow4Insects can be applied to the comparative study of insects with distinct phenotypes. “Using Fanflow4Insects, we are going to annotate insects that produce useful substances. The ultimate goal of this study is to make it possible to design molecular networks in insects using computer simulation,” said Bono.
The Gr64 cluster of gustatory receptors promotes survival and proteostasis of epithelial cells in Drosophila
by Michael E. Baumgartner, Alex Mastrogiannopoulos, Iwo Kucinski, Paul F. Langton, Eugenia Piddini in PLOS Biology
A set of genes that promote sweet taste sensation is also crucial for protein management during fly development, according to a new study by Eugenia Piddini of the University of Bristol, United Kingdom, and colleagues. The finding expands the understanding of a key process in successful development, and suggests a connection between taste-related genes and disorders of protein aggregation.
Protein homeostasis, or proteostasis, is the set of processes that maintain cellular proteins in a functional state, and eliminate damaged proteins that cannot be repaired. Ribosomes are multi-protein molecular machines that synthesize proteins, and mutations in genes that encode ribosomal proteins not only impair protein synthesis but also disrupt proteostasis, leading to chronic proteotoxic stress. That stress, in turn, has a host of cellular consequences and results in delayed development and other irregularities.
To better understand the disorders caused by such disruption of proteostasis, the authors compared gene expression in normal versus ribosomal protein mutant flies during the pupal stage of development. Unexpectedly, they found that a group of genes encoding six gustatory (taste) receptors, called Gr64 genes, were upregulated in the mutant cells.
This finding was unexpected because the Gr64 receptors had previously been known to be present in adult fly neurons, where they help the animal taste sugars, fatty acids, and glycerol. In ribosomal protein mutant flies with just one (rather than two) working copies of the Gr64 genes, there was an increase in cell death via a process called apoptosis. Complete elimination of the Gr64 genes induced multiple morphological defects in the ribosomal mutants, but had little to no effect in cells with normal ribosomal proteins.
Cells bearing ribosomal protein mutants are at a disadvantage compared to normal cells, and are often eliminated in developing tissue where both occur. Mutants carrying only one set of Gr64 genes were even worse off, the authors found, losing out to normal cells at an even greater rate. When the level of Gr64 proteins was variably and quantitatively reduced, the team showed that the most direct effect of reduction was on the function of the proteasome and autophagosome, two different routes by which damaged proteins are removed and recycled.
The connection between promotion of proteostasis and the sense of taste is likely through the molecular mechanism of the Gr64 proteins, which regulate calcium flow; changes in calcium levels are used as a signal transducer in sensory cells, and also regulate multiple proteostatic processes, including both proteosome function and autophagy. Intriguingly, dysregulated and out-of-place gustatory and olfactory receptors have been detected in the affected brain tissue in several human diseases characterized by loss of protein homeostasis, including Alzheimer’s disease and Parkinson’s disease.
“Our work suggests that gustatory receptors play a previously unrecognized role in maintaining protein homeostasis during development in the fly,” Piddini said, “and points more generally toward the connection between calcium-modulating proteins and disorders of protein aggregation and proteotoxic stress.”
Piddini adds, “What I find truly fascinating about our findings is that they underscore the little we understand about how cells adapt to cope with proteotoxic stress. Our experimental strategy could be used further as a way to search and discover additional new proteostasis genes.”
Coauthor Michael Baumgartner concludes, “These findings emphasize an important theme in cell biology: context is everything. It’s easy to see the name ‘gustatory receptor’ and think that’s the end of the story, but evolution can and will repurpose almost anything if it ends up being advantageous. This highlights the possibility that the seemingly hyper-specialized gustatory receptors might be more flexible than previously appreciated.”
A DNA origami rotary ratchet motor
by Anna-Katharina Pumm, Wouter Engelen, Enzo Kopperger, Jonas Isensee, Matthias Vogt, Viktorija Kozina, Massimo Kube, Maximilian N. Honemann, Eva Bertosin, Martin Langecker, Ramin Golestanian, Friedrich C. Simmel, Hendrik Dietz in Nature
A research team led by the Technical University of Munich (TUM) has succeeded for the first time in producing a molecular electric motor using the DNA origami method. The tiny machine made of genetic material self-assembles and converts electrical energy into kinetic energy. The new nanomotors can be switched on and off, and the researchers can control the rotation speed and rotational direction.
Be it in our cars, drills or the automatic coffee grinders — motors help us perform work in our everyday lives to accomplish a wide variety of tasks. On a much smaller scale, natural molecular motors perform vital tasks in our bodies. For instance, a motor protein known as ATP synthase produces the molecule adenosine triphosphate (ATP), which our body uses for short-term storage and transfer of energy.
While natural molecular motors are essential, it has been quite difficult to recreate motors on this scale with mechanical properties roughly similar to those of natural molecular motors like ATP synthase. A research team has now constructed a working nanoscale molecular rotary motor using the DNA origami method. The team was led by Hendrik Dietz, Professor of Biomolecular Nanotechnology at TUM, Friedrich Simmel, Professor of Physics of Synthetic Biological Systems at TUM, and Ramin Golestanian, director at the Max Planck Institute for Dynamics and Self-Organization.
The novel molecular motor consists of DNA — genetic material. The researchers used the DNA origami method to assemble the motor from DNA molecules. This method was invented by Paul Rothemund in 2006 and was later further developed by the research team at TUM. Several long single strands of DNA serve as a basis to which additional DNA strands attach themselves to as counterparts. The DNA sequences are selected in such a way that the attached strands and folds create the desired structures.
“We’ve been advancing this method of fabrication for many years and can now develop very precise and complex objects, such as molecular switches or hollow bodies that can trap viruses. If you put the DNA strands with the right sequences in solution, the objects self-assemble,” says Dietz.
The new nanomotor made of DNA material consists of three components: base, platform and rotor arm. The base is approximately 40 nanometers high and is fixed to a glass plate in solution via chemical bonds on a glass plate. A rotor arm of up to 500 nanometers in length is mounted on the base so that it can rotate. Another component is crucial for the motor to work as intended: a platform that lies between the base and the rotor arm. This platform contains obstacles that influence the movement of the rotor arm. To pass the obstacles and rotate, the rotor arm must bend upward a little, similar to a ratchet.
Without energy supply, the rotor arms of the motors move randomly in one direction or the other, driven by random collisions with molecules from the surrounding solvent. However, as soon as AC voltage is applied via two electrodes, the rotor arms rotate in a targeted and continuous manner in one direction.
“The new motor has unprecedented mechanical capabilities: It can achieve torques in the range of 10 piconewton times nanometer. And it can generate more energy per second than what’s released when two ATP molecules are split,” explains Ramin Golestanian, who led the theoretical analysis of the mechanism of the motor.
The targeted movement of the motors results from a superposition of the fluctuating electrical forces with the forces experienced by the rotor arm due to the ratchet obstacles. The underlying mechanism realizes a so-called “flashing Brownian ratchet.” The researchers can control the speed and direction of the rotation via the direction of the electric field and also via the frequency and amplitude of the AC voltage.
“The new motor could also have technical applications in the future. If we develop the motor further we could possibly use it in the future to drive user-defined chemical reactions, inspired by how ATP synthase makes ATP driven by rotation. Then, for example, surfaces could be densely coated with such motors. Then you would add starting materials, apply a little AC voltage and the motors produce the desired chemical compound,” says Dietz.
Second law of information dynamics
by Melvin M. Vopson, S. Lepadatu in AIP Advances
Genetic mutations could be predicted before they occur using a new law of physics, according to a study from the University of Portsmouth.
The paper finds the second law of information dynamics, or ‘infodynamics’, behaves differently to the second law of thermodynamics — a discovery that could have massive implications for future developments in genome research, evolutionary biology, computing, big data, physics, and cosmology. Lead author Dr Melvin Vopson is from the University’s School of Mathematics and Physics. He said: “In physics, there are laws that govern everything that happens in the universe, for example how objects move, how energy flows, and so on. Everything is based on the laws of physics.
“One of the most powerful laws is the second law of thermodynamics, which establishes that entropy — a measure of disorder in an isolated system — can only increase or stay the same, but it will never decrease.”
This is an undisputed law linked to the arrow of time, which shows that time only goes one way. It flows in a single direction and can’t go backwards. He said: “Imagine two transparent glass boxes. In the left side you have red gas molecules, which you can see, like red smoke. In the right side, you have blue smoke, and in between them is a barrier. If you remove the barrier, the two gases will start mixing and the colour will change. There is no process that this system can undergo to separate by itself blue and red again.
“In other words, you cannot lower the entropy or organise the system to how it was before without energy expense, because the entropy only stays constant or increases over time.”
Dr Vopson is an information physicist. His work explores information systems, which can be anything from the disc in a laptop to the DNA and RNA in living organisms. This paper was written in collaboration with Dr Serban Lepadatu from the University of Central Lancashire.
Dr Vopson added: “If the second law of thermodynamics states that entropy needs to stay constant or increase over time, I thought that perhaps information entropy would be the same. “But what Dr Lepadatu and I found was the exact opposite — it decreases over time. The second law of information dynamics works exactly in opposition to the second law of thermodynamics.”
Dr Vopson claims this could be what drives genetic mutations in biological organisms. “The worldwide consensus is that mutations take place at random and then natural selection dictates whether the mutation is good or bad for an organism,” he explained. If the mutation is beneficial for an organism, it will be kept.
“But what if there is a hidden process that drives these mutations? Every time we see something we don’t understand, we describe it as ‘random’ or ‘chaotic’ or ‘paranormal’, but it’s only our inability to explain it.
“If we can start looking at genetic mutations from a deterministic point of view, we can exploit this new physics law to predict mutations — or the probability of mutations — before they take place.”
Dr Vopson and colleagues analysed real Covid-19 (Sars-CoV-2) genomes and found that their information entropy decreased over time: “The best example of something that undergoes a number of mutations in a short space of time is a virus. The pandemic has given us the ideal test sample as Sars-CoV-2 mutated into so many variants and the data available is unbelievable.
“The Covid data confirms the second law of infodynamics and the research opens up unlimited possibilities. Imagine looking at a particular genome and judging whether a mutation is beneficial before it happens. This could be game-changing technology which could be used in genetic therapies, the pharmaceutical industry, evolutionary biology, and pandemic research.”
Aerosol capture and coronavirus spike protein deactivation by enzyme functionalized antiviral membranes
by Rollie Mills, Ronald J. Vogler, Matthew Bernard, Jacob Concolino, Louis B. Hersh, Yinan Wei, Jeffrey Todd Hastings, Thomas Dziubla, Kevin C. Baldridge, Dibakar Bhattacharyya in Communications Materials
A team of University of Kentucky researchers led by College of Engineering Professor Dibakar Bhattacharyya, Ph.D., and his Ph.D. student, Rollie Mills, have developed a medical face mask membrane that can capture and deactivate the SARS-CoV-2 spike protein on contact.
At the beginning of the COVID-19 pandemic in 2020, Bhattacharyya, known to friends and colleagues as “DB,” along with collaborators across disciplines at UK, received a grant from the National Science Foundation (NSF) to create the material.
SARS-CoV-2 is covered in spike proteins, which allow the virus to enter host cells once in the body. The team developed a membrane that includes proteolytic enzymes that attach to the protein spikes and deactivate them.
“This new material can filter out the virus like the N95 mask does, but also includes antiviral enzymes that completely deactivate it. This innovation is another layer of protection against SARS-CoV-2 that can help prevent the virus from spreading,” said DB, the director of UK’s Center of Membrane Sciences. “It’s promising to the development new products that can protect against SARS-CoV-2 and a number of other human pathogenic viruses.”
The team developed the membrane, which was fabricated through an existing collaboration with a large-scale membrane manufacturer. It was then tested using SARS-CoV-2 spike proteins that were immobilized on synthetic particles. Not only could the material filter out coronavirus-sized aerosols, but it was also able to destroy the spike proteins within 30 seconds of contact.
The study reports that the membrane provided a protection factor above the Occupational Safety and Health Administration’s standard for N95 masks, meaning that it could filter at least 95% of airborne particles.
“These membranes have been proven to be a promising system of advancement toward the new generation of respiratory face masks and enclosed-environment filters that can significantly reduce coronavirus transmission by virus protein deactivation and enhanced aerosol particle capture,” the study reports.
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