TL;DR
- Biologists discovered that a mutation in the ROR2 gene is linked to beak size reduction in numerous breeds of domestic pigeons. Surprisingly, different mutations in ROR2 also underlie a human disorder called Robinow syndrome. The ROR2 signaling pathway plays an important role in the craniofacial development of all vertebrates.
- A new study details how an established physics theory governing bubble and droplet formation led to a new understanding of the principles organizing the contents of living cells. The work marks a seismic shift in researchers’ ability both to understand and control the complex soft materials within our cells.
- Studying a species of beetle mite, an international research team has demonstrated for the first time that animals can survive over very long periods of time (possibly millions of years) entirely without sex.
- New ‘reporter viruses’ developed by researchers make it much easier to observe SARS-CoV-2 and its variants in cells and live animals in the lab, enabling faster screening of potential anti-viral drugs, vaccines and neutralizing antibodies.
- Researchers seek to point a way toward a unified theory for how DNA changes shape when expressing genes. The scientists use an approach called statistical mechanics to explore the phenomenon of so-called expression waves of gene regulation. The group hopes to reconcile a long-standing gulf between the two scientific fields most involved in the topic, using concepts common to biology and physics.
- Cancer cells proliferate despite a myriad of stresses that would kill any ordinary cell. Now, researchers have gained insight into how they may be doing this through the downstream activity of a powerful estrogen receptor. The discovery offers clues to overcoming resistance to therapies like tamoxifen that are used in many types of breast cancer.
- Researchers have developed a microneedle patch that delivers a COVID-19 DNA vaccine into the skin, causing strong immune responses in cells and mice. Importantly, the patch can be stored for over 30 days at room temperature.
- Machine learning can pinpoint ‘genes of importance’ that help crops to grow with less fertilizer, according to a new study. It can also predict additional traits in plants and disease outcomes in animals, illustrating its applications beyond agriculture.
- Researchers have discovered how Rift Valley fever virus enters cells, pointing the way to new therapies to treat deadly Rift Valley fever.
- A protein acts as a molecular switch with a crucial role in determining whether we feel hungry or full. By determining of the protein’s 3D structure, researchers were able to visualize the molecular structures of the hormones with which this protein — melanocortin 4 receptor (MC4R) — interacts.
- 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
A ROR2 coding variant is associated with craniofacial variation in domestic pigeons
by Elena F. Boer, Hannah F. Van Hollebeke, Emily T. Maclary, Carson Holt, Mark Yandell, Michael D. Shapiro in Current Biology
Biologists discovered that a mutation in the ROR2 gene is linked to beak size reduction in numerous breeds of domestic pigeons. Surprisingly, different mutations in ROR2 also underlie a human disorder called Robinow syndrome. The ROR2 signaling pathway plays an important role in the craniofacial development of all vertebrates.
Charles Darwin was obsessed with domestic pigeons. He thought they held the secrets of selection in their beaks. Free from the bonds of natural selection, the 350-plus breeds of domestic pigeons have beaks of all shapes and sizes within a single species (Columba livia). The most striking are beaks so short that they sometimes prevent parents from feeding their own young. Centuries of interbreeding taught early pigeon fanciers that beak length was likely regulated by just a few heritable factors. Yet modern geneticists have failed to solve Darwin’s mystery by pinpointing the molecular machinery controlling short beaks — until now.
In a new study, biologists from the University of Utah discovered that a mutation in the ROR2 gene is linked to beak size reduction in numerous breeds of domestic pigeons. Surprisingly, mutations in ROR2 also underlie a human disorder called Robinow syndrome.
“Some of the most striking characteristics of Robinow syndrome are the facial features, which include a broad, prominent forehead and a short, wide nose and mouth, and are reminiscent of the short-beak phenotype in pigeons,” said Elena Boer, lead author of the paper who completed the research as a postdoctoral fellow at the U and is now a clinical variant scientist at ARUP Laboratories. “It makes sense from a developmental standpoint, because we know that the ROR2 signaling pathway plays an important role in vertebrate craniofacial development.”
The researchers bred two pigeons with short and medium beaks — the medium-beaked male was a Racing Homer, a bird bred for speed with a beak length similar to the ancestral rock pigeon. The small-beaked female was an Old German Owl, a fancy pigeon breed that has a little, squat beak.
“Breeders selected this beak purely for aesthetics to the point that it’s detrimental — it would never appear in nature. So, domestic pigeons are a huge advantage for finding genes responsible for size differences,” said Michael Shapiro, the James E. Talmage Presidential Endowed Chair in Biology at the U and senior author of the paper. “One of Darwin’s big arguments was that natural selection and artificial selection are variations of the same process. Pigeon beak sizes were instrumental in figuring out how that works.”
The short- and medium-beaked parents produced an initial F1 brood of children with intermediate-length beaks. When the biologists mated the F1 birds to one another, the resulting F2 grandchildren had beaks ranging from big to little, and all sizes in between. To quantify the variation, Boer measured beak size and shape in the 145 F2 individuals using micro-CT scans generated at the University of Utah Preclinical Imaging Core Facility.
“The cool thing about this method is that it allows us to look at size and shape of the entire skull, and it turns out that it’s not just beak length that differs — the braincase changes shape at the same time,” Boer said. “These analyses demonstrated that beak variation within the F2 population was due to actual differences in beak length and not variation in overall skull or body size.”
Next, the researchers compared the pigeons’ genomes. First, using a technique called quantitative trait loci (QTL) mapping, they identified DNA sequence variants scattered throughout the genome, and then looked to see if those mutations appeared in the F2 grandkids’ chromosomes.
“The grandkids with small beaks had the same piece of chromosome as their grandparent with the small beak, which told us that piece of chromosome has something to do with small beaks,” said Shapiro. “And it was on the sex chromosome, which classical genetic experiments had suggested, so we got excited.”
The team then compared the entire genome sequences of many different pigeon breeds; 56 pigeons from 31 short-beaked breeds and 121 pigeons from 58 medium- or long-beaked breeds. The analysis showed that all individuals with small beaks had the same DNA sequence in an area of the genome that contains the ROR2 gene.
“The fact that we got the same strong signal from two independent approaches was really exciting and provided an additional level of evidence that the ROR2 locus is involved,” said Boer.
The authors speculate that the short-beak mutation causes the ROR2 protein to fold in a new way, but the team plans to do functional experiments to figure out how the mutation impacts craniofacial development.
The lure of the domestic pigeon that mesmerized Darwin is still captivating the curious to this day. Many of the blood samples that the research team used for genome sequencing were donated from members of the Utah Pigeon Club and National Pigeon Association, groups of pigeon enthusiasts who continue to breed pigeons and participate in competitions to show off the striking variation among breeds.
“Every paper our lab has published in the last 10 years has relied on their samples in some way,” said Shapiro. “We couldn’t have done this without the pigeon breeding community.”
Nucleation landscape of biomolecular condensates
by Shimobayashi, S.F., Ronceray, P., Sanders, D.W. et al.in Nature
The heady math that describes how bubbles form in a glass of Champagne has inspired a framework for engineering living cells.
A study details how an established physics theory governing bubble and droplet formation led to a new understanding of the principles organizing the contents of living cells. The work marks a seismic shift in researchers’ ability both to understand and control the complex soft materials within our cells.
“This approach is common in materials science, but we’ve adapted it to do something unprecedented in cells,” said principal investigator Clifford Brangwynne, the June K. Wu ’92 Professor in Engineering and director of the Princeton Bioengineering Initiative.
The current work follows Brangwynne’s discovery more than a decade ago that cellular proteins organize into liquid structures inside the cell. That insight gave rise to a new field of study examining how parts of cells form much like oil drops coalescing in water. Scientists have puzzled ever since over the exact details of how those structures assemble. But it’s a hard thing to measure the squishy dynamics of individual molecules inside a cell, where mysterious, overlapping processes roil chaotically as minute structures form and dissolve a thousand times per second.
Postdoctoral researcher Shunsuke Shimobayashi had studied soft matter physics at the Kyoto University and wondered whether his background working on organic compounds called lipids might illuminate anything interesting about the problem. If protein molecules condense out of their surroundings the way oil separates from water, maybe the math that described the first steps in that process, called nucleation, would prove useful in proteins as well.
Shimobayashi turned to classical nucleation theory, a pillar of materials science. Its equations had powered some of the most profound technological transformations of the 20th century, from the climate models that first revealed global warming to the fertilizers that helped lift billions of people out of starvation.
He was also keenly aware of a critical distinction: those equations describe simple, inanimate systems, but the inside of a cell is in turmoil. “It’s a much more complex material environment for biomolecules,” Shimobayashi said. But he pushed ahead, collaborating with theorists Pierre Ronceray and Mikko Haataja, professor of mechanical and aerospace engineering. The researchers stripped the theory down to its two most important parameters, adapting it to try to understand how the process might work in cells. Then to test the theory, Shimobayashi turned to an advanced protein tool developed in Brangwynne’s lab in 2018 that provided an ideal, simplified system that mimics how the process occurs naturally in cells. Putting them together, the results came as something of a shock.
When Shimobayashi tried to induce the droplets to seed instantaneously, the system failed. But when he seeded the droplets more slowly, they nucleated at precisely defined locations, in a way that lined up perfectly with his adapted theory. He had predicted how, where and when the protein droplets formed with what Brangwynne called “remarkable accuracy.”
The team next turned back to the messy complexity of native cell structures. When they accounted for all the processes that act on protein concentrations, they found that the theory worked just as well. They had quantified the molecule-by-molecule assembly of proteins into the complex liquid structures that regulate life’s most basic routines. Not only do these structures look and act like oil in water, Shimobayashi said, they also form droplets in the same basic nucleation patterns, clustering around minute variations in their environment at rates that can be predicted with the same quantitative precision as other kinds of materials.
With that predictive power comes an accelerated engineering capacity, according to Brangwynne. He believes quantifying biomolecular processes and developing predictive models in the mold of physics will lead to a world in which we no longer watch passively as our loved ones succumb to diseases like Alzheimer’s.
“We first have to understand how it works, with quantitative mathematical frameworks that are the bedrock of society’s engineering marvels. And then we can take the next steps, to manipulate biological systems with greater control,” Brangwynne said. “We need to be able to turn the knobs.”
Haplotype divergence supports long-term asexuality in the oribatid mite Oppiella nova
by Alexander Brandt, Patrick Tran Van, Christian Bluhm, Yoann Anselmetti, Zoé Dumas, Emeric Figuet, Clémentine M. François, Nicolas Galtier, Bastian Heimburger, Kamil S. Jaron, Marjorie Labédan, Mark Maraun, Darren J. Parker, Marc Robinson-Rechavi, Ina Schaefer, Paul Simion, Stefan Scheu, Tanja Schwander, Jens Bast in Proceedings of the National Academy of Sciences
In the framework of an international research project, a team of scientists have demonstrated for the first time that asexual reproduction can be successful in the long term. The animal they studied is the beetle mite Oppiella nova. Until now, the survival of an animal species over a geologically long period of time without sexual reproduction was considered very unlikely, if not impossible. However, the team of zoologists and evolutionary biologists from the Universities of Cologne and Göttingen as well as the University in Lausanne (Switzerland) and the University of Montpellier (France), demonstrated for the first time the so-called Meselson effect in animals in the ancient asexual beetle mite species O. nova. The Meselson effect describes a characteristic trace in the genome of an organism that suggests purely asexual reproduction.
So far, scientists have seen the great evolutionary advantage of sexual reproduction in the genetic diversity produced in offspring by the encounter of two different genomes that a pair of parents can supply. In organisms with two sets of chromosomes, i.e. two copies of the genome in each of their cells, such as humans and also beetle mite species that reproduce sexually, sex ensures a constant ‘mixing’ of the two copies. That way, genetic diversity between different individuals is ensured, but the two copies of the genome within the same individual remain on average very similar.
However, it is also possible for asexually reproducing species, which produce genetic clones of themselves, to introduce genetic variance into their genomes and thus adapt to their environment during evolution. But (contrasting sexual species) the lack of sexual reproduction and thus ‘mixing’ in asexual species causes the two genome copies to independently accumulate mutations, or changes in genetic information, and become increasingly different within one individual: the two copies evolve independently of one another. The Meselson effect describes the detection of these differences in the chromosome sets of purely asexual species. ‘That may sound simple. But in practice, the Meselson effect has never been conclusively demonstrated in animals — until now,’ explained Prof. Tanja Schwander from the Department of Ecology and Evolution of the University of Lausanne.
The existence of ancient asexual animal species like O. nova are difficult for evolutionary biologists to explain because asexual reproduction seems to be very disadvantageous in the long run. Why else do almost all animal species reproduce purely sexually? Animal species such as O. nova, which consist exclusively of females, are therefore also called ‘ancient asexual scandals.’ Proving that the ancient asexual scandals really do reproduce exclusively asexually, as hypothesized (and that they have been doing so for a very long time), is a very complex undertaking: According to first author of the study Dr Alexander Brandt of the University of Lausanne, ‘There could be, for example, some kind of “cryptic” sexual exchange that is not known. Or not yet known. For example, very rarely a reproductive male could be produced after all — possibly even “by accident.” “ Purely asexual reproduction, however, at least theoretically leaves behind a particularly characteristic trace in the genome: the Meselson effect.
For their study, the researchers collected different populations of Oppiella nova and the closely related, but sexually reproducing species Oppiella subpectinata in Germany and sequenced and analysed their genetic information. ‘A Sisyphean task,’ said Dr Jens Bast, Emmy Noether junior research group leader at the University of Cologne’s Institute of Zoology.
‘These mites are only one-fifth of a millimetre in size and difficult to identify.’ In addition, analysing the genome data required computer programmes specifically designed for this purpose. Hence, Brandt, Schwander and Bast consulted the experienced soil scientist and taxonomer Dr. Christian Bluhm at the Forest Research Institute Baden-Württemberg, Patrick Tran Van, a bioinformatician specializing in evolutionary genomics as well as the soil ecologist Prof. Stefan Scheu from the University of Göttingen.
Their efforts were ultimately rewarded: they succeeded in proving the Meselson effect. ‘Our results clearly show that O. nova reproduces exclusively asexually. When it comes to understanding how evolution works without sex, these beetle mites could still provide a surprise or two,’ Bast concluded. The results show: the survival of a species without sexual reproduction is quite rare, but not impossible. The research team will now try to find out what makes these beetle mites so special.
Exosome-mediated stable epigenetic repression of HIV-1
by Surya Shrivastava, Roslyn M. Ray, Leo Holguin, Lilliana Echavarria, Nicole Grepo, Tristan A. Scott, John Burnett, Kevin V. Morris in Nature Communications
In a new study supported by the National Institutes of Health, researchers used exosomes, tiny nanoparticles capable of being taken up by cells, to deliver novel protein into the cells of mice infected with HIV. The protein attached to HIVs’ genetic material and prevented it from replicating, resulting in reduced levels of HIV in the bone marrow, spleen, and brain. The study paves the way for the development of novel delivery systems for suppressing HIV.
“These results demonstrate the potential of exosome engineering for delivering epigenetics-based therapeutics capable of silencing HIV gene expression into brain tissues — an area where HIV has traditionally been able to hide from HIV treatments,” said Jeymohan Joseph, Ph.D., chief of the HIV Neuropathogenesis, Genetics, and Therapeutics Branch within NIMH’s Division of AIDS Research.
HIV attacks the immune system by infecting a type of white blood cell in the body that is vital to fighting off infection. Without treatment, HIV can destroy these white blood cells, reducing the body’s ability to mount an immune response — eventually resulting in AIDS. Although researchers have been working to develop new therapies to treat and cure HIV and AIDS, this quest is challenging for many reasons. One reason is that HIV can enter a dormant-like state, hiding in the body and evading treatments, only to reactivate at a later date. HIV hiding in the brain is particularly difficult to access, as the blood-brain barrier often prevents treatments from entering into those tissues.
One avenue researchers have been pursuing in their efforts to try to cure HIV is what is sometimes called a “block and lock” approach, particularly for targeting HIV in the brain. This method attempts to block the virus’ ability to replicate itself and lock it in its dormant state.
Kevin Morris, Ph.D., of City of Hope and the Menzies Health Institute Queensland at Griffith University, Australia, led an investigation into a new approach for blocking and locking HIV in mice. The researchers use exosomes, tiny nanoparticles capable of being taken up by cells, to deliver a novel recombinant anti-HIV protein, called ZPAMt, into cells infected with HIV. The ZPAMt protein was designed by researchers to attach to a region of the virus called LTR that is critical for virus replication. The protein has an epigenetic marker in it that changes the way HIVs’ genetic information is expressed, suppressing it, and making the virus unable to divide and multiply. The exosomes are able to cross the blood brain barrier and enter into the brain making this treatment capable of targeting this hard-to-reach organ.
When researchers administered this exosome-based treatment to mice infected with HIV, they found that the exosome-delivered protein was capable of silencing the HIV-infected cells and that the HIV-infected mice showed suppression of HIV expression in the bone marrow, spleen, and brain.
“This exciting body of work demonstrates we can deliver therapeutic payloads to HIV-infected cells systemically using exosomes. This is an innovative technology that could be a future delivery method for use not only in HIV but also for treating various other diseases of the brain such as Parkinson’s, Alzheimer’s, and addiction,” said Dr. Morris.
These findings demonstrate that exosomes can be used to deliver proteins into HIV-infected cells in the body — including the hard-to-reach brain — to silence replication of HIV. In the future, the researchers hope to continue their work by using exosomes to deliver gene-excision machinery capable of cutting the HIV out of the genome of infected people. In addition, they plan to study the use of exosomes to deliver treatments that can assist anti-HIV CAR T-cells in killing HIV-infected cells. Ultimately, the researchers hope to expand the use of exosomes beyond HIV — for instance, to target and control factors associated with drug addiction.
Evolutionarily informed machine learning enhances the power of predictive gene-to-phenotype relationships
by Cheng, CY., Li, Y., Varala, K. et al. in Nature Communications
Machine learning can pinpoint “genes of importance” that help crops to grow with less fertilizer, according to a new study. It can also predict additional traits in plants and disease outcomes in animals, illustrating its applications beyond agriculture.
Using genomic data to predict outcomes in agriculture and medicine is both a promise and challenge for systems biology. Researchers have been working to determine how to best use the vast amount of genomic data available to predict how organisms respond to changes in nutrition, toxins, and pathogen exposure — which in turn would inform crop improvement, disease prognosis, epidemiology, and public health. However, accurately predicting such complex outcomes in agriculture and medicine from genome-scale information remains a significant challenge.
NYU researchers and collaborators in the U.S. and Taiwan tackled this challenge using machine learning, a type of artificial intelligence used to detect patterns in data.
“We show that focusing on genes whose expression patterns are evolutionarily conserved across species enhances our ability to learn and predict ‘genes of importance’ to growth performance for staple crops, as well as disease outcomes in animals,” explained Gloria Coruzzi, Carroll & Milton Petrie Professor in NYU’s Department of Biology and Center for Genomics and Systems Biology and the paper’s senior author.
“Our approach exploits the natural variation of genome-wide expression and related phenotypes within or across species,” added Chia-Yi Cheng of NYU’s Center for Genomics and Systems Biology and National Taiwan University, the lead author of this study. “We show that paring down our genomic input to genes whose expression patterns are conserved within and across species is a biologically principled way to reduce dimensionality of the genomic data, which significantly improves the ability of our machine learning models to identify which genes are important to a trait.”
As a proof-of-concept, the researchers demonstrated that genes whose responsiveness to nitrogen are evolutionarily conserved between two diverse plant species — Arabidopsis, a small flowering plant widely used as a model organism in plant biology, and varieties of corn, America’s largest crop — significantly improved the ability of machine learning models to predict genes of importance for how efficiently plants use nitrogen. Nitrogen is a crucial nutrient for plants and the main component of fertilizer; crops that use nitrogen more efficiently grow better and require less fertilizer, which has economic and environmental benefits.
The researchers conducted experiments that validated eight master transcription factors as genes of importance to nitrogen use efficiency. They showed that altered gene expression in Arabidopsis or corn could increase plant growth in low nitrogen soils, which they tested both in the lab at NYU and in cornfields at the University of Illinois.
“Now that we can more accurately predict which corn hybrids are better at using nitrogen fertilizer in the field, we can rapidly improve this trait. Increasing nitrogen use efficiency in corn and other crops offers three key benefits by lowering farmer costs, reducing environmental pollution, and mitigating greenhouse gas emissions from agriculture,” said study author Stephen Moose, Alexander Professor of Crop Sciences at the University of Illinois at Urbana-Champaign.
Moreover, the researchers proved that this evolutionarily informed machine learning approach can be applied to other traits and species by predicting additional traits in plants, including biomass and yield in both Arabidopsis and corn. They also showed that this approach can predict genes of importance to drought resistance in another staple crop, rice, as well as disease outcomes in animals through studying mouse models.
“Because we showed that our evolutionarily informed pipeline can also be applied in animals, this underlines its potential to uncover genes of importance for any physiological or clinical traits of interest across biology, agriculture, or medicine,” said Coruzzi.
“Many key traits of agronomic or clinical importance are genetically complex and hence it’s difficult to pin down their control and inheritance. Our success proves that big data and systems level thinking can make these notoriously difficult challenges tractable,” said study author Ying Li, faculty in the Department of Horticulture and Landscape Architecture at Purdue University.
Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide
by Heyder N. et al. in Cell Research
A protein — measuring just a few nanometers in size — acts as a molecular switch with a crucial role in determining whether we feel hungry or full. By determining of the protein’s 3D structure, researchers from Charité — Universitätsmedizin Berlin were able to visualize the molecular structures of the hormones with which this protein — melanocortin 4 receptor (MC4R) — interacts. The researchers report that this enabled them to describe the molecular mechanisms involved in the receptor’s activation and inhibition. These new findings could stimulate the development of optimized drugs to treat patients with severe overweight and obesity patients.
Studies exploring the nature of weight control ‘switches’ are more important than ever. We need to be able to treat genetic disorders that result in an inability to feel satiety after eating and which, even in young sufferers, cause severe and difficult-to-treat obesity. At the same time, obesity is one of the most pressing global challenges. Estimates suggest that 1.6 billion adults and 650 million children worldwide are classified as overweight or obese. The condition is associated with an increased risk of comorbidities such as cardiovascular disease and diabetes mellitus. Steadily increasing incidence rates and long-term consequences are driving global research efforts to decipher the mechanisms of appetite regulation at the molecular and ultimately at the atomic level. In addition to exploring the impact of genetic defects on appetite and hunger, research efforts also focus on finding potential targets for drug interventions.
In their recently published study, the team led by Dr. Patrick Scheerer, Head of Protein X-ray Crystallography and Signal Transduction (Scheerer Lab) at Charité’s Institute of Medical Physics and Biophysics, focused on one of the key players in hunger (and therefore weight) control in humans: the melanocortin 4 receptor (MC4R). Primarily found in the brain, this receptor protein is controlled by hormones that produce important satiety signals by binding to it. Activation of MC4R by stimulating hormones (α-/-MSH) results in the feeling of satiety. Conversely, inhibition by the hormone’s natural antagonist, known as Agouti-related protein (AgRP), results in increased hunger feeling. Genetic defects resulting in the functional impairment of this protein ‘switch’ often led to mild or even severe obesity in humans. Prof. Dr. Peter Kühnen, physician-scientist at the Institute of Experimental Pediatric Endocrinology, specializes in the treatment of patients with genetically induced impairments in the transduction of satiety signals. As part of his search for new treatment options for these types of obesity, the endocrinology specialist has devoted extensive efforts to studying the signaling pathways underlying human body weight regulation. He has also explored mutations in the genes encoding the relevant cellular messengers and receptors and analyzed the potential of drugs that might be able to replace individual messengers.
The drug-based treatment of pathologically increased appetite continues to face the same challenge: “To date, all of these pharmacological interventions have been dogged by side effects. These range from abnormal darkening of the skin — the hormone melanocortin also being responsible for skin and hair pigmentation — to cardiovascular events,” says Prof. Kühnen, who was also involved in the current study and whose work supporting the development of new, low-side-effect drugs was awarded the Paul-Martini Prize in 2020. “The reason for these undesirable side effects lies in the nature of the currently available drugs,” explains study lead Dr. Scheerer. He adds: “Instead of addressing a single target, they are usually directed at a range of receptors from the same family which, unfortunately, play different roles in our bodies. The more we know about the interactions between the components involved, the easier it will be to target interventions.”
As part of the current study, the researchers were able to elucidate and visualize the 3D molecular structure of the hormone receptor MC4R, a member of the G-protein-coupled receptor (GPCR) family. Given that the protein’s tiny size is expressed in nanoscale dimensions, conventional optical methods were inadequate for the task. “Using a state-of-the art imaging technology known as cryo-electron microscopy, we were able to visualize the receptor’s three-dimensional structure at a resolution of around 0.26 nanometers” says the study’s first author, Nicolas Heyder, a researcher at the Institute of Medical Physics and Biophysics. “We visualized the structures of two receptor-effector complexes, both of which contain the G-protein which is coupled to the receptor inside the cell. The differences between the two complexes are due to their being bound to two different hormones, namely setmelanotide and NDP-α-MSH. Both received their marketing authorization in the past two years, and both are stabilized by a calcium ion in the hormone binding pocket of MC4R.” In addition, the researchers found that the two receptor structures showed minor yet important differences in the way they bound both the drugs and the G-protein.
“These molecular details provide important information on why and how various ligands — i.e., messenger molecules — exert specific effects on different MC4R signaling pathways. For a pharmacological intervention, this is of major importance,” says Nicolas Heyder.
In their study results, the researchers describe previously unknown details regarding the mechanisms underlying melanocortin 4 receptor function: how it is activated, how it is blocked, and how the interaction between a hormone and the receptor protein produces a signal inside the cell.
“We are now able to identify the smallest differences in the interactions between receptors and hormones. These could prove important for the continued refinement of new drugs which would previously have been associated with side effects,” says Dr. Scheerer. He adds: “Now that the precise structure of the hormone-binding pocket is known, it can be targeted directly.” This is key to the translational use of knowledge on both the endocrinological aspects (in this case hormone regulation) and structural characteristics of interacting proteins.
The research team was able to show that how a previously known receptor-deactivator — or antagonist — binds to the receptor almost identical to the receptor-activating agonist, with only one significant difference. “This difference pinpoints the precise site that blocks the receptor, and which contains a sensitive switch that is responsible for activating the protein,” explains Dr. Scheerer.
ERα is an RNA-binding protein sustaining tumor cell survival and drug resistance
by Yichen Xu, Peiwei Huangyang, Ying Wang, Lingru Xue, Emily Devericks, Hao G. Nguyen, Xiuyan Yu, Juan A. Oses-Prieto, Alma L. Burlingame, Sohit Miglani, Hani Goodarzi, Davide Ruggero in Cell
Cancer cells proliferate despite a myriad of stresses — from oxygen deprivation to chemotherapy — that would kill any ordinary cell. Now, researchers at UC San Francisco have gained insight into how they may be doing this through the downstream activity of a powerful estrogen receptor. The discovery offers clues to overcoming resistance to therapies like tamoxifen that are used in many types of breast cancer.
Estrogen receptor α (ERα) drives more than 70 percent of breast cancers. The new research discovered that in addition to its well-known activity in the nucleus, it can also help malignant cells overcome innate anti-cancer mechanisms and develop resistance to treatment.
In the nucleus, ERα regulates the conversion of DNA to messenger RNA (mRNA), a process known as transcription. Once formed, the mRNA strand travels from the nucleus into the cytoplasm, where it instructs ribosomes to make protein, a process known as translation. To their surprise, the researchers found that ERα plays a role in this process as well by binding to the newly formed mRNA.
“The RNA-centric function of the estrogen receptor has so far been hidden behind its well-established role as a transcription factor, and may have been supporting cancer progression on the sly,” said Yichen Xu, PhD, a postdoctoral fellow in urology at UCSF and the first author of the study.
Using breast cancer cell lines, the research team saw how ERα tends to bind to RNAs, particularly messenger RNAs (mRNAs) involved in cancer progression. Some of these mRNAs keep cells from committing suicide when they accumulate too many harmful mutations. Others help them proliferate under extremely difficult conditions, such as lack of oxygen or nutrients. Still others help them evade therapeutic interventions.
“Cancer cells are constantly being exposed to stress, and these cells have learned to live with it,” said Davide Ruggero, PhD, the senior author of the study, a professor of urology and the Helen Diller Family Endowed Chair in Basic Research at UCSF. “Many compounds used to kill cancer induce stress in the cancer, and most of the cancer cells die. But some eventually find a way to bypass the stress induced by the therapy.”
Endocrine therapies, such as tamoxifen, block the transcription activity of ERα in a cancer cell’s nucleus. Although they can be highly effective at first for most patients with ERα-positive breast cancer, a significant number develop drug resistance.
To understand ERα’s role in this, Ruggero’s team analyzed cancer cells from 14 patients diagnosed with ERα-positive breast cancer and found they had elevated levels of ERα mRNA targets. Then they experimented with breast cancer cell lines that had acquired resistance to tamoxifen, both in tissue culture and in mouse xenografts. Inhibiting the ERα RNA-binding activity restored tamoxifen’s potency against the tumors in mice. It also made the cells in culture more sensitive to stress and apoptosis.
A better understanding of ERα’s many functions could help optimize current treatments — like tamoxifen — as well as lead to new therapeutic targets. Compounds that target translational control in cancer are already in the clinic and can now be tested for potency against breast cancers that are associated with ERα expression.
Much more work needs to be done, however, to really understand how ERα controls RNA biology in the cytoplasm. And other regulators of RNA could yet be discovered.
“One of the reasons why we haven’t cured cancer is because we still don’t fully understand how it works,” Ruggero said. “If we start from the most basic point of view, we might be able to discover new things.”
Lrp1 is a host entry factor for Rift Valley fever virus
by Safder S. Ganaie, Madeline M. Schwarz, Cynthia M. McMillen, David A. Price, Annie X. Feng, Joseph R. Albe, Wenjie Wang, Shane Miersch, Anthony Orvedahl, et. al. in Cell
Rift Valley fever virus causes economically devastating outbreaks of hemorrhagic fever in livestock such as sheep, goats and cattle. These mosquito-borne outbreaks lead to infection in people working with dead or dying animals, sometimes causing hundreds of human cases and dozens of deaths.
Rift Valley fever, for which there is no specific treatment, has been limited to Africa and the Arabian Peninsula. But mosquitoes capable of transmitting the virus can be found all over the world, necessitating a need to understand and control the virus.
Researchers at Washington University School of Medicine in St. Louis and the University of Pittsburgh Center for Vaccine Research and School of Public Health have discovered that the virus gets inside cells by taking advantage of a protein normally involved in taking up low-density lipoproteins (LDL, the carriers of so-called bad cholesterol) from the blood. The discovery could lead to therapies that prevent Rift Valley fever or reduce its impact by interfering with the ability of the virus to get into cells.
“For people in areas where Rift Valley fever is endemic, an outbreak threatens not only their livelihood but their health,” said co-senior author Gaya K. Amarasinghe, PhD, a professor of pathology & immunology and of biochemistry & molecular biophysics at Washington University. “People have a 1% to 2% chance of death if they get infected with this virus, which doesn’t sound like much, but it’s about the same as COVID-19. The disease is much more severe in domesticated animals, especially young animals, which get very ill and die in large numbers. This virus has been flying under the radar, but given that it’s transmitted by mosquitoes that are found everywhere, it could spread into other parts of the world and become a serious issue.”
The World Health Organization has listed Rift Valley fever as a prioritized disease likely to cause epidemics in the near future. The virus spreads easily among domesticated animals via mosquito bite. People also can be infected by mosquito bite, but most people who become infected are workers exposed to infected animal body fluids as they care for sick animals or dispose of their remains.
To find out how the virus invades cells, first author Safder Ganaie, PhD, a postdoctoral researcher who works with Amarasinghe, grew the virus on mouse cells in a dish. By systematically disrupting normal mouse genes, Ganaie and colleagues found that the virus failed to infect mouse cells that lacked certain genes, notably the gene for LDL receptor-related protein 1 (Lrp1). Further experiments showed that the virus needs LRP1 to infect mouse, hamster, cow, monkey and human cells, indicating that the virus uses the same protein across distantly related species.
The finding constitutes an opportunity. If the virus needs LRP1 to infect cells, then temporarily taking LRP1 out of commission may limit its ability to spread in the body, thereby reducing disease. The researchers used a protein that effectively does this. Called RAP, the protein attaches to LRP1 and fends off anything else that tries to attach.
The researchers infected a group of mice with the virus and simultaneously treated them with RAP. A second group of mice also was infected but was left untreated for comparison. Most of the treated mice survived, while all of the untreated mice died. Further, the treated mice had lower levels of virus throughout their bodies on the third day after infection compared with the untreated mice.
RAP itself is not a good prospect for drug development, since it’s a normal mammalian protein that plays a role in many important biological processes. But the results suggest that targeting LRP1 may lead to therapeutics for Rift Valley fever.
“This finding is the key to understanding how Rift Valley fever virus spreads not only throughout the human body but also how it is able to infect mosquitoes and different species of mammals. Knowing how the virus spreads will help us develop targeted therapies, which currently do not exist for Rift Valley fever,” said co-senior author Amy Hartman, PhD, an associate professor of infectious diseases & microbiology at the University of Pittsburgh. “This discovery opens up new opportunities to study virus-host interactions at the cellular and organismal level and enriches our understanding of the basic biology of mosquito-transmitted emerging viruses.”
The discovery that Rift Valley fever virus uses LRP1 to get inside cells is interesting because the protein is better known for its role in cholesterol metabolism. It also is thought to play a role in Alzheimer’s disease and possibly in infections by the intestinal bacterium C. difficile. It’s not clear why these disparate biological processes are linked, but Amarasinghe, Hartman and their collaborators already have several projects underway to explore these connections.
Separable Microneedle Patch to Protect and Deliver DNA Nanovaccines Against COVID-19
by Yue Yin, Wen Su, Jie Zhang, Wenping Huang, Xiaoyang Li, Haixia Ma, Mixiao Tan, Haohao Song, Guoliang Cao, Shengji Yu, Di Yu, Ji Hoon Jeong, Xiao Zhao, Hui Li, Guangjun Nie, Hai Wang in ACS Nano
More than 2 billion people worldwide are fully vaccinated against COVID-19. However, many who live in resource-limited countries haven’t been able to get vaccines, partly because these areas lack temperature-controlled shipping and storage facilities. Now, researchers r have developed a microneedle patch that delivers a COVID-19 DNA vaccine into the skin, causing strong immune responses in cells and mice. Importantly, the patch can be stored for over 30 days at room temperature.
To date, the U.S. Food and Drug Administration has authorized three vaccines for use during the COVID-19 pandemic: one based on protein, and two on RNA. All of them must be kept refrigerated or frozen, which limits their distribution to remote or resource-limited areas. In addition, the vaccines must be administered by a healthcare worker as an injection into a muscle. Because immune cells aren’t typically found in muscles, scientists have investigated various ways to deliver vaccines into the skin, which contains abundant antigen-presenting cells (APCs) and could therefore generate a stronger immune response. Hui Li, Guangjun Nie, Hai Wang and colleagues wanted to develop a microneedle patch that efficiently delivers a COVID-19 vaccine under the skin, causing potent and durable immunity without the need for a cold chain or painful injections.
The researchers based their vaccine on DNA, which is easier to make than RNA or protein. It’s also more stable than RNA. However, in clinical trials, intramuscular DNA vaccines have been limited in their effectiveness because, unlike RNA or protein, the DNA must find its way inside the cell nucleus to work. By delivering the vaccine into APC-rich skin rather than muscle, the researchers reasoned that they could increase the chances that the DNA would enter the nucleus of an APC.
To make their delivery system, the team attached DNA sequences encoding either the SARS-CoV-2 spike protein or nucleocapsid protein to the surface of non-toxic nanoparticles. Inside the nanoparticles was an adjuvant — a molecule that helps stimulate an immune response. Then, the researchers coated a microneedle patch with the vaccine nanoparticles. The small rectangular patch contained 100 biodegradable microneedles, each less than 1/10 the diameter of a bee’s stinger, that could painlessly penetrate the skin’s outer layer. The researchers tested the system in mice, showing that the spike-protein-encoding microneedle patch caused strong antibody and T-cell responses, with no observable side effects. Because the vaccine patches can be stored at room temperature for at least 30 days without losing efficacy, they could be an important tool for developing COVID-19 vaccines with global accessibility, the researchers say.
Self-organization of whole-gene expression through coordinated chromatin structural transition
by Giovanna Zimatore, Masa Tsuchiya, Midori Hashimoto, Andrzej Kasperski, Alessandro Giuliani in Biophysics Reviews
At more than 2 meters long, the human DNA molecule uses intricate folding patterns to fit into cells while locally unfolding to express genes. Such phenomena, however, are difficult to measure in experiments, and theoretical frameworks explaining them continue to be at odds with one another.
Researchers in Italy, Japan, and Poland seek to point a way toward a unified theory for how DNA changes shape when expressing genes. The scientists use an approach called statistical mechanics to explore the phenomenon of so-called expression waves of gene regulation. The group hopes to reconcile a long-standing gulf between the two scientific fields most involved in the topic.
“Many scholars at the crossroad between physics and biology are now approaching what is probably the most crucial puzzle of biology,” said co-author Alessandro Giuliani. “How is it possible that, starting from the same genetic background in the fertilized egg, around 400 highly differentiated cell types can arise, each endowed with a specific physiological role?”
Biology-based theories often center on regulator proteins, called transcription factors, that biochemically conduct a symphony of genes to be expressed together. By contrast, many physicists have focused on expression waves, the rhythmic changes in expression levels across the genome, driven by relaxation and condensing of the DNA molecule itself.
“It is something like the so-called hola, common in soccer and in other sport events, in which the spectators stand up simultaneously giving rise to a ‘wave’ spreading all over the stadium,” Giuliani said.
To get at the heart of the issue, the group focuses on a specific type of cell found in breast cancer with a proven track record of consistently behaving the same way to stimuli.
They used statistical mechanics to make sense of how DNA molecules fold by assessing the collective behavior of a huge number of microscopic players in terms of ensemble properties, unlike classical top-down perspectives, like Newton’s laws. Ultimately, the researchers landed in favor of expression waves, acknowledging that while transcription factors play a vital role, they are second fiddle to the changing shape of DNA.
To unify these two perspectives, the authors present their conclusion using concepts common to biology and physics, limiting the use of mathematics to intuitive approaches such as recurrence quantification analysis and the classical statistical method of principal component analysis.
Next, they look to apply the same approach to identify ecological tipping points based on the makeup of species in particular habitats.
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