TL;DR
- Researchers have developed an injectable therapy based on nanofibers that has enabled paralyzed mice with severe spinal cord injuries to regain the ability to walk.
- Scientists successfully induced gene expression from a DNA and evolution through continuous replication extracellularly using cell-free materials alone for the first time. By adding the genes necessary for transcription and translation to the artificial genomic DNA, it could be possible to develop artificial cells that can grow autonomously, and it will be expected to produce efficient useful substances.
- Researchers using mouse models found that stress hormones suppressed the innate immune system that normally protects the gut from invasive Enterobacteriaceae, a group of bacteria including E. coli which has been linked to Crohn’s disease.
- Scientists are a step closer to breeding plants with genes from only one parent. New research shows the underlying mechanism behind eliminating half the genome and could make for easier and more rapid breeding of crop plants with desirable traits such as disease resistance.
- A team of researchers has demonstrated for the first time one way that a small molecule turns a single cell into something as large as a tree. For half a century, scientists have known that all plants depend on this molecule, auxin, to grow. Until now, they didn’t understand exactly how auxin sets growth in motion.
- Biologists have struggled to study rare and transient muscle cells involved in the process, but engineers have lifted the curtain on these elusive dynamics with the launch of scMuscle, one of the largest single-cell databases of its kind.
- Researchers have identified a new group of molecules that have an antibacterial effect against many antibiotic-resistant bacteria. Since the properties of the molecules can easily be altered chemically, the hope is to develop new, effective antibiotics with few side effects.
- Scientists have engineered bacteria that can detect specific molecules in the gut.
- In a study that builds on earlier research that identified macrophages as essential to regeneration in the axolotl, a highly regenerative salamander, a scientist has identified the source of these critical white blood cells as the liver. By giving scientists a place to look for pro-regenerative macrophages in humans, the discovery brings science a step closer to the ability to regenerate tissues and organs lost to injury or disease.
- Galápagos giant tortoises can weigh well over 300 pounds and often live over 100 years. So what’s the secret to their evolutionary success? A new study concludes that compared with other turtles, these animals evolved to have extra copies of genes — called duplications — that may protect against the ravages of aging, including cancer. Laboratory tests on Galápagos giant tortoise cells corroborate the idea that the animals have developed such defenses.
- 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
Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury
by Z. Álvarez, A. N. Kolberg-Edelbrock, I. R. Sasselli, J. A. Ortega, R. Qiu, Z. Syrgiannis, P. A. Mirau, F. Chen, S. M. Chin, S. Weigand, E. Kiskinis, S. I. Stupp in Science
Northwestern University researchers have developed a new injectable therapy that harnesses “dancing molecules” to reverse paralysis and repair tissue after severe spinal cord injuries.
In a new study, researchers administered a single injection to tissues surrounding the spinal cords of paralyzed mice. Just four weeks later, the animals regained the ability to walk.
By sending bioactive signals to trigger cells to repair and regenerate, the breakthrough therapy dramatically improved severely injured spinal cords in five key ways: (1) The severed extensions of neurons, called axons, regenerated; (2) scar tissue, which can create a physical barrier to regeneration and repair, significantly diminished; (3) myelin, the insulating layer of axons that is important in transmitting electrical signals efficiently, reformed around cells; (4) functional blood vessels formed to deliver nutrients to cells at the injury site; and (5) more motor neurons survived.
After the therapy performs its function, the materials biodegrade into nutrients for the cells within 12 weeks and then completely disappear from the body without noticeable side effects. This is the first study in which researchers controlled the collective motion of molecules through changes in chemical structure to increase a therapeutic’s efficacy.
“Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease,” said Northwestern’s Samuel I. Stupp, who led the study. “For decades, this has remained a major challenge for scientists because our body’s central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease. We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.”
Stupp is Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering at Northwestern, where he is founding director of the Simpson Querrey Institute for BioNanotechnology (SQI) and its affiliated research center, the Center for Regenerative Nanomedicine. He has appointments in the McCormick School of Engineering, Weinberg College of Arts and Sciences and Feinberg School of Medicine.
According to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with a spinal cord injury in the United States. Life for these patients can be extraordinarily difficult. Less than 3% of people with complete injury ever recover basic physical functions. And approximately 30% are re-hospitalized at least once during any given year after the initial injury, costing millions of dollars in average lifetime health care costs per patient. Life expectancy for people with spinal cord injuries is significantly lower than people without spinal cord injuries and has not improved since the 1980s.
“Currently, there are no therapeutics that trigger spinal cord regeneration,” said Stupp, an expert in regenerative medicine. “I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients. Also, new science to address spinal cord injury could have impact on strategies for neurodegenerative diseases and stroke.”
The secret behind Stupp’s new breakthrough therapeutic is tuning the motion of molecules, so they can find and properly engage constantly moving cellular receptors. Injected as a liquid, the therapy immediately gels into a complex network of nanofibers that mimic the extracellular matrix of the spinal cord. By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.
“Receptors in neurons and other cells constantly move around,” Stupp said. “The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibers. By making the molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”
Stupp and his team found that fine-tuning the molecules’ motion within the nanofiber network to make them more agile resulted in greater therapeutic efficacy in paralyzed mice. They also confirmed that formulations of their therapy with enhanced molecular motion performed better during in vitro tests with human cells, indicating increased bioactivity and cellular signaling.
“Given that cells themselves and their receptors are in constant motion, you can imagine that molecules moving more rapidly would encounter these receptors more often,” Stupp said. “If the molecules are sluggish and not as ‘social,’ they may never come into contact with the cells.”
Once connected to the receptors, the moving molecules trigger two cascading signals, both of which are critical to spinal cord repair. One signal prompts the long tails of neurons in the spinal cord, called axons, to regenerate. Similar to electrical cables, axons send signals between the brain and the rest of the body. Severing or damaging axons can result in the loss of feeling in the body or even paralysis. Repairing axons, on the other hand, increases communication between the body and brain.
The second signal helps neurons survive after injury because it causes other cell types to proliferate, promoting the regrowth of lost blood vessels that feed neurons and critical cells for tissue repair. The therapy also induces myelin to rebuild around axons and reduces glial scarring, which acts as a physical barrier that prevents the spinal cord from healing.
“The signals used in the study mimic the natural proteins that are needed to induce the desired biological responses. However, proteins have extremely short half-lives and are expensive to produce,” said Zaida Álvarez, the study’s first author and former research assistant professor in Stupp’s laboratory. “Our synthetic signals are short, modified peptides that — when bonded together by the thousands — will survive for weeks to deliver bioactivity. The end result is a therapy that is less expensive to produce and lasts much longer.”
While the new therapy could be used to prevent paralysis after major trauma (automobile accidents, falls, sports accidents and gunshot wounds) as well as from diseases, Stupp believes the underlying discovery — that “supramolecular motion” is a key factor in bioactivity — can be applied to other therapies and targets.
“The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinson’s disease and Alzheimer’s disease,” Stupp said. “Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signaling could be applied universally across biomedical targets.”
Concurrent evolution of anti-aging gene duplications and cellular phenotypes in long-lived turtles
by Scott Glaberman, Stephanie E Bulls, Juan Manuel Vazquez, Ylenia Chiari, Vincent J Lynch in Genome Biology and Evolution
Galápagos giant tortoises can weigh well over 300 pounds and often live over 100 years. So what’s the secret to their evolutionary success?
A new study concludes that compared with other turtles, these animals evolved to have extra copies of genes — called duplications — that may protect against the ravages of aging, including cancer.
Laboratory tests on Galápagos giant tortoise cells corroborate the idea that the animals have developed such defenses, says Vincent Lynch, an evolutionary biologist at the University at Buffalo.
Specifically, experiments showed that the creatures’ cells are super sensitive to certain types of stress relating to damaged proteins. When exposed to these pressures, the cells self-destruct much more readily than other turtle cells through a process called apoptosis, the research found. Destroying glitchy cells before they have the chance to form tumors could help the tortoises evade cancer, Lynch says.
“In the lab, we can stress the cells out in ways that are associated with aging and see how well they resist that distress. And it turns out that the Galápagos tortoise cells are really, really good at killing themselves before that stress has a chance to cause diseases like cancer,” says Lynch, PhD, associate professor of biological sciences in the UB College of Arts and Sciences.
The findings both confirm and build on results of past research, such as a 2018 study by another team that also used genetic analyses to explore longevity and age-related disease in giant tortoises.
Authors of the new paper in Genome Biology and Evolution include Lynch; Galápagos giant tortoise experts Scott Glaberman, PhD, and Ylenia Chiari, PhD, at George Mason University; Stephanie Bulls at the University of South Alabama, now at George Mason University; and Juan Manuel Vazquez, PhD, at the University of California, Berkeley.
The findings are particularly intriguing because — all things being equal — huge animals that live for a long time should have the highest cancer rates. That’s because big, long-lived things have many more cells, and the more cells a body has, the more opportunities there are for cancerous mutations to arise.
One major focus of Lynch’s work is understanding the biological mechanisms that help big animals like Galápagos tortoises live long and prosper. (His team explored this question in elephants in a 2021 study). The research is driven by simple curiosity. But the findings could have practical implications, too.
“If you can identify the way nature has done something — the way certain species have evolved protections — maybe you can find a way to translate those discoveries into something that benefits human health and disease,” Lynch says. “We’re not going to go treating humans with Galápagos tortoise genes, but maybe we can find a drug that mimics certain important functions.”
“Studies like this demonstrate why preserving biodiversity is so important,” says Glaberman, the paper’s first author and an assistant professor of environmental science and policy at George Mason University. “Extreme species like Galápagos giant tortoises probably hold many secrets for dealing with major human challenges like aging and cancer, and even climate change. Our study also shows that even within turtles, different species look, act and function differently, and losing any species to extinction means that a piece of unique biology will be lost to the world forever.”
Epigenetically mismatched parental centromeres trigger genome elimination in hybrids
by Mohan P. A. Marimuthu, Ravi Maruthachalam, Ramesh Bondada, Sundaram Kuppu, Ek Han Tan, Anne Britt, Simon W. L. Chan, Luca Comai in Science Advances
Scientists are a step closer to breeding plants with genes from only one parent. New research led by plant biologists at the University of California, Davis, shows the underlying mechanism behind eliminating half the genome and could make for easier and more rapid breeding of crop plants with desirable traits such as disease resistance.
The work stems from a discovery made over a decade ago by the late Simon Chan, associate professor of plant biology in the UC Davis College of Biological Sciences, and colleagues.
Plants, like other sexual organisms, inherit a matching set of chromosomes from each parent. In order to transmit a favorable trait, such as pest or drought resistance, to all their offspring, the plant would have to carry the same genetic variant on each chromosome. But creating plants that “breed true” in this way can take generations of cross-breeding.
In 2010, Chan and postdoctoral fellow Ravi Maruthachalam serendipitously discovered a way to eliminate the genetic contribution from one parent while breeding the lab plant Arabidopsis. They had modified a protein called CENH3, found in the centromere, a structure in the center of a chromosome. When they tried to cross wildtype Arabidopsiswith plants with modified CENH3, they got plants with half the normal number of chromosomes. The part of the genome from one parent plant had been eliminated to create a haploid plant.
But replicating Chan’s exact strategy outside Arabidopsis has so far proved fruitless, said Professor Luca Comai, UC Davis Department of Plant Biology and Genome Center, who is senior author on the new paper. Recently, other labs have created plants with one set of chromosomes by manipulating CENH3, but it’s not clear how the results are related.
“The mechanistic basis of CENH3 effects on haploid induction was mysterious,” Comai said. There appear to be different rules for each species, he said.
Much of that mystery has now been cleared up. Mohan Marimuthu, researcher at the UC Davis Genome Center and Department of Plant Biology, with Comai, Maruthachalam (now at the Indian Institute of Science Education and Research, Kerala) and colleagues found that when CENH3 protein is altered, it is removed from the DNA in the egg before fertilization, weakening the centromere.
“In the subsequent embryonic divisions, the CENH3-depleted centromeres contributed by the egg fail to compete with the CENH3-rich ones contributed by the sperm and the female genome is eliminated,” Comai said.
The finding that any selective depletion of CENH3 engenders centromere weakness explains the original results by Chan and Maruthachalam as well as new results from other labs in wheat and maize, Comai said. This new knowledge should make it easier to induce haploids in crop plants, he said.
Continuous Cell-Free Replication and Evolution of Artificial Genomic DNA in a Compartmentalized Gene Expression System
by Hiroki Okauchi, Norikazu Ichihashi in ACS Synthetic Biology
Professor Norikazu Ichihashi and his colleagues at the University of Tokyo have successfully induced gene expression from a DNA, characteristic of all life, and evolution through continuous replication extracellularly using cell-free materials alone, such as nucleic acids and proteins for the first time.
The ability to proliferate and evolve is one of the defining characteristics of living organisms. However, no artificial materials with these characteristics have been created. In order to develop an artificial molecular system that can multiply and evolve, the information (genes) coded in DNA must be translated into RNA, proteins must be expressed, and the cycle of DNA replication with those proteins must continue over a long period in the system. To date, it has been impossible to create a reaction system in which the genes necessary for DNA replication are expressed while those genes simultaneously carry out their function.
The group succeeded in translating the genes into proteins and replicating the original circular DNA with the translated proteins by using a circular DNA carrying two genes necessary for DNA replication (artificial genomic DNA) and a cell-free transcription-translation system. Furthermore, they also successfully improved the DNA to evolve to a DNA with a 10-fold increase in replication efficiency by continuing this DNA replication cycle for about 60 days.
By adding the genes necessary for transcription and translation to the artificial genomic DNA developed by the group, it could be possible to develop artificial cells that can grow autonomously simply by feeding them low-molecular-weight compounds such as amino acids and nucleotides, in the future. If such artificial cells can be created, we can expect that useful substances currently produced using living organisms (such as substances for drug development and food production) will become more stable and easier to control.
This research has been led by Professor Norikazu Ichihashi, a research director of the project “Development of a self-regenerative artificial genome replication-transcription-translation system” in the research area “Large-scale genome synthesis and cell programming” under the JST’s Strategic Basic Research Programs CREST (Team type). In this research area, JST aims to elucidate basic principles in relation to the structure and function of genomes for the creation of a platform technology for the use of cells.
A reaction solution containing all the factors necessary for the RNA transcription from genes encoded in DNA and translation into proteins outside the cell. The present study used the reconstituted PURE system (Shimizu et al. Nat Biotechnol. 2001), composed entirely of purified, known proteins and RNA. Hence, the system is free of unknown elements. This system was developed by Yoshihiro Shimizu (RIKEN Center for Frontier Biosciences) and his colleagues in the Takuya Ueda’s laboratory at the University of Tokyo.
Psychological stress impairs IL22-driven protective gut mucosal immunity against colonising pathobionts
by Christopher R. Shaler, Alexandra A. Parco, Wael Elhenawy, Jasmeen Dourka, Jennifer Jury, Elena F. Verdu, Brian K. Coombes in Nature Communications
A possible link between psychological stress and Crohn’s disease flare-ups has been identified by a McMaster University-led study.
Researchers using mouse models found that stress hormones suppressed the innate immune system that normally protects the gut from invasive Enterobacteriaceae, a group of bacteria including E. coli which has been linked to Crohn’s disease.
Key to innate immunity is the protective barrier of epithelial cells in the gut, which rely on molecular signals from immune cells to keep out harmful microbes, repair the cell wall and secrete mucus. Without properly functioning immune cells, the epithelial cellular wall can break down, allowing microbes associated with Crohn’s disease to invade the gut and trigger symptom flare-ups.
“The main takeaway is that psychological stress impedes the body’s ability to fight off gut bacteria that may be implicated in Crohn’s disease. Innate immunity is designed to protect us from microbes that do not belong in the gut, like harmful bacteria,” said senior author Brian Coombes, professor and chair of biochemistry and biomedical sciences at McMaster.
“When our innate immune system functions properly, it prevents harmful bacteria from colonizing us, but when it breaks down, it leaves an opening for pathogens to colonize locations they normally cannot and cause illness.”
Coombes said that removing stress hormones in the mouse models restored proper function to immune cells and epithelial cells, blocking the invasion of harmful microbes.
While this discovery could lead to new treatments for Crohn’s disease, Coombes emphasizes these findings are still at the pre-clinical stage and more work needs to be done.
“The more we know about what triggers Crohn’s disease, the closer we come to new treatments and potentially even disease prevention,” said Coombes.
Crohn’s disease is an inflammatory condition that causes inflammation, ulcers and scarring in the digestive system. While its root cause is still not fully understood, Coombes said patients with the disease often have an altered gut microbiome dominated by Enterobacteriaceae like E. coli.
Large-scale integration of single-cell transcriptomic data captures transitional progenitor states in mouse skeletal muscle regeneration
by David W. McKellar, Lauren D. Walter, Leo T. Song, Madhav Mantri, Michael F. Z. Wang, Iwijn De Vlaminck, Benjamin D. Cosgrove in Communications Biology
When a muscle becomes injured, it repairs itself using a flurry of cellular activity, with stem cells splitting and differentiating into many types of specialized cells, each playing an important role in the healing process.
Biologists have struggled to study rare and transient muscle cells involved in the process, but Cornell engineers have lifted the curtain on these elusive dynamics with the launch of scMuscle, one of the largest single-cell databases of its kind. Co-senior authors are Ben Cosgrove and Iwijn De Vlaminck, both associate professors of biomedical engineering in the College of Engineering.
Recent advances in single-cell RNA sequencing allow biologists to identify tens of thousands of cells from a single tissue sample, but because muscle stem cells account for less than 1% of those cells — with their short-lived transient cell offspring being even more rare — sequencing experiments simply can’t capture the complete picture of muscle regeneration.
It’s a problem that Cosgrove ran into when he published a 2020 cell atlas containing 35,000 individual cells involved in the repair process. But of those cells, fewer than 200 of them were committed or fusing myogenic cells — the rare transient states that sequencing struggles to document.
“Imagine if you had a paint-by-numbers picture and you only colored in a quarter of the numbers,” said Cosgrove, who co-led the development of scMuscle along with De Vlaminck and doctoral student David McKellar. “We just couldn’t collect enough data ourselves to paint the whole picture of these subtle transitions as cells mature and specialize.”
The Cornell team knew there were other large sequencing datasets being developed, each capturing their own share of data. So, they used advanced computational techniques to start merging collections to paint the fuller picture. They combined 88 publicly available datasets with several of their own, leading to the scMuscle database, which houses the transcriptomic data from approximately 365,000 cells involved in muscle injury over a wide range of ages and experimental conditions.
“We liken it to creating a mosaic with multiple artists. It assembles into a richer and more complicated painting,” Cosgrove said. “Now we have a comprehensive picture of the very rare cell types that we know are involved in skeletal muscle repair, but weren’t previously sampled.”
The scMuscle database provides another important piece of information that single sequencing experiments fail to produce — spatial data that details how cells organize and interact across the tissue landscape.
“It’s well known in biology that your neighbors make your identity,” Cosgrove said, “and now we can identify molecular factors that are uniquely communicating between cell types and depict their spatial patterns in the injury zone.”
Since soft-launching the scMuscle database in January, hundreds of researchers across the world have accessed it, searching for information such as sex-specific gene expression patterns during aging, and what gene expression signatures define different cell types involved in disease processes.
One finding reported by Cosgrove and the team answered a long-standing question about how many genes are expressed by the differentiating offspring of stem cells as they specialize in mature muscle tissue.
“It turns out the cells are really diversifying gene expression signatures and turning on all sorts of genes as the start to differentiate,” Cosgrove said, “and then as soon as they begin to fuse, they hit this bottleneck and their gene expression patterns become locked in place and very restricted.”
Cosgrove said the scMuscle database will continue to serve as a powerful tool for biologists and others seeking a new view of rare cellular activity in muscle regeneration, and hopes to attract funding to help with hosting and continually integrating new data into it as the field grows.
TMK-based cell-surface auxin signalling activates cell-wall acidification
by Wenwei Lin, Xiang Zhou, Wenxin Tang, Koji Takahashi, Xue Pan, Jiawei Dai, Hong Ren, Xiaoyue Zhu, Songqin Pan, Haiyan Zheng, William M. Gray, Tongda Xu, Toshinori Kinoshita, Zhenbiao Yang in Nature
A team of researchers led by UC Riverside has demonstrated for the first time one way that a small molecule turns a single cell into something as large as a tree. For half a century, scientists have known that all plants depend on this molecule, auxin, to grow. Until now, they didn’t understand exactly how auxin sets growth in motion.
The word auxin is derived from the Greek word “auxein,” meaning “to grow.” There are two main pathways that auxin uses to orchestrate plant growth, and one of them is now described in a new article.
Plant cells are encased in shell-like cell walls, whose primary layer has three major components: cellulose, hemicellulose, and pectin.
“Cellulose works like rebar in a high rise, providing a broad base of strength. It’s reinforced by hemicellulose chains and sealed in by pectin,” said UCR botany professor and research team leader Zhenbiao Yang.
These components define the shape of plant cells, resulting in sometimes-surprising formations like the puzzle-piece-shaped leaf epidermis cells that Yang has been studying for the last two decades. These shapes help tightly glue cells together and provide physical strength for plants against elements such as the wind. With everything locked so tightly by the cell walls, how is movement and growth possible?
One theory posits that when plants are ready to grow, auxin causes their cells to become acidic, loosening the bonds between components and allowing the walls to soften and expand. This theory was proposed half a century ago, but how auxin activates the acidification remained a mystery until now.
Yang’s team discovered auxin creates that acidity by triggering the pumping of protons into the cell walls, lowering their pH levels. The lower pH activates a protein, expansin, appropriately named because it breaks down links between cellulose and hemicellulose, allowing the cells to expand.
The pumping of protons into the cell wall also drives water uptake into the cell, building inner pressure. If the cell wall is loose enough and there is enough pressure inside the cell, it will expand.
“Like a balloon, expansion depends on how thick the outsides are, versus how much air you’re blowing in,” Yang explained. “Lowering the pH in a cell wall can allow water outside of a cell to move in, fueling turgor pressure and expansion.”
There are two known mechanisms by which auxin regulates growth. One is the pH lowering that Yang’s team described. Another is auxin’s ability to turn on gene expression in the nucleus of the plants’ cells, which in turn increases the amount of expansion and other growth-regulating factors in the cell. The latter mechanism also lowers the pH of the cell and facilitates growth. UC San Diego professor of cell biology Mark Estelle is a leading authority in this field. He discovered and researches this other mechanism.
“Dr. Yang’s recent work represents a significant advance in our understanding of how auxin regulates cell expansion. It’s been known that acidification of the extracellular space promotes cell expansion but it wasn’t known how this happens,” Estelle said. “It’s exciting to see an old problem being solved.”
It is an understatement to say that auxin simply “contributes” to plant growth. It is essential to nearly every aspect of a plant’s growth and development, including aspects that are important to agriculture such as fruit, seed and root development, shoot branching, and leaf formation. Even the plant’s correct responses to gravity and light depend on auxin to ensure roots head down while the shoots grow up toward light.
Not only could a deeper understanding of auxin benefit agriculture and renewable energy production, it could one day influence medicine as well.
“Understanding how the basic biology works may eventually have an impact on human health,” Yang said. “As our knowledge expands, we may learn that processes in humans are analogous.”
THCz: Small molecules with antimicrobial activity that block cell wall lipid intermediates
by Elisabeth Reithuber, Torbjörn Wixe, Kevin C. Ludwig, Anna Müller, Hanna Uvell, Fabian Grein, Anders E. G. Lindgren, Sandra Muschiol, Priyanka Nannapaneni, Anna Eriksson, Tanja Schneider, Staffan Normark, Birgitta Henriques-Normark, Fredrik Almqvist, Peter Mellroth in Proceedings of the National Academy of Sciences
Researchers at Karolinska Institutet, Umeå University, and the University of Bonn have identified a new group of molecules that have an antibacterial effect against many antibiotic-resistant bacteria. Since the properties of the molecules can easily be altered chemically, the hope is to develop new, effective antibiotics with few side effects.
The increasing resistance to antibiotics in the world is alarming while few new types of antibiotics have been developed in the past 50 years. There is therefore a great need to find new antibacterial substances.
The majority of antibiotics in clinical use work by inhibiting the bacteria’s ability to form a protective cell wall, causing the bacteria to crack (cell lysis). Besides the well-known penicillin, that inhibit enzymes building up the wall, newer antibiotics such as daptomycin or the recently discovered teixobactin bind to a special molecule, lipid II. Lipid II is needed by all bacteria to build up the cell wall. Antibiotics that bind to this cell wall building block are usually very large and complex molecules and therefore more difficult to improve with chemical methods. These molecules are in addition mostly inactive against a group of problematic bacteria, which are surrounded by an additional layer, the outer membrane, that hinders penetration of these antibacterials.
“Lipid II is a very attractive target for new antibiotics. We have identified the first small antibacterial compounds that work by binding to this lipid molecule, and in our study, we found no resistant bacterial mutants, which is very promising,” says Birgitta Henriques Normark, professor at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and one of the article’s three corresponding authors.
In this study, researchers at Karolinska Institutet and Umeå University in Sweden have tested a large number of chemical compounds for their ability to lyse pneumococci, bacteria that are the most common cause of community-acquired pneumonia. The initial tests were carried out in collaboration with the Chemical Biology Consortium Sweden (CBCS), a national research infrastructure at SciLifeLab. After a careful follow-up of active compounds from this screening, the researchers, in collaboration with the University of Bonn in Germany, found that a group of molecules called THCz inhibits the formation of the cell wall of the bacterium by binding to lipid II. The molecules could also prevent the formation of the sugar capsule that pneumococci need to escape the immune system and to cause disease.
“The advantage of small molecules like these is that they are more easy to change chemically. We hope to be able to change THCz so that the antibacterial effect increases and any negative effects on human cells decrease,” says Fredrik Almqvist, professor at the Department of Chemistry at Umeå University and one of the corresponding authors.
In laboratory experiments, THCz have an antibacterial effect against many antibiotic-resistant bacteria, such as methicillin-resistant staphylococci (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PNSP). An antibacterial effect was also found against gonococci, which causes gonorrhoea, and mycobacteria, bacteria that can cause severe diseases such as tuberculosis in humans. The researchers were unable to identify any bacteria that developed resistance to THCz in a laboratory environment.
“We will now also initiate attempts to change the THCzmolecule, allowing it to penetrate the outer cell membrane found in some, especially intractable, multi-resistant bacteria,” says Tanja Schneider, professor at the Institute of Pharmaceutical Microbiology at the University of Bonn and one of the corresponding authors.
Identification of the Adult Hematopoietic Liver as the Primary Reservoir for the Recruitment of Pro-regenerative Macrophages Required for Salamander Limb Regeneration
by Ryan J. Debuque, Andrew J. Hart, Gabriela H. Johnson, Nadia A. Rosenthal, James W. Godwin in Frontiers in Cell and Developmental Biology
In a seminal 2013 study, MDI Biological Laboratory scientist James Godwin, Ph.D., discovered that a type of white blood cell called a macrophage is essential to limb regeneration in the axolotl, a Mexican salamander that is nature’s champion of regeneration.
Without macrophages, which are part of the immune system, regeneration did not take place. Instead of regenerating a limb, the axolotl formed a scar at the site of the injury, which acted as a barrier to regeneration, just as it would in a mammal such as a mouse or human. In terms of regenerative capability, Godwin had turned the salamander into a mammal. In a follow-up 2017 study, he found the same to be true in heart tissue.
Now, in a study that builds on his earlier research, Godwin has identified the origin of pro-regenerative macrophages in the axolotl as the liver. By providing science with a place to look for pro-regenerative macrophages in humans — the liver, rather than the bone marrow, which is the source of most human macrophages — the finding paves the way for regenerative medicine therapies in humans.
Although the prospect of regrowing a human limb may be unrealistic in the short term due to a limb’s complexity, regenerative medicine therapies could potentially be employed in the shorter term in the treatment of the many diseases in which scarring plays a pathological role, including heart, lung and kidney disease, as well as in the treatment of scarring itself — for instance, in the case of burn victims.
“In our earlier research, we found that scar-free healing hinges on a single cell type, the macrophage,” Godwin said. “This finding means we have a way in. If axolotls can regenerate by having a single cell type as their guardian, then maybe we can achieve scar-free healing in humans by populating our bodies with an equivalent guardian cell type, which would open up the opportunity for regeneration.”
In addition to the MDI Biological Laboratory, the research was conducted at the Australian Regenerative Medicine Institute (ARMI), with which Godwin was formerly associated, and The Jackson Laboratory (JAX) in Bar Harbor, Maine, where he holds a joint appointment. The MDI Biological Laboratory and ARMI have a partnership agreement to promote research and education on regeneration and the development of new therapies to improve human health.
If the regenerative process at the site of an injury can be compared to a party — an analogy Godwin often uses — his research has revealed the category of guest who attends and, now, where the guests come from and how and when they get there. The next step will be to nail down their specific identities, or as he puts it, the “flavors” of macrophages required for regeneration, and how they interact with other guests.
That research will revolve around the study of scarring, or fibrosis, which in adult mammals blocks regeneration through its effect on tissue function and integrity.
Although it remains to be seen if achieving scar-free healing in mammals will allow regeneration to proceed -other processes may also be involved — Godwin believes that may be the case. Because mammals already possess the machinery for regeneration — young mice can regenerate, as can human newborns — mammalian regeneration may simply be a matter of removing the barrier posed by scarring.
“In axolotls, macrophages act as a brake on fibrosis, or scarring,” he said. “Humans may possess macrophages that are doing their hardest to repair the damage, but are being held back. If we can engineer human macrophages to promote scar-free healing, we might be able to achieve a huge improvement in repair with just a little tweak. Wouldn’t it be awesome if we didn’t have to do anything other than that?”
In an intriguing insight into a potential route to engineering regeneration in adult mammals, Godwin noted that the primary source of macrophages at the site of a wound in the developing mouse is the liver, just as his recent research found it to be in the axolotl; the mouse loses its ability to regenerate when the source of macrophages shifts to the bone marrow shortly after birth, as it also does in humans.
Though Godwin’s recent research focused on the origin of pro-regenerative macrophages, its most significant contribution may be the development of a toolkit for profiling and sorting immune cells. While the axolotl is a powerful model in regenerative biology research, that research has been held back by the lack of tools for assessing the diverse roles of the immune cells that are critical to the regenerative process.
Godwin, who is an immunologist, originally chose to examine the function of the immune system in regeneration because of its role in preparing the wound for repairs. Using the new toolkit, he now plans to systematically alter the axolotl’s genes to assess the functions of macrophages, starting with the interaction between macrophages and fibroblasts, a type of connective tissue cell responsible for directing wound repair.
“We want to find out what so special about the interaction between macrophages and fibroblasts in axolotl regeneration,” he said. “We have the luxury in the salamander of being able to work out which macrophage functions are essential to scar suppression and regeneration, gene by gene if we have to. If we can find out what that is, then maybe we can get that interaction happening in mammals.”
Once he has profiled the functions of axolotl macrophages at the site of an injury, Godwin’s goal will then be to use the mouse model to either tease elusive pro-regenerative macrophages out of the mammalian system or engineer mammalian macrophages to be more an axolotl’s. His work in the mouse model is supported by his appointment at The Jackson Laboratory, which focuses on mouse biology and genetics.
“In elucidating the differences between macrophages in the axolotl and mouse, James is carrying on a tradition of comparative biology that has been the focus of research at the MDI Biological Laboratory for more than 120 years,” said President Hermann Haller, M.D. “His discoveries demonstrate that our approach of gaining insight into human health from the comparative study of animal models is as powerful as ever.”
Engineering ligand-specific biosensors for aromatic amino acids and neurochemicals
by Austin G. Rottinghaus, Chenggang Xi, Matthew B. Amrofell, Hyojeong Yi, Tae Seok Moon in Cell Systems
That feeling in your gut? Well, it’s in your head, but some of it does truly start in the gastrointestinal tract.
Some of the trillions of bacteria living in your gut — among viruses, eukaryotes and archaea — synthesize some of the neurotransmitters that are responsible for your nerves, anxiety and euphoria. When you don’t have enough — or you have too much — of any of these hormones, your mental health can suffer.
Tae Seok Moon, associate professor in the Department of Energy, Environmental & Chemical Engineering at the McKelvey School of Engineering at Washington University in St. Louis, says he’s experienced this imbalance himself. And he’s working on a fix: genetically engineered bacteria that can monitor chemical production from inside a person’s gut and fix any imbalances.
“It is a difficult job to do,” Moon said, “to keep your neurotransmitters balanced.” But he has already begun. In 2017, Moon was awarded a grant to engineer a probiotic specifically aimed at protecting people from the negative health effects of adrenaline surges.
Moon’s method involves the development of a “bacterial sensor” that can detect certain chemicals in a person’s gut. He has been working on similar sensors in his lab with the goal of ultimately genetically engineering a type of modular system with different sensors. He had already developed sensors for temperature, pH, oxygen levels, light, pollutants and other disease-related chemicals.
Moon isn’t the first person to develop such sensors, but until now, they have mostly suffered from lack of specificity. Sensors can have difficulty when it comes to differentiating between similarly structured molecules.
“Specificity in engineering is one of the big challenges,” Moon said. “But we have proved that this can be done.”
The proof is in the genetically engineered Escherichia coli Nissle 1917 (EcN) bacterium, which has a sensor for one — and only one — type of molecule.
The team was able to start with a sensor pathway found naturally in bacteria. First author Austin Rottinghaus, a PhD student in Moon’s lab, and other lab members used computer modeling to explore how mutations would affect the pathway’s sensitivity. The researchers were able to develop a sensor pathway that was sensitive to the molecules they were interested in — and only those molecules.
The sensors were incorporated into EcN, turning the bacteria into precision hunters. They could discriminate between phenylalanine (Phe) and tyrosine (Tyr), two structurally similar molecules associated with the disorders (PKU) and type 2 tyrosinemia, respectively. The team also developed sensors for the similarly structured phenylethylamine (PEA) and tyramine (Tyra) — both found in food and in the gut.
With this proof of concept, Moon’s lab can now work on developing an actuator — a protein that will act based on information gathered by the sensor. For instance, PKU is a genetic disease which causes babies to accumulate too much phenylalanine. A completely engineered bacteria might have a sensor to detect the amino acid and an actuator that can degrade it if the levels of phenylalanine are too high. These kinds of engineered organisms can be useful beyond a medical setting. They also can be used to monitor food quality or to regulate pathways for microbial metabolic engineering, the processes used to create many pharmaceuticals, fuels, or other chemicals.
Because of his experiences, however, Moon is personally most interested in bacteria that can sense the levels of neurotransmitters in the gut. “If the levels are too high, the bacteria produce an enzyme that degrades the target chemical. If it’s too low,” he said, “the bacteria produce an enzyme that can synthesize more of it.”
About 95 percent of the hormone serotonin is synthesized by bacteria in the gut. When this and other neurotransmitters are out of whack, a person can suffer greatly, Moon said. He wants to put an end to this suffering.
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