Messenger RNAs with multiple “tails” could lead to more effective therapeutics

Graphic showing scientists adding "tails" to mRNA molecules
Illustration Credit: Catherine Boush, Broad Communications

Messenger RNA (mRNA) made its big leap into the public limelight during the pandemic, thanks to its cornerstone role in several COVID-19 vaccines. But mRNAs, which are genetic sequences that instruct the body to produce proteins, are also being developed as a new class of drugs. For mRNAs to have broad therapeutic uses, however, the molecules will need to last longer in the body than those that make up the COVID vaccines. 

Researchers from the Broad Institute of MIT and Harvard and MIT have engineered a new mRNA structure by adding multiple “tails” to the molecules that boosted mRNA activity levels in cells by 5 to 20 times. The team also showed that their multi-tailed mRNAs lasted 2 to 3 times longer in animals compared to unmodified mRNA, and when incorporated into a CRISPR gene-editing system, resulted in more efficient gene editing in mice. 

The new mRNAs, reported in Nature Biotechnology, could potentially be used to treat diseases that require long-lasting treatments that edit genes or replace faulty proteins. 

“The use of mRNA in COVID vaccines is fantastic, which prompted us to explore how we could expand the possible therapeutic applications for mRNA,” said Xiao Wang, senior author of the new paper, a core institute member at the Broad and an assistant professor of chemistry at MIT. “We’ve shown that non-natural structures can function so much better than naturally occurring ones. This research has given us a lot of confidence in our ability to modify mRNA molecules chemically and topologically.”

Decoding the plant world’s complex biochemical communication networks

PhD candidate Shannon Stirling in Natalia Dudareva’s Lab, transfers DNA into a petunia by using a syringe to inject bacterium into the stigma to activate targeted genes, then isolating the resulting proteins.
Photo Credit: Purdue Agricultural Communications / Tom Campbell

A Purdue University-led research team has begun translating the complex molecular language of petunias. Their grammar and vocabulary are well hidden, however, within the countless proteins and other compounds that fill floral cells.

Being rooted to the ground, plants can’t run away from insects, pathogens or other threats to their survival. But plant scientists have long known that they do send warnings to each other via scent chemicals called volatile organic compounds.

“They use volatiles because they can’t talk,” said Natalia Dudareva, Distinguished Professor of Biochemistry and Horticulture and Landscape Architecture at Purdue. “Plants inform neighboring plants about pathogen attacks. It looks almost like immunization. Under normal conditions, you don’t see any changes in the receiver plant. But as soon as a receiver plant is infected, it responds much faster. It’s prepared for response.”

Plant scientists have long known about this immunization-like priming, but until a few years ago, they had no way to study the process. They needed a marker showing that the plants had detected the volatile compounds.

Dudareva and 13 co-authors describe new details of the detection process in the March 22, 2024, issue of the journal Science. The team includes researchers from Purdue; Université Jean Monnet Saint-Etienne in France; and the University of California, Davis.

Two keys needed to crack three locks for better engineered blood vessels

Two proteins can trigger the signaling cascades needed to help differentiate stem cells into endothelial cells that can form tubular-like vessels in a dish, according to a team led by Penn State researchers. The finding has implications for developing drug-testing platforms and other clinical applications. 
Image Credit: Lian Lab / Pennsylvania State University

Blood vessels engineered from stem cells could help solve several research and clinical problems, from potentially providing a more comprehensive platform to screen if drug candidates can cross from the blood stream into the brain to developing lab-grown vascular tissue to support heart transplants, according to Penn State researchers. Led by Xiaojun “Lance” Lian, associate professor of biomedical engineering and of biology, the team discovered the specific molecular signals that can efficiently mature nascent stem cells into the endothelial cells that comprise the vessels and regulate exchanges to and from the blood stream.

They published their findings in Stem Cell Reports. The team already holds a patent on foundational method developed 10 years ago and has filed a provisional application for the expanded technology described in this paper.

The reserchers found they could achieve up to a 92% endothelial cell conversion rate by applying two proteins — SOX17 and FGF2 — to human pluripotent stem cells. This type of stem cell, which the researchers derived from a federally approved stem cell line, can differentiate into almost any other cell type if provided the right proteins or other biochemical signals. SOX17 and FGF2 engage three markers in stem cells, triggering a growth cascade that not only converts them to endothelial cells but also enables them to form tubular-like vessels in a dish.

The aging brain: protein mapping furnishes new insights

Stained mouse microvessels under the fluorescence microscope (green: vascular endothelium, red: cell nuclei). 
Image Credit: © Dichgans Lab

For the neurons in the brain to work smoothly and be able to process information, the central nervous system needs a strictly regulated environment. This is maintained by the blood-brain barrier, whereby specialized brain endothelial cells lining the inner walls of blood vessels regulate the exchange of molecules between the circulatory and nervous systems. Earlier studies have shown that various functions that are dependent on these cells, such as the integrity of the blood-brain barrier or the regulation of blood supply to the brain, decline over the course of a person’s life. This dysregulation leads to a dysfunction of the brain vasculature and is therefore a major contributor to medical conditions such as strokes and dementia.

However, the molecular changes that underlie this loss of function have remained largely obscure. To improve our mechanistic understanding, researchers carry out molecular profiling studies to investigate the different components of brain endothelial cells and collect their findings in large databases. “The transcriptome – that is to say, the RNA contained in endothelial cells – has since been quite comprehensively mapped,” says LMU professor Martin Dichgans, Director of the Institute for Stroke and Dementia Research at University of Munich Hospital and Principal Investigator at the SyNergy Cluster of Excellence. “What has been lacking is corresponding data on the complete set of proteins in the cells, the proteome.” A study recently published in the journal Nature Aging, which had major contributions by researchers from LMU and SyNergy, has now closed this knowledge gap.

Bees need food up to a month earlier than provided by recommended pollinator plants

Buff-tailed bumblebee (Bombus terrestris).
Photo Credit Matthias Becher

New research from the Universities of Oxford and Exeter has revealed that plant species recommended as “pollinator friendly” * in Europe begin flowering up to a month too late in the spring to effectively contribute to bee conservation.

This “hungry gap” results in low colony survival and low production of queens for the following year.

The results showed that pollen and nectar availability during the early colony founding stage is a critical, and previously under-appreciated, factor in bee colony success. **

The study has been published in the journal Insect Conservation and Diversity. 

Senior author Dr Tonya Lander (Department of Biology, University of Oxford) said: “The results give us a simple and practical recommendation to help bees: to enhance hedgerows with early blooming species, especially ground ivy, red dead-nettle, maple, cherry, hawthorn, and willow, which improved colony success rate from 35% to 100%. This approach focuses on existing hedgerows in agricultural land and doesn’t reduce farm cropping area, so can appeal to land managers whilst also providing important conservation outcomes for pollinators.” 

These were assessed using the BEE-STEWARD model, which integrates data and runs simulations to predict how changes in different factors may impact bee populations over time.

Rays were more diverse 150 million years ago than previously thought

Aellopobatis bavarica: The newly discovered species, complete fossils are only known from Germany. This species is also the largest species of all and can grow up to 170 cm in size.
Photo Credit: Türtscher et al.

New fossil ray species discovered in Bavarica, Germany: Aellopobatis bavarica from the Late Jurassic

In a new study recently published in the journal Papers in Paleontology, an international team of scientists led by paleobiologist Julia Türtscher from the University of Vienna has explored the puzzling world of rays that lived 150 million years ago and discovered a previously hidden diversity – including a new ray species. This study significantly expands the understanding of these ancient cartilaginous fish and provides further insights into a past marine ecosystem.

In her new study, paleobiologist Julia Türtscher from the Institute of Paleontology at the University of Vienna examined 52 fossil rays from the Late Jurassic period. These rays are 150 million years old, from a time when Europe was largely covered by the sea, except for a few islands, comparable to today's Caribbean. The Late Jurassic specimens are particularly valuable to scientists because they are among the oldest known fully preserved ray specimens. As only the teeth of fossilized rays are usually preserved, such rare skeletal finds provide exciting insights into the early evolution of this group. Although the exceptionally well-preserved fossils (from Germany, France, and the UK) have been known for some time, they have been largely unexplored. Türtscher's study is the first comprehensive analysis of the variation in body shape in these rays.

Product that kills agricultural pests also deadly to native Pacific Northwest snail

Pacific sideband snail.
Photo Credit: William P. Leonard

A product used to control pest slugs on farms in multiple countries is deadly to least one type of native woodland snail endemic to the Pacific Northwest, according to scientists who say more study is needed before the product gains approval in the United States.

Dee Denver of the Oregon State University College of Science led a 10-week laboratory project that showed the effect of a biotool marketed as Nemaslug on the Pacific sideband snail. The study was published today in PLOS One.

Nemaslug is based on the organism Phasmarhabditis hermaphrodita, a species of tiny, parasitic worm known as a nematode.

The speed of the Pacific sidebands’ demise depended on the concentration of Nemaslug exposure and the size and maturity of the snails, but by the end of the study all 90 were dead, whereas all 30 snails in a control group were still alive.

“This finding is a big deal because there are strong efforts to bring this commercialized nematode to U.S. markets to control invasive pests, such as the gray field slug, that cause damage to a variety of agricultural crops,” said Denver, who heads OSU’s Department of Integrated Biology and directs the university’s School of Life Sciences.

Research offers hope for preventing post-COVID ‘brain fog’ by targeting brain’s blood vessels

Blood vessel endothelial cells (green) and basement membrane (red) in the brain.
Image Credit: Sarah Lutz

Among the many confounding symptoms in patients recovering from a COVID-19 infection are memory loss and difficulty learning. Yet little is known about the mechanisms of cognitive impairments like these, commonly called brain fog. 

In a new study, researchers at the University of Illinois Chicago have identified a mechanism that causes neurological problems in mice infected with SARS-CoV-2, the virus behind COVID-19. The researchers also found a treatment that helped prevent these changes. Sarah Lutz, assistant professor of anatomy and cell biology in the College of Medicine, led the research, which was published in the journal Brain.

The team focused on the blood-brain barrier, which plays a role in other neurological diseases, such as multiple sclerosis. Normally, this barrier protects the brain from potentially harmful cells or molecules circulating in the bloodstream. But the infected mice, researchers found, had leaky blood-brain barrier vessels and impaired memory or learning.

To understand why, the researchers looked at blood vessels from the brains of infected mice to see which genes were most altered. They found a significant decrease in a signaling pathway called Wnt/beta-catenin, which helps maintain the health of the blood-brain barrier and protects the brain from damage.

New reactor could save millions when making ingredients for plastics and rubber from natural gas

Illustration Credit: Courtesy of University of Michigan / Department of Chemical Engineering

A new way to make an important ingredient for plastics, adhesives, carpet fibers, household cleaners and more from natural gas could reduce manufacturing costs in a post-petroleum economy by millions of dollars, thanks to a new chemical reactor designed by University of Michigan engineers.

The reactor creates propylene, a workhorse chemical that is also used to make a long list of industrial chemicals, including ingredients for nitrile rubber found in automotive hoses and seals as well as blue protective gloves. Most propylene used today comes from oil refineries, which collect it as a byproduct of refining crude oil into gasoline.

As oil and gasoline fall out of vogue in favor of natural gas, solar, and wind energy, production of propylene and other oil-derived products could fall below the current demand without new ways to make them.

Natural gas extracted from shale holds one potential alternative to propylene sourced from crude oil. It’s rich in propane, which resembles propylene closely enough to be a promising precursor material, but current methods to make propylene from natural gas are still too inefficient to bridge the gap in supply and demand.

“It’s very hard to economically convert propane into propylene,” said Suljo Linic, the Martin Lewis Perl Collegiate Professor of Chemical Engineering and the corresponding author of the study published in Science.

New vaccine against a highly fatal tropical disease – and potential bioterror weapon – demonstrates efficacy in animal studies

Burkholderia pseudomallei infecting a human cell. The bacteria (red) are polymerizing actin (green).
 Photo Credit: Courtesy of Christopher T. French.

In a mouse study, UCLA researchers tested a vaccine against the bacterium that causes melioidosis and found it was highly protective against the disease, which is endemic in many tropical areas, causing approximately 165,000 cases with 89,000 fatalities around the world each year. 

The bacterium, called Burkholderia pseudomallei, is spread through contact with contaminated soil and water through inhalation, ingestion or broken skin. It is so dangerous that it is categorized as a Tier 1 Select Agent of bioterrorism, and it can cause rapidly fatal pneumonia when inhaled in low doses. If aerosolized and unleashed in a terror attack, it could lead to widespread death.

To date there are no licensed vaccines against the bacterium, said senior author Dr. Marcus Horwitz, Distinguished Professor of Medicine, in the division of infectious diseases, and of Microbiology, Immunology and Molecular Genetics at the David Geffen School of Medicine at UCLA.

“A safe and effective vaccine is needed to prevent this disease as melioidosis is often difficult to diagnose, requires very lengthy treatment lasting three to six months, and has a high fatality rate even in high resource settings,” Horwitz said. “Such a vaccine would be of great benefit to people living in endemic regions, travelers, and military personnel stationed in these areas, and it would also reduce the risk from an intentional release of B. pseudomallei in a bioterrorist attack.”