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Mouse brain tissue kept alive for several weeks in laboratory

Mouse brain tissue kept alive for several weeks in laboratory

Researchers from Japan have kept small portions of mouse brain tissue alive and viable for a period of 25 days, isolating in a culture. This has highly increased the timeline in which the isolated brain tissue can keep the functions intact extending days to weeks. This can affect the research in therapeutic drugs in a positive way. The findings have been published in the Analytical Sciences journal.

The key to success was a new technique that combines a special kind of membrane with an improved microfluidic device. Microfluidic devices use small channels for delivery of fluid into tissues and are better than the normal culture dishes specially for ex vivo tissue experiments. They can also be customized highly and mimic certain kinds of cell behaviors. They also require small volume samples thus making it easy to study the cell interactions. 

However, only a few days is not sufficient to understand how body systems react to various things. The main problem is to keep a balance. Tissues dry quickly so the system has to be kept moist along with nutrients in a wet culture medium. Too much moisture prevents cells to exchange gases which the tissue needs thus drowning it finally. This problem had to be tackled by the researchers. 

This device has a semi-permeable microfluidic channel that is surrounded by an artificial membrane and solid walls. These are made from polydimethylsiloxane, a polymer mainly used in microfluidic devices. The tissue does not sit in the bath consisting of the culture medium but instead, the fluid circulates through the channel, passing by the membrane to keep the tissues most while still maintaining the exchange of gases between cells. 

Nobutoshi Ota, a biochemist at RIKEN Center for Biosystems Dynamics Research said that the medium flow was difficult to be controlled as the microchannel between the porous membrane and PDMS walls were not normal. The team got success after repeated trials and modifications to the membrane while adjusting the flow rates of the inlet and outlet.

A small part of the brain named suprachiasmatic nucleus(SCN)  was used which is responsible for keeping the circadian and biological rhythms intact in mammals. Neuronal cells in SCN exchange information by keeping the motion of peptides and molecules between cells intact. This is ideal for studying cell interactions. 

The mice from where the SCNs were harvested had been edited genetically such that the circadian rhythm in the brain was connected to the production of a fluorescent protein indicating if everything was working properly. 

The fluorescence was active for 25 days compared to that of a normal culture dish where after 10 hours the activity control reduced by 6 percent. The experiment lasted for only 25 days since it was the cutoff time for this experiment. It could have lasted well beyond 100 days. 

Researchers believe that this can also be used for remaining organ tissues with the possibility for human organs that are grown in the laboratory. This will improve the research in organogenesis by culturing and observation which is needed for the growth of organs and tissue. 

Journal Reference: Analytical Sciences

For the first time, meat has been grown in space

For the first time, meat has been grown in space

Technology has changed almost every aspect of our lives and now it is also influencing the way astronauts eat food. The first astronauts took their meals from tubes similar to the kinds of toothpaste, however, now the astronauts can have fruits and ice cream with a seasoning of liquid pepper and salt on their meals. Although there are restrictions to food, for example, any food leaving crumbs are considered dangerous as these particles can clog the electrical systems or air filters of the spacecraft. 

The foods also need to last for longer time periods if the resupply missions go wrong somehow. As a result, tech companies are trying new techniques to grow food in the spacecraft itself. Aleph Farms, an Israeli food-startup oversaw meat growth in space for the first time by using a 3D printer. It is not a fully new experiment as the company has cooked lab-grown steaks from December 2018 suggesting meat growth in different kinds of environment. 

Aleph Farms extracts cells from a cow by using biopsy which is then kept in a broth of nutrients. It simulates the environment inside the body of a cow and then they are grown into steak pieces. The taste is not exactly the same but it resembles the flavor and texture of regular beef. 

CEO and co-founder, Didier Toubia said that they are the only company to grow fully-textured meat which has all the muscle fibers and blood vessels needed for the tissues. For growing meat in space, the company had to tweak their process a bit. The cow cells along with nutrient broth were placed in closed vials. They were loaded to the Soyuz MS-15 spacecraft in Kazakhstan. It took off for the Russian end of the International Space Station on September 25, orbiting 400 kilometers from the surface of the earth. 

On arrival at the station, the vials were inserted into a magnetic printer from 3D Bioprinting Solutions, a Russian company. Cells were replicated by the printer for producing muscle tissues. They returned to Earth without any consumption by the astronauts. It was a conceptual experiment and the company hopes to provide sources of protein in missions to deep space, moon, and Mars in the future.

In 2015, romaine lettuce was grown by astronauts in the International Space Station. NASA is creating a “space garden” for making lettuce, carrots and other fruits on Gateway, a space station proposed to orbit Moon.  

Meat printing suggests the companies can pursue this in the harsh environments where there is a scarcity of land or water. It takes almost 5200 gallons of water to produce a kilogram of steak. Cultured meat, on the other hand, uses 10 times less land and water than normal livestock agriculture. It also quicker to cook. Aleph Farms calls its meat, “minute steak” as it only takes a few minutes to cook. 

We have to find ways to produce food while conserving the natural resources as the resources for the food industry lead to 37 percent of greenhouse gas emissions worldwide. Aleph Farms said that their experiment was a response to such issues and the Americans, Russians, Israelis, and Arabs need to unite for addressing the climate and food security concerns. 

Curiosity obtains traces of salt in the last lakes of Gale Crater

Curiosity obtains traces of salt in the last lakes of Gale Crater

The lakes on Earth turn salty on drying out and the same incident happened when the Curiosity Mars climbed to identify the younger rocks. It found some of the salts which were left behind gathering insights on life could have prospered, rather than the mere survival on Mars. Gale crater was selected in part as it provides the possibility to investigate sedimentary rocks of different ages layered on top of each other. Curiosity has found periodic clay-bearing deposits containing 30-50 percent calcium sulfate by weight as reported in a Nature Geoscience paper.

All the rocks are 3.3-3.7 billion years old dating to the Hesperian period. Likewise, rich deposits have not been found in the older rocks of the crater. According to Dr. William Rapin of the California Institute of Technology and co-authors, the salts are present due to the percolation in the rocks by the waters of the bygone lakes which were very salty. Older rocks were much less salty although they were also exposed to the waters. Curiosity might detect more recent examples even though the younger ones were never touched by water.

Like a desert lake on Earth, the waters of the Gale crater evaporated, leaving a saltier residue, but it was an intermittent process on Mars that lasted 400 million years. The rocks have been subjected to forces of weathering over this vast time period even without water, and the calcium sulfate-enhanced portions are more resistant to erosion, producing mini versions of the formations in places such as Monument Valley, where harder rocks extend above the terrain.

Curiosity found a 10-meter (33-feet) slope containing 26-36 percent magnesium sulfate, in the 150 meters (500 feet) of calcium sulfate-enriched layers. Researchers believe that before the deposition of more soluble salts, it precipitated out first.

The paper mentions that their outcomes do not compromise the life search in the Gale crater. Terrestrial magnesium sulfate-rich and hypersaline lakes are known to sustain halotolerant biota while the preservation of biosignatures may be supported by crystallization of sulfate salts.

The occasional bursts of salty water are observed even today hence it is not unique to Gale crater in having such salts. As the planet dried, sulfate deposits have been identified by Martian orbiters across several places on Mars and it is the first instance where a rover has been operated its instruments over these samples. The periodic bursts of sulfate salts found by Curiosity showed Gale crater had many rounds of drying with several wet periods rather than one single great drought.

Journal Reference: Nature Geoscience

Researchers awarded the Nobel Prize in Medicine for their discovery of cells adapting to low oxygen

Researchers awarded the Nobel Prize in Medicine for their discovery of cells adapting to low oxygen

The Nobel Assembly has awarded the 2019 Nobel Prize in Physiology or Medicine to William Kaelin, Sir Peter Ratcliffe, and Gregg Semenza for their discoveries of the ways in which cells sense and adapt to the availability of oxygen.

The molecular switch that helps our cells to adjust to lowering oxygen levels was discovered by the three researchers. This is necessary because it offers a hypoxic reaction when the oxygen levels change i.e. the change when altitude changes, when exercising or when getting a cut.

There are various ways by which our body handles this such as forming new blood vessels, increase of blood cell production, cells adapting to certain metabolic changes. An example of the latter situation is the production of lactic acid in muscle cells during heavy exercise. The energy captured in food is released by the cells using oxygen in a reaction called aerobic respiration. Cells can also perform anaerobic respiration to avoid using oxygen but this is not sustainable as well as inefficient in the long term for humans. The three Nobel laureates and their colleagues discovered this ability to switch from one mode to the other.

It is known that the increase in the erythropoietin hormone (EPO) is produced by the kidneys in low-oxygen conditions and in anemic people. Semenza, working at Johns Hopkins University demonstrated that the increase in EPO which stimulates the production of red blood cells is stimulated by a specific gene known as hypoxia response element or HRE.

HIF-1α is one of the proteins produced by the gene found to be oxygen sensitive which disappears in the abundance of oxygen. The cells were more likely to show symptoms of hypoxia which lack the von Hippel-Lindau gene (connected to cancer). This was discovered by William Kaelin and his team from the Dana-Farber Cancer Institute.

A relation between VHL and HIF-1α was created by Ratcliffe and his group from Oxford University and the Francis Crick Institute. They figured out the molecular details of the working of these mechanisms and also that the protein cannot be destroyed without the gene. From general metabolism and exercise response to embryo development and the functioning of the immune system, HIF-1α plays very crucial roles. It also affects conditions like anemia, cancer, strokes, and heart attacks. At present, EPO is being studied as a potential method to fight against the cancer cells by preventing them access to oxygen and nutrients.

More than half of the trees native to Europe are at risk of dying

More than half of the trees native to Europe are at risk of dying

The International Union for Conservation of Nature has reported that more than half of the known trees in Europe are at the risk of getting extinct. Few of these trees have been in existence before the previous ice age but the perennial woods of Europe are in more danger than the birds, bees, butterflies in the sixth mass extinction. 

According to the European Red List of the IUCN, only freshwater mollusks and leafy plants have more risk of extinction than the trees. Thus they are a highly endangered group of species. After the evaluation of the 454 tree species native to Europe, analysts identified that 42 percent of the species face regional extinction threats. More than half of the endemic trees existing in Europe are in danger of dying out while 15 percent are in the category of critically endangered species. What’s alarming is that even among the trees in the safe zone, a dozen are on the edge of shifting to the threatened category while there is no data on 13 percent of the species. 

Luc Bas, Director of the European Office of the IUCN said that human-led activities have resulted in the decline of the population and increased the extinction risk for several important species all across Europe. This report reveals the status of several species that have been overlooked while they are an integral part of the ecosystems of Europe, contributing to a better planet. 

The number of known plant extinctions has quadrupled since the 18th century. A study published in June reveals that an average of three plant species has disappeared every year since 1900. This rate of extinction is 500 times faster than the natural expectations and twice the number of extinctions faced by mammals, birds, and amphibians. As per the report of IUCN, 38 percent of the examined species in Europe face danger from invasive species. This is followed by wood harvesting, deforestation, development of cities along with climate change, fires and land management. 

In the analysis, it was found that three-quarters of the tree species in the Sorbus genus such as Mountain Ash, were assessed to be threatened and a third to be critically endangered. 22 species were unable to get assessed due to a lack of proper information. Tim Rich, taxonomist who was involved in the study said that he has been quite worried as along with saplings, big ash trees have been affected to a large extent. He found a dead ash tree every five to ten meters in the Pembrokeshire area while driving there. 

The positive side is almost 80 percent of the native species of trees are identified in at least one protected area, while many are present in arboreta and botanic gardens. Craig Hilton-Taylor, head of Red List Unit of IUCN said that European trees with their diversity are an important source for food and shelter for several animals also with an important economic role. We should be taking care of our trees unless it gets too late. 

Researchers find application of Golden Ratio in the human skull

Researchers find application of Golden Ratio in the human skull

A new study has compared human skulls to other animals resulting in the claim that our heads tend to follow the golden ratio – the special number associated with beauty. The findings appear in The Journal of Craniofacial Surgery. 

The Golden ratio is denoted by the irrational number phi equating to nearly 1.618 and is a famous mathematical concept. Neurologists from John Hopkins, Rafael Tamargo, and Jonathan Pindrik claim in their new study that phi might indicate some kind of sophistication going in the brain box. They mention that the human skull denotes the elegant harmony of both structure and function as it has evolved over millennia. The paper compares 100 human craniums physiologically normal with 70 others representing six different mammals. 

The Nasioiniac arc connects the point on nasal bones with a bump located at the back of the head known as the inion. Distances were measured from the nasal bone to a point on skull known as bregma and from bregma to inion. The cranial features were selected as representative distances corresponding to significant neural structures in humans as well as other animals. 

The ratio of the distance from bregma to the inion and bregma to the nasion equals 1.6 which is also the ratio of nasion to the inion and bregma to the inion. 1.6 is quite close to the golden ratio so the researchers think there might be something interesting here. Tamargo said that the other mammals surveyed had ratios nearing the golden ratio with an increase in the sophistication of species. This might have significant evolutionary and anthropological implications. However, these implications are not clear. The ratio has been spotted in several physiological structures in recent years which prompts the doubt if there is at all any biological significance. 

There are two numbers a and b, a being greater. Their ratio is a:b. When (a+b): a equals a:b, then it is considered as the Golden Ratio first named by Luca Pacioli in 1509. Even the great artist Leonardo Da Vinci used it for major artistic proportions. 

It has been found that the spiral shell of nautilus follows this ratio in the form of a golden spiral. The real question is if we are influenced by selection bias when looking for the applications of this ratio or it is actually followed in the evolutionary process. In 2015, Eve Torrence, a mathematics professor at Randolph-Macon College said that it is quite silly to assume that only the golden ratio reflects some sort of perfection since humans are quite diverse. 

It is up to debate in the scientific community if the golden ratio found in the human skull’s midline indicates some complexity or is just a mere observation. 

Reference: The Journal of Craniofacial Surgery

Engineered viruses could fight drug resistance

Engineered viruses could fight drug resistance

In the battle against antibiotic resistance, many scientists have been trying to deploy naturally occurring viruses called bacteriophages that can infect and kill bacteria.

Bacteriophages kill bacteria through different mechanisms than antibiotics, and they can target specific strains, making them an appealing option for potentially overcoming multidrug resistance. However, quickly finding and optimizing well-defined bacteriophages to use against a bacterial target is challenging.

In a new study, MIT biological engineers showed that they could rapidly program bacteriophages to kill different strains of E. coli by making mutations in a viral protein that binds to host cells. These engineered bacteriophages are also less likely to provoke resistance in bacteria, the researchers found.

“As we’re seeing in the news more and more now, bacterial resistance is continuing to evolve and is increasingly problematic for public health,” says Timothy Lu, an MIT associate professor of electrical engineering and computer science and of biological engineering. “Phages represent a very different way of killing bacteria than antibiotics, which is complementary to antibiotics, rather than trying to replace them.”

The researchers created several engineered phages that could kill E. coli grown in the lab. One of the newly created phages was also able to eliminate two E. coli strains that are resistant to naturally occurring phages from a skin infection in mice.

Lu is the senior author of the study, which appears in the Oct. 3 issue of Cell. MIT postdoc Kevin Yehl and former postdoc Sebastien Lemire are the lead authors of the paper.

Engineered viruses

The Food and Drug Administration has approved a handful of bacteriophages for killing harmful bacteria in food, but they have not been widely used to treat infections because finding naturally occurring phages that target the right kind of bacteria can be a difficult and time-consuming process.

To make such treatments easier to develop, Lu’s lab has been working on engineered viral “scaffolds” that can be easily repurposed to target different bacterial strains or different resistance mechanisms.

“We think phages are a good toolkit for killing and knocking down bacteria levels inside a complex ecosystem, but in a targeted way,” Lu says.

In 2015, the researchers used a phage from the T7 family, which naturally kills E.coli, and showed that they could program it to target other bacteria by swapping in different genes that code for tail fibers, the protein that bacteriophages use to latch onto receptors on the surfaces of host cells.

While that approach did work, the researchers wanted to find a way to speed up the process of tailoring phages to a particular type of bacteria. In their new study, they came up with a strategy that allows them to rapidly create and test a much greater number of tail fiber variants.

From previous studies of tail fiber structure, the researchers knew that the protein consists of segments called beta sheets that are connected by loops. They decided to try systematically mutating only the amino acids that form the loops, while preserving the beta sheet structure.

“We identified regions that we thought would have minimal effect on the protein structure, but would be able to change its binding interaction with the bacteria,” Yehl says.

They created phages with about 10,000,000 different tail fibers and tested them against several strains of E. coli that had evolved to be resistant to the nonengineered bacteriophage. One way that E. coli can become resistant to bacteriophages is by mutating “LPS” receptors so that they are shortened or missing, but the MIT team found that some of their engineered phages could kill even strains of E. coli with mutated or missing LPS receptors.

This helps to overcome one of the limiting factors in using phages as antimicrobials, which is that bacteria can generate resistance by mutating receptors that the phages use to enter bacteria, says Rotem Sorek, a professor of molecular genetics at the Weizmann Institute of Science.

“Through deep understanding of the biology entailing the phage-bacteria recognition, together with smart bioengineering approaches, Lu and his team managed to design a large library of phage variants, each of which has the potential to recognize a slightly different receptor. They show that treating bacteria with this library rather than with a single phage limits the emergence of resistance,” says Sorek, who was not involved in the study.

Other targets

Lu and Yehl now plan to apply this approach to targeting other resistance mechanisms used by E. coli, and they also hope to develop phages that can kill other types of harmful bacteria. “This is just the beginning, as there are many other viral scaffolds and bacteria to target,” Yehl says. The researchers are also interested in using bacteriophages as a tool to target specific strains of bacteria that live in the human gut and cause health problems.

“Being able to selectively hit those nonbeneficial strains could give us a lot of benefits in terms of human clinical outcomes,” Lu says.

The research was funded by the Defense Threat Reduction Agency, the National Institutes of Health, the U.S. Army Research Laboratory/Army Research Office through the MIT Institute for Soldier Nanotechnologies, and the Koch Institute Support (core) Grant from the National Cancer Institute.

Materials provided by Massachusetts Institute of Technology

Scientists study how wasps learn for better trap

Scientists study how wasps learn for better trap

On lingering warm fall days, hungry wasps are often unwelcome guests at picnics and tailgates, homing in on hamburgers and buzzing bottles.

It’s worse in parts of the southern United States, where paper wasp species swarm air traffic control towers and other tall, solitary buildings during fall mating season.

Scientists at Washington State University aim to take the sting out of these encounters. Partnering with the U.S. Department of Defense, WSU entomologists are studying wasps’ ability to learn and respond to chemical signals, with the goal of building a better paper wasp trap.

Hungry, unwanted visitors

The European paper wasp, Polistes dominula, gains its name from the paper it makes to build its umbrella-shaped nests, often found under eaves across North America.

While less aggressive than their yellowjacket cousins, from whom they subtly differ in appearance, paper wasps will deliver a painful sting if their nests are threatened.

Paper wasps will occasionally feed on nectar and fermenting substances, but also prey on insects as a protein source for their young. That makes human food especially attractive as summer ends and insect prey, such as aphids and caterpillars, become rare.

Megan Asche holds a vial containing a paper wasp.

Doctoral student Megan Asche views captive wasps in a vial at her WSU lab.

“They’re looking for protein and sugar,” said Megan Asche, a WSU Department of Entomology doctoral student. “That’s why they show up at your house, zoom around your garbage can, and take a bite out of your sandwich.”

Paper wasps can be hard to eliminate from homes and yards, because they’re different from other wasp species.

“They’re not attracted to the same things that yellowjackets and hornets are,” Asche said. “We’re trying to find something that works better for these animals—a better wasp trap.”

Buzzing the control tower

Funded by a five-year, $366,000 Department of Defense grant, Asche’s research is spurred by an annual wasp invasion of military airstrips in the southern U.S.

Like many flying insects, paper wasps seek a preferred place to mate. Drones look for queens at places called hill-topping sites: “Basically a really tall thing surrounded by flat, open space,” Asche said. “An air control tower is exactly what wasps are looking for.”

The presence of thousands of wasps in and around the tower, crawling on radar screens and personnel, makes the job of air traffic controllers much harder.

“We need to figure out what we can use to attract wasps away from the towers,” Asche said.

Can wasps learn?

Paper wasps tending a growing nest.

Paper wasps tending a growing nest. Swarming during fall mating season, wasps can pose a challenge at air traffic control towers (Photo by Megan Asche).

To do that, she is studying wasps’ ability to learn and react to chemical signals.

“Wasps are a lot more flexible in their behavior than most insects,” Asche said. “They eat a lot of different foods, plants, and animals, so they’re capable of adjusting to their environment and changing their routine.”

In Asche’s lab, wasps are put into a flight tunnel—a large see-through plastic box with electric fans on both ends. Near one end is a nozzle emitting scent, either extracted from flowers or isolated from the wasps themselves.

Wasps are released one at a time into the tunnel, and Asche carefully notes how they react to the scent.

“That’s a perfect flight!” Asche remarked as one male wasp was put through the paces. He soon reacted to the odor, questing and landing near the nozzle’s tip.

“I’m trying to see how quickly they can learn,” she explained. “If we understand how they learn, we can teach them to associate an odor with food, and replace it with a working trap.”

Deciphering wasps’ chemical signals

Asche and other WSU entomologists are also exploring the chemistry behind wasp reactions. They are isolating and identifying the compounds they use to communicate and congregate.

The team has had surprising success using synthetic lures to successfully trap and remove wasps, both in Washington state and the southern U.S.

“Paper wasps are a beneficial part of our ecology, but they don’t belong in our buildings,” Asche said. “For people who don’t want to interact with wasps, our research could really bring peace of mind.”

Materials provided by Washington State University

Scientists detect new structures in tooth enamel to explain its incredible strength

Scientists detect new structures in tooth enamel to explain its incredible strength

A recent glance at the nanostructure of tooth enamel helps to explain the unbelievable resilience of the hardest substance in the human body.

The outer layer of the tooth enamel which surrounds and shields other tissue inside the tooth appears like bone but is actually living tissue. The teeth once developed has no natural capability to self-regrow or repair. Tooth enamel, a very hard substance, harder than steel is produced during the mineralization process and new investigation helps to answer the reason behind its exceptional resilience.

Pupa Gilbert, a biophysicist from the University of Wisconsin-Madison said that every time while chewing, enormous pressure is applied on tooth enamel several hundred times per day. Our enamel being unique manages to do it the whole lifetime, so the question arises how does it prevent any failure?

The answer is the “hidden structure” of tooth enamel which is a microscopic structural arrangement of the nanocrystals forming the outer layer of the teeth. These very minute crystals measuring less than one-thousandth the thickness of a human hair which is also found in the teeth of other animals are made of a kind of calcium apatite known as hydroxyapatite. The work appears in Nature Communications. 

Gilbert said that they didn’t have the methods to look at the structure of enamel before this study but they can determine and visualize the color orientation of individual nanocrystals and observe several of them at once with a method called polarisation-dependent imaging contrast (PIC) mapping.

He added that this electron microscopy method reveals the architecture of complex biominerals to the human eye. The scientists found that the hydroxyapatite nanocrystals were not oriented in the way that they had earlier assumed while using the PIC mapping technique. The crystals in enamel are grouped into structures called rods and inter-rods but the team identified misorientations of the crystal between adjacent nanocrystals ranging between 1 and 30 degrees.

The authors wrote in the paper that they have suggested that the misorientation of adjacent enamel nanocrystals provides a toughening mechanism i.e., a transverse crack can propagate across crystal interfaces if all crystals are eco-oriented whereas a crack primarily propagates along with the crystal interfaces if the crystals are misoriented.

The molecular dynamics simulations carried out by the team support the concept as testing this hypothesis in human teeth in real life is not feasible. The cracking is circulated more rapidly through crystal networks that didn’t look like human teeth misorientations (of 1 to 30 degrees) in a computer model configured to simulate the spreading of cracking through the enamel.

The team said that this range of nanocrystal misorientation may portray a sweet spot in crack deflection, selected by the long evolutionary history of the enamel. This sweet spot, crystals that are 1–30° apart may maximize the release of energy along with strengthening. The observed misorientations in enamel play a major mechanical role as crack deflection is an important toughening mechanism. They increase the toughness of enamel at the nanoscale, which is essential to withstand the powerful masticatory forces, nearing 1,000 newtons, repeated several thousand times per day.

Journal Reference: Nature Communications. 

Delivery system can make RNA vaccines more powerful

Delivery system can make RNA vaccines more powerful

Vaccines made from RNA hold great potential as a way to treat cancer or prevent a variety of infectious diseases. Many biotech companies are now working on such vaccines, and a few have gone into clinical trials.

One of the challenges to creating RNA vaccines is making sure that the RNA gets into the right immune cells and produces enough of the encoded protein. Additionally, the vaccine must stimulate a strong enough response that the immune system can wipe out the relevant bacteria, viruses, or cancer cells when they are subsequently encountered.

MIT chemical engineers have now developed a new series of lipid nanoparticles to deliver such vaccines. They showed that the particles trigger efficient production of the protein encoded by the RNA, and they also behave like an “adjuvant,” further boosting the vaccine effectiveness. In a study of mice, they used this RNA vaccine to successfully inhibit the growth of melanoma tumors.

“One of the key discoveries of this paper is that you can build RNA delivery lipids that can also activate the immune system in important ways,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.

Anderson is the senior author of the study, which appears in the Sept. 30 issue of Nature Biotechnology. The lead authors of the study are former postdocs Lei Miao and Linxian Li and former research associate Yuxuan Huang. Other MIT authors include Derfogail Delcassian, Jasdave Chahal, Jinsong Han, Yunhua Shi, Kaitlyn Sadtler, Wenting Gao, Jiaqi Lin, Joshua C. Doloff, and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute.

Vaccine boost

Most traditional vaccines are made from proteins produced by infectious microbes, or from weakened forms of the microbes themselves. In recent years, scientists have explored the idea of making vaccines using DNA that encodes microbial proteins. However, these vaccines, which have not been approved for use in humans, have so far failed to produce strong enough immune responses.

RNA is an attractive alternative to DNA in vaccines because unlike DNA, which has to reach the cell nucleus to become functional, RNA can be translated into protein as soon as it gets into the cell cytoplasm. It can also be adapted to target many different diseases.

“Another advantage of these vaccines is that we can quickly change the target disease,” he says. “We can make vaccines to different diseases very quickly just by tinkering with the RNA sequence.”

For an RNA vaccine to be effective, it needs to enter a type of immune cell called an antigen-presenting cell. These cells then produce the protein encoded by the vaccine and display it on their surfaces, attracting and activating T cells and other immune cells.

Anderson’s lab has previously developed lipid nanoparticles for delivering RNA and DNA for a variety of applications. These lipid particles form tiny droplets that protect RNA molecules and carry them to their destinations. The researchers’ usual approach is to generate libraries of hundreds or thousands of candidate particles with varying chemical features, then screen them for the ones that work the best.

“In one day, we can synthesize over 1,000 lipid materials with multiple different structures,” Miao says. “Once we had that very large library, we could screen the molecules and see which type of structures help RNA get delivered to the antigen-presenting cells.”

They discovered that nanoparticles with a certain chemical feature — a cyclic structure at one end of the particle — are able to turn on an immune signaling pathway called stimulator of interferon genes (STING). Once this pathway is activated, the cells produce interferon and other cytokines that provoke T cells to leap into action.

“Broad applications”

The researchers tested the particles in two different mouse models of melanoma. First, they used mice with tumors engineered to produce ovalbumin, a protein found in egg whites. The researchers designed an RNA vaccine to target ovalbumin, which is not normally found in tumors, and showed that the vaccine stopped tumor growth and significantly prolonged survival.

Then, the researchers created a vaccine that targets a protein naturally produced by melanoma tumors, known as Trp2. This vaccine also stimulated a strong immune response that slowed tumor growth and improved survival rates in the mice.

Anderson says he plans to pursue further development of RNA cancer vaccines as well as vaccines that target infectious diseases such as HIV, malaria, or Ebola.

“We think there could be broad applications for this,” he says. “A particularly exciting area to think about is diseases where there are currently no vaccines.”

Materials provided by Massachusetts Institute of Technology