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Several Down syndrome features may be linked to a hyperactive antiviral immune response – new research

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Several Down syndrome features may be linked to a hyperactive antiviral immune response – new research

Addressing the increased risks of certain diseases among those with Down syndrome could improve their quality of .
Halfpoint Images/Moment via Getty Images

Joaquin Espinosa, University of Colorado Anschutz Medical Campus

People with Down syndrome, or trisomy 21, a genetic caused by an extra copy of human chromosome 21, experienced a remarkable increase in life expectancy during the 20th century. In the early 1900s, less than 20% of newborns with Down syndrome survived past age 5. In the U.S. , more than 90% of babies with this condition live past age 10 and have a life expectancy of nearly 60 years. These increases were likely fueled by greater inclusion in general society, the discontinuation of institutionalization in psychiatric facilities and better medical care.

Despite these advances, people with trisomy 21 experience an increased risk of many co-occurring conditions, such as congenital heart defects, autoimmune conditions, autism spectrum disorders and Alzheimer's disease. On the other hand, people with Down syndrome tend to have lower levels of hypertension and certain types of cancers.

Karyotype of Down syndrome, with a circle around three copies of chromosome 21
Down syndrome is also called trisomy 21 because those with the condition have three copies of chromosome 21.
Kateryna Kon/Science Photo Library via Getty Images

Understanding how an extra chromosome 21 causes these risks and resiliencies could advance collective understanding of major medical conditions that also affect the general population. For example, the increased risk of Alzheimer's disease among adults with Down syndrome can be explained in part by the presence of a gene on chromosome 21 that to excess production of the beta-amyloid proteins and plaques characteristic of Alzheimer's.

In our newly published research, my research team and I found that genes involved in controlling the immune system are critical to the of multiple hallmarks of Down syndrome. Our findings contribute to a growing body of research on the immune system's important role in the appearance and severity of some of the negative effects of trisomy 21, supporting the idea that restoring immune balance could help improve the quality of life of people with the condition.

When too much of a good thing is bad

The genes we identified, which encode what are called interferon receptors, are an important part of the immune system's antiviral defense. These genes enable our cells to recognize a set of proteins called interferons, which virus-infected cells produce to alert the yet uninfected cells around them about the presence of a virus during an infection.

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While interferons do trigger a beneficial immune response against viral infections, chronic interferon hyperactivity could have detrimental effects. Too much interferon signaling is known to be harmful in medical conditions such as systemic lupus erythematosus, a group of genetic disorders known as interferonopathies and severe COVID-19.

3D model of human interferon-beta structure
Interferons are involved in antiviral immune responses.
Nevit Dilmen/Wikimedia Commons, CC BY-SA

Notably, four of the six human interferon receptor genes are located on chromosome 21. Most people have only two copies of each chromosome and so would have only two copies of these genes. Because people with Down syndrome have three copies of chromosome 21, they also have three copies of the interferon receptor genes on it. This contributes to the overproduction of interferon receptors seen in those with Down syndrome.

Our team wanted to know whether this extra copy of interferon receptor genes, with the roughly 200 other genes located on chromosome 21, contribute to features of Down syndrome. To do this, we used a mouse model of Down syndrome. In this mouse model, a large region of its genome that is equivalent to a large portion of human chromosome 21 is triplicated to reproduce many features of Down syndrome.

Using CRISPR gene editing technology, we reduced the number of interferon receptor genes from three to the typical two, leaving all other triplicated genes intact. We found that correcting the number of interferon receptor genes significantly reduced abnormal gene expression patterns across multiple tissue types, both during embryonic development and in adult mice. These mice also had more regulated immune responses, normal heart development, reduced developmental delays, improved performance on memory and learning tasks and even a more typical skull and facial morphology.

Overall, our findings suggest that the tripling of interferon receptor genes may cause a number of key traits of Down syndrome.

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Therapeutic implications and future directions

Our research indicates that many, though not all, aspects of Down syndrome may be associated with hyperactivity of the immune system's interferon response. It also supports the possibility of using that attenuate this response to treat some of the negative health effects of trisomy 21.

Our team is currently leading two clinical trials to test the safety and efficacy of one such drug, tofacitinib (Xeljanz). This drug belongs to a class of drugs known as JAK inhibitors used to treat autoinflammatory conditions. One trial focuses on autoimmune skin conditions more common in Down syndrome. The second trial focuses on Down syndrome regression disorder, or DSRD, a rare but devastating neurological condition that can result in loss of speech, sleep disruptions, difficulty moving and hallucinations. There is evidence that suggests that a subset of DSRD cases may be caused by immune dysregulation affecting the brain.

Person with Down syndrome holding a potted plant in a nursery
Treating the common health risks that occur with Down syndrome could help improve quality of life.
Flashpop/DigitalVision via Getty Images

Our study findings also further investigation into the effects of interferon hyperactivity on fetal development more generally. Two of the key traits of Down syndrome that we found were affected by the tripling of interferon receptors – congenital heart disease and skull and facial shape – develop in utero.

Though our research shows promise on the potential of JAK inhibitors and other drugs that modulate the immune system to improve health outcomes in Down syndrome, more research in people is needed to determine their safety and efficacy.The Conversation

Joaquin Espinosa, Professor of Pharmacology, University of Colorado Anschutz Medical Campus

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Boeing’s Starliner is about to launch − if successful, the test represents an important milestone for commercial spaceflight

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theconversation.com – Wendy Whitman Cobb, Professor of Strategy and Security Studies, Air – 2024-05-02 07:24:25

Boeing's Starliner spacecraft on approach to the International Station during an uncrewed test in 2022.

Bob Hines/NASA

Wendy Whitman Cobb, Air University

If all goes well late on May 6, 2024, NASA astronauts Butch Wilmore and Suni Williams will blast off into space on Boeing's Starliner spacecraft. Launching from the Kennedy Space Center, this last crucial test for Starliner will test out the new spacecraft and take the pair to the International Space Station for about a week.

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Part of NASA's commercial crew program, this long-delayed mission will represent the vehicle's first crewed launch. If successful, it will give NASA – and in the future, space tourists – more options for getting to low Earth orbit.

Two people wearing blue jumpsuits hug in front of a plane.

Suni Williams, right, and Butch Wilmore, the two astronauts who will crew the Starliner test.

AP Photo/Terry Renna

From my perspective as a space policy expert, Starliner's launch represents another significant milestone in the development of the commercial space industry. But the mission's troubled history also shows just how difficult the path to space can be, even for an experienced company like Boeing.

Origins and development

the retirement of NASA's space shuttle in 2011, NASA invited commercial space companies to the agency transport cargo and crew to the International Space Station.

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In 2014, NASA selected Boeing and SpaceX to build their respective crew vehicles: Starliner and Dragon.

Boeing's vehicle, Starliner, was built to carry up to seven crew members to and from low Earth orbit. For NASA missions to the International Space Station, it will carry up to four at a time, and it's designed to remain docked to the station for up to seven months. At 15 feet, the capsule where the crew will sit is slightly bigger than an Apollo command module or a SpaceX Dragon.

Boeing designed Starliner to be partially reusable to reduce the cost of getting to space. Though the Atlas V rocket it will take to space and the service module that supports the craft are both expendable, Starliner's crew capsule can be reused up to 10 times, with a six-month turnaround. Boeing has built two flightworthy Starliners to date.

A conical vehicle sitting on a flat vehicle.

The Starliner capsule in transit.

AP Photo/John Raoux

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Starliner's development has come with setbacks. Though Boeing received US$4.2 from NASA, compared with $2.6 billion for SpaceX, Boeing spent more than $1.5 billion extra in developing the spacecraft.

On Starliner's first uncrewed test flight in 2019, a series of software and hardware failures prevented it from getting to its planned orbit as well as docking with the International Space Station. After testing out some of its systems, it landed successfully at White Sands Missile Range in New Mexico.

In 2022, after identifying and making more than 80 fixes, Starliner conducted a second uncrewed test flight. This time, the vehicle did successfully dock with the International Space Station and landed six days later in New Mexico.

The inside of a Starliner holds a few astronauts. Crew members first trained for the launch in a simulator.

Still, Boeing delayed the first crewed launch for Starliner from 2023 to 2024 because of additional problems. One involved Starliner's parachutes, which help to slow the vehicle as it returns to Earth. Tests found that some links in those parachute lines were weaker than expected, which could have caused them to break. A second problem was the use of flammable tape that could pose a fire hazard.

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A major question stemming from these delays concerns why Starliner has been so difficult to develop. For one, NASA officials admitted that it did not provide as much oversight for Starliner as it did for SpaceX's Dragon because of the agency's familiarity with Boeing.

And Boeing has experienced several problems recently, most visibly with the safety of its airplanes. Astronaut Butch Wilmore has denied that Starliner's problems reflect these troubles.

But several of Boeing's other space activities beyond Starliner have also experienced mechanical failures and budget pressure, the Space Launch System. This system is planned to be the main rocket for NASA's Artemis program, which plans to return humans to the Moon for the first time since the Apollo era.

Significance for NASA and commercial spaceflight

Given these difficulties, Starliner's success will be important for Boeing's future space efforts. Even if SpaceX's Dragon can successfully transport NASA astronauts to the International Space Station, the agency needs a backup. And that's where Starliner in.

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Following the Challenger explosion in 1986 and the Columbia shuttle accident in 2003, NASA retired the space shuttle in 2011. The agency was left with few options to get astronauts to and from space. Having a second commercial crew vehicle provider means that NASA will not have to depend on one company or vehicle for space launches as it previously had to.

Perhaps more importantly, if Starliner is successful, it could compete with SpaceX. Though there's no crushing demand for space right now, and Boeing has no plans to market Starliner for tourism anytime soon, competition is important in any market to down costs and increase innovation.

More such competition is likely coming. Sierra Space's Dream Chaser is planning to launch later this year to transport cargo for NASA to the International Space Station. A crewed version of the space plane is also being developed for the next round of NASA's commercial crew program. Blue Origin is working with NASA in this latest round of commercial crew contracts and developing a lunar lander for the Artemis program.

A conical white spacecraft with two rectangular solar panels in space, with the Earth in the background.

SpaceX's dragon capsule.

NASA TV via AP

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Though SpaceX has made commercial spaceflight look relatively easy, Boeing's rocky experience with Starliner shows just how hard spaceflight continues to be, even for an experienced company.

Starliner is important not just for NASA and Boeing, but to demonstrate that more than one company can find success in the commercial space industry. A successful launch would also give NASA more confidence in the industry's ability to operations in Earth's orbit while the agency focuses on future missions to the Moon and beyond.The Conversation

Wendy Whitman Cobb, Professor of Strategy and Security Studies, Air University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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Brain cancer in children is notoriously hard to treat – a new mRNA cancer vaccine triggers an attack from within

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theconversation.com – Christina von Roemeling, Assistant Professor of Neurosurgery, of Florida – 2024-05-01 10:01:09

How cancer vaccines are delivered into the body influences their effectiveness.

Liuhsihsiang/iStock via Getty Images Plus

Christina von Roemeling, University of Florida and John Ligon, University of Florida

Brain cancers remain among the most challenging tumors to treat. They often don't respond to traditional treatments because many chemotherapies are unable to penetrate the protective barrier around the brain. Other treatments like radiation and surgery can with lifelong debilitating side effects.

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As a result, brain cancer is the leading cause of cancer-related death in children. Brain tumors in frequently do not respond to treatments developed for adults, likely due to the fact that pediatric brain cancers are not as well-studied as adult brain cancers. There is an urgent need to develop new treatments specific to children.

We developed a new messenger-RNA, or mRNA, cancer vaccine, described in newly published research, that can deliver treatments more effectively in children who have brain cancer and teach their immune systems to fight back.

Close-up of child's hand with IV line placed held by adult's hand

Cancer treatments designed for adults may not necessarily work as well in children.

Virojt Changyencham/Moment via Getty Images

How do cancer vaccines work?

The immune system is a complex network of cells, tissues and organs whose primary function is to continuously surveil the body for threats posed by foreign invaders – pathogens that tissues and make you sick. It accomplishes this by recognizing antigens, or abnormal proteins or molecules, on pathogens. T cells that recognize these antigens seek out and destroy the pathogens.

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Your immune system also protects you from domestic threats like cancer. Over time, your cells sustain DNA damage from either internal or external stressors, leading to mutations. The proteins and molecules produced from mutated DNA look quite different from the ones cells typically produce, so your immune system can recognize them as antigens. Cancer develops when cells accumulate mutations that enable them to continue to grow and divide while simultaneously going undetected by the immune system.

In 1991, scientists identified the first tumor antigen, helping lay the framework for modern-day immunotherapy. Since then, researchers have identified many new tumor antigens, facilitating the development of cancer vaccines. Broadly, cancer vaccines deliver tumor antigens into the body to teach the immune system to recognize and attack cancer cells that display those antigens. Although all cancer vaccines conceptually work very similarly, they each significantly vary in the way they are developed and the number and combination of antigens they carry.

Cancer vaccines help the immune system differentiate between healthy cells and tumor cells.

One of the biggest differences among cancer vaccines is how they are created. Some vaccines use protein fragments, or peptides, of tumor antigens that are directly given to patients. Other vaccines use viruses reengineered to express cancer antigens. Even more complex are vaccines where a patient's own immune cells are collected and trained to recognize cancer antigens in a laboratory before being delivered back to the patient.

Currently, there is a lot of excitement and focus among researchers on developing mRNA-based cancer vaccines. Whereas DNA is the blueprint of which proteins to make, mRNA is a copy of the blueprint that tells cells how to build these proteins. Thus, researchers can use mRNA to create blueprint copies of potential antigens.

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mRNA cancer vaccines

The pandemic brought significant attention to the potential of using mRNA-based vaccines to stimulate the immune system and protection against the antigens they encode for. But researchers have been investigating the use of mRNA vaccines for treating various cancers since before the pandemic.

Our team of scientists in the Brain Tumor Immunotherapy Program at University of Florida has spent the past 10 years developing and optimizing mRNA vaccines to treat brain cancer.

Cancer vaccines have significant challenges. One key hurdle is that these vaccines may not always trigger a strong enough immune response to eradicate the cancer completely. Moreover, tumors are not made up of one type of cancer cell, but rather a complex mix of cancer cells that each harbors its own unique cocktail of mutations.

Our cancer vaccine seeks to address these issues in a number of ways.

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Diagram of lipid molecules formed a spherical shell around single-stranded mRNAs

Lipid nanoparticles can carry therapeutic mRNA into the body.

Buschmann et al. 2021/ Wikimedia Commons, CC BY-SA

First, we designed our vaccines by using the RNA of a patients' own cancer cells as a template for the mRNA inside our nanoparticles. We also packaged our cancer vaccine inside of nanoparticles made up of specialized lipids, or fat molecules. We maximized the amount of mRNA packaged within each nanoparticle by sandwiching them between lipid layers like the layers of an onion. In this way, we increase the likelihood that the mRNA molecules in our nanoparticles produce enough tumor antigens from that patient's cancer to activate an immune response.

Also, instead of injecting nanoparticles into the skin, muscle or directly into the tumor, as is commonly done for many therapeutic cancer vaccines, our mRNA nanoparticles are injected into the bloodstream. From there, they travel to organs throughout the body involved in the immune response to teach the body to fight against the cancer. By doing so, we've found that the immune system launches a near immediate and powerful response. Within six hours of receiving the vaccine, there is a significant increase in the amount of blood markers connected to immune activation.

Looking to the future

Our mRNA-based vaccines are currently undergoing early-phase clinical trials to treat real patients with brain cancer.

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We administered our mRNA-based vaccine to four adult patients with glioblastoma who had relapsed after previous treatment. All patients survived several months longer than the expected average survival at this advanced stage of illness. We expect to treat children with a type of brain tumor called pediatric high-grade glioma by the end of the year.

Importantly, mRNA vaccines can be developed to treat any kind of cancer, childhood brain tumors. Our Pediatric Cancer Immunotherapy Initiative focuses on developing new immune-based therapies for children afflicted with cancer. After developing an mRNA vaccine for glioma in chidren, we will expand to treat other kinds of pediatric brain cancers like medulloblastoma and potentially treat other kinds of cancers like skin cancer and bone cancer.

We are hopeful that mRNA-based vaccines may to more children being cured of their brain tumors.The Conversation

Christina von Roemeling, Assistant Professor of Neurosurgery, University of Florida and John Ligon, Assistant Professor of Hematology, University of Florida

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The perilous past and promising future of a toxic but nourishing crop

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theconversation.com – Stephen Wooding, Assistant Professor of Anthropology and Heritage Studies, University of California, Merced – 2024-05-01 07:36:48

A grower shows off his lush cassava garden.

Stephen Wooding, CC BY-ND

Stephen Wooding, University of California, Merced

The three staple crops dominating modern diets – corn, rice and wheat – are familiar to Americans. However, fourth place is held by a dark horse: cassava.

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While nearly unknown in temperate climates, cassava is a key source of nutrition throughout the tropics. It was domesticated 10,000 years ago, on the southern margin of the Amazon basin in Brazil, and spread from there throughout the region. With a scraggly stem a few meters tall, a handful of slim branches and modest, hand-shaped leaves, it doesn't look like anything special. Cassava's humble appearance, however, belies an impressive combination of productivity, toughness and diversity.

Five people sit in background with several piles of peeled and unpeeled cassava tubers

People preparing to cassava, with some peeled tubers in the foreground.

Philippe Giraud/Corbis Historical via Getty Images

Over the course of millennia, Indigenous peoples bred it from a weedy wild plant into a crop that stores prodigious quantities of starch in potatolike tubers, thrives in Amazonia's poor soils and is nearly invulnerable to pests.

Cassava's many assets would seem to make it the ideal crop. But there's a problem: Cassava is highly poisonous.

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How can cassava be so toxic, yet still dominate diets in Amazonia? It's all down to Indigenous ingenuity. For the past 10 years, my collaborator, César Peña, and I have been studying cassava gardens on the Amazon and its myriad tributaries in Peru. We have discovered scores of cassava varieties, growers using sophisticated breeding strategies to manage its toxicity, and elaborate methods for processing its dangerous yet nutritious products.

Long history of plant domestication

One of the most formidable challenges by early humans was getting enough to eat. Our ancient ancestors relied on hunting and gathering, catching prey on the and collecting edible plants at every . They were astonishingly good at it. So good that their populations soared, surging out of humanity's birthplace in Africa 60,000 years ago.

Even so, there was room for improvement. Searching the landscape for food burns calories, the very resource being sought. This paradox forced a trade-off for the hunter-gatherers: burn calories searching for food or conserve calories by staying home. The trade-off was nearly insurmountable, but humans found a way.

A little more than 10,000 years ago, they cleared the hurdle with one of the most transformative innovations in history: plant and animal domestication. People discovered that when plants and animals were tamed, they no longer needed to be chased down. And they could be selectively bred, producing larger fruits and seeds and bulkier muscles to eat.

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Cassava was the champion domesticated plant in the neotropics. After its initial domestication, it diffused through the region, reaching sites as far north as Panama within a few thousand years. Growing cassava didn't completely eliminate people's need to search the forest for food, but it lightened the load, providing a plentiful, reliable food supply close to home.

, almost every rural family across the Amazon has a garden. Visit any household and you will find cassava roasting on the fire, being toasted into a chewy flatbread called casabe, fermenting into the beer called masato, and steaming in soups and stews. Before adopting cassava in these roles, though, people had to figure out how to deal with its toxicity.

Processing a poisonous plant

One of cassava's most important strengths, its pest resistance, is provided by a powerful defense system. The system relies on two chemicals produced by the plant, linamarin and linamarase.

These defensive chemicals are found inside cells throughout the cassava plant's leaves, stem and tubers, where they usually sit idle. However, when cassava's cells are damaged, by chewing or crushing, for instance, the linamarin and linamarase react, releasing a burst of noxious chemicals.

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One of them is notorious: cyanide gas. The burst contains other nasty substances as well, compounds called nitriles and cyanohydrins. Large doses of them are lethal, and chronic exposures permanently damage the nervous system. Together, these poisons deter herbivores so well that cassava is nearly impervious to pests.

Nobody knows how people first cracked the problem, but ancient Amazonians devised a complex, multistep process of detoxification that transforms cassava from inedible to delicious.

two women in hats peeling and shredding tubers

Women grind the cassava's starchy tubers into shreds.

Stephanie Maze/Corbis Historical via Getty Images

It begins with grinding cassava's starchy roots on shredding boards studded with fish teeth, chips of rock or, most often today, a rough sheet of tin. Shredding mimics the chewing of pests, causing the release of the root's cyanide and cyanohydrins. But they drift away into the air, not into the lungs and stomach like when they are eaten.

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Next, the shredded cassava is placed in rinsing baskets where it is rinsed, squeezed by hand and drained repeatedly. The action of the releases more cyanide, nitriles and cyanohydrins, and squeezing rinses them away.

Finally, the resulting pulp can be dried, which detoxifies it even further, or cooked, which finishes the process using heat. These steps are so effective that they are still used throughout the Amazon today, thousands of years since they were first devised.

man standing next to large vat with fire beneath, under thatch roof

People cooking cassava in the traditional way in the 1970s.

Education Images/Universal Images Group via Getty Images

A powerhouse crop poised to spread

Amazonians' traditional methods of grinding, rinsing and cooking are a sophisticated and effective means of converting a poisonous plant into a meal. Yet, the Amazonians pushed their efforts even further, taming it into a true domesticated crop. In addition to inventing new methods for processing cassava, they began keeping track and selectively growing varieties with desirable characteristics, gradually producing a constellation of types used for different purposes.

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In our travels, we have found more than 70 distinct cassava varieties that are highly diverse, physically and nutritionally. They include types ranging in toxicity, some of which need laborious shredding and rinsing and others that can be cooked as is, though none can be eaten raw. There are also types with different tuber sizes, growth rates, starch production and drought tolerance.

Their diversity is prized, and they are often given fanciful names. Just as American supermarkets stock apples called Fuji, Golden Delicious and Granny Smith, Amazonian gardens stock cassavas called bufeo (dolphin), arpón (harpoon), motelo (tortoise) and countless others. This creative breeding cemented cassava's place in Amazonian cultures and diets, ensuring its manageability and usefulness, just as the domestication of corn, rice and wheat cemented their places in cultures elsewhere.

While cassava has been ensconced in South and Central America for millennia, its story is far from over. In the age of climate change and mounting efforts toward sustainability, cassava is emerging as a possible world crop. Its durability and resilience make it easy to grow in variable environments, even when soils are poor, and its natural pest resistance reduces the need to protect it with industrial pesticides. In addition, while traditional Amazonian methods for detoxifying cassava can be slow, they are easy to replicate and speed up with modern machinery.

two workers in white coats, hair caps and gloves show off white clumps they are bagging

Workers package frozen cassava in bags at a Florida food processing plant.

Juan Silva/The Image Bank via Getty Images

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Furthermore, the preference of Amazonian growers to maintain diverse types of cassava makes the Amazon a natural repository for genetic diversity. In modern hands, they can be bred to produce new types, fitting purposes beyond those in Amazonia itself. These advantages spurred the first export of cassava beyond South America in the 1500s, and its range quickly spanned tropical Africa and Asia. Today, production in nations such as Nigeria and Thailand far outpaces production in South America's biggest producer, Brazil. These successes are raising optimism that cassava can become an eco-friendly source of nutrition for populations globally.

While cassava isn't a familiar name in the U.S. just yet, it's well on its way. It has long flown under the radar in the form of tapioca, a cassava starch used in pudding and boba tea. It's also the shelves in the snack aisle in the form of cassava chips and the baking aisle in naturally gluten- flour. Raw cassava is an emerging presence, too, showing up under the names “yuca” and “manioc” in stores catering to Latin American, African and Asian populations.

Track some down and give it a try. Supermarket cassava is perfectly safe, and recipes abound. Cassava fritters, cassava fries, cassava cakes … cassava's possibilities are nearly endless.


This article was co-authored by César Rubén Peña.The Conversation

Stephen Wooding, Assistant Professor of Anthropology and Heritage Studies, University of California, Merced

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This article is republished from The Conversation under a Creative Commons license. Read the original article.

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