The basic fact that Taiwan is part of China will not change regardless of the elections result of the region: FM

The elections of the Taiwan region are China's internal affairs and regardless of the result, it will not change the basic fact that Taiwan is part of China and there is only one China in the world, Chinese Foreign Ministry spokesperson Mao Ning said at a press conference on Friday.

Mao's remarks came in response to a question about how the results of the regional leader election on the island of Taiwan, scheduled on Saturday, will affect the cross-Straits relations.

During the press conference, a reporter also mentioned an anonymous official from the White House reportedly said that the US is committed to the one-China policy, does not support "Taiwan independence" and supports cross-Straits dialogue.

Mao said that the one-China principle is a prevailing international consensus and the political foundation of the China-US relationship. "Taiwan independence" is the biggest threat to cross-Straits peace and stability and is doomed to failure.

US leaders have repeatedly said that they are committed to the one-China policy, do not support "Taiwan independence," do not support "two Chinas" or "one China, one Taiwan," and do not seek to use the Taiwan question as a tool to contain China, said Mao.

We hope the US will honor these commitments, handle Taiwan-related issues prudently and properly, stop official interactions with Taiwan, stop sending wrong signals to "Taiwan independence" separatist forces, and refrain from interfering in the elections of the Taiwan region in any form, the spokesperson said.

If the US truly hopes to safeguard peace and stability in the Taiwan Strait, it needs to explicitly oppose "Taiwan independence" and support China's peaceful reunification, said Mao.

China steps up financial support for housing rental market

China's central bank and top financial regulator on Friday issued a guideline on stepping up financial support for the housing rental market, vowing to offer more innovative credit products and services for housing rentals and to expand financing channels for the housing rental market.

The guideline from the People's Bank of China (PBC) and the National Administration of Financial Regulation (NAFR) is the latest effort by Chinese policymakers to stabilize the real estate market, by both defusing risks and meeting housing needs for key population groups such as young workers.

The guideline contains a total of 17 measures in four areas. Financial support will focus on key areas and weak links in the housing rental market, mainly in large cities, and will focus on addressing housing difficulties for groups such as new urban residents and young workers.

The guideline aims to offer financial support for various entities to build, renovate and operate long-term rental housing, revitalize exiting housing inventory, and increase the supply of affordable and commercial rental housing.

Among the main measures, the guideline, which was sent to the PBC and the NAFR's local branches and various types of banks, calls for an increase in credit support for housing rental development and construction. Commercial banks are being encouraged to extend loans for entities, including real estate developers, for developing and constructing rental housing projects. The standard loan term would be three years and will not exceed five years.

On the purchasing side, the guideline also encouraged commercial banks to extend loans for entities that purchase housing rental for employees. The term for such loans cannot exceed 30 years and the amount should not exceed 80 percent of the property value.

China has made stabilizing the real estate market a top priority for economic work in 2024. The tone-setting Central Economic Work Conference held in December called for active and prudent efforts to defuse risks in the property sector, address the reasonable financing needs of real estate enterprises, and accelerate the development of a new model for the real estate sector.

Also on Friday, following a national central bank meeting, the PBC vowed to actively support the stable and sound development of the real estate market, strengthen monitoring, and take various credit policies to meet the reasonable financial needs of various types of real estate companies.

Xi’s ‘second integration’ proposal holds great significance for art education: Gao Shiming

The China Academy of Art has welcomed the celebration of its 95th anniversary since its ­establishment in the recently inaugurated Liangzhu campus in East ­China's Zhejiang Province. As the nation's first comprehensive national institution for higher artistic education, the art academy mirrors the evolution of contemporary Chinese art and artistic education over the last century.

Gao Shiming, president of the academy, told the Global Times that Chinese President Xi Jinping's emphasis on the need to combine fine traditional culture with the Marxist stand, viewpoint and approach, also known as the "second integration," holds significant implications for art education. In addition, humanity is entering the "second Renaissance," to which China is making global contributions. 

At a meeting on cultural inheritance and development in June, Xi called for the integration of the basic tenets of Marxism with traditional Chinese culture, known as the "second integration," which builds on the Communist Party of China's "first integration" of theoretical synthesis - the integration of the basic tenets of Marxism with China's specific reality, the Xinhua News Agency reported.

Ma Yifu, a renowned Chinese scholar, once asserted that Marxism has reactivated a socialist gene that exists in Chinese traditional cultural thought and social history, Gao said. 

Common core values

Traditional Chinese culture and Marxism share common core values, such as the concept of equality. Chinese philosopher Wang Yangming's proposal of "cultivating moral consciousness, envisioning every individual as a saint," aligns with Marx's perspective on equality.

Similarly, the integration of Marxism and China's fine traditional culture has been vividly manifested in Chinese art, placing the people at the center and elevating them as the social subjects.

For instance, in the 1950s and 1950s, the Zhejiang school of figure painting, led by Fang Zengxian, employed techniques traditionally used for emperors, bodhisattvas and flora to portray ordinary farmers. This marked a significant period in China's millennia-old art history.

From its inception, the China Academy of Art envisioned an academic mission of "introducing Western art, organizing Chinese art, reconciling Eastern and Western art, and creating contemporary art." Over the last 95 years, the institution has walked alongside the history of modern Chinese art, responding to national crises and reinventing itself in the face of contemporary challenges.

During this period, two scholarly ideas have consistently unfolded: One represented by the inaugural dean, Lin Fengmian, which embodies the "integration of Chinese and Western styles." The other school of thought, pioneered by figures like Huang Binhong and Zhao Wuji, follows the path of "innovation within tradition." Zhao created a form of modern painting from within the folds of Chinese tradition. He activated certain elements of Chinese tradition by using modern art, creating an alternative, distinct and unique form of modern painting that gained global recognition.

"The last 95 years have seen the China Academy of Art charting a path in modern art education deeply rooted in the Chinese soil, reflecting a journey of artistic revival that is both grounded in tradition and independently innovative," Gao said. 

What does a Renaissance require? "Prosperous technology, flourishing arts, developed commerce and a gathering of talents - we have all these elements now," Gao said.

'Second Renaissance'

He explained that the first Renaissance was catalyzed by an external factor - the Age of Discovery. Today, the internet serves as the great navigation of the 21st century. People in the world are not just witnessing a Renaissance in China but a global Renaissance in which China has started contributing to the world. 

In the 21st century, art education in China has taken on a more significant role, serving as a catalyst for societal innovation. The current Chinese society craves innovation, creativity and self-transcendence. Igniting the primitive innovative capabilities of the entire nation is crucial. 

"I often tell students not to confine themselves to being artists within the art realm but to become artists of the world," Gao said, adding that contemporary society demands the need for not just traditional artists but countless art professionals with the ability to innovate and imagine, solving real-world problems. This is the fundamental goal of the China Academy of Art - to foster a culture in which the entire art community contributes to the construction of a beautiful China and the high-quality development of the nation.

In the era of the first ­Renaissance, the world was not peaceful. Today, the world faces constant conflicts, making culture and art even more crucial as forces of reflection and reconciliation, guiding people into a more essential and expansive realm, allowing humanity a sense of transcendence.

The great French writer Flaubert once said, "Art and science met at the foot of the mountain and parted ways at the summit." The difficulty lies in people's journey not yet "reaching the summit," as people have technologized science and turned tools into technology. 

Gao believes there's no need to rush; scientists and artists can engage in more philosophical exchanges. Simultaneously, people can start with specific initiatives, such as promoting a course called "illusion." 

Scientists delve into the internal and physiological mechanisms of illusions, while artists design various illusions. This is a tangible course ­illustrating the fusion of science and art. 

From another perspective, in the era of general artificial intelligence, people might leverage AI to become individuals with more extensive space and creative capabilities, akin to Da Vinci's versatility. 

"As artificial intelligence advances, human artistic intelligence also grows," he said.

From day one, a frog’s developing brain is calling the shots

Frog brains get busy long before they’re fully formed. Just a day after fertilization, embryonic brains begin sending signals to far-off places in the body, helping oversee the layout of complex patterns of muscles and nerve fibers. And when the brain is missing, bodily chaos ensues, researchers report online September 25 in Nature Communications.

The results, from brainless embryos and tadpoles, broaden scientists’ understanding of the types of signals involved in making sure bodies develop correctly, says developmental biologist Catherine McCusker of the University of Massachusetts Boston. Scientists are familiar with short-range signals among nearby cells that help pattern bodies. But because these newly described missives travel all the way from the brain to the far reaches of the body, they are “the first example of really long-range signals,” she says.
Celia Herrera-Rincon of Tufts University in Medford, Mass., and colleagues came up with a simple approach to tease out the brain’s influence on the growing body. Just one day after fertilization, the scientists lopped off the still-forming brains of African clawed frog embryos. These embryos survive to become tadpoles even without brains, a quirk of biology that allowed the researchers to see whether the brain is required for the body’s development.
The answer was a definite — and surprising — yes, Herrera-Rincon says. Long before the brain is mature, it’s already organizing and guiding organ behavior, she says. Brainless tadpoles had bungled patterns of muscles. Normally, muscle fibers form a stacked chevron pattern. But in tadpoles lacking a brain, this pattern didn’t form correctly. “The borders between segments are all wonky,” says study coauthor Michael Levin, also of Tufts University. “They can’t keep a straight line.”
Nerve fibers that crisscross tadpoles’ bodies also grew in an abnormal pattern. Levin and colleagues noticed extra nerve fibers snaking across the brainless tadpoles in a chaotic pattern, “a nerve network that shouldn’t be there,” he says.

Muscle and nerve abnormalities are the most obvious differences. But brainless tadpoles probably have more subtle defects in other parts of their bodies, such as the heart. The search for those defects is the subject of ongoing experiments, Levin says.
In addition to keeping patterns on point, the young frog brain may protect its body from chemical assaults. A molecule that binds to certain proteins on cells in the body had no effect on normal embryos. But when given to brainless embryos, the same molecule caused their spinal cords and tails to grow crooked. These results suggest that early in development, brains keep embryos safe from agents that would otherwise cause harm.

“The brain is instructing cells that are really a long way away from it,” Levin says. While the precise identities of these long-range signals aren’t known, the researchers have some ideas. When brainless embryos were dosed with a drug that targets cells that typically respond to the chemical messenger acetylcholine, the muscle pattern improved. Similarly, the addition of a protein called HCN2 that can tweak the activity of cells also seemed to improve muscle development. More work is needed before scientists know whether these interventions are actually mimicking messaging from the early brain, and if so, how.

Frog development isn’t the same as mammalian development, but frog development “is pretty applicable to human biology,” McCusker says. In fundamental ways, humans and frogs are built from the same molecular toolbox, she says. So the results hint that a growing human brain might also interact similarly with a growing human body.

Here’s what really happened to Hanny’s Voorwerp

The weird glowing blob of gas known as Hanny’s Voorwerp was a 10-year-old mystery. Now, Lia Sartori of ETH Zurich and colleagues have come to a two-pronged solution.

Hanny van Arkel, then a teacher in the Netherlands, discovered the strange bluish-green voorwerp, Dutch for “object,” in 2008 as she was categorizing pictures of galaxies as part of the Galaxy Zoo citizen science project.

Further observations showed that the voorwerp was a glowing cloud of gas that stretched some 100,000 light-years from the core of a massive nearby galaxy called IC 2497. The glow came from radiation emitted by an actively feeding black hole in the galaxy.
To excite the voorwerp’s glow, the black hole and its surrounding accretion disk, the active galactic nucleus, or AGN, should have had the brightness of about 2.5 trillion suns; its radio emission, however, suggested the AGN emitted the equivalent of a relatively paltry 25,000 suns. Either the AGN was obscured by dust, or the black hole slowed its eating around 100,000 years ago, causing its brightness to plunge.

Sartori and colleagues made the first direct measurement of the AGN’s intrinsic brightness using NASA’s NuSTAR telescope, which observed IC 2497 in high-energy X-rays that cut through the dust.

They found that the AGN is obscured by dust and it is dimmer than expected; the feeding has slowed way down. The team reported on arXiv.org on November 20 that IC 2497’s heart is as bright as 50 billion to 100 billion suns, meaning it dropped in brightness by a factor of 50 in the past 100,000 years — a less dramatic drop than previously thought.
“Both hypotheses that we thought before are true,” Sartori says.

Sartori plans to analyze NuSTAR observations of other voorwerpjes to see if their galaxies’ black holes are also in the process of shutting down — or even booting up.

“If you look at these clouds, you get information on how the black hole was in the past,” she says. “So we have a way to study how the activity of supermassive black holes varies on superhuman time scales.”

Editor’s note: This story was updated December 5, 2017, to clarify that the brightness measured by the researchers came from the accretion disk around an actively eating black hole, not the black hole itself.

Pollinators are usually safe from a Venus flytrap

Out of the hundreds of species of carnivorous plants found across the planet, none attract quite as much fascination as the Venus flytrap. The plants are native to just a small section of North Carolina and South Carolina, but these tiny plants can now be found around the world. They’re a favorite among gardeners, who grow them in homes and greenhouses.

Scientists, too, have long been intrigued by the plants and have extensively studied the famous trap. But far less is known about the flower that blooms on a stalk 15 to 35 centimeters above — including what pollinates that flower.
“The rest of the plant is so incredibly cool that most folks don’t get past looking at the active trap leaves,” says Clyde Sorenson, an entomologist at North Carolina State University in Raleigh. Plus, notes Sorenson’s NCSU colleague Elsa Youngsteadt, an insect ecologist, because flytraps are native to just a small part of North and South Carolina, field studies can be difficult. And most people who raise flytraps cut off the flowers so the plant can put more energy into making traps.

Sorenson and Youngsteadt realized that the mystery of flytrap pollination was sitting almost literally in their backyard. So they and their colleagues set out to solve it. They collected flytrap flower visitors and prey from three sites in Pender County, North Carolina, on four days in May and June 2016, being careful not to damage the plants.

“This is one of the prettiest places where you could work,” Youngsteadt says. Venus flytraps are habitat specialists, found only in certain spots of longleaf pine savannas in the Carolinas. “They need plenty of sunlight but like their feet to be wet,” says Sorenson. In May and June, the spots of savanna where the flytraps grow are “just delightful,” he says. And other carnivorous plants can be found there, too, including pitcher plants and sundews.
The researchers brought their finds back to the lab for identification. They also cataloged what kind of pollen was on flower visitors, and how much.
Nearly 100 species of arthropods visited the flowers, the team reports February 5 in American Naturalist. “The diversity of visitors on those flowers was surprising,” says Youngsteadt. However, only three species — a sweat bee and two beetles — appeared to be the most important, as they were either the most frequent visitors or carriers of the most pollen.
The study also found little overlap between pollinators and prey. Only 13 species were found both in a trap and on a flower, and of the nine potential pollinators in that group, none were found in high numbers.

For a carnivorous plant, “you don’t want to eat your pollinators,” Sorenson says. Flytraps appear to be doing a good job at that.

There are three ways that a plant can keep those groups separate, the researchers note. Flowers and traps could exist at different times of the year. However, that’s not the case with Venus flytraps. The plants produce the two structures at separate times, but traps stick around and are active during plant flowering.

Another possibility is the spatial separation of the two structures. Pollinators tend to be fliers while prey were more often crawling arthropods, such as spiders and ants. This matches up with the high flowers and low traps. But the researchers would like to do some experiments that manipulate the heights of the structures to see just how much that separation matters, Youngsteadt says.

The third option is that different scents or colors produced by flowers and traps might lure in different species to each structure. That’s another area for future study, Youngsteadt says. While attraction to scent and color are well documented for traps, little is now known about those factors for the flowers.

Venus flytraps are considered vulnerable to extinction, threatened by humans, Sorenson notes. The plant’s habitat is being destroyed as the population of the Carolinas grows. What is left of the habitat is being degraded as fires are suppressed (fires help clear vegetation and keep sunlight shining on the flytraps). And people steal flytraps from the wild by the thousands.

While research into their pollinators won’t help with any of those threats, it could aid in future conservation efforts. “Anything we can do to better understand how this plant reproduces will be of use down the road,” Sorenson says.

But what really excites the scientists is that they discovered something new so close to home. “One of the most thrilling parts of all this,” Sorenson says, “is that this plant has been known to science for [so long], everyone knows it, but there’s still a whole lot of things to discover.”

The Neil Armstrong biopic ‘First Man’ captures early spaceflight’s terror

First Man is not a movie about the moon landing.

The Neil Armstrong biopic, opening October 12, follows about eight years of the life of the first man on the moon, and spends about eight minutes depicting the lunar surface. Instead of the triumphant ticker tape parades that characterize many movies about the space race, First Man focuses on the terror, grief and heartache that led to that one small step.

“It’s a very different movie and storyline than people expect,” says James Hansen, author of the 2005 biography of Armstrong that shares the film’s name and a consultant on the film.
The story opens shortly before Armstrong’s 2-year-old daughter, Karen, died of a brain tumor in January 1962. That loss hangs over the rest of the film, setting the movie’s surprisingly somber emotional tone. The cinematography is darker than most space movies. Colors are muted. Music is ominous or absent — a lot of scenes include only ambient sound, like a pen scratching on paper, a glass breaking or a phone clicking into the receiver.
Karen’s death also seems to motivate the rest of Armstrong’s journey. Getting a fresh start may have been part of the reason why the grieving Armstrong (portrayed by Ryan Gosling) applied to the NASA Gemini astronaut program, although he never explicitly says so. And without giving too much away, a private moment Armstrong takes at the edge of Little West crater on the moon recalls his enduring bond with his daughter.

Hansen’s book also makes the case that Karen’s death motivated Armstrong’s astronaut career. Armstrong’s oldest son, Rick, who was 12 when his father landed on the moon, agrees that it’s plausible. “But it’s not something that he ever really definitively talked about,” Rick Armstrong says.

Armstrong’s reticence about Karen — and almost everything else — is true to life. That’s not all the film got right. Gosling captured Armstrong’s gravitas as well as his humor, and Claire Foy as his wife, Janet Armstrong, “is just amazing,” Rick Armstrong says.

Beyond the performances, the filmmakers, including director Damien Chazelle and screenwriter Josh Singer, went to great lengths to make the technical aspects of spaceflight historically accurate. The Gemini and Apollo cockpits Gosling sits in are replicas of the real spacecraft, and he flipped switches and hit buttons that would have controlled real flight. Much of the dialog during space scenes was taken verbatim from NASA’s control room logs, Hansen says.

The result is a visceral sense of how frightening and risky those early flights were. The spacecraft rattled and creaked like they were about to fall apart. The scene of Armstrong’s flight on the 1966 Gemini 8 mission, which ended early when the spacecraft started spinning out of control and almost killed its passengers, is terrifying. The 1967 fire inside the Apollo 1 spacecraft, which killed astronauts Ed White, Gus Grissom and Roger Chaffee, is gruesome.

“We wanted to treat that one with extreme care and love and get it exactly right,” Hansen says. “What we have in that scene, none of it’s made up.”

Even when the filmmakers took poetic license, they did it in a historical way. A vomit-inducing gyroscope that Gosling rides in during Gemini astronaut training was, in real life, used for the earlier Mercury astronauts, but not for Gemini, for instance. Since the Mercury astronauts never experienced the kind of dizzying rotation that the gyroscope mimicked, NASA dismantled it before the next group of astronauts arrived.

“They probably shouldn’t have dismantled it,” Hansen says — it did simulate what ended up happening in the Gemini 8 accident. So the filmmakers used the gyroscope experience as foreshadowing.

Meanwhile, present-day astronauts are not immune to harrowing brushes with death: a Russian Soyuz capsule carrying two astronauts malfunctioned October 11, and the astronauts had to evacuate in an alarming “ballistic descent.” NASA is currently talking about when and how to send astronauts back to the moon from American soil. The first commercial crew astronauts, who will test spacecraft built by Boeing and SpaceX, were announced in August.

First Man is a timely and sobering reminder of the risks involved in taking these giant leaps.

Loneliness is bad for brains

SAN DIEGO — Mice yanked out of their community and held in solitary isolation show signs of brain damage.

After a month of being alone, the mice had smaller nerve cells in certain parts of the brain. Other brain changes followed, scientists reported at a news briefing November 4 at the annual meeting of the Society for Neuroscience.

It’s not known whether similar damage happens in the brains of isolated humans. If so, the results have implications for the health of people who spend much of their time alone, including the estimated tens of thousands of inmates in solitary confinement in the United States and elderly people in institutionalized care facilities.

The new results, along with other recent brain studies, clearly show that for social species, isolation is damaging, says neurobiologist Huda Akil of the University of Michigan in Ann Arbor. “There is no question that this is changing the basic architecture of the brain,” Akil says.
Neurobiologist Richard Smeyne of Thomas Jefferson University in Philadelphia and his colleagues raised communities of multiple generations of mice in large enclosures packed with toys, mazes and things to climb. When some of the animals reached adulthood, they were taken out and put individually into “a typical shoebox cage,” Smeyne said.

This abrupt switch from a complex society to isolation induced changes in the brain, Smeyne and his colleagues later found. The overall size of nerve cells, or neurons, shrunk by about 20 percent after a month of isolation. That shrinkage held roughly steady over three months as mice remained in isolation.
To the researchers’ surprise, after a month of isolation, the mice’s neurons had a higher density of spines — structures for making neural connections — on message-receiving dendrites. An increase in spines is a change that usually signals something positive. “It’s almost as though the brain is trying to save itself,” Smeyne said.

But by three months, the density of dendritic spines had decreased back to baseline levels, perhaps a sign that the brain couldn’t save itself when faced with continued isolation. “It’s tried to recover, it can’t, and we start to see these problems,” Smeyne said.

The researchers uncovered other worrisome signals, too, including reductions in a protein called BDNF, which spurs neural growth. Levels of the stress hormone cortisol changed, too. Compared with mice housed in groups, isolated mice also had more broken DNA in their neurons.

The researchers studied neurons in the sensory cortex, a brain area involved in taking in information, and the motor cortex, which helps control movement. It’s not known whether similar effects happen in other brain areas, Smeyne says.

It’s also not known how the neural changes relate to mice’s behavior. In people, long-term isolation can lead to depression, anxiety and psychosis. Brainpower is affected, too. Isolated people develop problems reasoning, remembering and navigating.

Smeyne is conducting longer-term studies aimed at figuring out the effects of neuron shrinkage on thinking skills and behavior. He and his colleagues also plan to return isolated mice to their groups to see if the brain changes can be reversed. Those types of studies get at an important issue, Akil says. “The question is, ‘When is it too far gone?’”

How locust ecology inspired an opera

Locust: The Opera finds a novel way to doom a soprano: species extinction.

The libretto, written by entomologist Jeff Lockwood of the University of Wyoming in Laramie, features a scientist, a rancher and a dead insect. The scientist tenor agonizes over why the Rocky Mountain locust went extinct at the dawn of the 20th century. He comes up with hypotheses, three of which unravel to music and frustration.

The project hatched in 2014. “Jeff got in his head, ‘Oh, opera is a good way to tell science stories,’ which takes a creative mind to think that,” says Anne Guzzo, who composed the music. Guzzo teaches music theory and composition at the University of Wyoming.
locust brought famine and ruin to farms across the western United States. “This was a devastating pest that caused enormous human suffering,” Lockwood says. Epic swarms would suddenly descend on and eat vast swaths of cropland. “On the other hand, it was an iconic species that defined and shaped the continent.” Lockwood had written about the locust’s mysterious and sudden extinction in the 2004 book Locust , but the topic “begged in my mind for the grandeur of opera.” He spent several years mulling how to create a one-hour opera for three singers about the swarming grasshopper species.
Then the ghost of Hamlet’s father, in the opera “Amleto,” based on Shakespeare’s play, inspired a breakthrough. Lockwood imagined a spectral soprano locust, who haunted a scientist until he figured out what killed her kind.

To make one locust soprano represent trillions, Guzzo challenged her music theory class to find ways of evoking the sound of a swarm. They tried snapping fingers, rattling cardstock and crinkling cellophane. But “the simplest answer was the most elegant,” Guzzo says — tasking the audience with shivering sheets of tissue paper in sequence, so that a great wave of rustling swept through the auditorium.

For the libretto, Lockwood took an unusually data-driven approach. After surveying opera lengths and word counts, he paced his work at 25 to 30 words per minute, policing himself sternly. If a scene was long by two words, he’d find two to cut.
He wrote the dialogue not in verse, but as conversation, some of it a bit professorial. Guzzo asked for a few line changes. “I just couldn’t get ‘manic expressions of fecundity’ to fit where I wanted it to,” she says.
Eventually, the scientist solves the mystery, but takes no joy in telling the beautiful locust ghost that humans had unwittingly doomed her kind by destroying vital locust habitat. For tragedy, Lockwood says, “there has to be a loss tinged with a kind of remorse.”

The opera, performed twice in Jackson, Wyo., will next be staged in March in Agadir, Morocco.

A gut-brain link for Parkinson’s gets a closer look

Martha Carlin married the love of her life in 1995. She and John Carlin had dated briefly in college in Kentucky, then lost touch until a chance meeting years later at a Dallas pub. They wed soon after and had two children. John worked as an entrepreneur and stay-at-home dad. In his free time, he ran marathons.

Almost eight years into their marriage, the pinky finger on John’s right hand began to quiver. So did his tongue. Most disturbing for Martha was how he looked at her. For as long as she’d known him, he’d had a joy in his eyes. But then, she says, he had a stony stare, “like he was looking through me.” In November 2002, a doctor diagnosed John with Parkinson’s disease. He was 44 years old.

Carlin made it her mission to understand how her seemingly fit husband had developed such a debilitating disease. “The minute we got home from the neurologist, I was on the internet looking for answers,” she recalls. She began consuming all of the medical literature she could find.

With her training in accounting and corporate consulting, Carlin was used to thinking about how the many parts of large companies came together as a whole. That kind of wide-angle perspective made her skeptical that Parkinson’s, which affects half a million people in the United States, was just a malfunction in the brain.Martha Carlin married the love of her life in 1995. She and John Carlin had dated briefly in college in Kentucky, then lost touch until a chance meeting years later at a Dallas pub. They wed soon after and had two children. John worked as an entrepreneur and stay-at-home dad. In his free time, he ran marathons.

Almost eight years into their marriage, the pinky finger on John’s right hand began to quiver. So did his tongue. Most disturbing for Martha was how he looked at her. For as long as she’d known him, he’d had a joy in his eyes. But then, she says, he had a stony stare, “like he was looking through me.” In November 2002, a doctor diagnosed John with Parkinson’s disease. He was 44 years old.

Carlin made it her mission to understand how her seemingly fit husband had developed such a debilitating disease. “The minute we got home from the neurologist, I was on the internet looking for answers,” she recalls. She began consuming all of the medical literature she could find.

With her training in accounting and corporate consulting, Carlin was used to thinking about how the many parts of large companies came together as a whole. That kind of wide-angle perspective made her skeptical that Parkinson’s, which affects half a million people in the United States, was just a malfunction in the brain.
“I had an initial hunch that food and food quality was part of the issue,” she says. If something in the environment triggered Parkinson’s, as some theories suggest, it made sense to her that the disease would involve the digestive system. Every time we eat and drink, our insides encounter the outside world.

John’s disease progressed slowly and Carlin kept up her research. In 2015, she found a paper titled, “Gut microbiota are related to Parkinson’s disease and clinical phenotype.” The study, by neurologist Filip Scheperjans of the University of Helsinki, asked two simple questions: Are the microorganisms that populate the guts of Parkinson’s patients different than those of healthy people? And if so, does that difference correlate with the stooped posture and difficulty walking that people with the disorder experience? Scheperjans’ answer to both questions was yes.

Carlin had picked up on a thread from one of the newest areas of Parkinson’s research: the relationship between Parkinson’s and the gut. Other than a small fraction of cases that are inherited, the cause of Parkinson’s disease is unknown. What is known is that something kills certain nerve cells, or neurons, in the brain. Abnormally misfolded and clumped proteins are the prime suspect. Some theories suggest a possible role for head trauma or exposure to heavy metals, pesticides or air pollution.
People with Parkinson’s often have digestive issues, such as constipation, long before the disease appears. Since the early 2000s, scientists have been gathering evidence that the malformed proteins in the brains of Parkinson’s patients might actually first appear in the gut or nose (people with Parkinson’s also commonly lose their sense of smell).
From there, the theory goes, these proteins work their way into the nervous system. Scientists don’t know exactly where in the gut the misfolded proteins come from, or why they form, but some early evidence points to the body’s internal microbial ecosystem. In the latest salvo, scientists from Sweden reported in October that people who had their appendix removed had a lower risk of Parkinson’s years later (SN: 11/24/18, p. 7). The job of the appendix, which is attached to the colon, is a bit of a mystery. But the organ may play an important role in intestinal health.

If the gut connection theory proves true — still a big if — it could open up new avenues to one day treat or at least slow the disease.

“It really changes the concept of what we consider Parkinson’s,” Scheperjans says. Maybe Parkinson’s isn’t a brain disease that affects the gut. Perhaps, for many people, it’s a gut disease that affects the brain.

Gut feeling
London physician James Parkinson wrote “An essay on the shaking palsy” in 1817, describing six patients with unexplained tremors. Some also had digestive problems. (“Action of the bowels had been very much retarded,” he reported of one man.) He treated two people with calomel — a toxic, mercury-based laxative of the time — and noted that their tremors subsided.

But the digestive idiosyncrasies of the disease that later bore Parkinson’s name largely faded into the background for the next two centuries, until neuroanatomists Heiko Braak and Kelly Del Tredici, now at the University of Ulm in Germany, proposed that Parkinson’s disease might arise from the intestine. Writing in Neurobiology of Aging in 2003, they and their colleagues based their theory on autopsies of Parkinson’s patients.
The researchers were looking for Lewy bodies, which contain clumps of a protein called alpha-synuclein. The presence of Lewy bodies in the brain is a hallmark of Parkinson’s, though their exact role in the disease is still under investigation.

Lewy bodies form when alpha-synuclein, which is produced by neurons and other cells, starts curdling into unusual strands. The body encapsulates the abnormal alpha-synuclein and other proteins into the round Lewy body bundles. In the brain, Lewy bodies collect in the cells of the substantia nigra, a structure that helps orchestrate movement. By the time symptoms appear, much of the substantia nigra is already damaged.

Substantia nigra cells produce the chemical dopamine, which is important for movement. Levodopa, the main drug prescribed for Parkinson’s, is a synthetic replacement for dopamine. The drug has been around for a half-century, and while it can alleviate symptoms for a while, it does not slow the destruction of brain cells.

In patient autopsies, Braak and his team tested for the presence of Lewy bodies, as well as abnormal alpha-s­ynuclein that had not yet become bundled together. Based on comparisons with people without Parkinson’s, the researchers found signs that Lewy bodies start to form in the nasal passages and intestine before they show up in the brain. Braak’s group proposed that Parkinson’s disease develops in stages, migrating from the gut and nose into the nerves to reach the brain.

Neural highway
Today, the idea that Parkinson’s might arise from the intestine, not the brain, “is one of the most exciting things in Parkinson’s disease,” says Heinz Reichmann, a neurologist at the University of Dresden in Germany. The Braak theory couldn’t explain how the Lewy bodies reach the brain, but Braak speculated that some sort of pathogen, perhaps a virus, might travel along the body’s nervous system, leaving a trail of Lewy bodies.

There is no shortage of passageways: The intestine contains so many nerves that it’s sometimes called the body’s second brain. And the vagus nerve offers a direct connection between those nerves in the gut and the brain (SN: 11/28/15, p. 18).

In mice, alpha-synuclein can indeed migrate from the intestine to the brain, using the vagus nerve like a kind of intercontinental highway, as Caltech researchers demonstrated in 2016 (SN: 12/10/16, p. 12). And Reichmann’s experiments have shown that mice that eat the pesticide rotenone develop symptoms of Parkinson’s. Other teams have shown similar reactions in mice that inhale the chemical. “What you sniff, you swallow,” he says.

To look at this idea another way, researchers have examined what happens to Parkinson’s risk when people have a weak or missing vagus nerve connection. There was a time when doctors thought that an overly eager vagus nerve had something to do with stomach ulcers. Starting around the 1970s, many patients had the nerve clipped as an experimental means of treatment, a procedure called a vagotomy. In one of the latest studies on vagotomy and Parkinson’s, researchers examined more than 9,000 patients with vagotomies, using data from a nationwide patient registry in Sweden. Among people who had the nerve cut down low, just above the stomach, the risk of Parkinson’s began dropping five years after surgery, eventually reaching a difference of about 50 percent compared with people who hadn’t had a vagotomy, the researchers reported in 2017 in Neurology.
The studies are suggestive, but by no means definitive. And the vagus nerve may not be the only possible link the gut and brain share. The body’s immune system might also connect the two, as one study published in January in Science Translational Medicine found. Study leader Inga Peter, a genetic epidemiologist at the Icahn School of Medicine at Mount Sinai in New York City, was looking for genetic contributors to Crohn’s disease, an inflammatory bowel condition that affects close to 1 million people in the United States.

She and a worldwide team studied about 2,000 people from an Ashkenazi Jewish population, which has an elevated risk of Crohn’s, and compared them with people without the disease. The research led Peter and colleagues to suspect the role of a gene called LRRK2. That gene is involved in the immune system — which mistakenly attacks the intestine in people who have Crohn’s. So it made sense for a variant of that gene to be involved in inflammatory disease. The researchers were thrown, however, when they discovered that versions of the gene also appeared to increase the risk for Parkinson’s disease.

“We refused to believe it,” Peter says. The finding, although just a correlation, suggested that whatever the gene was doing to the intestine might have something to do with Parkinson’s. So the team investigated the link further, reporting results in the August JAMA Neurology.

In their analysis of a large database of health insurance claims and prescriptions, the scientists found more evidence of inflammation’s role. People with inflammatory bowel disease were about 30 percent more likely to develop Parkinson’s than people without it. But among those who had filled prescriptions for an anti-inflammatory medication called antitumor necrosis factor, which the researchers used as a marker for reduced inflammation, Parkinson’s risk was 78 percent lower than in people who had not filled prescriptions for the drug.

Belly bacteria
Like Inga Peter, microbiologist Sarkis Mazmanian of Caltech came upon Parkinson’s disease almost by accident. He had long studied how the body’s internal bacteria interact with the immune system. At lunch one day with a colleague who was studying autism using a mouse version of the disease, Mazmanian asked if he could take a look at the animals’ intestines. Because of the high density of nerves in the intestine, he wanted to see if the brain and gut were connected in autism.

Neurons in the gut “are literally one cell layer away from the microbes,” he says. “That made me feel that at least the physical path or conduit was there.” He began to study autism, but wanted to switch to a brain disease with more obvious physical symptoms. When he learned that people with Parkinson’s disease often have a long history of digestive problems, he had his subject.

Mazmanian’s group examined mice that were genetically engineered to overproduce alpha-synuclein. He wanted to know whether the presence or absence of gut bacteria influenced symptoms that developed in the mice.

The results, reported in Cell in 2016, showed that when the mice were raised germ free — meaning their insides had no microorganisms — they showed no signs of Parkinson’s. The animals had no telltale gait or balance problems and no constipation, even though their bodies made alpha-synuclein (SN: 12/24/16 & 1/7/17, p. 10). “All the features of Parkinson’s in the animals were gone when the animals had no microbiome,” he says.

However, when gut microbes from people diagnosed with Parkinson’s were transplanted into the germ-free mice, the mice developed symptoms of the disease — symptoms that were much more severe than those in mice transplanted with microbes from healthy people.

Mazmanian suspects that something in the microbiome triggers the misfolding of alpha-synuclein. But this has not been tested in humans, and he is quick to say that this is just one possible explanation for the disease. “There’s likely no one smoking gun,” he says.

Microbial forces
If the microbiome is involved, what exactly is it doing to promote Parkinson’s? Microbiologist Matthew Chapman of the University of Michigan in Ann Arbor thinks it may have something to do with chemical signals that bacteria send to the body. Chapman studies biofilms, which occur when bacteria form resilient colonies. (Think of the slime on the inside a drain pipe.)

Part of what makes biofilms so hard to break apart is that fibers called amyloids run through them. Amyloids are tight stacks of proteins, like columns of Legos. Scientists have long suspected that amyloids are involved in degenerative diseases of the brain, including Alzheimer’s. In Parkinson’s, amyloid forms of alpha-synuclein are found in Lewy bodies.

Despite amyloids’ bad reputation, the fibers themselves aren’t always undesirable, Chapman says. Sometimes they may provide a good way of storing proteins for future use, to be snapped off brick by brick as needed. Perhaps it’s only when amyloids form in the wrong place, like the brain, that they contribute to disease. Chapman’s lab group has found that E. coli bacteria, part of the body’s normal microbial population, produce amyloid forms of some proteins when they are under stress.

When gut bacteria produce amyloids, the body’s own cells could also be affected, wrote Chapman in 2017 in PLOS Pathogens with an unlikely partner: neurologist Robert Friedland of the University of Louisville School of Medicine in Kentucky. “This is a difficult field to study because it’s on the border of several fields,” Friedland says. “I’m a neurologist who has little experience in gastro­enterology. When I talked about this to my colleagues who are gastroenterologists, they’ve never heard that bacteria make amyloid.”
Friedland and collaborators reported in 2016 in Scientific Reports that when E. coli in the intestines of rats started to produce amyloid, alpha-synuclein in the rats’ brains also congealed into the amyloid form. In their 2017 paper, Chapman and Friedland suggested that the immune system’s reaction to the amyloid in the gut might have something to do with triggering amyloid formation in the brain.

In other words, when gut bacteria get stressed and start to produce their own amyloids, those microbes may be sending cues to nearby neurons in the intestine to follow suit. “The question is, and it’s still an outstanding question, what is it that these bacteria are producing that is, at least in animals, causing alpha-synuclein to form amyloids?” Chapman says.

Head for a cure
There is, in fact, a long list of questions about the microbiome, says Scheperjans, the neurologist whose paper Martha Carlin first spotted. So far, studies of the microbiomes of human patients are largely limited to simple observations like his, and the potential for a microbiome connection has yet to reach deeply into the neurology community. But in O­ctober, for the second year in a row, Scheperjans says, the International Congress of Parkinson’s Disease and Movement Disorders held a panel discussing connections to the microbiome.

“I got interested in the gastrointestinal aspects because the patients complained so much about it,” he says. While his study found definite differences in the bacteria of people with Parkinson’s, it’s still too early to know how that might matter. But Scheperjans hopes that one day doctors may be able to test for microbiome changes that put people at higher risk for Parkinson’s, and restore a healthy microbe population through diet or some other means to delay or prevent the disease.
One way to slow the disease might be shutting down the mobility of misfolded alpha-synuclein before it has even reached the brain. In Science in 2016, neuroscientist Valina Dawson and colleagues at Johns Hopkins University School of Medicine and elsewhere described using an antibody to halt the spread of bad alpha-synuclein from cell to cell. The researchers are working now to develop a drug that could do the same thing.

The goal is to one day test for the early development of Parkinson’s and then be able to tell a patient, “Take this drug and we’re going to try to slow and prevent progression of disease,” she says.

For her part, Carlin is doing what she can to speed research into connections between the microbiome and Parkinson’s. She quit her job, sold her house and drained her retirement account to pour money into the cause. She donated to the University of Chicago to study her husband’s microbiome. And she founded a company called the BioCollective to aid in microbiome research, providing free collection kits to people with Parkinson’s. The 15,000 microbiome samples she has collected so far are available to researchers.

Carlin admits that the possibility of a gut connection to Parkinson’s can be a hard sell. “It’s a difficult concept for people to wrap their head around when you are taking a broad view,” she says. As she searches for answers, her husband, John, keeps going. “He drives, he runs biking programs in Denver for people with Parkinson’s,” she says. Anything to keep the wheels turning toward the future.One way to slow the disease might be shutting down the mobility of misfolded alpha-synuclein before it has even reached the brain. In Science in 2016, neuroscientist Valina Dawson and colleagues at Johns Hopkins University School of Medicine and elsewhere described using an antibody to halt the spread of bad alpha-synuclein from cell to cell. The researchers are working now to develop a drug that could do the same thing.

The goal is to one day test for the early development of Parkinson’s and then be able to tell a patient, “Take this drug and we’re going to try to slow and prevent progression of disease,” she says.

For her part, Carlin is doing what she can to speed research into connections between the microbiome and Parkinson’s. She quit her job, sold her house and drained her retirement account to pour money into the cause. She donated to the University of Chicago to study her husband’s microbiome. And she founded a company called the BioCollective to aid in microbiome research, providing free collection kits to people with Parkinson’s. The 15,000 microbiome samples she has collected so far are available to researchers.

Carlin admits that the possibility of a gut connection to Parkinson’s can be a hard sell. “It’s a difficult concept for people to wrap their head around when you are taking a broad view,” she says. As she searches for answers, her husband, John, keeps going. “He drives, he runs biking programs in Denver for people with Parkinson’s,” she says. Anything to keep the wheels turning toward the future.