Doctor with a syringe on the background of DNA.
Steve, a 60-year-old resident of the DC area who works in manufacturing, was always physically fit. In college, he played lacrosse in Division I, the highest level of intercollegiate athletics in the United States. Later, he stayed active by swimming, biking, and running--up until something strange happened around two years ago.
"It was hard for me to even get upstairs. I wasted away."
Steve, who requested that his last name be withheld to protect his privacy, started to notice weakness first in his toes, then his knees. On a trip to the zoo, he had trouble keeping up. Then some months later, the same thing happened on a family hike. What was supposed to be a four-mile trek up to see a waterfall ended for him at the quarter-mile mark. He turned around and struggled back to the start just as everyone else was returning from the excursion.
Alarmed, he sought out one doctor after the next, but none could diagnose him. The disabling weakness continued to creep up his legs, and by the time he got in to see a top neurologist at Johns Hopkins University last January, he was desperate for help.
"It was hard for me to even get upstairs," he recalls. "I wasted away and had lost about forty-five pounds."
The neurologist, Dr. Michael Polydefkis, finally made the correct diagnosis based on Steve's rapid progression of symptoms, a skin and nerve biopsy, and a genetic test. It turned out that Steve had a rare inherited disease called hereditary transthyretin amyloidosis. Transthyretin is a common blood protein whose normal function is to transport vitamins and hormones in the body. When patients possess certain genetic mutations in the transthyretin gene, the resulting protein can misfold, clump and produce amyloid, an aggregate of proteins, which then interferes with normal function. Many organs are affected in this disease, but most affected are the nervous system, the GI tract, and the heart.
Dr. Michael Polydefkis, Steve's neurologist at Johns Hopkins Bayview Medical Center in Baltimore, MD.
(Courtesy of Dr. Polydefkis)
For the 50,000 patients like Steve around the world, the only treatment historically has been a liver transplant—a major, risky operation. The liver makes most of the transthyretin in a person's body. So if a person who carries a genetic mutation for a disease-causing form of transthyretin has their liver transplanted, the new liver will stop making the mutant protein. A few drugs can slow, but do not stop the disease.
Since it is a genetic condition, a regular "drug" can't tackle the problem.
"For almost all of medicine from the 18th century to today, drugs have been small molecules, typically natural, some invented by humans, that bind to proteins and block their functions," explains Dr. Phillip Zamore, chair of the department of Biomedical Sciences at the University of Massachusetts Medical School. "But with most proteins (including this one), you can't imagine how that would ever happen. Because even if it stuck, there's no reason to think it would change anything. So people threw up their hands and said, 'Unless we can find a protein that is "druggable" in disease X, we can't treat it.'"
To draw a car analogy, treating a disease like Steve's with a small molecule would be like trying to shut down the entire car industry when all you can do is cut the power cord to one machine in one local factory. With few options, patients like Steve have been at a loss, facing continual deterioration and disability.
"It's more obvious how to be specific because we use the genetic code itself to design the drug."
A Radical New Approach
Luckily, Dr. Polydefkis knew of an experimental drug made by a biotech company that Dr. Zamore co-founded called Alnylam Pharmaceuticals. They were doing something completely different: silencing the chemical blueprint for protein, called RNA, rather than targeting the protein itself. In other words, shutting down all the bad factories across the whole car industry at once – without touching the good ones.
"It's more obvious how to be specific," says Dr. Zamore, "because we use the genetic code itself to design the drug."
For Steve's doctor, the new drug, called patisiran, is a game changer.
"It's the dawn of molecular medicine," says Dr. Polydefkis. "It's really a miraculous development. The ability to selectively knock down or reduce the amount of a specific protein is remarkable. I tell patients this is science fiction that is now becoming reality."
A (Very) Short History
The strategy of silencing RNA as a method of guiding drug development began in 1998. Basic research took six years before clinical testing in humans began in 2004. Just a few months ago, in November, the results of the first double-blind, placebo-controlled phase III trials were announced, testing patisiran in patients--and they surpassed expectations.
"The results were remarkably positive," says Dr. Polydefkis. "Every primary and secondary outcome measure target was met. It's the most positive trial I have ever been associated with and that I can remember in recent memory."
FDA approval is expected to come by summer, which will mark the first official sanction of a drug based on RNA inhibition (RNAi). Experts are confident that similar drugs will eventually follow for other diseases, like familial hypercholesterol, lipid disorders, and breathing disorders. Right now, these drugs must get into the liver to work, but otherwise the future treatment possibilities are wide open, according to Dr. Zamore.
"It doesn't have to be a genetic disease," he says. "In theory, it doesn't have to be just one gene, although I don't think anyone knows how many you could target at once. There is no precedent for targeting two."
Dr. Phillip Zamore, chair of the RNA Therapeutics Institute at the University of Massachusetts Medical School.
(Courtesy of Dr. Zamore)
Alnylam, the leading company in RNAi therapeutics, plans to strategically design other new drugs based on what they have learned from this first trial – "so with each successive experience, with designing and testing, you get better at making more drugs. In a way, that's never happened before...This is a lot more efficient of a way to make drugs in the future."
And unlike gene therapy, in which a patient's own genetic code is permanently altered, this approach does not cause permanent genetic changes. Patients can stop taking it like any other drug, and its effects will vanish.
How Is Steve?
Last February, Steve started on the drug. He was granted early access since it is not yet FDA-approved and is still considered experimental. Every 21 days, he has received an IV infusion that causes some minor side effects, like headaches and facial flushing.
"The good news is, since I started on the drug, I don't see any more deterioration other than my speech."
So far, it seems to be effective. He's gained back 20 pounds, and though his enunciation is still a bit slurred, he says that his neuropathy has stopped. He plans to continue the treatment for the rest of his life.
"The good news is, since I started on the drug, I don't see any more deterioration other than my speech," he says. "I think the drug is working, but would I have continued to deteriorate without the drug? I'm not really sure."
Dr. Polydefkis jumps in with a more confident response: "If you ask me, I would say 100 percent he would have kept progressing at a fairly rapid pace without the drug. When Steve says the neuropathy has stopped, that's music to my ears."
NASA astronaut Frank Rubio floats by the International Space Station’s “window to the world.” Yesterday, he returned from the longest single spaceflight by a U.S. astronaut on record - over one year. Exploring deep space will require even longer missions.
Yesterday, NASA astronaut Frank Rubio returned to Earth after over one year, the longest single spaceflight for a U.S. astronaut. But this is just the start; longer and more complex missions into deep space loom ahead, from returning to the moon in 2025 to eventually sending humans to Mars. To ensure that these missions succeed, NASA is increasing efforts to study the biological effects and prevent harm.
The dangers of microgravity are real
A NASA report published in 2016 details a long list of incidents and near-misses caused – at least partly – by space-induced changes in astronauts’ vision and coordination. These issues make it harder to move with precision and to judge distance and velocity.
According to the report, in 1997, a resupply ship collided with the Mir space station, possibly because a crew member bumped into the commander during the final docking maneuver. This mishap caused significant damage to the space station.
Returns to Earth suffered from problems, too. The same report notes that touchdown speeds during the first 100 space shuttle landings were “outside acceptable limits. The fastest landing on record – 224 knots (258 miles) per hour – was linked to the commander’s momentary spatial disorientation.” Earlier, each of the six Apollo crews that landed on the moon had difficulty recognizing moon landmarks and estimating distances. For example, Apollo 15 landed in an unplanned area, ultimately straddling the rim of a five-foot deep crater on the moon, harming one of its engines.
Spaceflight causes unique stresses on astronauts’ brains and central nervous systems. NASA is working to reduce these harmful effects.
NASA
Space messes up your brain
In space, astronauts face the challenges of microgravity, ionizing radiation, social isolation, high workloads, altered circadian rhythms, monotony, confined living quarters and a high-risk environment. Among these issues, microgravity is one of the most consequential in terms of physiological changes. It changes the brain’s structure and its functioning, which can hurt astronauts’ performance.
The brain shifts upwards within the skull, displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes.
That’s partly because of how being in space alters blood flow. On Earth, gravity pulls our blood and other internal fluids toward our feet, but our circulatory valves ensure that the fluids are evenly distributed throughout the body. In space, there’s not enough gravity to pull the fluids down, and they shift up, says Rachael D. Seidler, a physiologist specializing in spaceflight at the University of Florida and principal investigator on many space-related studies. The head swells and legs appear thinner, causing what astronauts call “puffy face chicken legs.”
“The brain changes at the structural and functional level,” says Steven Jillings, equilibrium and aerospace researcher at the University of Antwerp in Belgium. “The brain shifts upwards within the skull,” displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes. Some of the displaced cerebrospinal fluid goes into cavities within the brain, called ventricles, enlarging them. “The remaining fluids pool near the chest and heart,” explains Jillings. After 12 consecutive months in space, one astronaut had a ventricle that was 25 percent larger than before the mission.
Some changes reverse themselves while others persist for a while. An example of a longer-lasting problem is spaceflight-induced neuro-ocular syndrome, which results in near-sightedness and pressure inside the skull. A study of approximately 300 astronauts shows near-sightedness affects about 60 percent of astronauts after long missions on the International Space Station (ISS) and more than 25 percent after spaceflights of only a few weeks.
Another long-term change could be the decreased ability of cerebrospinal fluid to clear waste products from the brain, Seidler says. That’s because compressing the brain also compresses its waste-removing glymphatic pathways, resulting in inflammation, vulnerability to injuries and worsening its overall health.
The effects of long space missions were best demonstrated on astronaut twins Scott and Mark Kelly. This NASA Twins Study showed multiple, perhaps permanent, changes in Scott after his 340-day mission aboard the ISS, compared to Mark, who remained on Earth. The differences included declines in Scott’s speed, accuracy and cognitive abilities that persisted longer than six months after returning to Earth in March 2016.
By the end of 2020, Scott’s cognitive abilities improved, but structural and physiological changes to his eyes still remained, he said in a BBC interview.
“It seems clear that the upward shift of the brain and compression of the surrounding tissues with ventricular expansion might not be a good thing,” Seidler says. “But, at this point, the long-term consequences to brain health and human performance are not really known.”
NASA astronaut Kate Rubins conducts a session for the Neuromapping investigation.
NASA
Staying sharp in space
To investigate how prolonged space travel affects the brain, NASA launched a new initiative called the Complement of Integrated Protocols for Human Exploration Research (CIPHER). “CIPHER investigates how long-duration spaceflight affects both brain structure and function,” says neurobehavioral scientist Mathias Basner at the University of Pennsylvania, a principal investigator for several NASA studies. “Through it, we can find out how the brain adapts to the spaceflight environment and how certain brain regions (behave) differently after – relative to before – the mission.”
To do this, he says, “Astronauts will perform NASA’s cognition test battery before, during and after six- to 12-month missions, and will also perform the same test battery in an MRI scanner before and after the mission. We have to make sure we better understand the functional consequences of spaceflight on the human brain before we can send humans safely to the moon and, especially, to Mars.”
As we go deeper into space, astronauts cognitive and physical functions will be even more important. “A trip to Mars will take about one year…and will introduce long communication delays,” Seidler says. “If you are on that mission and have a problem, it may take eight to 10 minutes for your message to reach mission control, and another eight to 10 minutes for the response to get back to you.” In an emergency situation, that may be too late for the response to matter.
“On a mission to Mars, astronauts will be exposed to stressors for unprecedented amounts of time,” Basner says. To counter them, NASA is considering the continuous use of artificial gravity during the journey, and Seidler is studying whether artificial gravity can reduce the harmful effects of microgravity. Some scientists are looking at precision brain stimulation as a way to improve memory and reduce anxiety due to prolonged exposure to radiation in space.
Other scientists are exploring how to protect neural stem cells (which create brain cells) from radiation damage, developing drugs to repair damaged brain cells and protect cells from radiation.
To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
Additionally, NASA is scrutinizing each aspect of the mission, including astronaut exercise, nutrition and intellectual engagement. “We need to give astronauts meaningful work. We need to stimulate their sensory, cognitive and other systems appropriately,” Basner says, especially given their extreme confinement and isolation. The scientific experiments performed on the ISS – like studying how microgravity affects the ability of tissue to regenerate is a good example.
“We need to keep them engaged socially, too,” he continues. The ISS crew, for example, regularly broadcasts from space and answers prerecorded questions from students on Earth, and can engage with social media in real time. And, despite tight quarters, NASA is ensuring the crew capsule and living quarters on the moon or Mars include private space, which is critical for good mental health.
Exploring deep space builds on a foundation that began when astronauts first left the planet. With each mission, scientists learn more about spaceflight effects on astronauts’ bodies. NASA will be using these lessons to succeed with its plans to build science stations on the moon and, eventually, Mars.
“Through internally and externally led research, investigations implemented in space and in spaceflight simulations on Earth, we are striving to reduce the likelihood and potential impacts of neurostructural changes in future, extended spaceflight,” summarizes NASA scientist Alexandra Whitmire. To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
Swiss researchers have found a type of brain cell that appears to be a hybrid of the two other main types — and it could lead to new treatments for brain disorders.
A new brain cell: Researchers at the Wyss Center for Bio and Neuroengineering and the University of Lausanne believe they’ve definitively proven that some astrocytes do actively participate in neurotransmission, making them a sort of hybrid of neurons and glial cells.
According to the researchers, this third type of brain cell, which they call a “glutamatergic astrocyte,” could offer a way to treat Alzheimer’s, Parkinson’s, and other disorders of the nervous system.
“Its discovery opens up immense research prospects,” said study co-director Andrea Volterra.
The study: Neurotransmission starts with a neuron releasing a chemical called a neurotransmitter, so the first thing the researchers did in their study was look at whether astrocytes can release the main neurotransmitter used by neurons: glutamate.
By analyzing astrocytes taken from the brains of mice, they discovered that certain astrocytes in the brain’s hippocampus did include the “molecular machinery” needed to excrete glutamate. They found evidence of the same machinery when they looked at datasets of human glial cells.
Finally, to demonstrate that these hybrid cells are actually playing a role in brain signaling, the researchers suppressed their ability to secrete glutamate in the brains of mice. This caused the rodents to experience memory problems.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Andrea Volterra, University of Lausanne.
But why? The researchers aren’t sure why the brain needs glutamatergic astrocytes when it already has neurons, but Volterra suspects the hybrid brain cells may help with the distribution of signals — a single astrocyte can be in contact with thousands of synapses.
“Often, we have neuronal information that needs to spread to larger ensembles, and neurons are not very good for the coordination of this,” researcher Ludovic Telley told New Scientist.
Looking ahead: More research is needed to see how the new brain cell functions in people, but the discovery that it plays a role in memory in mice suggests it might be a worthwhile target for Alzheimer’s disease treatments.
The researchers also found evidence during their study that the cell might play a role in brain circuits linked to seizures and voluntary movements, meaning it’s also a new lead in the hunt for better epilepsy and Parkinson’s treatments.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Volterra.
