Next year, a neurologist will test CRISPR base editing in a trial of five people with muscular dystrophy to see if their muscles accept corrected cells and whether they multiply and take over the function of damaged cells.
As you read this text, you will surely use several muscles without being aware of them: Your heart muscle pumps blood through your arteries, your eye muscles let you follow the words in this sentence, and your hand muscles hold the tablet or cell phone. Muscles make up 40 percent of your body weight; we usually have 656 of them. Now imagine they are slowly losing their strength. No training, no protein shake can rebuild their function.
This is the reality for most people in Simone Spuler’s outpatient clinic at the Charité Hospital in Berlin, Germany: Almost all of her 2,500 patients have muscular dystrophy, a progressive illness striking mostly young people. Muscle decline leads to a wheelchair and, eventually, an early death due to a heart attack or the inability to breathe. In Germany alone, 300,000 people live with this illness, the youngest barely a year old. The CDC estimates that its most common form, Duchenne, affects 1 in every 3,500 to 6,000 male births each year in the United States.
The devastating progression of the disease is what motivates Spuler and her team of 25 scientists to find a cure. In 2019, they made a spectacular breakthrough: For the first time, they successfully used mRNA to introduce the CRISPR-Cas9 tool into human muscle stem cells to repair the dystrophy. “It’s really just one tiny molecule that doesn’t work properly,” Spuler explains.
CRISPR-Cas9 is a technology that lets scientists select and alter parts of the genome. It’s still comparatively new but has advanced quickly since its discovery in the early 2010s. “We now have the possibility to repair certain mutations with genetic editing,” Spuler says. “It’s pure magic.”
She projects a warm, motherly air and a professional calm that inspires trust from her patients. She needs these qualities because the 60-year-old neurologist has one of the toughest jobs in the world: All day long, patients with the incurable diagnosis of muscular dystrophy come to her clinic, and she watches them decline over the years. “Apart from physiotherapy, there is nothing we can recommend right now,” she says. That motivated her early in her career, when she met her first patients at the Max Planck Institute for Neurobiology near Munich in the 1990s. “I knew I had 30, 40 years to find something.”
She learned from the luminaries of her profession with postdocs at the University of California San Diego, Harvard and Johns Hopkins, before serving as a clinical fellow at the Mayo Clinic. In 2005, the Charité offered her the opportunity to establish a specialized clinic for myasthenia, or muscular weakness. An important influence on Spuler, she says, has been the French microbiologist Emmanuelle Charpentier, who received the Nobel Prize in 2020 along with Jennifer Doudna for their CRISPR research, and has worked in Berlin since 2015.
When CRISPR was first introduced, it was mainly used to cut through DNA. However, the cut can lead to undesired side effects. For the muscle stem cells, Spuler now uses a base editor to repair the damaged molecule with super fine scissors or tweezers.
“Apart from physiotherapy, there is nothing we can recommend right now,” Spuler says about her patients with limb-girdle muscular dystrophy.
Pablo Castagnola
Last year, she proved that the method works in mice. Injecting repaired cells into the rodents led to new muscle fibers and, in 2021 and 2022, she passed the first safety meetings with the Paul-Ehrlich Institute, which is responsible for approving human gene editing trials in Germany. She raised the nearly four million Euros needed to test the new method in the first clinical trial in humans with limb-girdle muscular dystrophy, beginning with one muscle that can easily be measured, such as the biceps.
This spring, Weber and his parents drove the 400 miles from Munich to Berlin. At Spuler’s lab, her team took a biopsy from muscles in his left arm. The first two steps – extraction and repair in a culture dish – went according to plan; Spuler was able to repair the mutation in Weber’s cells outside his body.
Next year, Weber will be the youngest participant when Spuler starts to test the method in a trial of five people “in vivo,” inside their bodies. This will be the real moment of truth: Will the participants’ muscles accept the corrected cells? Will the cells multiply and take over the function of damaged cells, just like Spuler was able to do in her lab with the rodents?
The effort is costly and complex. “The biggest challenge is to make absolutely sure that we don’t harm the patient,” Spuler says. This means scanning their entire genomes, “so we don’t accidentally damage or knock out an important gene.”
Weber, who asked not to be identified by his real name, is looking forward to the trial and he feels confident that “the risks are comparatively small because the method will only be applied to one muscle. The worst that can happen is that it doesn’t work. But in the best case, the muscle function will improve.”
He was so impressed with the Charité scientists that he decided to study biology at his university. He’s read extensively about CRISPR, so he understands why he has three healthy siblings. “That’s the statistics,” the biologist in training explains. “You get two sets of genes from each parent, and you have to get two faulty mutations to have muscular dystrophy. So we fit the statistics exactly: One of us four kids inherited the mutation.”
It was his mother, a college teacher, and father, a physicist by training, who heard about Spuler’s research. Even though Weber does not live at home anymore, having a chronically ill son is nearly a full-time job for his mother, Annette. The Berlin visit and the trial are financed separately through private sponsors, but the fights with Weber’s health insurance are frustrating and time-consuming. “Physiotherapy is the only thing that helps a bit,” Weber says, “and yet, they fought us on approving it every step of the way.”
Spuler does not want to evoke unrealistic expectations. “Patients who are wheelchair-bound won’t suddenly get up and walk."
Her son continues to exercise as much as possible. Riding his bicycle to the university has become too difficult, so he got an e-scooter. He had to give up competitive tennis because he does not have the stamina for a two-hour match, but he can still play with his dad or his buddies for an hour. His closest friends know about the diagnosis. “They help me, for instance, to lift something heavy because I can’t do that anymore,” Weber says.
The family was elated to find medical support at the Munich Muscle Center by the German Alliance for Muscular Patients and then at Spuler’s clinic in Berlin. “When you hear that this is a progressive illness with no chance of improvement, your world collapses as a parent,” Annette Weber says. “And then all of a sudden, there is this woman who sees scientific progress as an opportunity. Even just to be able to participate in the study is fantastic.”
Spuler does not want to evoke unrealistic expectations. “Patients who are wheelchair-bound won’t suddenly get up and walk,” she says. After all, she will start by applying the gene editor to only one muscle, “but it would be a big step if even a small muscle that is essential to grip something, or to swallow, regains function.”
Weber agrees. “I understand that I won’t regain 100 percent of my muscle function but even a small improvement or at least halting the deterioration is the goal.”
And yet, Spuler and others are ultimately searching for a true solution. In a separate effort, Massachusetts-based biotech company Sarepta announced this month it will seek expedited regulators’ approval to treat Duchenne patients with its investigational gene therapy. Unlike Spuler’s methods, Sarepta focuses specifically on the Duchenne form of muscular dystrophy, and it uses an adeno-assisted virus to deliver the therapy.
Spuler’s vision is to eventually apply gene editing to the entire body of her patients. To speed up the research, she and a colleague founded a private research company, Myopax. If she is able to prove that the body accepts the edited cells, the technique could be used for other monogenetic illnesses as well. “When we speak of genetic editing, many are scared and say, oh no, this is God’s work,” says Spuler. But she sees herself as a mechanic, not a divine being. “We really just exchange a molecule, that’s it.”
If everything goes well, Weber hopes that ten years from now, he will be the one taking biopsies from the next generation of patients and repairing their genes.
Drones are just one of several new technologies that are rising to the challenge of more frequent wildfires.
Robots have been a game-changer. Inspired by Paris, the Los Angeles Fire Department (LAFD) was the first in the U.S. to deploy a firefighting robot in 2021, the Thermite Robotics System 3 – RS3, for short.
RS3 is a 3,500-pound turbine on a crawler—the size of a Smart car—with a 36.8 horsepower engine that can go for 20 hours without refueling. It can plow through hazardous terrain, move cars from its path, and pull an 8,000-pound object from a fire.
All that while spurting 2,500 gallons of water per minute with a rear exhaust fan clearing the smoke. At a recent trade show, RS3 was billed as equivalent to 10 firefighters. The Los Angeles Times referred to it as “a droid on steroids.”
Robots such as the Thermite RS3 can plow through hazardous terrain and pull an 8,000-pound object from a fire.
Los Angeles Fire Department
The advantage of the robot is obvious. Operated remotely from a distance, it greatly reduces an emergency responder’s exposure to danger, says Wade White, assistant chief of the LAFD. The robot can be sent into airplane fires, nuclear reactors, hazardous areas with carcinogens (think East Palestine, Ohio), or buildings where a roof collapse is imminent.
Advances for firefighters are taking many other forms as well. Fibers have been developed that make the firefighter’s coat lighter and more protective from carcinogens. New wearable devices track firefighters’ biometrics in real time so commanders can monitor their heat stress and exertion levels. A sensor patch is in development which takes readings every four seconds to detect dangerous gases such as methane and carbon dioxide. A sonic fire extinguisher is being explored that uses low frequency soundwaves to remove oxygen from air molecules without unhealthy chemical compounds.
The demand for this technology is only increasing, especially with the recent rise in wildfires. In 2021, fires were responsible for 3,800 deaths and 14,700 injuries of civilians in this country. Last year, 68,988 wildfires burned down 7.6 million acres. Whether the next generation of firefighting can address these new challenges could depend on special cameras, robots of the aerial variety, AI and smart systems.
Fighting fire with cameras
Another key innovation for firefighters is a thermal imaging camera (TIC) that improves visibility through smoke. “At a fire, you might not see your hand in front of your face,” says White. “Using the TIC screen, you can find the door to get out safely or see a victim in the corner.” Since these cameras were introduced in the 1990s, the price has come down enough (from $10,000 or more to about $700) that every LAFD firefighter on duty has been carrying one since 2019, says White.
TICs are about the size of a cell phone. The camera can sense movement and body heat so it is ideal as a search tool for people trapped in buildings. If a firefighter has not moved in 30 seconds, the motion detector picks that up, too, and broadcasts a distress signal and directional information to others.
To enable firefighters to operate the camera hands-free, the newest TICs can attach inside a helmet. The firefighter sees the images inside their mask.
TICs also can be mounted on drones to get a bird’s-eye, 360 degree view of a disaster or scout for hot spots through the smoke. In addition, the camera can take photos to aid arson investigations or help determine the cause of a fire.
More help From above
Firefighters prefer the term “unmanned aerial systems” (UAS) to drones to differentiate them from military use.
A UAS carrying a camera can provide aerial scene monitoring and topography maps to help fire captains deploy resources more efficiently. At night, floodlights from the drone can illuminate the landscape for firefighters. They can drop off payloads of blankets, parachutes, life preservers or radio devices for stranded people to communicate, too. And like the robot, the UAS reduces risks for ground crews and helicopter pilots by limiting their contact with toxic fumes, hazardous chemicals, and explosive materials.
“The nice thing about drones is that they perform multiple missions at once,” says Sean Triplett, team lead of fire and aviation management, tools and technology at the Forest Service.
Experts predict we’ll see swarms of drones dropping water and fire retardant on burning buildings and forests in the near future.
The UAS is especially helpful during wildfires because it can track fires, get ahead of wind currents and warn firefighters of wind shifts in real time. The U.S. Forest Service also uses long endurance, solar-powered drones that can fly for up to 30 days at a time to detect early signs of wildfire. Wildfires are no longer seasonal in California – they are a year-long threat, notes Thanh Nguyen, fire captain at the Orange County Fire Authority.
In March, Nguyen’s crew deployed a drone to scope out a huge landslide following torrential rains in San Clemente, CA. Emergency responders used photos and videos from the drone to survey the evacuated area, enabling them to stay clear of ground on the hillside that was still sliding.
Improvements in drone batteries are enabling them to fly for longer with heavier payloads. Experts predict we’ll see swarms of drones dropping water and fire retardant on burning buildings and forests in the near future.
AI to the rescue
The biggest peril for a firefighter is often what they don’t see coming. Flashovers are a leading cause of firefighter deaths, for example. They occur when flammable materials in an enclosed area ignite almost instantaneously. Or dangerous backdrafts can happen when a firefighter opens a window or door; the air rushing in can ignite a fire without warning.
The Fire Fighting Technology Group at the National Institute of Standards and Technology (NIST) is developing tools and systems to predict these potentially lethal events with computer models and artificial intelligence.
Partnering with other institutions, NIST researchers developed the Flashover Prediction Neural Network (FlashNet) after looking at common house layouts and running sets of scenarios through a machine-learning model. In the lab, FlashNet was able to predict a flashover 30 seconds before it happened with 92.1% success. When ready for release, the technology will be bundled with sensors that are already installed in buildings, says Anthony Putorti, leader of the NIST group.
The NIST team also examined data from hundreds of backdrafts as a basis for a machine-learning model to predict them. In testing chambers the model predicted them correctly 70.8% of the time; accuracy increased to 82.4% when measures of backdrafts were taken in more positions at different heights in the chambers. Developers are working on how to integrate the AI into a small handheld device that can probe the air of a room through cracks around a door or through a created opening, Putorti says. This way, the air can be analyzed with the device to alert firefighters of any significant backdraft risk.
Early wildfire detection technologies based on AI are in the works, too. The Forest Service predicts the acreage burned each year during wildfires will more than triple in the next 80 years. By gathering information on historic fires, weather patterns, and topography, says White, AI can help firefighters manage wildfires before they grow out of control and create effective evacuation plans based on population data and fire patterns.
The future is connectivity
We are in our infancy with “smart firefighting,” says Casey Grant, executive director emeritus of the Fire Protection Research Foundation. Grant foresees a new era of cyber-physical systems for firefighters—a massive integration of wireless networks, advanced sensors, 3D simulations, and cloud services. To enhance teamwork, the system will connect all branches of emergency responders—fire, emergency medical services, law enforcement.
FirstNet (First Responder Network Authority) now provides a nationwide high-speed broadband network with 5G capabilities for first responders through a terrestrial cell network. Battling wildfires, however, the Forest Service needed an alternative because they don’t always have access to a power source. In 2022, they contracted with Aerostar for a high altitude balloon (60,000 feet up) that can extend cell phone power and LTE. “It puts a bubble of connectivity over the fire to hook in the internet,” Triplett explains.
A high altitude balloon, 60,000 feet high, can extend cell phone power and LTE, putting a "bubble" of internet connectivity over fires.
Courtesy of USDA Forest Service
Advances in harvesting, processing and delivering data will improve safety and decision-making for firefighters, Grant sums up. Smart systems may eventually calculate fire flow paths and make recommendations about the best ways to navigate specific fire conditions. NIST’s plan to combine FlashNet with sensors is one example.
The biggest challenge is developing firefighting technology that can work across multiple channels—federal, state, local and tribal systems as well as for fire, police and other emergency services— in any location, says Triplett. “When there’s a wildfire, there are no political boundaries,” he says. “All hands are on deck.”
A new test called the EyeBox could provide a more objective - and portable - tool to measure whether people have concussions in stadiums and hospitals.
Concussion affects around 42 million people worldwide. While it’s increasingly common in the news because of sports injuries, anything that causes damage to the head, from a fall to a car accident, can result in a concussion. The sudden blow or jolt can disrupt the normal way the brain works. In the immediate aftermath, people may suffer from headaches, lose consciousness and experience dizziness, confusion and vomiting. Some recover but others have side effects that can last for years, particularly affecting memory and concentration.
There is no simple standard-of-care test to confirm a concussion or rule it out. Neither do they appear on MRI and CT scans. Instead, medical professionals use more indirect approaches that test symptoms of concussions, such as assessments of patients’ learning and memory skills, ability to concentrate and problem solving. They also look at balance and coordination. Most tests are in the form of questionnaires or symptom checklists. Consequently, they have limitations, can be biased and may miss a concussion or produce a false positive. Some people suspected of having a concussion may ordinarily have difficulties with literary and problem-solving tests because of language challenges or education levels.
Another problem with current tests is that patients, particularly soldiers who want to return to combat and athletes who would like to keep competing, could try and hide their symptoms to avoid being diagnosed with a brain injury. Trauma physicians who work with concussion patients have the need for a tool that is more objective and consistent.
“This type of assessment doesn’t rely on the patient's education level, willingness to follow instructions or cooperation. You can’t game this.” -- Uzma Samadani, founder of Oculogica
“The importance of having an objective measurement tool for the diagnosis of concussion is of great importance,” says Douglas Powell, associate professor of biomechanics at the University of Memphis, with research interests in sports injury and concussion. “While there are a number of promising systems or metrics, we have yet to develop a system that is portable, accessible and objective for use on the sideline and in the clinic. The EyeBOX may be able to address these issues, though time will be the ultimate test of performance.”
The EyeBOX as a window inside the brain
Using eye movements to diagnose a concussion has emerged as a promising technique since around 2010. Oculogica combined eye movements with AI to develop the EyeBOX to develop an unbiased objective diagnostic tool.
“What’s so great about this type of assessment is it doesn’t rely on the patient's education level, willingness to follow instructions or cooperation,” says Uzma Samadani, a neurosurgeon and brain injury researcher at the University of Minnesota, who founded Oculogica. “You can’t game this. It assesses functions that are prompted by your brain.”
In 2010, Samadani was working on a clinical trial to improve the outcome of brain injuries. The team needed some way to measure if seriously brain injured patients were improving. One thing patients could do was watch TV. So Samadani designed and patented an AI-based algorithm that tracks the relationship between eye movement and concussion.
The EyeBOX test requires patients to watch movie or music clips for 220 seconds. An eye tracking camera records subconscious eye movements, tracking eye positions 500 times per seconds as patients watch the video. It collects over 100,000 data points. The device then uses AI to assess whether there’s any disruptions from the normal way the eyes move.
Cranial nerves are responsible for transmitting information between the brain and the body. Many are involved in eye movement. Pressure caused by a concussion can affect how these nerves work. So tracking how the eyes move can indicate if there’s anything wrong with the cranial nerves and where the problem lies.
If someone is healthy, their eyes should be able to focus on an object, follow movement and both eyes should be coordinated with each other. The EyeBox can detect abnormalities. For example, if a patient’s eyes are coordinated but they are not moving as they should, that indicates issues in the central brain stem, whilst only one eye moving abnormally suggests that a particular nerve section is affected.
Uzma Samadani with the EyeBOX device
Courtesy Oculogica
“The EyeBOX is a monitor for cranial nerves,” says Samadani. “Essentially it’s a form of digital neurological exam. “Several other eye-tracking techniques already exist, but they rely on subjective self-reported symptoms. Many also require a baseline, a measure of how patients reacted when they were healthy, which often isn’t available.
VOMS (Vestibular Ocular Motor Screen) is one of the most accurate diagnostic tests used in clinics in combination with other tests, but it is subjective. It involves a therapist getting patients to move their head or eyes as they focus or follow a particular object. Patients then report their symptoms.
The King-Devick test measures how fast patients can read numbers and compares it to a baseline. Since it is mainly used for athletes, the initial test is completed before the season starts. But participants can manipulate it. It also cannot be used in emergency rooms because the majority of patients wouldn’t have prior baseline tests.
Unlike these tests, EyeBOX doesn’t use a baseline and is objective because it doesn’t rely on patients’ answers. “It shows great promise,” says Thomas Wilcockson, a senior lecturer of psychology in Loughborough University, who is an expert in using eye tracking techniques in neurological disorders. “Baseline testing of eye movements is not always possible. Alternative measures of concussion currently in development, including work with VR headsets, seem to currently require it. Therefore the EyeBOX may have an advantage.”
A technology that’s still evolving
In their last clinical trial, Oculogica used the EyeBOX to test 46 patients who had concussion and 236 patients who did not. The sensitivity of the EyeBOX, or the probability of it correctly identifying the patient’s concussion, was 80.4 percent. Meanwhile, the test accurately ruled out a concussion in 66.1 percent of cases. This is known as its specificity score.
While the team is working on improving the numbers, experts who treat concussion patients find the device promising. “I strongly support their use of eye tracking for diagnostic decision making,” says Douglas Powell. “But for diagnostic tests, we would prefer at least one of the sensitivity or specificity values to be greater than 90 percent. Powell compares EyeBOX with the Buffalo Concussion Treadmill Test, which has sensitivity and specificity values of 73 and 78 percent, respectively. The VOMS also has shown greater accuracy than the EyeBOX, at least for now. Still, EyeBOX is competitive with the best diagnostic testing available for concussion and Powell hopes that its detection prowess will improve. “I anticipate that the algorithms being used by Oculogica will be under continuous revision and expect the results will improve within the next several years.”
“The color of your skin can have a huge impact in how quickly you are triaged and managed for brain injury. People of color have significantly worse outcomes after traumatic brain injury than people who are white.” -- Uzma Samadani, founder of Oculogica
Powell thinks the EyeBOX could be an important complement to other concussion assessments.
“The Oculogica product is a viable diagnostic tool that supports clinical decision making. However, concussion is an injury that can present with a wide array of symptoms, and the use of technology such as the Oculogica should always be a supplement to patient interaction.”
Ioannis Mavroudis, a consultant neurologist at Leeds Teaching Hospital, agrees that the EyeBOX has promise, but cautions that concussions are too complex to rely on the device alone. For example, not all concussions affect how eyes move. “I believe that it can definitely help, however not all concussions show changes in eye movements. I believe that if this could be combined with a cognitive assessment the results would be impressive.”
The Oculogica team submitted their clinical data for FDA approval and received it in 2018. Now, they’re working to bring the test to the commercial market and using the device clinically to help diagnose concussions for clients. They also want to look at other areas of brain health in the next few years. Samadani believes that the EyeBOX could possibly be used to detect diseases like multiple sclerosis or other neurological conditions. “It’s a completely new way of figuring out what someone’s neurological exam is and we’re only beginning to realize the potential,” says Samadani.
One of Samadani’s biggest aspirations is to help reduce inequalities in healthcare because of skin color and other factors like money or language barriers. From that perspective, the EyeBOX’s greatest potential could be in emergency rooms. It can help diagnose concussions in addition to the questionnaires, assessments and symptom checklists, currently used in the emergency departments. Unlike these more subjective tests, EyeBOX can produce an objective analysis of brain injury through AI when patients are admitted and assessed, unrelated to their socioeconomic status, education, or language abilities. Studies suggest that there are racial disparities in how patients with brain injuries are treated, such as how quickly they're assessed and get a treatment plan.
“The color of your skin can have a huge impact in how quickly you are triaged and managed for brain injury,” says Samadani. “As a result of that, people of color have significantly worse outcomes after traumatic brain injury than people who are white. The EyeBOX has the potential to reduce inequalities,” she explains.
“If you had a digital neurological tool that you could screen and triage patients on admission to the emergency department you would potentially be able to make sure that everybody got the same standard of care,” says Samadani. “My goal is to change the way brain injury is diagnosed and defined.”