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.
When Martin Weber climbs the steps to his apartment on the fifth floor in Munich, an attentive observer might notice that he walks a little unevenly. “That’s because my calf muscles were the first to lose strength,” Weber explains.
About three years ago, the now 19-year-old university student realized that he suddenly had trouble keeping up with his track team at school. At tennis tournaments, he seemed to lose stamina after the first hour. “But it was still within the norm,” he says. “So it took a while before I noticed something was seriously wrong.” A blood test showed highly elevated liver markers. His parents feared he had liver cancer until a week-long hospital visit and scores of tests led to a diagnosis: hereditary limb-girdle muscular dystrophy, an incurable genetic illness that causes muscles to deteriorate.
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.
Declining numbers of insects, coupled with climate change, can have devastating effects for people in more ways than one. But clever use of technologies like AI could keep them buzzing.
And because many insects serve as food for other species—bats, birds and freshwater fish—they’re an integral part of the ecosystem’s food chain. “If you like to eat good food, you should thank an insect,” says Scott Hoffman Black, an ecologist and executive director of the Xerces Society for Invertebrate Conservation in Portland, Oregon. “And if you like birds in your trees and fish in your streams, you should be concerned with insect conservation.”
Deforestation, urbanization, and agricultural spread have eaten away at large swaths of insect habitat. The increasingly poorly controlled use of insecticides, which harms unintended species, and the proliferation of invasive insect species that disrupt native ecosystems compound the problem.
“There is not a single reason why insects are in decline,” says Jessica L. Ware, associate curator in the Division of Invertebrate Zoology at the American Museum of Natural History in New York, and president of the Entomological Society of America. “There are over one million described insect species, occupying different niches and responding to environmental stressors in different ways.”
Jessica Ware, an entomologist at the American Museum of Natural History, is using DNA methods to monitor insects.
Credit:D.Finnin/AMNH
In addition to habitat loss fueling the decline in insect populations, the other “major drivers” Ware identified are invasive species, climate change, pollution, and fluctuating levels of nitrogen, which play a major role in the lifecycle of plants, some of which serve as insect habitants and others as their food. “The causes of world insect population declines are, unfortunately, very easy to link to human activities,” Lehmann says.
Climate change will undoubtedly make the problem worse. “As temperatures start to rise, it can essentially make it too hot for some insects to survive,” says Emily McDermott, an assistant professor in the Department of Entomology and Plant Pathology at the University of Arkansas. “Conversely in other areas, it could potentially also allow other insects to expand their ranges.”
Without Pollinators Humans Will Starve
We may not think much of our planet’s getting warmer by only one degree Celsius, but it can spell catastrophe for many insects, plants, and animals, because it’s often accompanied by less rainfall. “Changes in precipitation patterns will have cascading consequences across the tree of life,” says David Wagner, a professor of ecology and evolutionary biology at the University of Connecticut. Insects, in particular, are “very vulnerable” because “they’re small and susceptible to drying.”
For instance, droughts have put the monarch butterfly at risk of being unable to find nectar to “recharge its engine” as it migrates from Canada and New England to Mexico for winter, where it enters a hibernation state until it journeys back in the spring. “The monarch is an iconic and a much-loved insect,” whose migration “is imperiled by climate change,” Wagner says.
Warming and drying trends in the Western United States are perhaps having an even more severe impact on insects than in the eastern region. As a result, “we are seeing fewer individual butterflies per year,” says Matt Forister, a professor of insect ecology at the University of Nevada, Reno.
There are hundreds of butterfly species in the United States and thousands in the world. They are pollinators and can serve as good indicators of other species’ health. “Although butterflies are only one group among many important pollinators, in general we assume that what’s bad for butterflies is probably bad for other insects,” says Forister, whose research focuses on butterflies. Climate change and habitat destruction are wreaking havoc on butterflies as well as plants, leading to a further indirect effect on caterpillars and butterflies.
Different insect species have different levels of sensitivity to environmental changes. For example, one-half of the bumblebee species in the United States are showing declines, whereas the other half are not, says Christina Grozinger, a professor of entomology at the Pennsylvania State University. Some species of bumble bees are even increasing in their range, seemingly resilient to environmental changes. But other pollinators are dwindling to the point that farmers have to buy from the rearing facilities, which is the case for the California almond industry. “This is a massive cost to the farmer, which could be provided for free, in case the local habitats supported these pollinators,” Lehmann says.
For bees and other insects, climate change can harm the plants they depend on for survival or have a negative impact on the insects directly. Overly rainy and hot conditions may limit flowering in plants or reduce the ability of a pollinator to forage and feed, which then decreases their reproductive success, resulting in dwindling populations, Grozinger explains.
“Nutritional deprivation can also make pollinators more sensitive to viruses and parasites and therefore cause disease spread,” she says. “There are many ways that climate change can reduce our pollinator populations and make it more difficult to grow the many fruit, vegetable and nut crops that depend on pollinators.”
Disease-Causing Insects Can Bring More Outbreaks
While some much-needed insects are declining, certain disease-causing species may be spreading and proliferating, which is another reason for human concern. Many mosquito types spread malaria, Zika virus, West Nile virus, and a brain infection called equine encephalitis, along with other diseases as well as heartworms in dogs, says Michael Sabourin, president of the Vermont Entomological Society. An animal health specialist for the state, Sabourin conducts vector surveys that identify ticks and mosquitoes.
Scientists refer to disease-carrying insects as vector species and, while there’s a limited number of them, many of these infections can be deadly. Fleas were a well-known vector for the bubonic plague, while kissing bugs are a vector for Chagas disease, a potentially life-threatening parasitic illness in humans, dogs, and other mammals, Sabourin says.
As the planet heats up, some of the creepy crawlers are able to survive milder winters or move up north. Warmer temperatures and a shorter snow season have spawned an increasing abundance of ticks in Maine, including the blacklegged tick (Ixodes scapularis), known to transmit Lyme disease, says Sean Birkel, an assistant professor in the Climate Change Institute and Cooperative Extension at the University of Maine.
Coupled with more frequent and heavier precipitation, rising temperatures bring a longer warm season that can also lead to a longer period of mosquito activity. “While other factors may be at play, climate change affects important underlying conditions that can, in turn, facilitate the spread of vector-borne disease,” Birkel says.
For example, if mosquitoes are finding fewer of their preferred food sources, they may bite humans more. Both male and female mosquitoes feed on sugar as part of their normal behavior, but if they aren’t eating their fill, they may become more bloodthirsty. One recent paper found that sugar-deprived Anopheles gambiae females go for larger blood meals to stay in good health and lay eggs. “More blood meals equals more chances to pick up and transmit a pathogen,” McDermott says, He adds that climate change could reduce the number of available plants to feed on. And while most mosquitoes are “generalist sugar-feeders” meaning that they will likely find alternatives, losing their favorite plants can make them hungrier for blood.
Similar to the effect of losing plants, mosquitoes may get turned onto people if they lose their favorite animal species. For example, some studies found that Culex pipiens mosquitoes that transmit the West Nile virus feed primarily on birds in summer. But that changes in the fall, at least in some places. Because there are fewer birds around, C. pipiens switch to mammals, including humans. And if some disease-carrying insect species proliferate or increase their ranges, that increases chances for human infection, says McDermott. “A larger concern is that climate change could increase vector population sizes, making it more likely that people or animals would be bitten by an infected insect.”
Science Can Help Bring Back the Buzz
To help friendly insects thrive and keep the foes in check, scientists need better ways of trapping, counting, and monitoring insects. It’s not an easy job, but artificial intelligence and molecular methods can help. Ware’s lab uses various environmental DNA methods to monitor freshwater habitats. Molecular technologies hold much promise. The so-called DNA barcodes, in which species are identified using a short string of their genes, can now be used to identify birds, bees, moths and other creatures, and should be used on a larger scale, says Wagner, the University of Connecticut professor. “One day, something akin to Star Trek’s tricorder will soon be on sale down at the local science store.”
Scientists are also deploying artificial intelligence, or AI, to identify insects in agricultural systems and north latitudes where there are fewer bugs, Wagner says. For instance, some automated traps already use the wingbeat frequencies of mosquitoes to distinguish the harmless ones from the disease-carriers. But new technology and software are needed to further expand detection based on vision, sound, and odors.
“Because of their ubiquity, enormity of numbers, and seemingly boundless diversity, we desperately need to develop molecular and AI technologies that will allow us to automate sampling and identification,” says Wagner. “That would accelerate our ability to track insect populations, alert us to the presence of new disease vectors, exotic pest introductions, and unexpected declines.”
Certain gases used for anesthesia are 3,000 times more damaging for the climate than CO2. Some anesthesiologists are pointing to other solutions.
On the whole, the medical sector is responsible for a disproportionally large percentage of greenhouse gas emissions, with the U.S. as the biggest culprit. According to a key paper published in 2020 in Health Affairs, the health industry “is among the most carbon-intensive service sectors in the industrialized world,” accounting for between 4.4 percent and 4.6 percent of greenhouse gas emissions. “It’s not just anesthesia but health care that has a problem,” says Jodi Sherman, anesthesiology professor and Medical Director of the Program on Healthcare Environmental Sustainability at Yale University as well as co-director of the Lancet Planetary Health Commission on Sustainable Healthcare. In the U.S., health care greenhouse gas emissions make up about 8.5 percent of domestic greenhouse gas emissions. They rose 6 percent from 2010 to 2018, to nearly 1,700 kilograms per person, more than in any other nation.
Of course, patients worry primarily about safety, not sustainability. Yet, Koch emphasizes that “as doctors, we have the responsibility to do no harm, and this includes making sure that we use resources as sustainably as possible.” Studies show that 2018 greenhouse gas and toxic air pollutant emissions resulted in the loss of 388,000 disability-adjusted life years in the U.S. alone. “Disease burden from health care pollution is of the same order of magnitude as deaths from preventable medical errors, and should be taken just as seriously,” Sherman cautions.
When Koch, the anesthesiologist, started discussing sustainable options with colleagues, the topic was immediately met with plenty of interest. Her experience is consistent with the latest representative poll of the nonprofit Foundation Health in Germany. Nine out of ten doctors were interested in urgently finding sustainable solutions for medical services but lacked knowhow and resources. For teaching purposes, Sherman and her team have developed the Yale Gassing Greener app that allows anesthesiologists to compare how much pollution they can avoid through choosing different anesthesia methods. Sherman also published professional guidelines intended to help her colleagues better understand how various methods affect carbon emissions.
Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
A solution espoused by both Sherman and Koch is comparatively simple: They stopped using desflurane, which is by far the most damaging of all inhalation gases to the climate. Its greenhouse effect is 2,590 times stronger than carbon dioxide. The Yale New Haven Hospital already stopped using desflurane in 2013, becoming the first known healthcare organization to eliminate a drug based on environmental grounds. Sherman points out that this resulted in saving more than $1.2 million in costs and 1,600 tons of CO2 equivalents, about the same as the exhaust from 360 passenger vehicles per year.
At the Charité, Koch claims that switching to other anesthesiology choices, such as propofol, has eliminated 90 percent of the climate gas emissions in the anesthesiology department since 2016. Young anesthesiologists are still taught to use desflurane as the standard because desflurane is absorbed less into the patients’ bodies, and they wake up faster. However, Koch who has worked as an anesthesiologist since 2006, says that with a little bit of experience, you can learn when to stop giving the propofol so it's timed just as well with a person’s wake-up process. In addition, “patients are less likely to feel nauseous after being given propofol,” Koch says. Intravenous drugs might require more skill, she adds, "but there is nothing unique to the drug desflurane that cannot be accomplished with other medications.”
Desflurane isn’t the only gas to be concerned about. Nitrous oxide is the second most damaging because it’s extremely long-lived in the environment, and it depletes the ozone layer. Climate-conscious anesthesiologists are phasing out this gas, too, or have implemented measures to decrease leaks.
Internationally, 192 governments agreed in the Kyoto protocol of 2005 to reduce halogenated hydrocarbons – resulting from inhalation gases, including desflurane and nitrous oxide – because of their immense climate-warming potential, and in 2016, they pledged to eliminate them by 2035. However, the use of inhalation anesthetics continues to increase worldwide, not least because more people access healthcare in developing countries, and because people in industrialized countries live longer and therefore need more surgeries. Significant traces of inhalation gases have been found in Antarctica and the Himalayas, far from the vast majority of surgery rooms.
Certain companies are now pushing new technology to capture inhalation gases before they are released into the atmosphere, but both Sherman and Koch believe marketing claims of 99 percent efficiency amount to greenwashing. After investigating the technology first-hand and visiting the company that is producing such filters in Germany, Koch concluded that such technology only reduces emissions by 25 percent. And Sherman believes such initiatives are akin to the fallacy of recycling plastic. In addition to questioning their efficiency, Sherman fears such technology “gives the illusion there is a magical solution that means I don’t need to change my behavior, reduce my waste and choose less harmful options.”
Financial interests are at play, too. “Desflurane is the most expensive inhalation gas, and some think, the most expensive must be the best,” Koch says. Both Koch and Sherman lament that efforts to increase sustainability in the medical sector are entirely voluntary in their countries and led by a few dedicated individual professionals while industry-wide standards and transparency are needed, a notion expressed in the American Hospital Association’s Sustainability Roadmap.
Susanne Koch, an anesthesiologist in Berlin, wants her colleagues to stop using a gas called desflurane, which is by far the most damaging of all inhalation gases to the climate.
Adobe Stock
Other countries have done more. The European Union recommends reducing inhalation gases and even contemplated a ban of desflurane, except in medical emergencies. In 2008, the National Health Service (NHS) created a Sustainable Development Unit, which measures CO2 emissions in the U.K. health sector. NHS is the first national health service that pledged to reach net zero carbon by 2040. The carbon footprint of the NHS fell by 26 percent from 1990 to 2019, mostly due to reduced use of certain inhalers and the switch to renewable energy for heat and power. “The evidence that the climate emergency is a health emergency is overwhelming,” said Nick Watts, the NHS Chief Sustainability Officer, in a press release, “with health professionals already needing to manage its symptoms.”
Sherman is a leading voice in demanding action in the U.S. To her, comprehensive solutions start with the mandatory, transparent measurement of emissions in the health sector to tackle the biggest sources of pollution. While the Biden administration highlighted its efforts to reduce these kinds of emissions during the United Nations Climate Conference (COP27) in November 2022 and U.S. delegates announced that more than 100 health care organizations signed the voluntary Health Sector Climate Pledge, with the aim to reduce emissions by 50 percent in the next eight years, Sherman is convinced that voluntary pledges are not enough. “Voluntary measures are insufficient,” she testified in congress. “The vast majority of U.S. health care organizations remain uncommitted to timely action. Those that are committed lack policies and knowledge to support necessary changes; even worse, existing policies drive inappropriate consumption of resources and pollution.”
Both Sherman and Koch look at the larger picture. “Health care organizations have an obligation to their communities to protect public health,” Sherman says. “We must lead by example. That includes setting ambitious, science-based carbon reduction targets to achieve net zero emissions before 2050. We must quantify current emissions and their sources, particularly throughout the health care supply chains.”