CRISPR base editing gives measure of hope to people with muscular dystrophy
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.
Staying well in the 21st century is like playing a game of chess
This article originally appeared in One Health/One Planet, a single-issue magazine that explores how climate change and other environmental shifts are increasing vulnerabilities to infectious diseases by land and by sea. The magazine probes how scientists are making progress with leaders in other fields toward solutions that embrace diverse perspectives and the interconnectedness of all lifeforms and the planet.
On July 30, 1999, the Centers for Disease Control and Prevention published a report comparing data on the control of infectious disease from the beginning of the 20th century to the end. The data showed that deaths from infectious diseases declined markedly. In the early 1900s, pneumonia, tuberculosis and diarrheal diseases were the three leading killers, accounting for one-third of total deaths in the U.S.—with 40 percent being children under five.
Mass vaccinations, the discovery of antibiotics and overall sanitation and hygiene measures eventually eradicated smallpox, beat down polio, cured cholera, nearly rid the world of tuberculosis and extended the U.S. life expectancy by 25 years. By 1997, there was a shift in population health in the U.S. such that cancer, diabetes and heart disease were now the leading causes of death.
The control of infectious diseases is considered to be one of the “10 Great Public Health Achievements.” Yet on the brink of the 21st century, new trouble was already brewing. Hospitals were seeing periodic cases of antibiotic-resistant infections. Novel viruses, or those that previously didn’t afflict humans, began to emerge, causing outbreaks of West Nile, SARS, MERS or swine flu.In the years that followed, tuberculosis made a comeback, at least in certain parts of the world. What we didn’t take into account was the very concept of evolution: as we built better protections, our enemies eventually boosted their attacking prowess, so soon enough we found ourselves on the defensive once again.
At the same time, new, previously unknown or extremely rare disorders began to rise, such as autoimmune or genetic conditions. Two decades later, scientists began thinking about health differently—not as a static achievement guaranteed to last, but as something dynamic and constantly changing—and sometimes, for the worse.
What emerged since then is a different paradigm that makes our interactions with the microbial world more like a biological chess match, says Victoria McGovern, a biochemist and program officer for the Burroughs Wellcome Fund’s Infectious Disease and Population Sciences Program. In this chess game, humans may make a clever strategic move, which could involve creating a new vaccine or a potent antibiotic, but that advantage is fleeting. At some point, the organisms we are up against could respond with a move of their own—such as developing resistance to medication or genetic mutations that attack our bodies. Simply eradicating the “opponent,” or the pathogenic microbes, as efficiently as possible isn’t enough to keep humans healthy long-term.
Instead, scientists should focus on studying the complexity of interactions between humans and their pathogens. “We need to better understand the lifestyles of things that afflict us,” McGovern says. “The solutions are going to be in understanding various parts of their biology so we can influence how they behave around our systems.”
Genetics and cell biology, combined with imaging techniques that allow one to see tissues and individual cells in actions, will enable scientists to define and quantify what it means to be healthy at the molecular level.
What is being proposed will require a pivot to basic biology and other disciplines that have suffered from lack of research funding in recent years. Yet, according to McGovern, the research teams of funded proposals are answering bigger questions. “We look for people exploring questions about hosts and pathogens, and what happens when they touch, but we’re also looking for people with big ideas,” she says. For example, if one specific infection causes a chain of pathological events in the body, can other infections cause them too? And if we find a way to break that chain for one pathogen, can we play the same trick on another? “We really want to see people thinking of not just one experiment but about big implications of their work,” McGovern says.
Jonah Cool, a cell biologist, geneticist and science officer at the Chan Zuckerberg Initiative, says that it’s necessary to define what constitutes a healthy organism and how it overcomes infections or environmental assaults, such as pollution from forest fires or toxins from industrial smokestacks. An organism that catches a disease isn’t necessarily an unhealthy one, as long as it fights it off successfully—an ability that arises from the complex interplay of its genes, the immune system, age, stress levels and other factors. Modern science allows many of these factors to be measured, recorded and compared. “We need a data-driven, deep-phenotyping approach to defining healthy biological systems and their responses to insults—which can be infectious disease or environmental exposures—and their ability to navigate their way through that space,” Cool says.
Genetics and cell biology, combined with imaging techniques that allow one to see tissues and individual cells in actions, will enable scientists to define and quantify what it means to be healthy at the molecular level. “As a geneticist and cell biologist, I believe in all these molecular underpinnings and how they arise in phenotypic differences in cells, genes, proteins—and how their combinations form complex cellular states,” Cool says.
Julie Graves, a physician, public health consultant, former adjunct professor of management, policy and community health at the University of Texas Health Science Center in Houston, stresses the necessity of nutritious diets. According to the Rockefeller Food Initiative, “poor diet is the leading risk factor for disease, disability and premature death in the majority of countries around the world.” Adequate nutrition is critical for maintaining human health and life. Yet, Western diets are often low in essential nutrients, high in calories and heavy on processed foods. Overconsumption of these foods has contributed to high rates of obesity and chronic disease in the U.S. In fact, more than half of American adults have at least one chronic disease, and 27 percent have more than one—which increases vulnerability to COVID-19 infections, according to the 2018 National Health Interview Survey.
Further, the contamination of our food supply with various agricultural and industrial toxins—petrochemicals, pesticides, PFAS and others—has implications for morbidity, mortality, and overall quality of life. “These chemicals are insidiously in everything, including our bodies,” Graves says—and they are interfering with our normal biological functions. “We need to stop how we manufacture food,” she adds, and rid our sustenance of these contaminants.
According to the Humane Society of the United States, factory farms result in nearly 40 percent of emissions of methane. Concentrated animal feeding operations or CAFOs may serve as breeding grounds for pandemics, scientists warn, so humans should research better ways to raise and treat livestock. Diego Rose, a professor of food and nutrition policy at Tulane University School of Public Health & Tropical Medicine, and his colleagues found that “20 percent of Americans’ diets account for about 45 percent of the environmental impacts [that come from food].” A subsequent study explored the impacts of specific foods and found that substituting beef for chicken lowers an individual’s carbon footprint by nearly 50 percent, with water usage decreased by 30 percent. Notably, however, eating too much red meat has been associated with a variety of illnesses.
In some communities, the option to swap food types is limited or impossible. For example, “many populations live in relative food deserts where there’s not a local grocery store that has any fresh produce,” says Louis Muglia, the president and CEO of Burroughs Wellcome. Individuals in these communities suffer from an insufficient intake of beneficial macronutrients, and they’re “probably being exposed to phenols and other toxins that are in the packaging.” An equitable, sustainable and nutritious food supply will be vital to humanity’s wellbeing in the era of climate change, unpredictable weather and spillover events.
A recent report by See Change Institute and the Climate Mental Health Network showed that people who are experiencing socioeconomic inequalities, including many people of color, contribute the least to climate change, yet they are impacted the most. For example, people in low-income communities are disproportionately exposed to vehicle emissions, Muglia says. Through its Climate Change and Human Health Seed Grants program, Burroughs Wellcome funds research that aims to understand how various factors related to climate change and environmental chemicals contribute to premature births, associated with health vulnerabilities over the course of a person’s life—and map such hot spots.
“It’s very complex, the combinations of socio-economic environment, race, ethnicity and environmental exposure, whether that’s heat or toxic chemicals,” Muglia explains. “Disentangling those things really requires a very sophisticated, multidisciplinary team. That’s what we’ve put together to describe where these hotspots are and see how they correlate with different toxin exposure levels.”
In addition to mapping the risks, researchers are developing novel therapeutics that will be crucial to our armor arsenal, but we will have to be smarter at designing and using them. We will need more potent, better-working monoclonal antibodies. Instead of directly attacking a pathogen, we may have to learn to stimulate the immune system—training it to fight the disease-causing microbes on its own. And rather than indiscriminately killing all bacteria with broad-scope drugs, we would need more targeted medications. “Instead of wiping out the entire gut flora, we will need to come up with ways that kill harmful bacteria but not healthy ones,” Graves says. Training our immune systems to recognize and react to pathogens by way of vaccination will keep us ahead of our biological opponents, too. “Continued development of vaccines against infectious diseases is critical,” says Graves.
With all of the unpredictable events that lie ahead, it is difficult to foresee what achievements in public health will be reported at the end of the 21st century. Yet, technological advances, better modeling and pursuing bigger questions in science, along with education and working closely with communities will help overcome the challenges. The Chan Zuckerberg Initiative displays an optimistic message on its website: “Is it possible to cure, prevent, or manage all diseases by the end of this century? We think so.” Cool shares the view of his employer—and believes that science can get us there. Just give it some time and a chance. “It’s a big, bold statement,” he says, “but the end of the century is a long way away.”Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.
Alzheimer’s prevention may be less about new drugs, more about income, zip code and education
That your risk of Alzheimer’s disease depends on your salary, what you ate as a child, or the block where you live may seem implausible. But researchers are discovering that social determinants of health (SDOH) play an outsized role in Alzheimer’s disease and related dementias, possibly more than age, and new strategies are emerging for how to address these factors.
At the 2022 Alzheimer’s Association International Conference, a series of presentations offered evidence that a string of socioeconomic factors—such as employment status, social support networks, education and home ownership—significantly affected dementia risk, even when adjusting data for genetic risk. What’s more, memory declined more rapidly in people who earned lower wages and slower in people who had parents of higher socioeconomic status.
In 2020, a first-of-its kind study in JAMA linked Alzheimer’s incidence to “neighborhood disadvantage,” which is based on SDOH indicators. Through autopsies, researchers analyzed brain tissue markers related to Alzheimer’s and found an association with these indicators. In 2022, Ryan Powell, the lead author of that study, published further findings that neighborhood disadvantage was connected with having more neurofibrillary tangles and amyloid plaques, the main pathological features of Alzheimer's disease.
As of yet, little is known about the biological processes behind this, says Powell, director of data science at the Center for Health Disparities Research at the University of Wisconsin School of Medicine and Public Health. “We know the association but not the direct causal pathway.”
The corroborative findings keep coming. In a Nature study published a few months after Powell’s study, every social determinant investigated affected Alzheimer’s risk except for marital status. The links were highest for income, education, and occupational status.
Clinical trials on new Alzheimer’s medications get all the headlines but preventing dementia through policy and public health interventions should not be underestimated.
The potential for prevention is significant. One in three older adults dies with Alzheimer's or another dementia—more than breast and prostate cancers combined. Further, a 2020 report from the Lancet Commission determined that about 40 percent of dementia cases could theoretically be prevented or delayed by managing the risk factors that people can modify.
Take inactivity. Older adults who took 9,800 steps daily were half as likely to develop dementia over the next 7 years, in a 2022 JAMA study. Hearing loss, another risk factor that can be managed, accounts for about 9 percent of dementia cases.
Clinical trials on new Alzheimer’s medications get all the headlines but preventing dementia through policy and public health interventions should not be underestimated. Simply slowing the course of Alzheimer’s or delaying its onset by five years would cut the incidence in half, according to the Global Council on Brain Health.
Minorities Hit the Hardest
The World Health Organization defines SDOH as “conditions in which people are born, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life.”
Anyone who exists on processed food, smokes cigarettes, or skimps on sleep has heightened risks for dementia. But minority groups get hit harder. Older Black Americans are twice as likely to have Alzheimer’s or another form of dementia as white Americans; older Hispanics are about one and a half times more likely.
This is due in part to higher rates of diabetes, obesity, and high blood pressure within these communities. These diseases are linked to Alzheimer’s, and SDOH factors multiply the risks. Blacks and Hispanics earn less income on average than white people. This means they are more likely to live in neighborhoods with limited access to healthy food, medical care, and good schools, and suffer greater exposure to noise (which impairs hearing) and air pollution—additional risk factors for dementia.
Related Reading: The Toxic Effects of Noise and What We're Not Doing About it
Plus, when Black people are diagnosed with dementia, their cognitive impairment and neuropsychiatric symptom are more advanced than in white patients. Why? Some African-Americans delay seeing a doctor because of perceived discrimination and a sense they will not be heard, says Carl V. Hill, chief diversity, equity, and inclusion officer at the Alzheimer’s Association.
Misinformation about dementia is another issue in Black communities. The thinking is that Alzheimer’s is genetic or age-related, not realizing that diet and physical activity can improve brain health, Hill says.
African Americans are severely underrepresented in clinical trials for Alzheimer’s, too. So, researchers miss the opportunity to learn more about health disparities. “It’s a bioethical issue,” Hill says. “The people most likely to have Alzheimer’s aren’t included in the trials.”
The Cure: Systemic Change
People think of lifestyle as a choice but there are limitations, says Muniza Anum Majoka, a geriatric psychiatrist and assistant professor of psychiatry at Yale University, who published an overview of SDOH factors that impact dementia. “For a lot of people, those choices [to improve brain health] are not available,” she says. If you don’t live in a safe neighborhood, for example, walking for exercise is not an option.
Hill wants to see the focus of prevention shift from individual behavior change to ensuring everyone has access to the same resources. Advice about healthy eating only goes so far if someone lives in a food desert. Systemic change also means increasing the number of minority physicians and recruiting minorities in clinical drug trials so studies will be relevant to these communities, Hill says.
Based on SDOH impact research, raising education levels has the most potential to prevent dementia. One theory is that highly educated people have a greater brain reserve that enables them to tolerate pathological changes in the brain, thus delaying dementia, says Majoka. Being curious, learning new things and problem-solving also contribute to brain health, she adds. Plus, having more education may be associated with higher socioeconomic status, more access to accurate information and healthier lifestyle choices.
New Strategies
The chasm between what researchers know about brain health and how the knowledge is being applied is huge. “There’s an explosion of interest in this area. We’re just in the first steps,” says Powell. One day, he predicts that physicians will manage Alzheimer’s through precision medicine customized to the patient’s specific risk factors and needs.
Raina Croff, assistant professor of neurology at Oregon Health & Science University School of Medicine, created the SHARP (Sharing History through Active Reminiscence and Photo-imagery) walking program to forestall memory loss in African Americans with mild cognitive impairment or early dementia.
Participants and their caregivers walk in historically black neighborhoods three times a week over six months. A smart tablet provides information about “Memory Markers” they pass, such as the route of a civil rights march. People celebrate their community and culture while “brain health is running in the background,” Croff says.
Photos and memory prompts engage participants in the SHARP program.
OHSU/Kristyna Wentz-Graff
The project began in 2015 as a pilot study in Croff’s hometown of Portland, Ore., expanded to Seattle, and will soon start in Oakland, Calif. “Walking is good for slowing [brain] decline,” she says. A post-study assessment of 40 participants in 2017 showed that half had higher cognitive scores after the program; 78 percent had lower blood pressure; and 44 percent lost weight. Those with mild cognitive impairment showed the most gains. The walkers also reported improved mood and energy along with increased involvement in other activities.
It’s never too late to reap the benefits of working your brain and being socially engaged, Majoka says.
In Milwaukee, the Wisconsin Alzheimer’s Institute launched the The Amazing Grace Chorus® to stave off cognitive decline in seniors. People in early stages of Alzheimer’s practice and perform six concerts each year. The activity provides opportunities for social engagement, mental stimulation, and a support network. Among the benefits, 55 percent reported better communication at home and nearly half of participants said they got involved with more activities after participating in the chorus.
Private companies are offering intervention services to healthcare providers and insurers to manage SDOH, too. One such service, MyHello, makes calls to at-risk people to assess their needs—be it food, transportation or simply a friendly voice. Having a social support network is critical for seniors, says Majoka, noting there was a steep decline in cognitive function among isolated elders during Covid lockdowns.
About 1 in 9 Americans age 65 or older live with Alzheimer’s today. With a surge in people with the disease predicted, public health professionals have to think more broadly about resource targets and effective intervention points, Powell says.
Beyond breakthrough pills, that is. Like Dorothy in Kansas discovering happiness was always in her own backyard, we are beginning to learn that preventing Alzheimer’s is in our reach if only we recognized it.