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.
Sparklers produce a beautiful display of light and heat by burning metal dust, which contains iron. The recent work of Canadian and Dutch researchers suggests we can use iron as a cheap, carbon-free fuel.
Iron as a fuel
Iron is abundantly available and cheap. More importantly, the byproduct of burning iron is rust (iron oxide), a solid material that is easy to collect and recycle. Neither burning iron nor converting its oxide back produces any carbon in the process.
Iron oxide is potentially renewable by reacting with electricity or hydrogen to become iron again.
Iron has a high energy density: it requires almost the same volume as gasoline to produce the same amount of energy. However, iron has poor specific energy: it’s a lot heavier than gas to produce the same amount of energy. (Think of picking up a jug of gasoline, and then imagine trying to pick up a similar sized chunk of iron.) Therefore, its weight is prohibitive for many applications. Burning iron to run a car isn’t very practical if the iron fuel weighs as much as the car itself.
In its powdered form, however, iron offers more promise as a high-density energy carrier or storage system. Iron-burning furnaces could provide direct heat for industry, home heating, or to generate electricity.
Plus, iron oxide is potentially renewable by reacting with electricity or hydrogen to become iron again (as long as you’ve got a source of clean electricity or green hydrogen). When there’s excess electricity available from renewables like solar and wind, for example, rust could be converted back into iron powder, and then burned on demand to release that energy again.
However, these methods of recycling rust are very energy intensive and inefficient, currently, so improvements to the efficiency of burning iron itself may be crucial to making such a circular system viable.
The science of discrete burning
Powdered particles have a high surface area to volume ratio, which means it is easier to ignite them. This is true for metals as well.
Under the right circumstances, powdered iron can burn in a manner known as discrete burning. In its most ideal form, the flame completely consumes one particle before the heat radiating from it combusts other particles in its vicinity. By studying this process, researchers can better understand and model how iron combusts, allowing them to design better iron-burning furnaces.
Discrete burning is difficult to achieve on Earth. Perfect discrete burning requires a specific particle density and oxygen concentration. When the particles are too close and compacted, the fire jumps to neighboring particles before fully consuming a particle, resulting in a more chaotic and less controlled burn.
Presently, the rate at which powdered iron particles burn or how they release heat in different conditions is poorly understood. This hinders the development of technologies to efficiently utilize iron as a large-scale fuel.
Burning metal in microgravity
In April, the European Space Agency (ESA) launched a suborbital “sounding” rocket, carrying three experimental setups. As the rocket traced its parabolic trajectory through the atmosphere, the experiments got a few minutes in free fall, simulating microgravity.
One of the experiments on this mission studied how iron powder burns in the absence of gravity.
In microgravity, particles float in a more uniformly distributed cloud. This allows researchers to model the flow of iron particles and how a flame propagates through a cloud of iron particles in different oxygen concentrations.
Existing fossil fuel power plants could potentially be retrofitted to run on iron fuel.
Insights into how flames propagate through iron powder under different conditions could help design much more efficient iron-burning furnaces.
Clean and carbon-free energy on Earth
Various businesses are looking at ways to incorporate iron fuels into their processes. In particular, it could serve as a cleaner way to supply industrial heat by burning iron to heat water.
For example, Dutch brewery Swinkels Family Brewers, in collaboration with the Eindhoven University of Technology, switched to iron fuel as the heat source to power its brewing process, accounting for 15 million glasses of beer annually. Dutch startup RIFT is running proof-of-concept iron fuel power plants in Helmond and Arnhem.
As researchers continue to improve the efficiency of burning iron, its applicability will extend to other use cases as well. But is the infrastructure in place for this transition?
Often, the transition to new energy sources is slowed by the need to create new infrastructure to utilize them. Fortunately, this isn’t the case with switching from fossil fuels to iron. Since the ideal temperature to burn iron is similar to that for hydrocarbons, existing fossil fuel power plants could potentially be retrofitted to run on iron fuel.
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
Leaps.org talks with Dr. Tom Oxley, founding CEO of Synchron, a company that's taking a unique - and less invasive - approach to "brain-computer interfaces" for patients with ALS and other mobility challenges.
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In our conversation, Dr. Oxley talks about “Bluetooth brain”; the critical role of AI in the present and future of BCIs; how BCIs compare to voice command technology; regulatory frameworks for revolutionary technologies; specific people with paralysis who’ve been able to regain some independence thanks to the Stentrode; what it means to be a neurointerventionist; how to scale BCIs for more people to use them; the risks of BCIs malfunctioning; organic implants; and how BCIs help us understand the brain, among other topics.
Dr. Oxley received his PhD in neuro engineering from the University of Melbourne in Australia. He is the founding CEO of Synchron and an associate professor and the head of the vascular bionics laboratory at the University of Melbourne. He’s also a clinical instructor in the Deepartment of Neurosurgery at Mount Sinai Hospital. Dr. Oxley has completed more than 1,600 endovascular neurosurgical procedures on patients, including people with aneurysms and strokes, and has authored over 100 peer reviewed articles.
Links:
Synchron website - https://synchron.com/
Assessment of Safety of a Fully Implanted Endovascular Brain-Computer Interface for Severe Paralysis in 4 Patients (paper co-authored by Tom Oxley) - https://jamanetwork.com/journals/jamaneurology/art...
More research related to Synchron's work - https://synchron.com/research
Tom Oxley on LinkedIn - https://www.linkedin.com/in/tomoxl
Tom Oxley on Twitter - https://twitter.com/tomoxl?lang=en
Tom Oxley TED - https://www.ted.com/talks/tom_oxley_a_brain_implant_that_turns_your_thoughts_into_text?language=en
Tom Oxley website - https://tomoxl.com/
Novel brain implant helps paralyzed woman speak using digital avatar - https://engineering.berkeley.edu/news/2023/08/novel-brain-implant-helps-paralyzed-woman-speak-using-a-digital-avatar/
Edward Chang lab - https://changlab.ucsf.edu/
BCIs convert brain activity into text at 62 words per minute - https://med.stanford.edu/neurosurgery/news/2023/he...
Leaps.org: The Mind-Blowing Promise of Neural Implants - https://leaps.org/the-mind-blowing-promise-of-neural-implants/
Tom Oxley