Advances Bring First True Hope to Spinal Cord Injury Patients
Seven years ago, mountain biking near his home in Whitefish, Montana, Jeff Marquis felt confident enough to try for a jump he usually avoided. But he hesitated just a bit as he was going over. Instead of catching air, Marquis crashed.
Researchers' major new insight is that recovery is still possible, even years after an injury.
After 18 days on a ventilator in intensive care and two-and-a-half months in a rehabilitation hospital, Marquis was able to move his arms and wrists, but not his fingers or anything below his chest. Still, he was determined to remain as independent as possible. "I wasn't real interested in having people take care of me," says Marquis, now 35. So, he dedicated the energy he formerly spent biking, kayaking, and snowboarding toward recovering his own mobility.
For generations, those like Marquis with severe spinal cord injuries dreamt of standing and walking again – with no realistic hope of achieving these dreams. But now, a handful of people with such injuries, including Marquis, have stood on their own and begun to learn to take steps again. "I'm always trying to improve the situation but I'm happy with where I'm at," Marquis says.
The recovery Marquis and a few of his fellow patients have achieved proves that our decades-old understanding of the spinal cord was wrong. Researchers' major new insight is that recovery is still possible, even years after an injury. Only a few thousand nerve cells actually die when the spinal cord is injured. The other neurons still have the ability to generate signals and movement on their own, says Susan Harkema, co-principal investigator at the Kentucky Spinal Cord Injury Research Center, where Marquis is being treated.
"The spinal cord has much more responsibility for executing movement than we thought before," Harkema says. "Successful movement can happen without those connections from the brain." Nerve cell circuits remaining after the injury can control movement, she says, but leaving people sitting in a wheelchair doesn't activate those sensory circuits. "When you sit down, you lose all the sensory information. The whole circuitry starts discombobulating."
Harkema and others use a two-pronged approach – both physical rehabilitation and electrical stimulation – to get those spinal cord circuits back into a functioning state. Several research groups are still honing this approach, but a few patients have already taken steps under their own power, and others, like Marquis, can now stand unassisted – both of which were merely fantasies for spinal cord injury patients just five years ago.
"This really does represent a leap forward in terms of how we think about the capacity of the spinal cord to be repaired after injury," says Susan Howley, executive vice president for research for the Christopher & Dana Reeve Foundation, which supports research for spinal cord injuries.
Jeff Marquis biking on a rock before his accident.
This new biological understanding suggests the need for a wholesale change in how people are treated after a spinal cord injury, Howley says. But today, most insurance companies cover just 30-40 outpatient rehabilitation sessions per year, whether you've sprained your ankle or severed your spinal cord. To deliver the kind of therapy that really makes a difference for spinal cord injury patients requires "60-80-90 or 150 sessions," she says, adding that she thinks insurance companies will more than make up for the cost of those therapy sessions if spinal cord injury patients are healthier. Early evidence suggests that getting people back on their feet helps prevent medical problems common among paralyzed people, including urinary tract infections, which can require costly hospital stays.
"Exercise and the ability to fully bear one's own weight are as crucial for people who live with paralysis as they are for able-bodied people," Howley notes, adding that the Reeve Foundation is now trying to expand the network of facilities available in local communities to offer this essential rehabilitation.
"Providing the right kind of training every day to people could really improve their opportunity to recover," Harkema says.
It's not entirely clear yet how far someone could progress with rehabilitation alone, Harkema says, but probably the best results for someone with a severe injury will also require so-called epidural electrical stimulation. This device, implanted in the lower back for a cost of about $30,000, sends an electrical current at varying frequencies and intensities to the spinal cord. Several separate teams of researchers have now shown that epidural stimulation can help restore sensation and movement to people who have been paralyzed for years.
Epidural stimulation boosts the electrical signal that is generated below the point of injury, says Daniel Lu, an associate professor and vice chair of neurosurgery at the UCLA School of Medicine. Before a spinal cord injury, he says, a neuron might send a message at a volume of 10 but after injury, that volume might drop to a two or three. The epidural stimulation potentially trains the neuron to respond to the lower volume, Lu says.
Lu has used such stimulators to improve hand function – "essentially what defines us" – in two patients with spinal cord injuries. Both increased their grip strength so they now can lift a cup to drink by themselves, which they couldn't do before. He's also used non-invasive stimulation to help restore bladder function, which he says many spinal cord injury patients care about as much as walking again.
A closeup of the stimulator.
Not everyone will benefit from these treatments. People whose injury was caused by a cut to the spinal cord, as with a knife or bullet, probably can't be helped, Lu says, adding that they account for less than 5 percent of spinal cord injuries.
The current challenge Lu says is not how to stimulate the spinal cord, but where to stimulate it and the frequency of stimulation that will be most effective for each patient. Right now, doctors use an off-the-shelf stimulator that is used to treat pain and is not optimized for spinal cord patients, Harkema says.
Swiss researchers have shown impressive results from intermittent rather than continuous epidural stimulation. These pulses better reflect the way the brain sends its messages, according to Gregoire Courtine, the senior author on a pair of papers published Nov. 1 in Nature and Nature Neuroscience. He showed that he could get people up and moving within just a few days of turning on the stimulation. Three of his patients are walking again with only a walker or minimal assistance, and they also gained voluntary leg movements even when the stimulator was off. Continuous stimulation, this research shows, actually interferes with the patients' perception of limb position, and thus makes it harder for them to relearn to walk.
Even short of walking, proper physical rehabilitation and electrical stimulation can transform the quality of life of people with spinal cord injury, Howley and Harkema say. Patients don't need to be able to reach the top shelf or run a marathon to feel like they've been "cured" from their paralysis. Instead, recovering bowel, bladder and sexual functions, the ability to regulate their temperature and blood pressure, and reducing the breakdown of skin that can lead to a life-threatening infection can all be transformative – and all appear to improve with the combination of rehabilitation and electrical stimulation.
Howley cites a video of one of Harkema's patients, Stefanie Putnam, who was passing out five to six times a day because her blood pressure was so low. She couldn't be left alone, which meant she had no independence. After several months of rehabilitation and stimulation, she can now sit up for long periods, be left alone, and even, she says gleefully, cook her own dinner. "Every time I watch it, it brings me to tears," Howley says of the video. "She's able to resume her normal life activity. It's mind-boggling."
The work also suggests a transformation in the care of people immediately after injury. They should be allowed to stand and start taking steps as soon as possible, even if they cannot do it under their own power, Harkema says. Research is also likely to show that quickly implanting a stimulator after an injury will make a difference, she says.
There may be medications that can help immediately after an injury, too. One drug currently being studied, called riluzole, has already been approved for ALS and might help limit the damage of a spinal cord injury, Howley says. But testing its effectiveness has been a slow process, she says, because it needs to be given within 12 hours of the initial injury and not enough people get to the testing sites in time.
Stem cell therapy also offers promise for spinal cord injury patients, Howley says – but not the treatments currently provided by commercial stem cell clinics both in the U.S. and overseas, which she says are a sham. Instead, she is carefully following research by a California-based company called Asterias Biotherapeutics, which announced plans Nov. 8 to merge with a company called BioTime.
Asterias and a predecessor company have been treating people since 2010 in an effort to regrow nerves in the spinal cord. All those treated have safely tolerated the cells, but not everyone has seen a huge improvement, says Edward Wirth, who has led the trial work and is Asterias' chief medical director. He says he thinks he knows what's held back those who didn't improve much, and hopes to address those issues in the next 3- to 4-year-long trial, which he's now discussing with the U.S. Food and Drug Administration.
So far, he says, some patients have had an almost complete return of movement in their hands and arms, but little improvement in their legs. The stem cells seem to stimulate tissue repair and regeneration, he says, but only around the level of the injury in the spinal cord and a bit below. The legs, he says, are too far away to benefit.
Wirth says he thinks a combination of treatments – stem cells, electrical stimulation, rehabilitation, and improved care immediately after an injury – will likely produce the best results.
While there's still a long way to go to scale these advances to help the majority of the 300,000 spinal cord injury patients in the U.S., they now have something that's long been elusive: hope.
"Two or three decades ago there was no hope at all," Howley says. "We've come a long way."
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman
Nobel Prize goes to technology for mRNA vaccines
When Drew Weissman received a call from Katalin Karikó in the early morning hours this past Monday, he assumed his longtime research partner was calling to share a nascent, nagging idea. Weissman, a professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, and Karikó, a professor at Szeged University and an adjunct professor at UPenn, both struggle with sleep disturbances. Thus, middle-of-the-night discourses between the two, often over email, has been a staple of their friendship. But this time, Karikó had something more pressing and exciting to share: They had won the 2023 Nobel Prize in Physiology or Medicine.
The work for which they garnered the illustrious award and its accompanying $1,000,000 cash windfall was completed about two decades ago, wrought through long hours in the lab over many arduous years. But humanity collectively benefited from its life-saving outcome three years ago, when both Moderna and Pfizer/BioNTech’s mRNA vaccines against COVID were found to be safe and highly effective at preventing severe disease. Billions of doses have since been given out to protect humans from the upstart viral scourge.
“I thought of going somewhere else, or doing something else,” said Katalin Karikó. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
Unlocking the power of mRNA
Weissman and Karikó unlocked mRNA vaccines for the world back in the early 2000s when they made a key breakthrough. Messenger RNA molecules are essentially instructions for cells’ ribosomes to make specific proteins, so in the 1980s and 1990s, researchers started wondering if sneaking mRNA into the body could trigger cells to manufacture antibodies, enzymes, or growth agents for protecting against infection, treating disease, or repairing tissues. But there was a big problem: injecting this synthetic mRNA triggered a dangerous, inflammatory immune response resulting in the mRNA’s destruction.
While most other researchers chose not to tackle this perplexing problem to instead pursue more lucrative and publishable exploits, Karikó stuck with it. The choice sent her academic career into depressing doldrums. Nobody would fund her work, publications dried up, and after six years as an assistant professor at the University of Pennsylvania, Karikó got demoted. She was going backward.
“I thought of going somewhere else, or doing something else,” Karikó told Stat in 2020. “I also thought maybe I’m not good enough, not smart enough. I tried to imagine: Everything is here, and I just have to do better experiments.”
A tale of tenacity
Collaborating with Drew Weissman, a new professor at the University of Pennsylvania, in the late 1990s helped provide Karikó with the tenacity to continue. Weissman nurtured a goal of developing a vaccine against HIV-1, and saw mRNA as a potential way to do it.
“For the 20 years that we’ve worked together before anybody knew what RNA is, or cared, it was the two of us literally side by side at a bench working together,” Weissman said in an interview with Adam Smith of the Nobel Foundation.
In 2005, the duo made their 2023 Nobel Prize-winning breakthrough, detailing it in a relatively small journal, Immunity. (Their paper was rejected by larger journals, including Science and Nature.) They figured out that chemically modifying the nucleoside bases that make up mRNA allowed the molecule to slip past the body’s immune defenses. Karikó and Weissman followed up that finding by creating mRNA that’s more efficiently translated within cells, greatly boosting protein production. In 2020, scientists at Moderna and BioNTech (where Karikó worked from 2013 to 2022) rushed to craft vaccines against COVID, putting their methods to life-saving use.
The future of vaccines
Buoyed by the resounding success of mRNA vaccines, scientists are now hurriedly researching ways to use mRNA medicine against other infectious diseases, cancer, and genetic disorders. The now ubiquitous efforts stand in stark contrast to Karikó and Weissman’s previously unheralded struggles years ago as they doggedly worked to realize a shared dream that so many others shied away from. Katalin Karikó and Drew Weissman were brave enough to walk a scientific path that very well could have ended in a dead end, and for that, they absolutely deserve their 2023 Nobel Prize.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.