Jeff Marquis and Kelly Thomas, fellow research participants and spinal cord injury patients, in a rehab session.
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.
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."
Phages, which are harmless viruses that destroy specific bacteria, are becoming useful tools to protect our food supply.
Food producers and packagers fight bacteria by potent chemicals, with chlorine being the go-to disinfectant. Cattle carcasses, for example, are typically washed by chlorine solutions as the animals' intestines are removed. Leafy greens are bathed in water with added chlorine solutions. However, because the same "bath" can be used for multiple veggie batches and chlorine evaporates over time, the later rounds may not kill all of the bacteria, sparing some. The natural and organic producers avoid chlorine, substituting it with lactic acid, a more holistic sanitizer, but even with all these efforts, some pathogens survive, sickening consumers and causing food recalls. As we farm more animals and grow more produce, while also striving to use fewer chemicals and more organic growing methods, it will be harder to control bacteria's spread.
"It took us a long time to convince the FDA phages were safe and efficient alternatives. But we had worked with them to gather all the data they needed, and the FDA was very supportive in the end."
Luckily, bacteria have their own killers. Called bacteriophages, or phages for short, they are viruses that prey on bacteria only. Under the electron microscope, they look like fantasy spaceships, with oblong bodies, spider-like legs and long tails. Much smaller than a bacterium, phages pierce the microbes' cells with their tails, sneak in and begin multiplying inside, eventually bursting the microbes open—and then proceed to infect more of them.
The best part is that these phages are harmless to humans. Moreover, recent research finds that millions of phages dwell on us and in us—in our nose, throat, skin and gut, protecting us from bacterial infections as part of our healthy microbiome. A recent study suggested that we absorb about 30 billion phages into our bodies on a daily basis. Now, ingeniously, they are starting to be deployed as anti-microbial agents in the food industry.
A Maryland-based phage research company called Intralytix is doing just that. Founded by Alexander Sulakvelidze, a microbiologist and epidemiologist who came to the United States from Tbilisi, the capital of Georgia, Intralytix makes and sells five different FDA-approved phage cocktails that work against some of the most notorious food pathogens: ListShield for Listeria, SalmoFresh for Salmonella, ShigaShield for Shigella, another foodborne bug, and EcoShield for E.coli, including the infamous strain that caused the Jack in the Box outbreak in 1993 that killed four children and sickened 732 people across four states. Last year, the FDA granted its approval to yet another Intralytix phage for managing Campylobacter contamination, named CampyShield. "We call it safety by nature," Sulakvelidze says.
Intralytix grows phages inside massive 1500-liter fermenters, feeding them bacterial "fodder."
Photo credit: Living Radiant Photography
Phage preparations are relatively straightforward to make. In nature, phages thrive in any body of water where bacteria live too, including rivers, lakes and bays. "I can dip a bucket into the Chesapeake Bay, and it will be full of all kinds of phages," Sulakvelidze says. "Sewage is another great place to look for specific phages of interest, because it's teeming with all sorts of bacteria—and therefore the viruses that prey on them."
In lab settings, Intralytix grows phages inside massive 1500-liter fermenters, feeding them bacterial "fodder." Once phages multiply enough, they are harvested, dispensed into containers and shipped to food producers who have adopted this disinfecting practice into their preparation process. Typically, it's done by computer-controlled sprayer systems that disperse mist-like phage preparations onto the food.
Unlike chemicals like chlorine or antibiotics, which kill a wide spectrum of bacteria, phages are more specialized, each feeding on specific microbial species. A phage that targets salmonella will not prey on listeria and vice versa. So food producers may sometimes use a combo of different phage preparations. Intralytix is continuously researching and testing new phages. With a contract from the National Institutes of Health, Intralytix is expanding its automated high-throughput robot that tests which phages work best against which bacteria, speeding up the development of the new phage cocktails.
Phages have other "talents." In her recent study, Jaroni found that phages have the ability to destroy bacterial biofilms—colonies of microorganisms that tend to grow on surfaces of the food processing equipment, surrounding themselves with protective coating that even very harsh chemicals can't crack.
"Phages are very clever," Jaroni says. "They produce enzymes that target the biofilms, and once they break through, they can reach the bacteria."
Convincing the FDA that phages were safe to use on food products was no easy feat, Sulakvelidze says. In his home country of Georgia, phages have been used as antimicrobial remedies for over a century, but the FDA was leery of using viruses as food safety agents. "It took us a long time to convince the FDA phages were safe and efficient alternatives," Sulakvelidze says. "But we had worked with them to gather all the data they needed, and the FDA was very supportive in the end."
The agency had granted Intralytix its first approval in 2006, and over the past 10 years, the company's sales increased by over 15-fold. "We currently sell to about 40 companies and are in discussions with several other large food producers," Sulakvelidze says. One indicator that the industry now understands and appreciates the science of phages was that his company was ranked as Top Food Safety Provider in 2021 by Food and Beverage Technology Review, he adds. Notably, phage sprays are kosher, halal and organic-certified.
Intralytix's phage cocktails to safeguard food from bacteria are approved for consumers in addition to food producers, but currently the company sells to food producers only. Selling retail requires different packaging like easy-to-use spray bottles and different marketing that would inform people about phages' antimicrobial qualities. But ultimately, giving people the ability to remove pathogens from their food with probiotic phage sprays is the goal, Sulakvelidze says.
It's not the company's only goal. Now Intralytix is going a step further, investigating phages' probiotic and therapeutic abilities. Because phages are highly specialized in the bacteria they target, they can be used to treat infections caused by specific pathogens while leaving the beneficial species of our microbiome intact. In an ongoing clinical trial with Mount Sinai, Intralytix is now investigating a potential phage treatment against a certain type of E. coli for patients with Crohn's disease, and is about to start another clinical trial for treating bacterial dysentery.
"Now that we have proved that phages are safe and effective against foodborne bacteria," Sulakvelidze says, "we are going to demonstrate their potential in therapeutic applications."
This article was first published by Leaps.org on October 27, 2021.