Phages, which are harmless viruses that destroy specific bacteria, are becoming useful tools to protect our food supply.
Every year, one in seven people in America comes down with a foodborne illness, typically caused by a bacterial pathogen, including E.Coli, listeria, salmonella, or campylobacter. That adds up to 48 million people, of which 120,000 are hospitalized and 3000 die, according to the Centers for Disease Control. And the variety of foods that can be contaminated with bacterial pathogens is growing too. In the 20th century, E.Coli and listeria lurked primarily within meat. Now they find their way into lettuce, spinach, and other leafy greens, causing periodic consumer scares and product recalls. Onions are the most recent suspected culprit of a nationwide salmonella outbreak.
Some of these incidents are almost inevitable because of how Mother Nature works, explains Divya Jaroni, associate professor of animal and food sciences at Oklahoma State University. These common foodborne pathogens come from the cattle's intestines when the animals shed them in their manure—and then they get washed into rivers and lakes, especially in heavy rains. When this water is later used to irrigate produce farms, the bugs end up on salad greens. Plus, many small farms do both—herd cattle and grow produce.
"Unfortunately for us, these pathogens are part of the microflora of the cows' intestinal tract," Jaroni says. "Some farmers may have an acre or two of cattle pastures, and an acre of a produce farm nearby, so it's easy for this water to contaminate the crops."
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.
It's all part of balancing bureaucracy with research goals for Williams, a leading expert on racial trauma and psychedelic medicine, as well as obsessive compulsive disorder (OCD), at the University of Ottawa. She's exploring the use of hallucinogenic substances like MDMA and psilocybin — commonly known as ecstasy and magic mushrooms, respectively — to help people of color address the psychological impacts of systemic racism. A prolific researcher, Williams also works as an expert witness, offering clinical evaluations for racial trauma cases.
Scientists have long known that psychedelics produce an altered state of consciousness and openness to new perspectives. For people with mental health conditions who haven't benefited from traditional therapy, psychedelics may be able to help them discover what's causing their pain or trauma, including racial trauma—the mental and emotional injury spurred by racial bias.
"Using psychedelics can not only bring these pain points to the surface for healing, but can reduce the anxiety or response to these memories and allow them to speak openly about them without the pain they bring," Williams says. Her research harnesses the potential of psychedelics to increase neuroplasticity, which includes the brain's ability to build new pathways.
"People of color are dealing with racism all the time, in large and small ways, and even dealing with racism in healthcare, even dealing with racism in therapy."
But she says therapists of color aren't automatically equipped to treat racial trauma. First, she notes, people of color are "vastly underrepresented in the mental health workforce." This is doubly true in psychedelic-assisted psychotherapy, in which a person is guided through a psychedelic session by a therapist or team of therapists, then processes the experience in subsequent therapy sessions.
"On top of that, the therapists of color are getting the same training that the white therapists are getting, so it's not even really guaranteed that they're going to be any better at helping a person that may have racial trauma emerging as part of their experience," she says.
In her own training to become a clinical psychologist at the University of Virginia, Williams says she was taught "how to be a great psychologist for white people." Yet even people of color, she argues, need specialized training to work with marginalized groups, particularly when it comes to MDMA, psilocybin and other psychedelics. Because these drugs can lower natural psychological defense mechanisms, Williams says, it's important for providers to be specially trained.
"People of color are dealing with racism all the time, in large and small ways, and even dealing with racism in healthcare, even dealing with racism in therapy. So [they] generally develop a lot of defenses and coping strategies to ward off racism so that they can function." she says. This is particularly true with psychedelic-assisted psychotherapy: "One possibility is that you're going to be stripped of your defenses, you're going to be vulnerable. And so you have to work with a therapist who is going to understand that and not enact more racism in their work with you."
Williams has struggled to find funding and institutional approval for research involving psychedelics, or funding for investigations into racial trauma or the impacts of conditions like OCD and post-traumatic stress disorder (PTSD) in people of color. With the bulk of her work focusing on OCD, she hoped to focus on people of color, but found there was little funding for that type of research. In 2020, that started to change as structural racism garnered more media attention.
After the killing of George Floyd, a 46-year-old Black man, by a white police officer in May 2020, Williams was flooded with media requests. "Usually, when something like that happens, I get contacted a lot for a couple of weeks, and it dies off. But after George Floyd, it just never did."
Monnica Williams, clinical psychologist at the University of Ottawa
Williams was no stranger to the questions that soon blazed across headlines: How can we mitigate microaggressions? How do race and ethnicity impact mental health? What terms should we use to discuss racial issues? What constitutes an ally, and why aren't there more of them? Why aren't there more people of color in academia, and so many other fields?
Now, she's hoping that the increased attention on racial justice will mean more acceptance for the kind of research she's doing.
In fact, Williams herself has used psychedelics in order to gain a better understanding of how to use them to treat racial trauma. In a study published in January, she and two other Black female psychotherapists took MDMA in a supervised setting, guided by a team of mental health practitioners who helped them process issues that came up as the session progressed. Williams, who was also the study's lead author, found that participants' experiences centered around processing and finding release from racial identities, and, in one case, of simply feeling wholly human without the burden of racial identity for the first time.
The purpose of the study was twofold: to understand how Black women react to psychedelics and to provide safe, firsthand, psychedelic experiences to Black mental health practitioners. One of the other study participants has since gone on to offer psychedelic-assisted psychotherapy to her own patients.
Psychedelic research, and psilocybin in particular, has become a hot topic of late, particularly after Oregon became the first state to legalize it for therapeutic use last November. A survey-based, observational study with 313 participants, published in 2020, paved the way for Williams' more recent MDMA experiments by describing improvements in depression, anxiety and racial trauma among people of color who had used LSD, psilocybin or MDMA in a non-research setting.
Williams and her team included only respondents who reported a moderate to strong psychoactive effect of past psychedelic consumption and believed these experiences provided "relief from the challenging effects of ethnic discrimination." Participants reported a memorable psychedelic experience as well as its acute and lasting effects, completing assessments of psychological insight, mystical experience and emotional challenges experienced during psychedelic experience, then describing their mental health — including depression, anxiety and trauma symptoms — before and after that experience.
Still, Williams says addressing racism is much more complex than treating racial trauma. "One of the questions I get asked a lot is, 'How can Black people cope with racism?' And I don't really like that question," she says. "I think it's important and I don't mind answering it, but I think the more important question is, how can we end racism? What can Black people do to stop racism that's happening to them and what can we do as a society to stop racism? And people aren't really asking this question."
A movie still from the 1966 film "Fantastic Voyage"
"Chemotherapy is delivered systemically," Bionaut-founder and CEO Michael Shpigelmacher says. "Often only a small percentage arrives at the location where it is actually needed."
But what if it was possible to send a tiny robot through the body to attack a tumor or deliver a drug at exactly the right location?
Several startups and academic institutes worldwide are working to develop such a solution but Bionaut Labs seems the furthest along in advancing its invention. "You can think of the Bionaut as a tiny screw that moves through the veins as if steered by an invisible screwdriver until it arrives at the tumor," Shpigelmacher explains. Via Zoom, he shares the screen of an X-ray machine in his Culver City lab to demonstrate how the half-transparent, yellowish device winds its way along the spine in the body. The nanobot contains a tiny but powerful magnet. The "invisible screwdriver" is an external magnetic field that rotates that magnet inside the device and gets it to move and change directions.
The current model has a diameter of less than a millimeter. Shpigelmacher's engineers could build the miniature vehicle even smaller but the current size has the advantage of being big enough to see with bare eyes. It can also deliver more medicine than a tinier version. In the Zoom demonstration, the micorobot is injected into the spine, not unlike an epidural, and pulled along the spine through an outside magnet until the Bionaut reaches the brainstem. Depending which organ it needs to reach, it could be inserted elsewhere, for instance through a catheter.
"The hope is that we can develop a vehicle to transport medication deep into the body."
Imagine moving a screw through a steak with a magnet — that's essentially how the device works. But of course, the Bionaut is considerably different from an ordinary screw: "At the right location, we give a magnetic signal, and it unloads its medicine package," Shpigelmacher says.
To start, Bionaut Labs wants to use its device to treat Parkinson's disease and brain stem gliomas, a type of cancer that largely affects children and teenagers. About 300 to 400 young people a year are diagnosed with this type of tumor. Radiation and brain surgery risk damaging sensitive brain tissue, and chemotherapy often doesn't work. Most children with these tumors live less than 18 months. A nanobot delivering targeted chemotherapy could be a gamechanger. "These patients really don't have any other hope," Shpigelmacher says.
Of course, the main challenge of the developing such a device is guaranteeing that it's safe. Because tissue is so sensitive, any mistake could risk disastrous results. Over the past four years, Bionaut has tested its technology in dozens of healthy sheep and pigs with no major adverse effects. Sheep make a good stand-in for humans because their brains and spines are similar to ours.
The Bionaut device is about the size of a grain of rice.
Bionaut Labs
"As the Bionaut moves through brain tissue, it creates a transient track that heals within a few weeks," Shpigelmacher says. The company is hoping to be the first to test a nanobot in humans. That could happen as early as 2023, Shpigelmacher says.
Once the technique has been perfected, further applications could include addressing other kinds of brain disorders that are considered incurable now, such as Alzheimer's or Huntington's disease. "Microrobots could serve as a bridgehead, opening the gateway to the brain and facilitating precise access of deep brain structure – either to deliver medication, take cell samples or stimulate specific brain regions," Shpigelmacher says.
Robot-assisted hybrid surgery with artificial intelligence is already used in state-of-the-art surgery centers, and many medical experts believe that nanorobotics will be the instrument of the future. In 2016, three scientists were awarded the Nobel Prize in Chemistry for their development of "the world's smallest machines," nano "elevators" and minuscule motors. Since then, the scientific experiments have progressed to the point where applicable devices are moving closer to actually being implemented.
Bionaut's technology was initially developed by a research team lead by Peer Fischer, head of the independent Micro Nano and Molecular Systems Lab at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany. Fischer is considered a pioneer in the research of nano systems, which he began at Harvard University more than a decade ago. He and his team are advising Bionaut Labs and have licensed their technology to the company.
"The hope is that we can develop a vehicle to transport medication deep into the body," says Max Planck scientist Tian Qiu, who leads the cooperation with Bionaut Labs. He agrees with Shpigelmacher that the Bionaut's size is perfect for transporting medication loads and is researching potential applications for even smaller nanorobots, especially in the eye, where the tissue is extremely sensitive. "Nanorobots can sneak through very fine tissue without causing damage."
In "Fantastic Voyage," Raquel Welch's adventures inside the body of a dissident scientist let her swim through his veins into his brain, but her shrunken miniature submarine is attacked by antibodies; she has to flee through the nerves into the scientist's eye where she escapes into freedom on a tear drop. In reality, the exit in the lab is much more mundane. The Bionaut simply leaves the body through the same port where it entered. But apart from the dramatization, the "Fantastic Voyage" was almost prophetic, or, as Shpigelmacher says, "Science fiction becomes science reality."