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.
In 2013, the Human Brain Project set out to build a realistic computer model of the brain over ten years. Now, experts are reflecting on HBP's achievements with an eye toward the future.
Scholars have found that the project did help advance neuroscience more than some detractors initially expected, specifically in the area of brain simulations and virtual models. Using an interdisciplinary approach of combining technology, such as AI and digital simulations, with neuroscience, the HBP worked to gain a deeper understanding of the human brain’s complicated structure and functions, which in some cases led to novel treatments for brain disorders. Lastly, through online platforms, the HBP spearheaded a previously unmatched level of global neuroscience collaborations.
Simulating a human brain stirs up controversy
Right from the start, the project was plagued with controversy and condemnation. One of its prominent critics was Yves Fregnac, a professor in cognitive science at the Polytechnic Institute of Paris and research director at the French National Centre for Scientific Research. Fregnac argued in numerous articles that the HBP was overfunded based on proposals with unrealistic goals. “This new way of over-selling scientific targets, deeply aligned with what modern society expects from mega-sciences in the broad sense (big investment, big return), has been observed on several occasions in different scientific sub-fields,” he wrote in one of his articles, “before invading the field of brain sciences and neuromarketing.”
"A human brain model can simulate an experiment a million times for many different conditions, but the actual human experiment can be performed only once or a few times," said Viktor Jirsa, a professor at Aix-Marseille University.
Responding to such critiques, the HBP worked to restructure the effort in its early days with new leadership, organization, and goals that were more flexible and attainable. “The HBP got a more versatile, pluralistic approach,” said Viktor Jirsa, a professor at Aix-Marseille University and one of the HBP lead scientists. He believes that these changes fixed at least some of HBP’s issues. “The project has been on a very productive and scientifically fruitful course since then.”
After restructuring, the HBP became a European hub on brain research, with hundreds of scientists joining its growing network. The HBP created projects focused on various brain topics, from consciousness to neurodegenerative diseases. HBP scientists worked on complex subjects, such as mapping out the brain, combining neuroscience and robotics, and experimenting with neuromorphic computing, a computational technique inspired by the human brain structure and function—to name just a few.
Simulations advance knowledge and treatment options
In 2013, it seemed that bringing neuroscience into a digital age would be farfetched, but research within the HBP has made this achievable. The virtual maps and simulations various HBP teams create through brain imaging data make it easier for neuroscientists to understand brain developments and functions. The teams publish these models on the HBP’s EBRAINS online platform—one of the first to offer access to such data to neuroscientists worldwide via an open-source online site. “This digital infrastructure is backed by high-performance computers, with large datasets and various computational tools,” said Lucy Xiaolu Wang, an assistant professor in the Resource Economics Department at the University of Massachusetts Amherst, who studies the economics of the HBP. That means it can be used in place of many different types of human experimentation.
Jirsa’s team is one of many within the project that works on virtual brain models and brain simulations. Compiling patient data, Jirsa and his team can create digital simulations of different brain activities—and repeat these experiments many times, which isn’t often possible in surgeries on real brains. “A human brain model can simulate an experiment a million times for many different conditions,” Jirsa explained, “but the actual human experiment can be performed only once or a few times.” Using simulations also saves scientists and doctors time and money when looking at ways to diagnose and treat patients with brain disorders.
Compiling patient data, scientists can create digital simulations of different brain activities—and repeat these experiments many times.
The Human Brain Project
Simulations can help scientists get a full picture that otherwise is unattainable. “Another benefit is data completion,” added Jirsa, “in which incomplete data can be complemented by the model. In clinical settings, we can often measure only certain brain areas, but when linked to the brain model, we can enlarge the range of accessible brain regions and make better diagnostic predictions.”
With time, Jirsa’s team was able to move into patient-specific simulations. “We advanced from generic brain models to the ability to use a specific patient’s brain data, from measurements like MRI and others, to create individualized predictive models and simulations,” Jirsa explained. He and his team are working on this personalization technique to treat patients with epilepsy. According to the World Health Organization, about 50 million people worldwide suffer from epilepsy, a disorder that causes recurring seizures. While some epilepsy causes are known others remain an enigma, and many are hard to treat. For some patients whose epilepsy doesn’t respond to medications, removing part of the brain where seizures occur may be the only option. Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
“We apply such personalized models…to precisely identify where in a patient’s brain seizures emerge,” Jirsa explained. “This guides individual surgery decisions for patients for which surgery is the only treatment option.” He credits the HBP for the opportunity to develop this novel approach. “The personalization of our epilepsy models was only made possible by the Human Brain Project, in which all the necessary tools have been developed. Without the HBP, the technology would not be in clinical trials today.”
Personalized simulations can significantly advance treatments, predict the outcome of specific medical procedures and optimize them before actually treating patients. Jirsa is watching this happen firsthand in his ongoing research. “Our technology for creating personalized brain models is now used in a large clinical trial for epilepsy, funded by the French state, where we collaborate with clinicians in hospitals,” he explained. “We have also founded a spinoff company called VB Tech (Virtual Brain Technologies) to commercialize our personalized brain model technology and make it available to all patients.”
The Human Brain Project created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own.
Other experts believe it’s too soon to tell whether brain simulations could change epilepsy treatments. “The life cycle of developing treatments applicable to patients often runs over a decade,” Wang stated. “It is still too early to draw a clear link between HBP’s various project areas with patient care.” However, she admits that some studies built on the HBP-collected knowledge are already showing promise. “Researchers have used neuroscientific atlases and computational tools to develop activity-specific stimulation programs that enabled paraplegic patients to move again in a small-size clinical trial,” Wang said. Another intriguing study looked at simulations of Alzheimer’s in the brain to understand how it evolves over time.
Some challenges remain hard to overcome even with computer simulations. “The major challenge has always been the parameter explosion, which means that many different model parameters can lead to the same result,” Jirsa explained. An example of this parameter explosion could be two different types of neurodegenerative conditions, such as Parkinson’s and Huntington’s diseases. Both afflict the same area of the brain, the basal ganglia, which can affect movement, but are caused by two different underlying mechanisms. “We face the same situation in the living brain, in which a large range of diverse mechanisms can produce the same behavior,” Jirsa said. The simulations still have to overcome the same challenge.
Understanding where in the patients’ brains seizures arise can give scientists a better idea of how to treat them and whether to use surgery versus medications.
The Human Brain Project
A network not unlike the brain’s own
Though the HBP will be closing this year, its legacy continues in various studies, spin-off companies, and its online platform, EBRAINS. “The HBP is one of the earliest brain initiatives in the world, and the 10-year long-term goal has united many researchers to collaborate on brain sciences with advanced computational tools,” Wang said. “Beyond the many research articles and projects collaborated on during the HBP, the online neuroscience research infrastructure EBRAINS will be left as a legacy even after the project ends.”
Those who worked within the HBP see the end of this project as the next step in neuroscience research. “Neuroscience has come closer to very meaningful applications through the systematic link with new digital technologies and collaborative work,” Jirsa stated. “In that way, the project really had a pioneering role.” It also created a level of interconnectedness within the neuroscience research community that never existed before—a network not unlike the brain’s own. “Interconnectedness is an important advance and prerequisite for progress,” Jirsa said. “The neuroscience community has in the past been rather fragmented and this has dramatically changed in recent years thanks to the Human Brain Project.”
According to its website, by 2023 HBP’s network counted over 500 scientists from over 123 institutions and 16 different countries, creating one of the largest multi-national research groups in the world. Even though the project hasn’t produced the in-silico brain as Markram envisioned it, the HBP created a communal mind with immense potential. “It has challenged us to think beyond the boundaries of our own laboratories,” Jirsa said, “and enabled us to go much further together than we could have ever conceived going by ourselves.”
