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.
A mosquito under the microscope.
The association between climate and infectious disease is poorly understood, says Irina Tezaur, a computational scientist at Sandia National Laboratories. “Correlations have been observed but it’s not known if these correlations translate to causal relationships.”
To make accurate longer-term predictions, scientists need more empirical data, multiple datasets specific to locations and diseases, and the ability to calculate risks that depend on unpredictable nature and human behavior. Another obstacle is that climate scientists and epidemiologists are not collaborating effectively, so some researchers are calling for a multidisciplinary approach, a new field called Outbreak Science.
Climate scientists are far ahead of epidemiologists in gathering essential data.
Earth System Models—combining the interactions of atmosphere, ocean, land, ice and biosphere—have been in place for two decades to monitor the effects of global climate change. These models must be combined with epidemiological and human model research, areas that are easily skewed by unpredictable elements, from extreme weather events to public environmental policy shifts.
“There is never just one driver in tracking the impact of climate on infectious disease,” says Joacim Rocklöv, a professor at the Heidelberg Institute of Global Health & Heidelberg Interdisciplinary Centre for Scientific Computing in Germany. Rocklöv has studied how climate affects vector-borne diseases—those transmitted to humans by mosquitoes, ticks or fleas. “You need to disentangle the variables to find out how much difference climate makes to the outcome and how much is other factors.” Determinants from deforestation to population density to lack of healthcare access influence the spread of disease.
Even though climate change is not the primary driver of infectious disease today, it poses a major threat to public health in the future, says Rocklöv.
The promise of predictive modeling
“Models are simplifications of a system we’re trying to understand,” says Jeremy Hess, who directs the Center for Health and the Global Environment at University of Washington in Seattle. “They’re tools for learning that improve over time with new observations.”
Accurate predictions depend on high-quality, long-term observational data but models must start with assumptions. “It’s not possible to apply an evidence-based approach for the next 40 years,” says Rocklöv. “Using models to experiment and learn is the only way to figure out what climate means for infectious disease. We collect data and analyze what already happened. What we do today will not make a difference for several decades.”
To improve accuracy, scientists develop and draw on thousands of models to cover as many scenarios as possible. One model may capture the dynamics of disease transmission while another focuses on immunity data or ocean influences or seasonal components of a virus. Further, each model needs to be disease-specific and often location-specific to be useful.
“All models have biases so it’s important to use a suite of models,” Tezaur stresses.
The modeling scientist chooses the drivers of change and parameters based on the question explored. The drivers could be increased precipitation, poverty or mosquito prevalence, for instance. Later, the scientist may need to isolate the effect of one driver so that will require another model.
There have been some related successes, such as the latest models for mosquito-borne diseases like Dengue, Zika and malaria as well as those for flu and tick-borne diseases, says Hess.
Rocklöv was part of a research team that used test data from 2018 and 2019 to identify regions at risk for West Nile virus outbreaks. Using AI, scientists were able to forecast outbreaks of the virus for the entire transmission season in Europe. “In the end, we want data-driven models; that’s what AI can accomplish,” says Rocklöv. Other researchers are making an important headway in creating a framework to predict novel host–parasite interactions.
Modeling studies can run months, years or decades. “The scientist is working with layers of data. The challenge is how to transform and couple different models together on a planetary scale,” says Jeanne Fair, a scientist at Los Alamos National Laboratory, Biosecurity and Public Health, in New Mexico.
Disease forecasting will require a significant investment into the infrastructure needed to collect data about the environment, vectors, and hosts a tall spatial and temporal resolutions.
And it’s a constantly changing picture. A modeling study in an April 2022 issue of Nature predicted that thousands of animals will migrate to cooler locales as temperatures rise. This means that various species will come into closer contact with people and other mammals for the first time. This is likely to increase the risk of emerging infectious disease transmitted from animals to humans, especially in Africa and Asia.
Other things can happen too. Global warming could precipitate viral mutations or new infectious diseases that don’t respond to antimicrobial treatments. Insecticide-resistant mosquitoes could evolve. Weather-related food insecurity could increase malnutrition and weaken people’s immune systems. And the impact of an epidemic will be worse if it co-occurs during a heatwave, flood, or drought, says Hess.
The devil is in the climate variables
Solid predictions about the future of climate and disease are not possible with so many uncertainties. Difficult-to-measure drivers must be added to the empirical model mix, such as land and water use, ecosystem changes or the public’s willingness to accept a vaccine or practice social distancing. Nor is there any precedent for calculating the effect of climate changes that are accelerating at a faster speed than ever before.
The most critical climate variables thought to influence disease spread are temperature, precipitation, humidity, sunshine and wind, according to Tezaur’s research. And then there are variables within variables. Influenza scientists, for example, found that warm winters were predictors of the most severe flu seasons in the following year.
The human factor may be the most challenging determinant. To what degree will people curtail greenhouse gas emissions, if at all? The swift development of effective COVID-19 vaccines was a game-changer, but will scientists be able to repeat it during the next pandemic? Plus, no model could predict the amount of internet-fueled COVID-19 misinformation, Fair noted. To tackle this issue, infectious disease teams are looking to include more sociologists and political scientists in their modeling.
Addressing the gaps
Currently, researchers are focusing on the near future, predicting for next year, says Fair. “When it comes to long-term, that’s where we have the most work to do.” While scientists cannot foresee how political influences and misinformation spread will affect models, they are positioned to make headway in collecting and assessing new data streams that have never been merged.
Disease forecasting will require a significant investment into the infrastructure needed to collect data about the environment, vectors, and hosts at all spatial and temporal resolutions, Fair and her co-authors stated in their recent study. For example real-time data on mosquito prevalence and diversity in various settings and times is limited or non-existent. Fair also would like to see standards set in mosquito data collection in every country. “Standardizing across the US would be a huge accomplishment,” she says.
Understanding how climate change contributes to the spread of disease is critical for thwarting future calamities.
Jeanne Fair
Hess points to a dearth of data in local and regional datasets about how extreme weather events play out in different geographic locations. His research indicates that Africa and the Middle East experienced substantial climate shifts, for example, but are unrepresented in the evidentiary database, which limits conclusions. “A model for dengue may be good in Singapore but not necessarily in Port-au-Prince,” Hess explains. And, he adds, scientists need a way of evaluating models for how effective they are.
The hope, Rocklöv says, is that in the future we will have data-driven models rather than theoretical ones. In turn, sharper statistical analyses can inform resource allocation and intervention strategies to prevent outbreaks.
Most of all, experts emphasize that epidemiologists and climate scientists must stop working in silos. If scientists can successfully merge epidemiological data with climatic, biological, environmental, ecological and demographic data, they will make better predictions about complex disease patterns. Modeling “cross talk” and among disciplines and, in some cases, refusal to release data between countries is hindering discovery and advances.
It’s time for bold transdisciplinary action, says Hess. He points to initiatives that need funding in disease surveillance and control; developing and testing interventions; community education and social mobilization; decision-support analytics to predict when and where infections will emerge; advanced methodologies to improve modeling; training scientists in data management and integrated surveillance.
Establishing a new field of Outbreak Science to coordinate collaboration would accelerate progress. Investment in decision-support modeling tools for public health teams, policy makers, and other long-term planning stakeholders is imperative, too. We need to invest in programs that encourage people from climate modeling and epidemiology to work together in a cohesive fashion, says Tezaur. Joining forces is the only way to solve the formidable challenges ahead.
This article originally appeared in One Health/One Planet, a single-issue magazine that explores how climate change and other environmental shifts are increasing vulnerabilities to infectious diseases by land and by sea. The magazine probes how scientists are making progress with leaders in other fields toward solutions that embrace diverse perspectives and the interconnectedness of all lifeforms and the planet.
