How Bacteria-Killing Viruses May Save Us From Antibiotic Resistance
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
Hand-counting bacteriophage plaques during a titer test.
In my hometown of Pittsburgh, it is not uncommon to read about cutting-edge medical breakthroughs, because Pittsburgh is the home of many innovations in medical science, from the polio vaccine to pioneering organ transplantation. However, medical headlines from Pittsburgh last November weren't heralding a new discovery for once. They were carrying a plea—for a virus.
Phages are weapons of bacterial destruction, but despite recognition of their therapeutic potential for over 100 years, there are zero phage products commercially available to medicine in the United States.
Specifically, a bacteria-killing virus that could attack and control a certain highly drug-resistant bacterial infection ravaging the newly transplanted lungs of a 25-year-old woman named Mallory Smith. The culprit bacteria, Burkholderia cepacia, is a notoriously vicious bacterium that preys on patients with cystic fibrosis who, throughout their life, are exposed to course after course of antibiotics, often fostering a population of highly resistant bacteria that can become too formidable for modern medicine to combat.
What Smith and her physicians desperately needed was a tool that would move beyond failed courses of antibiotics. What they sought was called a bacteriophage. These are naturally occurring ubiquitous viruses that target not humans, but bacteria. The world literally teems with "phages" and one cannot take a bite or drink of anything without encountering them. These weapons of bacterial destruction are exquisitely evolved to target bacteria and, as such, are not harmful to humans. However, despite recognition of their therapeutic potential for over 100 years, there are zero bacteriophage products commercially available to medicine in the United States, at a time when antibiotic resistance is arguably our most pressing public health crisis. Just this week, a new study was published in the Proceedings of the National Academy of Sciences detailing the global scope of the problem.
Why Were These Promising Tools Forgotten?
Phages weren't always relegated to this status. In fact, in the early 20th century phages could be found on American drug store shelves and were used for a variety of ailments. However, the path-breaking discovery and development of antimicrobials agents such as the sulfa drugs and, later the antibiotic penicillin, supplanted the world of phage therapeutics in the United States and many other places.
Fortunately, phage therapy never fully disappeared, and research and clinical use continued in Eastern European nations such as Georgia and Poland.
The antibiotic age revolutionized medicine in a way that arguably no other innovation has. Not only did antibiotics tame many once-deadly infectious diseases, but they made much of modern medicine – from cancer chemotherapy to organ transplantation to joint replacement – possible. Antibiotics, unlike the exquisitely evolved bacteriophage, possessed a broader spectrum of activity and were active against a range of bacteria. This non-specificity facilitated antibiotic use without the need for a specific diagnosis. A physician does not need to know the specific bacterial genus and species causing, for example, a skin infection or pneumonia, but can select an antibiotic that covers the likely culprits and use it empirically, fully expecting the infection to be controlled. Unfortunately, this non-specificity engendered the overuse of antibiotics whose consequences we are now suffering. A bacteriophage, on the other hand, will work against one specific bacterial species and is evolved for just that role.
Phages to the Rescue
As the march of antibiotic resistance has predictably continued since the dawn of the antibiotic age, the prospect of resurrecting phage therapy has been increasingly viewed as one solution. Fortunately, phage therapy never fully disappeared, and research and clinical use continued in Eastern European nations such as Georgia and Poland. However, much of that experience has remained opaque to the medical community at large and questions about dosage, toxicity, efficacy, and method of delivery left many questions without full answers.
Though real questions remained regarding phage use, dire circumstances of prolific antibiotic resistance necessitated their use in the U.S. in two prominent instances involving life-threatening infections. The first case involved an Acinetobacter baumanii infection of the pancreas in a San Diego man in which phages were administered intravenously in 2016. The other case, also in 2016, involved the instillation of phages, fished out of a pond, into the chest cavity of man with a Pseudmonas aeruginosa infection of a prosthetic graft of the aorta. Both cases were successful and were what fueled the Pittsburgh-based plea for Burkholderia phages.
The phages you begin with may not be the ones you end up with, as Darwinian evolutionary pressures will alter the phage in order to keep up with the ongoing evolution of its bacterial target.
How Phages Differ from Other Medical Products
It might seem surprising that in light of the urgent need for new treatments for drug-resistant infections, the pharmaceutical armamentarium is not teeming with phages like a backyard pond. However, phages have been difficult to fit into the current regulatory framework that operates in most developed countries such as the U.S. because of their unique characteristics.
Phages are not one homogenous product like a tablet of penicillin, but a cocktail of viruses that change and evolve as they replicate. The phages you begin with may not be the ones you end up with, as Darwinian evolutionary pressures will alter the phage in order to keep up with the ongoing evolution of its bacterial target. The cocktail may not just contain one specific phage, but a range of phages that all target some specific bacteria in order to increase efficacy. These phage cocktails might also need adjusting to keep pace with bacterial resistance. Additionally, the concentration of phage in a human body after administration is not so easy to predict as phage numbers will rise and fall based on the number of target bacteria that are present.
All of these characteristics make phages very unique when viewed through a regulatory lens, and necessitate the creation of new methods to evaluate them, given that regulatory approval is required. Using phages in the U.S. now requires FDA permission through an investigational new drug application, which can be expedited during an emergency situation. FDA scientists are actively involved in understanding the best means to evaluate bacteriophage therapy and several companies are in early-stage development, though no major clinical trials in the U.S. are currently underway.
One FDA-approved application of phages has seen them used on food products at delis and even in slaughterhouses to diminish the quantity of bacteria on certain meat products.
Would That Humans Were As Lucky As Bologna
Because of the regulatory difficulties with human-use approval, some phage companies have taken another route to develop phage products: food safety. Food safety is a major public health endeavor, and keeping food that people consume safe from E.coli, Listeria, and Salmonella, for example, are rightfully major priorities of industry. One FDA-approved application of phages has seen them used on food products at delis and even in slaughterhouses to diminish the quantity of bacteria on certain meat products.
This use, unlike that for human therapeutic purposes, has found success with regulators: phages, not surprisingly, have been granted the "generally regarded as safe (GRAS)" designation.
A Phage Directory
Tragically Mallory Smith succumbed to her infection despite getting a dose of phages culled from sludge in the Philippines and Fiji. However, her death and last-minute crusade to obtain phages has prompted the call for a phage directory. This directory could catalog the various phages being studied and the particular bacteria they target. Such a searchable index will facilitate the rapid identification and – hopefully – delivery of phages to patients.
If phage therapy is to move from a last-ditch emergency measure to a routine tool for infectious disease physicians, it will be essential that the hurdles they face are eliminated.
Moving Beyond Antibiotics
As we move increasingly toward a post-antibiotic age in infectious disease, moving outside of the traditional paradigm of broad-spectrum antibiotics to non-traditional therapeutics such as bacteriophages and other novel products will become increasingly necessary. Already, clinical trials are underway in various populations, including a major trial in European burn patients.
It is important to understand that there are important scientific and therapeutic questions regarding dose, route of administration and other related questions that need to be addressed before phage use becomes more routine, and it is only through clinical trials conducted with the hope of eventual commercialization that these answers will be found. If phage therapy is to move from a last-ditch emergency measure to a routine tool for infectious disease physicians, it will be essential that the hurdles they face are eliminated.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA
Astronaut and Expedition 64 Flight Engineer Soichi Noguchi of the Japan Aerospace Exploration Agency displays Extra Dwarf Pak Choi plants growing aboard the International Space Station. The plants were grown for the Veggie study which is exploring space agriculture as a way to sustain astronauts on future missions to the Moon or Mars.
Astronauts at the International Space Station today depend on pre-packaged, freeze-dried food, plus some fresh produce thanks to regular resupply missions. This supply chain, however, will not be available on trips further out, such as the moon or Mars. So what are astronauts on long missions going to eat?
Going by the options available now, says Christel Paille, an engineer at the European Space Agency, a lunar expedition is likely to have only dehydrated foods. “So no more fresh product, and a limited amount of already hydrated product in cans.”
For the Mars mission, the situation is a bit more complex, she says. Prepackaged food could still constitute most of their food, “but combined with [on site] production of certain food products…to get them fresh.” A Mars mission isn’t right around the corner, but scientists are currently working on solutions for how to feed those astronauts. A number of boundary-pushing efforts are now underway.
The logistics of growing plants in space, of course, are very different from Earth. There is no gravity, sunlight, or atmosphere. High levels of ionizing radiation stunt plant growth. Plus, plants take up a lot of space, something that is, ironically, at a premium up there. These and special nutritional requirements of spacefarers have given scientists some specific and challenging problems.
To study fresh food production systems, NASA runs the Vegetable Production System (Veggie) on the ISS. Deployed in 2014, Veggie has been growing salad-type plants on “plant pillows” filled with growth media, including a special clay and controlled-release fertilizer, and a passive wicking watering system. They have had some success growing leafy greens and even flowers.
"Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources."
A larger farming facility run by NASA on the ISS is the Advanced Plant Habitat to study how plants grow in space. This fully-automated, closed-loop system has an environmentally controlled growth chamber and is equipped with sensors that relay real-time information about temperature, oxygen content, and moisture levels back to the ground team at Kennedy Space Center in Florida. In December 2020, the ISS crew feasted on radishes grown in the APH.
“But salad doesn’t give you any calories,” says Erik Seedhouse, a researcher at the Applied Aviation Sciences Department at Embry-Riddle Aeronautical University in Florida. “It gives you some minerals, but it doesn’t give you a lot of carbohydrates.” Seedhouse also noted in his 2020 book Life Support Systems for Humans in Space: “Integrating the growing of plants into a life support system is a fiendishly difficult enterprise.” As a case point, he referred to the ESA’s Micro-Ecological Life Support System Alternative (MELiSSA) program that has been running since 1989 to integrate growing of plants in a closed life support system such as a spacecraft.
Paille, one of the scientists running MELiSSA, says that the system aims to recycle the metabolic waste produced by crew members back into the metabolic resources required by them: “The aim is…to come [up with] a closed, sustainable system which does not [need] any logistics resupply.” MELiSSA uses microorganisms to process human excretions in order to harvest carbon dioxide and nitrate to grow plants. “Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources,” Paille adds.
Microorganisms play a big role as “fuel” in food production in extreme places, including in space. Last year, researchers discovered Methylobacterium strains on the ISS, including some never-seen-before species. Kasthuri Venkateswaran of NASA’s Jet Propulsion Laboratory, one of the researchers involved in the study, says, “[The] isolation of novel microbes that help to promote the plant growth under stressful conditions is very essential… Certain bacteria can decompose complex matter into a simple nutrient [that] the plants can absorb.” These microbes, which have already adapted to space conditions—such as the absence of gravity and increased radiation—boost various plant growth processes and help withstand the harsh physical environment.
MELiSSA, says Paille, has demonstrated that it is possible to grow plants in space. “This is important information because…we didn’t know whether the space environment was affecting the biological cycle of the plant…[and of] cyanobacteria.” With the scientific and engineering aspects of a closed, self-sustaining life support system becoming clearer, she says, the next stage is to find out if it works in space. They plan to run tests recycling human urine into useful components, including those that promote plant growth.
The MELiSSA pilot plant uses rats currently, and needs to be translated for human subjects for further studies. “Demonstrating the process and well-being of a rat in terms of providing water, sufficient oxygen, and recycling sufficient carbon dioxide, in a non-stressful manner, is one thing,” Paille says, “but then, having a human in the loop [means] you also need to integrate user interfaces from the operational point of view.”
Growing food in space comes with an additional caveat that underscores its high stakes. Barbara Demmig-Adams from the Department of Ecology and Evolutionary Biology at the University of Colorado Boulder explains, “There are conditions that actually will hurt your health more than just living here on earth. And so the need for nutritious food and micronutrients is even greater for an astronaut than for [you and] me.”
Demmig-Adams, who has worked on increasing the nutritional quality of plants for long-duration spaceflight missions, also adds that there is no need to reinvent the wheel. Her work has focused on duckweed, a rather unappealingly named aquatic plant. “It is 100 percent edible, grows very fast, it’s very small, and like some other floating aquatic plants, also produces a lot of protein,” she says. “And here on Earth, studies have shown that the amount of protein you get from the same area of these floating aquatic plants is 20 times higher compared to soybeans.”
Aquatic plants also tend to grow well in microgravity: “Plants that float on water, they don’t respond to gravity, they just hug the water film… They don’t need to know what’s up and what’s down.” On top of that, she adds, “They also produce higher concentrations of really important micronutrients, antioxidants that humans need, especially under space radiation.” In fact, duckweed, when subjected to high amounts of radiation, makes nutrients called carotenoids that are crucial for fighting radiation damage. “We’ve looked at dozens and dozens of plants, and the duckweed makes more of this radiation fighter…than anything I’ve seen before.”
Despite all the scientific advances and promising leads, no one really knows what the conditions so far out in space will be and what new challenges they will bring. As Paille says, “There are known unknowns and unknown unknowns.”
One definite “known” for astronauts is that growing their food is the ideal scenario for space travel in the long term since “[taking] all your food along with you, for best part of two years, that’s a lot of space and a lot of weight,” as Seedhouse says. That said, once they land on Mars, they’d have to think about what to eat all over again. “Then you probably want to start building a greenhouse and growing food there [as well],” he adds.
And that is a whole different challenge altogether.
The Science of Why Adjusting to Omicron Is So Tough
A brain expert weighs in on the cognitive biases that hold us back from adjusting to the new reality of Omicron.
We are sticking our heads into the sand of reality on Omicron, and the results may be catastrophic.
Omicron is over 4 times more infectious than Delta. The Pfizer two-shot vaccine offers only 33% protection from infection. A Pfizer booster vaccine does raises protection to about 75%, but wanes to around 30-40 percent 10 weeks after the booster.
The only silver lining is that Omicron appears to cause a milder illness than Delta. Yet the World Health Organization has warned about the “mildness” narrative.
That’s because the much faster disease transmission and vaccine escape undercut the less severe overall nature of Omicron. That’s why hospitals have a large probability of being overwhelmed, as the Center for Disease Control warned, in this major Omicron wave.
Yet despite this very serious threat, we see the lack of real action. The federal government tightened international travel guidelines and is promoting boosters. Certainly, it’s crucial to get as many people to get their booster – and initial vaccine doses – as soon as possible. But the government is not taking the steps that would be the real game-changers.
Pfizer’s anti-viral drug Paxlovid decreases the risk of hospitalization and death from COVID by 89%. Due to this effectiveness, the FDA approved Pfizer ending the trial early, because it would be unethical to withhold the drug from people in the control group. Yet the FDA chose not to hasten the approval process along with the emergence of Omicron in late November, only getting around to emergency authorization in late December once Omicron took over. That delay meant the lack of Paxlovid for the height of the Omicron wave, since it takes many weeks to ramp up production, resulting in an unknown number of unnecessary deaths.
We humans are prone to falling for dangerous judgment errors called cognitive biases.
Widely available at-home testing would enable people to test themselves quickly, so that those with mild symptoms can quarantine instead of infecting others. Yet the federal government did not make tests available to patients when Omicron emerged in late November. That’s despite the obviousness of the coming wave based on the precedent of South Africa, UK, and Denmark and despite the fact that the government made vaccines freely available. Its best effort was to mandate that insurance cover reimbursements for these kits, which is way too much of a barrier for most people. By the time Omicron took over, the federal government recognized its mistake and ordered 500 million tests to be made available in January. However, that’s far too late. And the FDA also played a harmful role here, with its excessive focus on accuracy going back to mid-2020, blocking the widespread availability of cheap at-home tests. By contrast, Europe has a much better supply of tests, due to its approval of quick and slightly less accurate tests.
Neither do we see meaningful leadership at the level of employers. Some are bringing out the tired old “delay the office reopening” play. For example, Google, Uber, and Ford, along with many others, have delayed the return to the office for several months. Those that already returned are calling for stricter pandemic measures, such as more masks and social distancing, but not changing their work arrangements or adding sufficient ventilation to address the spread of COVID.
Despite plenty of warnings from risk management and cognitive bias experts, leaders are repeating the same mistakes we fell into with Delta. And so are regular people. For example, surveys show that Omicron has had very little impact on the willingness of unvaccinated Americans to get a first vaccine dose, or of vaccinated Americans to get a booster. That’s despite Omicron having taken over from Delta in late December.
What explains this puzzling behavior on both the individual and society level? We humans are prone to falling for dangerous judgment errors called cognitive biases. Rooted in wishful thinking and gut reactions, these mental blindspots lead to poor strategic and financial decisions when evaluating choices.
These cognitive biases stem from the more primitive, emotional, and intuitive part of our brains that ensured survival in our ancestral environment. This quick, automatic reaction of our emotions represents the autopilot system of thinking, one of the two systems of thinking in our brains. It makes good decisions most of the time but also regularly makes certain systematic thinking errors, since it’s optimized to help us survive. In modern society, our survival is much less at risk, and our gut is more likely to compel us to focus on the wrong information to make decisions.
One of the biggest challenges relevant to Omicron is the cognitive bias known as the ostrich effect. Named after the myth that ostriches stick their heads into the sand when they fear danger, the ostrich effect refers to people denying negative reality. Delta illustrated the high likelihood of additional dangerous variants, yet we failed to pay attention to and prepare for such a threat.
We want the future to be normal. We’re tired of the pandemic and just want to get back to pre-pandemic times. Thus, we greatly underestimate the probability and impact of major disruptors, like new COVID variants. That cognitive bias is called the normalcy bias.
When we learn one way of functioning in any area, we tend to stick to that way of functioning. You might have heard of this as the hammer-nail syndrome: when you have a hammer, everything looks like a nail. That syndrome is called functional fixedness. This cognitive bias causes those used to their old ways of action to reject any alternatives, including to prepare for a new variant.
Our minds naturally prioritize the present. We want what we want now, and downplay the long-term consequences of our current desires. That fallacious mental pattern is called hyperbolic discounting, where we excessively discount the benefits of orienting toward the future and focus on the present. A clear example is focusing on the short-term perceived gains of trying to return to normal over managing the risks of future variants.
The way forward into the future is to defeat cognitive biases and avoid denying reality by rethinking our approach to the future.
The FDA requires a serious overhaul. It’s designed for a non-pandemic environment, where the goal is to have a highly conservative, slow-going, and risk-averse approach so that the public feels confident trusting whatever it approved. That’s simply unacceptable in a fast-moving pandemic, and we are bound to face future pandemics in the future.
The federal government needs to have cognitive bias experts weigh in on federal policy. Putting all of its eggs in one basket – vaccinations – is not a wise move when we face the risks of a vaccine-escaping variant. Its focus should also be on expediting and prioritizing anti-virals, scaling up cheap rapid testing, and subsidizing high-filtration masks.
For employers, instead of dictating a top-down approach to how employees collaborate, companies need to adopt a decentralized team-led approach. Each individual team leader of a rank-and-file employee team should determine what works best for their team. After all, team leaders tend to know much more of what their teams need, after all. Moreover, they can respond to local emergencies like COVID surges.
At the same time, team leaders need to be trained to integrate best practices for hybrid and remote team leadership. Companies transitioned to telework abruptly as part of the March 2020 lockdowns. They fell into the cognitive bias of functional fixedness and transposed their pre-existing, in-office methods of collaboration on remote work. Zoom happy hours are a clear example: The large majority of employees dislike them, and research shows they are disconnecting, rather than connecting.
Yet supervisors continue to use them, despite the existence of much better methods of facilitating colalboration, which have been shown to work, such as virtual water cooler discussions, virtual coworking, and virtual mentoring. Leaders also need to facilitate innovation in hybrid and remote teams through techniques such as virtual asynchronous brainstorming. Finally, team leaders need to adjust performance evaluation to adapt to the needs of hybrid and remote teams.
On an individual level, people built up certain expectations during the first two years of the pandemic, and they don't apply with Omicron. For example, most people still think that a cloth mask is a fine source of protection. In reality, you really need an N-95 mask, since Omicron is so much more infectious. Another example is that many people don’t realize that symptom onset is much quicker with Omicron, and they aren’t prepared for the consequences.
Remember that we have a huge number of people who are asymptomatic, often without knowing it, due to the much higher mildness of Omicron. About 8% of people admitted to hospitals for other reasons in San Francisco test positive for COVID without symptoms, which we can assume translates for other cities. That means many may think they're fine and they're actually infectious. The result is a much higher chance of someone getting many other people sick.
During this time of record-breaking cases, you need to be mindful about your internalized assumptions and adjust your risk calculus accordingly. So if you can delay higher-risk activities, January and February might be the time to do it. Prepare for waves of disruptions to continue over time, at least through the end of February.
Of course, you might also choose to not worry about getting infected. If you are vaccinated and boosted, and do not have any additional health risks, you are very unlikely to have a serious illness due to Omicron. You can just take the small risk of a serious illness – which can happen – and go about your daily life. If doing so, watch out for those you care about who do have health concerns, since if you infect them, they might not have a mild case even with Omicron.
In short, instead of trying to turn back the clock to the lost world of January 2020, consider how we might create a competitive advantage in our new future. COVID will never go away: we need to learn to live with it. That means reacting appropriately and thoughtfully to new variants and being intentional about our trade-offs.