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
How sharing, hearing, and remembering positive stories can help shape our brains for the better
Across cultures and through millennia, human beings have always told stories. Whether it’s a group of boy scouts around a campfire sharing ghost stories or the paleolithic Cro-Magnons etching pictures of bison on cave walls, researchers believe that storytelling has been universal to human beings since the development of language.
But storytelling was more than just a way for our ancestors to pass the time. Researchers believe that storytelling served an important evolutionary purpose, helping humans learn empathy, share important information (such as where predators were or what berries were safe to eat), as well as strengthen social bonds. Quite literally, storytelling has made it possible for the human race to survive.
Today, neuroscientists are discovering that storytelling is just as important now as it was millions of years ago. Particularly in sharing positive stories, humans can more easily form relational bonds, develop a more flexible perspective, and actually grow new brain circuitry that helps us survive. Here’s how.
How sharing stories positively impacts the brain
When human beings share stories, it increases the levels of certain neurochemicals in the brain, neuroscientists have found. In a 2021 study published in Proceedings of the National Academy of Sciences (PNAS), Swedish researchers found that simply hearing a story could make hospitalized children feel better, compared to other hospitalized children who played a riddle game for the same amount of time. In their research, children in the intensive care unit who heard stories for just 30 minutes had higher levels of oxytocin, a hormone that promotes positive feelings and is linked to relaxation, trust, social connectedness, and overall psychological stability. Furthermore, the same children showed lower levels of cortisol, a hormone associated with stress. Afterward, the group of children who heard stories tended to describe their hospital experiences more positively, and even reported lower levels of pain.
Annie Brewster, MD, knows the positive effect of storytelling from personal experience. An assistant professor at Harvard Medical School and the author of The Healing Power of Storytelling: Using Personal Narrative to Navigate Illness, Trauma, and Loss, Brewster started sharing her personal experience with chronic illness after being diagnosed with multiple sclerosis in 2001. In doing so, Brewster says it has enabled her to accept her diagnosis and integrate it into her identity. Brewster believes so much in the power of hearing and sharing stories that in 2013 she founded Health Story Collaborative, a forum for others to share their mental and physical health challenges.“I wanted to hear stories of people who had found ways to move forward in positive ways, in spite of health challenges,” Brewster said. In doing so, Brewster believes people with chronic conditions can “move closer to self-acceptance and self-love.”
While hearing and sharing positive stories has been shown to increase oxytocin and other “feel good” chemicals, simply remembering a positive story has an effect on our brains as well. Mark Hoelterhoff, PhD, a lecturer in clinical psychology at the University of Edinburgh, recalling and “savoring” a positive story, thought, or feedback “begins to create new brain circuitry—a new neural network that’s geared toward looking for the positive,” he says. Over time, other research shows, savoring positive stories or thoughts can literally change the shape of your brain, hard-wiring someone to see things in a more positive light.How stories can change your behavior
In 2009, Paul Zak, PhD, a neuroscientist and professor at Claremont Graduate University, set out to measure how storytelling can actually change human behavior for the better. In his study, Zak wanted to measure the behavioral effects of oxytocin, and did this by showing test subjects two short video clips designed to elicit an emotional response.
In the first video they showed the study participants, a father spoke to the camera about his two-year-old son, Ben, who had been diagnosed with terminal brain cancer. The father told the audience that he struggled to connect with and enjoy Ben, as Ben had only a few months left to live. In the end, the father finds the strength to stay emotionally connected to his son until he dies.
The second video clip, however, was much less emotional. In that clip, the same father and son are shown spending the day at the zoo. Ben is only suggested to have cancer (he is bald from chemotherapy and referred to as a ‘miracle’, but the cancer isn’t mentioned directly). The second story lacked the dramatic narrative arc of the first video.
Zak’s team took blood before and after the participants watched one of the two videos and found that the first story increased the viewers’ cortisol and oxytocin, suggesting that they felt distress over the boy’s diagnosis and empathy toward the boy and his father. The second narrative, however, didn’t increase oxytocin or cortisol at all.
But Zak took the experiment a step further. After the movie clips, his team gave the study participants a chance to share money with a stranger in the lab. The participants who had an increase in cortisol and oxytocin were more likely to donate money generously. The participants who had increased cortisol and oxytocin were also more likely to donate money to a charity that works with children who are ill. Zak also found that the amount of oxytocin that was released was correlated with how much money people felt comfortable giving—in other words, the more oxytocin that was released, the more generous they felt, and the more money they donated.
How storytelling strengthens our bond with others
Sharing, hearing, and remembering stories can be a powerful tool for social change–not only in the way it changes our brain and our behavior, but also because it can positively affect our relationships with other people
Emotional stimulation from telling stories, writes Zak, is the foundation for empathy, and empathy strengthens our relationships with other people. “By knowing someone’s story—where they come from, what they do, and who you might know in common—relationships with strangers are formed.”
But why are these relationships important for humanity? Because human beings can use storytelling to build empathy and form relationships, it enables them to “engage in the kinds of large-scale cooperation that builds massive bridges and sends humans into space,” says Zak.
Storytelling, Zak found, and the oxytocin release that follows, also makes people more sensitive to social cues. This sensitivity not only motivates us to form relationships, but also to engage with other people and offer help, particularly if the other person seems to need help.
But as Zak found in his experiments, the type of storytelling matters when it comes to affecting relationships. Where Zak found that storytelling with a dramatic arc helps release oxytocin and cortisol, enabling people to feel more empathic and generous, other researchers have found that sharing happy stories allows for greater closeness between individuals and speakers. A group of Chinese researchers found that, compared to emotionally-neutral stories, happy stories were more “emotionally contagious.” Test subjects who heard happy stories had greater activation in certain areas of their brains, experienced more significant, positive changes in their mood, and felt a greater sense of closeness between themselves and the speaker.
“This finding suggests that when individuals are happy, they become less self-focused and then feel more intimate with others,” the authors of the study wrote. “Therefore, sharing happiness could strengthen interpersonal bonding.” The researchers went on to say that this could lead to developing better social networks, receiving more social support, and leading more successful social lives.
Since the start of the COVID pandemic, social isolation, loneliness, and resulting mental health issues have only gotten worse. In light of this, it’s safe to say that hearing, sharing, and remembering stories isn’t just something we can do for entertainment. Storytelling has always been central to the human experience, and now more than ever it’s become something crucial for our survival.
Want to know how you can reap the benefits of hearing happy stories? Keep an eye out for Upworthy’s first book, GOOD PEOPLE: Stories from the Best of Humanity, published by National Geographic/Disney, available on September 3, 2024. GOOD PEOPLE is a much-needed trove of life-affirming stories told straight from the heart. Handpicked from Upworthy’s community, these 101 stories speak to the breadth, depth, and beauty of the human experience, reminding us we have a lot more in common than we realize.
A new type of cancer therapy is shrinking deadly brain tumors with just one treatment
MRI scans after a new kind of immunotherapy for brain cancer show remarkable progress in one patient just days after the first treatment.
Few cancers are deadlier than glioblastomas—aggressive and lethal tumors that originate in the brain or spinal cord. Five years after diagnosis, less than five percent of glioblastoma patients are still alive—and more often, glioblastoma patients live just 14 months on average after receiving a diagnosis.
But an ongoing clinical trial at Mass General Cancer Center is giving new hope to glioblastoma patients and their families. The trial, called INCIPIENT, is meant to evaluate the effects of a special type of immune cell, called CAR-T cells, on patients with recurrent glioblastoma.
How CAR-T cell therapy works
CAR-T cell therapy is a type of cancer treatment called immunotherapy, where doctors modify a patient’s own immune system specifically to find and destroy cancer cells. In CAR-T cell therapy, doctors extract the patient’s T-cells, which are immune system cells that help fight off disease—particularly cancer. These T-cells are harvested from the patient and then genetically modified in a lab to produce proteins on their surface called chimeric antigen receptors (thus becoming CAR-T cells), which makes them able to bind to a specific protein on the patient’s cancer cells. Once modified, these CAR-T cells are grown in the lab for several weeks so that they can multiply into an army of millions. When enough cells have been grown, these super-charged T-cells are infused back into the patient where they can then seek out cancer cells, bind to them, and destroy them. CAR-T cell therapies have been approved by the US Food and Drug Administration (FDA) to treat certain types of lymphomas and leukemias, as well as multiple myeloma, but haven’t been approved to treat glioblastomas—yet.
CAR-T cell therapies don’t always work against solid tumors, such as glioblastomas. Because solid tumors contain different kinds of cancer cells, some cells can evade the immune system’s detection even after CAR-T cell therapy, according to a press release from Massachusetts General Hospital. For the INCIPIENT trial, researchers modified the CAR-T cells even further in hopes of making them more effective against solid tumors. These second-generation CAR-T cells (called CARv3-TEAM-E T cells) contain special antibodies that attack EFGR, a protein expressed in the majority of glioblastoma tumors. Unlike other CAR-T cell therapies, these particular CAR-T cells were designed to be directly injected into the patient’s brain.
The INCIPIENT trial results
The INCIPIENT trial involved three patients who were enrolled in the study between March and July 2023. All three patients—a 72-year-old man, a 74-year-old man, and a 57-year-old woman—were treated with chemo and radiation and enrolled in the trial with CAR-T cells after their glioblastoma tumors came back.
The results, which were published earlier this year in the New England Journal of Medicine (NEJM), were called “rapid” and “dramatic” by doctors involved in the trial. After just a single infusion of the CAR-T cells, each patient experienced a significant reduction in their tumor sizes. Just two days after receiving the infusion, the glioblastoma tumor of the 72-year-old man decreased by nearly twenty percent. Just two months later the tumor had shrunk by an astonishing 60 percent, and the change was maintained for more than six months. The most dramatic result was in the 57-year-old female patient, whose tumor shrank nearly completely after just one infusion of the CAR-T cells.
The results of the INCIPIENT trial were unexpected and astonishing—but unfortunately, they were also temporary. For all three patients, the tumors eventually began to grow back regardless of the CAR-T cell infusions. According to the press release from MGH, the medical team is now considering treating each patient with multiple infusions or prefacing each treatment with chemotherapy to prolong the response.
While there is still “more to do,” says co-author of the study neuro-oncologist Dr. Elizabeth Gerstner, the results are still promising. If nothing else, these second-generation CAR-T cell infusions may someday be able to give patients more time than traditional treatments would allow.
“These results are exciting but they are also just the beginning,” says Dr. Marcela Maus, a doctor and professor of medicine at Mass General who was involved in the clinical trial. “They tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease.”