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
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
Is there a robot nanny in your child's future?
From ROBOTS AND THE PEOPLE WHO LOVE THEM: Holding on to Our Humanity in an Age of Social Robots by Eve Herold. Copyright © 2024 by the author and reprinted by permission of St. Martin’s Publishing Group.
Could the use of robots take some of the workload off teachers, add engagement among students, and ultimately invigorate learning by taking it to a new level that is more consonant with the everyday experiences of young people? Do robots have the potential to become full-fledged educators and further push human teachers out of the profession? The preponderance of opinion on this subject is that, just as AI and medical technology are not going to eliminate doctors, robot teachers will never replace human teachers. Rather, they will change the job of teaching.
A 2017 study led by Google executive James Manyika suggested that skills like creativity, emotional intelligence, and communication will always be needed in the classroom and that robots aren’t likely to provide them at the same level that humans naturally do. But robot teachers do bring advantages, such as a depth of subject knowledge that teachers can’t match, and they’re great for student engagement.
The teacher and robot can complement each other in new ways, with the teacher facilitating interactions between robots and students. So far, this is the case with teaching “assistants” being adopted now in China, Japan, the U.S., and Europe. In this scenario, the robot (usually the SoftBank child-size robot NAO) is a tool for teaching mainly science, technology, engineering, and math (the STEM subjects), but the teacher is very involved in planning, overseeing, and evaluating progress. The students get an entertaining and enriched learning experience, and some of the teaching load is taken off the teacher. At least, that’s what researchers have been able to observe so far.
To be sure, there are some powerful arguments for having robots in the classroom. A not-to-be-underestimated one is that robots “speak the language” of today’s children, who have been steeped in technology since birth. These children are adept at navigating a media-rich environment that is highly visual and interactive. They are plugged into the Internet 24-7. They consume music, games, and huge numbers of videos on a weekly basis. They expect to be dazzled because they are used to being dazzled by more and more spectacular displays of digital artistry. Education has to compete with social media and the entertainment vehicles of students’ everyday lives.
Another compelling argument for teaching robots is that they help prepare students for the technological realities they will encounter in the real world when robots will be ubiquitous. From childhood on, they will be interacting and collaborating with robots in every sphere of their lives from the jobs they do to dealing with retail robots and helper robots in the home. Including robots in the classroom is one way of making sure that children of all socioeconomic backgrounds will be better prepared for a highly automated age, when successfully using robots will be as essential as reading and writing. We’ve already crossed this threshold with computers and smartphones.
Students need multimedia entertainment with their teaching. This is something robots can provide through their ability to connect to the Internet and act as a centralized host to videos, music, and games. Children also need interaction, something robots can deliver up to a point, but which humans can surpass. The education of a child is not just intended to make them technologically functional in a wired world, it’s to help them grow in intellectual, creative, social, and emotional ways. When considered through this perspective, it opens the door to questions concerning just how far robots should go. Robots don’t just teach and engage children; they’re designed to tug at their heartstrings.
It’s no coincidence that many toy makers and manufacturers are designing cute robots that look and behave like real children or animals, says Turkle. “When they make eye contact and gesture toward us, they predispose us to view them as thinking and caring,” she has written in The Washington Post. “They are designed to be cute, to provide a nurturing response” from the child. As mentioned previously, this nurturing experience is a powerful vehicle for drawing children in and promoting strong attachment. But should children really love their robots?
ROBOTS AND THE PEOPLE WHO LOVE THEM: Holding on to Our Humanity in an Age of Social Robots by Eve Herold (January 9, 2024).
St. Martin’s Publishing Group
The problem, once again, is that a child can be lulled into thinking that she’s in an actual relationship, when a robot can’t possibly love her back. If adults have these vulnerabilities, what might such asymmetrical relationships do to the emotional development of a small child? Turkle notes that while we tend to ascribe a mind and emotions to a socially interactive robot, “simulated thinking may be thinking, but simulated feeling is never feeling, and simulated love is never love.”
Always a consideration is the fact that in the first few years of life, a child’s brain is undergoing rapid growth and development that will form the foundation of their lifelong emotional health. These formative experiences are literally shaping the child’s brain, their expectations, and their view of the world and their place in it. In Alone Together, Turkle asks: What are we saying to children about their importance to us when we’re willing to outsource their care to a robot? A child might be superficially entertained by the robot while his self-esteem is systematically undermined.
Research has emerged showing that there are clear downsides to child-robot relationships.
Still, in the case of robot nannies in the home, is active, playful engagement with a robot for a few hours a day any more harmful than several hours in front of a TV or with an iPad? Some, like Xiong, regard interacting with a robot as better than mere passive entertainment. iPal’s manufacturers say that their robot can’t replace parents or teachers and is best used by three- to eight-year-olds after school, while they wait for their parents to get off work. But as robots become ever-more sophisticated, they’re expected to perform more of the tasks of day-to-day care and to be much more emotionally advanced. There is no question children will form deep attachments to some of them. And research has emerged showing that there are clear downsides to child-robot relationships.
Some studies, performed by Turkle and fellow MIT colleague Cynthia Breazeal, have revealed a darker side to the child-robot bond. Turkle has reported extensively on these studies in The Washington Post and in her book Alone Together. Most children love robots, but some act out their inner bully on the hapless machines, hitting and kicking them and otherwise trying to hurt them. The trouble is that the robot can’t fight back, teaching children that they can bully and abuse without consequences. As in any other robot relationship, such harmful behavior could carry over into the child’s human relationships.
And, ironically, it turns out that communicative machines don’t actually teach kids good communication skills. It’s well known that parent-child communication in the first three years of life sets the stage for a very young child’s intellectual and academic success. Verbal back-and-forth with parents and care-givers is like fuel for a child’s growing brain. One article that examined several types of play and their effect on children’s communication skills, published in JAMA Pediatrics in 2015, showed that babies who played with electronic toys—like the popular robot dog Aibo—show a decrease in both the quantity and quality of their language skills.
Anna V. Sosa of the Child Speech and Language Lab at Northern Arizona University studied twenty-six ten- to sixteen- month-old infants to compare the growth of their language skills after they played with three types of toys: electronic toys like a baby laptop and talking farm; traditional toys like wooden puzzles and building blocks; and books read aloud by their parents. The play that produced the most growth in verbal ability was having books read to them by a caregiver, followed by play with traditional toys. Language gains after playing with electronic toys came dead last. This form of play involved the least use of adult words, the least conversational turntaking, and the least verbalizations from the children. While the study sample was small, it’s not hard to extrapolate that no electronic toy or even more abled robot could supply the intimate responsiveness of a parent reading stories to a child, explaining new words, answering the child’s questions, and modeling the kind of back- and-forth interaction that promotes empathy and reciprocity in relationships.
***
Most experts acknowledge that robots can be valuable educational tools. But they can’t make a child feel truly loved, validated, and valued. That’s the job of parents, and when parents abdicate this responsibility, it’s not only the child who misses out on one of life’s most profound experiences.
We really don’t know how the tech-savvy children of today will ultimately process their attachments to robots and whether they will be excessively predisposed to choosing robot companionship over that of humans. It’s possible their techno literacy will draw for them a bold line between real life and a quasi-imaginary history with a robot. But it will be decades before we see long-term studies culminating in sufficient data to help scientists, and the rest of us, to parse out the effects of a lifetime spent with robots.
This is an excerpt from ROBOTS AND THE PEOPLE WHO LOVE THEM: Holding on to Our Humanity in an Age of Social Robots by Eve Herold. The book will be published on January 9, 2024.
Story by Big Think
In rare cases, a woman’s heart can start to fail in the months before or after giving birth. The all-important muscle weakens as its chambers enlarge, reducing the amount of blood pumped with each beat. Peripartum cardiomyopathy can threaten the lives of both mother and child. Viral illness, nutritional deficiency, the bodily stress of pregnancy, or an abnormal immune response could all play a role, but the causes aren’t concretely known.
If there is a silver lining to peripartum cardiomyopathy, it’s that it is perhaps the most survivable form of heart failure. A remarkable 50% of women recover spontaneously. And there’s an even more remarkable explanation for that glowing statistic: The fetus‘ stem cells migrate to the heart and regenerate the beleaguered muscle. In essence, the developing or recently born child saves its mother’s life.
Saving mama
While this process has not been observed directly in humans, it has been witnessed in mice. In a 2015 study, researchers tracked stem cells from fetal mice as they traveled to mothers’ damaged cardiac cells and integrated themselves into hearts.
Evolutionarily, this function makes sense: It is in the fetus’ best interest that its mother remains healthy.
Scientists also have spotted cells from the fetus within the hearts of human mothers, as well as countless other places inside the body, including the skin, spleen, liver, brain, lung, kidney, thyroid, lymph nodes, salivary glands, gallbladder, and intestine. These cells essentially get everywhere. While most are eliminated by the immune system during pregnancy, some can persist for an incredibly long time — up to three decades after childbirth.
This integration of the fetus’ cells into the mother’s body has been given a name: fetal microchimerism. The process appears to start between the fourth and sixth week of gestation in humans. Scientists are actively trying to suss out its purpose. Fetal stem cells, which can differentiate into all sorts of specialized cells, appear to target areas of injury. So their role in healing seems apparent. Evolutionarily, this function makes sense: It is in the fetus’ best interest that its mother remains healthy.
Sending cells into the mother’s body may also prime her immune system to grow more tolerant of the developing fetus. Successful pregnancy requires that the immune system not see the fetus as an interloper and thus dispatch cells to attack it.
Fetal microchimerism
But fetal microchimerism might not be entirely beneficial. Greater concentrations of the cells have been associated with various autoimmune diseases such as lupus, Sjogren’s syndrome, and even multiple sclerosis. After all, they are foreign cells living in the mother’s body, so it’s possible that they might trigger subtle, yet constant inflammation. Fetal cells also have been linked to cancer, although it isn’t clear whether they abet or hinder the disease.
A team of Spanish scientists summarized the apparent give and take of fetal microchimerism in a 2022 review article. “On the one hand, fetal microchimerism could be a source of progenitor cells with a beneficial effect on the mother’s health by intervening in tissue repair, angiogenesis, or neurogenesis. On the other hand, fetal microchimerism might have a detrimental function by activating the immune response and contributing to autoimmune diseases,” they wrote.
Regardless of a fetus’ cells net effect, their existence alone is intriguing. In a paper published earlier this year, University of London biologist Francisco Úbeda and University of Western Ontario mathematical biologist Geoff Wild noted that these cells might very well persist within mothers for life.
“Therefore, throughout their reproductive lives, mothers accumulate fetal cells from each of their past pregnancies including those resulting in miscarriages. Furthermore, mothers inherit, from their own mothers, a pool of cells contributed by all fetuses carried by their mothers, often referred to as grandmaternal microchimerism.”
So every mother may carry within her literal pieces of her ancestors.