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
Niklas Anzinger is the founder of Infinita VC based in the charter city of Prospera in Honduras. Infinita focuses on a new trend of charter cities and other forms of alternative jurisdictions. Healso hosts a podcast about how to accelerate the future by unblocking “stranded technologies”.This spring he was a part of the network city experiment Zuzalu spearheaded by Ethereum founder Vitalik Buterin where a few hundred invited guests from the spheres of longevity, biotechnology, crypto, artificial intelligence and investment came together to form a two-monthlong community. It has been described as the world’s first pop-up city. Every morning Vitalians would descend on a long breakfast—the menu had been carefully designed by famed radical longevity self-experimenter Bryan Johnson—and there is where I first met Anzinger who told me about Prospera. Intrigued to say the least, I caught up with him later the same week and the following is a record of our conversation.
Q. We are sitting here in the so-called pop-up network state Zuzalu temporarily realized in the village of Lusticia Bay by the beautiful Mediterranean Sea. To me this is an entirely new concept: What is a network state?
A. A network state is a highly aligned online community that has a level of in-person civility; it crowd-funds territory, and it eventually seeks diplomatic recognition. In a way it's about starting a new country. The term was coined by the crypto influencer and former CTO of Coinbase Balaji Srinivasan in a book by the same title last year [2022]. What many people don't know is that it is a more recent addition or innovation in a space called competitive governance. The idea is that you have multiple jurisdictions competing to provide you services as a customer. When you have competition among governments or government service providers, these entities are forced to provide you with a better service instead of the often worse service at higher prices or higher taxes that we're currently getting. The idea went from seasteading, which was hardly feasible because of costs, to charter cities getting public/private partnerships with existing governments and a level of legal autonomy, to special economic zones, to now network states.
Q. How do network states compare to charter cities and similar jurisdictions?
A. Charter cities and special economic zones were legal forks from other existing states. Dubai, Shenzhen in China, to some degree Hong Kong, to some degree Singapore are some examples. There's a host of other charter cities, one of which I'm based in myself, which is Prospera located in Honduras on the island Roatán. Charter cities provide the full stack of governance; they provide new laws and regulations, business registration, tax codes and governance services, Estonia style: you log on to the government platform and you get services as a citizen.
When conceptualizing network states, Balagi Srinivasan turns the idea of a charter city a bit on its head: he doesn't want to start with this full stack because it's still very hard to get these kinds of partnerships with government. It's very expensive and requires lots of experience and lots of social capital. He is saying that network states could instead start as an online community. They could have a level of alignment where they trade with each other; they have their own economy; they meet in person in regular gatherings like we're doing here in Zuzulu for two months, and then they negotiate with existing governments or host cities to get a certain degree of legal autonomy that is centered around a moral innovation. So, his idea is: don't focus on building a completely new country or city; focus on a moral innovation.
Q. What would be an example of such a moral innovation?
A. An example would be longevity—life is good; death is bad—let's see what we can do to foster progress around that moral innovation and see how we can get legal forks from the existing system that allow us to accelerate progress in that area. There is an increasing realization in the science that there are hallmarks of aging and that aging is a cause of other diseases like cancer, ALS or Alzheimer's. But aging is not recognized as a disease by the FDA in the United States and in most countries around the world, so it's very hard to get scientific funding for biotechnology that would attack the hallmarks of aging and allow us potentially to reverse aging and extend life. This is a significant shortcoming of existing government systems that groups such as the ones that have come together here in Montenegro are now seeking alternatives too. Charter cities and now network states are such alternatives.
Q. Would it not be better to work within the current systems, and try to improve them, rather than abandon them for new experimental jurisdictions?
A. There are numerous failures of public policies. These failures are hard, if not impossible, to reverse, because as soon as you have these policies, you have entrenched interests who benefit from the regulations. The only way to disrupt incumbent industries is with start-ups, but the way the system is set up makes it excessively hard for such start-ups to become big companies. In fact, larger companies are weaponizing the legal system against small companies, because they can afford the lawyers and the fixed cost of compliance.
I don't believe that our institutions in many developed countries are beyond hope. I just think it's easier to change them if you could point at successful examples. ‘Hey, this country or this zone is already doing it very successfully’; if they can extend people’s lifespan by 10 years, if they can reduce maternal mortality, and if they have a massive medical tourism where people come back healthier, then that is just very embarrassing for the FDA.
Q. Perhaps a comparison here would be the relationship between Hong Kong and China?
A. Correct, so having Hong Kong right in front of your door … ‘Hey, this capitalism thing seems to work, why don't we try it here?’ It was due to the very bold leadership by Deng Xiaoping that they experimented with it in the development zone of Shenzhen. It worked really well and then they expanded with more special economic zones that also worked.
Próspera is a private city and special economic zone on the island of Roatán in the Central American state of Honduras.
Q. Tell us about Prospera, the charter city in Honduras, that you are intimately connected with.
A. Honduras is a very poor country. It has a lot of crime, never had a single VC investment, and has a GDP per capita of 2,000 per year. Honduras has suffered tremendously. The goal of these special economic zones is to bring in economic development. That's their sole purpose. It's a homegrown innovation from Honduras that started in 2009 with a very forward-thinking statesman, Octavio Sanchez, who was the chief of staff to the president of Honduras, and then president. He had his own ideas about making Honduras a more decentralized system, where more of the power lies in the municipalities.
Inspired by the ideas of Nobel laureate economist Paul Romer, who gave a famous Ted Talk in 2009 about charter cities, Sanchez initiated a process that lasted for years and eventually led to the creation of a special economic zone legal regime that’s anchored in the Hunduran constitution that provides the highest legal autonomy in the world to these zones. There are today three special economic zones approved by the Honduran government: Prospera, Ciudad Morazan and Orchidea.
Q. How did you become interested and then involved in Prospera?
A. I read about it first in an article by Scott Alexander, a famous rationalist blogger, who wrote a very long article about Prospera, and I thought, this is amazing! Then I came to Prospera and I found it to be one of the most if not the most exciting project in the world going on right now and that it also opened my heart to the country and its people. Most of my friends there are Honduran, they have been working on this for 10 or more years. They want to remake Honduras and put it on the map as the place in the world where this legal and governance innovation started.
Q. To what extent is Prospera autonomous relative to the Honduran government?
A. What's interesting about the Honduran model is that it's anchored within the Honduran constitution, and it has a very clear framework for what's possible and what's not possible, and what's possible ensures the highest degree of legal autonomy anywhere seen in the world. Prospera has really pushed the model furthest in creating a common law-based polycentric legal system. The idea is that you don't have a legislature, instead you have common law and it's based on the best practice common law principles that a legal scholar named Tom W. Bell created.
One of the core ideas is that as a business you're not obligated to follow one regulatory monopoly like the FDA. You have regulatory flexibility so you can choose what you're regulated under. So, you can say: ‘if I do a medical clinic, I do it under Norwegian law here’. And you even have the possibility to amend it a bit. You're still required to have liability insurance, and have to agree to binding arbitration in case there's a legal dispute. And your insurance has to approve you. So, under that model the insurance becomes the regulator and they regulate through prices. The limiting factor is criminal law; Honduran criminal law fully applies. So does immigration law. And we pay taxes.
Q. Is there also an idea of creating a kind of healthy living there, and encourage medical tourism?
A. Yes, we specifically look for legal advantages in autonomy around creating new drugs, doing clinical trials, doing self-medication and experimentation. There is a stem cell clinic here and they're doing clinical trials. The island of Roatán is very easily accessible for American tourists. It's a beautiful island, and it's for regulatory reasons hard to do stem cell therapies in the United States, so they're flying in patients from the United States. Most of them are very savvy and often have PhDs in biotech and are able to assess the risk for themselves of taking drugs and doing clinical trials. We're also going to get a wellness center, and there have been ideas around establishing a peptide clinic and a compound pharmacy and things like that. We are developing a healthcare ecosystem.
Q. This kind of experimental tourism raises some ethical issues. What happens if patients are harmed? And what are the moral implications for society of these new treatments?
A. As a moral principle we believe in medical freedom: people have rights over their bodies, even at the (informed) risk of harm to themselves if no unconsenting third-parties are harmed; this is a fundamental right currently not protected effectively.
What we do differently is not changing ethical norms around safety and efficacy, we’re just changing the institutional setup. Instead of one centralized bureaucracy, like the FDA, we have regulatory pluralism that allows different providers of safety and efficacy to compete under market rules. Like under any legal system, common law in Prospera punishes malpractice, fraud, murder etc. This system will still produce safe and effective drugs, and it will still work with common sense legal notions like informed consent and liability for harm. There are regulations for medical practice, there is liability insurance and things like that. It will just do so more efficiently than the current way of doing things (unless it won’t, in which case it will change and evolve – or fail).
A direct moral benefit ´to what we do is that we increase accessibility. Typical gene therapies on the market cost $1 million dollars in the US. The gene therapy developed in Prospera costs $25,000. As to concern about whether such treatments are problematic, we do not share this perspective. We are for advancing science responsibly and we believe that both individuals and society stand to gain from improving the resiliency of the human body through advanced biotechnology.
Q. How does Prospera relate to the local Honduran population?
A. I think it's very important that our projects deliver local benefits and that they're well anchored in local communities. Because when you go to a new place, you're seen as a foreigner, and you're seen as potentially a danger or a threat. The most important thing for Prospera and Ciudad Morazan is to show we're creating jobs; we're creating employment; we're improving people's lives on the ground. Prospera is directly and indirectly employing 1,100 people. More than 2/3 of the people who are working for Prospera are Honduran. It has a lot of local service workers from the island, and it has educated Hondurans from the mainland for whom it's an alternative to going to the United States.
Q. What makes a good Prosperian citizen?
A. People in Prospera are very entrepreneurial. They're opening companies on a small scale. For example, Vehinia, who is the cook in the kitchen at Prospera, she's from the neighboring village and she started an NGO that is now funding a school where children from the local village can go to instead of a school that's 45 minutes away. There's very much a spirit of ‘let's exchange and trade with each other’. Some people might see that as a bit too commercial, but that's something about the culture that people accept and that people see as a good thing.
Q. Five years from now, if everything goes well, what do we see in Prospera?
A. I think Prospera will have at least 10,000 residents and I think Honduras hopefully will have more zones. There could be zones with a thriving industrial sector and sort of a labor-intensive economy and some that are very strong in pharmaceuticals, there could also be other zones for synthetic biology, and other zones focused on agriculture. The zones of Prospera, Ciudad Morazan and Orchidea are already showing the results we want to see, the results that we will eventually be measured by, and I'm tremendously excited about Honduras.
How to Measure Your Stress, with Dr. Rosalind Picard
Today’s podcast guest is Rosalind Picard, a researcher, inventor named on over 100 patents, entrepreneur, author, professor and engineer. When it comes to the science related to endowing computer software with emotional intelligence, she wrote the book. It’s published by MIT Press and called Affective Computing.
Dr. Picard is founder and director of the MIT Media Lab’s Affective Computing Research Group. Her research and engineering contributions have been recognized internationally. For example, she received the 2022 International Lombardy Prize for Computer Science Research, considered by many to be the Nobel prize in computer science.
Through her research and companies, Dr. Picard has developed wearable sensors, algorithms and systems for sensing, recognizing and responding to information about human emotion. Her products are focused on using fitness trackers to advance clinical quality treatments for a range of conditions.
Meanwhile, in just the past few years, numerous fitness tracking companies have released products with their own stress sensors and systems. You may have heard about Fitbit’s Stress Management Score, or Whoop’s Stress Monitor – these features and apps measure things like your heart rhythm and a certain type of invisible sweat to identify stress. They’re designed to raise awareness about forms of stress such as anxieties and anger, and suggest strategies like meditation to relax in real time when stress occurs.
But how well do these off-the-shelf gadgets work? There’s no one more knowledgeable and experienced than Rosalind Picard to explain the science behind these stress features, what they do exactly, how they might be able to help us, and their current shortcomings.
Dr. Picard is a member of the National Academy of Engineering and a Fellow of the National Academy of Inventors, and a popular speaker who’s given over a hundred invited keynote talks and a TED talk with over 2 million views. She holds a Bachelors in Electrical Engineering from Georgia Tech, and Masters and Doctorate degrees in Electrical Engineering and Computer Science from MIT. She lives in Newton, Massachusetts with her husband, where they’ve raised three sons.
In our conversation, we discuss stress scores on fitness trackers to improve well-being. She describes the difference between commercial products that might help people become more mindful of their health and products that are FDA approved and really capable of advancing the science. We also talk about several fascinating findings and concepts discovered in Dr. Picard’s lab including the multiple arousal theory, a phenomenon you’ll want to hear about. And we explore the complexity of stress, one reason it’s so tough to measure. For example, many forms of stress are actually good for us. Can fitness trackers tell the difference between stress that’s healthy and unhealthy?
Show links:
- Dr. Picard’s book, Affective Computing
- Dr. Picard’s bio
- Dr. Picard on Twitter
- Dr. Picard’s company, Empatica - https://www.empatica.com/ - The FDA-cleared Empatica Health Monitoring Platform provides accurate, continuous health insights for researchers and clinicians, collected in the real world
- Empatica Twitter
- Dr. Picard and her team have published hundreds of peer-reviewed articles across AI, Machine Learning, Affective Computing, Digital Health, and Human-computer interaction.
- Dr. Picard’s TED talk
Rosalind Picard