Doctor with a syringe on the background of DNA.
Steve, a 60-year-old resident of the DC area who works in manufacturing, was always physically fit. In college, he played lacrosse in Division I, the highest level of intercollegiate athletics in the United States. Later, he stayed active by swimming, biking, and running--up until something strange happened around two years ago.
"It was hard for me to even get upstairs. I wasted away."
Steve, who requested that his last name be withheld to protect his privacy, started to notice weakness first in his toes, then his knees. On a trip to the zoo, he had trouble keeping up. Then some months later, the same thing happened on a family hike. What was supposed to be a four-mile trek up to see a waterfall ended for him at the quarter-mile mark. He turned around and struggled back to the start just as everyone else was returning from the excursion.
Alarmed, he sought out one doctor after the next, but none could diagnose him. The disabling weakness continued to creep up his legs, and by the time he got in to see a top neurologist at Johns Hopkins University last January, he was desperate for help.
"It was hard for me to even get upstairs," he recalls. "I wasted away and had lost about forty-five pounds."
The neurologist, Dr. Michael Polydefkis, finally made the correct diagnosis based on Steve's rapid progression of symptoms, a skin and nerve biopsy, and a genetic test. It turned out that Steve had a rare inherited disease called hereditary transthyretin amyloidosis. Transthyretin is a common blood protein whose normal function is to transport vitamins and hormones in the body. When patients possess certain genetic mutations in the transthyretin gene, the resulting protein can misfold, clump and produce amyloid, an aggregate of proteins, which then interferes with normal function. Many organs are affected in this disease, but most affected are the nervous system, the GI tract, and the heart.
Dr. Michael Polydefkis, Steve's neurologist at Johns Hopkins Bayview Medical Center in Baltimore, MD.
(Courtesy of Dr. Polydefkis)
For the 50,000 patients like Steve around the world, the only treatment historically has been a liver transplant—a major, risky operation. The liver makes most of the transthyretin in a person's body. So if a person who carries a genetic mutation for a disease-causing form of transthyretin has their liver transplanted, the new liver will stop making the mutant protein. A few drugs can slow, but do not stop the disease.
Since it is a genetic condition, a regular "drug" can't tackle the problem.
"For almost all of medicine from the 18th century to today, drugs have been small molecules, typically natural, some invented by humans, that bind to proteins and block their functions," explains Dr. Phillip Zamore, chair of the department of Biomedical Sciences at the University of Massachusetts Medical School. "But with most proteins (including this one), you can't imagine how that would ever happen. Because even if it stuck, there's no reason to think it would change anything. So people threw up their hands and said, 'Unless we can find a protein that is "druggable" in disease X, we can't treat it.'"
To draw a car analogy, treating a disease like Steve's with a small molecule would be like trying to shut down the entire car industry when all you can do is cut the power cord to one machine in one local factory. With few options, patients like Steve have been at a loss, facing continual deterioration and disability.
"It's more obvious how to be specific because we use the genetic code itself to design the drug."
A Radical New Approach
Luckily, Dr. Polydefkis knew of an experimental drug made by a biotech company that Dr. Zamore co-founded called Alnylam Pharmaceuticals. They were doing something completely different: silencing the chemical blueprint for protein, called RNA, rather than targeting the protein itself. In other words, shutting down all the bad factories across the whole car industry at once – without touching the good ones.
"It's more obvious how to be specific," says Dr. Zamore, "because we use the genetic code itself to design the drug."
For Steve's doctor, the new drug, called patisiran, is a game changer.
"It's the dawn of molecular medicine," says Dr. Polydefkis. "It's really a miraculous development. The ability to selectively knock down or reduce the amount of a specific protein is remarkable. I tell patients this is science fiction that is now becoming reality."
A (Very) Short History
The strategy of silencing RNA as a method of guiding drug development began in 1998. Basic research took six years before clinical testing in humans began in 2004. Just a few months ago, in November, the results of the first double-blind, placebo-controlled phase III trials were announced, testing patisiran in patients--and they surpassed expectations.
"The results were remarkably positive," says Dr. Polydefkis. "Every primary and secondary outcome measure target was met. It's the most positive trial I have ever been associated with and that I can remember in recent memory."
FDA approval is expected to come by summer, which will mark the first official sanction of a drug based on RNA inhibition (RNAi). Experts are confident that similar drugs will eventually follow for other diseases, like familial hypercholesterol, lipid disorders, and breathing disorders. Right now, these drugs must get into the liver to work, but otherwise the future treatment possibilities are wide open, according to Dr. Zamore.
"It doesn't have to be a genetic disease," he says. "In theory, it doesn't have to be just one gene, although I don't think anyone knows how many you could target at once. There is no precedent for targeting two."
Dr. Phillip Zamore, chair of the RNA Therapeutics Institute at the University of Massachusetts Medical School.
(Courtesy of Dr. Zamore)
Alnylam, the leading company in RNAi therapeutics, plans to strategically design other new drugs based on what they have learned from this first trial – "so with each successive experience, with designing and testing, you get better at making more drugs. In a way, that's never happened before...This is a lot more efficient of a way to make drugs in the future."
And unlike gene therapy, in which a patient's own genetic code is permanently altered, this approach does not cause permanent genetic changes. Patients can stop taking it like any other drug, and its effects will vanish.
How Is Steve?
Last February, Steve started on the drug. He was granted early access since it is not yet FDA-approved and is still considered experimental. Every 21 days, he has received an IV infusion that causes some minor side effects, like headaches and facial flushing.
"The good news is, since I started on the drug, I don't see any more deterioration other than my speech."
So far, it seems to be effective. He's gained back 20 pounds, and though his enunciation is still a bit slurred, he says that his neuropathy has stopped. He plans to continue the treatment for the rest of his life.
"The good news is, since I started on the drug, I don't see any more deterioration other than my speech," he says. "I think the drug is working, but would I have continued to deteriorate without the drug? I'm not really sure."
Dr. Polydefkis jumps in with a more confident response: "If you ask me, I would say 100 percent he would have kept progressing at a fairly rapid pace without the drug. When Steve says the neuropathy has stopped, that's music to my ears."
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.
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