A Fierce Mother vs. a Fatal Mutation
Editor's Note: In the year 2000, Amber Salzman was a 39-year-old mom from Philadelphia living a normal life: working as a pharmaceutical executive, raising an infant son, and enjoying time with her family. But when tragedy struck in the form of a ticking time bomb in her son's DNA, she sprang into action. Her staggering triumphs after years of turmoil exemplify how parents today can play a crucial role in pushing science forward. This is her family's story, as told to LeapsMag's Editor-in-Chief Kira Peikoff.
For a few years, my nephew Oliver, suffered from symptoms that first appeared as attention deficit disorder and then progressed to what seemed like Asperger's, and he continued to worsen and lose abilities he once had. After repeated misdiagnoses, he was finally diagnosed at age 8 with adrenoleukodystrophy, or ALD – a degenerative brain disease that puts kids on the path toward death. We learned it was an X-linked disease, so we had to test other family members. Because Oliver had it, that meant his mother, my sister, was carrier, which meant I had a 50-50 chance of being a carrier, and if I was, then my son had a 50-50 chance of getting the bad gene.
You know how some people win prizes all the time? I don't have that kind of luck. I had a sick feeling when we drew my son's blood. It was almost late December in the year 2000. Spencer was 1 and climbing around like a monkey, starting to talk—a very rambunctious kid. He tested positive, along with Oliver's younger brother, Elliott.
"The only treatment at the time was an allogenic stem cell transplant from cord blood or bone marrow."
You can imagine the dreadful things that go through your mind. Everything was fine then, but he had a horrific chance that in about 3 or 4 years, a bomb would go off. It was so tough thinking that we were going to lose Oliver, and then Spencer and Elliott were next in line. The only treatment at the time was an allogenic stem cell transplant from cord blood or bone marrow, which required finding a perfect match in a donor and then undergoing months of excruciating treatment. The mortality rate can be as high as 40 percent. If your kid was lucky enough to find a donor, he would then be lucky to leave the hospital 100 days after a transplant with a highly fragile immune system.
At the time, I was at GlaxoSmithKline in Research and Development, so I did have a background in working with drug development and I was fortunate to report to the chairman of R&D, Tachi Yamada.
I called Tachi and said, "I need your advice, I have three or four years to find a cure. What do I do?" He did some research and said it's a monogenic disease—meaning it's caused by only one errant gene—so my best bet was gene therapy. This is an approach to treatment that involves taking a sample of the patient's own stem cells, treating them outside the body with a viral vector as a kind of Trojan Horse to deliver the corrected gene, and then infusing the solution back into the patient, in the hopes that the good gene will proliferate throughout the body and stop the disease in its tracks.
Tachi said to call his friend Jim Wilson, who was a leader in the field at UPenn.
Since I live in Philadelphia I drove to see Jim as soon as possible. What I didn't realize was how difficult a time it was. This was shortly after Jesse Gelsinger died in a clinical trial for gene therapy run by UPenn—the first death for the field—and research had abruptly stopped. But when I met with Jim, he provided a road map for what it would take to put together a gene therapy trial for ALD.
Meanwhile, in parallel, I was dealing with my son's health.
After he was diagnosed, we arranged a brain MRI to see if he had any early lesions, because the only way you can stop the disease is if you provide a bone marrow transplant before the disease evolves. Once it is in full force, you can't reverse it, like a locomotive that's gone wild.
"He didn't recover like other kids because his brain was not a normal brain; it was an ALD brain."
We found he had a brain tumor that had nothing to do with ALD. It was slow growing, and we would have never found it otherwise until it was much bigger and caused symptoms. Long story short, he ended up getting the tumor removed, and when he was healing, he didn't recover like other kids because his brain was not a normal brain; it was an ALD brain. We knew we needed a transplant soon, and the gene therapy trial was unfortunately still years away.
At the time, he was my only child, and I was thinking of having additional kids. But I didn't want to get pregnant with another ALD kid and I wanted a kid who could provide a bone marrow transplant for my son. So while my son was still OK, I went through 5 cycles of in vitro fertilization, a process in which hormone shots stimulated my ovaries to produce multiple eggs, which were then surgically extracted and fertilized in a lab with my husband's sperm. After the embryos grew in a dish for three to five days, doctors used a technique called preimplantation genetic diagnosis, screening those embryos to determine which genes they carry, in order to try to find a match for Spencer. Any embryo that had ALD, we saved for research. Any that did not have ALD but were not a match for Spencer, we put in the freezer. We didn't end up with a single one that was a match.
So he had a transplant at Duke Children's Hospital at age 2, using cord blood donated from a public bank. He had to be in the hospital a long time, infusing meds multiple times a day to prevent the donor cells from rejecting his body. We were all excited when he made it out after 100 days, but then we quickly had to go back for an infection he caught.
We were still bent on moving forward with the gene therapy trials.
Jim Wilson at Penn explained what proof of concept we needed in animals to go forward to humans, and a neurologist in Paris, Patrick Aubourg, had already done that using a vector to treat ALD mice. But he wasn't sure which vector to use in humans.
The next step was to get Patrick and a team of gene therapy experts together to talk about what they knew, and what needed to be done to get a trial started. There was a lot of talk about viral vectors. Because viruses efficiently transport their own genomes into the cells they infect, they can be useful tools for sending good genes into faulty cells. With some sophisticated tinkering, molecular biologists can neuter normally dangerous viruses to make them into delivery trucks, nothing more. The biggest challenge we faced then was: How do we get a viral vector that would be safe in humans?
Jim introduced us to Inder Verma, chair of the scientific advisory board of Cell Genesys, a gene therapy company in California that was focused on oncology. They were the closest to making a viral vector that could go into humans, based on a disabled form of HIV. When I spoke to Inder, he said, "Let's review the data, but you will need to convince the company to give you the vector." So I called the CEO and basically asked him, "Would you be willing to use the vector in this horrific disease?" I told him that our trial would be the fastest way to test their vector in humans. He said, "If you can convince my scientists this is ready to go, we will put the vector forward." Mind you, this was a multi-million-dollar commitment, pro bono.
I kept thinking every day, the clock is ticking, we've got to move quickly. But we convinced the scientists and got the vector.
Then, before we could test it, an unrelated clinical trial in gene therapy for a severe immunodeficiency disease, led to several of the kids developing leukemia in 2003. The press did a bad number and scared everyone away from the field, and the FDA put studies on hold in the U.S. That was one of those moments where I thought it was over. But we couldn't let it stop. Nothing's an obstacle, just a little bump we have to overcome.
Patrick wanted to do the study in France with the vector. This is where patient advocacy is important in providing perspective on the risks vs. benefits of undergoing an experimental treatment. What nobody seemed to realize was that the kids in the 2003 trial would have died if they were not first given the gene therapy, and luckily their leukemia was a treatable side effect.
Patrick and I refused to give up pushing for approval of the trial in France. Meanwhile, I was still at GSK, working full time, and doing this at night, nonstop. Because my day job did require travel to Europe, I would stop by Paris and meet with him. Another sister of mine who did not have any affected children was a key help and we kept everything going. You really need to continually stay engaged and press the agenda forward, since there are so many things that pop up that can derail the program.
Finally, Patrick was able to treat four boys with the donated vector. The science paper came out in 2009. It was a big deal. That's when the venture money came in—Third Rock Ventures was the first firm to put big money behind gene therapy. They did a deal with Patrick to get access to the Intellectual Property to advance the trial, brought on scientists to continue the study, and made some improvements to the vector. That's what led to the new study reported recently in the New England Journal of Medicine. Of 17 patients, 15 of them are still fine at least two years after treatment.
You know how I said we felt thrilled that my son could leave the hospital after 100 days? When doing the gene therapy treatment, the hospital stay needed is much quicker. Shortly after one kid was treated, a physician in the hospital remarked, "He is fine, he's only here because of the trial." Since you get your own cells, there is no risk of graft vs. host disease. The treatment is pretty anticlimactic: a bag of blood, intravenously infused. You can bounce back within a few weeks.
Now, a few years out, approximately 20 percent of patients' cells have been corrected—and that's enough to hold off the disease. That's what the data is showing. I was blown away when it worked in the first two patients.
The formerly struggling field is now making a dramatic comeback.
Just last month, the first two treatments involving gene therapy were approved by the FDA to treat a devastating type of leukemia in children and an aggressive blood cancer in adults.
Now I run a company, Adverum Biotechnologies, that I wish existed back when my son was diagnosed, because I want people who are like me, coming to me, saying: "I have proof of concept in an animal, I need to get a vector suitable for human trials, do the work needed to file with the FDA, and move it into humans." Our company knows how to do that and would like to work with such patient advocates.
Often parents feel daunted to partake in similar efforts, telling me, "Well, you worked in pharma." Yes, I had advantages, but if you don't take no for an answer, people will help you. Everybody is one degree of separation from people who can help them. You don't need a science or business background. Just be motivated, ask for help, and have your heart in the right place.
Having said that, I don't want to sound judgmental of families who are completely paralyzed. When you get a diagnosis that your child is dying, it is hard to get out of bed in the morning and face life. My sister at a certain point had one child dying, one in the hospital getting a transplant, and a healthy younger child. To expect someone like that to at the same time be flying to an FDA meeting, it's hard. Yet, she made critical meetings, and she and her husband graciously made themselves available to talk to parents of recently diagnosed boys. But it is really tough and my heart goes out to anyone who has to live through such devastation.
Tragically, my nephew Oliver passed away 13 years ago at age 12. My other nephew was 8 when he had a cord blood transplant; our trial wasn't available yet. He had some bad graft vs. host disease and he is now navigating life using a wheelchair, but thank goodness, it stopped the disease. He graduated Stanford a year ago and is now a sports writer for the Houston Chronicle.
As for my son, today he is 17, a precocious teenager applying to colleges. He also volunteers for an organization called the Friendship Circle, providing friends for kids with special needs. He doesn't focus on disability and accepts people for who they are – maybe he would have been like that anyway, but it's part of who he is. He lost his cousin and knows he is alive today because Oliver's diagnosis gave us a head start on his.
My son's story is a good one in that he had a successful transplant and recovered.
Once we knew he would make it and we no longer needed our next child to be a match, we had a daughter using one of our healthy IVF embryos in storage. She is 14 now, but she jokes that she is technically 17, so she should get to drive. I tell her, they don't count the years in the freezer. You have to joke about it.
I am so lucky to have two healthy kids today based on advances in science.
And I often think of Oliver. We always try to make him proud and honor his name.
[Editor's Note: This story was originally published in November 2017. We are resurfacing archive hits while our staff is on vacation.]
Salzman and her son Spencer, 17, who is now healthy.
(Courtesy of Salzman)
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.
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