The Cure of a Lifetime

Episode 131

Quinn:
Welcome to Important Not Important. My name is Quinn Emmett, and this is science for people who give a shit. Folks, I have spent the last two years trying to understand and focusing on what we do best here. And it's increasingly clear that that is answering the question, what can I do about climate? What can I do about COVID or cancer or hunger, clean water, maternal health, air pollution, or some other make or break issue. We tell you what's happening, who's involved, how to think about it and what the hell you can do about it.

Quinn:
I want to tell you a couple of quick stories. 14 years ago, my beloved cousin was suddenly diagnosed with cancer. We share a birthday. I love her. She was so young and I didn't know how to help. I wasn't a doctor, wasn't a scientist. I mean, clearly I'm still not either of those, but I wasn't anything that could directly help her. Someone told me about Team In Training, which is the fundraising arm of the Leukemia & Lymphoma Society. Now, they bring supporters together to train and run marathons and triathlons and raise money to fight blood cancers. Running and sweating, I could do this. I can sweat. I can raise a ton of cash. I can donate it all to the doctors and researchers who actually know what the hell they're doing. I was elated. I have a part to play. I can play my part.

Quinn:
And that's important because I can use this thing I know how to do for good. I can help myself feel better on one hand, but maybe also contribute to fixing the larger problem itself. My cousin survived. She's flourishing. She's getting married. So when one of my best friends got cancer a couple of years ago, I did the same thing, I ran and I ran and I ran and I raised a truckload of money for research and for his treatments, because I felt equally desperate, but a little more empowered. My friend's name was Andy and Andy didn't make it. But I think I'm here today doing this because of him.

Quinn:
This feeling, needing, but also being able to do something to help, to also feel better. The whole thing just stuck with me and now we're here today and you're here today trapped with me. I'm here today. I've got this whole thing where I've realized the best answer to the question what can I do is what can you do? There's so many things you can do, because there's so many of you and you've each got these wonderful talents and passions and there's so much to do, right. While climate and COVID are these global issues that touch everyone and everything, there's a million other situations and moments that challenge each of us in unique ways that can make us feel helpless. Sometimes even alone. A loved one facing a rare disease is among those and among the scariest, because we are very often not the person best suited to directly help that person, if anyone can help at all.

Quinn:
Jafar Tabebordbar was in his early thirties, living and working as an accountant in Shiraz Iran when he became a father. It was 1986, nearly a decade after the 1979 Revolution and Jafar's muscles were already beginning to wither. As his sons grew and watched their father Jafar lost his balance, his ability to walk, to drive and eventually the reliable use of his hands. There were no answers, no treatments to be found. So two questions haunted his sons as they grew, what was causing their father's suffering? Would they get it next?

Quinn:
My guest today 30 years later is Dr. Sharif Tabebordbar, Jafar's oldest son and the man closest to a cure. Sharif received his bachelor's and master's degrees in biotechnology from the University of Tehran and a PhD in developmental and regenerative biology from Harvard University. He's the recipient of distinction into teaching award from Derek Bok Center for teaching and learning at Harvard, from the Albert J Ryan Foundation for outstanding graduate students in biomedical sciences, of the Excellence in Research Award and the Career Development Award from the American Society of Gene and Cell Therapy and the ROYAN International Research Award in regenerative medicine. In 2020, Sharif was listed as a finalist in the MIT 35 Innovators Under 35 competition. In 2021, Sharif and others posted an article in the journal Cell that may change the world. All of these years later, thousands of miles away, Jafar's son Sharif has figured out how to help. He stands on the cusp of transforming gene therapy for nearly all muscle wasting diseases.

Quinn:
Dr. Tabebordbar welcome.

Dr. Sharif Tabebordbar:
Thank you.

Quinn:
Of course. Thank you so much for coming on the show today. So excited to share your story and your work with the folks out there. And again like we talked a little bit about offline because of everything that's going on, this is what happens with climate and COVID and things like that. We often forget about all of the other things that are happening on a day to day basis in science and in the world regardless. Whether that's work like yours or just getting clean water to folks or getting food to folks.

Quinn:
It's so important to really focus on stories like yours, because there's a lot of folks who are coming to us, that's why we call it science for people who give a shit, who are touched by science in some way. I mean, we've all been trapped in our living rooms for the past two years because of it. So if you didn't think it was going to find you, here we are. And there's people who are going like, what can I do? And I feel like your story is so beautiful and practical and pragmatic, but also a difficult one. I'm excited to get into that.

Dr. Sharif Tabebordbar:
No, I appreciate it so much. And I'm really happy to be on your podcast.

Quinn:
You say that now, give it some time. You can join our other 130 guests with all their regrets. Sharif, we do like to start with one important question, because I like for the show to be informative and compelling and dramatic and actionable, but also have a little levity here and there. So one question we ask to set the tone, we like to ask, Sharif, why are you vital to the survival of the species? And I encourage you to be bold and honest because you are here for a reason.

Dr. Sharif Tabebordbar:
That is a very bold question. Why am I essential to the survival of this species? I think the work that I'm doing is going to help certain individuals who are born with genetic diseases that they had no control over live a better life. I think my work is vital to equity and to give people more equal opportunities to live their life. I think the species will survive without me, but probably there would be more people who live a better quality of life.

Quinn:
I think that's pretty wonderful. I joke, I try to empower my children who are very privileged and relatively healthy. When they say, "Well, what are you doing at work today?" I'm like, "I've got a podcast." Meanwhile, there's folks like you out there, as we like to say, on the front lines of the future, just working on these truly miraculous things. So thank you for that. And thank you for answering my ridiculous question. And so Sharif, I actually usually save this particular question for the end, but it actually in your case seems better to just start at the beginning, considering your work and your family. When was the first time in your life when you realized you actually had the power of change or the power to do something meaningful, to help in some way?

Dr. Sharif Tabebordbar:
I think there were a few people who really had a major experience in the path that I chose for my life. I would like to give shout out to them whenever I get a chance. I think one of those people was a very good friend of mine, Eric Wang, who has family members affected by certain form of genetic muscle disease. And I saw his story. I saw that basically he devoted his life and career into studying that disease and trying to find treatments for that. And when I saw him, it was always in the back of my mind that I need to do something about this, but I didn't know where exactly to start to have the most meaningful impact.

Dr. Sharif Tabebordbar:
And watching Eric's story, watching how he actually found all the right people, put a team together, tried to basically move toward that goal with surrounding himself by really wonderful people, inspired me. And it gave me the motivation that I want to do the same thing. I want to find the right people who are going to help me, who are going to be part of this journey, and then I'm going to try as hard as I can to make this happen. So I think meeting Eric Wang was one of the highlights of my journey.

Quinn:
So how old were you, if you could frame that for us, when you encountered Dr. Wang and had this moment where you realized, oh, I could build something like this.

Dr. Sharif Tabebordbar:
I think I was 22 years old.

Quinn:
Okay.

Dr. Sharif Tabebordbar:
But again, since I was a high school student, it was always in the back of my mind that I need to do something to help people who are born with genetic diseases. Because in my mind, the fact that you're born with some mutations in your DNA, that you absolutely have no control over is very unfair. Life is unfair in general. There are things that you can change and there are things that you can't. But this one was a very true example of you're born with something you have no control over. And this is completely unfair. There is got to be a way to change this. There is got to be a way to help people who are born this way. And that was always my motivation. That was always the reason that I chose my majors in school when I went to college and then graduate school. But meeting Eric was the defining moment that I can actually do something meaningful about this. I can study. I can do research, but how can you make an impact? How can you make a change that actually is going to change people's lives?

Quinn:
Sure. I appreciate that from obviously surface level obviously, but a thousand other ways. I mean, everyone here knows I look like this. I was born healthy in America, in the late 20th Century. And that's about as lucky as it gets. As my dad calls it, it's the lucky sperm club. I've never wanted or needed for food or water. I don't have any particular genetic issues, but along this journey of the work I do here, I've come to realize more and more every day. And I try to build a show and a series of conversations that are more inclusive of lived experiences that are different than mine, so that I can try to truly understand these things. We see it every day which is, start in America, or you can look at New Delhi. The people who deal with the air pollution that it's not a genetic disease per se, but it is something that they did not ask for. Or water quality or whatever it might have been.

Quinn:
But genetic disease is so specific because we've only really come to understand it very recently. So I wonder at what point in your youth, before meeting Eric, high school, whenever it might have been earlier than that, as you watched your dad suffer, when did you, I guess, realize that this was something that he didn't ask for. That there wasn't some chemical thing. He wasn't a smoker. It wasn't a car accident. It wasn't any of these things that you realized, oh, this is the ultimate unfairness. Not only did he not do anything to instigate it, but we don't know what it is or why it is.

Dr. Sharif Tabebordbar:
It was when I was a teenager. I mean, my dad lived a healthy life as well. He was not a smoker. It was not his lifestyle that was causing the issue. And the condition that he has was a very progressive condition. So I do remember when I was very young, he would talk okay. He limped a little bit, but he got around. I even remember him riding a bike. And then over time, it was declining and he couldn't ride a bike and then he couldn't take a walk with us in the park anymore because he was very afraid that he was going to fall. At some point he stopped driving. It wasn't safe anymore. And eventually he got wheelchair bound. I think the time that I realized there's something going on that has to do with genetics, it was when I was a teenager, maybe I was 14 or 15 years old.

Quinn:
When you're young, it's a hard thing to wrap your head around. Because like you said, there's an immense amount of injustice in this world and we're realizing that. And in many ways, we've worked to alleviate that, but we still have a long way to go. We've made huge strides against poverty and childhood diseases, but there's still so many who suffer from them. But I think about my six year old, who's constantly complaining that something is unfair, because he's the third child and gets the short thrift. And I have to remind him that the complaint something is unfair does not apply to him in the global sense. But there is this sense of looking around and going like, how could this be? Why him? Why does this have to happen if his lifestyle is not contributing this into some way? You said you had that feeling when you were 14 and 15. Now, from what I understand, you then had to compete for a spot at the University of Tehran, is that correct?

Dr. Sharif Tabebordbar:
Right.

Quinn:
And what were the odds of actually getting in?

Dr. Sharif Tabebordbar:
So the way the university entrance exam in Iran works is that every single high school student in the country needs to take part in this four or five hours exam in one day at one specific time. And basically you choose the major of your career based on the results from that exam. So it's very high stakes and a lot of people spend more than a year of their life to just study for that one exam. So I did spend about a year and a half basically not doing anything else other than studying for this one four hour exam. And it was extremely stressful. I was, I think, 17 years, 18 years old at that time.

Dr. Sharif Tabebordbar:
There was this one program that I was really passionate about. It was called the biotechnology program at University of Tehran. And it had everything that I really loved about biology and genetics and genetic engineering. They'd give you a very interdisciplinary view of different sciences, prepared you for getting into biomedical science, but it was extremely competitive. I think they accepted about 10 students each year. And a few of those students were actually from... we have also this other competition named Olympiads for different sciences and then folks who get a gold medal in the Olympiads, they don't need to take part in this university entrance exam. So a few of the spots already gets filled with people who get gold medals from Olympians.

Quinn:
So it's not really 10, it's actually like five or six.

Dr. Sharif Tabebordbar:
It's five or six.

Quinn:
And out of how many kids, at least when you were going up, were taking this exam on this one day at this one specific time across Iran?

Dr. Sharif Tabebordbar:
It depends year to year. It's different. When I looked up the specific year that I took the exam, I think it was 1.2 million people that took that exam. So it's a very large community that's competing against each other. You actually get ranked from number one to whatever number.

Quinn:
Oh no.

Dr. Sharif Tabebordbar:
It's pretty intense.

Quinn:
Oh geez.

Dr. Sharif Tabebordbar:
I ranked seven in that exam on that year. I was lucky enough to get into that program. That was something that I really worked hard for. Fortunately that panned out.

Quinn:
I mean, you say you were lucky enough to get in, obviously that set up so much of the rest of your life and where you are today, but you also said you worked for a year and a half doing basically nothing else on that. What do you feel like set you apart in that moment besides just hard work from 1.293 million other kids of the same age on the same day. What gets you there? What puts you over the top?

Dr. Sharif Tabebordbar:
I think it's motivation. It's actually wanting to do something really... like persistence, not letting failure stop you. There have been moments during that year and a half that I had bad days. I took a lot of practice exams and there were days that I didn't do well, but you get down, you get pumped when you don't get the results that you expect. But then I think coming up and having the mindset, what can I learn from this failure? How can I do better next time? What went wrong that I had this bad experience? And it took a while for me to come to that stage that I could actually take it. I could not collapse when something goes wrong. But over time I learned that I would prepare myself for the worst, but then a good outcome happens, I'm going to be really happy.

Dr. Sharif Tabebordbar:
I'm going to do my best. I'm going to do anything in my capacity to make sure that I do well. But then there is a very good chance that it doesn't go well and it's okay. It's fine. It happens and you just got to take a step back at that point. Take a look at what happened, learn from it and do better next time. So I think perseverance and really wanting to do something is really important. It's like you obviously work hard. You have to also try to learn from your mistakes and get better over time. I think that's maybe something that helped me.

Quinn:
I mean, it seems like it's two things. You had such a specific intimate motivation clearly at home to set yourself up for success so that you could work on something related to this to go on to meet Eric, to build a team, to work with a team. But I imagine that... were there practice tests along the way? How did those go? Were you seeing indicators that you would be successful or was it, oh shit, I've got to work hard?

Dr. Sharif Tabebordbar:
I did. So that's the other thing. I think the other thing that really helped me out was peer pressure. So I went to a school that was part of a system that was called NODET or National Organization for Development of Exceptional Talents. And that's the system that we have in Iran. That's also an entrance exam for high school students, I think elementary and high school students to get into that system. And once you get in, then you are surrounded by people who are competitive and intense and they want to succeed. So there was a lot of peer pressure. I do remember that year, the class that we had was 17 people. And there were three of us who were fiercely competing with each other. There was this one guy, his name was Sayed Khayeshi and he's now I think an eye surgeon back in Iran. He ranked first in the whole country, almost in every single practice exam that he took.

Quinn:
Oh my God. Oh wait, they ranked the practice ones too?

Dr. Sharif Tabebordbar:
Yeah. You get ranked on all these exams. It's sounds so very stressful. And then I usually ranked second. There were a couple instances that it got flipped, but it was this extremely fierce competition between me and Sayed.

Quinn:
Oh my God.

Dr. Sharif Tabebordbar:
And that really helped me. That pushed me to the edge. I was like, I really want to be the first one right now, so how can I make that happen? But surrounding yourself with people who are competitive and intense can help, as long as it's a healthy competition.

Quinn:
It can be a fine line, certainly at that age. And when the spots are so few, when they're like, it's 10 and it's actually four to five. Oh my God. The fact that the practice tests were ranked and shared along the way, I mean, I definitely would've been somewhere in the six digits and just been like, "Well, that's it guess I'm a baker." And baking's great, but are we helping people? That's incredible.

Quinn:
Wow. So it seems like though your practice and your success there and your trials and tribulations, I feel like there's this whole thing in the past couple years, of trust the science, follow the science and that's impeccable, but there's a... I'm not sure if you've ever seen the movie The Princess Bride, but there's this quote that says, I do not think that word means what you think it means. And it's the idea of we have to remind people what science is. It's not this ultimatum or a threshold that you cross. It's a process where... and I imagine with the work that came before you in your field and that you're doing now, even with your recent advancements, that I have to imagine, and please correct me if I'm wrong, that you expect failure most of the time. I mean, you're going out to prove yourself wrong over and over and over and over. Do I have that wrong?

Dr. Sharif Tabebordbar:
That's usually how it works in pre-clinical studies. So when you do rodent studies or earlier studies. When you get to the point that you get into human clinical trials, there are a lot of... the regulation is much harder. They don't allow you to obviously go into human clinical trials if you don't have the right safety measures, for good reasons, obviously. So when you get to the human clinical trial stage, it's a risk to a certain stage, but there is always risking. So yes, to some extent you have to always prepare for the worst, but be as prepared as possible.

Quinn:
I think about these mRNA vaccines that are incredible. And everyone's like, "Oh, they're great. They're really great." And it's like, we got to put these things in context. I mean, the decades of work that went into them and vaccines along the way, and the research. The human clinical trials of anything are the metaphor, the tip of the iceberg and the rest of the iceberg's just decades of failure and learning and processes along the way. I imagine you didn't just show up on the scene after finishing in the top 10 and just be like, I've got the answer.

Dr. Sharif Tabebordbar:
No, it takes a very long time.

Quinn:
I always describe to folks, I endeavor... I'm a liberal arts major, which in the US is feelings and emotions and ethics and things like that. So flashcards were not my jam. Like I said, I would've finished in a not great place in your exam. But I do really try in this broader generalistic sense, to synthesize all of these different things, out of respect, but also so it's more of a conversation than an interview to try to get in the US, we call a "301", which is not a 401, not a 101 in each of these conversations ahead of time. I've tried really hard to understand the technical description of your work and I am floating in the ether around it. So I think I figured out sort of an analogy, but I wonder if for the people, if you could describe to us in technical terms what it is that you are working on and then I will try to, I don't want to say dumb it down, but make it something that people like me can try to understand, at least the implications of and where we are. Go for it.

Dr. Sharif Tabebordbar:
No, I can definitely try. When folks have specific changes in their DNA, in basically the genetic material that codes for the proteins that make your body, then there would be some specific protein that go missing or they cannot perform the function that they usually perform. So that's when they call it a mutation. There is a change in the DNA that basically results in some sort of defect in the body. And sequencing the human genome, which happened nearly two decades ago, helped to understand what are the cause of each different genetic diseases. What are the genes that are mutated, that are changed, that cause the diseases that we see in the human population, Huntington's disease, cystic fibrosis, Duchenne muscular dystrophy, Tay-Sachs disease, the spinal muscular atrophy. And a lot of these diseases are actually caused by changes in one specific chain, in one specific piece of DNA.

Quinn:
Out of how many pieces?

Dr. Sharif Tabebordbar:
I think it's more than 30,000 protein quoting genes in the body. Research in the last 25, 30 years have shown that if you compensate and restore the healthy copy of that gene, the version of the gene that's not mutated to the cells, to the body, you can actually definitely inhibit the progression of the disease, and in some cases even reverse the symptom. So the earlier that you intervene is going to be better obviously because there is less damage to the body. So the question is now, you know what gene is mutated, you know what gene is broken, you know that if you put it back, it's going to fix it. How do you actually do it? How do you put this gene back in to the body?

Quinn:
To be clear folks, he's not asking me the answer to the question. That's not how this goes. This is a rhetorical question.

Dr. Sharif Tabebordbar:
No, I'm just trying to elaborate in a non-technical term.

Quinn:
Don't worry, he's got it.

Dr. Sharif Tabebordbar:
No worries. And the best way that scientists have found to do this is actually to use viruses, but a specific type of viruses, viruses that are not pathogenic. So specifically after the pandemic, whenever we hear the word virus, everybody's like, ooh, something bad is going to happen. But there are actually a lot of viruses that we encounter on a daily basis. We get infected with what we never know, because they're not associated with disease. They're endemic in the human population. We all have seen it at some point in our life, but they're not causing disease. That's why we don't really know about them. One of those viruses is called adeno-associated virus viruses or AAV. And it's extremely a small virus that can get into the bloodstream, can get into different tissues in the body, mainly towards the liver. But we usually don't know about it, because again, you don't get sick unless you have some adenovirus or herpes infection.

Dr. Sharif Tabebordbar:
It could potentially be a very exciting tool. Because it has the capability to get into human tissues. It's not causing disease. How can we use this for delivering these genes or for basically doing gene therapy? And the way researchers have developed this tool is that they have taken out the indigenous genes for the virus. So basically whatever that virus was quoting itself and replaced it with the healthy copy of the gene that they would like to deliver to the body.

Dr. Sharif Tabebordbar:
So basically what you're doing is that you're using the shell of the virus, what we call the capsid of the virus, the surface of it, as a FedEx truck to deliver the genes to the tissues that we want. We basically load it up with the healthy copy of the gene, inject it into blood. And then we need to give it the exact address of, okay, you need to take this gene to the muscle tissue. You need to take this gene to the heart. You need to take this gene to the lung. And I think the most important bottleneck during the last two decades was giving the right address to this FedEx machine.

Quinn:
Wonder if you can describe that a little bit, because there was a hurdle for quite a while, where the side effects were, to put it lightly, detrimental. Could you talk about that? So again, people can understand how difficult it's been to get to where we are.

Dr. Sharif Tabebordbar:
Yes, definitely. The viruses that are normally present in nature, we call them naturally occurring viruses. So these are the ones that have evolved in nature for many, many years. And those viruses, then they enter the bloodstream, different animal models, including humans. They mainly get into the liver tissue. And part of the reason is that liver is responsible for removing whatever foreign that gets into your body. But at the same time, they have been evolved in nature to interact with liver cells or hepatocytes more. And the very first generation of gene therapies just use these naturally occurring capsids. Actually almost every gene therapy that's in clinical trials right now are using naturally occurring capsids. And for that a specific reason, most of these drugs after injection into the bloodstream, almost 90% of them will end up into liver.

Dr. Sharif Tabebordbar:
And then there would be about 10% that goes into other tissues, but that definitely overloads the liver. That would introduce an extremely high dose of virus. That's a massive viral infection into liver. And that has unfortunately resulted in a few instances of serious adverse effects in one specific trial for pediatric disease and named [inaudible 00:29:38] muscular myopathy. There have been four deaths after injection of the gene therapy, out of 17 patients or 18 patients that got injected, which has been really tragic and dramatic. And the main reason for that has been associated with liver toxicity because 90% of it ends up in the liver, then you need to inject an extremely high amount. So the remaining 10% is essentially enough to give you therapeutic efficacy. But then when you get 90% of it into the liver, it causes liver toxicity in these kids.

Dr. Sharif Tabebordbar:
The bottleneck and major hurdle at this point for gene therapy is not therapeutic efficacy. We know that if you get enough of these drugs into the right tissue, it's going to fix the problem. The problem is how do you do it safely? How do you do it in a way that you're not going to have serious adverse effect? And a lot of this is associated with the dose of the virus they've injected. The higher the dose of the virus, the higher the chances of toxicity.

Dr. Sharif Tabebordbar:
Other than liver toxicity, there are some other aspects of the immune system, specifically they're called complement activation. It gets technical. But you basically activate the immune system in ways that could result not only in liver toxicity, but also in kidney injury and other associated effects. So the main point that FDA is really concerned about at this point, a lot of gene therapy companies are struggling with is how can we lower the dose? How can we make gene therapy safer? And one way to do this is obviously to give a better address to these viruses that we use for delivering [inaudible 00:31:24], to tell them you should not go into the liver, you should go to the tissue that we would like you to, but how do you do that?

Quinn:
Because that seems obvious. So why wouldn't we have done that before? Is that technological?

Dr. Sharif Tabebordbar:
It's mainly technological advances, and also being able to do hight throughput experiments. Because sequencing is getting cheaper and cheaper every day. And the ability for us to synthesize DNA fragments that we can use for our experiments at a much higher pace for cheaper. We can actually do thousands and thousands of experiments in one experiment, because we can pull all of them together. So what could have taken maybe a couple of years to do, it could take a couple of months. And it also is the fact that because now we are at a stage that gene therapy has a lot of promise, a lot of people from different fields of science have taken interest into it. And that adds a lot of value because they bring in new expertise. People sure make high throughput libraries now they're interested in gene therapy and they bring their own set of a skillset to this. And then when you put all of these sets together, science advances much faster.

Quinn:
Do you guys need podcasters because I know a guy.

Dr. Sharif Tabebordbar:
Yeah. That would certainly help.

Quinn:
Sure. Interesting. Okay. So it's a combination of technological because we really just sequenced the genome. It was really not that long ago. And the cost structure for doing that has come down. The ability to do, like you said, these immense libraries to do multiple experiences at a time. And then bringing in interdisciplinary folks who can ask better questions and bring both more and different perspectives. We see this all the time. It's not an insult to some specific field. It's just that more varied thought tends to so span the options of how to move forward. Because like you said, you know it works. It's just the mechanism for getting there wasn't doing it, and you didn't know how to say, drop the package at this house, which Amazon knows how to do at my house very well.

Quinn:
I think about the analogy of... and please again, correct me if I'm wrong, because that's my entire life and I actually enjoy it. But I think about the analogy of, again, going back to those mRNA vaccines, which among the most incredible human achievements in both their efficacy and the timeliness obviously, and another thing that really only possible in 2020, 2021 with how far we've come. And so for many folks. they're very new and they're exotic, which is part of the success and part of the issues with the understanding around them. But in reality, they've been in development for decades and we know they could work. But I think about Dr. Katalin Karikó and she cracked one of those hurdles, which is making sure the body doesn't freak out with inflammation when we use them. And that unlocked our ability to actually use them. Is that analogous to your contribution to the field to saying, oh, now we know how to direct this to a specific address or am I completely off base, which is entirely possible?

Dr. Sharif Tabebordbar:
No, you're not off at all. For mRNA vaccines, there have been years and years of different groups working on showing how to make modified RNA, how to basically optimize it in a way that it's safe in delivering into cells and into body in general. Can we use that for gene therapy? And I think through those experiences, folks actually understood that mRNA could be really good tools for actually inducing immune response, for producing a protein for a very short amount of time. That immune system sees it, and then you can induce massive immune response. I think if the pandemic did not happen, there was a chance that we could not unlock the potential of mRNA for generating vaccines because you need a very large number of people to do these type of chemical trials. But what we see right now is not that we suddenly come up with the idea of using mRNA to make vaccines. It was 20 years of work that went into it.

Dr. Sharif Tabebordbar:
And it's the exact same thing for our case. We learned so much from the work of people who have studied fundamentals of AAV biology. How the capsid is formed. What is the crystal structure of the capsid? How can we modify it in a way that we can still make virus because we are changing the surface of the capsid. We are evolving these capsid in a way that we want to give it new instructions. How would we able to do this while not preserving the basic biology of the virus?

Dr. Sharif Tabebordbar:
Right. So what we did was learning from all these basic aspects of biology and bringing new sets of technologies into it, looking at it from a different perspective that what could be the reason that previous attempts for making this happen have not been as successful? How can we change? And that took us a few years too. I think it took about two to four years to come up with this technology that we can actually implement to specifically find those viruses or engineer those viruses to get into the muscle tissue. But having the knowledge from the research that has been done previously was definitely essential.

Quinn:
So it's interesting to me, because again, these two situations, the work you're doing and for instance, these COVID-19 mRNA vaccines. Like you said, they both stand on decades of research and a lot of left turns and incredible well intended folks working their entire careers to make these things work. And on the one hand going, I know it works. I don't know how to get us there right. Safely, at least without hurting people. And I always think about chemotherapy and things like this. These blunt instruments we have, the best answers we have. But you made a point that we might not be where we are with these mRNA vaccines, now going, holy shit, what else can these things do if the end of people who needed them wasn't every person on the planet suddenly?

Dr. Sharif Tabebordbar:
Yeah.

Quinn:
But rare muscle diseases haven't had that moment, thankfully, but you've still made quite the jump. And I think about, and I read a little bit about, at one point you were finally able, after years of going, what the hell is going on with my dad? He didn't induce this in any way knowingly and the environment around him, again, unlike New Delhi or LA how it used to be, whatever it might be, what's going on and much less, how can I treat him? But at some point on a day you were actually finally able to sequence his genome. What happened that day? What surprised you? What scared you and how has that contributed to where you are now?

Dr. Sharif Tabebordbar:
Over the years, that has always been a question in my head. We know that it's a progressive muscle condition. There was a lot of information out there that this could be associated with some sort of muscular dystrophy, but there was no formal diagnosis. And whenever I talked with my dad, I was like, "Okay, I think we need to get to the bottom of this. We need to see what exactly this is. We know that it's a degenerative muscle condition. We don't know what exactly it is." And his answer mainly was, "Well, why would it matter if there is no cure?" It's like, well, it does matter because then if there is a potential treatment, then you could potentially get enrolled in clinical trials. And I am personally in the camp of people who would like to have more than less information.

Dr. Sharif Tabebordbar:
The other part of it was I think also selfish that I wanted to see if I have it or not. We did perform sequencing. We started with a small subset of genes and we did not find any mutation in those genes. Most of the genes that were involved in genetic muscle disease. And that was the point that I really understood where we stand on genetic diagnosis because a lot of folks do have... they're in the same boat as my dad. They have symptoms, but they just can't figure out what it is. They keep going to different doctors that we can sequence the whole genome now, but how can you pinpoint that one specific nucleotide change that gets associated with your disease. There could be multiple different changes in different genes that may or may not have an effect on the health of the human body. But pinpointing it to that specific diseases is still a challenge. A lot of people deal with that.

Dr. Sharif Tabebordbar:
So we did sequence basically every single protein coating gene in his body, and we still did not find anything. And I was like, "Wait, this does not make any sense. What is going on here?" So I started talking to people who, specifically at Harvard who were more working on diagnosing genetic diseases with the focus on genetic muscles diseases. I have a very good friend [inaudible 00:40:18] who's a assistant professor at Yale right now. And he mentioned that, have you looked at repetitive areas in the genome? There are some parts of the genome that you have multiple repeats of the same sequence. And with the current technologies that we sequence the genome, you can't really find out if there is something wrong with those repetitive regions.

Quinn:
Sorry. Is repetition usually instructive of something going wrong or is that just something that's normal?

Dr. Sharif Tabebordbar:
No, it's normal. It's normally present in the human genome.

Quinn:
Okay. So he said check out the repetitions.

Dr. Sharif Tabebordbar:
Yeah. So basically if there is a change in those repetitive regions, we can't really pick it up by doing sequencing because it gets complicated, but because of the way the sequencing is done.

Quinn:
Sure.

Dr. Sharif Tabebordbar:
And they said, "Well, there are other ways that you can change these areas, but then you need to do specific experiments." And he introduced me to Peter Jones at University of Nevada who actually does a lot of these type of analysis for FSHD particularly. When he analyzed the DNA for my father's sample, he called me up and said, "Yeah, it's FSHD type 1." And his second question was, do you know what that means? And I said, yes. He said, yeah, you have 50% chance of having this disease. Do you want to get tested? And my immediate answer was, yes, I want to get tested.

Quinn:
Because you want more information.

Dr. Sharif Tabebordbar:
Yeah. That's why it happened. I had to communicate that to my father, that we finally have an answer to what your condition is. The journey of diagnosis ended at that point.

Quinn:
How long between your new friend, Peter, who finally was able to diagnose your father... When he said what the disease was, were you aware of it or was it entirely new to you?

Dr. Sharif Tabebordbar:
No, I knew what FSHD is.

Quinn:
Okay.

Dr. Sharif Tabebordbar:
That was something that we thought about, for sure, as a potential.

Quinn:
How long in between him helping you understand what it was to you discovering the answer to whether you would get it or not; hours, days, weeks?

Dr. Sharif Tabebordbar:
I think two or three weeks. So I had to send a sample to him and then he needed to analyze it. And he gave me a call and I completely remember that day. He told me that you are the luckiest guy among the unluckiest. I was what does that even mean? He said, "Well, you inherited that gene from your father, but what happened was that," again, this gets really technical, but when the germ cells are being generated, there is this whole phenomenon of recombination that happens, that the very last part of that toxic gene that I inherited was recombined with a different chromosome that didn't have that point. And he said that this doesn't happen often. I have not seen it before, but you've got the gene, you just got a truncated version of that gene. And that's why you're not sick. And I was like, "What are the chances?"

Quinn:
I mean, quite literally, I can't even fathom what the chances might be for... like you said, you're the luckiest of the unlucky. If this is an incredibly rare thing that it took decades to diagnose in the first place and experts who had no idea. And the first test showed nothing, and then you just happen to not get it. I mean, it's incredible. So what did that mean for your father's condition and treatment? Are there any answers for him today?

Dr. Sharif Tabebordbar:
I think what really changed was the fact that I knew where to focus on. Before that, my main focus was developing a specific technology that help the genetic muscle disease community as a whole. And I think the advancement that we made by develop my AAV is going to change the whole field. It's going to affect every single genetic muscle disease treatment. And I would like to focus on developing these type of technologies going forward, developing better regulatory elements that express the gene in the muscle or addressing other major challenges. But at the same time, I know that I really want to figure out how to treat the [inaudible 00:44:39]. So I want to put a lot of focus, a lot of effort into first, understanding this better, second, developing effective treatments for people who have this type of disease, because I have seen firsthand how it can affect their life.

Quinn:
And now you have moved on to doing that more specifically. You've left the Harvard, MIT combo, the broad, to head out to sunny San Diego. So what does that mean? When were you like, this is the time to start actually applying this?

Dr. Sharif Tabebordbar:
I think when we developed the technology, it was quite striking to see how much more effective we are compared to this natural occurring capsids. We can go with doses 10 to 100 times lower compared to what people are using in the clinic. And that could definitely solve the issue for toxicity, at least in the pre-clinical studies. We may see unforeseen incidents happening in the clinic and we need to be prepared for that. But there is a very good chance. I think the time point that made me make that decision was when we saw the reaction from the community. When we saw how muscle disease researchers, gene therapy researchers are reacting to our finding. It was not ignored. It was something that people appreciated. People said that this is it. This has a really good chance of solving this problem.

Dr. Sharif Tabebordbar:
And I personally was in the [inaudible 00:46:10] that I wanted to go into academia and I wanted to start the research lab and I wanted to do academic research. But when that happened, it occurred to me, this is your chance. If you want to really actually do it, you have to go all in. You have to make sure that you put all your effort and energy in making sure that this goes right. This is done properly and actually get some medicines for these patients. So I think that was the points that gave me the confidence that I need to make this move. It was getting out of my comfort zone. It was doing something that I had not done before, but I think that was the right decision. I'm really happy that I made that change.

Dr. Sharif Tabebordbar:
We have started a company now on the same technology. We are building a team. We are moving technology forward towards clinic as fast as possible. It's really fun. It's a fun ride to see it go through, and then think about the questions of what would happen when we inject our first patient. That is quite exciting.

Quinn:
Before I make another analogy to Michael Owen signing with Real Madrid later in his career to test new waters, I can understand to some folks in the community, how this would seem like a natural evolution of both your career in the field. But at the same time, we talk a lot here about things that are... Again, if mRNA was like, "Hey, guess what? It's everybody." I know you've got a couple of pharmaceutical companies making a lot of money off that, and they've made huge contributions, of course. And they made those contributions with a lot of federal backing. But there's a lot of areas, rare cancers, childhood cancers, diseases like this one, even though there's a wealth of diseases and genetic diseases and muscle dystrophy diseases, relative to something like heart disease. They're much smaller and they don't get the funding.

Quinn:
America has, for some insane reason, made it very difficult to get technologies out of the lab and commercialized because often there's just not enough profit behind that. So what you're doing is actually pretty fundamental and pretty important because there's just not a lot of that in a field like this, where we see, oh shit, we might be able to actually do this and make a huge difference pretty quickly to, again, a relatively smaller group of folks, but a group of folks who are suffering nonetheless. And again, we just sequenced this thing. We've just made these strides. You've just been able to look at it more deeply and see yes, we can see the whole genome, but where is the broken part or where is the repetitive part in broken part? This is actually quite a big moment for the field.

Dr. Sharif Tabebordbar:
It is indeed. I think it changes the game a little bit, because we know that there is definitely path forward for having safe and effective products. It's easier to justify dedicating funding. It's easier to go out there and say that, hey, look, we have shown that this is possible in these animal models at a very low dose and we have a very good chance of making it happen in humans. So I hope at least that it makes it easier for allocating more resources for researching gene therapy for genetic muscle disease.

Quinn:
I mean, you would think if you finished top five among a million plus students taking these practice tests and these tests and flip flapping first and second, that this is where you would end up as someone who transparently stands on the shoulder of so many decades of research while you were growing up and watching your dad deal with this progressive disease. But at the same time, it's got to feel pretty incredible to feel like now I can actually make this impact to the people who are suffering with it. The people who like you said like your father didn't do anything to induce this voluntarily in any way.

Dr. Sharif Tabebordbar:
Yeah. You're very kind to me, but yes, it does feel incredible. It is what I have worked for many, many years. And the fact that we see there is a path forward now. The fact that I can actually now think about you're going to be injecting patients sometime soon, it gives me chills. It gives me a lot of excitement. And I keep thinking about it that we are actually going to see the impact of the drugs that we're developing in patient's lives. There could be people who may not need to sit on wheelchairs anymore. There could be kids who can live a normal life, play with their classmates and with their friends instead of being on a ventilator. So that is really incredible. That what makes me get out of the bed every day.

Quinn:
It's incredible. I mean, these are the stories we hope to tell here to both, again, shine a light on your work, but also to inspire and encourage other folks who are feeling adrift in some ways or feeling challenged or feeling intimately touched again by something like this who are going, what can I do? And you've chased a pretty direct line trying to solve this for yourself, for your father and your family and all the other folks, again, who are dealing with this pretty incredible.

Dr. Sharif Tabebordbar:
The point that I try to communicate to folks quite often is that when you have unfortunate events happening in your life, there are a few ways that it can go. You can really feel bad and say that well, life is unfair and I can't do anything about it and give up. Or you can actually think about it. This is a challenge. This can give my life a mission. This can make me understand that what do I want to do in my life? And if you go the second way, and if you find a specific way that you can use what you're good at, your talent and what you're passionate about and marry it with the mission of your life, then that's going to be key. I think all the very successful people that I've seen when I was in Boston or the people who I have encountered in my network, they're people who what they're really passionate about in life fit what they're really good at. And identifying those two are key.

Dr. Sharif Tabebordbar:
I think finding out where is your talent, because everybody's good at something. I'm terrible in music. I'm not good in art, but I'm a good scientist. I know how to solve puzzles. I know how to troubleshoot experiments. And identifying that talent, I think is as important as what do I want to do with my life. And then if you can put them together, then that's going to be the recipe for success. I think that could help people live a happier life to basically give it a positive esteem. This is what my PhD advisor [inaudible 00:52:49] has always told me, that there's going to be days that you would feel really down, that you have big, big failures for experiments that you've worked for so long, but always think about, how can I put a positive experience? How can I actually use this to solve a new challenge, to basically learn from it and leverage it to do something good and meaningful? Having that mindset is not easy, but it makes life much easier.

Quinn:
I love that. I mean, again, if anything encapsulates what we're trying to do here is that, it's help people answer that question and point them at the direction, because frankly our challenges and our opportunities are so many and so varied and often, so globally consequential or intimately consequential, it frankly doesn't matter what you're good at, because we need all of it. And every bit of it can contribute, whether you're an artist or you're good at music, or you're a scientist who can solve puzzles or me, I can plug in a microphone and convince people to come talk to me for a little while. It does matter and hopefully it'll move the needle for someone somewhere, if not many of us, especially those of us, again, who are born with something that is nearly undetectable for three decades, but they didn't instigate in any way, but they deserve to benefit from whatever science we can achieve along the way. So I appreciate all of your efforts and your time. Certainly.

Dr. Sharif Tabebordbar:
Thank you.

Quinn:
I'm going to ask you one last question before we get you out of here, total pivot. Doctor, as if you had time for anything like this, but what is a book you've read in the past year or so that's opened your mind to maybe a topic you hadn't considered before, or it's actually changed your thinking in some way. And we've got a whole list of recommendations we throw up on Bookshop for everybody I would be fascinated to hear.

Dr. Sharif Tabebordbar:
I think there are a couple of books that comes to my mind. One of them is Never Split the Difference by Chris Voss. And the other one is obviously Becoming by Michelle Obama.

Quinn:
I mean, do you know she read the audio book? So I set it up. I think my wife understood, but also chagrinned was... I would make it so Michelle Obama was the first thing I heard in the morning and then the last thing I heard at night and it was great. It was a really good period for me. Tell me about Never Split the Difference briefly.

Dr. Sharif Tabebordbar:
Never Split the Difference is a book that talks about how to negotiate and basically teaches you that everyday life is a negotiation. It's just how to think about interacting with people. What kind of perspective you have when you talk to other individuals and how to look at it from their perspective. How to answer questions... If you want to ask for something, how can you ask it in a way that takes other people's emotions into consideration, and basically enables you to come to agreements with people.

Dr. Sharif Tabebordbar:
The way, the tone that you have your conversations, have your requests or how do you answer these questions? Chris Voss was a FBI negotiator for hostages internationally. And it's basically from years of his experience. That has made a big impact in how I communicate with people and how I negotiate. But Becoming obviously was also another book that I learned everything is possible if you do it the right way, you really want to do it, and you have a support structure in front of you. The whole story of Obama's coming from the South Side of Chicago to the White House and how it happens, being ordinary people, not privileged individuals who worked their way up, that inspires me, obviously.

Quinn:
I love it. I'm going to reread Becoming, I'm going to sit down at night and read, Never Split the Difference to my six year old. And we're going to find a way forward and I'm very excited.

Dr. Sharif Tabebordbar:
There you go.

Quinn:
So thank you negotiating with terrorists. Sharif, I cannot thank you enough for your time today and your efforts and all of your work. I'm so excited to see it come to fruition, though I imagine there will be more obstacles and failures along the way, but I imagine that'll keep you pushing in that direction. Didn't get a lot of time to talk about Michael Owen and Liverpool, which I'm sure everybody's very upset about. I will come visit you and we'll have a whole separate conversation about that. I'm sure we could go on forever. The man who plays top 10 in Iran and the youngest player to win the Golden Boot. The analogies are many. Sharif, thank you so much. I really appreciate it.

Dr. Sharif Tabebordbar:
Thank you. It was a lot of fun. Thanks so much. And definitely let me know when you come to San Diego.

Quinn:
Absolutely. Thanks to our incredible guest today and thanks to all of you for tuning in. We hope this episode has made your commute or awesome workout or dishwashing or fucking dog walking late at night that much more pleasant. As a reminder, please subscribe to our free email newsletter at importantnotimportant.com. It is all the news most vital to our survival as a species.

Brian:
And you can follow us all over the internet. You can find us on Twitter @Importantnotimp.

Quinn:
That's just so weird.

Brian:
Also on Facebook and Instagram at Important, Not Important, Pinterest and Tumblr, the same thing. So check us out, follow us, share us, like us, you know the deal. And please subscribe to our show wherever you listen to things like this. And if you're really fucking awesome, rate us on Apple Podcast. Keep the lights on. Thanks. Please, and you can find the show notes from today right in your little podcast player and at our website importantnotimportant.com.

Quinn:
Thanks to the very awesome Tim Blane for our jamming music, to all of you for listening. And finally, most importantly to our moms for making us. Have a great day.

Brian:
Thanks guys.

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