AATS- Keynote Speaker Dr. Rothblatt: Doing the Impossible... Time and Again 5/14/2022

Thank you so much. Thank you, Sam. Wow, thank you so much, Dr. Keshavjee, for that beautiful introduction. And on the topic of impossible, you could probably knock me over with a feather right now because I would have never thought it was possible to appear at a podium a few moments after one of my great heroes, Dr. Joel Cooper. So, that alone is amazing for somebody who has studied lung transplantation for so many years and been in such awe of what Dr. Cooper and the Toronto General Hospital team achieved, to be at this podium. It's like, 'Wow, I would have thought that was impossible.' Well, I think the title of the talk that I'm giving today is a little bit of a misnomer in that there's nothing that I really try to undertake which is actually, in my view, impossible. In fact, when proposals come forward or ideas are vetted that are impossible, I issue going after those things that are truly impossible. I try to really limit myself to just going after projects that are, in fact, possible. Now, many things seem to be impossible, but it's just that they seem impossible. They're really possible. And I always try to revert to basically just physics and facts and to respect physics and facts. And if the physics and facts are supportive of something being achieved, even if 99 out of 100 people think it's impossible, I don't allow myself to be dissuaded by that. Now my favorite books to read when I was growing up were biographies about people who generally achieve things that people thought were impossible, but they knew very well that they weren't impossible. And examples of this are the inventions of Thomas Edison, the flights of Amelia Earhart, the discoveries of Madame Curie. All of these biographies gave me tremendous encouragement and confidence that everybody could think something was impossible, but if the facts and the physics were on your side, it was in fact not impossible at all and you could change the world in a very positive way. One of the great quotes that inspire me is this quote here from Orville Wright that you see on the screen, which is, 'If we all worked on the assumption that what is accepted as true is really true, then there would be little hope of advance.' So again, we have to be willing to question authority, to challenge the assumptions. And there's a kind of a nice sub quote there at the bottom from Chuck Yeager that of course one is going to have setbacks, but you back up, don't give up.

I started my career with communications law and MBA degrees from UCLA as Dr. Keshavjee noted, and then a PhD in xenotransplantation ethics from the UK. While my thesis advisor was England's leading medical ethicist, it was a recommendation from Sir John Vane that got me into the PhD program. I wanted to do a dissertation about xenotransplantation ethics, and that sounded pretty far out to everybody back in the 1990s. But Sir John, whose Nobel Prize was for discovering the mechanism of action of the COX-2 inhibitors, carried a great deal of weight, and I felt very proud that he added my dissertation, shown there on the far left, to his bookshelf containing those of his other students. Before moving into medical ethics, I had engineered new kinds of satellite communication systems. Each time, my goal was to do something with satellites that had never been done before, and almost by definition that most people thought was impossible. For example, in the 1980s, I showed with our GEOS Star satellite system that it was possible to send texts and messages from handheld transceivers to satellites 1/6 of the way all the way to the moon. In the 1990s, I used new kinds of satellites with spot beams to send television programming between studios in Latin America and hotel television antennas throughout the United States and South America. This was also thought to be not only technically challenging, but actually illegal because you were kind of broadcasting propaganda or programming into other countries' sovereignties. But I found a wormhole through all of these different legal regulations, and I showed that we weren't harming anyone. And as a result, my PanAmSat satellite system is today part and parcel of the largest network of global satellite communication systems.

When I next tried to use satellites to send dozens of channels of digital audio programming direct to vehicles with no visible antenna at all, nothing to point at the satellite, which is how SiriusXM would work, almost nobody believed me. Not the people in the Federal Communications Commission, not the people who would finance it, not the radio broadcasting industry, not even the person who followed me as CEO of SiriusXM. At the beginning, nobody thought that this would work. Our satellites would be about a tenth of the way to the moon and thus 100 times further than most space operations. But they would send high-speed data to non-steerable antennas on cars and aircraft. This could be done by using a new digital coding technique that would allow us to achieve signal gain digitally instead of just mechanically. This also had never been done before. And it was illegal to implement any of this without Federal Communications Commission approval. Furthermore, there were no spare frequencies to use. All the radio frequencies have been gobbled up by other things ranging from VHF television to garage door openers. And finally, can you imagine trying to finance such a billion-dollar system because the moment that you launch it, there's nobody that has anything to listen to your signals because it never existed before. So, try to tell Wall Street why you're going to have subscribers or listeners. They say, 'Why would somebody buy something to subscribe to something that doesn't yet exist?' Of course, it turned out to be a very great success with tens of millions of subscribers here in the United States. And it's in no small part to the magnetic attraction of this very famous personality named Howard Stern. To this day, I find it amazing that even though our current company, United Therapeutics, the company I started to save the life of my daughter and also helped save the lives of thousands of other patients, despite that fact, to this day, I get more people coming up to me and saying, 'Thank goodness, Martine, for Sirius XM radio. That saves my life each and every day.'

Anyway, it looks like it saved Howard Stern's life, too. I'm going to try to click this video on. This is an exciting time. I mean, you invented this whole deal and here we are. We're enjoying it. And as a broadcaster, I said this to you in the hall and I'll say it to you on the air. I thank you. If you hadn't invented this medium, I mean, the fact that I'm getting to look at the This is like me meeting Marconi. If you hadn't invented this medium, I would have been out of the radio business. It better when you said, 'This is like meeting Martin Luther King.' Oh, that's true. That's a whole other thing. But it's true. Did you say that? That's a whole other thing. But, it's true. Did you say that? I did. Where did you get that? I got to tell you something. I am so grateful that you invented this medium. I mean, I am flourishing here and also able to be part of something from the ground up. But, I mean, this has got to be nuts. This was a dream in your head and now you're seeing it all come together. So, as you can see from that video, you know, sometimes you can make a medicine that saves thousands of people's lives, but, you know, what really is so transformative is something like a satellite communications technology. Well, sometimes it's personal things, not professional things, that seem impossible, although in fact, they turn out not to be. And as you'll probably be able to tell from this next video clip, I felt pretty nervous up on stage and what you'll see in a moment at the Forbes Women's Forum. I felt pretty nervous because for the first 35 years of my life, I had lived very much as a man. Nevertheless, I knew in my soul every bit as much as I knew that I was a turner of the technologically impossible into the possible, that I knew just as clearly as that that I was a transgendered woman and not a cisgender man. I could no more not invent, I could no more not innovate, I could no more not build, than I could not come out as the female person that I truly was. After getting permission of over 40 years, Bina, and our four children, and despite getting resistance and even strong discouragement from my aerospace industry colleagues, I nevertheless transitioned from Martin to Martine in the full light of day. And here is how the NBC medical correspondent, Dr. Nancy Snyderman, saw it all.

31, almost 32.

Los Angeles kids who fell in love with each other, and Martine, when you met, you were not Martine.

Do you want to explain who you were?

No, I'm a transgender woman and so when we met and were married, we were a heterosexual couple. But we loved each other's souls and during the course of our 32 years, we've transitioned, becoming a transgender couple. And along the course of the way, we've had four children, now four grandchildren, four Labradoodles and a beagle, and Bina has about a couple dozen chickens. And so that's the story.

Yeah, she's a good journalist. She knows how to work the crowd. And she worked me, too. About the same time as my transitioning, our youngest daughter, named Jenny, was diagnosed with primary pulmonary hypertension, today called pulmonary arterial hypertension. Her right heart had dilated to about twice its normal size, and her pulmonary artery pressures were north of 80 mm of mercury. I had just seen the film called Lorenzo's Oil with Nick Nolte, in which a non-medical father tries to develop a cure to help his son's deadly medical condition. I tried to do the same thing, and fortunately, we have had a vastly more successful result. We converted Sir John Vane's invention of a continuously parenterally delivered prostacyclin analog into an ambulatory subcutaneous drug, and then turned that into an inhaled drug, and then finally into a pill. As a result, Jenny, our daughter, and thousands of other patients have never had to use the kind of intravenous pump that was previously used, and today she is in her 30s, working at United Therapeutics to help develop better medicines for other patients.

We are all aware that for most pulmonary hypertension patients, the existing medicines cannot forever hold back the progression of their disease, and that a need for better medicines, or a lung transplant cure, is always hanging above them like a Damocles sword. And it is this quest for a lung transplant cure that I've been working on since my PhD in xenotransplantation and that brought me into partnership with our August president, Dr. Shaf Keshavjee. Now, when I started in this field, I visited most of the fewer than 50 doctors who were then being recommended by the Pulmonary Hypertension Association to people anywhere in the US who had this disease. Just 50 doctors were treating the condition. And I asked them what was needed to get a medicine approved in time to save my daughter Jenny's life. While several said that more money for research was needed, I think the wisest answers were to get more people interested in the field because today nobody wants to treat it since all the patients rapidly die. 20 years later, there are now 5,000 patients treating Pulmonary Hypertension in North America, not 50. And there are 50,000 patients living with Pulmonary Hypertension, not 2,000 dying from it. There are now over 10 approved medicines to treat the condition, four from our company and six from several other companies, plus 20 companies are working to develop new medicines for Pulmonary Hypertension. So, I think people are now interested in this condition, but I don't feel that I can say mission accomplished because the disease usually progresses through all of these different approved therapies, and still to this day, there is only a lung transplant as an absolute cure for pulmonary hypertension. In this slide before you, you see just one story of our parenteral medicine, Remodulin, and I think it's like a paradigm of so many things that so many of you may be working on. And what seems to be so impossible, if you just chisel away at it, it becomes quite possible. For example, the molecule that we have developed into Remodulin was at that time in the freezer at Glaxo Welcome. And they saw no business reason whatsoever to develop it. They agreed to license it to me for $25,000, which is probably what they spend on their cafeteria costs in a day, because they thought there was absolutely no possibility that this drug would ever be worth anything at all. Part of the reason that they thought there was no hope for this drug is there was no way to deliver a drug with a 45-minute half-life, except through a very complicated parenteral delivery system. So, we did step by step. We redesigned an insulin pump to deliver this medicine. That worked perfectly fine. We found an obscure professor at the University of Illinois to develop a synthesis with which all the great chemists at Glaxo and Upjohn said there was no way to commercially synthesize this molecule in a way that could pass muster with the FDA for good manufacturing. And then, finally, as noted, we just follow a mantra of approve and then improve. In other words, get something that's good, and then make it better. Don't hold something off until you have the perfect solution. Today, this molecule has paid just in royalties to Glaxo over a billion dollars. And continues to generate well more than that amount of money year after year, but I think what's most important are the thousands of patients' lives that have been saved. And of course, to me personally, our own beautiful daughter, who rather than choosing to go off and just enjoy her life, which she'd have every right to do, she says, 'I want to enjoy my life, but I'll enjoy it the most if I'm helping other people to develop medicines to help their lives.'

In 2013, I was elected to the American Philosophical Society, a very wonderful organization that dates back to Thomas Jefferson, Benjamin Franklin, Benjamin Rush. And I gave a speech at the society where I described an approach to developing xenotransplants, xenografts, xeno lungs, and whatnot. And I shared a detailed schedule back there in 2013 of how we could accomplish the first xenotransplant by 2020. Thanks to our, and it was really met with, I'd say, pleasant disbelief by everybody in the room, except for one person. That was Dr. Tom Starzl, shown here next to me. He said, 'Martine, this is possible, and the best way for you to do it is to purchase this small company called Revivicor that the University of Pittsburgh Medical Center was funding, but due to bureaucratic stuff within UPMC, they didn't want to fund it anymore. So, they were going to go bankrupt. And if you fund this company and you work with them, I believe that you'll be able to achieve the dream you described to us.' The gene by gene birth and test method that I described at the APS has been pursued during the rest of the 2010s with discipline and determination. And along the way, I shifted to what I thought was a better approach for the lung than xenotransplantation, but kept using xenotransplantation for the kidney and the heart. And now, as you heard from the great presentation by the wonderful Dr. Bart Griffith this morning, just 2 years past my original forecast date, we accomplished the world's first successful transplant of a 10-gene modified xeno heart into a man and saving his life, Dr. David Bennett Sr. So, there's Bart and there's the patient. This all seems so completely impossible to so many. And there was a joke, as I'm sure most people in this room have heard, that xenotransplantation will be the future of transplantation and it will always be the future of transplantation. I think Dr. Griffith turned that very nicely on its head in his keynote remarks this morning. But I actually think that xenotransplantation will not always be the future of transplant for two reasons. One is the reason that Dr. Griffith explained this morning, that we're doing it now. It's been done. It's been proven. The graft did not reject. There are additional non-living xeno kidney grafts done by Dr. Montgomery at the University of Maryland, Dr. Jamie Lock at the University of Alabama. Things are being queued up to do clinical trials. So, I don't think it's going to be in the future because I think it's right now. But, the second reason is I think that we are at the cusp of even greater technologies, even more beneficent technologies to create an unlimited supply of transplantable thoracic and abdominal organs. And I'll talk a bit about that in a few minutes. I had a couple of videos here about the xeno heart transplant, but I'm sure Dr. Griffith really covered all of this much better. So, I'm going to kind of skip through these xeno heart videos and move on to something which I thought was truly exciting. And again, that seems so impossible to so many.

When I travel around and I speak to the different physicians who are treating patients with pulmonary hypertension, one of them that I met with in Texas was Dr. Adani Frost. And she said to me, 'Martine, the fastest, best way that you could expand the supply of transplantable lungs to help the patients with pulmonary hypertension is to go see Dr. Shaf Keshavjee at Toronto General Hospital.' And whenever I hear Toronto General Hospital, I kind of get the shivers. It's like, 'Wow, Mecca.' So, I went up there and I met with Dr. Keshavjee. Dr. Keshavjee showed me all of the data and the proof of his amazing innovation with lungs, doing things that people thought were impossible. For example, keeping a lung outside of a donor body for over 8, 9, 10 hours, in fact, up to 15, 20 and more hours because of having an EVLP circuit in the middle of that period of time. So, Dr. Keshavjee explained to me that the EVLP technology could reach so many more people if we provided it as a centralized service, so that every hospital didn't have to set up their own technical expertise. And with a centralized service, we could bring into this centralized service lungs that were so marginal that nobody was willing to transplant them and provide an opportunity under EVLP for physicians throughout North America and especially the United States, to have an extended opportunity to assess and evaluate the lung. In addition to that, we would need to build out a high-speed data network, so that transplant teams anywhere in North America could direct our technicians in examining an ex vivo lung, a lung living outside of the body under the glass dome of an EVLP chamber. To the people here at the American Association of Thoracic Society, I'm sure this is sort of of course. But to like 99% of the people in the world, this is pure science fiction, that you are keeping an organ, you're flying an organ from a donor. The organ nobody wants to transplant. Everybody's had an hour to look at it. 'Nah, we don't really want it.' You fly it for hours, drive it, you get to this centralized location, you put it under a dome, you treat the organ like a patient, and you provide an opportunity for transplant surgeons throughout the country to examine it, including experts at Toronto General Hospital. Once the experts clear it for transplant and a team wants to accept it, it's then cooled back down, put back in the vehicle, flown a second time to its location, and then transplanted, and then to find out that every one of those second transplants on the rebound, if you will, the patient has been able to successfully leave the hospital. It sounds to 99% of Americans like pure science fiction. But, this is what your community has accomplished. And it's something to be immensely, immensely proud. I feel immensely proud just to be sort of like the third rower in the boat, helping row this along to have it benefit more and more people. Today, we at United Therapeutics have been able to save well over 200 lives through this technology that I just described, with two centralized EVLP facilities, one in Silver Spring, Maryland, and one at the Mayo Clinic in Jacksonville. We're in the process of spooling up a third one at the Mayo in Arizona. And once the transplant team has decided that the organ is ready to go forward, as mentioned, all those transplants have been successful. We've increased the percentage of lungs that arrive at the centralized facility that are able to successfully go on to transplant from less than half of them, when we started, to about 2/3 of them today. Because we have basically doubled the amount of time that donor lungs are flown, we have focused a lot of attention on trying to accomplish these flights most efficiently and with a lower carbon footprint. Last year, Dr. Keshavjee directed the first flight of a transplanted lung by drone, by an electric drone with no carbon footprint at all over the skyline of downtown Toronto, one of the busiest and most built-up metropolitan areas in the world. Here's a view on the famous rooftop. And this is certainly a very interesting way to receive a donor organ in a carbon fiber box which had to be specially invented because the current UNOS shipment packaging was too heavy to be supported by a zero carbon drone, one that did not use jet fuel but just electric batteries. And Shaf was instrumental in designing this transport system. And as you'll see in the next clip, it was so exciting to be on the rooftop and actually experience what we called the Wings of Life.

Come on. Yeah, what is carbon fiber? How much? It's not carbon fiber. Okay. This whole thing. Here's playing on. No, that's perfect. All right. That was my favorite part. Perfect. All right. This is like magic. Really amazing, eh? Did you see that, Mark? I saw it. I saw it. I'm looking super into this. I'm just going to tell Mark to put the patient to sleep and come downstairs. This is our model. Okay. Oh, that's a good. That's where our company I sent that to. You can put it up this week. So, it's just an amazing thing. This is like less than 12 months ago. You would not believe how many regulatory approvals were required to fly a 50-lb box over downtown Toronto. And of course, we had to be perfectly right on it in our engineering, not only because of the life in the box, but because there was a life on the operating table and there on the phone, Dr. Keshavjee was giving the okay to the anesthesiology team to get started once he was pleased with how the lung looked. Everything worked out. The patient is doing very well, and I don't want to let anything out of the box here, but we are now preparing to expand this delivery method for hearts and for going much longer distances such as from Toronto Pearson Airport all the way to the hospital and for other from other major airports where aircraft arrive with donor organs.

Now, another thing that people kind of scoff at as a bit impossible, they say, 'Okay, you know, that's kind of nice. You delivered the organ with a zero carbon footprint. It went over all the traffic, but organs have to travel very long distances.' Well, right now in our company, we are working on the larger drone. You see it there in the middle, United Therapeutics. And due to advances in another type of fuel cell, different than lithium-ion batteries, we will be able to fly these drones for a range of 900 miles. So, 900 miles is a very reasonable range for transporting organs around North America. And very roughly speaking, the range of an electric aircraft to deliver an organ or any similar type of cargo that has a very high lift-to-drag ratio as this aircraft does here is basically equal to its energy density in nautical miles. So, many people are familiar with electric cars and those cars have batteries with an electric density of around 150 Wh/kg. So, if you just took your Tesla or whatever electric car batteries and you put them in a kind of sleek drone like this, they could probably go around 150 nautical miles. The ones that we've specially designed type of lithium-ion batteries that we've begun using now, and just last week we demonstrated, they are over 200 Wh/kg. So, they can go around 200 to 250 nautical miles. And I believe within the next 12 months, you'll see these type of aircraft, electric aircraft, zero carbon footprint, going some 250 nautical miles. But now we're on the cusp of an even better technology, which are hydrogen fuel cells, and you can have green hydrogen fuel cells, meaning that the hydrogen fuel has been created with a renewable energy source such as hydroelectric or solar or wind. And this hydrogen fuel cell has a much higher energy density than does the electric batteries that power our car. And in fact, the energy density of our hydrogen fuel cells is almost a thousand watt hours per kilogram after accounting for the efficiencies and everything, which means that they will be able to go just about a thousand or in my estimation about 900 nautical miles, and will be able to be flown autonomously. So, I plead with everybody in this room, open the bandwidth on the DCDs, follow the amazing presentation by Dr. Kwan earlier this morning, and take that data to heart. And as you all know well, there's a high multiple of DCD donors, DCD donatable organs for every BDD donor. And if we could just expand that bandwidth and use these kind of electric drones to go long distance, we could save a lot more lives and be saving the planet at the same time.

Now, as I alluded to before, I think xenotransplantation will not always be the future of transplantation. It's going to be the present, it's going to be the near future, but in my opinion, it's going to be transcended by 3D bioprinted organs. And right now, we are working on these 3D bioprinted organs within our company and have had some really fantastic and exciting proof of concept type of results in the rabbit and in the pig model. The basic process is that we print a scaffold. In this case, you're seeing me hold a scaffold of a lung, but the same process works for hearts, kidneys, and livers. And this scaffold is printed with a set of peptides that the FDA calls GRAS, an acronym for generally recognized as safe. So, there's no very lengthy regulatory process about getting scaffolds printed of this peptide material accepted by the FDA because they already accept that material as generally recognized as safe. And then there is a process of figuring out how to turn this inert scaffold into a magical viable organ. And there are a great many ways to think about doing this. One is to cellularize it in a bioreactor with allogeneic cell lines. Another possible way to do this is to cellularize it with perhaps MHC negative cell lines. Another way is to take some donor cells from the ultimate recipient, convert those cells into iPSC stem cells, and then redifferentiate those iPSC cells into the different type of cell lines that one thinks would create a minimally viable organ for transplantation. So, these are all of the different processes that we're working on. In my personal approach on technology, I find biotechnology much, much more difficult than aeronautical and satellite technology. Satellites are pretty well-behaved. They can misbehave and the sun pushes them around. Aircraft are a little bit less well-behaved, but they're still in the scheme of things pretty well-behaved. Most of us arrived here on some kind of an aircraft. Bodies can be very poorly behaved. And they can be the blackest of black boxes. In which case so many times we don't even know what we don't know. So, my approach to invention and innovation is what I call multiple shots on goal. Don't really put all of your eggs in one basket. Hence, we're pursuing the allogeneic decellularized organs, the allogeneic or the autologously cellularized grafts. Another approach is perhaps even implanting a scaffold with some type of cell seeding strategy. So, I really look to everybody here in the community to help us figure out our way to create an unlimited supply of transplantable organs that can be 3D biomanufactured. What I do know is that doing so does not violate any laws of physics. And I do know that the facts on the ground are that we can 3D bioprint grafts now down to even the very fine micron level dimensionality that you have in a native organ. Also in our experiments in rats and pigs, we have been very favorably impressed that these scaffolds do not leak and that they did not have thrombolytic properties. So, those were two very pleasant, delightful surprises. We have already begun the process of developing commercial techniques to produce the trillions of cells that would be needed for an unlimited supply of transplantable organs. We can very readily purchase millions of cells from multiple cell vendors, most of which are from digested donor organs that ended up not being transplanted. And then we have techniques and many other centers have techniques to expand those millions of cells into the billions of cells needed for the cellularization of any given organ, be it a lung, heart, kidney, or liver. The process of scaling up into the billions of cells from an iPSC cell sample is more complicated, but that's also being done. And depending on the cell type, some cell types are easier to expand than others, some are more well-behaved than others, but we are now able to expand even some of the most tricky cells in the lung, which we call AT2 cells. So, this is not science fiction. This is something that is being done in the 2020s, and I am as confident as any of those other inventions that I went through earlier in this talk that in this decade we will be transplanting in patients 3D bioprinted lungs at minimum and quite likely other organs as well. Here, what you see is I'm inspecting. We created a GMP, or good manufacturing process, for making these lungs in an assembly line fashion. And today we are generating at United Therapeutics over 500 GMP scaffolds a year, meaning that these scaffolds are so clean that the FDA says you can put a scaffold like this inside a human body. It's made to the same standards as our medicines are. So, we're producing over 500 scaffolds a year, and within the next couple years we will be producing over 500 cellularized scaffolds a year, which is more challenging, but that's the way we do it. It's kind of like approve and improve.