Thank you for welcoming me to the University of Vermont Medical Center. Being here brings back happy memories of my oldest granddaughter, Assada, being born here as one of the first babies in the new natural childbirth center. My presentation is called CQ Love Do because I believe creative inspiration depends upon C for curiosity, Q for questioning authority, love for acting lovingly, and finally do for doing practically. CQ Love Do.
My first chapter concerns the creation of satellite radio, better known as SiriusXM. My curiosity began at a NASA tracking station in the Seychelles Islands. While bumming my way around the world, I ended up as a keyboardist in a band of Seychellois musicians on Mahé, the main island. The lead guitarist one day asked if I would like to see the NASA tracking center on the island. It sounded pretty cool to me, so I agreed.
When we got to the top of the mountain on Mahé, I asked the engineer why their dome was so huge. It was larger than any house I saw in the Seychelles. He said because the size of a radio signal receiver is inversely proportional to the strength of the transmitted signal. Very weak signals from deep space required a huge collection area. I thought about that and then asked about the size of a receiver if a satellite transmitted from Earth's orbit. He said they would still need to be very large and would have to be precisely pointed directly at the satellite.
Later that night, I sat in my unscreened cabin with a cloud of moths around my head and a sea of cockroaches at my feet, thinking about what the NASA engineer had told me. If a weak signal from space was the reason for needing a large collection area, I reasoned that if it were possible to transmit a very strong signal from space, then only a small collection area would be needed to receive it. Therefore, I decided to launch a space transmitter that would be so large and so powerful that its signals could be received throughout the world with only a small and inexpensive piece of omnidirectional electronics. I felt that this could unite the world. And as a musician, I believed music had no enemies. So, the way to unite the world would be with music. Satellite radio. All I needed to do was launch the most powerful satellite to date.
When I came back to the United States, many people told me this dream was impossible. First, they said it was impossible to build a satellite powerful enough to be received with handheld devices. I disproved that with my handheld Geostar and Hummingbird GPS systems. Next, I was told that my dream was impossible because CD quality music, the standard at that time, required a much greater signal strength than mere navigation devices. I then countered that objection by working with the Fraunhofer Institute of Germany to use intelligent digital signal coding to make the signal more powerful. And then to further strengthen the signal, we shaped the satellite beam to focus on just one continent at a time, such as North America.
For every objection that people threw in my face, it was my love of the idea to unite the world through satellite radio that helped me find a solution. Detractors told me that I would never raise the money to do this because radio was supported by advertisers and when my system was launched, there would be too few people listening for advertisers to find it a worthy investment. I countered this objection with the idea of monthly subscription for quality satellite radio. Of course, I was told no one would pay for radio, but I countered that if they would pay for TV, they would be willing to pay for quality radio.
The next objection was that my dream was illegal because it was against the law to allow any company to control more than a couple of radio stations per city. I was asking for the right to control over 100 channels of radio in every city, town, and village. That, in their eyes, would be a monopoly. And to top it off, they claimed there were no open radio frequencies left available to assign for satellite radio. All of these objections would have worn me down, but I was powered by the love of doing the right thing. I knew that uniting people across vast distances by satellite radio would increase the love in this world. So I acted lovingly at all times.
Finally, I succeeded. Through research, I learned of some radio frequencies that were hidden in the vast haystack of the microwave frequency spectrum that were barely used, if at all. Finally, the FCC agreed to allow me to use those frequencies only because my service would address many unmet needs such as dozens of channels in rural areas and diversity content in urban areas. To this day, it even provides life-saving weather information to pilots in flight. I never expected that the most popular SiriusXM channel would be none other than Howard Stern, but I've had more people in rural areas thank me for bringing them Howard Stern than for creating life-saving medicines. Even Howard Stern is very appreciative as you can see in the following video.
This is 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 you in this is like me meeting Marlon Brando. If you hadn't invented this medium, I would have been out of the radio business.
I liked 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.
I did. You're a witty guy. But 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.
United Therapeutics, otherwise known as Unither, is the CQ Love Do chapter about life-saving medicines. While running Sirius, my daughter Genesis developed a rare life-threatening disease called pulmonary arterial hypertension or PAH for short. In this disease, the veins that carry blood to the heart, shown here in blue, are normal. But the arteries that carry blood from the heart, shown here in brown, get very narrow. You can see the difference between the fat arteries on the right, normal lungs, and the pruned brown arteries in the left, pulmonary arterial hypertension lungs. I had curiosity about the fact that the pulmonary arteries were the only arteries in the body that carried deoxygenated blood. You see, arteries carry blood from the heart. Most of our arteries carry blood from the heart to the rest of the body after the blood has been oxygenated in the lungs. But the pulmonary arteries carry deoxygenated blood because they are carrying blood from the heart to the lungs. I thought maybe there could be a medicine that keyed in on this very keen difference to act as a pulmonary selective vasodilator. If so, I hoped such a medicine could save our daughter's life. I was immediately greeted by authorities saying to me that I didn't know what I was talking about. I was, after all, the SiriusXM CEO, not a doctor. But I questioned that authority. I quit my job at Sirius, and I spent my full time trying to develop a medicine that would act just on the arteries that carried deoxygenated blood, the pulmonary arteries, and make them get wide and healthy again to save our daughter.
I cannot begin to tell you all the trials and tribulations. Believe it or not, I had even more detractors than at Sirius. When I found a molecule that just worked in deoxygenated arteries, but was locked up in a freezer at a giant pharmaceutical company, I was told that they would not develop it for Genesis because the disease was too rare for them to make significant profit from. When I tried to buy it out of the company, they told me it wouldn't be ethical to sell a medicine to someone without competency in the drug development. When I hired a team of drug developers and finally was able to buy it out of the company, I learned there was no way to create more than a couple of grams of this particular drug at a time because it was such an unstable molecule. Indeed, it took 23 steps to synthesize it and some of those were extremely flammable. When I finally found a chemist who could make enough of this molecule to use it in clinical trials, I learned there was no practical way to give it to patients outside of a hospital because it only worked for half of an hour inside of the bloodstream. And thus, the patients would need it pumped into their body 24/7 for every day of their life. When I found a way to do that unobtrusively and consistently with a pretty normal life via a subcutaneous palm-sized pump, the necessary clinical trial missed a statistical requirement for FDA approval by one percentage of a point. It was love, unmitigated love for our daughter Genesis that carried us through all of these trials and tribulations.
And with all of that, I've not even touched on the Wall Street trials and tribulations. Nobody wanted to invest in us because they thought there was no way to make money on a disease that only affected just a few thousand patients. Indeed, our first IPO at $1 per share fell flat. But finally, we got our first product approved called Remodulin. This product revolutionized the delivery of prostacyclin therapy, making continuous infusion for the first time consistent with an active lifestyle, something very important in a disease that strikes young women and men. Today, our stock price is over $100 per share. And the molecule that nobody wanted or believed in produces $1.5 billion a year in revenue, saves thousands of lives. And best of all, we also have inhaled and pill forms of that medicine, keeping many more thousands of people alive. In fact, 30,000 people are alive today with pulmonary arterial hypertension compared to only 3,000 people when our daughter was first diagnosed. That is because now the patients can often stay alive whereas before our medicines were approved virtually everybody with pulmonary arterial hypertension died within a few years. Most precious of all the courageous inspiration for this astounding story: our daughter Genesis is alive and healthy today in charge of digital graphics and virtual spaces at United Therapeutics. None of these medicines is a total cure. But by acting practically, I was able to keep a lot of people alive a lot longer until hopefully we do find a cure.
There is but one known cure for pulmonary hypertension and that is an organ transplant. Chapter 3 of CQ Love Do is the story of what we are doing to ensure that there is an organ for everyone who needs one. My interest in organs began because the only known cure for pulmonary arterial hypertension is a lung transplant. However, I became curious about why the number of patients on the lung transplant list was much much less than the number of people who died of end-stage lung disease. I was told the reason was that they had to strictly limit the number of people on the lung transplant list because there were not enough organ donors for the 1% of all the people who had end-stage lung disease.
I questioned authority that the problem was not lack of organ donors. 40% of all Americans carry organ donor cards, but barely one person in a hundred who need a lung transplant are able to get on the transplant list. Having two times as many organ donors would obviously not solve the problem of transplantable lungs. Even if every American was an organ donor, there would be way too few organs to save the number of people dying of organ disease. The reason is that most people do not die in a way that makes their organs transplantable, such as in a car accident or head trauma near a hospital. I realized that only by manufacturing organs, producing them like spare parts, would there ever be enough organs for everyone who needed them, such as enough lungs for everyone with pulmonary hypertension. I decided to transform the transplant paradigm of scarcity into the transplant paradigm of abundance.
Once again, I found myself powered by love. Again, love of my daughter who may yet need a lung transplant, but also love for all the thousands of our patients who take our medicines for many years, but then the medicines stop working for them and they need a lung. It will be a most challenging road to manufacture an unlimited number of transplantable organs. Only the unlimited reservoir of love can power you through that type of challenge. As a first step, I decided to try to save the thousands of lungs that are donated and not even used. Indeed, I learned that four out of five lungs donated are being thrown away because by the time the transplant surgeon looked at them, they were no longer viable implants. So, we funded the invention of a new technology called Xvivo lung perfusion or EVLP.
This technology is a machine that works like an artificial body to give a donated but unusable lung a chance to be restored so that it is good for transplantation. Here's a video of how it works.
The procedure table by EVLP specialists. Pressure lines are zeroed. Cannulas are connected up to the perfusion circuit and air is purged from the lines. The perfusion pump is started and with this step, the EVLP procedure clock starts. Perfusion continues over a 4 to 6 hour period with ongoing CMX documentation and assessment steps. These include bronchoscopy, X-rays, blood gas analysis both on a regular and an as-needed basis. Throughout this period, the IT specialists in our command center facilitate visual and data communication at Toronto General Hospital and the transplant surgeons, keeping them informed on an at least hourly basis. At the 3-hour mark of perfusion, the collective team makes an initial assessment of the lungs. If the decision is made to go ahead with transplantation, the primary EVLP specialist contacts the transplant center to arrange transportation. After all the data is collected and the Toronto General Hospital surgeon and transplant surgeon agree on cessation of EVLP, the case is locked and a disposition email is automatically sent to the Toronto General Hospital surgeon, the transplant surgeon and finally to the OPO which confirms transfer of custody to the transplant center. Cool down commences and once the cold temperature set point is reached, cannulas are clamped and the lungs are disconnected and moved to the back table. The EVLP procedure clock is stopped. The lungs are then flushed with solution and stored in Perfadex. The EVLP specialists remove the cannulas, staple the trachea, and perform a post-EVLP biopsy. PX1 clinical staff then prints out the CMX perfusion record for inclusion in the shipping container. The organ is then packaged according to UNOS protocol. Pictures are taken of internal and external labels. Original tissue typing materials are included in the packaging with the original donor chart and perfusion record. The organ is then brought to the loading dock by PX1 clinical staff for transport. Once loaded onto ground medical transport, the trip to the airport begins and the transplant center is advised of departure from PX1. The post-procedure checklist is initiated in CMX to close out the case. Ground medical transport arrives at the airport and the lungs are loaded onto the flight to the transplant center. The lungs arrive at the destination airport and are transferred to the ground medical transport. Finally, the lungs reach the transplant hospital and are transferred to custody of the hospital staff by the ground medical transport truck.
Over 400 lives have now been saved with this technology. The people with these artificially restored lungs have the same outcomes as those people whose organs come directly from a donor. I believe EVLP technology will allow us to save thousands of lives. However, to really solve the organ shortage problem, we need the technologies of xenotransplantation, regenerative medicine and ultimately self-gen organs from 3D printed scaffolds and the patient's very own DNA. At United Therapeutics, we are working on each of these ever more advanced technologies to expand the supply of organs from the tens of thousands to the hundreds of thousands and ultimately into the millions. We implement the do practically of CQ Love Do step by step achieving our goal with simpler technologies providing a platform for our development of more advanced technologies.
For the xenotransplant technology, we will need to build a designated pathogen-free facility known as DPF and operate it to regulatory satisfaction in every way from the veterinary care of the genetically modified pigs to the explantation of the xeno organs, their packaging and transport to the transplant surgeons. The FDA has laid out numerous guidelines to be taken into account for xenotransplantation, including archiving tissue samples for 50 years and one year of pivotal toxicology demonstrating efficacy without toxicity with special focus on monitoring immune-mediated toxicity. Here is the architecture firm Earlsway Kohl's design for the DPF facility at our Research Triangle Park, North Carolina campus. A three times larger facility if limited to pulmonary arterial hypertension would be needed to solve all lung transplant needs of people with PAH who are excluded from the transplant list. The design shown here would accommodate 3,000 lung pairs per year and cover about 30 acres, including waste treatment areas. Such a facility would most likely be used to triple America's ability to provide transplants for many end-stage lung diseases from pulmonary hypertension to pulmonary fibrosis and from cystic fibrosis to emphysema.
A huge increase in the available organs will require a new organ delivery technology because manufactured organs must be used within hours of their manufacture. In Chinese mythology, each moth represents an ancestor flying toward the light. We've adopted the acronym Manufactured Organ Transport Helicopter or MOTH to represent bringing an endless supply of transplantable organs into the light of science and medicine practiced at major transplant centers. This brief video shows our ultimate plan to manufacture a limited number of self-gen organs using 3D printing of scaffolds for recellularization with greatly expanded populations of differentiated inducible pluripotent stem cells. At the end, you'll see the TransMedics organ transport carts that are used today with restored allografts and how they will ultimately be loaded onto a fleet of electronically powered autonomously flown aircraft for delivery to transplant hospitals. E-Biop printers at United Therapeutics' Deco organ manufacturing center in Manchester, New Hampshire print the inert collagen scaffold of a lung from its larger proximal vessels and bronchi to its millions of distal arterioles. End-stage organ disease patients give up a few cells in a biopsy which will be transformed into inducible pluripotent stem cells all matching the patient's DNA to avoid any need for immunosuppressants.
It was just in the past decade that science has learned how to turn differentiated human cells back into stem cells. Thereafter, the newly made stem cells can be redifferentiated back into a wide variety of different types of cells. In our manufacturing laboratories, we will redifferentiate newly made stem cells from a patient into endothelial, epithelial, muscle, and connective tissue cells that match the patient's DNA. After expanding the numbers of these differentiated cells into the tens of billions needed to cellularize each organ, we stream them into the previously bioprinted scaffold. The entire process of cell expansion and recellularization via streaming takes about 2 to 3 months per organ. At the end of the process, there is a newly manufactured personalized organ that matches the DNA of the intended patient. Once removed from its bioreactor, the organ needs to be transplanted within hours. A TransMedics cart will be loaded onto an EHang manufactured organ transport helicopter or MOTH for delivery to the surgeon's operating room.
Next, I'd like to talk about how CQ Love Do applies to the new concept of mind cloning. In my work as a technologist, I learned that computer technology would soon be more powerful than human brains. I was very curious as to whether that would mean a mind could be transplanted to software the way a lung or heart function could be transplanted to a new organ. Of course, the authorities told me no way because they said brains are not computers. But I thought planes are not birds and yet they still manage to fly. So maybe even if minds did not work quite in the same way when they were coded in software as when coded in neurons, just as planes don't fly in quite the same way as do birds, that software minds could still be self-aware and feel emotion, even love. This was really questioning authority. Act lovingly. My partner of 33 years, Bina, and I one day said, 'Why don't we work on a project to let people extend their love forever? Their minds can be transplanted to software, and in the future, their software minds can be downloaded back into regenerated flesh bodies.' Our first experiment was a robot. Here's a brief video clip about how people perceive our love for each other.
