ECONOMY

Pharma CEO Faces Personal Fight for a New Breed of Organ Donors

“I went right ahead and did research on my own and found out what he was saying was true,” Martine Rothblatt would later recall. “There were no medicines for it. Everybody did die.”

A doctor at Children’s National Medical Center in Washington, D.C., had just told Rothblatt and her wife, Bina, that the couple’s youngest daughter, 9-year-old Jenesis, had a rare medical condition that likely gave her three years to live. The arteries between Jenesis’s heart and lungs had narrowed, choking off oxygen and placing an unsustainable burden on her heart as it struggled to send blood through her thinning blood vessels, like trying to push water through a hose with a kink in it. The condition, known as pulmonary arterial hypertension, was progressive, and there were no approved treatments, short of a lung transplant—almost unheard-of in children.

Rothblatt set out to make one. On the cusp of 40 in the mid-1990s, she was a wealthy, pioneering aerospace attorney and communications entrepreneur. Her startups included the satellite navigation company GeoStar and the company that would later come to be known as SiriusXM Satellite Radio. On a personal level, Rothblatt was in the process of transforming into the person she’d always been meant to be. Within months, she would undergo sex reassignment surgery and come out to the world as Martine.

But Rothblatt spent the nights after Jenesis’s diagnosis in the hospital’s basement library, studying the molecular biology of her daughter’s disease in medical journals. She looked up unfamiliar terms and concepts in textbooks, tracked down obscure articles mentioned in cryptic footnotes, and grew convinced that technology could solve her daughter’s problem. “I just felt like I had no choice,” she would later say. “My only purpose in life now was not to help move to the stars with satellites and stuff like that. Instead, it was to save Jenesis.”

A pharmaceutical company in North Carolina had what Rothblatt considered a promising chemical compound sitting unused on the shelf. When the company’s lawyers refused to license it to an individual, Rothblatt started a biotech company, assembled a team of scientists, and persuaded the pharma company to take her money. Then, using her windfall from Sirius’s recent initial public offering, they developed the compound into a workable drug, took it all the way through clinical trials, and won approval from the U.S. Food and Drug Administration. The medication saved Jenesis and tens of thousands of other people.

Today, Rothblatt’s biotech company, United Therapeutics Corp., is worth about $8 billion. More than 100,000 people around the world rely on it to produce the lifesaving medicine, called Remodulin, and Rothblatt is the highest-paid female executive in the U.S. At age 36, Jenesis is working for the company, too.

And yet Rothblatt has always known the work was only half done. Remodulin is a treatment, not a cure, and it’s tough to be certain how long it will hold off the disease for each patient. At some unknown point, Jenesis’s lungs might still fail. The only permanent solution remains a transplant, and in a good year, not even 1% of the patients who need lung transplants receive them. In 2019 about 250,000 people died of end-stage lung failure, too far down the transplant list or otherwise unable to get one.

So once again, Rothblatt has vowed to solve the problem threatening her daughter’s life. This time, it’s the global organ shortage. “I did the math,” she says. “So I decided to change the math.”

Backed by United’s nine-figure annual research and development budget and about $2 billion in cash, Rothblatt and her team have been quietly working to create manufacturing techniques that don’t require human donors. Through acquisition and collaborations, what began several years ago at United’s headquarters in downtown Silver Spring, Md., as a small effort to solve the long-term organ shortage problem has grown into a network of small labs and research facilities scattered across the U.S. that are experimenting with possible solutions.

In Jacksonville, Fla., a team of United engineers at a Mayo Clinic facility is testing a method of lung perfusion, a technology that can help assess whether damaged donor lungs are still be usable for transplantation. In Manchester, N.H., and Research Triangle Park, N.C., United has hired teams of scientists to try to figure out how to seed decellularized animal organs with human stem cells, a first step toward 3D-printed organs using patients’ own cell samples.

Now Rothblatt’s company is getting ready to move forward with perhaps the most sci-fi of these efforts: growing genetically modified, human-compatible organs in pigs.

At a Rothblatt-designed facility at the University of Alabama at Birmingham, some of the people who cloned Dolly the Sheep have been helping to create a small army of swine with custom-edited genes. Each pig will carry a minimum of 10 genetic modifications that scientists say will make their organs, already comparable in size to those in the human body, acceptable to human hosts. Kidneys are the first goal, but they won’t be the last. Instead of using a pig valve in a heart transplant, which has been a common procedure for decades, why not the whole heart? Or the lungs that might save Jenesis’s life?

Rothblatt’s team is tackling a challenge that has frustrated some of the world’s top scientists for decades. The human immune system is notoriously fickle when it comes to accepting organs that come from another human, let alone a pig. “An organ must interact with a body along hundreds of biochemical links, whereas a drug needs to interact along only a few,” Rothblatt says. “The biochemistry is orders of magnitude more challenging.”

Several analysts who cover United tell Bloomberg Businessweek that potential breakthroughs in any of these efforts seem too far away to factor into their estimates of the company’s revenue. Still, Rothblatt’s team has already made significant progress with gene editing. It has successfully transplanted genetically modified pig kidneys into several baboons, which have genetic codes 94% identical to those of humans and have all survived for more than six months since. At the end of 2020, United received FDA approval to use its first gene edit in medicine and food. (The tweak removes a common sugar in pig meat known to cause allergic reactions in humans.)

The team has been working to prepare more advanced gene-edited pigs for FDA review. Rothblatt, who declined to provide an update on United’s latest progress before publication, said last year that the company should be able to begin FDA-approved, late-stage human clinical trials with pig-grown kidneys as early as 2022. After that, she said, hearts and lungs would no longer sound like science fiction.

Back in 1954 a Boston doctor named Joseph Murray performed the first successful human organ transplant, transferring a kidney from 23-year-old Ronald Herrick to his twin brother, Richard. The genetic similarities allowed Ronald’s organ to survive in his brother without being attacked by Richard’s immune system as a foreign substance. In the early 1960s, French doctors managed to repeat the procedure using a donor who wasn’t related to the recipient, by using radiation to weaken the recipient’s immune system temporarily. Live heart and pancreas transplants followed by the end of the decade, and lung and intestine transplants began in the 1980s.

In 2019 doctors around the world performed more than 100,000 organ transplants from both deceased and living donors, according to the nonprofit United Network for Organ Sharing, a record. In the U.S., which accounted for about 40% of that total, patients and insurers spent $13 billion on transplants.

But the supply has never come close to meeting the demand. In the U.S., someone is added to the 107,000-person-long recipient waiting list every nine minutes, and an average of 17 people a day die waiting. Those numbers don’t account for the true need, because not everybody makes the list. Inclusion is based on a complex formula weighted to favor the patients most likely to survive and those thought to have the most to gain from a transplant. Kidneys alone represent a huge need: Around the world, hundreds of millions of people in end-stage renal disease are relying on dialysis to stay alive.

Scientists have been dreaming of solutions such as Rothblatt’s for decades, starting with heart valves grown in cows and pigs that have been chemically treated to avoid immune rejection. Most pig valves wear out after 15 years, but they still have a major advantage over more durable carbon-based mechanical valves. Patients who use the artificial parts must take anticoagulant drugs indefinitely to prevent stroke-causing blood clots from building up around them, whereas those with genetically engineered valves can live a mostly normal life—and get laughs at parties by claiming to be part pig.

Full-scale organs, however, are far more complicated and liable to prompt a fatal immune response. The field was largely abandoned in the wake of the AIDS crisis over fears that transplanting organs from other species might threaten humans with ancient retroviruses lying dormant in animals. In recent years, though, advances in gene-editing techniques have allowed molecular biologists to rewrite bodily blueprints with previously unimaginable speed and precision. In 2015, George Church, a pioneer in the use of gene editing in mammalian cells, announced that he and colleagues had used the technology to disable 62 retroviruses found in pig embryos.

“This is not a question of if this is going to work, it’s a question of when,” says Paul Sekhri, the president and chief executive officer of EGenesis, a United rival co-founded by Church that’s raised more than $263 million. EGenesis said this year that its latest $125 million from investors will be used largely to advance animal-to-human kidney transplants, which the company aims to bring to clinical trials in 2023.

Several analysts who cover the company say they wouldn’t bet against Rothblatt getting there faster. “Martine is a different kind of person in general,” says Liana Moussatos, an analyst at investment firm Wedbush Securities Inc. “From what I have seen, once she has her mind set on something, she’s going to figure it out.”

In 1974, while Rothblatt was a 20-year-old college kid visiting a remote tropical island in the Seychelles, a local mentioned it was home to a world-class NASA satellite-tracking station. Rothblatt, who was wandering the world in search of meaning beyond depressing headlines about Watergate and Vietnam, recalls being drawn to the futuristic spectacle “like a bee to a flower.”

At the facility, perched atop a palm-tree-lined tabletop mountain in the middle of the Indian Ocean, she met a NASA engineer who explained how the base’s two humongous white satellite dishes were receiving signals from a spacecraft orbiting Jupiter, 451 million miles away. It was a distance so vast, the engineer said, that detecting the transmitter’s weak signal was akin to spotting a New York City flashlight from Los Angeles.

What would happen, Rothblatt asked the engineer, if you built the probe’s transmitter as large as the receiving dishes? Could you then make the satellite dishes the size of a flashlight? When the engineer acknowledged it might be possible, Rothblatt glimpsed the future. “I’m going to build a big house-size satellite-transmitting antenna in orbit,” she would later recall thinking, “and connect the whole world together with tiny flashlight-size antennas.”

Rothblatt returned to the University of California at Los Angeles and wrote a bachelor’s thesis on international direct-broadcast satellites. Then she earned a JD/MBA and became a regulatory attorney and entrepreneur specializing in satellite and broadband technologies. By her late 30s, she was a leading voice in the field, having collaborated with governments and private clients around the world to figure out how to commercialize satellite tech. She’d poured her profits from GeoStar’s successful car-navigation business into Sirius and was raising four kids with her wife, Bina Aspen.

But in the early 1990s, Jenesis’s occasional shortness of breath became a more constant problem. What was once trouble keeping up during a ski trip was, a few years later, serious difficulty getting onto the school bus. Her lips turned blue, she experienced fainting spells, and she struggled to walk upstairs. In 1993 she received the pulmonary arterial hypertension diagnosis.

Months later, Sirius went public, so there was money. One day soon after, Rothblatt presented Jenesis’s pediatric cardiologist with a small pile of photocopied articles about the condition, along with a list of the names of 40-odd doctors who’d written about it. Would the cardiologist be willing to serve on a grant review committee if Rothblatt set up a foundation to accelerate the doctors’ research? (Yes.)

One of Rothblatt’s grantees told her about Burroughs Wellcome, then a midsize drug development company in North Carolina. Preliminary results suggested the Burroughs compound relaxed the smooth muscle tissue lining the arteries of the heart in ways that might restore normal blood flow to patients like Jenesis. But Burroughs had recently been acquired by Glaxo, which shut down the research—along with any project expected to yield less than $1 billion a year in revenue—and gave early retirement packages to the scientists involved.

Rothblatt marched into Glaxo for a meeting, so nervous she was shaking. Company officials said they weren’t going to restart drug development on the compound or license it to a nonprofit with no clinical development expertise and no employees. So Rothblatt started her own company and asked every member of the retired team to come work for it.

Bob Bell, Glaxo’s head of R&D at the time, recalls meeting Rothblatt during one of her later visits and thinking the chances of anyone developing the project Glaxo had shelved into a workable drug was less than 10%. Indeed, after finally persuading him and his superiors to license the compound, it took Rothblatt another year to find chemists capable of converting the chemical molecule into a medicine that could be manufactured on a large scale—a process that required 23 steps to safely produce it.

Bell became an enthusiastic backer and would eventually take great pride in the deal, which saved the life of his sister—now a United customer—among many others. And Glaxo gets 10% of the royalties on Remodulin’s profits. In the years since, those profits have run into the billions. “I think it’s the best business decision I’ve probably ever made,” Bell says.

But Remodulin was only the first part of Rothblatt’s plan. Next she wanted to master the intricacies of clinical trial design, something she saw as necessary to lead a biotech. The result was a doctorate in medical ethics at Barts and the London School of Medicine and Dentistry. In 2003 she published her doctoral dissertation, about animal-to-human transplants, as a book called Your Life or Mine: How Geoethics Can Resolve the Conflict Between Public and Private Interests in Xenotransplantation.

The body is “a kind of a machine,” Rothblatt wrote in the book, and, like cars and planes, could theoretically be kept going indefinitely if it were possible to swap out failing parts. Although the logistics of harvesting organs from the deceased, or from living donors, are “vastly more problematic than the ordering of spare parts from a manufacturer’s catalogue,” she noted, many people were working on the problem. “As a result of these activities, the science of extending human life through organ transplantation will soon be as mature as the practice of extending the lives of complex machines,” Rothblatt wrote.

Rothblatt’s starter pig facility is in Blacksburg, Va., a little less than 3 miles from the neo-Gothic campus of Virginia Tech. On a treeless gravel lot surrounded by rolling green hills, long rows of modular trailers the size of shipping containers emit a low, constant hum from their scores of fans and air filters.

Inside one of the trailers one afternoon last year, an enormous sow with mud-streaked haunches was reclining on an orange plastic grate as five baby piglets squealed, grunted, and climbed all over one another, attempting to nurse. There’s something unusual about this ensemble, says David Ayares, the executive overseeing United’s xenotransplantation programs under its subsidiary, Revivicor. The larger pig isn’t the piglets’ mom, but a slightly older version of each one of them. They’re all clones—each carrying the same exact genetic material, infused into the nucleus of an embryo by Ayares and his team, using the same techniques his old company used to clone Dolly back in the 1990s.

“We have knocked out four pig genes and added six human genes to make it more compatible,” Ayares says. “These are pigs that we’d be going forward with in kidney, heart, and lungs trials.”

The key to making the organs compatible with human recipients is twofold. First, scientists have to identify and eliminate each of the proteins in the pigs’ organs most likely to ring alarm bells in the human immune system. Then they have to figure out which human genes will produce the kind of biochemical secret handshake needed to trick the body into thinking the organ is a native resident.

The first task is painstaking. To speed it along, Rothblatt’s team developed a battery of lab tests that measure the ability of their genetically engineered pig cells to avoid rejection by a human immune system. Genetic analyses measure the activity of as many as 50,000 genes at once to spell out which ones are associated with organ rejection. In this way, the company is able to zero in on specific genes, then use engineering techniques to turn them on or off.

The work, however, is just beginning. Although Ayares and his team say they’ve solved most of the problems in pig kidneys and even hearts, far less finished is the proper genetic engineering needed for pig lungs that a human immune system would likely accept. The lungs are the body’s last line of defense against pathogens in the air and are thus far more prone to rejection than most other organs. Last year, Ayares said his team had increased lung survival from three hours to more than a month and would continue to build on that. But before they can begin human trials, they’d need to get to six months. And they still wouldn’t be done.

“Even the first lung that probably United is going to be able to transplant is going to be far from perfect,” says Hartaj Singh, an analyst at investment bank Oppenheimer & Co. “It’s going to be like the Model T Ford, and 100 years later, probably that lung will be that much better and will be much easier to give to patients.”

Jenesis recently celebrated her 36th birthday in good health, but Rothblatt and her team can’t help but feel they’re racing against the clock. Now a project leader for corporate telepresence and robotics at United, Jenesis has presented at sales meetings, summed up the company’s annual performance at the end-of-year holiday party, and shared her health challenges. (Long hikes are still out.)

“It becomes very real,” Ayares says of working with Jenesis and Martine on transplantation. “Because you go to a quarterly meeting, and instead of it being a bean counter across the table or someone who is designing a clinical trial, the person at the end of the table is Martine, telling you, ‘I want you to hit your milestone because my daughter needs a lung from your pig.’ If there are delays, or if there are things that go ahead of schedule, those are celebrations and challenges that are very personal.”
 
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