The entrepreneur dreaming of a factory of unlimited organs

Organs on demand is one of MIT Technology Review's 10 Breakthrough Technologies of 2023. Explore the rest of the list here.

I met the entrepreneur Martine Rothblatt for the first time at a meeting at West Point in 2015 that was dedicated to exploring how technology might expand the supply of organs for transplant. At any given time, the US transplant waiting list is about 100,000 people long. Even with a record 41,356 transplants last year in the US, 6,897 people died while waiting. Many thousands more never made the list at all.

Rothblatt arrived at West Point by helicopter, powering down over the Hudson River. It was an arrival suitable for a president, but it also brought to mind the delivery of an organ packed in dry ice, arriving somewhere just in time to save a person's life. I later learned that Rothblatt, an avid pilot with a flying exploit registered by Guinness World Records, had been at the controls herself.

Rothblatt's dramatic personal story was already well known. She had been a successful satellite entrepreneur, but after her daughter Jenesis was diagnosed with a fatal lung disease, she had started a biotechnology company, United Therapeutics. Drugs like the one that United developed are now keeping many patients like Jenesis alive. But she might eventually need a lung transplant. Rothblatt therefore had set out to solve that problem too, using technology to create what she calls an unlimited supply of transplantable organs."

Lawyer and entrepreneur Martine Rothblatt in a 2014 photo.PETER HAPAK/TRUNK ARCHIVE

The entrepreneur explained her plans with the help of an architect's rendering of an organ farm set on a lush green lawn, its tube-like sections connected whimsically in a snowflake pattern. Solar panels dotted the roofs, and there were landing pads for electric drones. The structure would house a herd of a thousand genetically modified pigs, living in strict germ-free conditions. There would be a surgical theater and veterinarians to put the pigs to sleep before cutting out their hearts, kidneys, and lungs. These lifesaving organs-designed to be compatible with human bodies-would be loaded into electric copters and whisked to transplant centers.

Back then, Rothblatt's vision seemed not only impossible but phantasmagoric," as she has called it. But in the last year it has come several steps closer to reality. In September 2021, a surgeon in New York connected a kidney from a genetically engineered pig developed by Rothblatt's company to a brain-dead person-an experiment to see whether the kidney survived. It did. Since then, US doctors have attempted another six pig-to-human transplants.

The most dramatic of these, and the only one in a living person, was a 2022 case in Maryland, where a 57-year-old man with heart failure lived two months with a pig heart supplied by Rothblatt's company. The surgeon, Bartley Griffith, said it was quite amazing" to be able to converse with a man with a pig's heart beating in his chest. The patient eventually died, but the experiment nonetheless demonstrated the first life-sustaining pig-to-human organ transplant. According to United, formal trials of pig organs could get underway in 2024.

At the center of all this is Rothblatt, a lawyer with a PhD in medical ethics whom New York magazine dubbed the Trans-Everything CEO." That isn't only because she changed her gender from male to female in midlife, as she writes in her book From Transgender to Transhuman. She's also a prolific philosopher on the ethics of the future who has advocated civil rights for computer programs, compared the traditional division of the sexes to racial apartheid, and founded a transhumanist religion, Terasem, which holds that death is optional and God is technological." She is a frank proponent of human immortality, whether it's achieved by creating software versions of living people or, perhaps, by replacing their organs as they age.

Since the pig organ transplants garnered front-page headlines, Rothblatt has been on a tour of medical meetings, taking the podium to describe the work. But she has rebuffed calls from journalists, including me. The reason: I promised myself no more interviews until I accomplished something I felt worthy of one," she wrote in an email. She included a list of the further successes she is aiming for. These include keeping a pig heart beating for three months in a patient, saving a person's life with a pig kidney, or keeping any animal alive with a 3D-printed lung, another technology United is developing.

The next big step for pig organs will be an organized clinical trial to prove they save lives consistently. United and two competitors, eGenesis and Makana Therapeutics, which have their own pigs, are all in consultation with the US Food and Drug Administration about how to conduct such a trial. Kidney transplants are likely to be first.

Many people are not on the list because of the scarcity of organs. Only the most ideal patients get listed."

Robert Montgomery

Before the larger human trials can begin, companies and doctors say, the FDA is asking them to perform one more series of experiments on monkeys. The agency is looking for consistent" survival of animals for six months or more, and it is requiring that the pigs be raised in special germ-free facilities. If you don't have those two things, it's going to be a hard stop," says Joseph Tector, a surgeon at the University of Miami and the founder of Makana.

Which company or hospital will start a trial first isn't clear. Tector says the atmosphere of competition is kept in check by the risk of missteps. Just two or three failed transplants could doom a program. Do we want to do the first trial? Sure we do. But it's really, really, important that we don't treat this like a race," he says. It's not the America's Cup."

Maybe not, but leading transplant centers are jockeying to be part of the trials and help make history. It's Who will be the astronauts?'" says Robert Montgomery, the New York University surgeon who carried out the first transplant of a pig kidney. We believe it's going to work and that it's going to change everything."

And that's not because pig organs will replace human-to-human transplants. Those work so well-kidney transplants succeed 98% of the time and often last 10 or 20 years-that pig organs almost certainly won't be as good. The difference is that if unlimited organs" really become available, it's going to vastly increase the number of people who might be eligible, uncorking needs currently masked by strict transplant rules and procedures.

Many people are not on the list because of the scarcity of organs. Only the most ideal patients get listed-the ones who have the highest likelihood of doing well," says Montgomery. There is a selection procedure that goes on. We don't really talk about it, but if there were unlimited organs, you could replace dialysis, replace heart assist devices, even replace medicines that don't work that well. I think there are a million people with heart failure, and how many get a transplant? Only 3,500."

A sick child

Before becoming a biotech entrepreneur, Rothblatt had started a satellite company; she'd been early to see that with a powerful enough satellite in stationary orbit over the Earth, receivers could shrink to the size of a playing card, an idea that became SiriusXM Radio. But her plans took a turn in the early 1990s, when her young daughter was diagnosed with pulmonary arterial hypertension. That's a rare disease in which the pressure in the artery between the lungs and the heart is too high. It is fatal within a few years.

Rothblatt started a biotechnology company, United Therapeutics, after learning that her daughter Jenesis (pictured in background) suffered from a deadly lung disease.AP PHOTO/JACQUELYN MARTIN

We had a problem: I was going to die," Jenesis-who now works for United in a project leader role-recalled during a 2017 speech.

Rothblatt and her wife were shocked when doctors said there wasn't a cure. Rothblatt has compared her feelings then to seeing black or rolling on the floor in helpless pain. But instead of giving up, she began attacking the problem. She would duck out of the ICU where her daughter was and visit the hospital library, reading everything she could about the disease, she has recalled.

Eventually she read about a drug that could lower arterial pressure but had been mothballed by the drug giant Glaxo. She badgered the company until they sold it to her for $25,000 and a promise of a 10% royalty, she recalls. According to Rothblatt, she received in return one bag of the chemical, a patent, and declarations that the drug would never work.

The drug, treprostinil sodium, did work; it was approved in 2002. You might expect that with just a few thousand patients affected by the disease, it would never make money. Once the drug was available, though, patients started to live, not die, and they needed to keep taking it. A family of related drugs now generates $1.5 billion in sales each year for United.

Though these drugs work well to ease symptoms, patients may eventually need new lungs. Rothblatt understood early on that the drugs were only a life-extending bridge to a lung transplant. Yet there aren't nearly enough human lungs to help everyone. And that was the real problem.

The most obvious place to get a lot of organs was from animals, but at the time xenotransplantation"-moving organs between species-didn't seem to have good prospects. Tests showed that organs from pigs would be viciously destroyed by the human immune system; this hyper-acute" rejection takes just minutes or hours. In the US, some scientists called for a moratorium in the face of public panic over whether a pig virus could jump to humans and cause a pandemic.

In 2011 United Therapeutics paid $7.6 million to purchase Revivicor, a struggling biotech company that, under its earlier name PPL Therapeutics, had funded the Scottish scientist Ian Wilmut's cloning of Dolly the sheep in 1996. Using cloning techniques, Revivicor had already produced pigs lacking one sugar molecule, alpha-gal, whose presence everywhere on pig organs was known to cause organ rejection within minutes. Now Rothblatt convened experts to prioritize a further eight to 12 genes for modification and undertake a moonshot to edit additional genes until we have an animal that could provide us with tolerable organs." She gave herself 10 years to do it, keeping in mind that time was running out for patients like Jenesis.

Getting into humans

By last year, United had settled on a list of 10 gene modifications. Three of these were knockouts," pig genes removed from the genome to eliminate molecules that alarm the human immune system. Another six were added human genes, which would give the organ a kind of stealth coating-helping to cover over differences between the pig and human immune systems that had developed since apes like us and pigs diverged from a common ancestor, 80 to 100 million years ago. A final touch: disabling a receptor that senses growth hormone. Pigs are bigger than we are; this change would keep the organ from growing too large.

Rothblatt understood early on that the drugs were only a life-extending bridge to a lung transplant.

Organs with these modifications, especially when combined with new types of immune suppression drugs, have been proving successful in monkeys. I think the genetic modifications they have made to these organs have been incredible. I will tell you that we have primates going for a year with a [pig] kidney with good function," says Leonardo Riella, director of kidney transplantation at Massachusetts General Hospital, in Boston.

By 2021, some transplant surgeons were ready to try the organs in humans-and so was Rothblatt. The obstacle was that before green-lighting a formal trial in humans, the FDA, in a meeting that fall, had asked for one further set of monkey experiments that would have all the planned procedures, drugs, and tests locked in and standardized. The FDA also wanted to see consistent evidence that the organs survive for a long time in monkeys-half a year or more, people briefed by the agency say.

Each experiment cost $750,000, according to Griffith, a transplant surgeon at the University of Maryland, and some doctors felt the monkeys could no longer tell them much more. We left that meeting [thinking], Does that mean we are sentenced for the next two years to keep doing what we were doing?'" Griffith remembers. What they really needed to see was how the organs fared in a human being-a question more monkeys wouldn't answer. We knew we hadn't learned enough," he says.

Montgomery, the NYU surgeon, recalls an hours-long conversation with Rothblatt after which United agreed he could try a kidney in a brain-dead person being kept alive on a ventilator. Because the individual was dead, no FDA approval would be needed. The thing about a xenograft is that it's far more complex than a drug. And that has been its Achilles' heel. That is why it has remained in animal models," he says. So this was an attempt to do an intermediary step to get it into the target species." That surgery occurred in September 2021, and the organ was attached to the subject for only 54 hours.

In Maryland, Griffith, a heart surgeon, conceived a different strategy. He asked the FDA to approve a compassionate use" study-essentially a Hail Mary attempt to save one life. To his surprise, the agency agreed, and in early 2022 he transplanted a pig heart into the chest of David Bennett Sr., a man with advanced heart failure who wasn't eligible for a human heart transplant. According to Rothblatt, Bennett was interviewed by four psychologists before undergoing surgery.

A genetically modified pig heart is prepared for transplantation at New York University in July 2022.JOE CARROTTA/NYU LANGONE HEALTH

To observers like Arthur Caplan, a bioethicist at New York University, the use of one-off transplants to gain information raises an ethical question. So are you thinking, This guy is a goner-maybe we can learn something'? But the guy is thinking, Maybe I can survive and get a bridge to a human heart,'" says Caplan. I think there is a little bit of a back-door experiment being carried out."

Bennett survived two months before his new heart gave out, making him the first person in the world to get a lifesaving transplant from a genetically engineered pig. To Rothblatt, it meant success-even on autopsy, there were no evident signs the organ had been rejected, exactly the result she had been working toward. There is no way to know if we could have made a better heart in the allotted time ... [but] this 10-gene heart seemed to work very well," she told an audience of doctors last April. In Griffith's view, the organ performed like a rock star."

But in the end Bennett died. And in Rothblatt's lectures, she has elided a serious misstep, one that some doctors suspect is what actually killed the patient. When Bennett was still alive in the hospital, researchers monitoring his blood discovered that the transplanted heart was infected with a pig virus. The germ, called cytomegalovirus, is well known to cause transplants to fail. The Maryland team could have further hurt Bennett's chances as they battled the infection, changing his drugs and giving him plasma.

Without the virus, would the heart have gone on beating? The closest Rothblatt has come to acknowledging the problem in public was telling a legal committee of the National Academy of Sciences that she didn't put the blame on the pig heart. If I were to put it in layman's terms, I would say the heart did not fail the patient," she said.

The bigger problem with the infection, and with Rothblatt's failure to own the error, is that United's pigs were supposed to be tested and free of germs. United's silence is unnerving, because if this virus could slip through, it's possible other, more harmful germs could as well. Rothblatt did not answer our questions about the virus.

Printing lungs

United says that it is now building a new, germ-proof pig facility, which will be ready in 2023 and support a clinical trial starting the following year. It's not the fantastical commercial pig factory shown in Rothblatt's architectural rendering, but it is a stepping-stone toward it. Eventually, Rothblatt believes, a single facility could supply organs for the whole country, delivering them via all-electric air ambulances. Over the summer, she claims, an aeronautics company she invested in, Beta Technologies, flew a vertical-lift electric plane from North Carolina to Arkansas, more than 1,000 nautical miles.

Ironically, pigs may never be a source of the lungs that Rothblatt's daughter may need. That is because lungs are delicate and more susceptible to immune attack. By 2018, the results were becoming clear. Each time the company added a new gene edit to the pigs, hearts and kidneys transplanted into monkeys would last an extra few weeks or months. But the lungs weren't improving. Time and again, after being transplanted into monkeys, the pig lungs would last two weeks and then suddenly fail.

I actually believe there is no part of the body that cannot be 3D-printed."

Martine Rothblatt

To create lungs, Rothblatt is betting on a different approach, establishing an organ manufacturing" company that is trying to make lungs with 3D printers. That effort is now operating out of a former textile mill in Manchester, New Hampshire, where researchers print detailed models of lungs from biopolymers. The eventual idea is to seed these structures with human cells, including (in one version of the technology) cells grown from the tissue of specific patients. These would be perfect matches, without the risk of immune rejection.

This past spring, Rothblatt unveiled a set of printed lungs" that she called the most complex 3D-printed object of any sort, anywhere, ever." According to United, the spongy structure, about the size of a football, includes 4,000 kilometers of capillary channels, detailed spaces mimicking lung sacs, and a total of 44 trillion voxels," or individual printed locations. The printing was performed with a method called digital light processing, which works by aiming a projector into a vat of polymer that solidifies wherever the light beams touch. It takes a while-three weeks-to print a structure this detailed, but the method permits the creation any shape, some no larger than a single cell. Rothblatt compared the precision of the printing process to driving across the US and never deviating more than the width of a human hair from the center line.

MICHAEL BYERS

I actually believe there is no part of the body that cannot be 3D-printed ... including colons and brain tissue," Rothblatt said while presenting the printed lung scaffolds in June at a meeting in California.

Some scientists say bioprinting remains a research project and question whether the lifeless polymers, no matter how detailed, should be compared to a real organ. It's a long way to go from that to a lung," says Jennifer Lewis, who works with bioprinting at Harvard University. I don't want to rain on the parade, and there has been significant investment, so some smart minds see something there. But from my perspective, that has been pretty hyped. Again, it's a scaffold. It's a beautiful shape, but it's not a lung." Lewis and other researchers question how feasible it will be to breathe real life into the printed structures. Sticking human cells into a scaffold is no guarantee they will organize into working tissue with the complex functions of a lung.

Rothblatt is aware of the doubters and knows how difficult the technology is. She knows that other people think it won't ever work. That isn't stopping her. Instead, she sees it as her next chance to solve problems other people can't. During an address to surgeons this year, Rothblatt rattled off the list of challenges ahead-including growing the trillions of cells that will be needed. What I do know is that doing so does not violate any laws of physics," she said, predicting that the first manufactured lungs would be placed in a person's chest cavity this decade.

She closed her talk with a scene from 2001: A Space Odyssey, the one where an ape-man hurls a bone upward and it takes flight as a space station circling the Earth. Except Rothblatt substituted a photograph of herself piloting the zero-carbon electric plane she believes will someday deliver unlimited organs around the country.