Dying is not very good for the lungs. Besides the lack of oxygenated blood circulating to these very vital organs, the death process leads to the inability to swallow or cough, causing secretions to build up in the lungs and create the characteristic “death rattle.” And in sudden deaths—due to an accident or injury, for example—the lungs can suffer even more damage. If a patient breathes in food or other fluid, widespread inflammation can harm the lungs.
You might be wondering why any of this matters. After all, death is death. But in the case of organ donation, lungs can live on in a recipient after their donor passes. Transplantable organs are in high demand, too: Potential recipients may spend an average of two to three years on a waiting list for a lung transplant. There’s even a national shortage of transplantable organs, in part due to late-stage injuries to otherwise healthy organs.
“To be a donor, someone has to die. The lungs don’t tolerate that process very well,” Ciara Shaver, a transplant pulmonary physician at Vanderbilt University Medical Center, told The Daily Beast. “So the reason we can only use between 20 and 30 percent of lungs is there’s new damage to lungs that happens within a day or two of someone becoming a donor.”
Shaver, along with her Vanderbilt colleagues Matt Bacchetta (a transplant surgeon and biomedical engineer) and Kelly Wu (a general surgery resident nicknamed “Kickass Kelly” by former labmates), have thought a lot about how to get these lungs back in transplantable shape. The team took inspiration from Walton Lillehei, the so-called “father of open-heart surgery.” He pioneered a procedure called cross-circulation in which one person (often a parent of the child patient) provided oxygen-filled blood to the patient undergoing heart surgery.
Cross-circulation for heart surgery is no longer used today because of the development of the heart-lung bypass machine, but the Vanderbilt researchers realized that applying this method in pigs could allow for something near-magical to happen to donated human lungs.
Bacchetta told The Daily Beast that the realization was like, “‘Oh, God,’ if we attach this we can have a heart, a liver or a kidney, a gut, and we can have all the hormonal regulation that’s required for organs to heal themselves.”
The team’s research demonstrating the potential for cross-circulation despite interactions between the porcine and human immune systems was published on March 31 in the journal Science Advances. In experiments, they hooked up four different donor lungs rejected for transplant to immunosuppressed pigs and measured their changes and the pig’s immune reaction over the course of the next 24 hours. Even though the pigs’ immune systems launched into action, exhibiting signs of inflammation and depositing antibodies on the donor lungs, the injured human lungs showed signs of improvement.
In the past year, transplant teams around the country have made headlines for successfully performing xenotransplantation of pig hearts and kidneys into human recipients. But there’s a reason these organs have been chosen as the test cases, Bacchetta said. They don’t require much modification before being transplanted into their recipients, and as long as rejection doesn’t occur, they’re essentially good to go.
“A human is not a pig and a pig is not a human, and your immune system knows that.”
— Ciera Shaver, Vanderbilt University Medical Center
The liver and lungs, in contrast, have been “an enormous hurdle” for xenotransplant surgeons, in part because an organ like the lungs is constantly being injured by inhaled particles and repairing itself. Existing preservation techniques such as ex vivo lung perfusion are not meant to support the organ for more than several hours and can’t perfectly replicate a living, breathing organism that could give the lungs hormonal cues to recover from injury.
While xenotransplant research has focused extensively on understanding the immune response a human has to a pig organ, there had not yet been an investigation into the opposite, the authors wrote in the paper. Beginning to answer how the pig immune system reacts to a human organ will be necessary to get cross-circulation to work correctly and for progressing to the next stage, which is transplantation, Shaver said,
“A human is not a pig and a pig is not a human, and your immune system knows that,” she said. When pig blood is cross-circulated, it’s critical to understand how much of that blood—and components of the pig immune system present within it—is getting into the human lung or sticking to its surface.
With the pig’s immune response better understood, the researchers can focus their attention on tamping it down, since it’s significantly easier to prevent antibodies from sticking to donor lungs than removing them once attached.
Even in the face of an immune response, though, the lungs looked great. At 24 hours, their ability to undergo gas exchange and the partial pressure of oxygen inside them increased, while negative signs like the number of early-stage dying cells decreased—evidence that the researchers interpreted as signs of recovery. To Shaver, this finding underscores the strength of cross-circulation as an approach.
“Not only can the lung fix itself from the damage that the donor lung had in the first place, but it can do it despite an immune response being mounted against it,” she said.
Already, the scientists are working on the framework to expand cross-circulation to other human organs, starting with the liver. Eventually, they hope to conduct trials in humans to determine whether organs cross-circulated in pigs can be tolerated without rejection. If the procedures are successful, this method could permanently change the landscape of organ donation.
“There’s a certain percentage of people who will die waiting for an organ, but there are so many people that don’t even get onto the list,” Bacchetta said. “If you could expand the number of donors, then you could actually start to think about expanding the eligibility. I think there’s an enormous amount of opportunity.”
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