On a recent Thursday afternoon, researchers Lanuza Faccioli and Zhiping Hu wheeled an inconspicuous black and white plastic cooler from an operating room at a hospital in downtown Pittsburgh. Inside was a badly scarred liver, just removed from a 47-year-old man undergoing a transplant to receive a new one from a donor.

But what if patients could avoid that fate? Faccioli and Hu are part of a University of Pittsburgh team led by Alejandro Soto-Gutiérrez attempting to revive badly damaged livers like these—as well as kidneys, hearts, and lungs. Using messenger RNA, the same technology used in some of the Covid-19 vaccines, they’re aiming to reprogram terminally ill organs to be fit and functioning again. With donor livers in short supply, they think mRNA could one day provide an alternative to transplants. The team plans to begin a clinical trial next year to test the idea in people with end-stage liver disease.

Alcohol use, hepatitis infection, and a buildup of fat in the liver can cause scarring over time. When there’s too much damage, the liver starts to fail. “Right now, if you get end-stage liver disease, it’s irreversible,” Soto-Gutiérrez says. “Well, we found that is not true. It is reversible.”

Soto-Gutiérrez and his team have been experimenting on rats and organs taken from people undergoing transplants at the University of Pittsburgh Medical Center, one of the busiest transplant centers in the US. To help design the mRNA and figure out how to deliver it to the human liver, they’ve partnered with Drew Weissman, a physician and immunologist at the University of Pennsylvania who won the 2023 Nobel Prize in Physiology or Medicine for his pioneering work on mRNA. Together, Soto-Gutiérrez and Weissman lead the Center for Transcriptional Medicine, launched in April with the goal of bringing these medicines to patients.

On the day I visited, I followed Faccioli and Hu through a maze of hallways until they deposited the freshly explanted liver at a pathology lab, where a team of scientists was anticipating the special delivery. After infusing the liver with an experimental mRNA therapy, they placed the organ in an oxygenated bath meant to maintain its function for several days.

A healthy liver is spongy and reddish-brown in color with a smooth appearance. But when the surgeons took this one out of the cooler, it was hard, marbled, and covered in bumps—evidence of cirrhosis, a type of end-stage liver disease. Over time, the man’s healthy liver cells had been replaced by scar tissue, and eventually, his liver stopped working. His only option was to get a new one.

Livers are the second most in-demand organ. In 2023, a record 10,660 liver transplants were performed in the US, driven in part by a steadily growing number of living donors. In a living liver transplant, a piece is taken from a healthy person’s liver and transplanted into a recipient. But even with this uptick in transplants, not everyone who needs a new liver receives one. Patients may have other health problems that disqualify them from a transplant, and others may die while waiting for one. In 2022, the latest year for which data is available, the Centers for Disease Control and Prevention recorded nearly 55,000 deaths due to chronic liver disease.

Living donor transplants are possible because of the liver’s unique capacity to regenerate itself—more so than any other organ in the body. In a healthy person, the liver can regrow to its normal size even after up to 90 percent of it has been removed. But disease and lifestyle factors can cause permanent damage, rendering the liver unable to repair itself.

When Soto-Gutiérrez was studying medicine at the University of Guadalajara in Mexico, his uncle died of liver disease. From then on, he became dedicated to finding a treatment for patients like his uncle. In the early years of his medical career, he noticed that some patients with scarred livers were bound to a hospital bed waiting for a transplant, while other people with cirrhosis were walking around, seemingly living normal lives. He figured there must be cellular differences in these livers.

He teamed up with UPMC transplant surgeon Ira Fox to look for transcription factors—master regulators that can dial up or down the expression of groups of genes—that can potentially reprogram injured organs. Genes rely on transcription factors to perform many essential functions in organs. Together, Soto-Gutiérrez and Fox have analyzed more than 400 failing livers donated by transplant patients. When they compared them with dozens of normal donated livers that acted as controls, they identified eight transcription factors essential for organ development and function.

They zeroed in on one in particular, HNF4 alpha, that seems to act like a main control panel, regulating much of the gene expression in liver cells. In healthy liver cells, levels of HNF4 alpha were turned up, and so were other proteins it controls. But in the cirrhotic livers they examined, HNF4 alpha was almost nonexistent.

The team needed a way to get the transcription factor into liver cells, so they turned to mRNA technology. Used in some of the Covid-19 vaccines, mRNA is a molecule that carries instructions for making proteins, including transcription factors. In the Covid vaccines, the mRNA codes for a part of the virus known as the spike protein. When injected into a person’s arm, the mRNA enters cells and kicks off the protein-making process. The body recognizes these spike proteins as foreign and generates antibodies and other defenders against it.

The Pitt team is using mRNA instead to essentially turn back time in injured organs. “What we’re proposing to do with mRNA is use it to deliver proteins that have the capacity to repair those damaged liver cells,” Weissman says. “Our hope is that we can treat end-stage liver disease and turn the livers around, maybe forever, or at least until patients can get a transplanted organ liver.” Instead of delivering instructions for a foreign protein to generate an immune response, they’re delivering the genetic code for producing a transcription factor—HNF4 alpha.

In a paper published in 2021, the approach revived human liver cells in lab dishes. The researchers have since tested the mRNA therapy in rats with cirrhosis and liver failure. They treated a group of rats every three days for three weeks while a second group served as a control. The animals that were receiving the injection of HNF4 alpha started being more active. The untreated rats continued to decline and eventually died, the expected result at their stage of disease. Some of the treated rats were still living six weeks after receiving the mRNA medicine. Those results have not yet been published in a peer reviewed journal.

The team is also testing the mRNA infusions in human livers removed from patients undergoing transplants—the process I got to observe. Unlike live rats, explanted human livers can’t be observed for weeks on end. Livers have to be retrieved quickly and infused with the mRNA treatment soon after they’re removed from the body. They stay fresh for just four days or so in a preservation fluid. Six hours after the mRNA infusion, levels of HNF4 alpha start going up and last for two to three days. When HNF4 alpha peaks, other essential liver proteins, such as albumin, start to increase as well. That’s important, Soto-Gutiérrez says, because maintaining those protein levels could mean the difference between a patient needing a transplant or not.

Ideally, Soto-Gutiérrez says the mRNA therapy would be something patients could get once a week or every other week in an outpatient facility and go back home. But initially, they’ll need to test the experimental treatment in very sick patients, likely ones that are hospitalized, to make sure it’s safe. The team is gathering data from the rat and human liver experiments to submit a clinical trial application to the Food and Drug Administration in the coming months.

While livers are the first target, Fox thinks other injured organs may be amenable to this approach. “We’ve been wondering whether the same process might be taking place in other organs,” he says. Currently, the team is searching for similar transcription factors in lungs with chronic obstructive pulmonary disease and kidneys with chronic kidney disease.

Josh Levitsky, a liver transplant specialist at Northwestern University who isn’t involved in the work, says new treatments for chronic liver disease are sorely needed. Current therapies can help slow down scar tissue buildup and ease symptoms but don’t address the underlying disease. “The concept of reprogramming and being able to reverse liver failure could be really game changing if it were to pan out in clinical studies,” he says.

But lots of questions remain. How much damage could be reversed? Would patients need to be on the therapy indefinitely? Or would their livers rebound enough to go off it? Could a liver ever be restored back to normal?

“It certainly has a lot of promise,” Levitsky says, “but the clinical development is going to take a long time.”