A healthy liver is spongy and reddish-brown with a smooth appearance. But when surgeons pulled it out of the fridge, it was hard, mottled 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 Over time, the man’s healthy liver cells had been replaced by scar tissue, and eventually his liver stopped working.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.
The liver is the second most in-demand organ. In 2023, A record 10,660 liver transplants were performed in the United States.driven in part by an increasing number of living donors. In a living liver transplant, a piece of a healthy person’s liver is taken and transplanted into a recipient. But even with this increase in transplants, not everyone who needs a new liver gets one. Patients may have other health problems that disqualify them for 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 Nearly 55,000 deaths from chronic liver disease were recorded.
Living donor transplants are possible because of the liver’s unique ability to regenerate itself, more than any other organ in the body. In a healthy person, the liver can grow back to its normal size even after up to 90 percent of it has been removed. But diseases and lifestyle factors can cause permanent damage, rendering the liver unable to repair itself.
When Soto-Gutierrez was studying medicine at the University of Guadalajara in Mexico, his uncle died of liver disease. From then on, he dedicated himself to finding a treatment for patients like his uncle. In the early years of his medical career, he noticed some patients with scarred livers tied to a hospital bed waiting for a transplant, while other people with cirrhosis walked around, seemingly leading normal lives. He thought there must be cellular differences in those livers.
Soto-Gutierrez and Fox teamed with UPMC transplant surgeon Ira Fox to search for transcription factors — master regulators that can turn up or down the expression of groups of genes — that can reprogram damaged organs. Genes rely on transcription factors to perform many essential functions in organs. Together, Soto-Gutierrez and Fox analyzed more than 400 damaged livers donated by transplant patients. When they compared them to dozens of normal donated livers that acted as controls, they identified eight transcription factors essential to organ development and function.
They focused on one in particular, HNF4 alpha, which appears to act as a master control panel, regulating much of the gene expression in liver cells. In healthy liver cells, levels of HNF4 alpha were elevated, as 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. mRNA, which is used in some of the COVID-19 vaccines, is a molecule that carries instructions for making proteins, including transcription factors. In COVID-19 vaccines, mRNA encodes a part of the virus known as the spike protein. When injected into a person’s arm, the mRNA enters cells and kick-starts the protein-making process. The body recognizes these spike proteins as foreign and generates antibodies and other defenses against them.