A fit liver is spongy, reddish-brown in color and glossy in appearance. But when surgeons removed it from the refrigerator, it was challenging, marbled, and covered in nodules—evidence of cirrhosis, a form of end-stage liver disease. Over time, the man’s fit liver cells were replaced by scar tissue, and eventually his liver stopped working. His only option was to get a up-to-date one.
Livers are the second most desired organ. In 2023 A record number of 10,660 liver transplants were performed in the USfueled in part by the ever-increasing number of living donors. In a live liver transplant, part of the liver is taken from a fit person and transplanted into the recipient. But even with this augment in transplants, not everyone who needs a up-to-date liver gets one. Patients may have other health problems that disqualify them from receiving a transplant, and others may die while waiting for a transplant. In 2022, the latest year for which data is available, the Centers for Disease Control and Prevention There have been almost 55,000 deaths caused by chronic liver disease.
Living donor transplants are possible because the liver has an extraordinary capacity for regeneration—more than any other organ in the body. In a fit person, the liver can grow back to normal size even after up to 90 percent of its parts have been removed. But disease and lifestyle factors can cause indefinite damage, preventing the liver from repairing itself.
When Soto-Gutiérrez was studying medicine at the University of Guadalajara in Mexico, his uncle died of liver disease. Since then, he has dedicated himself to finding treatments for patients like his uncle. Early in his medical career, he noticed that some patients with scarred livers were confined to hospital beds, waiting for transplants, while other people with cirrhosis walked around, seemingly leading normal lives. He concluded that there must be cellular differences in these livers.
He worked with UPMC transplant surgeon Ira Fox to look for transcription factors—master regulators that can upregulate or downregulate groups of genes—that could potentially reprogram damaged organs. Genes rely on transcription factors to perform many of the necessary functions in organs. Together, Soto-Gutiérrez and Fox analyzed more than 400 failing livers donated by transplant patients. When they compared them to dozens of normal livers donated as controls, they identified eight transcription factors necessary for organ development and function.
They focused on one in particular, HNF4 alpha, which appears to act as a master control panel, regulating most gene expression in liver cells. In fit liver cells, HNF4 alpha levels were elevated, as were other proteins it controls. But in the cirrhotic livers studied, HNF4 alpha was almost completely absent.
The team needed a way to get the transcription factor into liver cells, so they turned to mRNA technology. Used in some Covid-19 vaccines, mRNA is a molecule that carries instructions for making proteins, including transcription factors. In Covid vaccines, the mRNA encodes a part of the virus known as the spike protein. When injected into a person’s arm, the mRNA enters the cells and starts the process of making the protein. The body recognizes these spike proteins as foreign and generates antibodies and other defenses against them.