The scale of the unmet need is stark. In 2020, nearly 25,000 people were on the United States liver transplant waiting list, yet only about 38 percent of them received an organ. For many patients with end-stage liver disease, transplantation remains the only cure, and the shortage of donor organs means that thousands die or become too sick to qualify while waiting. Even those who do receive a transplant face a lifetime of immunosuppressive drugs, which carry risks of infection, cancer, and organ toxicity. Prometheus is designed to attack both problems at once: by creating a universal cell source that evades immune rejection and by manufacturing functional liver tissue on a scale that does not depend on deceased donors.

The project’s name is a deliberate nod to biology and mythology alike. Prometheus, the Greek Titan, was condemned to have his liver devoured daily, only for the organ to regenerate each night, a story long associated with the liver’s remarkable natural capacity for regeneration. The modern Prometheus project seeks to harness and extend that regenerative potential through engineering, building liver tissue in the laboratory that can engraft and function after transplantation.

At the technical core of the initiative is the creation of a universal, immune-compatible liver cell source derived from allogeneic hypoimmunogenic induced pluripotent stem cells. Induced pluripotent stem cells, or iPSCs, are adult cells reprogrammed back into an embryonic-like state, giving them the ability to differentiate into virtually any cell type in the body, including hepatocytes and the supporting vascular and stromal cells that a functioning liver tissue requires. By genetically engineering these cells to be hypoimmunogenic, meaning they are cloaked against the immune recognition mechanisms that normally trigger rejection, the team aims to produce cells that can be transplanted across patients without tissue matching and without the dangerous long-term immunosuppression that conventional transplantation demands.

Turning those cells into transplantable tissue requires more than biology; it demands engineering at scale. The Prometheus strategy combines cost-effective, scalable bioreactor culture methods with porous bed bioprinting, an additive manufacturing approach in which living cells and biomaterials are printed into three-dimensional architectures with interconnected porosity. That porosity is critical, because engineered tissue thicker than a few hundred microns cannot survive on diffusion alone. A printed liver construct must contain vascular-like channels that allow oxygen and nutrients to reach every cell and metabolic waste to be removed, both in the bioreactor during manufacturing and after implantation in the recipient’s body.

Dr. Shen framed the award as a convergence of disciplines that have too often worked in isolation. “This award allows us to bring together bioengineering, stem cell biology, and transplant medicine to build a liver that doesn’t require a donor match,” he said. “It’s a step toward making organ replacement scalable rather than scarce.” Within the Terasaki Institute itself, a dedicated faculty team will divide the technical challenges. Dr. Johnson V. John, Assistant Professor, is developing 3D-printing methods to build the structural and vascular components needed to support the tissue after transplantation. Dr. Vadim Jucaud, Assistant Professor, is working to establish perfusion through that architecture so the printed tissue can receive oxygen and nutrients throughout its volume. Dr. Menekse Ermis Sen, Terasaki Fellow, is developing the cell-manufacturing methods used to grow and scale the tissue’s biological components, a task that involves producing billions of functional cells under controlled, quality-assured conditions.

The collaboration extends well beyond a single institute. Co-investigators at Weill Cornell Medicine, The Pennsylvania State University, Washington University in St. Louis, Technion, Israel Institute of Technology, and Rice University contribute expertise spanning stem cell differentiation, immunology, and tissue engineering. “PROMETHEUS connects discoveries across traditionally separate fields into a unified approach to liver replacement,” said Dr. Shuibing Chen of Weill Cornell Medicine. “This collaboration gives us an opportunity to turn bold scientific ideas into solutions that could meaningfully change the lives of patients.” At Penn State, Dr. Xiaojun Lance Lian highlighted one of the field’s central obstacles: “A major challenge in developing off-the-shelf engineered tissues is creating a cell source that can evade immune rejection across different patients,” he said. The hypoimmunogenic iPSC platform at the heart of Prometheus is a direct answer to that challenge.

Industrial partnership plays a decisive role in translating laboratory science into manufacturable medicine. Pluristyx is supplying the induced pluripotent stem cell lines that serve as Prometheus’s starting cell source. “We are thrilled to support the Terasaki Institute and colleagues as they address the critical shortage of transplantable livers via this ARPA-H program,” said Dr. Benjamin Fryer, CEO of Pluristyx. He explained that the company’s iPSCs are purposefully supplied in a genetically engineered, pre-expanded, and quality-controlled form, and are available in an immune-cloaked format to enable the massive scale of manufacturing required to build replacement liver tissue. By incorporating the company’s patient-centric safety switch, FailSafe, the engineered liver tissues could, in principle, provide a safe, durable, and universal replacement without the need for tissue matching or dangerous long-term immunosuppression. Such built-in safety mechanisms are widely regarded as essential for any clinical product derived from pluripotent stem cells, since they offer a way to eliminate cells that proliferate abnormally after transplantation.

Even a perfectly engineered tissue must prove itself in the body, and that responsibility falls to the transplant immunology team at UCLA. “Engineering a liver is only the beginning; proving that it works after transplantation is the decisive challenge,” said Jerzy W. Kupiec-Weglinski, M.D., Ph.D., Terasaki Professor of Surgery at UCLA. “At UCLA, we will transplant bioprinted liver tissues into laboratory models and evaluate their engraftment, function, and regenerative capacity, helping transform the promise of bioprinting into a practical solution for organ failure and donor organ scarcity.” Engraftment, the process by which transplanted tissue integrates with the host’s vasculature and begins performing hepatic functions such as protein synthesis, detoxification, and bile production, is the benchmark against which every engineered liver construct must ultimately be judged.

If successful, Prometheus could establish a scalable, donor-independent path to liver replacement, easing a shortage that today leaves thousands of patients without options and reducing the lifelong burden of immunosuppression for those who do receive transplants. The project also carries a symbolic resonance for the institute that leads it. It builds upon the legacy of TIBI founder Dr. Paul I. Terasaki, whose pioneering development of donor-recipient compatibility testing transformed organ transplantation and whose work continues to guide the institute’s research. Where that earlier revolution made transplants safer by matching donors to recipients, the new effort aims to make matching unnecessary altogether. The research is funded, in part, by ARPA-H, and the views expressed by the investigators are their own, not official positions of the U.S. Government. For a field that has long promised engineered organs and struggled to deliver them, the Prometheus project represents one of the most comprehensively resourced attempts yet to move bioprinted liver tissue from the laboratory bench toward the clinic.

Subject of Research: Bioprinting of immune-compatible, transplantable liver tissue from induced pluripotent stem cells

Article Title: Terasaki Institute secures up to $19.8 million ARPA-H PRINT award for Prometheus liver bioprinting project

Article References: Terasaki Institute secures up to $19.8 million ARPA-H PRINT award for Prometheus liver bioprinting project. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: liver bioprinting, ARPA-H, PRINT program, Terasaki Institute, induced pluripotent stem cells, hypoimmunogenic cells, organ transplantation, immunosuppression, bioreactor culture, tissue engineering, regenerative medicine, organ shortage

The liver has long been considered the most difficult organ to transplant across species. Unlike the heart or kidney, whose failures can be bridged by dialysis or mechanical support, the liver performs hundreds of interlocking tasks: synthesising clotting factors and albumin, clearing toxins and ammonia, producing bile, and orchestrating immune surveillance through its unique sinusoidal vasculature. Previous pig-to-human attempts relied on auxiliary transplantation, in which the pig liver was added alongside the recipient’s own liver rather than replacing it, providing partial metabolic support without fully testing the xenograft’s capacity. Earlier work, including a 2024 case in which a gene-edited pig liver supported a patient for ten days, and a 2025 report of gene-modified pig-to-human liver xenotransplantation by the same Chinese group, demonstrated feasibility but left open the question of whether an orthotopic graft, placed where the human liver once sat, could sustain life-sustaining function on its own.

Central to the new study was the donor animal itself. The team used a pig engineered with six genetic modifications, or 6-GE, designed to blunt the three-pronged human immune attack on pig tissue. Three genes were knocked out: GGTA1, CMAH and B4GALNT2, which encode enzymes that decorate pig cell surfaces with carbohydrate antigens, including the galactose-alpha-1,3-galactose epitope, N-glycolylneuraminic acid and the Sd(a)-like antigen, against which humans carry preformed natural antibodies. Three human genes were added: CD46 and CD55, which regulate complement activation at the cell surface, and thrombomodulin (THBD), an anticoagulant protein that helps convert protein C to its activated form and dampens the inflammatory coagulation cascade. Polymerase chain reaction and Sanger sequencing confirmed the edits at the genomic level, and screening found no evidence of porcine endogenous retrovirus transmission or microchimerism in the recipient’s tissues during the observation window.

The recipient was a brain-dead individual, a model that allows researchers to evaluate xenograft function under genuine human physiology while respecting the ethical framework of organ donation. Brain death, however, is a double-edged sword: the dying brain triggers a storm of systemic inflammation and endothelial injury that can itself destabilise haemodynamics and complicate interpretation of graft outcomes. The surgical team performed the orthotopic transplant, removing the native liver and connecting the pig organ to the recipient’s portal vein, hepatic artery, hepatic veins and biliary system. Preoperative ultrasound confirmed that the diameters of the donor and recipient portal veins and hepatic arteries were compatible, a practical prerequisite that is far from trivial given the size and anatomical variability of both human and porcine vasculature.

Over 11 days of continuous monitoring, the xenograft demonstrated that a pig liver can execute core hepatic functions in a human host. The graft produced albumin continuously and generated bile with normal composition, findings that indicate functioning hepatocytes and an intact biliary epithelium, even though the absolute quantities remained below what a healthy human liver would deliver. Metabolomic analyses, deposited in a public database under accession OMIX017282, tracked the biochemical interplay between graft and host. Systemic haemodynamic stability was maintained throughout, meaning the recipient did not require escalating vasopressor support attributable to graft failure, and the pig liver did not provoke the catastrophic collapse that has historically accompanied cross-species organ transplants.

Yet the study is equally notable for what went wrong, and the authors are candid about it. Imaging and functional assessment revealed suboptimal hepatic perfusion arising from microthrombosis, the formation of microscopic clots within the graft’s sinusoidal vessels, which the researchers believe contributed substantially to the late-phase decline in hepatic function. Coagulation abnormalities emerged as progressive thrombocytopenia, a falling platelet count, alongside reduced activity of clotting factors. This pattern echoes the thrombocytopenia and coagulation dysregulation seen in pig-to-baboon liver transplants and in the landmark pig-to-human heart transplants, and it points to a fundamental incompatibility between pig endothelium and the human coagulation system that current genetic engineering has only partially resolved. The liver’s consumption of platelets and clotting factors, combined with impaired thrombomodulin-mediated protein C activation in the face of endothelial stress, appears to drive a vicious cycle of microvascular clotting and bleeding risk.

The immunological portrait drawn from histopathology was in some respects encouraging. Examination of biopsy and autopsy tissue found scant infiltration by T cells and B cells and minimal deposition of immunoglobulin G, suggesting that the adaptive immune response, the arm of immunity responsible for chronic cellular rejection, was largely held in check by the genetic modifications and the targeted immunosuppressive regimen. Instead, the dominant pathology was innate: prominent activation of innate immune cells and evidence of immunoglobulin M-mediated complement activation, the rapid, antibody-triggered cascade that has historically destroyed unmodified pig organs within minutes. That the classical hyperacute rejection was avoided, while a slower innate-driven injury emerged, marks a shift in the nature of the problem rather than its elimination.

The authors argue that these findings define the research agenda for the next phase of clinical translation. Endothelial damage, microthrombosis and coagulopathy now stand out as the critical challenges, and addressing them will likely require additional genetic modifications, such as further human anticoagulant and complement-regulatory transgenes, together with refined immunosuppressive protocols tailored to the liver’s distinctive immunology. The study also underscores the value of the brain-dead recipient model, which generates clinically relevant data without exposing a living patient to an unproven therapy, even as it cautions that the inflammatory milieu of brain death may exaggerate some forms of injury. Metabolomics, serial histology and comprehensive coagulation profiling of the kind reported here give transplant teams a granular, time-resolved picture of how a xenograft fails, information that no animal model can fully replicate.

For the field at large, the experiment represents a careful step forward rather than a breakthrough cure. Global shortages of donor livers leave millions of patients with end-stage liver disease facing limited options, and pig organs, which can be gene-edited, pathogen-screened and produced on demand, remain the most credible long-term solution. The demonstration that a six-gene-edited pig liver can sustain albumin and bile production and haemodynamic stability for 11 days in a human body, while the precise mechanisms of its gradual functional decline are documented at molecular resolution, converts xenogeneic liver transplantation from a speculative concept into an engineering problem with identifiable targets. Whether the next iteration of gene-edited donors and immunosuppressive strategies can extend graft survival from days to months, and ultimately to the years a clinical therapy would demand, will be decided by the coagulation and innate immune pathways this study has now brought into sharp focus.

Subject of Research: Orthotopic xenotransplantation of a six-gene-edited pig liver into a brain-dead human recipient

Article Title: Orthotopic liver xenotransplantation from gene-modified pig to decedent human

Article References: Tao, K., Yang, Z., Zhang, X., Zhang, H., Lin, Z., Yue, S., Yang, Y., Song, W., Wang, D., Liu, Z., Li, H., Chen, Y., Zhou, J., Ding, R., Sun, S., Yu, M., Li, J., Duan, W., Wang, Z., … Dou, K. (2026). Orthotopic liver xenotransplantation from gene-modified pig to decedent human. Nature Biomedical Engineering. https://doi.org/10.1038/s41551-026-01797-2

Image Credits: AI Generated

DOI: 10.1038/s41551-026-01797-2

Keywords: xenotransplantation, pig liver transplant, gene-edited pigs, orthotopic liver transplantation, brain-dead recipient, microthrombosis, coagulopathy, complement activation, thrombocytopenia, albumin production, bile production, organ shortage