Leading expert in liver disease and xenotransplantation, Dr. Simon Robson, MD, explains the current state and future of liver transplantation from animals. He details the major challenges of organ rejection and infection transmission. Genetic engineering of pig livers shows promise in overcoming these hurdles. Currently, animal liver transplants serve only as a temporary bridge to human donor transplantation. Dr. Simon Robson, MD, highlights significant progress, with survival times in preclinical models extending from days to many weeks.
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Xenotransplantation: The Future of Animal to Human Liver Transplants
Jump To Section
- Current State of Xenotransplantation
- Overcoming Organ Rejection
- Research Progress and Survival
- Infection Risks in Xenotransplantation
- Clinical Applications as a Bridge
- Human Liver Transplant Options
- Full Transcript
Current State of Xenotransplantation
Liver xenotransplantation involves transplanting organs from animals, primarily pigs, into humans. Dr. Simon Robson, MD, a leading researcher in the field, explains that this area is highly complex. The human body mounts a rapid and severe immune response against pig organs. This immediate rejection is a primary reason liver transplantation from animals does not work well today.
Preclinical models focus on transplanting genetically modified pig livers into primates like baboons. Past attempts to use pig livers as perfusion devices for patients with acute liver failure showed limited benefit. The conversation with Dr. Anton Titov, MD, underscores that the current technology is not yet ready for long-term human use.
Overcoming Organ Rejection
The major barrier to successful liver xenotransplantation is hyperacute organ rejection. Dr. Simon Robson, MD, details that this rejection is mediated by antibodies and complement activation. A key strategy involves genetic modification of donor pigs to remove specific sugar antigens, known as gal epitopes, that humans recognize as foreign.
However, deleting these antigens leads to another problem: excessive blood clot formation. Dr. Robson's research focuses on expressing human genes in pigs to prevent this clotting. Critical molecules include the CD39 enzyme, which removes ATP to prevent platelet activation, and thrombomodulin, a potent human anticoagulant. This genetic engineering is essential to make pig livers compatible with human physiology.
Research Progress and Survival
Significant research advances have been made in xenotransplantation over the past two decades. Dr. Simon Robson, MD, notes that initial survival times for primate recipients of pig organs were only one or two days. Through extensive collaboration and genetic modification, researchers have dramatically extended this survival.
Current models show pig kidneys can support life in a baboon for up to 68 days. Heart xenotransplants can last 20 to 30 days. Liver transplantation remains the most challenging organ. Despite progress, the function and survival of a transplanted pig liver are still measured in days, not months or years. This highlights the ongoing work needed to achieve lasting success.
Infection Risks in Xenotransplantation
A critical concern with transplanting animal organs is the risk of zoonotic infection transmission. Dr. Simon Robson, MD, discusses several viruses that could potentially jump from pigs to humans. These include hepatitis E virus, porcine endogenous retroviruses (PERVs), and pig cytomegalovirus.
Immunosuppressed transplant patients are particularly vulnerable to these infections. Other threats, like influenza viruses that move between pigs and humans, are also a consideration. Dr. Robson mentions the Reston ebola virus as an example of an animal virus that can transmit between species. Vigilant screening and genetic engineering are necessary to mitigate these infection risks in liver transplantation.
Clinical Applications as a Bridge
The most immediate clinical application for liver xenotransplantation is as a bridge therapy. Dr. Simon Robson, MD, explains that patients with acute liver failure have no equivalent to kidney dialysis. A genetically modified pig liver could function temporarily for 7 to 10 days in a human.
This brief period could allow a patient's own liver to recover or provide crucial time to locate a human donor organ. For now, pig liver transplantation is not a permanent solution. It is a stopgap measure to prevent death while awaiting a human-to-human transplant. This bridge concept represents a hopeful near-term use for the technology.
Human Liver Transplant Options
Dr. Simon Robson, MD, and Dr. Anton Titov, MD, also discuss current human liver transplant options. The gold standard for long-term survival remains transplantation from a human donor. This can come from a deceased, brain-dead donor or a living donor.
Living donor liver transplantation involves resecting up to 50% of a healthy person's liver. The donor's liver regenerates to its normal size within 6 to 8 weeks. Recipients often have excellent outcomes because the transplanted organ is healthy and not subjected to inflammatory stress. However, the surgery carries a risk for the healthy donor, underscoring the need for alternative organ sources like xenotransplantation.
Full Transcript
Liver transplantation from animals: hope and challenges explained by a leading expert in liver disease. How close are we to reliable transplantation of the liver from animals? How to overcome challenges to liver xenotransplantation? Liver transplantation from animals: hope and challenges explained.
Dr. Anton Titov, MD: Video interview with a leading expert in liver diseases from Harvard Medical School. Dr. Simon Robson has done liver xenotransplantation research for 20 years. Video interview with a leading expert in liver diseases about the current state of liver transplantation from animals. How close are we to transplanting animal organs into humans? There is progress in farming animal organs for human transplantation.
Dr. Simon Robson, MD: Problems are organ rejection and the transfer of animal infections. Liver transplantation from animals does not work very well today. Organ rejection happens by complement activation. Modification of pig liver by genetic engineering to prevent rejection is possible. Enzyme CD39 plays an important role in transplantation. It removes ATP.
Pig liver transplantation is possible as a temporary measure until a human donor liver is found. A medical second opinion helps to make sure the diagnosis of liver failure is correct and complete.
Dr. Simon Robson, MD: A medical second opinion in liver failure also helps to choose the best treatment to delay the need for a transplant. Animal viral infections are Reston Ebola type virus and pig cytomegalovirus. They can potentially transmit to human organ recipients.
Dr. Anton Titov, MD: Advantages of xenotransplantation are a ready source of organs from "farmed animals." Disadvantages are organ rejection and animal infections. Liver transplantation from animals is getting more advanced. Should animal organs be farmed for human transplants?
Dr. Simon Robson, MD: Yes, animal organs should be farmed if transplantation problems can be solved. Xenotransplantation: weighing individual benefit and risks is currently difficult for patients. Because animal donor organs are only a temporary measure in human transplantation. Liver transplantation from animals can help more patients now than before. Animal organs for human transplantation. Pig liver transplant to humans.
Dr. Anton Titov, MD: Liver transplantation. The liver is a biochemical laboratory of the body and has a remarkable capacity to regenerate.
Dr. Simon Robson, MD: But autoimmune and viral hepatitis, fatty liver disease, and metabolic syndromes can severely damage the liver. Sometimes only liver transplantation can help the patients. But there are very few liver donors compared with the number of patients who need liver transplantation. This brings us to the question of liver transplantation from animals (xenotransplantation). You have done major work on liver transplantation from animals. Liver transplantation from animals is one of your major clinical interests.
Dr. Anton Titov, MD: What is the current state of xenotransplantation technology? What are current advances in liver transplantation?
Dr. Simon Robson, MD: Liver xenotransplantation is a very complex field. We have been looking at transplanting liver from pigs to primates. The liver transplantation model we study is transplantation of genetically modified liver from pigs to baboons. This is a preclinical model of liver transplantation.
Dr. Simon Robson, MD: There were transplants from pigs into humans. Pig livers were also used as a perfusion device to correct metabolic problems in acute liver failure.
Dr. Anton Titov, MD: To clean toxins from human blood by passing it through a pig liver.
Dr. Simon Robson, MD: Those studies did not show any major benefit to human patients with acute liver failure. There is a problem with the use of swine liver, kidneys, and heart for transplantation into humans. The human body very rapidly rejects these pig organs. Organ rejection is mediated by antibodies. This is called complement activation. It is a very heightened immediate and innate immune response.
Dr. Simon Robson, MD: We can try to prevent acute rejection of the transplanted liver by modification of the pig liver. This modification removes major antigens, gal sugar epitopes, from the pig liver. These sugar antigens are present on pig liver.
Dr. Anton Titov, MD: But humans do not have them. We can delete these antigens from the pig liver used for liver transplantation. The problem then is excessive blood clot formation on the blood vessels in the donor pig liver. We work to solve this problem by expressing human anticoagulants and antithrombotic molecules. We express these molecules on the surface of pig liver blood vessel lining (endothelium).
Dr. Simon Robson, MD: The focus of my research has been the CD39 enzyme. CD39 is an enzyme that removes ATP. ATP activates platelets and initiates blood clot formation. We also work on thrombomodulin, which is a human anticoagulant. Pig equivalents of CD39 and thrombomodulin do not work in humans and baboons. What we do is we take the human gene and we insert the human gene into the pig.
Dr. Simon Robson, MD: This is similar to human complement activation regulatory genes. Human genes can be expressed in pigs. We express in pigs human clotting regulatory genes to prevent activation of clotting. I have been doing this research on liver xenotransplantation for 20 years. I collaborate in liver transplantation work with Dr. David Sachs from Massachusetts General Hospital, with Dr. Peter Cowan and Dr. Anthony d’Apice in Australia. We also work on liver transplantation and pig xenotransplantation with surgeon Dr. David Cooper in Pittsburgh.
Dr. Simon Robson, MD: We have achieved dramatic progress in xenotransplantation. First, the survival of xenotransplantation organ recipients was only one or two days. This was in a gal antigen knockout model.
Dr. Simon Robson, MD: Now survival after xenotransplantation lasts many weeks. Right now the transplanted pig kidney could survive for 68 days on life support in a baboon. Heart transplantation from pigs to baboons is not yet life-supporting after 20 or 30 days. The liver is a different issue.
Dr. Anton Titov, MD: The liver is so important in the generation of clotting factors. We can do genetic engineering of regulatory factors. We can block blood clotting activation in the transplanted organ. But with liver xenotransplantation, the life of the recipient is still measured in days. Today we can only use liver xenotransplantation as a bridge. In acute liver failure, we do not have "dialysis" as we have in acute kidney failure. A patient with acute liver failure can potentially get a pig liver transplant.
Dr. Simon Robson, MD: This transplanted pig liver will work for 7 to 10 days in a human patient. We hope that in 7 to 10 days a patient with acute liver failure who had pig liver transplantation can partially recover. During this period of time, a human cadaveric donor can be found for human-to-human liver transplantation. For now, pig liver transplantation to humans is only a bridge to human donor liver transplantation. Things can change in the future. There have been major advances in the liver transplantation field over the last 5 to 10 years.
Right now we are working on prolonging the survival of the xenotransplant in recipients. We also work on improving function in the transplanted liver. Lasting success of pig liver xenotransplantation is still a trip into the future. But we achieved some major advances in liver transplantation.
Dr. Anton Titov, MD: Today it is the human-to-human liver transplantation that is clinically significant for prolonged survival.
Dr. Simon Robson, MD: Correct. In acute liver failure patients, cadaveric liver transplantation can be done. This is liver transplantation from brain-dead donors.
Dr. Simon Robson, MD: Living donor liver transplantation can help patients with stable liver disease and chronic liver disease, for example, liver tumors.
Dr. Anton Titov, MD: Part of the liver can be resected from a family member or non-relative liver donor. Blood group matching must be done for such liver transplants. Surgeons can resect 50% of the liver from a living donor. Within 6 to 8 weeks, the remaining liver in the donor will be regenerated to its normal size and normal metabolic capacity. There are very good clinical outcomes in the recipient of liver transplantation from a living human donor.
Dr. Simon Robson, MD: Because the transplanted liver is not subject to any inflammatory stress. The liver that was stored in cold has inflammation and other problems. The liver from brain-dead donors also has problems that complicate liver transplantation. Patient clinical outcomes are good with living donor liver transplantation. The problem is that a normal healthy liver donor is subjected to potentially dangerous surgery in liver transplantation. There is a risk that the donor might die during surgery to take part of the liver for transplantation.
Dr. Anton Titov, MD: Pig liver transplantation carries a risk of infection and transfer of animal viruses to a human recipient.
Dr. Simon Robson, MD: This is a concern in liver transplantation from pig to human. There are pig viruses and bacteria that can cause disease in humans. There is hepatitis E in pigs. Hepatitis E virus can cause disease in humans. Also, there are pig retroviruses, for example, porcine endogenous retrovirus. This virus can be reactivated when the patient is immunosuppressed after liver transplantation. This can cause disease in humans. But infections don't seem to be a major problem in xenotransplantation.
Dr. Simon Robson, MD: There is also a pig cytomegalovirus that can be reactivated in a human patient after liver transplantation. Pig cytomegalovirus can damage the epithelial lining of blood vessels. There are concerns of Ebola virus infection during transplantation. There are other animal viruses that can jump from animals to humans. I find it interesting that Reston Ebola type virus was found in monkeys from the Philippines. These monkeys were brought to the United States. Fortunately, this Ebola type virus did not transmit to humans. But Reston Ebola virus did transmit from infected monkeys to other primates. It caused a lot of problems.
Dr. Simon Robson, MD: This Ebola type virus can also transmit to pigs, as was reported from the Philippines, where these monkeys came from. We know that in xenotransplantation we have to be concerned with influenza viruses. Influenza viruses can be transferred between pigs and humans. Pigs and birds are natural intermediate hosts for influenza viruses. But in xenotransplantation (and liver transplantation between animals and humans) we need to be concerned with other zoonotic infections.
Dr. Anton Titov, MD: These are infections that come from animals. Immunosuppression of patients after liver transplantation can predispose patients to these infections. This is an interesting area of transplantation research. There are a lot of discoveries in biology that are important.
Dr. Simon Robson, MD: This research has major clinical applications. We hope to find medicines or genetic modifications that prevent xenograft rejection after transplantation of organs from animals. Such a discovery will also have important meaning for other human diseases. This discovery will be particularly important for diseases where blood vessels are damaged.
Dr. Anton Titov, MD: Liver transplantation from animals: hope and challenges explained. Video interview with a leading liver transplantation expert. State of liver xenotransplantation.