Scientific Issues Raised by Xenotransplantation
[Source : Health Canada, Therapeutic Products Programme, December 2000. Reprinted with permission.]
1. What Is Xenotransplantation?
Xeno means “strange, or foreign.” The term xenotransplantation (pronounced zeeno-transplantation) is used to describe a transplant between any two species of animals,1 including humans.
Xenotransplantation most often refers to a procedure in which an organ (such as a kidney or liver) or live cells (such as brain cells) from a healthy animal are transplanted or grafted into a human patient. The transplanted or grafted material is called a xenotransplant or a xenograft.
When only cells are used, the material is often referred to as a cellular xenotransplant or cellular xenograft.
As well, there are certain kinds of xenotransplants which are not true transplants at all, because the animal organ or cells stay outside the patient’s body. These are called extra-corporeal (or outside-the-body) xenotransplants.
Which animals will be used as a source of xenotransplants?
The animals which are most biologically similar to humans are the non-human primates, such as chimpanzees, baboons, monkeys. Xenotransplants from these animals would probably work better and be more readily accepted by the immune systems of patients receiving them. However, some significant safety risks may be connected with using organs from non-human primates. The possibility of transmitting infectious diseases is one such risk. As well, the use of non-human primates raises a number of ethical issues.
Most people involved with xenotransplantation today think that pigs are likely to be the best choice for source animals. There are a number of reasons for this.
- Pigs can be raised in a highly controlled way, so that their organs are less likely to transmit infectious diseases to humans.
- Pig organs are about the right size for transplanting into humans
- Pigs (as well as other animals) can be bred to contain human genes. The reason for doing this is so the animal cells will be more readily accepted by a patient’s immune system. Genetically engineered pigs are called “transgenic pigs.”
- When they are raised in a controlled environment, pigs’ exposure to microorganisms can be minimized and their need for social interaction can be met.
The use of pigs in this way raises a number of ethical issues which are discussed in the booklet called Ethical and Social Issues Raised by Xenotransplantation.
2. What Kinds of Diseases Could Be Treated By Xenotransplantation?
Any disease that is treated by human-to-human transplants could potentially be treated by xenotransplantation. The most likely candidates for xenotransplantation in the near future are people with serious kidney, liver or heart disease, diabetes or Parkinson’s disease. People who need bone marrow transplants may also be candidates for this kind of transplant.
What diseases might be treated by cellular xenotransplants?
Cellular xenotransplants may be a way to treat people who have diabetes, Parkinson’s disease or certain other diseases. The treatment would involve replacing specific cells or tissues which do not work properly because of the disease. For diabetics, these are the islet cells of the pancreas, and for someone with Parkinson’s disease they would be certain brain cells. In both cases, the cells needed for the transplant are difficult to obtain from human donors.
What diseases might be treated by extra-corporeal xenotransplants?
People with liver failure might be treated with an extra-corporeal (outside-the-body) xenotransplant using a healthy pig liver. The patient’s blood circulation would be connected for a short while to a pig liver that is kept outside the patient’s body. In some cases, this might be all that is needed to allow the person’s own liver to recover and start working again. In other cases, the person’s own liver might not recover, but the transplant team would have more time to try to find a suitable human liver. This kind of short term procedure is sometimes called a bridge to transplant. In either case the extra-corporeal pig liver would only be temporary.
Other extra-corporeal xenotransplant treatments may be carried out using only a small number of living animal cells. For example, the animal cells may be included in a specialized device, such as a filter system. When the blood of a patient with liver failure is pumped through this filter system, the animal liver cells are able to do the work of the patient’s own liver, at least for a short while.
Is a xenotransplant intended to be permanent?
Not always. While organ transplants are generally intended to be permanent, some kinds of transplanted cells may need to be replaced regularly in order to function well and remain vital. Also, certain kinds of xenotransplants are not really true transplants at all, because the animal’s organ or cells stay outside the patient’s body and are used only in the short term, often as a bridge to transplant (see Glossary).
3. How Is Scientific Research on Xenotransplantation Carried Out?
Research on xenotransplantation follows the same steps as research into any other treatment for human disease. The first step involves studies that are carried out in the laboratory and/or on animals. These kinds of studies are called pre-clinical trials. They do not involve human patients.
Many xenotransplantation studies have been carried out using laboratory animals. As well as increasing scientists’ understanding of how well xenotransplantation works or does not work, they have helped scientists understand how xenotransplantation might be made safer and more successful for treating patients.
When pre-clinical studies show that the treatment is safe and effective in animals, the new treatment or therapeutic product is tested on patients, under very controlled conditions. This kind of testing is called a clinical trial or a clinical study. Usually, only small numbers of patients are involved. They volunteer to take part in the research and consent only after the potential risks and benefits of the study are fully explained to them. In Canada and in many other countries, clinical studies must be approved by a regulatory authority, usually a government health department or related agency.
In Canada, Health Canada regulates clinical trials involving xenotransplants. As of March 2000, no clinical trials have been approved by Health Canada.
4. Is Xenotransplantation Safe?
Safety concerns about xenotransplantation have to do with risks to patients and risks to other people who might come in close contact with xenotransplant patients. The latter risk group is often referred to as third parties. At the moment, many questions about safety issues have no sure answers. But there are a lot of questions, as you will see below:
What are the risks to the xenotransplant patient?
The 3 main risks are:
- whether the patient will be infected with an animal disease passed along in the xenotransplant;
- whether the xenotransplant will work well, especially if it is replacing an organ essential for life; and
- whether high levels of immunosuppressive drugs might be needed to avoid immune rejection, leaving the patient vulnerable to more frequent infectious diseases or cancer.
What kinds of microorganisms might be in animal organs or cells?
Like humans, animals may be infected with microorganisms or infectious agents that exist in the environment where they live.
In some cases, these microorganisms are species specific—meaning they will only infect one kind of animal. An example of this is the transmissible gastroenteritis virus of pigs. It causes severe diarrhea in pigs but doesn’t infect people at all.
Other kinds of microorganisms are not species specific. Some of them can infect animals and cause diseases in humans under non-transplant conditions. They are called zoonotic infections or zoonoses (pronounced zoo-oh-not-ic infections, and zoo-oh-no-sees).
A well known example of a zoonotic disease is influenza—the flu. The flu virus first infects birds and pigs. Even though it doesn’t make these animals sick, it does get passed on to people who are in contact with them. When one person gets sick with the flu, the virus may be passed along, easily, to others.
The word xenozoonosis (the plural form is xenozoonoses) refers to zoonotic diseases that may be passed to a patient through a xenotransplant.
Many kinds of mammals, including humans, have a type of virus in their cells known as “endogenous retroviruses.” These viruses are buried in their DNA and are passed from one generation to the next, usually without causing any harm in the host species. It is known that all pig cells contain such viruses called PERVs (pig, or porcine, endogenous retroviruses). These viruses have been a part of pig cells for thousands of years. They are NOT active and are normally harmless to the pigs.
Although scientists are aware of many animal microorganisms, new ones are still being discovered. In the past several years, at least 4 new pig viruses have been detected for the first time. At least one of these, the Nipah virus, has made people sick. New microorganisms that affect animals may be discovered in the future. It’s impossible to predict whether these might be able to cause disease in people or not.
Can a patient be infected with microorganisms that might be in a xenotransplant?
One of the safety questions related to xenotransplantation is whether the procedures will give microorganisms from animals the opportunity to move from one species to another, for example from pigs to humans. By putting living animal cells into direct contact with a patient’s blood and suppressed immune system, some of the natural barriers to infection are by-passed.
A particular concern is whether PERVs that might be present in a pig xenotransplant would become active and infect the human cells around it. Could a PERV infection cause illness in a human? At present there is very little scientific information available to answer these questions. A preliminary animal testing study has recently suggested that PERVs may infect guinea pigs when they receive an injection of purified PERVs. It’s also been demonstrated that in the laboratory PERVs can infect human cells and become active again. It’s not clear whether this could also happen in people exposed to PERVs in xenotransplants.
Would xenotransplant patients be more likely to get an animal infection than people who normally work closely with animals?
People have lived and worked in close contact with animals for centuries. Farmers, veterinarians, animal care workers and slaughterhouse workers are in regular contact not only with healthy animals but also with sick or dead animals, and with animal blood and organs. There is no evidence that people in these professions get any more infectious diseases than the rest of the population.
One recent study of people working with non-human primates (such as monkeys, baboons and chimpanzees) found that a few people tested positive for being infected with viruses from these animals, usually after being bitten by one or being cut with a broken test tube containing an animal’s blood. None of the people got sick from the animal viruses even though the accidents had occurred many years before.
In other cases individuals have become sick and/or died after becoming infected with viruses from non-human primates.
Do scientists know whether xenozoonoses are likely to occur?
No. Scientists do not know whether a patient who receives a xenotransplant will develop a xenozoonotic infection or what the severity of such an infection might be.
A relevant scientific paper was published in August 1999 [ Science 285:1236-1241, 1999]. It looked at blood samples from 160 patients who had been treated with living pig xenotransplants of one kind or another over the previous 12 years. Over 100 of the patients had been exposed to the pig tissue by extra-corporeal treatments, mostly using pig spleens (a widely used treatment in parts of Eastern Europe). Others had been exposed to pig skin grafts, or their blood had been circulated through a medical device containing pig liver cells.
The authors of the study drew the following conclusions from their data:
- There was no evidence of a long term PERV infection in any of the patients.
- Four patients had made antibodies to PERV proteins. This seemed to show that PERVs had been active in these patients, at least for a short while. But further study cast some doubt on this conclusion.
- About 14% of the samples showed that pig cells, and the PERVs contained inside the cells, could stay in the patients for a long time after their treatment ended.
- Only 4 patients had any unexplained symptoms following their treatments — skin rashes or a fever for several days. There was no sign of PERV infection in these 4 patients.
Can xenozoonoses be prevented?
Many of the microorganisms which infect animals are well known, and animals raised to be sources of xenotransplant organs would be cared for with very high standards of cleanliness. Most microorganisms could be screened out of a pig herd so that only animals known to be free of them would be used as xenotransplant sources.
On the other hand, as stated previously in this document, new animal diseases are always being discovered. It’s impossible to predict whether these might cause disease in people or not.
Although is unlikely that pigs can be raised so that they are completely free of PERVs, it may be possible, in the future, to develop vaccines that will protect people from PERV infection and other potential xenozoonoses. As well, if such diseases were to occur, new anti-viral drug therapies may be developed to treat them.
What are the risks to people who come into contact with xenotransplant recipients, and to the broader public?
If a xenotransplant patient did become infected with PERVs or other zoonotic infectious agents, they might or might not have obvious symptoms of infection. But in either case, would this infection spread to others, either by intimate or normal daily contact? This scenario is often referred to as the risk to third parties, since it refers to the potential for infection and/or possible harm not only to those who directly receive a xenotransplant, but to family, friends and other members of the community.
Because a complete understanding of the scientific issues related to the safety of xenotransplanation does not exist, some people argue that there are still too many unknowns to proceed with such procedures; they believe it would be better to take a cautious approach, waiting until more information is available through pre-clinical studies not involving humans. Others argue that only through careful clinical trials with small numbers of patients will we obtain the scientific data needed to evaluate the issues more accurately. Knowledgeable scientists, physicians, experts and various stakeholders fall on both sides of this ongoing debate.
5. What Is the History of Xenotransplantation in Humans?
Since 1900, there have been various reports of transplanting animal organs into dying patients. Early efforts did not meet with much success, but in the 1960s after successful human-to-human heart transplants were performed, more serious attempts at xenotransplantation began. Most of the xenotransplants involved kidneys, usually obtained from baboons or chimpanzees. A few patients lived as long as 9 months after their xenotransplant, but most did not survive for more than a few days or weeks. In 1984, there was the well publicized case of “Baby Fae,” a newborn girl who received a baboon heart and who died 20 days later. All of these xenotransplants ultimately failed because the person’s immune system rejected the transplanted organ.
In the early 1990s, more powerful drugs for preventing rejection of a human organ by a patient’s immune system were developed. These drugs provided hope that xenotransplants might also be more successful. Several patients received animal hearts or livers but did not survive more than 3 months. In 1995 one patient in the United States received bone marrow from a baboon. Although the baboon marrow was rejected by the patient’s body, the patient is still alive and appears not to have any harmful side-effects from being treated with the baboon bone marrow.
In the past few years there have been some encouraging results with cellular xenotransplants. In Sweden, 10 patients with diabetes received cells from the pancreas of pigs, to see if these new cells would produce insulin. None of the pig cells produced insulin in the long term, and none of the patients got sick from the transplanted pig cells. Currently, a clinical trial in the United States is transplanting specific brain cells from fetal pigs into patients with Parkinson’s disease. Early results indicate improvement in some patients’ condition.
Extra-corporeal xenotransplant treatments also look promising. A number of centres have reported perfusing, or pumping, a patient’s blood through an extra-corporeal pig liver when the person was facing life-threatening liver failure. This procedure was seen as a bridge to transplant. Other cases have involved hooking a patient up to an “artificial liver”—a medical device that contains pig liver cells within a special membrane and filter system. This has been used as a substitute liver, but only for a very short time.
Haven’t pig heart valves already been used to treat people?
Yes. Pig heart valves have been used safely for many years to treat patients with damaged hearts. Pig heart valves are not usually considered to be xenotransplants, however, because the valves are treated with special chemicals which kill the cells and destroy any potential microorganisms. Therefore pig valves do not seem to pose the same safety risk as living pig cells.
6. What scientific challenges must be overcome before xenotransplantation will be successful in humans?
The main scientific challenge to successful xenotransplantation is immune rejection. This is also a major factor in human-to-human organ transplantation.
What is immune rejection?
Our immune system protects us from things that are foreign, or not normally part of our healthy bodies. The most common threats to our health are germs, such as viruses or bacteria all around us. When foreign materials of any kind gets into our bodies, our immune system kicks into high gear by developing antibodies and specialized white blood cells to get rid of them.
What happens when immune rejection occurs during human-to-human organ transplants?
Except for identical twins, each person’s cells are slightly different from everyone else’s. This is the reason that testing is done to find the right match between an organ donor and the person who needs the transplant. But a perfect match is rarely possible. Most times, the transplant patient gets an organ that is only as close as possible under the circumstances. As a result, the patient’s immune system recognizes the cells of the new organ as slightly different than its own and tries to destroy these cells, just as if they were foreign bacteria or viruses. If the patient’s immune system is successful, then so much of the new organ is damaged or destroyed that it can’t work properly and we say it’s been “rejected” by the patient.
Can immune rejection be overcome in human-to-human organ transplants?
The development of new immunosuppressive drugs is one of the reasons that human-to-human transplants are now so successful. These drugs suppress the patient’s immune system, not allowing it to work as well as usual and giving the patient’s body a much greater chance of not rejecting the transplanted organ. Patients who receive human organs must usually take immunosuppressive drugs for the rest of their lives.
How does immune rejection work with whole organ xenotransplants?
When whole animal organs are used as xenotransplants, the problems with immune rejection are huge because animal and human tissues are so different. In fact, the organs may be so “mis-matched” that the xenotransplanted organ may be rejected within minutes of the transplant.
Is it possible to overcome immune rejection with whole organ xenotransplants?
Until recently it seemed impossible to overcome this. Even immunosuppressive drugs weren’t powerful enough to stop rejection in the few patients who had received whole animal organs. However, recent scientific advances may help solve some of these rejection problems. One solution may be the development of transgenic animals, where the animals are bred with specific human genes. The principle behind developing transgenic animals is this: the human gene present in the animal cells will help to reduce the chances of immune rejection in the xenotransplant patient. Pre-clinical studies suggest that this approach might work, at least for short term xenotransplants.
What about immune rejection of xenotransplants over the long term?
Although xenotransplants from transgenic animals may reduce the possibility of short term immune rejection, the longer the xenotransplant remains in the patient, the greater the chance the immune system will recognize it as foreign and start to reject it. At this time, even with the combination of transgenic animals and immunosuppressive drugs, the problems of immune rejection are not entirely solved.
Is immune rejection also a problem for extra-corporeal and cellular xenotransplants?
Extra-corporeal whole organ xenotransplants may also be affected by immune rejection and often stop working after a very short time because of widespread tissue damage. However, some cellular xenotransplants seem better able to resist immune rejection. For example, cells implanted within the brain are somewhat protected from immune rejection. Xenotransplants of pancreatic islet cells into diabetic patients may be encased in a special membrane that helps protect them from immune rejection.
Glossary of Words and Phrases2
Bridge to transplant - a short term procedure using an extra-corporeal xenotransplant that could buy a patient time until a human organ becomes available.
Clinical trials, clinical studies - research studies on new drugs or treatments which are carried out with human patients. The patients volunteer for this research and consent only after the potential risks and benefits of the study are fully explained to them.
Endogenous retrovirus - many species of mammals, including humans, have certain kinds of viruses or fragments of viruses in their cells. These are embedded in their DNA and are passed from one generation to the next, usually without causing any harm in the host species, for example PERVs (see below).
Extra-corporeal - outside the body; sometimes called ex vivo. The term refers to certain kinds of xenotransplants which are not true transplants at all, because the animal organ or cells are connected to but stay outside the patient’s body.
Immunosuppressive drugs - drugs which reduce the effectiveness of a patient’s normal immune system. They are given to patients who have received (human) transplants so that their immune system won’t reject the new, slightly “mis-matched” organ.
Immune rejection - a patient’s immune system will normally accept a transplanted organ (from either a human or an animal donor) only if it’s a fairly close match with its own tissue type. Antibodies and special white blood cells will attack the “foreign” cells in the transplant, and damage it so much that it cannot work properly. When this happens, doctors say that the patient’s immune system has rejected the new organ. It usually has to be removed.
Medical device - a combination of biological materials such as animal cells, and other materials such as an artificial membrane or filter system.
Microorganisms - very small living organisms such as viruses, bacteria or fungi that may cause infection and disease. Commonly known as germs or infectious agents.
Non-human primates - the group of animals which is biologically most similar to humans, including chimpanzees, baboons and monkeys.
PERVs - stands for pig (or porcine) endogenous retroviruses. PERVs have been a part of all pig cells for thousands of years. They are not active and are normally harmless to the pigs.
Pre-clinical studies - research studies on new drugs or treatments which do NOT use human patients. Pre-clinical studies are confined to laboratory or animal studies. (Studies that use people are called clinical trials—see above.)
Risk to third parties - refers to the indirect risk that people other than the xenotransplant patient might be exposed to. (The pig and the xenotransplant patient are considered to be the first two parties in the risk equation.) The risk to third parties refers to the possibility that a xenotransplant patient might be infected with an infectious agent, such as a virus, from the xenotransplant, and that this infection might be passed on to other people through intimate or daily contact.
Species specific - microorganisms that can only infect one species of animal—for example pigs or humans.
Transgenic animals - animals that contain a gene (or genes) from another kind of living organism, for example, pigs which contain a human gene.
Xeno - is used as a prefix and means strange or foreign.
Xenotransplant or xenograft - the living animal material that is transplanted into humans in xenotransplantation.
Xenotransplantation - a transplant procedure in which a human patient receives an organ (such as a kidney or liver) or living cells (such as brain cells) that come from a healthy animal instead of from a human donor. The same term can be used to describe a transplant between any two different species of animals.
Xenozoonosis (plural xenozoonoses) - zoonotic diseases that might be passed from animals to people by means of a xenotransplant.
Zoonoses, zoonotic infections - microorganisms carried by animals, which can also infect and/or cause diseases in humans under normal (non-transplant) conditions.
Notes
| 1 | Although humans are animals, the term animal will be used throughout the rest of this document to refer to non-human animals. |
| 2 | The terms in this glossary are defined in the context of a discussion of xenotransplantation |