Sunday November 23, 2008
Animal farming
By Dr MILTON LUM
Animals as a source of organs, tissues and cells? The issue is still being debated, and the science doesn’t appear encouraging at the moment.
THE function of the body’s tissues or organs may sometimes be damaged to the extent that it cannot meet the body’s needs. Medical devices may be available to treat the problem, for example, dialysis machines in kidney failure.
However, the devices are not as efficacious as the real organ. In such situations, transplantation may be a treatment option.
Donate your organs please ... Almost all scientific and media reports emphasise that the basis for xenotransplantation is the shortage of human organ donors. Organ transplantation is an effective form of treatment for end stage heart, liver and kidney failure. The expertise for the transplantation of other organs like the lung, pancreas and even the face are being continuously developed.
A summary of the different types of transplantation in the next few paragraphs provide a background to the discussion about xenotransplantation.
Autograft
This involves the taking of part of the patient’s own tissue from one part of the body to replace damaged tissue in another part, for example, skin grafts in burn victims.
In this procedure, skin is commonly taken from the thigh to replace skin elsewhere. The advantage of autografts is that, as it has the same genetic make-up of the recipient, there is no likelihood of the body rejecting it. However, the scope of autografts is very limited, as internal organs cannot be transplanted.
There is no data that animal organ transplants (AOT) have been successful. Chimpanzee kidneys, which were transplanted to patients with renal failure, and a baboon liver transplanted to a patient with liver failure, have all failed within a short time, due to the major immunological and physiological challenges the recipients had to deal with. – Reuters Cadaveric transplantation
This involves the transplantation of organs like the cornea, kidney, liver, heart and lungs from a just deceased person, who is often young and whose organs are in good functional order.
As the organ originates from a donor with a genetic make-up different from the recipient, the latter has to take medicines to prevent rejection. These medicines have side-effects and have to be taken for the rest of the recipient’s life.
In most instances, rapid decisions, both surgical and ethical ones, have to be made. The major problem is that there is a huge gap between supply and demand. The number of donors is but a small fraction of requirements.
Living donor transplantation
This involves transplantation from a living donor to a recipient. The donor may be related or unrelated to the recipient. The best donor is from an identical twin; the next best is from a blood sibling followed by a parent or another blood relative.
The reason is that the similarity in the genetic make-up between the donor and recipient should be as close one can get. This leads to a reduced likelihood of rejection and prolonged life of the recipient.
Unless the donor is an identical twin, the recipient has to take medicines to prevent rejection.
Living donors have donated bone marrow, kidneys and lobes of the liver and lungs.
The donor may have to go on the waiting list for an organ transplant if his or her remaining kidney fails.
The more crucial problems are that of coercion of the potential donor and commercialisation of donation.
Stem cell transplantation
This involves the transplantation of stem cells which are “master cells” that have the ability to become any tissue at all.
There are different types of stem cells i.e. embryonic and adult stem cells, induced pluripotent stem cells, embryonic germ cells and amniotic fluid stem cells. Most stem cell transplantations have involved those suffering from childhood leukaemia and neuroblastoma. There are ethical and rejection issues involved in stem cell transplantation.
There is much enthusiasm about the potential of stem cell transplantation. While much has been achieved, there is still an enormous amount of scientific work that needs to be done to realise the potential of a concept that is relatively simple but complex in translating theory into practice. – AP There is much enthusiasm about the potential of stem cell transplantation. While much has been achieved, there is still an enormous amount of scientific work that needs to be done to realise the potential of a concept that is relatively simple but complex in translating theory into practice.
Xenotransplantation
This involves the transplantation of animal organs into human recipients. The European Commission (EC) in 2003 and the Food and Drug Administration (FDA) of the United States in 2001 define xenotransplantation as “any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live tissues or organs retrieved from animals, or, human body fluids, cells, tissues or organs that have undergone ex vivo contact with live non-human animal cells, tissues or organs.”
As there are a diverse range of procedures grouped together under the banner of xenotransplantation, the Australian Government’s National Health and Medical Research Council (NHMRC) in 2005 distinguished two types of procedures:
·“In vivo transplants involving transplantation, implantation or infusion into a human recipient of live cells, tissues or organs from a non-human animal source; and
·Ex vivo procedures involving the transplantation, implantation or infusion into a human recipient of human body fluids, cells, tissues or organs that have had contact outside the body with live non-human animal cells, tissues or organs.”
The NHMRC developed new terminologies for the three different types of animal-to-human transplantation, namely:
· Animal external therapies (AET) – A range of procedures involving contact between human and animal cells/tissues outside of the body of the patient, such as:
1. Cells or fluids from the patient are perfused through animal cells and returned to the patient, for example, passage of blood from a patient with liver failure through an external device (hepatassist machine) containing pig liver cells (similar to a dialysis machine) or
2. Human cells or tissue pieces are cultured with animal cells in the laboratory in order to obtain a larger supply of human cells or tissue for transplantation, for example, growth of human skin grafts for wound healing (eg for burns) on a feeder layer of animal cells
· Animal cell therapies (ACT) – Procedures in which animal cells are transplanted or implanted into a human patient to compensate for deficient functioning of the patient’s own cells.
Transplanted cells can either be enclosed in a semi-permeable capsule (encapsulated) or have no such capsule, for example, nimal pancreatic cells to produce insulin for people with diabetes, and animal brain cells to produce dopamine for people with Parkinson’s disease.
· Animal organ transplants (AOT) – Procedures in which whole organs or tissues from an animal are transplanted or implanted into a human patient to replace a diseased or damaged organ or tissue, for example, heart, kidney, liver, skin, adrenal glands, etc.”
Xenotransplantation products have been defined by the NHMRC as “any live animal cell, tissue or organ that is used in an animal-to-human transplantation procedure (i.e. not including processed, non-viable products, such as pig heart valves).”
An important aspect of the definitions is that the non-human cells, tissues, or organs used in xenotransplantation and in the manufacture of xenotransplantation products must be alive.
Rationale for xenotransplantation
Almost all scientific and media reports emphasise that the basis for xenotransplantation is the shortage of human organ donors.
Apart from the potential for an inexhaustible supply of organs, there is also time for planned operations without the need for rushing to select the recipient. They point to the success rates of the use of pig heart valves in treating humans with valvular heart disease. Furthermore, pigs have been genetically manipulated so that rejection by the human recipient is reduced.
The rationale for animal external (AET) and cell (ACT) transplants are, however, more intricate than that of a shortage of human donors.
Risks of xenotransplantation
The recipient of any transplant has to face the problems of rejection as the body’s immune system attacks the transplant because it does not recognise it as part of the body. There are three types of rejection:
· Hyperacute rejection in which the organ is dead within 20 minutes of transplantation. This is usually not seen nowadays as a cross-match of the donor to the recipient is done prior to surgery.
· Acute rejection occurs within the first three months, when the body recognises the differences between the donated transplant and the recipient’s organ/tissue. This can usually be controlled with immunosuppressive medicines.
· Chronic rejection is similar to acute rejection and is worsened by increased blood pressure. All recipients of cadaveric organs usually succumb to chronic rejection. That is why the survival of those who have received a cadaveric transplant is still an average of 10 years post-transplantation, despite immunosuppressive medicines.
Safety is a major consideration with xenotransplantation. There is the risk that the human recipient may be infected by viruses or other diseases from animals and that this may spread to family, relatives, friends and the community.
When an infectious agent gains entry into a new host, its capacity to produce disease is not predictable, for example, HIV/AIDS, Ebola virus. Among the organisms of serious concern are herpes viruses, retroviruses, toxoplasmosis, filoviruses (Marburg and Ebola), monkey pox virus, and simian hemorrhagic virus.
The use of human cells, tissues, or organs that have had contact outside the body with live animal cells, tissues or organs, for example, human skin cells grown outside the body on a layer of animal cells and then used in humans for skin reconstruction, have the potential for transmission of an infectious disease from the animal source to the recipient.
The potential may be similar to that of live animal cells, tissues, or organs transplanted directly into a recipient.
Although experts disagree on the extent of the risk, all agree that the transfer of infection from animal to man cannot be completely ruled out especially when there is prolonged contact between animal and human tissues. The use of immunosuppressive medicines may also contribute to this risk.
The risk is highest in animal organ transplants (AOT), intermediate in animal cell therapies (ACT) and lowest in animal external therapies (AET).
The successful use of pig heart valves has contributed to the view that pigs are presumably safer donors than non-human primates. However, this presumption has not been fully explored. The discovery that porcine endogenous retroviruses (PERV) are capable of infecting human cells in the laboratory (in vitro) has raised concerns about the safe clinical application of xenotransplantation.
Much attention has been focused on the possibility that PERV, which are harmless in animals, may be transferred to humans and then get activated with the potential of spreading new diseases to humans.
Efficacy of xenotransplantation
There is no data that animal organ transplants (AOT) have been successful. Chimpanzee kidneys, which were transplanted to patients with renal failure, and a baboon liver transplanted to a patient with liver failure, have all failed within a short time, due to the major immunological and physiological challenges the recipients had to deal with.
Reports of trials of animal cell therapies (ACT) have shown a longer survival time of the transplanted cells. Some studies have reported some efficacy when animal pancreatic cells were transplanted to produce insulin for diabetic patients.
Studies of the transplantation of animal brain cells to produce dopamine for patients with Parkinson’s disease have reported that they were not efficacious.
Trials of animal external therapies (AET) have been more successful than AOTs and ACTs. There are trials in which blood from a patient with liver failure is passed through an external device (hepatassist machine) containing pig liver cells (similar to a dialysis machine) with some claims of efficacy. Human skin grafts grown on an animal feeder layer have been reported to be successful.
Public policy
Recommendations on xenotransplantation have been made by many organisations, including the Australian National Health and Medical Research Council (NHMRC), Council of Europe, the European Medicines Agency (EMEA), the United States Food and Drug Administration (FDA) and the World Health Organization (WHO). The common themes of their recommendations are:
· Xenotransplantation can only take place when there is an adequate regulatory framework in place;
· Research can only be done provided there is adherence to strict standards with oversight arrangements that would not allow research to proceed unless it is assessed as being safe, and potentially offers benefits to the recipients;
· Risks of transmission of known or unknown infections from animal to human should be minimised;
· Traceability and ongoing surveillance of patients is essential; and
· Public debate in this area should be encouraged.
The NHMRC also recommended that no animal-to-human whole organ transplants be permitted and that a review of its guidelines and recommendations be made in 2010. Earlier reviews can only be permitted if the national animal-to-human transplantation committee recommends that such a review is warranted based on new information on safety and efficacy.
The Health Ministry’s position is: “More clinical research is warranted in xenotransplantation as most of clinical research evidences retrieved in this text was mainly conducted in animal models. The issues regarding the ethical and religious should be considered.
“In addition, xenotransplantation also involves consideration of animal rights… The potential risk of non-human organs transmitting infectious agents, not yet detectable by current screening mechanisms must not be overlooked.”
What should potential recipients be told?
It is pertinent to note media announcements that more than 300 cases of stem cells treatment involving inbred rabbit foetuses have been carried out in Malaysia in the past three years (NST, January 29, 2008).
The rabbit foetuses are the animal source for the preparation of stem cell transplants. The announcements stated that such treatment can be given for a variety of conditions including Down’s syndrome, cerebral palsy, autism, diabetes, hormone deficiency disorders, early menopause, infertility, immune deficiency disorders e.g. AIDS, cancer and autoimmune diseases, impotence, depression, cirrhosis of the liver and chronic hepatitis (Mingguan Malaysia, April 13, 2008).
All research protocols stipulate that human subjects should give informed consent. As such, all patients to whom xenotransplantation is proposed and who are potential recipients of xenotransplantation products should be informed and understand the following:
· The reasons for proposing the therapy
· The evidence for its use and the areas of uncertainty surrounding it
· How different is it from standard treatment
· The tests that need to be carried out, and the risks and complications of such tests
· The likely risks, both short term and long term, including the risk of death
· The benefits
· The alternatives, if any
· The measures for safety monitoring and support if things go wrong
· The need for follow-up treatment
· The success rate of the transplantation in general and the success rate of the institution performing the transplantation
· The doctor’s experience in doing the procedure
· Whether there has been any form of ethical review and approval by the Health Ministry
· The likely future use of the therapy, if successful
Conclusion
While xenotransplantation offers potential, it is also fraught with medical issues that have yet to be surmounted. In addition, there are religious and ethical issues that have to be considered.
When there are limited or no options in the treatment of certain chronic or terminal conditions, hope can be an addictive drug. Doctors and regulators have the responsibility of tempering hope with realism. Strict compliance to research protocols with oversight arrangements from regulators is vital for patient safety.
Dr Milton Lum is Chairperson of the Commonwealth Medical Trust. This article is not intended to replace, dictate or define evaluation by a qualified doctor. The views expressed do not represent that of any organisation the writer is associated with. The views expressed are those of the writer and readers are advised to always consult expert advice before undertaking any changes to their lifestyles. The Star does not give any warranty on accuracy, completeness, functionality, usefulness or other assurances as to the content appearing in this column. The Star disclaims all responsibility for any losses, damage to property or personal injury suffered directly or indirectly from reliance on such information.
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