The Need of Organ Donors
In the United States, every 18 minutes a new name will be added to the 63,000 patients hoping for an organ transplant. Two thirds will have to wait over a year and many will die waiting .
Organizations and hospitals encourage organ donation and yet, donor supply increasingly fails to meet demand. The necessity has gone up (the failure of health education programs has led to an increase in the number of potential transplant recipients 1 ) and the number of donors has gone down (due to less accidental deaths).
One possible alternative to organ transplant is the use of artificial organs. Although great progress has been made in this area, it seems that it will be many years before these devices can be made small enough to be inserted into the patient and strong enough to last longer.
For some, using animals as organ donors seems to be the answer. Xenotransplantation 2 appears to be our only option for the foreseeable future. As technology develops, the transplantation of tissues and cells, as opposed to whole organs has an immense potential.
Development of Xenotransplantation
It was not until the 20 th century that we saw reports of actual xenotransplantation. A French surgeon, Dr. Alexis Carrel, had a vision not very dissimilar to the use of the genetically engineered pigs that are being created now, and asserted that the future of transplantation of organs for therapeutic purposes depended on the feasibility of xenotransplantation.
In 1984, Dr. Leonard Bailey used a baboon heart in a newborn baby known as “Baby Fae,” who was born with a severely deformed heart. The heart was rejected after 20 days mainly because of an incompatibility between the donor and recipient’s blood type.
1 Also called the host.
2 Xenotransplantation: The transplantation of an organ or tissue between members of different species.

Candidates
1.
The Great Apes: (Gorillas, chimpanzees, orangutans, and the gibbon.) The closeness of the phylogenetic 3 relationships between the great apes and the humans is illustrated by the fact that their
DNA sequence differs from ours by only 2%. We are much more compatible to them, than to any other mammal. The disadvantages of using great apes for xenotransplantation are that these animals are now endangered species.
2.
The Baboon: Adog-faced primate 4 with a short tail. This monkey lives in Africa and Arabia. It still survives in sufficient numbers in the wild to be considered as a potential donor. Some disadvantages of using this animal for xenotransplantation are that their organs are not large enough to adequately support the life of a large adult human.
3.
The Pig: Its anatomy 5 and physiology 6 are surprisingly similar to ours, in spite of the phylogenetic distance. Pigs are easy and cheap to maintain. They grow quickly to a size that would be sufficient to provide organs for the largest of adult humans. Pigs can be tissue-typed by a simple test using white blood cells. Having this information can be useful for matching prospective donor organ to the recipient.
Although experimental work with primates is continuing, the greatest potential for widespread xenotransplantation now lies with more distantly related species such as pigs. There are strong reasons for using them rather than higher primates for this purpose (the breeding of pigs to supply organs for xenotransplantation would be more ethically justified.)
3 Phylogeny: The origin and evolution of a group or race of animals or plants.
4 Primate: Any of the most highly developed order of animals.
5 Anatomy: The structure of an organism.
6 Physiology: The science dealing with the functions and vital processes of living organisms.

Problems with Organ Transplantation
The greater the genetic difference between an animal and man, the stronger the rejection response once the animal organ is transplanted into a human being. When a patient receives an organ, three potential rejection 7 obstacles have to be overcome:
1.
Hyperacute Rejection: This process is extremely rapid, occurring within minutes or hours. The rejection is associated with an attack on the transplanted organ by antibodies rather than T cells. Host blood clots throughout the donor organ causing dramatic failure. Natural antibodies reacting against pig antigens recognize an antigen termed the Gal epitope (a sugar molecule found on the surface of pig cells) and trigger this kind of rejection.
2.
Acute Vascular Rejection: Before an organ transplant is performed, the blood and tissue type of both recipient and donor are determined. In relation to the blood type, it is essential for them to be compatible. In relation to the tissue type, the rules are not so rigid. But the greater the disparity between recipient and donor, the stronger the risk of rejection. The recipient may recognize the newly transplanted organ as being foreign. The body can not differentiate between the non-self organ and the microorganisms that might cause infection. Therefore, the sophisticated mechanism of rejection is brought into play to destroy the intruder. This immune response 8 travels in the blood to the organ, which invades and destroys. Its function will deteriorate until it ceases to work and within a week, the transplanted organ will be totally destroyed.
3.
Chronic Rejection: This process is slow, frequently developing over a period of months or years. The exact cause by which it develops is uncertain. It may result from the combination of the effects of the
T lymphocytes and the antibodies 9 on the transplanted organ. Most patients eventually develop chronic rejection of the organ. For example, within the first 10 years of the transplant, half of the patients will lose their grafted organ.
7 Rejection: Process where the host immune response recognizes the transplanted organ or tissue as foreign and acts against it, leading to damage or destruction of the organ or tissue.
8 Carried out mainly by a group of white blood cells known as T lymphocytes.
9 Antibodies: Immunoglobulin proteins produced by B cells in response to stimulation by an antigen.
Antibodies circulate in the blood and bind to specific antigens on the cells of invading microorganisms or

Strategies to Overcome Rejection in Xenotransplantation
“In xenotransplantation, we are walking a fine line between asking the immune system to accept an organ from an animal, but still protect us from other threats, such as infectious disease." 10
Early rejection is likely to occur due to the presence of antibodies. Humans have very low levels of antibodies directed against other animals, but after being exposed to transplanted tissues, antibodies are produced rapidly. Treatment has to be administered to prevent the destruction of the organ transplanted.
Scientists are able to prevent hyperacute rejection by reducing antibody levels. Therapy can be aimed at the recipient by depleting him of the donor’s antibodies using the method of plasma exchange.
11 This process is combined with the administration of immunosuppressive drugs.
12
“The immunosuppressive drugs that we have available at present have some effect in delaying this form of rejection, although they are not as effective as they are against acute cellular rejection. Newer drugs currently in various stages of development may be more effective.” 13
All immunosuppressive drugs may cause side effects to the detriment of the patient who is taking them. Sometimes, the disease causing organ failure is replaced by another disease: the complications associated with prolonged immunosuppressive therapy.
Scientists are systematically evading the immune system’s defenses to make xenotransplantation a practical option. Jeffrey Platt, Professor of Experimental Surgery at Duke University Medical Center, has devoted his career to understanding how the immune system recognizes implanted tissue as foreign and destroys it. He engineered an animal organ to match a human organ as closely as possible, hoping to reduce or even eliminate the need for immunesuppressing drugs.
The experiment stopped hyperacute rejection by introducing two human genes into the pig’s hearts and testing them in baboons. These genes encoded two proteins called Delay Accelerating Factor (DAF) of transplanted tissues. Antibodies can activate, complement and destroy the foreign cells directly, or they can stimulate white blood cells to carry out the destruction.
10 Xenotransplantation: Animal Organs to Save Human Lives
11 The blood is withdrawn from the body of the recipient and its cellular constituents are separated from the remaining plasma. The plasma is then discarded and replaced by a salt or protein solution
12 Immunesuppresing Drugs: Drugs used to suppress the immune system, taken by transplant recipients to prevent organ rejection.

and CD59. Both DAF and CD59 guard blood components such as red blood cells and blood vessels from attack by the immune system. They work by snuffing out complement 14 cascade before it can act. Platt reasoned that if the researchers could put these proteins in pig cells, they might be able to stop the complement cascade from attacking the pig organs as well.
Transgenic 15 pigs are bred to express human regulators of complement. Human genetic material, containing the code for the human regulator proteins, is injected into the pig embryos. This small modification means the recipient’s complement cascade is not activated and the donor organ is accepted.
Platt's theory was proven correct. The May 1995 issue of the journal Nature Medicine reported that the researchers had succeeded in keeping a pig heart (containing the human proteins DAF and CD59) alive and functioning for 30 hours. Subsequent studies showed the heart could function for days without further treatments, when an unmodified pig heart would have been destroyed within minutes.
Furthermore, Platt and his colleagues studied what the complement systems "sees" when it identifies a pig organ as foreign. They identified a sugar molecule (produced by all mammals, except some monkeys, apes and humans) that acts as a flag for the human immune system. Sugar is made inside the cell and transported to its surface where it attracts the human antibodies circulating in the blood. The antibodies tag the sugar as foreign and the complement system destroys it.
Platt and his colleagues designed an experiment to stop the production of the sugar molecule so human antibodies would not recognize the pig organ as foreign. Preliminary results in mice show that without this “flag,” the human immune system has a harder time identifying the animal organ as foreign.
An organ attacked by the immune system can be destroyed in weeks or months in a process called
Acute Vascular Rejection. Platt identified this type of rejection. He showed its similarity to rejection seen in human to human transplants, (but it goes one stage further with the lymphocytes producing antibodies against the graft.) Acute vascular rejection is a major cause of rejection in all transplanted organs. A better understanding of it will help bring xenotransplantation closer to reality. In the near term it may also help reduce disability and death of human transplant patients.
13 Larry Cooper & Robert Lanza, X ENO THE P ROMISE OF A NIMAL T RANSPLANT INTO H UMANS 61 ( Academic
Press ed., 1997)
14 Complement: A key component of the immune system responsible for attacking and destroying foreign bodies.
15 Transgenic: Term used to describe an organism that, through genetic modification, has a heritable foreign gene.

Platt's research team is in the process of identifying the components of the blood clotting system that collect in foreign organs and cause deadly clots. Researchers know that the cell lining of the transplanted organ change in acute vascular rejection. These cells, called endothelial cells, change shape and begin churning out coagulation factors and other substances that lead to blood clots.
Chronic rejection is the final form of rejection that is very likely to occur in xenotransplantation.
Unlike other forms of rejection, which can destroy an organ in minutes, days, or weeks, chronic rejection may take months or years to have any effect.
At present, there is no effective treatment for it. The more advanced, the more opportunities for the organ to fail. Chronic rejection will probably develop faster in xenotransplantation in view of the great difference in tissue type between pig and human organs.
Other Risks in Xenotransplantation
We have to be extremely careful in eradicating microbes from the donor animal. The implantation of an animal organ into a human opens up a new dimension in the possible transfer of microbes between two species. When the animal organ is placed permanently within the human body, it may provide ideal conditions for reproduction and growth of any microorganisms transferred with it (possibly allowing their dispersal throughout the entire human body). This kind of infection is called xenosis.
Harvard physician, Dr. Jay Fishman, pointed out several reasons why infections following xenotransplantation may be greater than those following allotransplantation 16 :

Organisms transferred from pigs may not be identifiable by routine laboratory tests.

The infection may go unrecognized since the ways in which it presents itself in the patient may differ from the traditional clinical symptoms and signs of infection with which transplant physicians have become accustomed.

The infecting microbe might undergo changes in biological behavior or mutational adaptation. This may lead us to a more violent virus.

Having never been exposed to the porcine organism previously, the patient may have no preexisting immunity to the pathogen, which may, therefore, multiply unimpeded.

Even if a microbe is known not to cause disease in the donor pig, there is no guarantee that it will not cause disease in the human recipient.
Making the Animal Safe
We can minimize the risk of infection from donor pig to human recipient by making sure pigs remain infection-free throughout their lives.
The breeding herd should be delivered by caesarean 17 section and transferred immediately into isolators. Air entering the isolator will be filtered, and the food sterilized. The building in which they are housed will have to be specially designed and maintained. It will have to be thoroughly cleaned every day, so there will be no risk of contamination from any source. Temperature, light, and noise will be highly controlled. No insects will gain access to the pigs.
The initial group of pigs is removed from the isolators after two weeks. They will be artificially inseminated once they become sexually mature. The next litter of pigs will remain with their mothers for five days and then be placed in a separate facility (secured from any biohazards). The sows will receive vaccinations and will be raised as an isolated group within the facility. On several occasions, blood tests will be performed to ensure that the animals are disease free.
Same care will be given to the transportation of the pigs to the transplant centers. Organ procurement and tissue processing facilities will be built at the site where the animals are raised. After being anesthetized and scrubbed clean, the donor pigs will be moved into a sterile surgical suite where they will be prepared for surgery. The organs will be excised and transported in boxes of ice, rushed by road or air, and transplanted into patients.
The patients who receive pig organs will require monitoring throughout their lifetimes, as it occurs in any transplant patient today.
Porcine Viruses
16 The transplantation of organs or tissues between genetically different members of the same species.
17 Caesarean Section: The delivery of a baby by cutting through the mother’s abdominal and uterine walls.

Pigs appear to have been a source of deadly epidemics. In 1918, the human Spanish influenza killed more than 20 million people across the world. The cause may have been a mutation of a pig influenza virus spread from American pigs during World War I.
Other infectious agents transferred between pigs and humans have been identified, including the
Hendra-like virus (cause of an outbreak in Malaysia), the Circovirus, the Hepatitis E virus, and the
Cytomegalovirus (common in British pig herds, can be transmitted from mother to fetus, making it impossible to eliminate.)
The virus that concerns us most is the Porcine Endogenous Retrovirus 18 (PERV). It can’t be eliminated from the pig because it is inherited in the DNA. As the viruses have inserted their genetic code into sperm or egg cells, the offspring of the infected animals retain these viral genes, which are then passed from generation to generation. Most of these viruses are harmless to their hosts, but some have been associated with the development of cancerous conditions. PERVs may infect a recipient and then remain latent for many years.
In spite of the potential infectious risks of xenotransplantation, it continues to take place in the
United States. Pig brain cells are placed into brains of patients with Parkinson’s disease and epilepsy, and pig livers are being used in patients with hepatic failure with no reports of infectious-disease transmission.
The potential for disease and illness, in the form of cancer or possibly an AIDS-like condition, is sufficient to warrant both caution and investigation before xenotransplantation moves ahead. Once the species barrier is crossed, it is, without doubt, impossible to be confident that any viral infection could be contained. Even if a viral infection could be identified, it may be too late to stop the virus from spreading around the population, probably leading us to an “infectious Chernobyl.”
Animal Welfare
Some people think organs should be donated by humans and not harvested from animals. Animal activists see xenotransplantation as immoral in terms of their exploitation.
The great apes are now endangered species. They are not available in the numbers necessary to fulfill the requirements of organ transplantation or scientific research. A significant segment of the public

would oppose the planned killing of large numbers even if their organs would be life-saving to dying humans.
The use of pigs as organ donors may be ethically acceptable, but the acceptability lies in balancing the benefit to humans against the harm to them and possibly to humanity. Pigs have a vital interest in avoiding deliberately inflicted suffering, fulfilling their desires and instincts, and not being killed. Their housing conditions, their use, and their destruction, represent fundamental abuses of their moral right to have their vital interests respected. Pigs will be turned into spare part factories, plundered for their organs.
Genetically mutated and raised in artificial conditions, these remarkably intelligent animals face an unnatural and distressing existence.
Alternatives to Xenotransplantation
Animal organs are not the only way to meet the growing demand for organ transplants. We should increase the number of people carrying donor cards by educating the population on the need of organ transplants.
We can change the law to obligate the doctor to request organs from dying patients. Assuming the patient’s consent to donate organs, unless otherwise directed, can be a successful strategy.
Live donation should be expected, when possible, from individuals related to the patient. The organ for which the shortfall is the greatest is the kidney, which can be obtained from living donors. In the
United States, less than 10% of kidneys are obtained from this source, but in theory it could answer the entire demand for this organ.
Biologists are now considering the use of nuclear transfer techniques to clone individual cells as opposed to whole animals. It might be possible to obtain a specific differentiated cell from an animal, genetically modify it to resist rejection or to produce a substance, transfer its DNA of into an unfertilized egg from which the DNA has been removed, and stimulate multiplication to produce the desired cell type.
The aim would be to clone identical cells for specific human disorders (such as islets for diabetics, new skin for burn victims, or retinal tissue for patients at risk of blindness.)
18 Retroviruses are viruses that infect cells and then become inserted into the genetic material of the cells.

Conclusions (“Nothing could be worse than if in trying to save our lives we inadvertently engineered a plague.”) 19
Xenotransplantation research is being conducted not by universities, but by commercial pharmaceutical and biotechnology companies. At the same time, they are developing the market for drugs associated with this process. Its introduction into the care of patients with terminal organ failure will have major consequences on the cost of transplant services in all developed countries. The overall impact will be to increase health care expenditure due to the costs involved in the care of the animal donors.
Most new emerging human infectious diseases have their origins in other species. A direct method of establishing new infectious human diseases would be to implant infected tissues from a nonhuman species into humans.
Latent infection poses extreme difficulties for detection, control, and treatment. Unknown viruses are similarly problematic. Experimentation on animals will not provide us with all the answers. Humans frequently pose a unique problem that cannot be met in any experimental model. Those patients with nothing to lose (dying patients for whom no alternative medical therapy is available) will be able to function as guinea pigs for xenotransplantation.
As Frederick Murphy said, “In dealing with infectious diseases, the reality is that our best efforts may decrease but will never eliminate risk.” Society will have to determine if it is willing to take this risk.
We have to take into account for our cost/benefit analysis, not only the social and economical costs of xenotransplantation, but also, the suffering, the exploitation, and the destruction of animals in the process.
We are experiencing the greatest biological revolution the world has ever known. As technology develops, replacement therapy using animal tissues and organs may expand beyond imagination. The advent of new technologies may reduce the need for animal cells (human cells cloning, for example.) Only time will tell which of the options offered by modern biotechnological advances will prove to be the best.
As Allen Ginsberg said, “There is nothing to be learned from history anymore. We’re in science fiction now.”
19 See New Scientist Editorial 8 th August 1998.

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
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
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
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
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
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