Xenotransplantation : Is it ethical?
Background and challenges
In 1954, surgeon Joseph Murray started a revolution in
the Medical industry by performing the first human organ
transplant, a kidney transplant between identical twins(1). Initially, allotransplantation received some hindrance due to
the ability of the human immune system to reject any foreign object. With the
introduction of cyclosporin, a powerful drug that minimizes the rejection of
foreign tissue, allotransplantionpossibilities have expanded spectacularly(3). It is no longer necessary to have
an exact match of certain blood type markers for a successful human transplant.
This means organs from unrelated people can be used. Recipients have a
good chance today of living at least five years with an allograft. These days organ
transplantation is a norm. Each year about 20,000 Americans receive
life saving transplants of heart, kidneys , liver or lungs. Today,
allotransplantation faces a significant challenge because the need for this
procedure far exceeds the availability of donor organs. Each day,
approximately 10 Americans breathe their last breath waiting for organs to
become available. To meet this scarcity of human organs, doctors
along with pharmaceutical and biotechnology companies are
investigating an alternative to allotransplantation, xenotransplantation.
Xenotransplantation, (xeno) is a
greek word meaning “stranger”, involves transplanting or grafting of animal
organs, tissues, or cells to replace failing organs or to treat disease in
humans. These transplanted or grafted organ, tissue, or cell is
called a xenotransplant or xenograft. As documented in Table 1, the concept of xenotransplantation
dates as back as 1682, but it was not until the 1960's that the
technological world stimulated this idea for whole organ transplant. In
1963, Keith Reemtsma transplanted chimpanzee kidneys into thirteen
patients. Also, in 1964 Hardy and colleagues from the
University of Mississippi used a chimpanzee’s heart as a xenograft. The patients did not
survive for long but the transplanted organs showed no sign of rejection. This success inspired more
research and development in xenotransplantation, which resulted in the use
of this process for therapeutic effects, such as bone marrow
transplant in AIDS patients. Although, both whole organ and bone marrow
transplants received limited success, the use of pig's heart valves to
repair human hearts and porcine pancreatic islet cells to treat diabetesraises
the hopes of scientists that someday whole organ xenotransplantation will be
possible.
Two main challenges facing
xenotransplantation are the prospect of potential pathogens from animals, especially retroviruses from primates animals, and the
human immune response to xenogeneic tissue which is very strong and difficult
to manage. Due to the risks of retroviruses from primate animals, most
scientists have dropped the idea of taking xenotransplants from these species.
Today's scientist are looking at pig organs as replacements for primate organs.
The size of pig organs are about the same as that of humans. Also, pig heart
valves are routinely used in cardiac surgery. This suitable size and the
familiarity of scientists with their organs, make pigs the most appropriate
organ donors . Nevertheless, the question of immunological rejection
still remains.
Recently two scientists in PPL Therapeutics, have
produced five pigs that lack the gene that causes rejection. Immerge
BioTherapeutics and a team from the University of Missouri-Columbia have cloned
miniature pigs with the gene "knocked out" of their DNA(2). After these successes, it is not
optimistic to think that one day science will overcome the hurdles in
xenotransplantation and make it a reality.However, once we can transplant
animal organs in humans, should we? Xenotransplantation raises a large number
of ethical, medical, economical and social issues which have to be evaluated
before we decide to make use of this technology.
Issues
. public Health issue
The opponents of xenotransplantation
argue that introducing tissues and organs from another animal into a human may
unintentionally introduce a pathogen, sincethere is no way to screen for viruses that are not yet known. These viruses may mutate within
the human host and thereby create a new human disease. Viruses that are inoffensive to an
animal host, can be fatal to humans. For example, Macaque herpes is harmless to
Macaque monkeys, but lethal to humans. These viruses not only reside and
replicate in the patient, but also infect the patient's close contacts via
aerosol, blood or sexual transmission. It is possible that the virus
will infect a wide range of human population before the danger is
exposed. Alan.H.Berger, Executive Director Animal Protection Institute,
stated,” The possibility of letting loose an infectious disease into the
general population is real, and we have no way to try and stop it from
happening. If a disease gets out into the population, we'll have some enormous
problems with it(1)." Table 2 shows the different viruses that are
believed to have been transmitted to humans from animals. The most common
example is the HIV virus, which many believe may have started as a monkey
pathogen that crossed over into humans. Is it sensible to deal with
unknown viruses? Like the PERVvirus in pigs, which is not harmful in that
specie but may be dangerous to humans. Is it ethical to risk the health
of the entire human race just to save the life of a select few?
The proponents of xenotransplantation agree that it is
important to resolve this infection risk, but they also assert that there are
scientific means to determine if that risk is reasonable. They are raising
breeding transgenic animals, especially pigs and baboons, that they believe
will not carry diseases harmful to man (see Fig 1). They affirm that these animals
should be the safest to use for xenografts. Furthermore, experiments
on animals, usually primate animals that are genetically close to humans, have
shown that PERV replicates very poorly, doesn't spread, and doesn't produce
active infection. In these experiments, pig viruses were identified in these
animals. Although they infected animal cells in the transplanted animals, yet
it never produced an active or productive infection. In short
scientists believes that careful experiments, cautious breeding and
cloning can reduce the infection risk by a considerable margin. Quoting
Dr.Thomas Starzi “If you had these clean pigs, I think that the possibility of
infectious complications of that kind, or the emergence a of hot PERV virus, is
very remote(1).”
. Animal rights issue
For decades animal rights activists
have condemned the use of animals as a ladder to achieve medical success. On
the issue of animal experimentations, Dr. Dan Lyon, Director of Uncaged
Campaigns, a British animal rights group, said “It involves the deliberate
infliction of pain, suffering and death…. deliberate acts of violence are
wrong, whether it's to another human being or to any creature that can feel
pain and that has a basic will to live(1).” In the case of xenotransplantation their
concerns are higher. In other medical researches exploitation of animals
decreases as scientists progress in their study, but in the case of
xenotransplantation the use of animals will increase with time. Some
have concerns about the raising of animals whose sole purpose is to serve as
organ "donors" for humans. They call it a misuse of living
creatures. They claim that transgenictechnology can produce animals with
various painful physical abnormalities including arthritis, stomach ulcers,
muscular weakness, defective vision, and weakened immunity. Transgenic animals
are destined to spend their lives confined in unnatural, sterile environments,
unable to fulfill their basic behavioral needs. Do humans have the
right to inflict pain to animals for their own needs? Should we deprive animals
from their natural habitat so that some of us could spend a few more days on
this planet? The greatest concern of these activists is the use of
primate animals for xenotransplantation experiments. They argue that
primates are very intellectual species. Studies have shown that
primate animals are genetically close to humans and have the same traits,
intelligence, consciousness, self awareness, the ability to form intensions and
the ability to feel emotions such as sympathy, as humans. Is it acceptable
to use our genetic neighbor for our own welfare?
Doctors claim that animal
experimentations are essential to make any kind of progress in the field of
medical science. The dangers, like toxicity of a drug, in medical
treatment for human beings are unknown. Animals provides perfect alternative
for doctor and researchers to assess these problems in a biological
environment. In the words of Dr Robert Michler, Chief of Cardiothoraic Surgery,
Ohio State University, “there is no surrogate, there is no test tube, there is
no alternative milieu that will permit me to understand the behavior of
anything if it's not in an animal first, before going to a human(1).” Animal testing have helped
scientists to eradicate some deadly diseases from the face of this earth,
saving millions of life in this process, as Dr Robin Weiss puts it, “We would
not have eradicated smallpox and could not now be eradicating poliomyelitis without
the use of animals(1).” Is it immoral to save millions of lives
by conducting experiments on animals? The prospects for
xenotransplantation to save thousands of human lives are tremendous. As
mentioned in the introduction, approximately 10 Americans die every day, and
thousands more around the world, due to lack of donated organ.
Xenotransplantation have the potential to end this scarcity of organs. If
there are means to save some human lives without harming other humans, why not
use it.
. Economic issue
If xenotransplantation does
enter society, its cost will raise questions of justice in the society.
Who will get access to this technology? who will pay for the donor organ? How
should public health care dollars be allocated? Raising transgenic animals is
an expensive and time consuming process Currently it costs from
$25,000 to $100,000 to test just one pig for the presence of known bacteria and
viruses(3). The biotechnology company Nextran
explains that one of its pig organs will eventually cost the same as a human
organ. Furthermore, there will be a obligatory monitoring of initial
transplant recipients and their close contacts in order to determine the viral
effect. Thus, it can be infer that xenotransplantation will not be a
cost effective process. Infact, it has a potential to be more expensive than
allotransplant. The current transplant costs for human organs range
from $116,000 for a kidney to more than $300,000 for a liver(3). Factoring in years of follow-up care and
immunosuppressive drugs, the cost rises to about $400,000 for a liver
transplant and over $300,000 each for heart and lung transplants.
Xenotransplantation has the potential to cost a lot more than an
allotransplantation. It doesn't take a genius to infer that due to
this cost the ability to pay will determine access to a
xenotransplant. This undermines the whole concept on
researching on xenotransplantation to provide organs for those who need it.
Advocates of xenotransplantation
claims that initially xenotransplantation will be expensive, and that this is
the case with every new technology. However, if xenotransplantation
proves to be harmless and efficient, few years from now monitoring may not be
needed for that long period of time. Thus, if xenotransplantation is achieved,
its cost will reduce with time. Moreover, there will be an emergence of new
transgenic animal breeding companies that will diminish the cost of animal
organs. Eventually, the cost of xenotransplantation will be the
same, if not lower, than allotransplantation.
Ethical Evaluation
During the last half century, science
and technology have impacted each and every one of us. Whether in
school or work or at home, our actions are related to technology in some shape
or form. Today, technology is not only necessary for us to thrive,
but also to survive. But, just because a form of technology is
available, it does not mean we must apply it. A blissful society
demands, that before taking any action we should ethically evaluate the
morality of performing that deed.
An ethical decision making
process consists of four steps:
1) Recognizing the issues.
2) Identifying the stakeholders
3) Evaluating possible actions
4) Taking a final decision
In the issues section, I have already analyzed some
possible issues associated with the implication of xenotransplantation. In
the light of these issues, the crucial stakeholders are :
·
The patients – Since every patient wants to
get cured immediately and effectively
·
·
The donor animals – Since there will be transgenic
breeding of these animals for their organs
·
·
The doctors and researchers – Because
every doctor and researcher want to provide such treatments to these patients
·
·
Animals used for experiments – Since
millions of animal are passing through painful procedures for making
xenotransplantation a reality
·
·
The entire
human race – Because there is always a danger for a widespread disease from a
retrovirus
·
Now, that we have defined our stakeholders, let’s examine
the possible actions we can take to solve this debate.
1. We can increase the funding of
xenotransplantation research, so that scientists can triumph the scarcity of
organ as soon as possible.
2. We can ban xenotransplantation
completely, and invest in some alternative to overcome the shortage of organs.
Action 1
Consequences :
If we decide to go with the first choice and promote the
research of xenotransplantation, it is quite possible that the demand-supply
gap for organs will be reduced. Certainly, xenotransplantation can help
save lives of human beings who might die without it. But, this
technology also has the potential to be deadly, not just for the patient but
also for the entire society. There will always be a threat of unknown animal
viruses spreading in our surroundings.
Individual rights and fairness:
This action will honor the rights of the doctors
and researchers to perform their duty to save the lives of their patients
In addition, rights of the patients, to receive immediate treatment, will be
protected. However, animal rights will be violated. The bodies of these animals
will be manipulated, during and after the research, by painful medical
processes.. Furthermore, their freedom of moving around freely in
the environment will be taken away. Most importantly their organs will be
snatched from them without their consent.
Common good:
Medical research in this field will progress,
and some human lives will be saved every year with cleanly produced
animal organs.
Action 2
Consequences:
The second action will prompt the medical industry to
spend their time and money for the development of other alternatives to
xenotransplantation. Recently doctors in Louisville, Kentucky
successfully transplanted the world’s first self-contained mechanical heart,
known as AbioCor, into a diabetic man on July 3. This man, survived
longer than any known patients who were transplanted with a xenograft
heart. This proves that if worked on, there can be different ways to
diminish the requirements of human organs for transplantation. Furthermore,
it eliminates the animal abuse of action 1.
Individual rights and fairness:
Obviously the rights of animals to live a free life will
be maintained. Also , the cost of xenotransplantation will raise the issue of
justice in society. It will be impossible to make this technology
available to everyone who needs it. Only those people who can
afford it will be able to make use of this process. On the flip side
of the coin, the rights of doctors to perform their responsibility of applying
every possible means for transplanting the needed organ for their patients will
be taken away.
Common good
Doctors and researchers will stop looking at
xenotransplantation as an option, and more minds will be served in inventing
new technologies like AbioCor. Animals will born and live freely in
nature, and there will be a balance of justice and fairness in the
society.
Final Decision
Before taking a decision, we should always remember that
we are responsible not only for ourselves, but also for the brothers and
sisters of this world. We are part of a global community that
consists of both humans and non-humans. Certainly,
xenotransplantation promises to save the lives of few individuals, but it also
threatens to endanger the lives of many others, animals and humans
inclusive. Definitely, the ends of an action justifies its means,
and this utilitarian approach goes against xenotransplantation.
Conclusion:
I have raised my concerns on the dangers and threats
facing our society regarding this new technology, but I have tried
my best to allow the reader to evaluate this issue based on their his/her own
moral and ethical standings. In conclusion, I would just like the
reader to take a moment and think about all the 'impossible' achievement that
science and technology have accomplished in the past. My request to them is to
keep faith in the ability of modern age to come up with some new tools that
will end this organ shortage crisis, without polluting and manipulating the
environment.
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YEAR
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EVENT
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1962
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Bone from a dog was used to repair the skull of an
injured Russian aristocrat. The operation was reportedly a success but
angered the church.
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1963-4
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Baboon kidneys were grafted into six patients by
transplant pioneer Thomas Starzl in Denver, US. The patients survived between
19 and 98 days.
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1963-64
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Chimpanzee kidneys were transplanted into 12 patients
in New Orleans, US. Most failed within two months but one recipient survived
for nine months with no sign of rejection.
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1964
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A 68-year-old man received a chimpanzee heart in
Jackson, US, but only survived for two hours.
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1969-1974
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Three children received chimpanzee livers but only
survived between one and 14 days.
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1977
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25-year-old woman had a baboon heart transplanted
in Capetown, South Africa, and a moderate circulation was maintained but only
for six hours before acute rejection. The same group also used a chimpanzee
heart to assist the heart of a 60-year-old man. But despite high doses of
immunosupressant drugs the patient died after four days.
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1984
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The Baby Fae case: A newborn baby received a baboon
heart in California. Cyclosporine was used and she lived for 20 days.
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1992
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A four-drug cocktail assisted a baboon liver
transplant. The patient died of a brain haemorrhage after 71 days. The type
of rejection typical in cross-species transplantation was not seen.
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1993
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Baboon bone marrow and kidney transplant carried out in
Pittsburgh, US with same drug cocktail used as in 1992 case. However, the
patient's suppressed immune system succumbs to infection after 26 days.
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1993
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Dr.Thomas Starzl again attempts transplanting a baboon
liver into a patient
suffering from hepatitis B. This patient never regains consciousness
after the operation, and dies of infection under heavy immunosuppression.
Starzl, who had received permission for severalmore xenotransplant
operations, halts his program to perform furtherresearch regarding transplant
rejection.
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1995
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Scientists at Diacrin, Inc receive FDA permission
to begin clinical trials using fetal pig neurons to treat patients
suffering from Parkinson's disease.These Phase 1 trials when concluded show
efficacy and no safety problems, leading to Phase 2 trials in the late 1990s.
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1995
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In May, scientists from announce that they have developed
transgenic pig hearts that survive as long as 30 hours inside baboons, as
compared to the 60 to 90 minutesurvival time for regular pig hearts. In July,
the FDA approvesNextran's proposal to use transgenic pig livers as bridge
organs on up to ten
patients.
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1995
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AIDS patient Jeff Getty receives a transplant of baboon bone
marrow cells at San
Francisco General Hospital, performed by Dr. Suzanne Ilstaad.Because baboon
stem cells are resistant to AIDS, the hope was that they would help Getty's bone marrow
produce AIDS-fighting immune cells. The baboon cells do not take; they remain in
Getty's system for only two weeks
after the transplant. He is still alive and blood tests so far have
not revealed any baboon viruses in his system.
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1997
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Professor Robin Weiss discovers that viruses embedded in
every pig cell -- known as
porcine endogenous retroviruses (PERV) -- can infect human cells in
culture. In the journal Nature he reports that each pig cell carries approximately 50
copies of the PERV virus, and that up to three of them are capable of
infecting human cells. As a result, in October the FDA halts all clinical
trials until researchers can prove they have developed procedures to detect low
levels of PERV virus
infection. The moratorium is lifted in January 1998.
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1998
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Professor Fritz Bach of Harvard Medical School and colleagues
call for a
moratorium on human clinical xenotransplant trials until the public has
debated the risk.
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1999
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The FDA effectively bans use of nonhuman primates in
xenotransplants,
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1999
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A study of 160 people who had received various pig
tissues and/or cells reveals that none had been infected with the PERV
virus. The study was conducted by researchers at Imutran, in collaboration
with the CDC and reported in
the journal Science.
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2000
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Scientists at PPL Therapeutics in Scotland
announce in the journal Nature that they have cloned five piglets for the first time.
A team of Japanese
scientists announces in the journal Science that they have also cloned a piglet using a
different method.
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2000
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Scientists at Infigin announce in the journal
Nature Biotechnology that they have produced two litters of transgenic, cloned
pigs.
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2000
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The British animal rights organization Uncaged Campaigns
receives leaked documents of
an Imutran study of the survivability of pig organs in primates over a five-year period.
The study showed the average survival time was thirteen days, with a quarter of the
primates dying within two
days.
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2001
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The United Kingdom Xenotransplantation Regulatory Authority
(UKXIRA) publishes its
third annual report,
which states "Although alternative therapies are in development,
xenotransplantation may still offer the prospect of a viable treatment within a
worthwhile time frame. However, on the basis of current evidence, whole-organ
xenotransplantation, as a solution to the ongoing shortage of organs for
transplant, appears to be some way off." They conclude that they do not
support amoratorium on xenotransplantation, and that until the infection risk is understood,
they will assess particular procedures on a case-by-case basis.
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2001
|
Preliminary analysis of Phase 2 controlled trials
treating Parkinson's disease patients with injected pig neuro cells indicate a
setback. Although there were
improvements, the study found no difference in the improvements between the patients who
had been treated with the pig cells and those who had a placebo treatment.
|
Table 2 (viruses transmitted from
animals to humans ) (1)
|
"Bovine Spongiform Encephalopathy
(BSE)/Creutzfeldt-Jakob disease
More commonly known as "mad cow" disease,
bovine spongiform encephalopathy (BSE) is a progressive neurological disorder
in cattle which is believed to have caused a fatal brain disease known as
variant Creutzfeldt-Jakob disease (vCJD) in humans. The infectious agent
linked to both BSE and vCJD is unknown -- current theories point towards a
mutation in certain protein molecules known as prions. An outbreak of BSE in
Great Britain in the 1990s appears to have been caused by the consumption of
animal feed contaminated by infected sheep and/or cattle meat and bone meal.
The new variant of CJD has an incubation period of
several years before symptoms emerge. It tends to affect younger people -- as
of October 2000, the median age of death was 27.5 years. The first symptoms
include serious psychological or sensory problems, followed by poor muscle
coordination and mental confusion. The illness lasts for at least six months,
with an average length of thirteen months.
|
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filoviruses
The filovirus family of viruses, which include Ebola
and the Marburg virus, cause severe hemorrhagic fever in humans and non-human
primates. They are believed to be zoonotic viruses; however both their
origins and their means of transmission, remain unknown.
The Marburg virus was first identified in 1967, when an
outbreak occurred in Marburg and Frankfurt, Germany, as well as Belgrade. The
first infected humans were laboratory workers who worked with African green
monkeys in an effort to prepare polio vaccine. It is a rare disease in
humans, although highly infectious.
The Ebola virus is named for a river in the Democratic
Republic of Congo where it was first recognized in 1976. In 1995, a severe
outbreak occurred in what was then called Zaire, in which 80% of the 316
people known to have the disease died. There are several subtypes of the
Ebola virus -- one strain known as the Reston subtype was identified among
monkeys imported from the Philippines to research facilities in Reston, VA.
Several researchers became infected with this strain of the virus; however
none became ill.
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hantavirus
In May 1993, virologists in the southwestern U.S.
discovered an outbreak of a new strain of hantavirus, a group of viruses
transmitted to people by rodents that cause hemorrhagic fever and pneumonia.
This particular strain, which was eventually named Sin Nombre Virus (SNV)
caused seemingly healthy people to die suddenly of acute respiratory failure.
The human disease caused by SNV is known as hantavirus pulmonary syndrome
(HPS).
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Human Immunodeficiency Virus (HIV)
Researchers believe human immunodeficiency virus (HIV)
most likely originated in non-human primates, probably chimpanzees. There are
two types of HIV: HIV-1, which the predominant strain found in the United
States, and HIV-2, primarily found in West Africa. HIV-2 is believed to have
come from the sooty mangabey monkey. Scientists were unaware of the existence
of the HIV virus in primates, until it crossed over into humans.
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influenze
Some researchers believe that certain influenza viruses
live in birds and are then passed to pigs, who may pass them on to humans. In
1918, an epidemic of influenza known as the "Spanish flu" was
transferred from pigs to people and swept the globe, killing an estimated 20
to 40 million people. A 1997 flu outbreak in Hong Kong is thought to have
incubated in chickens and spread directly to humans. Farmers slaughtered over
a million chickens, which many experts believe likely prevented the disease
from spreading further.
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nipah virus
In 1999 an outbreak of a previously undiscovered virus
occurred among pig farmers in Malaysia. Named after the village where it was
first discovered, the Nipah virus caused a form of viral encephalitis, an
inflammation of the brain. This virus is not believed to be spread by human
to human contact -- most of the infected had direct contact with pigs. Over
one hundred pig farmers died after experiencing fever, headache, dizziness
and vomiting. More than two million pigs were slaughtered in an effort to
contain the disease.
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Allotransplant : An organ or tissue transplanted between
two members of the same species.
Allotransplantation: Human-to-human organ
transplantation.
Immunosuppressive agent : a drug used to diminish or
eliminate the immune reactions of an individual.
Pathogns: microscopic creatures that makes humans sick
e.g bacteria and viruses.
Rejection : human immune system attacks any foreign
object like an infection
Retrovirus : a retrovirus is a virus in which the genome
is formed by a single strand ribonucleic acid (RNA).
Transgenic animal : an animal carrying in its chromosomes
genes from another living cell, animal, vegetable, or a micororganism.
Viruses : bits of DNA or RNA surrounded by a protein
coat.
Xenograft : An organ or tissue transplanted from a member
of one species into another.
Xenotransplant : An organ or tissue transplanted from a
member of one species into another.
References:
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