IN CONTEXT
Rachel Hajar, MD, FACC*
Organ transplantation is undoubtedly one of the spectacular achievements in
medicine in the past 25 years. This issue of
Heart Views spotlights transplantation. Divisi
et al discuss the indications and complications
of lung transplantation and their experience
in their institution (p.53). Dr. O. Abboud reviews
the pathophysiology and management of hypertension
post renal transplant (p.57) and Dr. H.A. Hajar
recounts the story of the first Qatari heart
transplant recipient (p.85). The concept of
replacing diseased organs with healthy ones
through organ transplantation is not unique
to our time (p.79 ). It can be found in myths
of the ancient Greeks and was referred to by
even older civilizations. The epic journey began
in India and China over two thousand years ago
(1) and throughout the centuries, the idea fired
the imagination of a few visionaries who persevered
despite insurmountable odds. It was only at
the beginning of the 20th century, however,
that the first major breakthrough occurred with
Alexis Carrell’s discovery of joining blood
vessels. Carrell’s pioneering work paved the
way for organ transplantation (2). Nevertheless,
until the middle of the twentieth century, therapeutic
organ transplantation remained largely impossible
– a myth, or fantasy, or science fiction. Skin
and cornea were among the first successful transplants.
But the larger, more complex, and imbedded organs
posed countless problems. The kidney was the
first such organ to be successfully transplanted.
As in all transplant cases, the first attempts
in the early 1950s were made when the only other
alternative for the patient was death. Those
early patients briefly raised hopes by starting
a good recovery, but then succumbed. The future
of transplant surgery was very bleak. A decade
later, Medawar and Burnett demonstrated that
the body’s rejection of foreign tissue was an
immune response (2). Tissue typing and immune
suppression with drugs was used with limited
success. The immunosuppressive property of the
drug cyclosporine (see cover legend, iii) was
discovered by Borel in 1976 (3). Its revolutionary
impact on the success of organ transplantation
is unparalleled by any other medical or scientific
breakthrough in the long history of tissue and
organ transplantation. The addition of cyclosporine
to the immunosuppressant protocol dramatically
improved graft survival. According to the United
Network for Organ Sharing (UNOS), an organization
of transplant programs and laboratories in the
USA, graft survival at one year for living donor
kidney average about 90% (cadaver kidney 80%),
heart 82%, and lung, liver, and pancreas about
70% (4). Transplantation is now an established
and effective treatment for organ failure. Today,
thousands of people of all ages are admitted
to hospitals because of the malfunction of some
vital organ. According to UNOS, a new name is
added to the organ transplant waiting list every
16 minutes. As of June 29, 2001 the UNOS national
waiting list for organ transplant was 77,330.
In 2000, only 38% of those on the UNOS waiting
list received an organ transplant (4). This
number applies only to the USA and does not
reflect global need. For many patients the wait
is long, and many die before a life-saving organ
becomes available. The discrepancy between the
number of potential recipients and donor organs
is increasing annually by approximately 10 –
15% (5). The acute shortage of available donor
organs is the driving force behind the search
for alternative sources of donor organs. Possibilities
that are presently being examined include xenotransplantation,
(the transplantation of organs, tissues and
cells from animals into humans), growing new
organs, and mechanical artificial organs.
The first internal artificial heart (Abiocor) has been implanted in a patient
in July 2001. Although the technology is promising,
further trials are needed to evaluate its function
and its effect on the quality of life of patients.
Left ventricular assist devices (LVAD) were
designed to assist the heart to pump blood while
waiting for a transplant. Because of their large
size, they fit only in the abdominal cavity
and even there, they are too large to give to
small patients. However, LVADs could keep patients
with end-stage heart failure alive for months,
if not years. They are used in transplant centers
as a bridge to transplantation. Physicians have
noted that patients on LVAD for several months
awaiting a donor heart clinically improved (6).
This intriguing observation suggested that the
defect in sarcomere shortening found in myocytes
in patients with advanced heart failure (7)
maybe reversible through “unloading” the failing
heart. Consequently, LVAD currently used as
“bridges to heart transplantation” may become
“bridges to recovery” (8). The challenge was
to develop a LVAD small enough to go in the
chest but powerful enough to pump five liters
of blood a minute. A new, thumb-sized LVAD was
recently approved to be used in clinical trials
in Europe and the USA. As of June 2000, 33 patients
have been fitted with the device (9). Cardiac
unloading with long-term ventricular assistance
and replacement of the heart with a totally
implanted artificial heart have the potential
to prolong life greatly in patients with heart
failure. Artificial devices to replace complex
organs such as the liver are likely to be years
away.
s it possible to grow large complex organs such as hearts, livers, kidneys,
pancreas, bladders and intestines? Pioneering
research in the field of tissue engineering
provides an exciting strategy to fill the donor
shortage by creating semi-synthetic living organs
that can be used to replace failing human organs.
New organs can be formed by incorporating cells
harvested from a patient’s own cells into biodegradable
polymer three-dimensional scaffolds. The entire
structure of cells and scaffolding is transplanted
into the diseased organ where the cells replicate,
reorganize, and form new tissue. The artificial
polymers break down, leaving only a completely
natural organ – a neo-organ. Another way is
to inject a molecule of growth factor into a
wound or an organ that requires regeneration
to stimulate regeneration and growth (10). There
are still numerous obstacles that must be surmounted
before semi-synthetic living organs become a
reality. Engineered neo-organs require blood
vessels to supply them with nutrients. Tissue
engineers are exploring angiogenesis-stimulating
molecules that are already being used in clinical
trials to bypass blocked arteries to promote
growth of new blood vessels. The goal is to
grow organs within the person or regenerate
tissues internally rather than in an external,
artificial environment. However, scientists
predict that it will take at least 10 – 20 years
or more to grow an entire heart but tissues
such as heart valves and blood vessels maybe
available sooner (10). In the case of skin,
however, the future is here. A living skin product
is already available and has been approved by
the US Food and Drug Administration (10). Three
landmark discoveries in the late 1990s had a
dramatic and revolutionary impact in transplantation
research and the direction of tissue engineering:
a) the birth of “Dolly”, the cloned sheep in
February 1997. Wilmut and his Roslin Institute
team made the first breakthrough in reprogramming
an adult differentiated animal cell through
nuclear transfer or cloning; b) the discovery
in March 1997 that through gene transfer, telomerase
in normal cells could divide indefinitely and
such immortal cells were free of cancerous changes
(11); and c) the isolation and culture of human
embryonic stem cells, which could differentiate
into any type of tissue in the body (12,13).
Indeed, the potential of stem cell research
is vast and would revolutionize medicine. These
discoveries have inspired scientists to dream
of generating an unlimited supply of cells,
tissues, and organs for a wide range of degenerative
diseases such as cancer, Parkinson’s disease,
cardiovascular diseases, diabetes, and numerous
other diseases. The transplant material would
be derived from the patients themselves, who
would therefore require no immunosuppressive
drugs. Embryonic stem cells promise insights
and benefits to many areas of research and medicine.
As Rene Descartes, the French philosopher stated
in the 17th century: “All at present known in
it [medicine] is almost nothing in comparison
of what remains to be discovered . . . We could
free ourselves from an infinity of maladies
. . . and perhaps also even from the debility
of age, if we have sufficiently ample knowledge
of their causes, and all of the remedies provided
to us by nature.” Passionate controversy swirls
around the ethical, moral, legal, social and
religious ramifications of stem cell research
and cloning. Of particular concern is the phobia
of altering the human genetic germ line.
The cliché, “Medicine is not a field in which
sheep may safely graze” is a sardonic description
of the ferment going on in the field of transplantation
research in the 21st century. Over the past few
years, xenotransplantation has been gaining momentum
as a viable solution to the increasing shortage
of human donor organs. Recent developments in
understanding the barriers to successful xenotransplantation,
along with access to novel drugs and approaches
to manipulate the immune system through genetic
modification, are making xenotransplantation more
clinically feasible and bringing it much closer
to reality. Transplantation allows patients with
organ failure to resume a normal lifesyle. Xenotransplantation
offers the potential of an unlimited supply of
healthy donor organs. The most promising source
of animal organs for transplantation into humans
is the pig. Although primate-to-human transplant
might seem ideal since they are concordant species,
there are significant drawbacks to their use including
ethical concerns, transmission of infectious disease
and the cost of breeding and maintaining primates
(14). Pigs, on the other hand, have large litters,
they are easy to breed, and their organ size and
physiology are remarkably similar to that of humans.
A major obstacle in using pig organs in humans is hyperacute rejection, a
process that takes place immediately when an
organ is transplanted into a recipient of another
species (15). Humans have natural IgM antibodies
to alpha 1-3 galactose (alpha Gal) that is expressed
on all nucleated pig cells (15). After binding
to these preformed antibodies, serum complement
is activated, resulting in massive thrombosis
to vascular endothelium with vessel occlusion
and graft failure within minutes to hours of
the transplantation (16). The most promising
solution to hyperacute rejection is to modify
the genetic make-up of the donor through genetic
engineering. Recently, researchers have succeeded
in introducing human genes that encode the key
proteins called delay accelerating factor (DAF)
and CD59 in pig cells (17). These proteins play
a crucial role in a person’s immune system.
They guard blood components such as red blood
cells and blood vessels from attack by the complement
system. By producing transgenic pigs that express
human complement regulatory proteins (DAF and
CD59), which inhibit the injurious effect of
pig antibody mediated complement activation,
hyperacute rejection is now being overcome (18).
Another major barrier to xenotransplantation is acute vascular rejection, which
leads to graft destruction over a period of
days to weeks (19). There are still many unknown
mechanisms in the occurrence of acute vascular
rejection. Organ survival times of transgenic
pig hearts and kidneys in primates varied from
a few days to several weeks. Potent immunosuppressants
are being developed but these drugs are too
toxic for human use. It is hoped that a better
understanding of the underlying processes that
lead to acute vascular rejection may lead to
the development of new immunosuppressive drugs
and further attempts to genetically modify pig
genes (18).
A legitimate concern in xenotransplantation is the transmission of diseases
from animals to humans and termed as xenozoonosis
(20). The fear that xenotransplantation might
cause a new infectious disease epidemic is the
subject of intense debate and controversy. Many
researchers however, believe the risk is slight.
Some authorities argue that the potential threat
to public health of xenograft-derived diseases
presents unacceptable risks. The two types of
animal viruses that are especially troublesome
are herpes viruses and retroviruses. Both types
have been proven to be harmless in monkeys but
fatal to humans. HIV for example, is a retrovirus
that many researchers believe was transmitted
to humans from monkeys (20). There is agreement
that guidelines to minimize the risks are needed.
Xenotransplant recipients, their families, and
their health care providers must be monitored
closely for infectious disease complications.
In addition, pigs used for xenotransplantation
must be bred and raised in a special facility
under strict conditions (20). However, endogenous
retroviruses found in the DNA of all mammalian
species can not be “bred out” of xenotransplants
(18). Since 1997, there have been reassuring
studies that there is no appreciable current
evidence of porcine endogenous retrovirus infection
in human recipients of xenotransplants (21,22).
Nevertheless, the controversy continues. In
March 2001, the United Kingdom Xenotransplantation
Interim Regulatory Authority released its annual
report stating, “uncertainty about the safety
of xenotransplantation continues to be a significant
obstacle” and that the technology is unlikely
to solve problems of shortages of organs for
transplantation in the near future (23). The
Canadian Public Health Association, while acknowledging
the lack of scientific evidence to predict or
understand the risks, concluded that the technology
should not be banned and new laws may be required
to deal with the risk (23). The US Public Health
Service Guideline on Infectious Disease Issues
on Xenotransplantation expanded the definition
of xenotransplantation to include not only any
procedure that involves the transplantation,
implantation, or infusion of live cells, tissues,
or organs from a nonhuman source into a human
recipient, but also human body fluids, cells,
tissues, or organs that have had ex vivo contact
with live nonhuman animal cells, tissues, or
organs. The US guideline puts the primary responsibility
for designing and monitoring the conduct of
xenotransplantation clinical trials under the
sole responsibility of the sponsor. It recommends
life-long surveillance of xenotransplant recipients
and close contacts. The guideline also proposes
setting up a national xenotransplantation database
from all clinical centers that conduct xenotransplantation
trials and all animal facilities providing source
animals (23). The US Food and Drug Administration
(FDA) also issued a proposed rule that would
require public disclosure of clinical trials
involving xenotransplantation and gene therapy.
This ruling drew strong opposition from industry
(23). The controversy highlights many important
ethical issues related to the application and
regulation of new biotechnologies in this field.
In essence, the intense controversy surrounding xenotransplantation revolves
around ethical issues mentioned above. Additional
ethical issues include the use of animals, genetic
alterations of animal species, which groups
of patients should be included/excluded in clinical
trials, informed consent of research subjects,
and full public disclosure (18). Although xenotransplantation
is still experimental and many ethical issues
remain unresolved, the question of when to start
human trials is on the horizon. The xenotransplantation
committee of the FDA’s Center For Biologic Evaluation
And Research has recommended that before clinical
trials resume, the success rate of pig-to-primate
transplants should be raised from the present
50% organ survival rate for less than one month
to a 90% survival rate for two months, and a
50% rate for three months (18). Xenotransplantation
offers the potential to save lives and alleviate
human suffering. However, in our zeal to prolong
life, we must remember “there is dignity in
dying that physicians should not dare to deny.”
At the present time, xenotransplantation is
at the stage where allotransplantation was 50
years ago. Hopefully, with patience, cooperation,
and understanding from the public, patients,
the medical profession, researchers, and the
biotechnical industry, progress will be made
to make xenotransplantation a reality.
Cutting-edge technology is available at our fingertips to develop unlimited
supplies of autologous cells and organs for
transplantation. Each new step forward brings
with it new sets of ethical issues, but these
concerns could be responsibly addressed as long
as we keep in mind to use such sophisticated
scientific discoveries for the good of mankind.
New medical discoveries are thrilling but it
is well to remember what Hippocrates stated
over one thousand five hundred years ago: “Life
is short, and the Art long; the occasion fleeting;
experience fallacious, and judgment difficult.
The physician must not only be prepared to do
what is right himself, but also to make the
patient, the attendants, and externals cooperate”
(24). © 2001 Hamad Medical Corporation.
1. Kuss R, Bourget P. An illustrated history of organ
transplantation: the great
adventure of the century.
France: Laboratoires Sandoz, Rueil-Malmaison,
1992.
2. http://www.nobel.se/medicine/index.html
3. Grebenau, M. Cyclosporine - Persistence and Serendipity
4. http://www.unos.org
5. Cooper, DKC. Xenografting: how great is the clinical
need? Xeno. 1993;1:25 – 26.
6. Dipla K, Mattiello JA, Jeevanandam V, et al. Myocyte
recovery after
mechanical circulatory support in
humans with end-stage heart failure.
Circulation.1998;97:2316–2322
7. Koide M, Nagatsu M, Zile MR, et al. Premorbid
determinants of a left
ventricular dysfunction in a novel
model of gradually induced pressure
overload in theadult canine. Circulation. 1997;95:1601–1610.
8. Oz M, Argeriziano M, Catanase KA, et al. Bridgeexperience with long-
termimplantable left-ventricular assist devices:
are they an alternative
totransplantation? Circulation. 1997;95:1844–1852.
9. http://public.bcm.tmc.edu/pa/vad.htm - Baylor College of Medicine.Special
Edition. Baylor surgeons implant
first US patient with ventricular assist
device.June 8,2000.
10. Mooney DJ, Mikos AG. Growing new organs. Scientific American.
September 1999
11. Bodnar, A.G., Ouellette, M., Frolkis, M., et al..Extension of life-span by
introduction of telomerase into normal human cells.
Science 1998;279(5349):334-335.
12. Thomson, J.A., Itskovitz-Eldor, J., Shapiro, SS., et al.Embryonic stem cell
lines derived from humanblastocysts. Science 1998;282(5391):1145-1147.
13. Gearhart, J. New potential for human embryonic stem cells.
Science 1998;282(5391):1061-1062.
14. Chiche L, Adam R, Caillat-Zucman S, et al.Xenotransplantation: Baboons as
potential live donors? Transplantation 1993;55(6):1418 – 1421
15. Buhler L, Friedman T, Cooper DKC. Xenotransplantation - State Of The Art -
Update 1999.Frontiers in Bioscience 1999;4:416 – 432.
16. Sequino SP. Genetically modified animal organs forhuman transplantation.
World J Surg 1997;21(9):939 – 942.
17. Bigam D, Zhong R, Levy G, Grant D. Xenotransplantation.
Canadian J Surg 1999;42:12 – 16.
18. Vanderpool HY. Xenotransplantation:progress and
promise. BMJ 1999;319:311 – 313.
19. Platt JL. Xenotransplantation: recent progress and
current perspectives. Curr Opin Immunol 1996;8:721– 728.
20. Chapman LE, Salomon DR, Patterson AP.Xenotransplantation and
xenogeneic infections. N EnglJ Med 1995;333:1498 – 1501.
21. Heneine W, Tibeli AI, Switzer WM, et al. No evidence of infection with porcine
endogenous retrovirus in recipients of porcine islet-cell xenograft. Lancet
1998;352:695 – 699.
22. Patience C, Patton GS, Takeuchi Y, et al. No evidence of pig DNA or
retroviral infection in patients with short- term extracorporeal connection to
pig kidneys. Lancet 1998;352:699 – 701.
23. Sanyin S. Xenotransplantation gains momentum. The BioMed Net Magazine
HMS Beagle 2001;102. http//news.bmn.com.hmsbeagle.
24. Hippocrates. Aphorisms I.1 (tr. By Francis Adams)
http://classics.mit.edu/Hippocrates/aphorisms.1.i.html
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