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The advancement of organ transplantation with genetically modified pigs already involves patients living with porcine kidneys, ongoing clinical trials, and new research with livers and hearts, in an attempt to address the shortage that keeps thousands of people on or off waiting lists.
The possibility of using genetically modified pigs in organ transplantation is advancing as a response to the shortage that keeps thousands of patients on or off waiting lists. The technique, known as xenotransplantation, has moved beyond the theoretical realm and involves people living with genetically modified pig kidneys, in addition to ongoing clinical trials and new tests planned.
The shift comes amid intense pressure on the transplant system. In the United States, more than 100,000 patients are currently awaiting organs, most of them candidates for kidney transplants, while about 600,000 people are on dialysis and a similar number suffer from end-stage liver disease.
Organ transplantation faces long waiting lists and limited supply
The routine evaluation of donated organs exposes the dilemma faced by medical teams and patients. A kidney offer from a 68-year-old donor, diabetic, hypertensive, who died from a stroke, with normal kidney function but a biopsy showing scarring and inflammation, represents the type of difficult decision frequently encountered.
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The choice involves calculating risks, benefits, and the probable duration of the organ. For a patient over 60, with diabetes, high blood pressure, and several years of dialysis, even a compromised kidney can mean temporary relief from the machine used three times a week to filter blood.
Dialysis keeps patients alive but does not replace the quality of life associated with a successful transplant. For many, a few years with a functioning kidney can allow for travel, family time, and normal meals before a possible return to treatment.
Medicine advanced, but demand grew
Modern organ transplantation is the result of a transformation built over decades. In the early 20th century, the procedure was closer to science fiction than medical practice.
In the 1950s, recipients almost always died tragically. In the 1960s, some successful cases were recorded, but they were overshadowed by a series of failures.
The modern discipline that now saves lives emerged in the mid-1980s with the advent of cyclosporine, an immunosuppressant drug that changed the outcomes of procedures. When transplantation became a reality, waiting lists were short and primarily comprised young, healthy patients, except for the failing organ.
Today, transplant outcomes are more favorable than ever, but the waiting list has grown exponentially. The increase occurred largely because it began to include older patients with more health problems, whose organs failed due to chronic diseases such as diabetes and hypertension.
Many patients don’t even make it to the list
The shortage of organs forces medical teams to use already compromised organs, which can lead to unsatisfactory results. In some cases, the patient ends up returning to the waiting list after the transplanted organ stops functioning.
At the same time, many patients who could benefit from an organ transplant never even make it onto the list. Some are never referred because care teams assume they would be poor candidates or because they lack adequate access to the healthcare system.
Others are left off the list because there is no expectation that they will live long enough for an organ to become available, or because post-transplant outcomes would be poor. Since donations are limited, a program only proceeds when it predicts at least a 90% chance of one-year survival.
Genetically modified pigs gain ground
Xenotransplantation, or transplantation between different species, emerges as an alternative to change this scenario. While the idea may still seem unthinkable to many, there are already people living with genetically modified pig kidneys.
Two clinical trials with pig kidneys are underway. Another trial, with genetically modified pig livers to temporarily filter the blood of patients with liver failure, is about to recruit participants, while tests with pig hearts are expected to begin soon.
Pigs have become the preferred universal donors for practical reasons. They are of suitable size, have large litters of six to twelve piglets, a gestation period of three to four months, and low rearing costs.
Primates were used as donors until the late 1980s but presented significant obstacles. They reproduce slowly, are emotionally and ethically more difficult to use, many are too small, and they also raised concerns about infection risk.
Rejection was the biggest initial obstacle
The main problem with pigs was already known since the 1960s. A porcine organ transplanted into a primate, or likely into a human, would be rejected within minutes.
The cause lay in a sugar molecule present on the surface of most pig cells and absent in humans. Natural antibodies recognize these sugars and activate an immune response capable of rapidly destroying the organ after transplantation.
In the 1980s and 1990s, attempts to reduce this response had limited success. The cloning of Dolly the sheep in 1996 opened a new path by showing that it would be possible to modify pig cells in culture and clone animals without the gene responsible for this sugar.
The first pig of this type was generated in 2002. Companies like Novartis invested billions of dollars in the technology, but protests against animal genetics and the discovery of a virus present in the cells of virtually all pigs led investors to withdraw funding in the early 2000s.
CRISPR accelerated xenotransplantation
The last decade changed the pace of research with the advancement of CRISPR-Cas9. The gene-editing tool allows for the generation of transgenic animals in months, no longer in years.
With the technique, it became possible to modify dozens of genes to make pig organs more closely resemble human organs. It also became technically simple to add alterations aimed at reducing immune responses in the organs themselves.
Among the names linked to the advancement are Martine Rothblatt, founder of Sirius Satellite Radio and United Therapeutics, and George Church, a geneticist linked to the Human Genome Project and CRISPR gene editing. Church generated a pig with 69 modified genes.
The current generation of transgenic pig organs can likely sustain life for six months to a year, and some may last longer. However, the need for intense immunosuppression still limits the utility of these organs.
The expectation is that more genetically complex pigs will improve xenotransplantation outcomes, reduce extensive immunosuppression, and increase organ longevity. In the future, organ transplantation may include personalized organs, created based on genetic compatibility with specific recipients.
With information from Zme Science
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