Pig Kidney Xenotransplantation Performing in Human Body

We learned this week that US surgeons had successfully transplanted a kidney into a living human from a gene-edited pig, a first for the world.

According to news sources, the process represented a breakthrough in the field of xenotransplantation, which is the transplanting of organs, cells, or tissues from one species to another.

Gene-edited pigs offer "an endless supply of transplantable organs," according to a biotech CEO.

Proponents of xenotransplantation believe it is the answer to the global organ shortage. 1,445 Australians were on the waiting list for kidney donors as of December 2023. Over 89,000 people are waiting for kidneys in the US.

However, not everyone believes that using animal organs for human transplantation is the best solution to the organ scarcity or even if using animal organs for human transplantation is ethically acceptable.

The two main obstacles to the procedure's effectiveness are patients' exposure to animal infections and organ rejection.

However, over the last ten years, a novel technology and methodology called CRISPR/Cas9—often abbreviated as CRISPR—has shown the potential to address these problems.

What is CRISPR?

CRISPR gene editing makes use of a mechanism that exists in nature already. Bacteria and other microbes evolved CRISPR's "genetic scissors" to help them fight off viruses. Their biological apparatus enables them to assimilate and, in the end, cleave viral DNA.

Two scientific teams figured out how to use this bacterial immune system in 2012. This is composed of linked proteins called "Cas" (CRISPR-associated) proteins and repetitive DNA arrays.

Utilizing a specific Cas protein (Cas9) in conjunction with a "guide RNA" composed of a single molecule, the researchers discovered that they could direct the CRISPR/Cas9 complex to break and repair DNA at specific sites as desired. At the mending location, the system might potentially "knock in" new genes.

The two scientists in charge of these teams received a Nobel Prize in 2020 in recognition of their achievements.

69 genes in the donor pig were edited using CRISPR technology in the most recent xenotransplantation procedure in order to deactivate viral genes, "humanize" the pig by adding human genes, and eliminate undesirable pig genes.

A busy time for gene-edited xenotransplantation

Although the prospect of xenotransplantation has been given fresh hope because to CRISPR editing, even recent trials have shown that extreme caution is still necessary.

Two terminally ill patients who were not suitable for conventional heart transplants were given regulatory approval in 2022 and 2023 to receive a gene-edited pig heart. Ten genomic modifications were made to these pig hearts to improve their suitability for human transplantation. Nevertheless, a few weeks after the surgeries, both patients passed away.

We learned earlier this month that a group of Chinese surgeons (with the approval of the patient's family) transplanted a gene-edited pig liver into a man who was clinically dead. Up until the trial's ten-day deadline, the liver was operating normally.

How is this latest excmple different?

The kidney from the gene-edited pig was transplanted into a living, somewhat young, consenting adult who was also legally competent.

The donor pig has undergone an extremely high total number of gene modifications. The scientists say they have made 69 modifications to remove damaging pig genes, "humanize" the pig by adding human genes, and inactivate virus genes.

It is obvious that efforts are accelerating to convert these organs into transplantable products.

From biotech dream to clinical reality

The use of CRISPR gene editing in conventional medicine began just a few months ago.

The world's first CRISPR-based genome-editing therapy for human usage was approved by US and UK drug regulators in November. It is a treatment for severe types of sickle-cell disease.

The Casgevy treatment modifies the patient's own bone marrow stem cells using CRISPR/Cas-9. The goal is to create red blood cells with a healthy spherical form by destroying the defective gene that gives red blood cells their "sickle" shape.

Even if the patient's own cells are used in the treatment, the same basic idea underlies more recent clinical xenotransplants: inappropriate biological components can be modified to improve the patient's outcome.

We will discuss gene editing in further detail.

Regulators of gene technology and medicine are being asked more and more to allow new CRISPR and gene editing experimental trials.

But neither xenotransplantation nor the medicinal uses of this technology result in heritable alterations to the DNA.

In vitro (in the lab) early-stage embryonic cells are one example of the cells to which CRISPR modifications would need to be administered in order for this to happen.

In Australia, it is illegal to purposefully modify the human genome in a way that could result in 15 years in prison.

There isn't a single legal state in the world that specifically allows for heritable human genome modification. Some nations do not, however, have explicit laws governing the process.

Is this how things will go in the future?

But even without introducing heritable gene alterations, CRISPR-assisted xenotransplantation is still in its early stages.

Despite the headlines' seeming optimism, there is still not a single instance of a stable xenotransplantation in a living person that has lasted longer than seven months.

Although the so-called "compassionate use" exception has allowed for the recent transplant in the United States, traditional clinical trials for pig-human xenotransplantation have not yet started.

However, in order for such trials to be approved by regulators in the US or abroad, existing outcomes would probably need to be much improved.

Likewise, it would appear some time before any "off-the-shelf" xenotransplantation organs, such as kidneys that have been genetically altered, are approved by regulators.