In a world first, we heard last week that US surgeons had transplanted a kidney from a gene-edited pig into a living human. News reports said the procedure was a breakthrough in xenotransplantation – when an organ, cells or tissues are transplanted from one species to another. https://www.youtube.com/embed/cisOFfBPZk0?wmode=transparent&start=0 The world’s first transplant of a gene-edited pig kidney into a live human was announced last week.

Champions of xenotransplantation regard it as the solution to organ shortages across the world. In December 2023, 1,445 people in Australia were on the waiting list for donor kidneys. In the United States, more than 89,000 are waiting for kidneys.

One biotech CEO says gene-edited pigs promise “an unlimited supply of transplantable organs”.

Not, everyone, though, is convinced transplanting animal organs into humans is really the answer to organ shortages, or even if it’s right to use organs from other animals this way.

There are two critical barriers to the procedure’s success: organ rejection and the transmission of animal viruses to recipients.

But in the past decade, a new platform and technique known as CRISPR/Cas9 – often shortened to CRISPR – has promised to mitigate these issues.

What is CRISPR?

CRISPR gene editing takes advantage of a system already found in nature. CRISPR’s “genetic scissors” evolved in bacteria and other microbes to help them fend off viruses. Their cellular machinery allows them to integrate and ultimately destroy viral DNA by cutting it.

In 2012, two teams of scientists discovered how to harness this bacterial immune system. This is made up of repeating arrays of DNA and associated proteins, known as “Cas” (CRISPR-associated) proteins.

When they used a particular Cas protein (Cas9) with a “guide RNA” made up of a singular molecule, they found they could program the CRISPR/Cas9 complex to break and repair DNA at precise locations as they desired. The system could even “knock in” new genes at the repair site.

In 2020, the two scientists leading these teams were awarded a Nobel prize for their work.

In the case of the latest xenotransplantation, CRISPR technology was used to edit 69 genes in the donor pig to inactivate viral genes, “humanise” the pig with human genes, and knock out harmful pig genes. https://www.youtube.com/embed/UKbrwPL3wXE?wmode=transparent&start=0 How does CRISPR work?

A busy time for gene-edited xenotransplantation

While CRISPR editing has brought new hope to the possibility of xenotransplantation, even recent trials show great caution is still warranted.

In 2022 and 2023, two patients with terminal heart diseases, who were ineligible for traditional heart transplants, were granted regulatory permission to receive a gene-edited pig heart. These pig hearts had ten genome edits to make them more suitable for transplanting into humans. However, both patients died within several weeks of the procedures.

Earlier this month, we heard a team of surgeons in China transplanted a gene-edited pig liver into a clinically dead man (with family consent). The liver functioned well up until the ten-day limit of the trial.

How is this latest example different?

The gene-edited pig kidney was transplanted into a relatively young, living, legally competent and consenting adult.

The total number of gene edits edits made to the donor pig is very high. The researchers report making 69 edits to inactivate viral genes, “humanise” the pig with human genes, and to knockout harmful pig genes.

Clearly, the race to transform these organs into viable products for transplantation is ramping up.

From biotech dream to clinical reality

Only a few months ago, CRISPR gene editing made its debut in mainstream medicine.

In November, drug regulators in the United Kingdom and US approved the world’s first CRISPR-based genome-editing therapy for human use – a treatment for life-threatening forms of sickle-cell disease.

The treatment, known as Casgevy, uses CRISPR/Cas-9 to edit the patient’s own blood (bone-marrow) stem cells. By disrupting the unhealthy gene that gives red blood cells their “sickle” shape, the aim is to produce red blood cells with a healthy spherical shape.

Although the treatment uses the patient’s own cells, the same underlying principle applies to recent clinical xenotransplants: unsuitable cellular materials may be edited to make them therapeutically beneficial in the patient.

We’ll be talking more about gene-editing

Medicine and gene technology regulators are increasingly asked to approve new experimental trials using gene editing and CRISPR.

However, neither xenotransplantation nor the therapeutic applications of this technology lead to changes to the genome that can be inherited.

For this to occur, CRISPR edits would need to be applied to the cells at the earliest stages of their life, such as to early-stage embryonic cells in vitro (in the lab).

In Australia, intentionally creating heritable alterations to the human genome is a criminal offence carrying 15 years’ imprisonment.

No jurisdiction in the world has laws that expressly permits heritable human genome editing. However, some countries lack specific regulations about the procedure.

Is this the future?

Even without creating inheritable gene changes, however, xenotransplantation using CRISPR is in its infancy.

For all the promise of the headlines, there is not yet one example of a stable xenotransplantation in a living human lasting beyond seven months.

While authorisation for this recent US transplant has been granted under the so-called “compassionate use” exemption, conventional clinical trials of pig-human xenotransplantation have yet to commence.

But the prospect of such trials would likely require significant improvements in current outcomes to gain regulatory approval in the US or elsewhere.

By the same token, regulatory approval of any “off-the-shelf” xenotransplantation organs, including gene-edited kidneys, would seem some way off.

Christopher Rudge, Law lecturer, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Microplastics and nanoplastics are everywhere in our environment – including in our oceans and lakes, farmland, and even Arctic ice algae.

Microplastics have also been found inside of us – with studies detecting them in various tissues including in the lungs, blood, heart and placenta. Understandably, concern is rising about the potential risks of microplastics on our health.

However, while a growing body of research has focused on microplastics and nanoplastics, there’s still a lack of direct evidence that their presence in human tissues is harmful to our health – and it’s uncertain if they are related to particular diseases.

A new study has uncovered a correlation between microplastics and heart health, though. The researchers found that people who had detectable microplastics and nanoplastics in the plaque in their arteries had a higher risk of heart attack, stroke and death.

Heart health

The researchers looked at 257 people altogether. All of the patients were already undergoing preventative surgery to remove plaque from their carotid arteries (the main arteries that supply the brain with blood). This allowed the researchers to collect plaque samples and perform a chemical analysis. They then followed up with participants 34 months later.

Of the 257 participants, 150 were found to have the presence of microplastics and nanoplastics in their arterial plaque – mainly fragments of two of the most commonly used plastics in the world, polyethylene (used in grocery bags, bottles and food packaging) and polyvinyl chloride (used in flooring, cladding and pipes).

A statistical analysis of this data found that patients with microplastics and nanoplastics in their plaque had a higher risk of suffering a heart attack, stroke or death from any cause, compared with those who had no microplastics or nanoplastics in their plaque.

The researchers also analysed the macrophages (a type of immune cell that helps remove pathogens from the body) in the patients’ arteries. They found that participants who’d had microplastics and nanoplastics in their plaque also had evidence of plastic fragments in their macrophages.

They also looked at whether certain genes associated with inflammation (which can be a sign of disease) were switched on in the participants. They found that the participants who’d had microplastics and nanoplastics in their plaque also had signs of inflammation in their genes.

These results may suggest an accumulation of nanoplastics and microplastics in carotid plaque could partly trigger inflammation. This inflammation may subsequently change the way plaque behaves in the body, making it less stable and triggering it to form a blood clot – which can eventually block blood flow, leading to heart attacks and strokes.

Interestingly, the researchers also found the presence of nanoplastics and microplastics was more common in participants who had diabetes and cardiovascular disease. This raises a lot of questions which have yet to be answered – such as why microplastics were more common in these participants, and if there may be a correlation between other diseases and the presence of microplastics in the body.

Other health risks

This study only focused on patients who had carotid artery disease and were already having surgery to remove the build-up of plaque. As such, it’s unclear whether the findings of this study can be applied to a larger population of people.

However, it isn’t the first study to show a link between microplastics and nanoplastics with poor health. Research suggests some of this harm may be due to the way microplastics and nanoplastics interact with proteins in the body.

For example, some human proteins adhere to the surface of polystyrene nanoplastics, forming a layer surrounding the nanoparticle. The formation of this layer may influence the activity and transfer of nanoplastics in human organs.

Another study suggested that nanoplastics can interact with a protein called alpha-synuclein, which in mouse studies has been shown to play a crucial role in facilitating communication between nerve cells. These clumps of nanoplastics and protein may increase the risk of Parkinson’s disease.

My published PhD research in chicken embryos found that nanoplastics may cause congenital malformations due to the way they interact with a protein called cadherin6B. Based on the interactions myself and fellow researchers saw, these malformations may affect the embryo’s eyes and neural tube, as well as the heart’s development and function.

Given the fact that nanoplastics and microplastics are found in carotid plaque, we now need to investigate how these plastics got into such tissues.

In mice, it has been demonstrated that gut macrophages (a type of white blood cell) can absorb microplastics and nanoplastics into their cell membrane. Perhaps a similar mechanism is taking place in the arteries, since nanoplastics have been identified in samples of carotid plaque macrophages.

The findings from this latest study add to a growing body of evidence showing a link between plastic products and our health. It is important now for researchers to investigate the specific mechanisms by which microplastics and nanoplastics cause harm in the body.

Meiru Wang, Postdoctoral Researcher, Molecular Biology and Nanotoxicology, Leiden University

This article is republished from The Conversation under a Creative Commons license. Read the original article.