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.

Our brain is an extremely complex and delicate organ. Our body fiercely protects it by holding onto things that help it and keeping harmful things out, such as bugs that can cause infection and toxins.

It does that though a protective layer called the blood-brain barrier. Here’s how it works, and what it means for drug design.

First, let’s look at the circulatory system

Adults have roughly 30 trillion cells in their body. Every cell needs a variety of nutrients and oxygen, and they produce waste, which needs to be taken away.

Our circulatory system provides this service, delivering nutrients and removing waste.

Where the circulatory system meets your cells, it branches down to tiny tubes called capillaries. These tiny tubes, about one-tenth the width of a human hair, are also made of cells.

But in most capillaries, there are some special features (known as fenestrations) that allow relatively free exchange of nutrients and waste between the blood and the cells of your tissues.

It’s kind of like pizza delivery

One way to think about the way the circulation works is like a pizza delivery person in a big city. On the really big roads (vessels) there are walls and you can’t walk up to the door of the house and pass someone the pizza.

But once you get down to the little suburban streets (capillaries), the design of the streets means you can stop, get off your scooter and walk up to the door to deliver the pizza (nutrients).

We often think of the brain as a spongy mass without much blood in it. In reality, the average brain has about 600 kilometres of blood vessels.

The difference between the capillaries in most of the brain and those elsewhere is that these capillaries are made of specialised cells that are very tightly joined together and limit the free exchange of anything dissolved in your blood. These are sometimes called continuous capillaries.

This is the blood brain barrier. It’s not so much a bag around your brain stopping things from getting in and out but more like walls on all the streets, even the very small ones.

The only way pizza can get in is through special slots and these are just the right shape for the pizza box.

The blood brain barrier is set up so there are specialised transporters (like pizza box slots) for all the required nutrients. So mostly, the only things that can get in are things that there are transporters for or things that look very similar (on a molecular scale).

The analogy does fall down a little bit because the pizza box slot applies to nutrients that dissolve in water. Things that are highly soluble in fat can often bypass the slots in the wall.

Why do we have a blood-brain barrier?

The blood brain barrier is thought to exist for a few reasons.

First, it protects the brain from toxins you might eat (think chemicals that plants make) and viruses that often can infect the rest of your body but usually don’t make it to your brain.

It also provides protection by tightly regulating the movement of nutrients and waste in and out, providing a more stable environment than in the rest of the body.

Lastly, it serves to regulate passage of immune cells, preventing unnecessary inflammation which could damage cells in the brain.

What it means for medicines

One consequence of this tight regulation across the blood brain barrier is that if you want a medicine that gets to the brain, you need to consider how it will get in.

There are a few approaches. Highly fat-soluble molecules can often pass into the brain, so you might design your drug so it is a bit greasy.

Another option is to link your medicine to another molecule that is normally taken up into the brain so it can hitch a ride, or a “pro-drug”, which looks like a molecule that is normally transported.

Using it to our advantage

You can also take advantage of the blood brain barrier.

Opioids used for pain relief often cause constipation. They do this because their target (opioid receptors) are also present in the nervous system of the intestines, where they act to slow movement of the intestinal contents.

Imodium (Loperamide), which is used to treat diarrhoea, is actually an opioid, but it has been specifically designed so it can’t cross the blood brain barrier.

This design means it can act on opioid receptors in the gastrointestinal tract, slowing down the movement of contents, but does not act on brain opioid receptors.

In contrast to Imodium, Ozempic and Victoza (originally designed for type 2 diabetes, but now popular for weight-loss) both have a long fat attached, to improve the length of time they stay in the body.

A consequence of having this long fat attached is that they can cross the blood-brain barrier, where they act to suppress appetite. This is part of the reason they are so effective as weight-loss drugs.

So while the blood brain barrier is important for protecting the brain it presents both a challenge and an opportunity for development of new medicines.

Sebastian Furness, ARC Future Fellow, School of Biomedical Sciences, The University of Queensland

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