The first pig kidney has been transplanted into a living person. But we’re still a long way from solving organ shortages

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.

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.

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.

CRISPR technology is aiming to restore diseased red blood cells to their healthy round shape. Sebastian Kaulitzki/Shutterstock

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.The Conversation

Christopher Rudge, Law lecturer, University of Sydney

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

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Scientists Discover Potential HIV Cure that Eliminates Disease from Cells Using CRISPR-Cas Gene Editing

HIV-1 virus particles under electron micrograph with H9 T-cells (in blue) – Credit: National Institute of Allergy and Infectious Diseases
A new study has unveiled a likely future cure for HIV which uses molecular scissors to ‘cut out’ HIV DNA from infected cells. To cut out this virus, the team used CRISPR-Cas gene editing technology—a groundbreaking method that allows for precise alterations to a patient’s genome, for which its inventors won the Nobel Prize in Chemistry in 2020. One of the significant challenges in HIV treatment is the virus’s ability to integrate its genome into the host’s DNA, making it extremely difficult to eliminate—but the CRISPR-Cas tool provides a new means to isolate and target HIV DNA. Because HIV can infect different types of cells and tissues in the body, each with its own unique environment and characteristics, the researchers are searching for a way to target HIV in all of these situations. In this study, which is to be presented ahead of this year’s European Congress of Clinical Microbiology and Infectious Diseases, the authors used CRISPR-Cas and two guide RNAs against “conserved” HIV sequences. They focused on parts of the virus genome that stay the same across all known HIV strains and infected T cells. Their experiments showed outstanding antiviral performance, managing to completely inactivate HIV with a single guide RNA and cut out the viral DNA with two guide RNAs. “We have developed an efficient combinatorial CRISPR-attack on the HIV virus in various cells and the locations where it can be hidden in reservoirs, and demonstrated that therapeutics can be specifically delivered to the cells of interest,” said Associate professor Elena Herrera Carrillo from the University of Amsterdam AMC. “These findings
HIV AIDS virus (in yellow) infecting a human cell – Credit: National Cancer Institute
represent a pivotal advancement towards designing a cure strategy.” The team has a long way to go before their cure will be available to patients, but said, “These preliminary findings are very encouraging’. Currently, HIV can be kept in check with anti-retroviral medication, but no one has actually been cured—although three patients receiving stem cell transplants for blood cancer were subsequently declared free of the disease when their HIV became undetectable. “We hope to achieve the right balance between efficacy and safety of this CURE strategy,” said Dr. Carrillo. “Only then can we consider clinical trials of ‘cure’ in humans to disable the HIV reservoir.“Our aim is to develop a robust and safe combinatorial CRISPR-Cas regimen, striving for an inclusive ‘HIV cure for all’ that can inactivate diverse HIV strains across various cellular contexts. Scientists Discover Potential HIV Cure that Eliminates Disease from Cells Using CRISPR-Cas Gene Editing
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What can my blinking tell me about my health?

Dr. Trisha Pasricha. PHOTO: health.harvard.edu

Q: I feel like I’m blinking more often than usual. What can blinking tell me about my health? And why do we blink?

A: We blink about once every three to five seconds and usually don’t even realize it’s happening, despite losing an incredible amount of our daily visual input to blinking – up to 10 percent.

Blinking serves several practical purposes: It wets and cleans the surface of the cornea and can reflexively protect the eye from rapidly approaching objects. But that’s not quite the end of the story.

In some cases, a change in blinking might herald a health problem. Here are some reasons blinking may change that can tell you something about your health:

Slow or infrequent blinking: Decreased blinking can be one of the early signs of Parkinson’s disease. One important neurotransmitter influencing our ability to pay attention and show flexibility is dopamine. Several studies have found that the rate at which we spontaneously blink mirrors the neurotransmitter’s activity in our brains – the lower the dopamine, the more we fixate on one subject, and the less frequently we blink. And the hallmark of Parkinson’s is the loss of dopamine-producing nerve cells.

Patients with the autoimmune condition Graves’ disease also experience changes to their blinking pattern, which may be related to cornea damage. And other neurological conditions besides Parkinson’s, such as stroke, can slow the normal blinking rate. Slower blinking has also been associated with head injury among athletes.

Excessive blinking: Increased blinking can be a sign of sleepiness while trying to perform a demanding task such as driving while drowsy (if you notice this happening, keep everyone on the road safe and get some rest before continuing your journey). People who are suffering from pain or experiencing very bright lights also blink more frequently.

Excessive blinking can occur when your body tries to compensate for dry eye disease, which occurs for a number of reasons, including Sjogren’s syndrome or side effects from certain medications like antihistamines.

Dry eye disease is also incredibly common among frequent screen-users. We blink less frequently when we stare at our screens.

If you plan on spending hours in front of your computer, set 20-minute timers to step away for a minute or two from your screen. I also like the concept of “blind working” – closing your eyes for brief, deliberate breaks in your workday when you actually don’t need to have them open, such as during a telephone call or while waiting for a program to load. Heightened screen time may also be associated with damage to the glands that keep our eyes healthy as well as myopia.

– – –

Why do we blink?

In many situations, people blink in unexpected patterns that don’t seem to have anything to do with maintaining their eyes’ moisture.

In the 1920s, scientists studying this phenomenon wondered: If blinking was not simply there to dust off the corneas, what did it really mean?

Some of their observations made intuitive sense – they noted that people blink more frequently while smoking; smoke is a known corneal irritant. But they also found people blinked less frequently while reading than they did while talking, when the environment was otherwise the same – and oddly, that people reading almost always blinked at punctuation marks instead of text.

Other findings were just as puzzling. Unexpected sounds, even if not loud, caused children to blink. And people blinked more frequently when they became angry or anxious.

Decades of research has revealed that blinking is much more than the windshield wiper of the body but rather a window into the state of our minds – how carefully our attention is focused and whether we’re ready for new stimuli.

Studies have shown that increased spontaneous blinking can be a sign of gathering new information – especially when it challenges the “rules” of a known environment. For instance, babies in bilingual households blink more rapidly as they switch between hearing different languages spoken, which correlates to signaling in areas of the brain governed by dopamine. And people blink in synchrony when watching the same movie – researchers have found that we tend to stare continuously while the action of the main character unfolds, but we all start to blink unconsciously during the same implicit narrative breaks – such as when there’s a shot with no humans in the scene.

In a similar way, blinking plays a role in our social communication. Scientists have measured that when two people are communicating smoothly with each other and holding the other’s interest, their blinking patterns start to align.

– – –

How did humans evolve to blink?

Scientists believe blinking developed several times across evolutionary history – and in some cases, like with snakes, became lost again. A study of mudskippers published last year in the Proceedings of the National Academy of Sciences hypothesized that it was the transition from aquatic life to land that made blinking beneficial to survival – even for our own ancestors, who also emerged from the sea several hundred million years ago.

One reason blinking on land is critical is because the corneas of our eyes don’t have blood vessels and so they derive oxygen by diffusion from the environment surrounding them. Oxygen diffuses more easily across wet surfaces, and spontaneous blinking helps maintain a thin, fluid film layer on our eyes. Another reason is that dangerous objects travel much more quickly through thin air than they would through water – so blinking reflexively to shield the eyes from injury is significantly more important on land.

– – –

What I want my patients to knowPeople often buy laptop raisers or elevate their screens to eye level. Instead, try placing the screen at a 10-degree downward gaze angle (and ideally two to three feet away from you). Doing so may relax the muscles around your eye to help you blink more completely, and it can reduce tear evaporation. What can my blinking tell me about my health?
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Man Ignores Naysayers to Revive Tiny Sparrow with CPR – Watch the Moment his Patience is Rewarded

Submitted by Costakis Constantinou: In a heartwarming video, a 67-year-old actor from Cyprus became determined to use his CPR expertise to save a tiny, helpless sparrow. The avian creature was found unconsciousness following an “unfortunate pool mishap”. In the background of the video, you can hear a chorus of teasing and snickering, with voices urging him to dispose of the seemingly lifeless bird—but Costakis Constantinou remained undeterred. “Nobody thought this was possible or even worth trying,he  however, stayed focus and patiently continued,” his son Rolandos told GNN. With unwavering determination, he persistently, applied his life-saving skills until, against all odds, the sparrow gradually regained consciousness, fluttering back to life. “I can say with confidence that he was very, very happy, relieved, and satisfied when the little sparrow open its eyes and flied away.” When Rolandos rewatched the video again (see below), he got emotional and telephoned his dad to tell him how proud he was. “In the past he saved two people from heart attack by applying CPR. For some reason my father is at the right place the right time.” “I wanted to surprise him by sending over his video,” said Rolandos in an email. “I’m so proud of him.”Watch the moment his patience was rewarded…Man Ignores Naysayers to Revive Tiny Sparrow with CPR – Watch the Moment his Patience is Rewarded:
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How exercise increases brain volume — and may slow memory decline

Exercising for 25 minutes a week, or less than four minutes a day, could help to bulk up our brains and improve our ability to think as we grow older. A new study, which involved scanning the brains of more than 10,000 healthy men and women from ages 18 to 97, found that those who walked, swam, cycled or otherwise worked out moderately for 25 minutes a week had bigger brains than those who didn’t, whatever their ages.

Bigger brains typically mean healthier brains.

The differences were most pronounced in parts of the brain involved with thinking and memory, which often shrink as we age, contributing to risks for cognitive decline and dementia.

“This is an exciting finding and gives us more fuel for the idea that being physically active can help maintain brain volume across the life span,” said David Raichlen, a professor of biological sciences and anthropology at the University of Southern California. He studies brain health but was not involved with the new study.

The results have practical implications, too, about which types of exercise seem best for our brain health and how little of that exercise we may really need.

– – –

Little exercise, big brain

“We wondered, if we chose a very low threshold of exercise what would we see?” said Cyrus A. Raji, an associate professor of radiology and neurology at Washington University in St. Louis, who led the new study.

He and his colleagues were well aware that exercise is good for brains, especially as we age. Physically active older people are far less likely than the sedentary to develop Alzheimer’s disease or other types of memory loss and cognitive decline.

But he also knew that few people in the real world exercise much. “You hear that you need 10,000 steps a day,” he said, “or 150 minutes a week. But it’s very hard to reach” those goals.

Would less – even far less – exercise still help to build healthier brains, he and his colleagues wondered?

What about, for instance, 25 minutes of exercise a week, a sixth of the 150 minutes recommended in most formal exercise guidelines?

“It seemed an achievable amount for most people,” Raji said. But would it show effects on brains?

– – –

10,125 brain scans

He and his colleagues turned to existing brain scans for 10,125 mostly healthy adults of all ages who’d come to the university medical center for diagnostic tests. Beforehand, these patients had provided information about their medical histories and how often and strenuously they’d exercised during the past two weeks.

The researchers divided them into those who’d exercised for at least 25 minutes a week and those who hadn’t.

Then, with the aid of artificial intelligence, they began comparing scans and exercise habits, looking for differences in brain volume, or how much space a brain and its constituent parts fill. More volume is generally desirable.

A clear pattern quickly emerged. Men and women, of any age, who exercised for at least 25 minutes a week showed mostly greater brain volume than those who didn’t. The differences weren’t huge but were significant, Raji said, especially when the researchers looked deeper inside the organ.

There, they found that exercisers possessed greater volume in every type of brain tissue, including grey matter, made up of neurons, and white matter, the brain’s wiring infrastructure, which supports and connects the thinking cells.

More granularly, the exercisers tended to have a larger hippocampus, a portion of the brain essential for memory and thinking. It usually shrinks and shrivels as we age, affecting our ability to reason and recall.

They also showed larger frontal, parietal and occipital lobes, which, together, signal a healthy, robust brain.

– – –

Moderate exercise was best for brains

“It was surprising and encouraging” to see such widespread effects in the brains of people who were exercising so little, Raji said.

Of course, this study was associational, meaning it showed links between exercise and brain health, but not that exercise necessarily caused the improvements. So it’s possible other lifestyle factors or genetics were at play, or that people with big brains just happened to like exercise. But given the number of scans and the wide age range, Raji believes the effects of exercise on people’s brains were real and direct and would help to maintain our ability to think well as we grow older.

Exactly how exercise might be altering brains is impossible to say from this study. But Raji and his colleagues believe exercise reduces inflammation in the brain and also encourages the release of various neurochemicals that promote the creation of new brain cells and blood vessels.

In effect, exercise seems to help build and bank a “structural brain reserve,” he said, a buffer of extra cells and matter that could protect us somewhat from the otherwise inevitable decline in brain size and function that occurs as we age. Our brains may still shrink and sputter over the years. But, if we exercise, this slow fall starts from a higher baseline.

Perhaps best of all, the most effective exercise in the study was also relatively gentle. People who said they exercised moderately, meaning they could still chat as they worked out, wound up with somewhat greater brain volume than those who exercised more vigorously, such as by swift running.

But the numbers of vigorous exercisers were quite small, making comparisons suspect, Raji said, and their brain volume was still larger than among those who rarely, if ever, exercised at all.

Overall, any exercise of any type and in even small amounts is likely to be “a very good idea” for brain health, he said.Raichlen agrees. “Studies like this continue to provide strong evidence that moving your body even a small amount may have an impact on brain health, and that it is never too early, or too late, to start.”How exercise increases brain volume — and may slow memory declineImage Link Flickr
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