Tag: Transplant

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First fetus-to-fetus transplant in rats

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A fetal kidney retrieved 2 weeks after transplantation at 9 weeks of age.

The transplanted tissue grew into a kidney with identifiable parts, and the host’s blood vessels began infiltrating it.Credit: K. Morimoto et al./bioRxiv

Surgeons have transplanted kidney tissue from one rat fetus to another, while the recipient was still in its mother’s womb. The recipient pups were born as normal after 22 days, according to a preprint (not peer reviewed). The transplanted tissue grew into an organ with some functioning characteristics of a kidney. Blood vessels from the host fetus grew inside the donated tissue, lowering the risk of rejection. Nephrologist and study lead Takashi Yokoo has also tested transplanting mouse kidney tissue into rat fetuses, with some success. His long-term goal, he says, is to one day transplant pig organs into human fetuses that have fatal kidney-development disorders.

Nature | 5 min read

Reference: bioRxiv preprint (not peer reviewed)

China is launching an ambitious mission later this week to collect rocks from the side of the Moon that we never see from Earth. Spacecraft Chang’e-6 was originally built as a backup for the Chang’e-5 mission, which successfully returned 1.73 kilograms of samples from the Moon’s near side in 2020. If Chang’e-6 pulls off a difficult soft landing, the lander will drill and scoop up two kilograms of soil and rocks from the more rugged far side. The samples might help explain why the two sides of the Moon are so different, including their history of volcanic activity. “When those samples come back to Earth, they will be like a Christmas present — whoever opens it will be happily surprised,” says planetary geologist Carolyn van der Bogert.

Nature | 7 min read

A free browser plug-in from source-checking company RedacTek flags when a paper cites studies that are mentioned on PubPeer, a forum often used to discuss issues such as image manipulation or plagiarism. PubPeer’s own browser plug-in also alerts users when a study has been posted on the site, but doesn’t search through the references. The new tool also highlights when a study or any paper that it cites has been retracted, and also scores papers according to the number of self-citations — references to authors’ own studies.

Nature | 4 min read

Reference: RedacTek Chrome browser plug-in

Researchers used a generative AI tool trained on millions of protein sequences to design CRISPR gene-editing proteins, and were then able to show that some of these systems work as expected in the laboratory. Another team developed a model trained on microbial genomes, and used it to design fresh CRISPR systems, which comprise a DNA or RNA-cutting enzyme and RNA molecules that tell the molecular scissors where to cut. Natural CRISPRs — part of some microbes’ immune system — have limitations on the genes they can edit and the changes they can make. “Expanding the repertoire of editors, using AI, could help,” says synthetic biologist Alan Wong.

Nature | 5 min read

Reference: bioRxiv preprint 1 & preprint 2 (not peer reviewed)

Features & opinion

Wildlife managers in Alaska are planning to parachute elite fire-fighters into remote areas to fight fires that threaten permafrost. In the Yukon Flats National Wildlife Refuge, an area the size of Denmark, fires have long been allowed to burn themselves out unless they threaten human life and property. But as climate change increases the frequency of blazes, the fear is that frozen permafrost will release its carbon as it thaws. A preprint (not peer reviewed) suggests that the resulting emissions could equate with those from a major global economy over this century. “What we’re talking about is aggressive attacks on fires when they ignite in these areas,” says Earth-systems scientist Brendan Rogers. Once such fires get going, it’s often too late: “That carbon is lost.”

Nature | 6 min read

Reference: Research Square preprint (not peer reviewed)

Chan Zuckerberg CELL by GENE Discover is a collection of free and open-source tools for finding, querying, analysing, downloading and publishing data from 85 million single cells. There are thousands of single-cell data sets scattered across the internet, but collecting and curating them can be “a huge pain in the butt”, says bioinformatician Timothy Triche Jr. “People underestimate the degree to which the impact of this data is amplified by making it usable for anybody who wants to.”

Nature | 6 min read

Edward Dwight, age 90, is expected to join a six-person crew aboard Blue Origin, on the private space company’s seventh mission beyond Earth’s orbit next month. Dwight first aimed for the stars 60 years ago, as a young US Air Force captain. He was selected by US President John Kennedy in 1961 to be the nation’s first Black astronaut, but was passed over by Chuck Yeager, the head of the test pilot programme. Dwight recalls Yeager as a racist who wanted him off the programme. He says he considers anger a waste of time, but counters those who see his upcoming flight as justice being served. “It seems far too late for it to be justice,” says Dwight. “This is a natural occurrence that should have happened at some point.”

The New York Times | 6 min read

Infographic of the week

Infographic

The tree of life for angiosperms — flowering and fruiting plants that make up 90% of plants on land — has been redrawn using the genomic data from more than 9,500 species. “Our very existences are dependent on them,” says systematic biologist and co-author William Baker. “That’s why we really need to understand them.” (New Scientist | 3 min read)

Reference: Nature paper

See a full-size version of this image here. (Alexandre R. Zuntini et al./Nature)

QUOTE OF THE DAY

Naturalist Karla Bloem responds to a federal plan to cull half a million invasive barred owls (Strix varia) in an effort to save the northern spotted owl (Strix occidentalis caurina) from being the first US owl species to go extinct. (The New York Times | 10 min read)

Today I’m discovering that song lyrics are getting simpler and more repetitive, according to an analysis of around 350,000 English-language pop, rock, rap, R&B and country songs released between 1970 and 2020. Further research is needed to determine who put the bomp in the bomp bah bomp bah bomp and who put the ram in the rama lama ding dong.

Share your favourite song lyric of all time with me, plus any feedback on this newsletter, at [email protected].

Thanks for reading,

Flora Graham, senior editor, Nature Briefing

With contributions by Katrina Krämer and Sarah Tomlin

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First fetus-to-fetus transplant demonstrated in rats

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Surgeons in Japan have transplanted kidney tissue from one rat fetus to another, while the recipient was still in its mother’s womb. Study lead Takashi Yokoo, a nephrologist at Jikei University School of Medicine in Tokyo, says the surgery is the first step to one day transplanting fetal pig kidneys into human fetuses that develop without functioning kidneys.

“Our project is the first of its kind,” says Yokoo. Researchers have previously injected cells and amniotic fluid into fetuses1, including human ones, but these are the first reports of organ and tissue transplants in utero, he says.

Transplanting an organ before birth could allow it to grow and develop with the fetus, so that the organ is functioning at birth and has less risk of rejection.

“It’s lovely data,” says Glenn Gardener, a fetal surgeon at Mater Mothers’ Hospital in Brisbane, Australia.

Green kidneys

In their study, Yokoo and his colleagues genetically modified rats to express a green fluorescent protein in their kidneys, so that the tissue could be tracked. They then extracted the green kidney tissue from rat fetuses, and used a tiny needle to insert it under the skin in the backs of 18-day-old rat fetuses developing in their mothers’ wombs. The rat pups were born after the normal gestation period of around 22 days.

The tissue gradually developed, forming waste-filtering units known as glomeruli and well-divided inner and outer kidney structures. Two-and-a-half weeks later, the kidneys began to produce urine. “The timeline is considered to be almost identical to normal development,” says Yokoo. But because the transplanted kidney was not connected to the ureter, the urine had nowhere to go, so the researchers drained the kidney continuously until the rats were euthanized at around five months.

Of the nine fetuses surgically transplanted in four pregnant rats, eight developed fluorescent-green kidneys. In the ninth fetus, the transplanted tissue probably did not embed successfully, says Yokoo.

A close look at the kidneys revealed that the fetuses’ blood vessels had grown inside the donated tissue, which made them less likely to be rejected by the immune system. A major cause of organ-transplant rejection is incompatibility between donor blood vessels and the host’s body, says Gardener. “In this case, the host is infiltrating the organ, and you overcome that. That was really cool.”

The rat study results2 were posted on the bioRxiv preprint server on 20 April and have not yet been peer reviewed.

Pig, monkey, human

Yokoo’s long-term goal is to transplant fetal pig kidneys into human fetuses with Potter syndrome, a condition in which the unborn infant doesn’t develop functioning kidneys and usually dies hours after birth.

To test xenotransplantation — the use of animal organs in recipients of another species — Yokoo transplanted mouse kidney tissue into rat fetuses. The intervention was successful in four rats, and the kidneys developed for ten days without being rejected. By 18 days, the tissue showed signs of rejection, which could be quelled by immunosuppressant drugs. Yokoo says fetal tissue is less likely to induce an immune response than is adult tissue, which means that it does not need to be genetically modified before transplant to avoid rejection.

So far, researchers have attempted to genetically modify fully developed organs to bring xenotransplantation closer to the clinic. Last month, surgeons in the United States conducted the first transplant of a kidney from gene-edited pigs into a living adult. Surgeons in the United States and China have previously transplanted gene-modified pig hearts into living people, and gene-edited pig kidneys and a liver into people who lacked brain function.

Maturation of transplanted GFP-SD rat MNBs in neonates.

This stained image shows the filtering part, or glomerulus, of the maturing kidney.Credit: K. Morimoto et al./bioRxiv

Yokoo says he has also conducted pig-to-pig fetal transplants in 38 pig fetuses in 11 sows, and 18 recipient piglets were born. These results have not been published. He is also conducting pig-to-monkey fetal transplants in marmosets, and hopes to start work on cynomolgus macaques (Macaca fascicularis) in a few months.

Yokoo’s rat experiments are a “small first step, but a very important one” on the path to xenotransplantation in people in Japan, says Maria Yasuoka, a medical anthropologist who studies organ transplantation at Otaru University of Commerce in Hokkaido, Japan.

Gardener says the results in rats are fascinating but still a long way from being applicable to humans. Other researchers agree: “In principle, the prospect of organ transplantation in utero is an amazing concept,” says Ahmet Baschat, a specialist in fetal interventions at Johns Hopkins University in Baltimore, Maryland. “Scientifically, it’s novel. It’s a beginning.” But, Baschat says he wouldn’t get too excited yet.

Yokoo has started engaging with members of the public to inform them of the benefits of human fetal xenotransplantation and gain their trust. He plans to apply for approval to conduct research in people from ethics boards at his university and hospital, and Japan’s regulatory agency.

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Doctors Combined a Heart Pump and Pig Kidney Transplant in Breakthrough Surgery

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The kidney used in the latest NYU transplant was procured from a pig with a single genetic edit—the removal of a gene that produces a sugar known as alpha gal. This sugar appears on the surface of pig cells and seems to be responsible for rapid rejection in humans. The pig was engineered by Revivicor, a subsidiary of United Therapeutics Corporation.

Mandeep Mehra, a cardiologist and professor of medicine at Harvard Medical School, is excited by the NYU news. “It’s very innovative to combine the two,” he says, but the heart pump carries a risk of infection. Left ventricular assist devices require external batteries to power them. A wire comes out of the patient’s abdomen and connects to a controller and battery pack. “It’s that exit site that can be prone to infection,” he says.

Mehra says it also remains to be seen whether the single gene edit will be enough to prevent rejection and keep the kidney functioning for the long term. “The entire premise of gene editing was to overcome the immunological barrier,” he says.

Close up of surgeons in organ transplant surgery

PHOTOGRAPH: JOE CARROTTA FOR NYU LANGONE HEALTH

In the previous pig organ transplants in living patients, the animals had more modifications. The pig used for the heart transplants had 10 edits and the one used in Slayman’s procedure last month had 69. Yet with both Bennett’s and Faucett’s hearts, doctors noted signs of rejection. And even a week after Slayman’s surgery, his kidney showed early evidence of rejection—something his medical team hadn’t expected.

“The evolutionary distance between humans and pigs is 100 million years,” Mehra says. “Any gene editing needs to overcome that.”

The NYU’s team is taking a “less is more” approach with gene editing, Montgomery said, and instead relying on the pig’s thymus to help mediate the immune mismatch.

Pisano says she’s glad she took a chance on the procedure. She hopes she can leave the hospital so she can go shopping and play with her grandchildren. “The worst case scenario is that it doesn’t work,” she says, but even then she thinks it would be worthwhile. “It might work for the next person.”

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He Got a Pig Kidney Transplant. Now Doctors Need to Keep It Working

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Other than rejection of the organ, one of the most common transplant complications is infection. Doctors have to strike a balance when prescribing immunosuppressive drugs: too low a dose can lead to rejection, while too much can make a patient vulnerable to infection. Immunosuppressants are powerful drugs that can cause a range of side effects, including fatigue, nausea, and vomiting.

Despite the deaths of the two pig heart recipients, Riella is optimistic about Slayman’s transplant. For one, he says, Slayman was relatively healthy when he underwent the surgery. He qualified for a human kidney but because of his rare blood type he would likely need to wait six to seven years to get one. The two individuals who received pig heart transplants were so ill that they didn’t qualify for a human organ.

In addition to close monitoring and traditional immunosuppressants, Slayman’s medical team is treating him with an experimental drug called tegoprubart, developed by Eledon Pharmaceuticals of Irvine, California. Given every three weeks via an IV, tegoprubart blocks crosstalk between two key immune cells in the body, T cells and B cells, which helps suppress the immune response against the donor organ. The drug has been used in monkeys that have received gene-edited pig organs.

Hospital patient

Photograph: Massachusetts General Hospital

“It’s pretty miraculous this man’s out of the hospital a couple of weeks after putting in a pig kidney,” says Steven Perrin, Eledon’s president and chief scientific officer. “I didn’t think we would be here as quickly as we are.”

Riella is also hopeful that the 69 genetic alterations made to the pig that supplied the donor organ will help Slayman’s kidney keep functioning. Pig organs aren’t naturally compatible in the human body. The company that supplied the pig, eGenesis, used Crispr to add certain human genes, remove some pig genes, and inactivate latent viruses in the pig genome that could hypothetically infect a human recipient. The pigs are produced using cloning; scientists make the edits to a single pig cell and use that cell to form an embryo. The embryos are cloned and transferred to the womb of a female pig so that her offspring end up with the edits.

“We hope that this combination will be the secret sauce to getting this kidney to a longer graft survival,” Riella says.

There’s debate among scientists over how many edits pig organs need to last in people. In the pig heart transplants, researchers used donor animals with 10 edits developed by United Therapeutics subsidiary Revivicor.

There’s another big difference between this procedure and the heart surgeries: If Slayman’s kidney did stop working, Riella says, he could resume dialysis. The pig heart recipients had no back-up options. He says even if pig organs aren’t a long-term alternative, they could provide a bridge to transplant for patients like Slayman who would otherwise spend years suffering on dialysis.

“We’ve gotten so many letters, emails, and messages from people volunteering to be candidates for the xenotransplants, even with all the unknowns,” Riella says. “Many of them are struggling so much on dialysis that they’re looking for an alternative.”

The Mass General team plans to launch a formal clinical trial to transplant edited pig kidneys in more patients. They received special approval from the US Food and Drug Administration for just one procedure. For now, though, their main focus is on keeping Slayman healthy.

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