Pigs can save thousands of human lives through organ transplants

 Dr. Robert Montgomery made history last September when he became the first surgeon to successfully transplant a pig kidney into a living person. It’s a victory that’s especially sweet for the 62-year-old doctor, who’s only alive today because of a transplant. 

Montgomery was born with a heart condition that killed both his father and older brother, both of whom died young (his brother at 35, his dad at 52). He finally got a heart transplant in 2018, after years of waiting because he wasn’t “sick enough” to make the organ donor list.

So he knows all too well “what the waiting is like as a patient,” Montgomery, head of the NYU Langone Transplant Institute, told The Post. “The uncertainty of not knowing if you’re going to get an organ. I’m very aware of the people who don’t make it across the finish line.”

Although his patient was clinically brain-dead before the operation, the transplanted kidney remained functional for 54 hours, long enough to detect any immediate rejection. It’s a promising sign that xenotransplantation — the medical term for implanting other species’ organs and tissues into humans — may soon become the norm.

Dr. Robert Montgomery, a heart transplant recipient himself, made history when he became the first surgeon to successfully transplant a pig kidney into a living person.

Montgomery’s groundbreaking surgery was just the beginning of the huge strides in xenotransplantation over recent months. On Jan. 7, David Bennett, a 57-year-old man with end-stage heart disease, received a genetically modified pig heart at the University of Maryland Medical Center. 

Though he wasn’t considered an ideal candidate — he had a criminal history, as well as a history of ignoring advice from his doctors — Bennett, who remains (as of this writing) alive with his pig heart, became the public face of the thousands of patients who need an organ and are out of options.

Pig-to-human kidney transplant a success in latest organ donor breakthrough

“I want to live,” he said in an interview prior to the surgery. “I know it’s a shot in the dark, but it’s my last choice.”

In the US alone, there are over 106,000 people on the transplant waiting list, and around 17 die every day without getting a desperately needed kidney, heart or lung, according to the American Transplant Foundation. Human organ donors are on the rise — 12,588 in 2020, up by almost a thousand from the previous year — but it’s not nearly enough to meet the demand. In many cases, the best hope for a transplant is somebody else’s tragedy. For a patient to live, somebody else must die.

“This continues to be the single greatest unmet need in transplantation,” said Montgomery. “It’s a supply and demand problem. And it’s only getting worse every year.”

David Bennett (right), a 57-year-old with end-stage heart disease, received a genetically modified pig heart at the University of Maryland Medical Center.

Bartley Griffith

But that may change thanks to xenotransplantation’s recent watershed moments. Just a few decades ago, pig organ transplants were still the stuff of science fiction, the kind of technology that only existed in Margaret Atwood novels. 

“From the outside, I can see why it’d look like this happened out of nowhere,” said Montgomery. “But we’ve been laying the groundwork for these innovations for years.”

The pig organs used in both surgeries came from Revivicor, a Virginia-based biotechnology firm that’s been working to produce genetically modified pigs since 2003. (They’re a spin-off from another company, PPL Therapeutics, that cloned Dolly the sheep in the ‘90s.)

Doctors pose with the first genetically modified pig heart transplant, given to Bennett earlier this year — setting off a new animal organ gold rush.

University of Maryland Medical Center/Cover Images/INSTARimages.com

And they’re far from alone. The biotech eGenesis, another startup looking to harvest pig organs for transplants, raised $100 million in 2019 to clinically test their xenotransplant organs. (The company’s staff wears t-shirts bearing the company slogan “This pig might save your bacon.”)

Even Smithfield Foods, which packages and sells pork products like bacon, hot dogs, and sausages, opened a bioscience branch in 2017 — with an $80 million grant from the US Department of Defense — to start raising hogs specifically for organ transplants.

“It’s become a bit of a race to see who can get there first,” says Montgomery.

It’s not just the advances in science determining if xenotransplants become commonplace. It also matters if “the public is ready for this type of thing,” Montgomery said.

Though Bennett (in white sweater) was not considered an ideal recipient (he had a criminal history, as well as a history of ignoring advice from his doctors), he remains alive with his pig heart.

Byron Dillard

In a 1998 survey, just 42 percent of people said they’d be OK with a pig organ transplant, while 96 percent preferred a human organ. That number has slightly increased in recent years, according to a 2018 Pew survey. Now 57 percent, or six-in-ten Americans, think genetically engineering animals for transplant organs is acceptable, while 41 percent still aren’t convinced.

‘We shouldn’t be dependent on this paradigm that another human being has to die for somebody else to live.’

pig-organ pioneer Dr. Robert Montgomery

It doesn’t help that the history of xenotransplantation is filled with surreal and even macabre tales. Jean-Baptiste Denis, a 17th-century physician to the French king Louis XIV, preferred the blood of animals in transfusions because he believed they were less inclined towards “debauchery.” During the 1920s, a doctor named John Brinkley became briefly infamous for transplanting goat testicles into human scrotums to cure impotence. (Unsurprisingly, many of his patients died from infection.)

Human-to-human organ transplants became a reality in the mid-20th century — beginning in 1954 with the first successful kidney transplant — and almost immediately, organ shortage was an issue. Monkeys and chimpanzees were the first animals considered for transplants, if only because they’re genetically closest to humans.

Montgomery’s team at NYU Langone made news in October by successfully transplanting the first pig organ into a living person.

During the ’60s, several transplant surgeries were attempted using chimp kidneys, but only one patient survived for nine months — which was enough for Thomas Starzl, the pioneering transplant surgeon, to call it a “real beacon of hope.”

The most famous xenotransplant of the last century was Baby Fae, an infant born with a lethal heart defect who received a baboon heart in 1984. She died just days after the transplant, and public reaction was more shock than awe. The Washington Post warned of “medical adventurism,” and the Journal of Medical Ethics dismissed it as a “beastly business.”

At first, pig organs seemed more promising. “Pig organs are anatomically similar to human organs,” says Michael K. Gusmano, a professor of health policy at Lehigh University. Humans and pigs also share 98 percent of the same genes. But pig organs were still attacked by human immune systems as foreign invaders. In 1997, two Indian surgeons attempted a pig heart and lung transplant on a 32-year-old patient, and when he died, the surgeons were jailed for homicide, with the media describing it as “the plot of a horror movie.”

Genetically engineered pigs are already being used for everything from skin replacements for burn wounds to corneas to restore sight.

John Coletti

But then something changed. Researchers learned how to “humanize” pig hearts, said Bruno Reichart, a retired transplant surgeon and CEO of XTransplant, a company attempting to commercialize pig-to-human heart transplants. More scientifically, they found a way to cut out the “alpha-gal,” a sugar molecule in pig cells that triggers the human immune system.

The gene-editing tool CRISPR — developed in 2012, which went on to win a Nobel Prize in chemistry in 2020 — was used to alter genes that caused a pig’s heart to grow too large, enough to sustain a 600-pound pig. 

“We introduced enzymes that would find and cut specific points in a pig’s DNA and then change it to DNA that we prefer,” said Harvard geneticist and eGenesis co-founder George Church. “We edited pig genes to make them more like human genes.”

Richard Herrick (left) received twin brother Ron’s kidney for the first successful such transplantation in 1954.

AP

In 2015, a baboon was kept alive with a pig heart for 945 days, still a record. Reichart, who was involved in many of the baboon experiments, also helped develop an experimental nutrient solution that “successfully preserved porcine hearts out of the body for hours,” he told The Post. “That is more difficult when compared to human organs: you must perfuse porcine hearts with a cold solution containing nutrients, hormones and oxygen.”

Everything changed in late 2020, when the FDA approved the one-time emergency use of an organ from a genetically modified GalSafe pig, produced by Revivicor. It opened the floodgates for what The Atlantic described in 2017 as “Big Pork” — the companies looking to cash in on the pig organ transplant boom.

As companies now race to be the first with a medical breakthrough that will save lives and also generate billions in profits, there’s concern about whether some will cut corners to get there quicker. 

In the 1920s, Dr. John Brinkley (above) became infamous for transplanting goat testicles into human scrotums to cure impotence.

Wiki Commons

“That’s always a worry,” says Gusmano. “That’s why it is important for the industry to be carefully regulated, including surprise inspections. As with all medical drugs and devices, we cannot have a market with goods that people trust and are willing to use without appropriate regulation and oversight.”

Not everybody believes the burgeoning pig organ industry will have the best interests of the public in mind. Wired magazine recently called xenotransplantation “a capatalist myth,” adding that our medical systems “will always serve the most privileged at the expense of the least.”

Not so, said Church, who points out that the cost of a heart transplant in the US is around $1.66 million, according to the most recent estimates, while pig transplants, judging solely on the cost of the pig heart transplants for baboons, are a comparative steal at just $500,000.

“Engineered organs could reduce costs in all sorts of ways,” he said.

Pigs can grow up to 600 pounds. Researchers use genetic technology to rear smaller pig hearts that will fit the human body.

Peter Dazeley

The future of xenotransplantation is either cause for eager anticipation or cautious optimism, depending on who you ask.

Martine Rothblatt, the CEO of United Therapeutics — the company that owns Revivicor, which provided organs for all the recent xenotransplant breakthroughs — didn’t mince words in a 2015 TED Talk. “Just like we keep cars and planes and buildings going forever with an unlimited supply of building and machine parts, why can’t we create an unlimited supply of transplantable organs to keep people living indefinitely?”

Others aren’t as fast to claim that pig organs will become the new standard.

“Hearts will be possible,” says Reichart. “Kidneys will need more consistent preclinical results. Lungs and livers are more difficult.”

Martine Rothblatt, CEO of United Therapeutics says, “Just like we keep cars … going forever with an unlimited supply of … machine parts, why can’t we create an unlimited supply of transplantable organs to keep people living indefinitely?”

Ron Levine

Church, however, thinks the sky is the limit. “Blood cells, stem cells, eyes, skin, thymus, pancreas, bones, tendons, nerves, veins, gastrointestinal components,” he said, listing all the human parts that are or may soon be replaceable with pig tissue.

While heart and kidney transplants get all the attention, less flashy surgeries are happening every year, moving us closer to a world where pigs are becoming a one-stop-shop for human replacements. Genetically engineered pigs have already been used for everything from skin replacements for burn wounds to corneas to restore sight.

Montgomery tries to be pragmatic when discussing the future of pig organ transplants, but his enthusiasm and optimism are apparent. “I think it’s going to be in our lifetime,” he said. “And I say that as somebody in his early 60s. As long as there aren’t any major setbacks, I think I’ll be doing routine xenotransplants in the next ten years.”

In the US alone, there are over 106,000 people on the transplant waiting list, and around 17 die every day without getting a desperately needed organ.

PA Images/PA Images via Getty Images

For Montgomery, it isn’t enough that deserving patients get access to organ transplants. “We can have an unlimited supply,” he says. “The goal is to transplant people who previously weren’t thought of as good transplant candidates. There are 800,000 people with end-stage kidney disease, and only around 90,000 of them are on the list to get an organ transplant.”

All sorts of factors determine who does and doesn’t qualify for a donor organ, like age, medical history, and survivability odds. Some recent studies have even found that Black, Hispanic and low-income patients are less likely to get on a transplant list than white and wealthy patients.

But with an on-demand reserve of pig organs, waiting lists would become obsolete. “We shouldn’t be dependent on this paradigm that another human being has to die for somebody else to live,” Montgomery said. “We have to have something that’s more sustainable.”

https://nypost.com/2022/03/05/how-pig-organ-transplants-will-save-thousands-of-human-lives/

Possible common thread between many neurodegenerative diseases

 Take a cell-deep tour of a brain afflicted with Alzheimer's disease, and you will find minuscule clumps of protein that seem suspicious. Ever since the 1980s, when neuroscientists began identifying these protein tangles, researchers have discovered that other brain diseases have their own tangled-protein signatures.

"Each of these diseases has a unique protein tangle, or fibril, associated with it," said Anthony Fitzpatrick, PhD, principal investigator at Columbia's Zuckerman Institute. "These proteins associated with diseases have their own shapes and behaviors," added Dr. Fitzpatrick, also an assistant professor of biochemistry and molecular biophysics at Columbia University Irving Medical Center and a member of Columbia's Taub Institute for Research on Alzheimer's Disease and the Aging Brain.

Published today in Cell, the research by Dr. Fitzpatrick and an international team of 22 collaborators reveals a new fibril in diseased brains, one formed by a protein normally busy cleaning cells.

"We have a surprising and provocative result that we hope could have some bearing on managing neurodegenerative diseases," said undergraduate Andrew Chang, a co-first author on the paper in the Fitzpatrick lab. Drug researchers have long pursued the tangle-forming proteins as targets for new medicines, but this pursuit so far has largely delivered disappointing results.

Fibril-associated diseases, some common and some rare, collectively affect millions of people around the world. Their incidence is slated to increase as the population grows and people live longer. Untangling what is going on in these neurodegenerative diseases has a personal facet for Dr. Fitzpatrick: He lost an uncle to one of them, progressive supranuclear palsy (PSP).

"We have found that a protein called TMEM106B can form fibrils, and this behavior was not known before," said Xinyu Xiang, formerly a member of the Fitzpatrick lab at the Zuckerman Institute and now a graduate student at Stanford University's Department of Structural Biology. "This protein is a core component of lysosomes and endosomes, which are organelles that clean up the junk that builds up in our cells as we get older."

Normally, TMEM106B molecules span the membranes of those waste-management organelles. In a feat of laboratory sleuthing, Fitzpatrick's team discovered that TMEM106B molecules can split into two fragments. Fragments inside the organelles can then self-assemble into what the researchers suspect could be cell-hobbling fibrils.

To make this discovery, the researchers first extracted proteins from brain tissue donated by 11 patients who had died from three neurodegenerative diseases associated with misfolded proteins: PSP, dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). FTLD is the most prevalent form of dementia for those under 60 years of age.

"It's so motivating to remember that the only way we can do this research is because of people who generously donated their brains," said Marija Simjanoska, a co-first author and one of the three undergraduates working on the project.

Co-corresponding author Ian Mackenzie, MD, of the University of British Columbia, and co-authors Dennis Dickson, MD, and Leonard Pertrocelli, PhD, of the Mayo Clinic in Florida, helped procure this precious research resource. Joining Drs. Fitzpatrick and Mackenzie as co-corresponding authors on the paper is Michael Stowell, PhD, of the University of Colorado, Boulder. Filling out the 23-member team are researchers from several other institutions, including three in Belgium.

With a world-class cryogenic electron microscope (cryo-EM), the team took snapshots of individual protein molecules at many different angles. From these, the researchers constructed three-dimensional models of the protein in atomic detail. Those models, in turn, helped the researchers identify TMEM106B by making educated guesses about the exact sequence of the protein's amino-acid building blocks. Much in the way letters string into words with specific meanings, different amino-acid molecules build into proteins, each with its own shape and function.

The researchers fully expected that one of the long-known fibril-forming proteins, such as the tau protein in Alzheimer's disease, would end up matching with the models from the cryo-EM data. Instead, the matching exercise, which involved searching in a massive database of protein sequences, delivered a head-turning result.

The researchers found that the mysterious protein matched a 135-amino-acid fragment of TMEM106B. That was an exciting revelation because this same protein was identified more than a decade ago in a broad hunt for genes potentially associated with FTLD.

So far, the data in hand shows only that TMEM106B fibrils are present in diseased brain tissue, not that the fibrils cause the diseases. Still, Dr. Fitzpatrick points out, the prevalence of TMEM106B fibrils in tissue from different brain diseases, combined with the protein's normal place in lysosomes and endosomes, points toward a possible disease-causing role.

In their Cell paper, the researchers speculate that the formation of TMEM106B fibrils disrupts lysosome function, which, in turn, promotes the formation of fibrils made of the other known fibril-forming proteins. These malfunctions could kill brain cells, leading to dementia, movement problems, speech pathologies and other symptoms of Alzheimer's, PSP, FTLD and other brain diseases with telltale protein tangles.

"We now have a promising new lead," said Dr. Fitzpatrick. "It could point towards a common thread linking a range of neurodegenerative diseases and could open the way to new interventions."

This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorder and Stroke (UO1NS110438, U54NS110435); the Association for Frontotemporal Degeneration; Canadian Institutes of Health Research (74580); and MCDB Neurodegenerative Disease Fund.

---

Story Source:

Materials provided by Columbia University. Note: Content may be edited for style and length.

---

Journal Reference:

1. Andrew Chang, Xinyu Xiang, Jing Wang, Carolyn Lee, Tamta Arakhamia, Marija Simjanoska, Chi Wang, Yari Carlomagno, Guoan Zhang, Shikhar Dhingra, Manon Thierry, Jolien Perneel, Bavo Heeman, Lauren M. Forgrave, Michael DeTure, Mari L. DeMarco, Casey N. Cook, Rosa Rademakers, Dennis W. Dickson, Leonard Petrucelli, Michael H.B. Stowell, Ian R.A. Mackenzie, Anthony W.P. Fitzpatrick. Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell, 2022; DOI: 10.1016/j.cell.2022.02.026

https://www.sciencedaily.com/releases/2022/03/220304182948.htm

'Genetic baggage' accumulates in the genomes of aging mutant animals

 You are probably familiar with the term that some people carry "a lot of extra baggage." Usually that term refers to that person's emotional history, but in genetics and our genomes, "extra baggage" can also describe the transposons lurking in our genomes, a historical record of our genomes surviving traumatic invasions during evolution. Transposons are repetitive DNA sequences that have the capability to move (transpose) from one location to another in the genome (an organism's complete set of genetic instructions)and are considered important invaders of our genomes during evolution.

"Typically, when we are young and healthy, our genomes do a good job handling all these transposons, keeping them stored away. But what if during aging or in unhealthy mutants, how does one handle all this 'extra baggage' in our genomes?" a question asked by corresponding author Nelson Lau, PhD, associate professor of biochemistry at BUSM and Director of the BU Genome Science Institute.

In a new study in the journal of PLOS GENETICS, researchers from Boston University School of Medicine (BUSM) tested this question of how these mobile genetic elements can accumulate in the genomes of normal and mutant animals during a single life span. Their study used the model organism of fruit flies which have 12 percent of their genome made up of transposons and are a good proxy for humans, where transposons make up over 40 percent of our DNA.

According to the researchers, typically, young animals store away transposons neatly, so they remain organized and quiet. However, some researchers are now seeing transposons becoming activated during animal aging, when the natural processes to silence transposons decline with age. "Slowing the ravages of aging continues to be an important goal of biomedical research, and this study aimed to determine if transposons activated during aging can move and accumulate in older genomes," says Lau.

The Lau lab team used whole genome sequencing and bioinformatics to show that normal older fruit flies can keep transposons from accumulating in genomic DNA even though the transposon RNAs were still elevated during aging. However, sicker animals with mutations affecting RNA interference pathways appeared to pile up many more of these transposon copies in the genome during aging.

To see if this condition could be treated, the investigators used genetic tricks to improve the RNA interference pathways in flies, this helped the older flies prevent transposon RNA elevation in old age. In addition, they observed increased lifespan in these modified flies, an outcome that is akin to finding a great therapist who can talk you through issues and not letting the "extra baggage" like transposons continue to weigh you down.

Beyond the genome, the BUSM researchers also discovered that transposons could accumulate as extra-chromosomal circular DNAs. These mysterious circles are distinct from the genome and have also been seen to exist in cancer cells. Although genomic transposons only accumulate in mutant flies, these circles may accumulate even in normal flies.

Future efforts by the Lau lab will be to continue finding out how transposon circular DNAs amass during aging; and if the enhancement of RNA interference in older animals can also halt circular DNA in addition to transposon RNA. "Maybe we could all use some good therapy, not only for our emotional state but for our genomes as well," adds Lau.

This work was supported by NIH grants R01-AG052465, R21-HD088792 and R01-GM135215 to NCL; and Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK015602 to E.P.L.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

---

Story Source:

Materials provided by Boston University School of Medicine. Note: Content may be edited for style and length.

---

Journal Reference:

1. Nachen Yang, Satyam P. Srivastav, Reazur Rahman, Qicheng Ma, Gargi Dayama, Sizheng Li, Madoka Chinen, Elissa P. Lei, Michael Rosbash, Nelson C. Lau. Transposable element landscapes in aging Drosophila. PLOS Genetics, 2022; 18 (3): e1010024 DOI: 10.1371/journal.pgen.1010024

https://www.sciencedaily.com/releases/2022/03/220303141235.htm

Americans can order another round of free at-home Covid-19 tests next week

Americans can order additional free at-home Covid-19 tests supplied by the US government starting next week.

"If you already ordered free tests, tonight, I'm announcing you can order another group of tests. Go to Covidtest.gov starting next week and you can get more tests," President Joe Biden said during his Tuesday State of the Union address.

In January, the government launched its effort to provide free rapid antigen tests to any household that requested them through that website or by calling 800-232-0233. There was a limit of four tests per residential address.

The website now says every home in the US can order an additional set of four tests starting next week.

The President had announced in December his plan to make half a billion tests available to Americans by mail, as the Omicron variant was surging across the US.

The Biden administration initially made 500 million free tests available, but fewer than 300 million have been ordered, White House assistant press secretary Kevin Munoz said.

The White House previously said the tests were expected to ship about seven to 12 days after they are requested.

Covid-19 has killed more than 952,000 people and infected about 79.1 million in the United States since January 2020, according to data by Johns Hopkins University.

https://www.cnn.com/2022/03/01/politics/free-at-home-covid-tests-us-order-more/index.html

Another life-saving Covid drug identified

 UK experts say they have found another life-saving drug that can help people ill with Covid.

The anti-inflammatory baricitinib is normally used to treat rheumatoid arthritis.

Trials suggest it can cut death risk by about a fifth in patients needing hospital care for severe Covid.

It could be used with other Covid treatments, such as the cheap steroid dexamethasone, to save even more lives, researchers say.

That might halve deaths.

The NHS may soon recommend baricitinib based on these new results. A 10-day course of the pills costs around £250, although the NHS may be able to negotiate a discount.

Health and Social Care Secretary Sajid Javid said: "A big thank you to all of the researchers, doctors and volunteers involved in this work.

"Our medical and scientific experts will now consider the results before any decisions are made on next steps."

Although vaccines have been doing a great job at cutting infections and protecting lives, some people will still catch and become very sick with Covid.

And the Recovery trial has been testing existing medications on Covid patients to see if they help.

It has already identified dexamethasone, tocilizumab and a treatment called Ronapreve - discoveries that have changed clinical practice worldwide and been credited with saving hundreds of thousands, if not millions, of lives, experts say.

And now it appears some very ill Covid patients, including those on ventilators, fare much better if they receive baricitinib.

The benefit was on top of other proven life-saving Covid drugs.

One of the patients enrolled on the trial, Mark Rivvers, 51, from Cambridge, said: "I was in hospital for almost a month, mostly in an intensive-care unit.

"Everything in my body seemed to be fighting against everything else.

"I was on almost constant respiratory support, I developed sepsis, and I had pneumonia all across my lungs.

"But I saw it as my duty to take part in the Recovery trial because I knew that no matter what happened to me, I was doing something positive to help others.

"I'm really pleased about the result with baricitinib and hope that it can now be used to benefit many others."

There are now many drugs that can help fight Covid:

• anti-inflammatory drugs that stop the immune system overreacting with deadly consequences
• anti-viral drugs that make it harder for the coronavirus to replicate inside the body
• antibody therapies that mimic the immune system to attack the virus

Which treatments work best against Covid?

Recovery trial joint chief investigator Sir Martin Landray, professor of medicine and epidemiology, at Oxford Population Health, said: "It is now well established that in people admitted to hospital because of severe Covid, an overactive immune response is a key driver of lung damage.

"Today's results not only show that treatment with baricitinib improves the chances of survival for patients with severe Covid-19 but that this benefit is additional to that from other treatments that dampen down the overactive immune response, such as dexamethasone and tocilizumab.

"This opens up the possibility of using combinations of anti-inflammatory drugs to further drive down the risk of death for some of the sickest patients."

https://www.bbc.com/news/health-60601750