Tag Archives: organ transplant

In a world-first, dying man receives heart transplant from a pig

Surgeon Bartley Griffith (left) and patient David Bennett before the surgery. Credit: University of Maryland School of Medicine.

David Bennett, a 57-year-old American diagnosed with terminal heart disease, had spent the last six weeks bedridden attached to a machine that kept him alive. Due to this decaying condition, the man was not eligible for a heart transplant. It seems like there was no hope left, but the restriction only applied to human hearts. Mr. Bennett was given a second shot by doctors at the University of Maryland Medical Center who, during a grueling seven-hour surgery, replaced his failing heart with that of a genetically-modified pig. This is the first time the heart of a pig has been transplanted into a human, a procedure known as xenotransplantation.

A medical gamble

In the second half of 2021, surgeons at New York University Langone Health successfully grafted a pig kidney to a human. They actually did this twice. However, both patients were brain-dead and the kidneys from the ungulates were externally attached to the human body via a large blood vessel. By contrast, Mr. Bennett is conscious and could prove that xenotransplantation actually works in the real world.

Out of all mammals, a pig’s organs are the most compatible with those of humans in terms of size and metabolism. For many years, doctors have already been using pig valves in replacement surgeries. But even so, an untreated pig heart will be quickly and furiously rejected by the human body, which is why the animal used in the transplant had been genetically modified to knock out several genes that express molecules that humans do not. Biocompatibility can make or break a transplant and issues can appear even between organs sourced from humans, not to mention those belonging to an entirely different species. 

The procedure was deemed a success. The transplanted heart is beating a pulse and drives pressure, but it is too quick to draw definite conclusions. The patient might live only a few extra days or weeks, but he could just as well live another year — such is the nature of experimental medical procedures on the terminally ill.

“It’s working and it looks normal. We are thrilled, but we don’t know what tomorrow will bring us. This has never been done before,” said Dr. Bartley Griffith, the director of the cardiac transplant program at the University of Maryland and one of the doctors who performed the procedure.

More than 100,000 Americans are on organ transplant waiting lists. Demand far exceeds supply, with thousands dying each year in the U.S. before they get their chance at a transplant. Although more Americans received a human donor heart in 2021 than ever before, there’s still an acute shortage of organ donors. In this context, xenotransplantation represents a silver lining.

Scientists hope that animal-to-human organ transplants will become one day become the norm, revolutionizing the way we treat organ failure. However, entering this door is not without its many challenges. Organ rejection regularly occurs even between seemingly well-matched human donors and recipients.

Mr. Bennett decided to choose this unproven procedure because he had no other options. Although his condition is currently stable, his prognosis is rife with uncertainty. He is still hooked up to machines that assist in breathing and heart functioning and is scheduled to be taken off these machines next week. During this time, the patient will be closely monitored, especially in the first 48 hours that are particularly critical.

“It was either die or do this transplant,” Mr. Bennett said before the surgery, according to officials at the University of Maryland Medical Center. “I want to live. I know it’s a shot in the dark, but it’s my last choice.”

Credit: MaxPixel

Scientists grow mouse kidneys inside rats

Credit: MaxPixel

Credit: MaxPixel

Each year, thousands of people die because they’re too far down the transplant waiting list. Scientists would like to one-day avert such tragedies by replacing organs from human donors with organs grown in host animals such as pigs or sheep. Advanced stem cell techniques would ensure that each organ would be a 100% genetic match with the recipient, thereby avoiding lifelong immunosuppression — and the process would only take months. However, there are many challenges and pitfalls that need to be overcome along the way to this audacious goal. Most recently, Japanese researchers at the National Institute for Physiological Sciences in Okazaki have grown fully developed mouse kidneys inside rats, although their functionality is in question.

Chimera transplants

The kidneys formed from mouse pluripotent stem cells (PSCs), which the researchers injected into embryonic rats. The latter were genetically engineered to lack kidneys due to a mutation of Sall1  an essential gene expressed in the metanephric mesenchyme which is crucial for ureteric bud attraction toward the mesenchyme in mice. Mesenchyme is a type of connective tissue found mostly during the development of the embryo, while the ureteric bud eventually develops into part of the kidney’s drainage system. The altered embryos were then introduced into a surrogate rat.

Interestingly, the direction of interspecies organ generation matters. Previously, the same research team, led by Masumi Hirabayashi, inserted rat-derived PSCs in anephric Sall1 mutant mice but the rat kidneys didn’t grow inside mice. The researchers faced many other challenges. For instance, only one in four rat blastocysts (a distinctive stage of a mammalian embryo) could host mouse PSCs for kidney regeneration. This meant a lot of hard work for the researchers.

“We did not know whether species direction change between host blastocysts and pluripotent cells (mouse-to-rat vs rat-to-mouse) was the key to success,” Hirabayashi told me in an e-mail.

Unfortunately, the mutation also caused the rats to die shortly after birth, limiting the functional analysis that could take place of the kidneys. Even so, the researchers found that the mouse-derived kidneys had the same number of glomeruli as normal mouse kidneys. In addition, the organs had fully formed urethra-bladder junctions.

“The mutation (homogenous knockout of Sall1 gene) caused the rats to die shortly after birth, which limited the functional analysis of the complemented kidneys. Despite kidneys were successfully complemented, Sall1/KO rats could not grow. They could not drink milk. Sall1 is known to be highly expressed in the olfactory bulb. It is reported that Sall1 mutant mice have small olfactory bulbs in size, show abnormalities in neurogenesis, and have reduced mitral cells, likely rendering the newborn mice anosmic and therefore unable to suckle milk. Future challenge is to get adulthood survivors of the chimeric rats,” Hirabayashi said.

In the United States alone, there are more than 95,000 patients waiting for a kidney transplant — that’s 80% more demand than for any other organ. Harvesting organs from chimeric animals would be a paradigm changer in medicine, but scientists first need to perform a full characterization of the function and architecture of such organs. Besides safety, there are also many ethical considerations that need to be addressed.

Next, Hirabayashi and colleagues will repeat the same blastocyst complementation strategy with some tweaks. For human kidneys, much of the same process would apply, with pigs used as the host animal species.

The findings were reported in the journal Nature Communications.

Credit: University of Texas Medical Branch at Galveston.

Scientists transplant lab-grown lungs into pigs — they worked fine

Credit: University of Texas Medical Branch at Galveston.

Credit: University of Texas Medical Branch at Galveston.

In a landmark study of regenerative medicine, researchers at the University of Texas Medical Branch (UTMB) have transplanted bioengineered lungs into adult pigs, with no visible complications. This puts us one step closer to providing human patients in dire need of a transplant with the organs they need to survive.

According to the U.S. Department of Health & Human Services, 20 people die each day waiting for a transplant. Lung transplants are particularly problematic, with the number of people requiring one increasing worldwide, while the number of available transplantable organs has decreased. Lungs are harvested from only 15 percent of all cadaveric donors, whereas kidneys and livers are harvested from 88 percent and hearts from 30 percent of deceased donors

The first human lung transplant procedure was performed in 1963, and the recipient survived 18 days, ultimately succumbing to renal failure and malnutrition. Over time, the number of lung transplant procedures has increased, and the operation is now an accepted treatment for end-stage lung disease. In 2015, there were 4,122 adult lung transplants reported — and that’s not nearly enough. But what if it was possible to grow new, personalized organs for each patient in need of a transplant? Certainly, thousands of lives would be saved each year — and, today, we’re nearing such a goal.

“Our ultimate goal is to eventually provide new options for the many people awaiting a transplant,” said Nichols, professor of internal medicine and associate director of the Galveston National Laboratory at UTMB.

For years, Joan Nichols and Joaquin Cortiella from The University of Texas Medical Branch at Galveston have been working on bioengineering lungs. In 2014, they were the first to grow lung cells in a lab, and their method has been refined ever since to the point that the team is now able to bioengineer transplantable lungs.

The challenges were numerous, of course. For one, in terms of different cell types, the lung is probably the most complex of all organs. For instance, the cells near the entrance are very different from those deep in the lung,

The procedure first starts with a support scaffold, a protein structure of collagen and elastin onto which the new lung will grow. The scaffold is placed in a tank filled with a solution made of nutrients and the pig’s own lung cells, following a carefully designed protocol.

For 30 days, the bioengineered lungs grew in a bioreactor before being transplanted into adult pigs. The medical condition of the animals was assessed at ten hours, two weeks, one month, and two months following the operation, which allowed the team to construct a timeline of the lung tissue’s development. For instance, in just two weeks, the transplanted lungs had established a stable network of blood vessels, which it needs in order to survive.

All of the pigs that received the bioengineered lung remained healthy.

“We saw no signs of pulmonary edema, which is usually a sign of the vasculature not being mature enough,” the researchers wrote. “The bioengineered lungs continued to develop post-transplant without any infusions of growth factors, the body provided all of the building blocks that the new lungs needed.”

This study was only meant to evaluate how well a bioengineered lung could adapt to an adult host organism, with positive results so far. However, the team did not measure how much oxygenation the lungs had provided, which will be researched in the future. And, if all goes well, Nichols and Cortiella hope to grow and transplant bioengineered lungs into people within 5 to 10 years. Besides transplants, bioengineered lungs are a great testing medium for experimental drugs, another line of work that can save countless lives.

“It has taken a lot of heart and 15 years of research to get us this far, our team has done something incredible with a ridiculously small budget and an amazingly dedicated group of people,” they wrote.

The findings appeared in the journal Science Translational Medicine.

Transplant Organizations issue a guidance statement regarding Zika virus

The Zika virus has been in the headlines lately for its apparent association of microcephaly in the children of mothers infected when they were pregnant. While there is a strong correlation, a true causation has not been completely verified, and is still being investigated.  In most people the virus causes only very mild illness that resolves on its own (such as fever, rash, muscle aches, and headache), and in many individuals is completely asymptomatic. Occasionally, its effects can be more severe, such as leading to reported cases of Guillain-Barre syndrome (a severe neuromuscular illness causing paralysis). It is still not known exactly why some people may develop severe complications while the majority do not. Zika virus has been covered previously on the ZME website.

It is also known that while the Zika virus typically spreads by an insect vector (the mosquito Aedes aegypti in most cases), it is now thought to also spread by sexual contact. It is uncertain if transmission could occur thorough organ donation, but if virus is present in the blood or other body fluids, then this mode of transmission would be possible in principle. Due to concern that this unusual mode of transmission could affect a vulnerable population, the Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) has set up an Ad Hoc Disease Transmission Advisory Committee (DTAC) to provide information and recommendations to transplant physicians, and this month came out with the first guidelines. As a transplant physician myself ( I’m a pediatric nephrologist, caring for children with End-Stage Kidney Disease who will need or have received a kidney transplant), I recognize the need to be certain that our supply of donor organs are safe for our patients, and to be able to advise our current transplant patients about travel to areas where Zika is known to be endemic.

Organ transplant recipients (such as heart, liver, kidney, lung, etc) represent a vulnerable population. In order to prevent rejection of the donor organ, the patient must be immunosuppressed with medications, making it difficult to fight off infections that most of us wouldn’t be very bothered by. It is completely unknown, at the present time, how Zika virus would affect an immunosuppressed individual. It’s affects could remain mild, as it is in most people with a normal immune system, or it could have serious unforeseen consequences.

The DTAC advises caution for people who have already received a transplant, or those who are on the transplant list, if they will be traveling to a Zika endemic area. Those areas would include Mexico, Central America, and South America. They also recommend that when a donor is being considered (and that could include either a living donor or deceased donor), that the transplant center should take into account the donor’s recent travel history, and if they had recent symptoms of viral infection. Again, many people (around 20%) will not have any symptoms at all, making symptomatology an unreliable marker of infection. The committee does not feel that even these factors should result in absolute exclusion of that organ being used, but should be decided on an individual basis for each patient. Some patients may be in more urgent need of an organ, and may not survive if they have to wait too much longer for the next matching organ to come up. In other cases, a person may have already been on the transplant list for a very long time due to having built up a lot of antibodies to other potential donors, and may not get another matching offer for years.  It may be a decision that the patient, their family, and their transplant physicians need to make together if the organ in question is felt to be at a higher than average risk for Zika virus.

Unfortunately, routine screening methods are not yet available for use by clinical laboratories. Screening can be achieved by the CDC in suspected cases of Zika related illness, and therefore it is not yet recommended or possible for organ donor’s to be screened for Zika virus as part of a donor evaluation. With time we will likely have a better understanding of the risk that Zika poses to individuals immunosuppressed for organ transplant. We will also likely have better screening methods that will be more readily available. For now, I think it is prudent to take precautions until more is known, but feel that there is no reason to panic, since there is no evidence at this time that donor organs have been compromised in any way.

 

References and further reading:

“Guidances for organ donation and transplantation professionals regarding the Zika virus”.  Feb. 4 2016.  UNOS Newsroom.

 

Interim Guidelines for Pregnant Women During a Zika virus outbreak – United States 2016.  CDC Morbidity and Mortality Weekly Report.  Jan. 22. 2016.

 

Possible Association Between Zika virus infection and Microcephaly – Brazil 2015.  CDC Morbidity and Mortality Weekly Report.  Jan. 29, 2016.

newborn baby transplant

First new-born organ transplant in the UK saves two lives

In a first for the UK, doctors have transplanted the kidneys and liver cells of a newborn baby girl to two recipients. The procedure, a milestone in neonatal care, is set to become more common once the Royal College of Paediatrics and Child Health will release its new set of guidelines this year. Elsewhere, newborn organ transplants were also performed in Spain, USA, Canada and Australia, but this was the first such attempt in the UK. Doctors hope to see other clinics around the country performing the same service, which they said gave comfort to grieving families and had the potential to transform the lives of others.

Making good out of a tragedy

newborn baby transplant

Doctors in the UK perform the first ever baby organ transplant in the country. Image: Smart Mom

Doctors at Hammersmith hospital, UK, describe the case of a newborn girl who had been starved of oxygen before birth and despite resuscitation had profound brain damage. Her brave parents agreed to offer their baby girl’s organs for transplant, once they were informed she had no chance of survival. The operation went ahead when the girl’s heart stopped six days after she was born.

Operating on an infant is extremely difficult to delicate. During this stage, the kidneys only measure 5 cm in length. These were transplanted to patient whose own had failed, while her liver cells were transfused into a second patient. Information about the patients in question was not disclosed, but doctors say that despite the girl was only a few days old, her organs can sustain other infants, older children and even adults.

“We are pleased the first transplant of organs from a newborn in the UK was a success and we praise the brave decision of the family to donate their baby’s organs,” said Prof James Neuberger of NHS Blood and Transplant.

“The sad reality is for everybody to get the lifesaving transplant they are desperately in need of, more families who are facing the tragic loss of their young child will need to agree to donation.”

Dr Gaurav Atreja, who was involved in the transplant, told the BBC: “This turned out to be a positive thing for the family. They could see something positive out of a negative experience. We hope that neonatal units across the UK will actively start thinking about this noble cause.”

Organs are transplanted from a donor only when the donor is declared brain dead, yet there are no guidelines in this respect for infants less than two months old – doctors are not allowed to declare them brain dead. For babies older than two months, doctors can use a series of neurological tests, including the reaction of their pupils to bright light, to confirm brain stem death. If parents previously gave their consent, then the baby’s organs are quickly harvested.

Child Kidney

Given the success of this novel procedure in the UK, doctors hope that the Royal College of Paediatrics and Child Health, which is currently reviewing the matter, will allow newborn children to become eligible for donors as well. According to Joe Brierley, a consultant intensivist at Great Ormond Street children’s hospital, in most neonatal units one or two babies who die each year may be suitable organ donors.

“This is about giving the parents of a dying baby choices and their choice to help someone else is a fantastic gift for other parents. It won’t be right for some, but it will be for others,” he said for the Guardian. “Something good can come from the tragedy.”

damaged-vagina-surgery

Doctors surgically implant lab-grown vaginas

At the turn of the new year, we marveled how Swedish doctors transplanted no less than nine wombs in patients who suffered from Mayer-Rokitansky-Kuster-Hauser syndrome or MRKH. Now a team of researchers from Mexico and the US have gone a whole step further – they engineered vaginal tissue in the lab and transplanted it in four women diagnosed with MRKH. Eight years later, their reproductive organs are functioning normally and are sexually active.

About one in 4,500 women are diagnosed with MRKH,  a disease which causes the vagina not to form properly during development and, generally, is characterized by a missing uterus.  Current treatment is mostly through dilation, or in severe cases, surgical reconstruction of the vagina. One type of such surgery involves carving a canal by dissecting  the space where the vagina failed to form and lining it with a graft [McIndoe procedure]. Unfortunately, the grafts don’t contain all of the layers of the vagina, with the missing component that is most common being the muscle layer.

Doctors collected vaginal tissue samples from four women diagnosed with MRKH, aged 13—18 years, during May 2005 and August 2008. The cells from the vulvar tissue were cultured in a lab, then the researchers seeded epithelial and muscle cells onto biodegradable scaffolds which were designed following MRI scans. The scaffolds were incubated for seven days to allow the cells to expand and grow. Once these were deemed ready, they were surgically implanted to the patients.

damaged-vagina-surgery

All the patients fared well, except one case where a complication elicited a second surgery six months later, but everything fell in order for her too afterwards. Essentially, the doctors engineered in a lab vaginal organs and implanted them in humans – eight years later the extensive follow-up study concludes that the women are healthy and sexually active with the constructs in place.

It’s not only MRKH diagnosed women that may benefit from the findings of this pilot study. CAIS women, virilized CAH women,  intersex women, and any woman whose vagina was damaged may choose to follow the same procedure. Findings were published in The Lancet.

womb transplant

Swedish doctors perform nine womb transplants

womb transplant

Photo:Johan Wingborg/AP

Doctors from Sweden recently revealed they have successfully completed a total of nine womb transplants, marking a new milestone for a type of procedure that is still in its infancy and is considered highly risky. The transplanted wombs came from relatives, and the doctors hope report little complications have been witnessed. Ultimately, the doctors hope their patients will be able to carry a pregnancy – something no less than a fantastic breakthrough, if it were to happen.

The women taking part in the procedure were either born without an uterus  (one in 4,500 girls are born with a syndrome known as MRKH, which means they do not have a womb) or had to have it surgically removed due to cervical cancer.

The first womb transplant was carried out in Saudi Arabia in 2000, using a live donor, however the uterus had to be removed after three months because of a blood clot.  The second womb transplant was reported in Turkey last year, and a lot of people got their hopes up when they heard the patient even became pregnant. Unfortunately, the pregnancy failed after two months.

Nowadays, we’re already used to hearing about transplants of hearts, kidneys, liver and all kinds of vital organs through procedures which not so long ago were deemed extremely experimental, if not impossible by some. Recent medical advancements have set the bar even higher. Past few years have seen doctors focusing not only on life-saving operations, but on some other that improve the quality of life of the patients – things like hands, jaw or face transplants. For many of the women incapable of carrying a child, there would be no greater joy than that of being able to give birth.

Dr. Mats Brannstrom, already an authority figure in this pioneering field, is trying his best to make this possible. He first got the idea in 1998, when he removed the uterus of a young Australian woman who had cancer.

“I had to tell her that she would be cured from her cancer, but she could not become a mother because she does not have a uterus,” he said.

The woman suggested then transplanting a uterus from her own mother. The idea struck and stuck with him and upon returning to Sweden in 1999, Brannstrom  launched a research project on the issue. Researchers were able to bring about successful pregnancies in some animals using the procedure, and they believe chances of a successful human pregnancy are good.

From the womb

Fast-forward to 2014, Brannstrom and colleagues have completed nine womb transplants so far. The doctors report that all recipients are doing well, despite minor complications in some cases –  one woman had an infection in her newly received uterus and others had some minor rejection episodes, but these were overcome fast and without further issues. In fact, many of the women had had periods six weeks after the transplants, an early sign that the wombs were healthy and functioning.

Before surgery, all women had had their eggs harvested since the transplant operation does not connect any of the women’s uteruses to their fallopian tubes, so they are unable to get pregnant naturally. In vitro procedures were made to create embryos from the harvested eggs. These were frozen and doctors now plan on transferring them soon when the moment is right. If successful, it would mark the first child birth from a transplanted womb.

There are numerous voiced concerns, however. It’s unclear whether the baby born through a transplanted womb will be healthy. For instance, all the women involved in the program are forced to take anti-rejection medication, and while data from women who had received kidney transplants did not suggest their babies were at any increased risk from the drugs, we can’t still say for sure.

Pioneering work

Some, on the other hand, have voiced criticism concerning the use of live donors. The procedure involves a bigger chunk of the surrounding blood vessels to be taken to ensure adequate blood flow, raising the risk of complications for the donor. Considering this isn’t a life saving operation and the outcomes extremely unclear, some voices have been raised calling the procedure unethical.

“What remains to be seen is whether this is a viable option or if this is going to be confined to research and limited experimentation,” said Dr Yacoub Khalaf, director of the Assisted Conception unit at Guy’s and St Thomas’ hospital in London, who was unconnected to any of the womb transplant projects.

Brannstrom warned that the transplants might not result in children but remained optimistic.

“This is a research study,” he said. “It could lead to [the women] having a child, but there are no guarantees … what is certain is that they are making a contribution to science.”

Next month, he and colleagues will run the first-ever workshop on how to perform womb transplants and they plan to publish a scientific report on their efforts soon.