Lessons learned from first genetically-modified pig heart into human patient

A new study published today in The Lancet has revealed the most extensive analysis to date on what led to the eventual heart failure in the world's first successful transplant of a genetically-modified pig heart into a human patient. This groundbreaking procedure was conducted by University of Maryland School of Medicine (UMSOM) physician-scientists back in January 2022 and marked an important milestone for medical science.

The patient, 57-year-old David Bennett, Sr., was treated at the University of Maryland Medical Center. He experienced strong cardiac function with no obvious signs of acute rejection for nearly seven weeks after the surgery. A sudden onset of heart failure led to his death two months after the transplant. Since then, the transplant team has been conducting extensive studies into the physiologic processes that led to the heart failure to identify factors that can be prevented in future transplants to improve the odds of longer-term success.

"Our paper provides crucial insight into how a multitude of factors likely played a role in the functional decline of the transplanted heart," said study lead author Muhammad M. Mohiuddin, MD, Professor of Surgery and Scientific/Program Director of the Cardiac Xenotransplantation Program at UMSOM. "Our goal is to continue moving this field forward as we prepare for clinical trials of xenotransplants involving pig organs."

Mr. Bennett, who was in end-stage heart failure and nearing the end of his life, did not qualify for a traditional heart transplant. The procedure was authorized by the U.S. Food and Drug Administration under its expanded access (compassionate use) provision.

"We were determined to shed light on what led to the heart transplant dysfunction in Mr. Bennett, who performed a heroic act by volunteering to be the first in the world," said study co-author Bartley Griffith, MD, Professor of Surgery and The Thomas E. and Alice Marie Hales Distinguished Professor in Transplantation at UMSOM. "We want our next patient to not only survive longer with a xenotransplant but to return to normal life and thrive for months or even years."

To better understand the processes that led to dysfunction of the pig heart transplant, the research team performed extensive testing on the limited available tissues in the patient. They carefully mapped out the sequence of events that led to the heart failure demonstrating that the heart functioned well on imaging tests like echocardiography until day 47 after surgery.

The new study confirms that no signs of acute rejection occurred during the first several weeks after the transplant. Likely, several overlapping factors led to heart failure in Mr. Bennett, including his poor state of health prior to the transplant that led him to become severely immunocompromised. This limited the use of an effective anti-rejection regimen used in preclinical studies for xenotransplantation. As a result, the researchers found, the patient was likely more vulnerable to rejection of the organ from antibodies made by the immune system. The researchers found indirect evidence of antibody-mediated rejection based on histology, immunohistochemical staining and single cell RNA analysis.

The use of an intravenous immunoglobulin, IVIG, a drug that contains antibodies, may also have contributed to damage to the heart muscle cells. It was given to the patient twice during the second month after the transplant to help prevent infection, likely also triggering an anti-pig immune response. The research team found evidence of immunoglobulin antibodies targeting the pig vascular endothelium layer of the heart.

Lastly, the new study investigated the presence of a latent virus, called porcine cytomegalovirus (PCMV), in the pig heart, which may have contributed to the dysfunction of the transplant. Activation of the virus may have occurred after the patient's anti-viral treatment regimen was reduced to address other health issues. This may have initiated an inflammatory response causing cell damage. However, there is no evidence that the virus infected the patient or spread to organs beyond the heart. Improved PCMV testing protocols have been developed for sensitive detection and exclusion of latent viruses for future xenotransplants.

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Obesity treatment could offer dramatic weight loss without surgery or nausea

Imagine getting the benefits of gastric bypass surgery without going under the knife -- a new class of compounds could do just that. In lab animals, these potential treatments reduce weight dramatically and lower blood glucose. The injectable compounds also avoid the side effects of nausea and vomiting that are common with current weight-loss and diabetes drugs. Now, scientists report that the new treatment not only reduces eating but also boosts calorie burn.

The researchers will present their results today at the spring meeting of the American Chemical Society (ACS).

"Obesity and diabetes were the pandemic before the COVID-19 pandemic," says Robert Doyle, Ph.D., one of the two principal investigators on the project, along with Christian Roth, M.D. "They are a massive problem, and they are projected to only get worse."

Gastric bypass and related procedures, known collectively as bariatric surgery, offer one solution, often resulting in lasting weight loss and even remission of diabetes. But these operations carry risk, aren't suitable for everyone and aren't accessible for many of the hundreds of millions of people worldwide who are obese or diabetic. As an alternative, Doyle says, they could tackle their metabolic problems with a drug that replicates the long-term benefits of surgery.

Those benefits are linked to a post-bypass-surgery change in the gut's secretion levels of certain hormones -- including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) -- that signal fullness, curb appetite and normalize blood sugar. Current drugs that aim to replicate this effect primarily activate cellular receptors for GLP-1 in the pancreas and brain. That approach has shown great success in reducing weight and treating type 2 diabetes, drawing a lot of social media postings from celebrities in recent months. But many people can't tolerate the drugs' side effects, says Doyle. "Within a year, 80 to 90% of people who start on these drugs are no longer taking them." Doyle is at Syracuse University and SUNY Upstate Medical University, and Roth is at Seattle Children's Research Institute.

To address that drawback, various researchers have designed other treatments that interact with more than one type of gut hormone receptor. For example, Doyle's group created a peptide that activates two receptors for PYY, as well as the receptor for GLP-1. Dubbed GEP44, this compound caused obese rats to eat up to 80% less than they would typically eat. By the end of one 16-day study, they lost an average of 12% of their weight. That was more than three times the amount lost by rats treated with liraglutide, an injected drug that activates only the GLP-1 receptor and that is approved by the U.S. Food and Drug Administration for treating obesity. In contrast to liraglutide, tests with GEP44 in rats and shrews (a mammal that, unlike rats, is capable of vomiting) revealed no sign of nausea or vomiting, possibly because activating multiple receptors may cancel out the intracellular signaling pathway that drives those symptoms, Doyle says.

In its latest results, his team is now reporting that the weight loss caused by GEP44 can be traced not only to decreased eating, but also to higher energy expenditure, which can take the form of increased movement, heart rate or body temperature.

GEP44 has a half-life in the body of only about an hour, but Doyle's group has just designed a peptide with a much longer half-life. That means it could be injected only once or twice a week instead of multiple times a day. The researchers are now reporting that rats treated with this next-generation compound keep their new, slimmer physique even after treatment ends, which often isn't the case with currently approved drugs, Doyle says.

But weight loss isn't the only benefit of the peptide treatments. They also reduce blood sugar by pulling glucose into muscle tissue, where it can be used as fuel, and by converting certain cells in the pancreas into insulin-producing cells, helping replace those that are damaged by diabetes. And there's yet another benefit: Doyle and Heath Schmidt, Ph.D., of the University of Pennsylvania, recently reported that GEP44 reduces the craving for opioids such as fentanyl in rats. If that also works in humans, Doyle says, it could help addicts quit the illicit drugs or fend off a relapse.

The researchers have filed for patents on their compounds, and they plan to test their peptides in primates. They will also study how the treatments change gene expression and rewire the brain, and what that could mean for these compounds, as well as other types of medication.

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Archaeologists uncover early evidence of brain surgery in Ancient Near East

Archaeologists know that people have practiced cranial trephination, a medical procedure that involves cutting a hole in the skull, for thousands of years. They've turned up evidence that ancient civilizations across the globe, from South America to Africa and beyond, performed the surgery.

Now, thanks to a recent excavation at the ancient city of Megiddo, Israel, there's new evidence that one particular type of trephination dates back to at least the late Bronze Age.

Rachel Kalisher, a Ph.D. candidate at Brown University's Joukowsky Institute for Archaeology and the Ancient World, led an analysis of the excavated remains of two upper-class brothers who lived in Megiddo around the 15th century B.C. She found that not long before one of the brothers died, he had undergone a specific type of cranial surgery called angular notched trephination. The procedure involves cutting the scalp, using an instrument with a sharp beveled edge to carve four intersecting lines in the skull, and using leverage to make a square-shaped hole.

Kalisher said the trephination is the earliest example of its kind found in the Ancient Near East.

"We have evidence that trephination has been this universal, widespread type of surgery for thousands of years," Kalisher said. "But in the Near East, we don't see it so often -- there are only about a dozen examples of trephination in this entire region. My hope is that adding more examples to the scholarly record will deepen our field's understanding of medical care and cultural dynamics in ancient cities in this area."

Kalisher's analysis, written in collaboration with scholars in New York, Austria and Israel, was published on Wednesday, Feb. 22, in PLOS ONE.

Two brothers, up close

Israel Finkelstein, who co-authored the study and serves as director of the School of Archaeology and Maritime Cultures at the University of Haifa, said that 4,000 years ago, Megiddo stood at and controlled part of the Via Maris, an important land route that connected Egypt, Syria, Mesopotamia and Anatolia. As a result, the city had become one of the wealthiest and most cosmopolitan cities in the region by about the 19th century B.C., with an impressive skyline of palaces, temples, fortifications and gates.

"It's hard to overstate Megiddo's cultural and economic importance in the late Bronze Age," Finkelstein said.

According to Kalisher, the two brothers whose bones she analyzed came from a domestic area directly adjacent to Megiddo's late Bronze Age palace, suggesting that the pair were elite members of society and possibly even royals themselves. Many other facts bear that out: The brothers were buried with fine Cypriot pottery and other valuable possessions, and as the trephination demonstrates, they received treatment that likely wouldn't have been accessible to most citizens of Megiddo.

"These brothers were obviously living with some pretty intense pathological circumstances that, in this time, would have been tough to endure without wealth and status," Kalisher said. "If you're elite, maybe you don't have to work as much. If you're elite, maybe you can eat a special diet. If you're elite, maybe you're able to survive a severe illness longer because you have access to care."

In her analysis, Kalisher spotted several skeletal abnormalities in both brothers. The older brother had an additional cranial suture and an extra molar in one corner of his mouth, suggesting he may have had a congenital syndrome such as Cleidocranial dysplasia. Both of the brothers' bones show minor evidence of sustained iron deficiency anemia in childhood, which could have impacted their development.

Those developmental irregularities could explain why the brothers died young, one in his teens or early 20s and the other sometime between his 20s and 40s. But Kalisher said it's more likely that the two ultimately succumbed to an infectious disease. A third of one brother's skeleton, and half of the other brother's, shows porosity, legions and signs of previous inflammation in the membrane covering the bones -- which together suggest they had systemic, sustained cases of an infectious disease like tuberculosis or leprosy.

Kalisher said that while some skeletal evidence points to leprosy, it's tough to deduce cases of leprosy using bones alone. She's currently working with researchers at Germany's Max Planck Institute for Evolutionary Anthropology to conduct DNA analyses of specific lesions in the bones. If they find bacterial DNA consistent with leprosy, these brothers will be among the earliest documented examples of leprosy in the world.

"Leprosy can spread within family units, not just because of the close proximity but also because your susceptibility to the disease is influenced by your genetic landscape," Kalisher said. "At the same time, leprosy is hard to identify because it affects the bones in stages, which might not happen in the same order or with the same severity for everyone. It's hard for us to say for sure whether these brothers had leprosy or some other infectious disease."

It's also difficult to know, Kalisher said, whether it was the disease, the congenital conditions or something else that prompted one brother to undergo cranial surgery. But there's one thing she does know: If the angular notched trephination was meant to keep him alive, it didn't succeed. He died shortly after the surgery -- within days, hours or perhaps even minutes.

Digging into medical history

Despite all the evidence of trephination uncovered over the last 200 years, Kalisher said, there's still much archaeologists don't know. It's not clear, for example, why some trephinations are round -- suggesting the use of some sort of analog drill -- and some are square or triangular. Nor is it clear how common the procedure was in each region, or what ancient peoples were even trying to treat. (Doctors today perform a similar procedure, called a craniotomy, to relieve pressure in the brain.) Kalisher is pursuing a follow-up research project that will investigate trephination across multiple regions and time periods, which she hopes will shed more light on ancient medical practices.

"You have to be in a pretty dire place to have a hole cut in your head," Kalisher said. "I'm interested in what we can learn from looking across the scientific literature at every example of trephination in antiquity, comparing and contrasting the circumstances of each person who had the surgery done."

Aside from enriching colleagues' understanding of early trephinations, Kalisher said she hopes her analysis also shows the general public that ancient societies didn't necessarily live by "survival of the fittest" principles, as many might imagine.

"In antiquity, there was a lot more tolerance and a lot more care than people might think," Kalisher said. "We have evidence literally from the time of Neanderthals that people have provided care for one another, even in challenging circumstances. I'm not trying to say it was all kumbaya -- there were sex- and class-based divisions. But in the past, people were still people."

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World's first stem cell treatment for spina bifida delivered during fetal surgery

Three babies have been born after receiving the world's first spina bifida treatment combining surgery with stem cells. This was made possible by a landmark clinical trial at UC Davis Health.

The one-of-a-kind treatment, delivered while a fetus is still developing in the mother's womb, could improve outcomes for children with this birth defect.

Launched in the spring of 2021, the clinical trial is known formally as the "CuRe Trial: Cellular Therapy for In Utero Repair of Myelomeningocele." Thirty-five patients will be treated in total.

The three babies from the trial that have been born so far will be monitored by the research team until 30 months of age to fully assess the procedure's safety and effectiveness.

The first phase of the trial is funded by a $9 million state grant from the state's stem cell agency, the California Institute for Regenerative Medicine (CIRM).

"This clinical trial could enhance the quality of life for so many patients to come," said Emily, the first clinical trial participant who traveled from Austin, Tex. to participate. Her daughter Robbie was born last October. "We didn't know about spina bifida until the diagnosis. We are so thankful that we got to be a part of this. We are giving our daughter the very best chance at a bright future."

Spina bifida, also known as myelomeningocele, occurs when spinal tissue fails to fuse properly during the early stages of pregnancy. The birth defect can lead to a range of lifelong cognitive, mobility, urinary and bowel disabilities. It affects 1,500 to 2,000 children in the U.S. every year. It is often diagnosed through ultrasound.

While surgery performed after birth can help reduce some of the effects, surgery before birth can prevent or lessen the severity of the fetus's spinal damage, which worsens over the course of pregnancy.

"I've been working toward this day for almost 25 years now," said Diana Farmer, the world's first woman fetal surgeon, professor and chair of surgery at UC Davis Health and principal investigator on the study.

The path to a future cure

As a leader of the Management of Myelomeningocele Study (MOMS) clinical trial in the early 2000s, Farmer had previously helped to prove that fetal surgery reduced neurological deficits from spina bifida. Many children in that study showed improvement but still required wheelchairs or leg braces.

Farmer recruited bioengineer Aijun Wang specifically to help take that work to the next level. Together, they launched the UC Davis Health Surgical Bioengineering Laboratory to find ways to use stem cells and bioengineering to advance surgical effectiveness and improve outcomes. Farmer also launched the UC Davis Fetal Care and Treatment Center with fetal surgeon Shinjiro Hirose and the UC Davis Children's Surgery Center several years ago.

Farmer, Wang and their research team have been working on their novel approach using stem cells in fetal surgery for more than 10 years. Over that time, animal modeling has shown it is capable of preventing the paralysis associated with spina bifida.

It's believed that the stem cells work to repair and restore damaged spinal tissue, beyond what surgery can accomplish alone.

Preliminary work by Farmer and Wang proved that prenatal surgery combined with human placenta-derived mesenchymal stromal cells, held in place with a biomaterial scaffold to form a "patch," helped lambs with spina bifida walk without noticeable disability.

"When the baby sheep who received stem cells were born, they were able to stand at birth and they were able to run around almost normally. It was amazing," Wang said.

When the team refined their surgery and stem cells technique for canines, the treatment also improved the mobility of dogs with naturally occurring spina bifida.

A pair of English bulldogs named Darla and Spanky were the world's first dogs to be successfully treated with surgery and stem cells. Spina bifida, a common birth defect in this breed, frequently leaves them with little function in their hindquarters.

By their post-surgery re-check at 4 months old, Darla and Spanky were able to walk, run and play.

The world's first human trial

When Emily and her husband Harry learned that they would be first-time parents, they never expected any pregnancy complications. But the day that Emily learned that her developing child had spina bifida was also the day she first heard about the CuRe trial.

For Emily, it was a lifeline that they couldn't refuse.

Participating in the trial would mean that she would need to temporarily move to Sacramento for the fetal surgery and then for weekly follow-up visits during her pregnancy.

After screenings, MRI scans and interviews, Emily received the life-changing news that she was accepted into the trial. Her fetal surgery was scheduled for July 12, 2021, at 25 weeks and five days gestation.

Farmer and Wang's team manufactures clinical grade stem cells -- mesenchymal stem cells -- from placental tissue in the UC Davis Health's CIRM-funded Institute for Regenerative Cures. The cells are known to be among the most promising type of cells in regenerative medicine.

The lab is a Good Manufacturing Practice (GMP) Laboratory for safe use in humans. It is here that they made the stem cell patch for Emily's fetal surgery.

"It's a four-day process to make the stem cell patch," said Priya Kumar, the scientist at the Center for Surgical Bioengineering in the Department of Surgery, who leads the team that creates the stem cell patches and delivers them to the operating room. "The time we pull out the cells, the time we seed on the scaffold, and the time we deliver, is all critical."

A first in medical history

During Emily's historic procedure, a 40-person operating and cell preparation team did the careful dance that they had been long preparing for.

After Emily was placed under general anesthetic, a small opening was made in her uterus and they floated the fetus up to that incision point so they could expose its spine and the spina bifida defect. The surgeons used a microscope to carefully begin the repair.

Then the moment of truth: The stem cell patch was placed directly over the exposed spinal cord of the fetus. The fetal surgeons then closed the incision to allow the tissue to regenerate.

"The placement of the stem cell patch went off without a hitch. Mother and fetus did great!" Farmer said.

The team declared the first-of-its-kind surgery a success.

Delivery day

On Sept. 20, 2021, at 35 weeks and five days gestation, Robbie was born at 5 pounds, 10 ounces, 19 inches long via C-section.

"One of my first fears was that I wouldn't be able to see her, but they brought her over to me. I got to see her toes wiggle for the first time. It was so reassuring and a little bit out of this world," Emily said.

For Farmer, this day is what she had long hoped for, and it came with surprises. If Robbie had remained untreated, she was expected to be born with leg paralysis.

"It was very clear the minute she was born that she was kicking her legs and I remember very clearly saying, 'Oh my God, I think she's wiggling her toes!'" said Farmer, who noted that the observation was not an official confirmation, but it was promising. "It was amazing. We kept saying, 'Am I seeing that? Is that real?'"

Both mom and baby are at home and in good health. Robbie just celebrated her first birthday.

The CuRe team is cautious about drawing conclusions and says a lot is still to be learned during this safety phase of the trial. The team will continue to monitor Robbie and the other babies in the trial until they are 6 years old, with a key checkup happening at 30 months to see if they are walking and potty training.

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Stone age surgery: Earliest evidence of amputation found

A team of Indonesian and Australian researchers have uncovered the oldest case of surgical amputation to date in Borneo. The find presents a remarkable feat in human prehistory.

The discovery, published in Nature, describes the skeletal remains of a young adult found in a cave in Borneo, who had part of the left lower leg and left foot amputated, probably as a child, at least 31,000 years ago. The person survived the surgical procedure, living for at least another six to nine years.

The find presents a remarkable feat. It is notoriously difficult to prevent infections in surgical amputations, even to this day. Yet 30,000 years ago a community was able to successfully navigate veins, arteries, nerves, and tissue, and keep the wound clean so that it healed successfully. The individual went on the live into adulthood where an unknown cause eventually led to their death.

Bioarchaeologist and an expert in ancient skeletons, Dr Melandri Vlok, at University of Sydney said the find is "incredibly exciting and unexpected."

"The discovery implies that at least some modern human foraging groups in tropical Asia had developed sophisticated medical knowledge and skills long before the Neolithic farming transition," said Dr Vlok, who is co-lead author of the paper and a postdoctoral research associate in Sydney Southeast Asia Centre.

Studying bones

The skeleton of the young adult, possibly in their 20s when they died, was carefully buried within LiangTebo cave -- located Borneo in East Kalimantan, in a limestone karst area that harbours some of the world's earliest dated rock art.

The bones were uncovered by archaeologists from Griffith University and University of Western Australia (UWA) just days before borders closed for the COVID-19 pandemic in March 2020. The team was led by Professor Maxime Aubert and Dr Tim Maloney (Griffith University), Dr India Dilkes-Hall (UWA) and Mr Andika Priyatno from the Kalimantan Timur Cultural Heritage Preservation Centre.

The University of Sydney's Dr Vlok was invited to study the bones when they were brought back to Australia.

"No one told me they had not found the left foot in the grave," Dr Vlok said. "They kept it hidden from me to see what I would find."

As Dr Vlok laid the bones out, the left leg looked withered, and was the size of a child's, but the individual was an adult. She unwrapped the part of the leg that contained the stump and noticed the cut was clean, well healed and had no evidence of any infection. "The chances the amputation was an accident was so infinitely small," Dr Vlok said. "The only conclusion was this was stone age surgery."

Dr Vlok ran to the office to tell her research colleagues what she had found. "I told them I thought it looked like a surgical amputation," she said. "It wasn't until then that they said they already knew the foot was missing." Dr Vlok had just confirmed their suspicions. The foot was never placed in the grave to begin with.

An accident

While it is not entirely clear what led to the amputation, the individual also had a very well healed neck fracture and trauma to their collar bone that may have occurred during the same event, said Dr Vlok.

"An accident, such as a rock fall may have caused the injuries, and it was clearly recognised by the community that the foot had to be taken off for the child to survive," she said.

"It is an extremely rugged environment with steep mountains dotted with caves containing some of the oldest paintings created by our species," said Professor Aubert.

Archaeologists including excavation lead Dr Tim Maloney had to kayak into the valley and scale the enormous cliff to get into the cave, proving just how remarkable it was for someone with only one leg to have survived in such challenging terrain.

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Successful transplant of porcine heart into adult human with end-stage heart disease

In a first-of-its-kind surgery, a 57-year-old patient with terminal heart disease received a successful transplant of a genetically-modified pig heart and is still doing well three days later. It was the only currently available option for the patient. The historic surgery was conducted by University of Maryland School of Medicine (UMSOM) faculty at the University of Maryland Medical Center (UMMC), together known as the University of Maryland Medicine.

This organ transplant demonstrated for the first time that a genetically-modified animal heart can function like a human heart without immediate rejection by the body. The patient, David Bennett, a Maryland resident, is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits. He had been deemed ineligible for a conventional heart transplant at UMMC as well as at several other leading transplant centers that reviewed his medical records.

"It was either die or do this transplant. I want to live. I know it's a shot in the dark, but it's my last choice," said Mr. Bennett, the patient, a day before the surgery was conducted. He had been hospitalized and bedridden for the past few months. "I look forward to getting out of bed after I recover."

The U.S. Food and Drug Administration granted emergency authorization for the surgery on New Year's Eve through its expanded access (compassionate use) provision. It is used when an experimental medical product, in this case the genetically-modified pig's heart, is the only option available for a patient faced with a serious or life-threatening medical condition. The authorization to proceed was granted in the hope of saving the patient's life.

"This was a breakthrough surgery and brings us one step closer to solving the organ shortage crisis. There are simply not enough donor human hearts available to meet the long list of potential recipients," said Bartley P. Griffith, MD, who surgically transplanted the pig heart into the patient. Dr. Griffith is the Thomas E. and Alice Marie Hales Distinguished Professor in Transplant Surgery at UMSOM. "We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future."

Considered one of the world's foremost experts on transplanting animal organs, known as xenotransplantation, Muhammad M. Mohiuddin, MD, Professor of Surgery at UMSOM, joined the UMSOM faculty five years ago and established the Cardiac Xenotransplantation Program with Dr. Griffith. Dr. Mohiuddin serves as the program's Scientific/Program Director and Dr. Griffith as its Clinical Director.

"This is the culmination of years of highly complicated research to hone this technique in animals with survival times that have reached beyond nine months. The FDA used our data and data on the experimental pig to authorize the transplant in an end-stage heart disease patient who had no other treatment options," said Dr. Mohiuddin. "The successful procedure provided valuable information to help the medical community improve this potentially life-saving method in future patients."

About 110,000 Americans are currently waiting for an organ transplant, and more than 6,000 patients die each year before getting one, according to the federal government's organdonor.gov. Xenotransplantation could potentially save thousands of lives but does carry a unique set of risks, including the possibility of triggering a dangerous immune response. These responses can trigger an immediate rejection of the organ with a potentially deadly outcome to the patient.

Xenotransplants were first tried in the 1980s, but were largely abandoned after the famous case of Stephanie Fae Beauclair (known as Baby Fae) at Loma Linda University in California. The infant, born with a fatal heart condition, received a baboon heart transplant and died within a month of the procedure due to the immune system's rejection of the foreign heart. However, for many years, pig heart valves have been used successfully for replacing valves in humans.

Before consenting to receive the transplant, Mr. Bennett, the patient, was fully informed of the procedure's risks, and that the procedure was experimental with unknown risks and benefits. He had been admitted to the hospital more than six weeks earlier with life-threatening arrythmia and was connected to a heart-lung bypass machine, called extracorporeal membrane oxygenation (ECMO), to remain alive. In addition to not qualifying to be on the transplant list, he was also deemed ineligible for an artificial heart pump due to his arrhythmia.

Revivicor, a regenerative medicine company based in Blacksburg, VA, provided the genetically-modified pig to the xenotransplantation laboratory at UMSOM. On the morning of the transplant surgery, the surgical team, led by Dr. Griffith and Dr. Mohiuddin, removed the pig's heart and placed it in the XVIVO Heart Box, perfusion device, a machine that keeps the heart preserved until surgery.

The physician-scientists also used a new drug along with conventional anti-rejection drugs, which are designed to suppress the immune system and prevent the body from rejecting the foreign organ. The new drug used is an experimental compound made by Kiniksa Pharmaceuticals.

"This unprecedented and historic procedure highlights the importance of translational research which lays the groundwork for patients to benefit in the future. It is the culmination of our longstanding commitment to discovery and innovation in our xenotransplantation program," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "Our transplant surgeon-scientists are among the most talented in the country, and are helping to bring the promise of xenotransplantation to fruition. We hope it will one day become a standard of care for patients in need of organ transplants. As has happened throughout our history, the University of Maryland School of Medicine continues to address the most complex medical and scientific problems."

Bruce Jarrell, MD, President of the University of Maryland, Baltimore, who himself is a transplant surgeon, recalled: "Dr. Griffith and I began as organ transplant surgeons when it was in its infancy. Back then, it was the dream of every transplant surgeon, myself included, to achieve xenotransplantation and it is now personally gratifying to me to see this long-sought goal clearly in view. It is a spectacular achievement."

"This is truly a historic, monumental step forward. While we have long been at the forefront of research driving progress toward the promise of xenotransplantation as a viable solution to the organ crisis, many believed this breakthrough would be well into the future," said Bert W. O'Malley, MD, President and CEO, University of Maryland Medical Center. "I couldn't be more proud to say the future is now. Our skilled team of UMMC and UMSOM physician-scientists will continue to advance and adapt medical discovery for patient care that could offer a lifeline for more patients in dire need."

Mohan Suntha, MD, MBA, President and CEO, University of Maryland Medical System, added: "The University of Maryland Medical System is committed to working with our University of Maryland School of Medicine partners to explore, research, and in many cases implement the innovations in patient care that make it possible to improve quality of life and save lives. We appreciate the tremendous courage of this live recipient, who has made an extraordinary decision to participate in this groundbreaking procedure to not only potentially extend his own life, but also for the future benefit of others."

Organs from genetically modified pigs have been the focus of much of the research in xenotransplantation, in part because of physiologic similarities between pigs, human, and nonhuman primates. UMSOM received $15.7 million sponsored research grant to evaluate Revivicor genetically-modified pig UHearts™ in baboon studies.

Three genes -- responsible for rapid antibody-mediated rejection of pig organs by humans -- were "knocked out" in the donor pig. Six human genes responsible for immune acceptance of the pig heart were inserted into the genome. Lastly, one additional gene in the pig was knocked out to prevent excessive growth of the pig heart tissue, which totaled 10 unique gene edits made in the donor pig.

"We are thrilled to support the world-class team of transplant surgeons led by Dr. Griffith and Dr. Mohiuddin at the University of Maryland School of Medicine," said David Ayares, PhD, Chief Scientific Officer of Revivicor, Inc. "This transplant is groundbreaking, and is another step in the investigation of xeno organs for human use."

Dr. Mohiuddin, Dr. Griffith, and their research team spent the past five years perfecting the surgical technique for transplantation of pig hearts into non-human primates. Dr. Mohiuddin's xenotransplant research experience spans over 30 years during which time he demonstrated in peer-reviewed research that genetically-modified pig's hearts can function when placed in the abdomen for as long as three years. Success was dependent on the right combination of genetic modifications to the experimental donor pig UHeart™ and anti-rejection drugs, including some experimental compounds.

"As a cardiothoracic surgeon who does lung transplants, this is an amazing moment in the history of our field. Decades of research here at Maryland and elsewhere have gone into this achievement. This has the potential to revolutionize the field of transplantation by eventually eliminating the organ shortage crisis," said Christine Lau, MD, MBA the Dr. Robert W. Buxton Professor and Chair of the Department of Surgery at UMSOM and Surgeon-in-Chief at UMMC. "This is a continuation of steps to making xenotransplantation a life-saving reality for patients in need."

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