Per reporter: Wen Qiao Per editor: Gao Han
Xenotransplantation has ushered in a new major breakthrough.
On January 10, local time, the University of Maryland School of Medicine announced that the hospital's medical team successfully transplanted a transgenic pig heart into a patient with advanced heart disease for the first time. Currently, the patient is in good condition and the doctor will observe the patient over the next few weeks to assess whether the operation was successful. If successful, it would be the first organ transplant in the world to prove that a transgenic animal's heart can function like a human heart.
"This is a breakthrough surgery, we are one step closer to solving the organ shortage crisis, and there are simply not enough donor human hearts to meet the needs of a large number of potential recipients," said Bartley Griffiths, MD of the University of Maryland.
Although the scientific community regards this transplant as a pioneering attempt and offers great potential for solving the organ shortage, xenotransplantation is full of risks, immune rejection, viral infections and other issues still exist, and how to make animal organs and human organs fully compatible is a difficult challenge.
How do donor pigs do gene editing? Will genetically modified animal organs be the key to solving the organ shortage? The Daily Economic News exclusively interviewed George Church, director of the National Institutes of Health Center for Excellence in Genetic Sciences and professor of genetic engineering at Harvard University, known as the "father of synthetic biology," and Arthur L. Caplan, chair of the Department of Bioethics at New York University's Langone Medical Center.
George Church, who was predicted to win the Nobel Prize, has received Franklin Paul's scientific achievements, is a dual fellow of the American Academy of Sciences and the Academy of Engineering, and was named one of the 100 most influential people in the world by Time Magazine in 2017.
"Die or Transplant"
David Bennett, who underwent a "pig heart" transplant, is a 57-year-old patient with a terminal heart condition. The University of Maryland School of Medicine and several other transplant centers, after reviewing Bennett's medical records, determined that he was not eligible for routine human heart transplants and artificial heart pump surgery.
Xenograft became his only hope. "Die or do a transplant." I wanted to live, and I knew it was an attempt in the dark, but it was my last resort," Bennett said the day before the surgery.
On December 31, 2021, local time, the U.S. Food and Drug Administration (FDA) granted the emergency use of the transplant operation based on the provisions of expanded access (compassionate use).
(Editor's note: When a patient's life is in danger, if an experimental medical product becomes the only option to save their life, the product may be approved for use, in this case, the pig heart.) ）
On January 12, 2022 local time, 6 days after the operation, Dr. Griffith revealed that Bennett was in good condition. "It (the pig heart) seems to be quite happy with the new owner, which exceeded our expectations," he says. According to USA Today, Bennett has stopped using his cardiopulmonary machine, can breathe on his own and speak quietly.
The donor pigs are bred by regenerative pharmaceutical company Revivicor, and the entire breeding process is for the purpose of organ transplantation. "From a farming point of view, pigs are less difficult and less costly," George Church told the Daily Economic News.
Pigs were not initially the first choice for providing organs. According to reports, in the 1920s and 1990s, scientists have been experimenting with the heart, kidney and liver of baboons and other primates for transplantation, but transplants have not been successful due to reproductive difficulties, differences in organ size, cross-species infectious diseases and ethical issues.
In addition to the low cost of breeding mentioned by George Church, the physiological similarities between pigs and human and non-human primates also make it a more ideal substitute.
The gene editing behind pig heart transplantation
It is worth mentioning that the pig heart transplanted in this operation is not an ordinary pig heart, but a pig heart that has been genetically cultivated. The donor pigs performed a total of 10 gene edits. Among them, 3 genes in pigs that cause rapid immune rejection in the human body were eliminated, and 6 genes in the human body that help the immune system accept pig organs were inserted into the pig's genome. In order to prevent pig heart overgrowth, a pig gene was also removed.
Organs from transgenic pigs have been the focus of xenotransplantation research. "Now we have CRISPR genetic engineering, which can be used to modify animal genes, coupled with immune (rejection) inhibitory drugs used after transplantation, to make it easier for animal organs to function in humans." Arthur Kaplan told the Daily Economic News reporter.
(Editor's note: CRISPR is a genome editing technique that prunes, cuts, replaces, or adds dna sequences from organisms.) ）
The reporter noted that in the mid-90s, a major problem with pig organs was the endogenous retrovirus (PERV) of pigs, that is, the potentially pathogenic DNA strands in the animal genome, which could infect human patients and eventually lead to disease.
The research team led by George Church is committed to improving pigs' genes to make them more compatible with humans through CRISPR genetic engineering technology, thereby promoting the clinical application of xenotransplantation. Bennett's acceptance of the pig heart is based on the technological breakthrough of George Church's team, which was genetically edited. George Church told every reporter, "We have eliminated all endogenous retroviruses, about 25 to 60, depending on the breed of donor pigs, thus reducing the risk of zoonotic infection in (usually) immunosuppressed patients." ”
George Church's team's work, first published in 2015 and called it "the most extensive CRISPR editorial feat to date," also laid the groundwork for this pig heart transplant.
In addition, George Church also briefed reporters on other gene editing work in pigs in his lab, "Severe, rapid immune rejection is mediated by non-human sugars, so we have modified three such genes in pigs - GGTA1, CMAH and β4GalNT2." In human organ transplantation, severe but slower immune rejection occurs, which is associated with the major histocompatibility (MHC) gene, based on which we also modified similar genes in pigs. ”
"In addition to the above genes, there are genes that are involved in evading natural killer cells (such as HLAE/G) and anti-inflammatory genes (such as A20), as well as genes associated with blood complement and coagulation cascades." George Church added.
The antidote to organ shortages?
Organ transplantation is the only hope for many patients with organ failure. According to official data, there are currently more than 110,000 people in the United States waiting for organ transplants, and about 6,000 people die in waiting each year. If xenotransplantation can be achieved, tens of thousands of lives could be saved.
Bennett's case has given great encouragement to the scientific community, and many scientists see it as a pioneering operation that offers great potential hope for solving the organ shortage.
In addition to genetically modified pig hearts, genetically modified pig kidneys and pig livers are also promising for clinical xenotransplantation. Arthur Kaplan revealed in an interview that the New York University Langon Medical Center, where he is located, recently conducted a study in which genetically modified pig kidneys were transplanted in patients who had died and were maintained with a ventilator. Preliminary results suggest that rejection of xenotransplantation can be prevented in the first few days.
Asked about the prospect of xenotransplantation of genetically modified animal organs, George Church told the Daily Economic News: "We have found resistance to pathogens, aging, frostbite and cancer in animals, and these characteristics will also be improved in the xenotransplantation system of pigs." However, he also stressed that this does not mean that pigs are already resistant to various human-specific pathogens, such as HIV, polio, syphilis, etc.
While this transplant offers hope to the world, xenotransplantation is fraught with difficulties and risks, and triggering a severe immune rejection reaction can have fatal consequences for patients.
Arthur Kaplan believes that even if pig genes are modified through genetic engineering, the results will still be uncertain. "In the coming weeks, (Bennett) is still at risk of developing immune rejection and viral infections."
Xenotransplantation has a long way to go
In fact, before that, pig heart valves have long been successfully used to treat human heart disease, how is it different from pig heart transplantation? How to solve the problem of immune rejection? Arthur Kaplan told the Daily Economic News that "the heart valve of a pig has almost no blood, its main component is cartilage, and it does not produce any immune rejection." ”
George Church adds, "So far, pig heart valves are not living organs, function like leather, and need to be replaced as the receptors (hearts) grow. ”
It has been reported that when porcine heart valve surgery is performed, all the porcine cells in it have been removed before transplantation, so patients do not have to take immunosuppressive drugs.
In addition, in Arthur Kaplan's view, pigs and humans do not have the same lifespan, and pig hearts may age faster than humans. In response, George Church revealed, "My lab is working to extend the lifespan of dogs and humans, and [this method] may also be suitable for pigs." ”
Bennett, who has received a pig heart transplant, still faces a long road to recovery, and it remains to be seen whether xenotransplantation under gene editing can ignite hope for life.
Daily economic news