EDIT: Time Peach
It has been 9 days since the world's first pig heart transplant. At present, the 57-year-old patient is recovering well and is now able to walk on the ground. After the initial victory, some people can't help but ask, what can we learn from it?
On January 15, according to Professor Wu Zhongjun, director of the Artificial Organ Laboratory at the University of Maryland, the transgenic pig heart transplant patient had been detached from the extracorporeal membrane lung oxygenation 2 days ago and began to walk on the ground 1 day ago.
"It's been a crazy and exciting week"
It has been 9 days since the world's first swine heart transplant, and patients are currently showing OK.
"It's been a crazy and exciting week," said David Ayares, CEO of Donor Pig Revivicor.
After the initial victory, some people can't help but ask, what can we learn from it?
Nature asked, the first case of pig heart transplantation in humans, what can scientists learn?
Thrilling transplant surgery review
On Friday, in Baltimore, Maryland, a thrilling GMO pig heart transplant was staged, which was performed by a 57-year-old patient named David Bennett. (See https://mp.weixin.qq.com/s/z1a5Jrvg2LCO_3L5ECYJjQ for a link)
The researchers genetically edited the donor pigs, knocking out 4 genes to avoid rejection, which is currently the biggest risk to xenotransplantation.
The surgery used a brand new perfusion device to preserve the pig heart and took a newly developed drug to suppress the immune system.
The operation lasted a full 7 hours.
Bartley Griffit, MD, of the University of Maryland, who is the lead surgeon for the transplant, said, "This is a breakthrough procedure that brings us one step closer to tackling the problem of organ shortages. There simply aren't enough donor human hearts to meet the needs of a long list of potential recipients."
A pig heart with thousands of twists and turns
Do you know the twists and turns behind this surgery?
In fact, researchers have applied to the U.S. Food and Drug Administration (FDA) for clinical trials of swine heart transplantation, but have been rejected.
The FDA is concerned about whether the pigs come from medical-grade institutions and wants the researchers to transplant hearts into 10 baboons before proceeding to humans. Muhammad Mohiuddin, leader of the Xenotransplantation Research Team at the University of Maryland, recalls the process.
This time, Patient Bennett, 57, gave Mohiuddin's team a chance, a chance to transplant a pig's heart into the human body.
Prior to initiating xenografting, Bennett was unable to implement the traditional scheme. Because of his irregular heart rhythm, he could not accept a mechanical heart pump, and because he had a history of poor treatment that did not follow the doctor's advice, he could not receive a human heart transplant.
Faced with the danger of dying, Bennett accepted the pig heart. From a humanitarian point of view, the hospital agreed to the program of swine heart transplantation treatment of patients and obtained fda permission.
Third from left is Bennett
Three days after the operation, Mohiuddin believes that the operation went well and that "the heart function looks great".
After that, he and his team continue to monitor the patient's immune response and heart function, and he will also control clinical trials to get more feedback and experience.
In addition to surgery, what problems does pig heart transplantation give scientists?
After the first victory of pig heart transplantation, scientists will face more problems than the surgery itself.
(1) Ethical choice of pig heart transplantation
- Not all patients can get a surgical license, so who is eligible?
The above patient, Bennett, could not accept the mechanical heart pump because of his irregular heart rhythm, and because he had a history of poor treatment that did not follow the doctor's advice, he could not accept the human heart, while the situation of ordinary patients was completely different.
Jeremy Chapman, a retired transplant surgeon at the University of Sydney, said if Bennett's surgery proves successful and more teams try to perform similar surgeries in the future, regulators and ethicists will need to determine eligibility criteria for obtaining a pig organ transplant.
- Not all-time xenotransplantation can be performed, so what about the time to start this emergency procedure?
Chapman believes that xenotransplantation is not a conventional treatment, and the timing of initiating this emergency procedure is debatable.
That said, while patients wait a long time for a human heart, this is not enough to justify xenotransplantation.
And, the same is true for other organs, such as the kidneys.
Most patients waiting for a kidney transplant can be on dialysis to extend the time, Chapman said.
- Not all transplants take xenospecies, so how is the opportunity cost of xenotransplantation considered?
Chapman argues that regulators and ethicists need to decide which xenotransplantation experiments have a greater chance than the risk of having a person wait for human organs.
He likens the process to using experimental cancer drugs that are too dangerous to test on a human body.
According to Organdonor.gov statistics, in 2020, the greatest demand for organ transplantation is the kidney, followed by the liver, heart, lungs and others.
The data shows that in addition to the abundant supply of heart organs, kidney organs are far in short supply.
It seems that pig heart transplantation will also face various ethical tests.
(2) Regulatory restrictions on pig heart transplantation
At present, there are strict regulatory restrictions on the supply of pig organs.
Revivicor, a subsidiary of United Therapeutics alone, is the only donor pig with the right facilities and suitable for clinical use.
Revivicor's pigs are currently being raised near Birmingham, Alabama, while a larger facility will be built in Virginia, hoping to eventually supply hundreds of organs a year.
(3) Genetic combination testing is expensive
A pig heart transplant into a baboon, which contains multiple combination tests, costs about $500,000, which is very high for the average person.
For now, while the combination seems to work, it's unclear how many genes need to be modified to be necessary.
"Evaluating every genetic modification requires more scientific knowledge, and we need this information, because these modifications can also be harmful to the human body." Some scientists have said so.
Studies have found that in baboons who undergo a porcine kidney transplant, changes in growth hormone can cause problems in the urine.
(4) Restrictions on animal models
The researchers further said, "It is important to study human organ transplants because differences between species prevent us from further using the model to predict clinical outcomes."
In addition, researchers need to be able to study the physiology of a pig's heart, for example, whether it beats at the same speed as a human heart, and whether patients will repel transplants.
If you can get a pig that has been properly genetically modified, then pig kidney transplantation is also imperative.
However, despite the initial success of swine heart transplantation, it may take some time for other organs to be ready for clinical use.
Because there are fewer waiting lists for liver transplants, this makes it harder for doctors to justify pig liver transplants in humans.
Although there are many patients who need to undergo lung transplantation, scientists say that pig lung transplantation into primates is tricky and often produces a rejection reaction.
Non-human primates often have antibodies that humans don't have, and these antibodies attack proteins on pig organs, so a lot of work is required to make organs suitable for baboons rather than humans.
Xenotransplantation, the selection of pigs
"I think there's going to be a lot of interesting things to learn." The Nature authors write.
For decades, biomedical scientists around the world have pursued the transplantation of animal organs into the human body, known as xenotransplantation.
The success of last week's genetically modified pig heart transplantation marked the first time in human history that pig organs have been transplanted into a viable and rehabilitated human body.
As recently as 2021, surgeons at NYU Langone Health connected a pig's kidney to a brain-dead patient who was sustained by a ventilator and found the organs working properly.
At the time, the director of the Langon Transplant Institute at New York University in Manhattan said that "genetically engineered pigs" had the potential to become a sustainable, renewable source of organs.
To date, most xenograft studies have been conducted in non-human primates.
However, the first xenotransplantation began long before 1667.
At that time, two French doctors injected about 340 milliliters of sheep's blood into the blood vessels of a 15-year-old boy, and the little boy was rumored to have recovered. But according to medical theory, this is not possible, but this is the first attempt by mankind.
Today, there have been many reports of kidney, heart, liver and other transplants using chimpanzees, monkeys, baboons, sheep, pigs and other animals as donors.
Among these animals, pig organs are considered the most suitable donors for humans. Although pigs look very different from humans, they have similar organ structures.
In recent years, with the advent of CRISPR–Cas9 genome editing, major advances have been made in xenotransplantation. As a result, it becomes easier to create pig organs that do not produce a rejection reaction with the human body.
The CRISPR–Cas9 genome editing tool was proposed by the team of "gene scissor hand" Yang Luhan.
Thesis link: https://www.science.org/doi/abs/10.1126/science.aan4187
Yang Luhan used the CRISPR-Cas9 gene editing tool to overcome the problem of modifying 62 genes in a single cell of pigs, which not only greatly improved the efficiency of gene editing, but also shortened the time to breed genetically modified pigs.
In the latest transplant performed at the University of Maryland Medical Center (UMMC), doctors performed 10 gene edits on pigs.
More suitable pig organ donors are needed in the future
According to public information, Revivicor is the world's largest pig cloning company, with strong gene editing technology and cloning technology.
On December 14, 2021, the FDA approved the first intentional genomic alteration (IGA) in a domestic pig strain for human food and potential therapeutic uses— designed to eliminate alterations in α-galactose on the surface of porcine cells.
Revivicor's goal is to produce genetically modified pigs (GE) to provide human-compatible cells (i.e., islets) to treat diabetes as well as organs and tissues for use in transplant surgery (xenotransplantation).
For 20 years, Revivicor CEO David Ayares has been designing pigs, testing how various genetic modifications limit rejection in humans and other primates.
To make pig hearts for transplantation, the company eliminated pig genes that trigger attacks by the body's immune system and added human genes that help the body receive organs.
The final modifications were intended to prevent the heart from responding to growth hormone, ensuring that organs from animals remained the same size as humans.
Transplant doctors hope that the success of this operation will provide animal organs for more people.
Still, Megan Sykes, an immunologist at Columbia University, said, "There's still a long way to go to get there."
Excitingly, a lot of teams are ready to actively try.
Biology companies are busy
Right now, a number of biology companies are using different genetic modifications to design pigs for organ transplantation, although some don't have medical-grade facilities like United Therapeutics.
eGenesis, based in Cambridge, Massachusetts, is making pigs that cannot transmit retroviruses present in all pig genomes.
Founded in 2015 and headquartered in Massachusetts, eGenesis was co-founded by Harvard geneticist George Church and Luhan Yang, a 36-year-old postdoctoral fellow from China. (Link: https://mp.weixin.qq.com/s/Pbp-Akl9NI143mADbdH_Kg.)
In order to knock out the genes in pigs that may cause human diseases or organ rejection, the company used the gene scissors tool CRISPR-Cas9 to transplant organs from pigs into humans and promote the clinical application of xenotransplantation.
NZeno in Auckland, New Zealand, is breeding small pigs whose kidneys remain human-sized without growth hormone modifications.
The founder of NZeno is Paul Tan, who has extensive experience in developing porcine cells for diabetes and Parkinson's disease. The New Zealand Health Authority (Medsafe) has approved the use of swine cell transplantation for human clinical studies.
Paul feels that more agencies are genetically modifying pigs for transplantation, but have yet to disclose specific commercial information.
Although they acknowledge that these genetic modifications are expensive, companies such as United Therapeutics declined to disclose the cost of production per pig.
Still, as more companies get involved, scientists expect costs to fall in the future.
Dear officials, can you receive a pig organ transplant? Welcome to leave a message.
Resources:
https://www.nature.com/articles/d41586-022-00111-9