In fact, hundreds of thousands of patients are caught in such an unsolved predicament every year. According to data, in China, only 6% of patients who can be matched to donated organs in a timely manner. Looking at the world, this number cannot be raised higher – after all, the number of organs that can be donated is extremely limited.
In order to expand the “supply” of donated organs, scientists have even thought of a plan that sounds a bit ridiculous: transplanting animal organs into humans. For many people, such an idea is unheard of or even appalling. In fact, this possibility has been explored for decades, although it is no easier than landing on the moon.
However, the good news has come.
On January 7, 2022, 57-year-old Bannet David received a pig heart transplant because of heart failure and was not suitable for other treatment methods, and extended his life for nearly two months (59 days). In this regard, industry insiders said that their expectations were exceeded; after all, David suffered from serious underlying diseases and complications before the operation.
On May 9, 2022, the University of Maryland School of Medicine commemorates David Bennet, the first in history to receive a transgenic pig heart transplant | Source: University of Maryland School of Medicine official website (UMMC official website)
In the previous half a year, 3 brain-dead patients received pig kidney transplants one after another, and during the observation period, the pig kidney function was working well.
In the recent month, two more brain-dead patients also received pig heart transplants, and no hyperacute immune rejection occurred during the 72-hour observation period.
Together, these six cases have released a signal: pigs are bringing hope to the shortage of human organs.
For researchers and entrepreneurs who have been in the dark for decades, such hope is undoubtedly a shot in the arm. If the technical route of pig as a human organ donor is verified and feasible, it will be as significant as the overcoming of cancer, and it will become the Holy Grail of the medical profession, extending the lives of hundreds of thousands of people every year.
As the protagonist of transplanted organs, “donor pigs” are also taking the air.
These seemingly unremarkable little pigs cost about one million yuan per head for “research and development”, which is “too expensive.” Likewise, companies that develop and breed donor pigs are starting to receive more attention, which seems to be pushing pigs forward as human organ donors.
“Paige” takes the lead
In fact, the technical route of transplanting animal organs into humans, that is, xenotransplantation, is the originator of organ transplantation.
Hundreds of years ago, human beings first thought of organ donors as animals. At that time, there was no organ donation, and no human organs could be used for transplantation. However, due to the ineffectiveness of transplanting animal organs into humans, human donation came to mind. After years of exploration and experimentation, at present, the donor’s organs have become the most effective means of organ transplantation.
However, the new difficulty is that the number of human organs available is always very limited and the supply is in short supply. Xenogeneic organs “have to” come into people’s sight again.
But this time around, xenotransplantation has gone through nearly a century of exploration. Professor Chen Zhonghua, who has been deeply involved in this field for 40 years, summed up this exploration process as “four ice-breaking journeys”, and the “freezing period” experienced in the middle was 37 years, 11 years and 30 years respectively. He said that every time it encountered bottlenecks and failures, the exploration was forced to suspend until the next opportunity.
Apparently, xenotransplantation had been sitting on the bench for 30 years before the latest “glacial melt”. Professor Chen Zhonghua called it “silent 30 years”, but it was not a silent 30 years.
In the 1990s, pigs were regarded as the most ideal organ donors instead of monkeys. This is because pigs have organs similar in size to humans, are easy to genetically modify, and have the advantages of rapid reproduction. Gene-edited pigs can minimize immune rejection of human organs. Xenotransplantation has entered the research and exploration stage of “pig as a donor”. At the same time, the development of biotechnology such as cloning and immunosuppressive agents has once again provided impetus for the ice-breaking of xenotransplantation.
Baht has accumulated an inch, until the story that happened in the last year finally broke the 30-year silence.
In September, November and December 2021, two American teams transplanted gene-edited pig kidneys to 3 brain-dead human recipients, respectively. The transplanted organs survived for more than 2 days without hyperacute immune rejection.
These three cases are surprising because they are hard to come by.
Previously, gene-edited pig organs could only be transplanted into non-human primates (such as monkeys) to verify their safety and efficacy, and were not allowed for clinical human verification. However, although the genes of nonhuman primates are 80%-90% similar to those of humans, they are still very different. This forms a paradox: even if pig organs are continuously transplanted into monkeys, they cannot replace humans, and if the safety and efficacy of transplantation into humans cannot be verified, they cannot be used in the clinic.
The paradox didn’t take a turn until NYU professor Robert Montgometry suggested it. Professor Montgometry believes that a sub-clinical model can be inserted between monkeys and humans, that is, brain-dead patients. If the experiment is successful, it will be less controversial to enter human experiments. This ingenious proposal was finally approved by the U.S. Food and Drug Administration (FDA) in 2019.
The most exciting thing happened on January 7, 2022, when a patient with severe heart disease, David Bennett, was not suitable for a human heart transplant. Attending physician Bartley Griffith applied to the FDA for special approval for compassionate use, which allows doctors to resort to experimental treatments after exhausting all treatment options. David himself agreed to a transplant of a gene-edited pig heart.
After the surgery, David was in good health and watched the Super Bowl accompanied by paramedics. In the end, the gene-edited pig heart lasted 59 days for David.
At this point, the gene-edited pigs that have been exploring for decades have finally been “accidentally” verified in humans for the first time, and have lasted nearly two months of human life.
This “first time” is exciting. In contrast, the first human-to-human heart transplant in 1967 left the patient alive for only 18 days; the xenotransplantation in 1984, in which a little girl named BabyFae was transplanted into a baboon The heart also survived only 21 days.
There is no doubt that David’s case has brought a milestone in xenotransplantation.
Previously, due to ethical regulations, gene editing pigs have been difficult to verify by humans, which is the more challenging part of this innovation track. Therefore, when Bannet David accepted the pig heart by chance and survived for two months, the case was extremely cherished in the industry and outside the industry. David’s interpretation of the cause of death has also become a standard to verify whether the current technical route is mature or even right or wrong. It “has high hopes” that this is the dawn before the dawn of pig success as a xenogeneic organ donor.
After all, this is the biggest breakthrough in two decades. If this technological route is successful, it will bring hope of survival to hundreds of thousands of people.
Finally, on June 22, 2022, the “inspection report” came.
The New England Journal of Medicine, one of the four top medical journals, published a paper on Bannet David’s acceptance of gene-edited pig hearts, and the cause of his death was disclosed in detail by the team of attending physicians for the first time.
The results show that the current xenotransplantation technology can solve the problem of hyperacute immune rejection between pigs and humans, but the cause of David’s heart failure remains to be further explored, which may be the infection of porcine giant cells or other unknown causes. Impact. That is to say, although the prospects of this technical route are promising, more clinical cases are needed to test and iterate experience. It is worth noting that the US FDA will judge the possibility of clinical trials based on this in the near future.
When David’s case brought new hope for xenotransplantation, piglets as organ donors, as well as their R&D and breeding companies, also became the focus of attention.
How to create a “Million Golden Pig”
It is conceivable that if you want to “give birth” to a donor pig that can be used for organ transplantation, it is completely different from the meat pigs that are generally used for food. Pan Dengke, the founder of Zhongke Auger, which focuses on developing and cultivating organ donor pigs, told Geek Park that these piglets are “so expensive that no one can afford to talk.”
Unlike the meat pigs that are sold after six or seven months of raising, the donor pigs bred by Zhongke Oger are small pigs, their organ sizes are similar to those of the Chinese, and their bodies are well-proportioned. For the sake of stable genetics and batch breeding, such pigs are also required to have better disease resistance and reproduction. In this way, the gene-edited donor pigs may eventually become “humanized” pigs after generations of breeding iterations. If such pig organs are placed in the human body, the human body can recognize “it is “our own”. , then accept it.
Since the organs of the donor pigs will be used to save lives in the future, the requirements for the environment in which they are maintained—the breeding bases are quite strict. The staff said that it is necessary to “keep it like a baby, even if the hotel (guests) or ICU patients can’t live in such a high-level place.”
This is especially reflected in the measures related to biosecurity. The breeding base of donor pigs is required to meet the environmental standards of “ultra-clean foundation”, and the less pathogenic microorganisms are carried, the better. Under the care of breeders who specialize in animal experiments, all the milk eaten by the donor pigs must be sterilized, and the feed formula must also be traced to prevent any potential microbial infection.
Interestingly, donor pigs also need to undergo caesarean section like humans when giving birth. This is not to fear that it will be difficult to give birth, but to prevent piglets from passing through the birth canal (there may be microorganisms), and wrap them in a relatively sterile uterus. The piglets are cut out and placed in a sterilized incubator for careful maintenance.
Since the birth of a piglet, files tracking its entire life cycle have been recorded and monitored 24 hours a day, 365 days a year. In this way, what is its pedigree, gene identification records, what disease, what condition, and even its daily physiological and biochemical indicators are “traceable”.
David’s gene-edited pig heart
After that, when the pig of what genotype is needed for breeding and breeding, the pig will “go” to test the effect, one generation, two generations, three generations… Iterative optimization is continued, and as a product, it is constantly improved until it reaches standard for clinical use. At present, the GTKO miniature pig of Zhongke Auger has been iterated for 11 generations.
In fact, there is a consensus in the industry on which major genes to knock out or insert, namely: knocking out several specific pig genes to prevent immune rejection and abnormal organ growth; at the same time, knocking in several specific human transgenes , to promote the expression of regulatory functional proteins.
Then why do you need to keep exploring gene combinations and breeding iterations? Even iterative genotypes have become the core competitiveness of breeding donor pigs.
Pandenke explained: “Getting a good humanized genetic pig is like winning the lottery”, “It is easy to knock out or insert which genes, but it is not so easy to express a gene, and after verifying the effect, these genes It can be stably inherited, and others have consistent effects.” This requires a lot of key technologies and clinical experience across fields.
The technical accumulation of Zhongke Auger is inseparable from the experience of the founder Pan Dengke himself. In 2005, Pan Dengke graduated from China Agricultural University with a Ph.D. In this year, he and his team made the first somatic cell cloned pig in China. Since 2008, he has focused on the research of xenotransplantation, and in 2018, he decided to build an industrialized platform for xenotransplantation and founded Zhongke Auger.
An example is, “An American colleague edited a gene and the expression effect is very good, but you may not be able to imitate it after six or seven years.” If the expression effect of a gene is not good, then try to replace other genes. After modifying one or two genes, it is necessary to keep breeding and breeding until the gene combination with the most ideal expression effect appears, and then a stable product can be cultivated and a germline can be cultivated.
This is also the ultimate goal of breeding donor pigs. On the one hand, it is necessary to iterate to produce pigs that can truly meet the standards of the Master. After the human body receives gene-edited pig organ transplantation, the effect of transplantation is at least the same as or even better than that of human organ donation. On the other hand, in order to achieve consistent mass production of donor pigs and achieve a stable level of production, we can respond to market demands.
Donor pig, take off towards the wind
In theory, once the genotypes of pigs are determined, organs can be “produced” in a factory and standardized way like the production of industrial products. This means that patients can be transplanted at any time and treated as needed, regardless of timing, quantity and quality.
Based on this prospect, some companies have begun to cultivate such donor pigs industrially. From gene editing, to cloning and breeding, to germline breeding, they have gradually established a one-stop breeding platform for donor pigs.
As early as 2004, the German team invested a lot of money in the industrial layout for the next 20 years, cultivating genetically modified pigs and xenogeneic islets, hearts and kidneys.
In the United States, the exploration of donor pigs is more active, and many cases of industry-university research and development have emerged.
It is the industry leader Revivicor that provides pig hearts to Bannet David this time. Revivicor’s predecessor, PPL Therapeutics, successfully made the world’s first cloned sheep, Dolly, in 1996, with profound technical accumulation. Notably, in 2011, Revivicor was acquired by the US biopharmaceutical giant United Therapeutics.
As far as the exploration in the field of xenotransplantation is concerned, in 2001, Revivicor successfully bred alpha-gal knockout pigs. In 2020, the pig received FDA approval to be used as an alternative in human therapy.
Another company, eGenesis, founded in 2015, has broken through the xenotransplantation program in the direction of gene editing. Its founders, Professor George Church and Dr. Yang Luhan, are from Harvard University. The team hopes to use the CRISPR gene editing tool to create safe and human-compatible pig organs. In 2019, eGenesis raised $125 million in Series C financing and plans to file for clinical trials by the end of 2022.
In addition, there are also some Chinese companies in this industry. Among them, Hunan Sino, a well-known company in the industry, has been deeply involved in this field for 20 years; their ultimate goal is to relieve the plight of diabetic patients through xenotransplantation of pig islets.
Obviously, entrepreneurs in this track need to cultivate for a long time, and entrepreneurs who are in it need a strong belief to persevere. After all, for the technical route of donor pigs, there is no certain future in sight.
And such beliefs often come from special empathy. On the one hand, entrepreneurs who have plunged into this track have seen the technical prospects of donor pigs—relieving countless life plights; on the other hand, many people bet on this track for reasons that cannot be rejected: they were once patients, or There are such patients in the family.
The aforementioned Professor Robert Montgometry, who proposed the subclinical model, was a heart patient. Four years ago, he underwent a heart transplant, which prompted him to think about xenotransplantation options. In recent years, he has been committed to promoting xenotransplantation: from proposing subclinical models, breaking the paradox that cannot be clinically implemented, to finally practicing subclinical models (the two cases of pig kidney transplantation mentioned above in brain-dead patients were performed by Montgometry team-led), and he continues to push donor pigs into the clinic.
Indeed, other than for reasons like this, it is hard to imagine the possibility of burning money for decades just to change a life. After all, the overall technical route of xenotransplantation is still at an early stage, with great uncertainty and a long blood return cycle. Especially in the past ten years, high investment, long cycle, and high uncertainty are projects that investors are reluctant to touch.
Fortunately, this predicament seems to be loosened.
In the past year, the clinical trials of pig organ masters have made more people see the prospect of donor pigs, and more people have begun to understand the technical route to solve the organ shortage. This keeps the entrepreneurs involved in overall optimism. After all, innovation breakthroughs in many fields are driven by extreme cases.
At the same time, under the concept of hard technology, many investors have begun to turn their attention to the biomedical track, so xenotransplantation has more possibilities to be seen.
Of course, this track still needs more experience to accumulate, but more people participating in this event have a greater chance of winning.
Just like the vision of Thomas Starzl, the father of modern transplantation who has gone through 3 cycles of xenotransplantation: History tells us that what was unthinkable yesterday and barely achievable today will often become routine operations tomorrow.
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