my country has become the second largest country for organ transplantation in the world. According to statistics, about 300,000 people in my country are waiting for organ transplants every year, but only more than 20,000 people can complete the transplant every year, which makes a large number of patients have to wait in the torment of illness.
Allowing pigs to provide transplanted organs to humans is the most effective solution at the moment.
On January 7, 2022, the University of Maryland School of Medicine announced the world’s first successful live human implantation of a gene-edited pig heart. Heart patient David Bennett, 57, is recovering well after receiving a heart transplant from genetically modified pigs. But 59 days after the operation, he died as his condition worsened. On May 4, MIT Tethnology Review revealed that porcine cytomegalovirus was detected in pig hearts, and this clue may become the direct cause of David’s death. But why does cytomegalovirus appear in the heart of pigs? Will this affect the future of pigs as donor organs? The jury is still out.
Pig organ transplants to humans still look promising, but the road is tortuous.
Chinese companies are also exploring in this area. Dr. Pan Dengke, the founder of Zhongke Auger, won the second prize of National Science and Technology Progress Award twice for China’s first somatic cell cloned pig and xenogeneic liver transplantation. It is understood that the company has made a series of major progress in the transplantation of multi-gene modified humanized pig tissues and organs (liver, kidney, pancreatic islets) into non-human primates. Dr. Pan said in a previous interview: “Zhongke Auger’s xenotransplantation research will strive to enter clinical trials in the next three years.”
Dr. Pandenke was a guest in the “Rebuild” column of Founder Park by Geek Park | Source: Screenshot of Rebuild’s live broadcast
On May 29th, in the live broadcast of Rebuild in Geek Park, Dr. Pandenke introduced the current status of the xenotransplantation industry to us, analyzed the impact of the operation at the University of Maryland on the xenotransplantation industry, and imagined the future development of xenotransplantation.
Why choose “pig” for xenotransplantation?
Founder Park: From a professional perspective, how do you interpret this experiment at the University of Maryland?
Pan Dengke : An epoch-making operation recognized by the industry, it can be said that it has created a new era of xenotransplantation.
The pig heart for this experiment came from the American company Revivicor, which has been cultivating pig organs since 2002. The two scientists in charge of the experiment, Professor Muhammad M. Mohiuddin, one of the world’s foremost experts in animal organ transplantation, and the renowned transplant surgeon Bartley P. Griffith, Perform a heart transplant. Since 2016, I have tried pig organ transplantation. The pig organs have been transplanted into baboons, and the survival period has been more than 8 months. It can be said that the entire immunization plan is very mature, just waiting for a suitable patient.
The patient this time, David Bennett, is a 57-year-old arrhythmia patient. He had heart valve surgery more than ten years ago, and his physical condition is not very good. It started two weeks before New Year’s Day. Relying on ECMO machines, have been waiting in line for hearts. However, because he had been in prison before, and his reputation was not good, the hope of queuing was very slim. In addition, the arrhythmia made him unable to accept the mechanical artificial pump. The patient had no other way, so he agreed to this plan.
On the legal front, in 2020, the U.S. Food and Drug Administration (FDA) approved the first knockout pigs that can be used for both human food consumption and as a source of potential therapy. There is also a “compassionate use” program in the United States. When the patient has no way to do it under the existing treatment technology, if there is a technology that can treat the patient and benefit the patient, the treatment technology can be reported to the FDA for approval. On December 31, 2021, the FDA granted emergency authorization for compassionate use amid endangered patients.
The FDA agreed to approve the trial, this time using an immunosuppressive anti-CD40 antibody drug in Phase II clinical trials to prevent rejection of xenografts.
Being able to live two months in such a poor condition is a huge improvement, not a failure. This is a real life extension, showing the world that the entry of xenogeneic organs into the human body is already a definite signal.
Founder Park: What is the development of xenotransplantation technology?
Pandenke : The concept of xenotransplantation actually predates human-to-human organ transplantation. In the 1920s, when people didn’t dare to touch people, they thought of transplanting animal organs to humans, but the subsequent development It still revolves around human-to-human organ transplantation, but after the human-to-human technology matures, it faces the problem of organ shortage. Xenotransplantation has always been a way to solve the clinical organ shortage.
With the development of biotechnology such as cloning technology, transgenic technology, gene editing technology, etc., the organs of baboons and gorillas were first used in the 1960s, but the survival situation was not particularly ideal, and finally switched to pigs, and in the human body Previously, experiments were conducted on non-human primates. In the United States, baboons were mainly used, and monkeys were used in China.
Experimental data of pig organ transplantation into non-human primates | Source: Zhongke Auger
This graph is the survival time of pig organs on non-human primates since 1989. At first, transgenic technology was used, and the effect was average before 2000. After the cloning technology came out, everyone saw hope after 2000. The survival time was prolonged to a certain extent. Hyperacute rejection was solved by gene knockout, and then it entered another one. The low point, because in addition to hyperacute rejection, xenotransplantation also has the problem of thrombosis caused by mismatch. From 2005 to 2015, it entered a long-term exploration process. After 2016, the survival time reached more than one year. In 2019, international discussions began to discuss whether it could enter clinical trials.
Founder Park: Why did you choose to use pigs instead of other primates?
Pandenke : In 1963, chimpanzees were used to perform kidney and heart transplants on humans. Many cases were performed. The longest survival time was 9 months. Usually, they failed. First, it was limited by the technical level at that time. It’s a matter of immunosuppressants. In the 1960s, immunosuppressants had just started, and allotransplantation had not been developed. When using chimpanzees, there was also rejection, which could not be solved.
The second problem is that the growth cycle of non-human primates is relatively long, and many are singletons, and the reproduction is relatively slow. And chimpanzees and baboons are currently difficult to clone and genetically modify.
The third is the ethical issue. Non-human primates are very close to humans, and it is difficult to obtain social recognition in terms of animal ethics, but most people have no objection to pigs. In addition, non-human primates are too close to humans, and the closer they are, the easier it is to spread diseases. For example, the known AIDS may be transmitted by chimpanzees in Africa. It is also based on these reasons that from the 1960s to the 1990s, non-human primates were studied for almost 30 years, but they were finally rejected.
Pigs are chosen for the following reasons.
After long-term domestication of pigs, organs such as the heart and kidneys are very similar to those of humans, and their metabolism is also very close to that of humans. However, in the 1990s, cloning technology and gene editing technology had not yet come out, and genetic modification could not be done well to solve the problem of rejection, and the progress was relatively slow. After the successful cloning of pigs in 2000, pigs have more than one litter, and can give birth to more than a dozen pigs. The growth period of half a year has also solved the problem of growth cycle. As can be seen from the graph below, with the development of technology, the survival time of pig organs on non-human primate receptors has also been prolonged.
Pig survival time on non-human primate receptors | Source: Zhongke Auger
Secondly, pigs have relatively little ethical problems. Pigs and humans are not far from each other, and the risk of spreading diseases is lower. In addition, it is easy to carry out genetic modification, so pigs are selected.
Founder Park: What are the current challenges in pig-based xenotransplantation?
Pandenko : The biggest problem is rejection. Compared with non-human primates, pigs and humans have a greater rejection. However, after nearly 20 years of research, with the maturity of genetic modification and cloning technology, more than 30 loci have been explored and modified, and the ideal combination of gene modification is a challenge currently facing
The second is transgenic technology, which is relatively difficult. At present, it is internationally recognized that pigs are different from humans mainly have three antigens. We can remove 90% of the antigens. In addition to these three antigens, there are 10%. This is also an opportunity for us. We developed ten years later than foreign countries, but if we can find a fourth antigen, it will also promote this matter even more.
Finally, there is the issue of immunosuppressants and acute rejection. The progress of allogeneic transplantation is due to the development of inhibitors. Xenotransplantation should also follow the same path. The development and application of immunosuppressive agents for xenogeneics will definitely promote The development of xenotransplantation. In addition, this Maryland hospital operation proved that hyperacute rejection can be resolved, but acute rejection and chronic rejection are next.
Founder Park: Why are transplant organs so scarce? If the problem of organ transplantation is solved in the future, how might it be solved?
Pandenke : Organ shortage is a global problem. The United States is the largest country, and our country should be the second largest. There is a need for matching between people, mainly because the number is not enough. The United States is a big donor country, and four patients are waiting for an organ. In China, there are 300,000 people waiting for organ transplants every year, but only about 18,000 people can get organs every year. In 1984, there was a case of transplanting a baboon’s heart into a baby in the United States. The direct reason was that the organ could not be waited for.
In addition, with the improvement of the quality of life, except for people who died in accidents such as car accidents, normal people’s organs are dead when they are in their 80s and 90s, and they cannot be donated for transplantation. Donor quantity and quality issues.
The way to use pig organs for transplantation to solve the organ shortage is to first transform pigs, apply gene editing and transgenic technologies, etc., and then adopt standardized and factory-based feeding. The country and society must have a group of talented people who are committed to this matter and have been promoting this matter, as well as solving regulatory and legal issues.
Current status and future of xenotransplantation
Founder Park: What is the approximate cost of raising such a pig? What are the main challenges?
Pan Dengke : At present, we mainly use our country’s unique Guangxi Bama miniature pigs, which weigh 40 to 50 kilograms when they grow up, which is similar to the weight of a human. In recent years, we mainly use the kidneys. The experiments at the Maryland hospital used large pigs that needed to specifically remove the growth hormone gene so the organs couldn’t grow too large.
Guangxi Bama miniature pig | Source: Official website of Guangxi Department of Commerce
At present, the research and development cost of cultivating a donor pig for transplantation is about 1 million yuan. Because cloning technology and transgenic technology are used, the cost of cloning a pig is about 50,000 yuan. Later, transgenic technology and organ transplantation into monkeys are required. The surgery on the body also costs hundreds of thousands of dollars. In the follow-up, it is necessary to verify that it can be bred and whether it can be inherited naturally from generation to generation.
But the value of pigs is not limited to this, the heart and kidney can be transplanted, the skin can be made of collagen, and the cornea can also be used. These can be used comprehensively, so that the initial investment will have a better return.
Organ donor pigs have relatively high requirements on the cultivation environment. Similar to cell culture laboratories, we call them “ultra-clean facilities”. All feed and water must be sterilized. The feed needs to be specially customized. Wear protective clothing, which can isolate some pathogenic microorganisms and external parasites, so as to ensure that pigs do not bring infectious diseases to humans.
The problem of rejection is solved, and so is the problem of effectiveness. Next is the issue of biosafety, which is mainly to remove potential pathogenic microorganisms through purification.
Founder Park: Why did you decide to start a business in the field of xenotransplantation? How did you think about it at the time?
Pan Dengke : During my Ph.D., the project I did was to clone miniature pigs. After graduation, I went to the Chinese Academy of Agricultural Sciences. At that time, Professor Feng Shutang was working on the breeding of miniature pig inbred lines. I also joined the research group and used cloning technology to cultivate organ donors. pig. In 2008, I participated in the national major special project on genetically modified animals, but the market for genetically modified pigs did not accept the market, so I wanted to find a new direction.
At that time, many teams in the United States and Germany were working on xenotransplantation projects. There were very few domestic ones doing this. It was very difficult. I thought I should do it. Since there is such a technology, we must do something practical. At that time, it was decided to knock out the Alpha-Gal (α-1,3 galactosyltransferase) gene first. In 2008, I applied for an 863 project, and it took two years to overcome this. I was also fortunate enough to find some assistants. From 2008 to 2018, we completed the work that took about 20 years abroad in ten years. In this way, I have decided on my own direction, and I have been seeking cooperation with scientific research institutes in the follow-up preclinical trials around pigs.
In 2018, many companies in the United States were discussing clinical trials of organ transplants in humans. At this time, they felt that if they did not fix intellectual property rights in a corporate form, and at the same time pulled social capital to operate, they might become more and more distant from foreign countries. , after all, the team of scientific research institutes is relatively small, and there is not enough funds to support from laboratory technology to industrial technology.
In addition, international xenotransplantation experts have also been calling for not staying in the experimental stage, but entering the clinical trial stage. Secondly, what gives me confidence is that many foreign talents have returned to China, such as Professor Dai Yifan, Professor Deng Shaoping, etc. At the same time, many well-known international experts in xenotransplantation have come to China for guidance and exchanges.
Xenotransplantation is a global problem. It is not a problem that a certain country is facing a shortage of organs, and it is not a problem that can be solved by a certain company or a certain team. A lot of knowledge and technology needs to be shared and communicated.
Founder Park: What is the current technology status of xenotransplantation in China? At what level?
Pandenke : China is one of the best in the world in terms of animal cloning and transgenic technology. We mentioned hyperacute rejection just now. Pigs have an α-1,3 galactosidase. The knockout of this gene is from the United States. What the two teams did was done by Chinese as the backbone. One is Professor Lai Liangxue; the other is Professor Dai Yifan, who was doing it at Revivicor, the company that provided pigs for this Maryland Hospital operation.
In China, there are also Professor Deng Shaoping, an international expert in islet transplantation and xenotransplantation; Professor Chen Gang from Wuhan Tongji Hospital, who made important discoveries in pig-baboon experiments on xenotransplantation of kidneys while studying in Canada. The domestic shortcomings are that there is still a gap between the investment in scientific research and the experts who carry out preclinical trials compared with the United States.
There are mainly two companies in the United States. This time, Revivicor, which cooperated with the University of Maryland, is also the largest cloning pig company in the world. This company was the first to knock out α-1,3 galactosidase, and it has persisted since 2002 to the present. The donor pigs for pig organ transplants in the past ten years are provided to various medical institutions in the United States.
Another American company, eGenesis, was co-founded by Professor George Church of Harvard University and Dr. Luhan Yang, and Professor George Church is an international expert in gene editing technology. eGenesis plans to file clinical trials for kidney and islet transplantation by the end of 2022.
Founder Park: What other businesses does Zhongke Auger have now?
Pandenke: In addition to xenotransplantation, there are also biological materials. There are now heart valves from cattle and pigs in the society. After we have genetically removed biological materials, the valves have become low immunogenicity, which is similar to human immunity. Very close, very good biological material. There is also pig skin that can extract collagen as a filler for cosmetic injections.
I mentioned before that the organs of pigs are very similar to those of humans, so is it possible to make some disease models? Recently, a university contacted us and wanted to make a model of polycystic kidney disease. This disease is a hereditary disease and there is no specific medicine. We made this model with genetic modification technology. There are also models of heart disease, which can be used to study disease and gene therapy.
You can also try cell therapy in pigs, using human stem cells on immunodeficient pigs to see the effect of treatment. Immunodeficient pigs do not reject human stem cells, and then clinical trials on humans can be conducted.
Founder Park: The future of organ transplantation?
Pan Dengke : From the perspective of approval, for example, according to the clinical phase I, phase II, and phase III of the drug, many people think that this thing cannot be achieved within ten or fifteen years, but if it is a new technology, it may not be the case. of.
In 2015, when I communicated with the International Xenotransplantation Chairman, he thought that xenotransplantation would also go the way of allotransplantation. From the 1950s to the 1980s, allotransplantation has gone through 30 years, and now with the development of immunosuppressants, xenotransplantation has a history of 30 years. I believe that the last few years are the eve of xenotransplantation entering clinical trials.
None of the previous four experiments in the United States can be called clinical trials, and they are all preclinical trials or compassionate use cases for brain-dead patients. Domestically, it is believed that clinical trials such as brain death will be carried out in about three years. Now that hyperacute rejection has been resolved, as well as the approval of immunosuppressants, ethical issues, and policy issues, we can enter the real clinical trial stage in three to five years.
Xenotransplantation is not intended to replace allografts, but to complement human organ transplants, because there must be minimal differences between people. However, with the longevity of human beings, the source of organs is getting less and less and the quality is getting worse and worse, and the organs of pigs are definitely getting better and better, and the technology will continue to be iterated. In addition to transforming pigs, it is also possible to combine stem cells in the future to grow human organs in pigs, which are completely human cells.
Why was xenotransplantation first proposed in the 1990s? Because other technologies such as artificial hearts were immature at the time, but now we think that xenotransplantation is still the most feasible and fastest one. Of course, it also faces the challenges of artificial heart, stem cell islet treatment, etc. However, for large organs like the heart and kidney, there may not be much hope for cultivating an organ in vitro within 20 years. With the iteration of technology, various technologies must be crossed, and better development will also be found.
Founder Park: How do you convince yourself of a startup that takes 10-15 years to build?
Pan Dengke : I used to be engaged in scientific research, and I think it is very difficult to produce a product in a lifetime. I have been doing xenotransplantation for 15 years, and found that it needs to be promoted by corporatization, but in the process of doing it, I found that there are problems other than technology that need to be solved, which is not so easy. However, after 2015, some experts I contacted gave me a lot of confidence. They all believed that a transplant would enter the stage of clinical trials within five years, and now it has been tested in humans.
The other is the sense of personal responsibility. If no one in China insists on doing such a thing and waits until it is almost clinical, then the gap between China and foreign countries will become wider and wider.
Since we have done this, we must be responsible for the employees, for the previous persistence, and for the career that I have been engaged in for most of my life.
About “Rebuild”
“Rebuild” is an event under Geek Park that has been launched for eight years. Many top domestic and foreign companies have come to this stage to communicate with each other and improve the technology industry’s perception and understanding of trends. Since 2021, Rebuild has been iterating as a group of leading companies with technology as the core driving force in different fields, focusing on technological innovation and new changes in technology; exploring industrial development and new trends in industry direction as the core content of the bi-monthly live broadcast column. In each issue, we will invite innovative entrepreneurs and scientific research scholars to our activities to attract more talents and capital to pay attention and participate in innovative technology in emerging fields.
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