Last October, the University of Maryland Medical Center admitted a patient named David Bennett, who was kept alive only by an extracorporeal life support system, extracorporeal membrane pulmonary oxygenation (ECMO). His condition was not suitable for a conventional heart transplant.
On Jan. 7 of this year, medical experts at the medical center performed a special transplant operation on Bennett, in which they transplanted a genetically modified pig heart into Bennett's body, the first of its kind in the world.
Although Bennett died about 2 months after receiving a porcine heart transplant, the procedure is still considered a major breakthrough. The pig heart transplant gave Bennett an alternative to death and provided new hope for the many patients waiting for human organs.
Bennett is convinced that even if the surgery fails, doctors and scientists can gain valuable experience from this operation. on September 2, Bennett's surgeon, Bartley Griffith, co-director of the xenograft heart transplant program at the University of Maryland School of Medicine, also said in an exclusive interview with NKJV's Earthlink that they have learned a lot from this surgery, and they realize that the results in the lab can be made a reality through surgery become a reality.
Interview with Bartlett Griffiths on September 2, by NKJV's Earthlink. /by NKJV Outside Matters
He explained that the current findings suggest that the cause of Bennett's death was related to latent porcine cytomegalovirus. He hopes to perform the next xenograft soon, and this time they will improve the sensitivity of the virus test.
During Griffith's 40-year medical career, he has witnessed many major breakthroughs in the field of organ transplantation, and now he hopes to devote his knowledge to the study of allogeneic organ transplantation. In the interview, he also expressed his respect for Chinese doctors and hopes to continue working closely with them in the future.
On September 2, NKJV connected with Bartlett Griffiths. / Screenshot from Earthlink video
First person to die from a transplanted pig heart may have been caused by a swine virus
NKJV: In June, the team associated with the University of Maryland Medical Center released a statement saying that Bennett's death was related to heart failure caused by a complex set of factors. Can you explain the current findings on the cause of his death in simple terms?
Bartlett Griffiths: We are still conducting research on a variety of possible causes of the disease. For now, the greater possibility is that we failed to detect latent porcine cytomegalovirus (pCMV) in the donor animals, which may have ultimately led to Bennett's death.
Although the virus did not infect David's other organs, it replicated and proliferated in the donor heart, or damaged the blood vessels entering the heart. We believe that the virus affected the heart capillaries when the incubation period ended and it became active. These capillaries carry blood and nutrients to the muscles, and when they stop functioning, blood flows randomly into the heart, causing it to swell. Also, without the capillaries to transport nutrients, the heart muscle can become necrotic.
Within a short time, David's heart was as abnormally swollen as the injury after twisting his ankle. Eventually, the heart muscle was also destroyed because most, if not all, of the blood vessels were destroyed. Also, although difficult to prove, we have not ruled out the possibility of an unusual rejection of the donor heart.
Bartlett Griffiths. Photo by interviewee
NK: The statement from the University of Maryland Medical Center also mentioned a drug that may have caused David Bennett's death.
Bartlett Griffiths: The drug is human immunoglobulin (IVIG), which is marketed as a drug that is injected through a blood transfusion, from the human body, with concentrated immunoglobulins. We typically use it in patients with very low autoimmunoglobulins.
When David became ill, we thought he had an infection, so the drug was administered intravenously to supplement his immunoglobulin. This is our routine when a patient has low immunoglobulin.
Unfortunately, the human immunoglobulins we inject or contain anti-pig antibodies in humans. Almost everyone has some form of anti-pig antibodies in their blood. We also did tests on human immunoglobulin before it was administered and it did not cause damage to the organs, but we are still not sure if it ultimately damaged the donor pig heart.
We hope to have the next allogeneic organ transplant as soon as possible
NK: What do you think is the main thing you learned from this surgery?
Bartlett Griffiths: We knew very little about xenotransplantation before, and after operating on David, we could be sure: the results from the lab could become a reality through surgery.
The genetically modified pig hearts functioned normally, everything was fine for the surgery, and the immunosuppression protocol we used (i.e., the way the immune system is suppressed by specific drugs) seemed to work. If everything else had gone very well, too, and if we had had a more perfect, latent virus-free donor, then we would be having a completely different conversation right now. We might be talking about David going on with his life and returning home, and that would be a miracle.
The procedure has always been considered experimental in nature. It was clear to the patients who underwent the surgery, as well as to our regulatory agencies, that the alternative to surgery for David would be death. Without the surgery, he would remain on medication, would not have a high quality of life, would live no more than a month or two, and he would never leave the hospital. We did not have high expectations prior to the surgery. We did not promise David (that we could help him extend) an extra day or even an extra hour of life.
In fact, we consider it a miracle that David survived 60 days after surgery. However, we are so saddened by his death that we will not shout victory for it.
David Bennett (right) and Bartlett Griffiths, Maryland, USA, January 2022. Photo/IC photo
We learned a lot from this procedure, including new knowledge in science and procedures for patient care, which may become part of another patient's medical plan.
NK: How do you feel about David Bennett's surgery now that you look back on it? What was the significance of that surgery?
Bartlett Griffiths: I wanted to have another surgery as soon as possible to gain more knowledge to prove that our efforts and David's trust in us were worthwhile.
David is convinced that even if it doesn't survive, we can still learn a lot. I think we've learned almost everything we can from David, and it's time to apply it to the next patient.
This surgery was the pinnacle of my career. It is very inspiring to be able to contribute to the advancement of the field of allogeneic organ transplantation. I hope to be able to bring 40 years of experience and research to bear on the development of this field. I would be very happy to be able to contribute again at the end of my career.
Next time will improve sensitivity to detection of porcine cytomegalovirus
NK: What are your plans for the next similar surgery?
Bartlett-Griffith: At this time we have no immediate plans to perform the next similar procedure, but we are encouraged by our medical center to continue our work on this and by Revivicor, United Therapeutics, the company that provided the donor heart, to continue to perform similar procedures on humans. The U.S. Food and Drug Administration (FDA) may allow us to perform one or two more similar procedures. The procedures we are talking about now will be reviewed by regulatory agencies and performed when the patient has no other options.
If given permission, I believe we will also learn a lot from the second surgery. As this develops, we can operate on more patients in more medical centers. Xenotransplantation would then not be limited to the laboratory or to achieving results in more specific populations.
David Bennett receives a genetically modified pig heart transplant in Maryland, U.S., Jan. 7, 2022, local time. Photo/IC photo
More knowledge will increase the likelihood of success before the procedure is performed on multiple patients at multiple medical centers in 2023 or 2024. While Revivicor has successfully tested for porcine cytomegalovirus for the past decade, and we had no reason to doubt its detection process before, with this procedure, we know the possible effects of this virus and also have an improved detection method that will significantly reduce the likelihood of virus test failure in the future.
NK: If another pig heart transplant were to be performed, the big change would be to make sure that there was no porcine cytomegalovirus in the donor heart, right?
Bartlett Griffiths: Yes, next time we'll do several different tests. I don't think there is a perfect donor animal, but we can work to improve the sensitivity of the assay. This type of assay is called nested PCR, and small amounts of DNA in the blood can be detected this way.
NK: You have been working in this field for many years, can you tell us about the development of allogeneic organ transplantation?
Bartlett Griffiths: In the 1980s, when I was just completing my medical training, we were just beginning to perform heart transplants at the University of Pittsburgh. We were joined by a wonderful surgeon, Thomas Starzl, who is considered an important figure in modern transplantation.
He chose to start cyclosporine and tacrolimus, drugs that would later become key to improving the success of heart, lung, kidney and liver transplants. The discovery and application of these drugs was not straightforward; some doubted their effectiveness, others felt they were harmful, and the process went through the usual scientific debates and twists and turns, but Dr. Staats did not give up on advancing their application.
We have now worked in the field of transplantation for many years and have patients who have lived for another 20+ years after surgery, who are either going to have their second or third transplant, and some young patients who have families of their own after surgery.
Just as Barnard's surgery in December 1967 proved the possibility of heart transplantation, this year's surgery showed us the possibility of allogeneic organ transplantation (Note: Christian Barnard, the South African surgeon who performed the world's first heart transplant).
File photo: South African surgeon Christian Barnard. Photo/IC photo
Now we begin to turn the page: what if we could have an unlimited supply of organs? If allogeneic organ transplants came to market, this would change the fate of many patients. Those patients who have been denied an organ transplant would not have to wait. Because of the shortage of organs, we sometimes need to make the difficult decision to exclude patients who are older or have a history of cancer. All of these patients may be able to extend their lives with an allogeneic organ transplant.
Eventually, humans may develop a "universal organ" that is suitable for transplantation and does not cause any immune rejection, and organ transplantation will be as easy as blood transfusion.
In addition, cloning technology is the key to xenotransplantation with its increasing simplicity and precision. This began with the familiar cloning of Dolly the sheep, whose team went on to become the first to clone a pig, and the scientists who later established Revivicor, a field in which they have worked for many years and are able to genetically modify with precision. This cloning technique, once successful, could last for a long time, and it would not be so difficult to produce a group of genetically modified animals that did not carry a virus.
NK: In your opinion, what is the biggest challenge facing allogeneic organ transplants today?
Bartlett Griffiths: The biggest challenge is immune rejection. A foreign organ, after all, is not part of the body, and many people's bodies will see it as foreign and engage in immune rejection, just as the human body will reject bacteria or other foreign objects.
It still amazes me that human organ transplants can be successful and that patients can survive without immune rejection after receiving another person's organ. With medications, most of the time the transplanted organ can function successfully, which may extend the patient's life by 12 to 15 years. When I first started in this field, there was only a 50% chance that a patient would live an additional year after receiving a heart transplant, whereas today a patient may live an additional 15 years.
In the 40 years that I have been working, we have made so much progress between the careers of one scientist, imagine what kind of progress we will witness after the careers of two scientists?
Beyond the Heart of the Pig: Pancreas Transplant Could Help Treat Diabetes
NK: There are other allogeneic organ transplants available, and they use things like pig kidneys or baboon hearts. What are the alternatives to the pig heart for xenotransplantation?
Bartlett Griffiths: In terms of xenografts, we're working on lungs, kidneys, liver and pancreas, where we're not so sure about the liver, whose transplantation is very difficult, and pancreas transplantation could help treat diabetes. In terms of donor animal selection, we think the porcine organ is very suitable, its shape and function are similar to humans, and pigs reproduce and grow extremely fast.
The donor pigs used by David were over 100 days old. In addition, we have demonstrated that pig hearts function properly in humans with normal pumping function and we will continue our studies with pigs.
David Bennett receives a genetically modified pig heart transplant in Maryland, U.S., Jan. 7, 2022, local time. Photo/IC photo
At the same time, the use of pigs for allogeneic organ transplantation did not provoke strong public sentiment. I respect animal rights protection experts around the world who do not feel that any animal's life should be taken away and sent to the table. I also understand them to some extent, but humans have always bred and eaten pigs. We don't hear particularly much opposition to their use as donor animals.
Now, it may be easier to perform xenotransplants between baboons and humans than between humans and pigs, but baboons are too small and generally the baboons used in the tests weighed only 50 pounds (about 22.68 kg). Other larger non-human primates are apes or chimpanzees. However, the scientific community and associated advisors have decided that xenotransplantation with these precious, slow-growing and intelligent animals is not appropriate.
From a commercial point of view, it is difficult to produce commercially successful non-human primates because they can take up to 20 years to grow to a suitable size. Baby Fae is a special case; she is an infant and only needs a juvenile animal organ for transplantation.
(Note: In the 1980s, a terminally ill infant (i.e., Baby Faye) received a heart transplant from a baboon in the United States and died 21 days after the operation.)
NKJV: Allogeneic pancreas transplantation, if successful, may become a major advancement in human medicine with increasing numbers of diabetic patients. What is the progress of allogeneic pancreas transplantation now?
Bartlett Griffiths: Allogeneic pancreas transplantation is a huge opportunity and may be more promising than the other organs we are discussing. Revivicor has put research on the pancreas on hold during this past period, but I believe this will be an important goal for the future. It would be amazing if diabetics could live a normal life without insulin injections.
NK: You talked about how complicated it would be to perform an allogeneic liver transplant, can you explain that?
Bartlett Griffiths: The liver is a chemical factory that makes chemicals based on the original donor animal. In fact, the heart is a pump, and the liver, as an organ that produces bile, is more complex for transplantation.
In both of the baboon liver transplants that I have been involved in at the University of Pittsburgh, the donor organs appear to be defective in that they do not drain bile properly. Therefore, we need to start with simpler organs for allogeneic organ transplantation.
"The goal is to achieve freedom of human organ transplantation."
NK: Is there a serious global organ shortage?
Bartlett Griffiths: There's no question it's very serious. People need kidneys all over the world, and kidney dialysis is another option, but in the long run, people who choose kidney transplants live better and longer than those who choose dialysis. I work in the heart and lung field, and many patients need heart transplants and are late in waiting.
NK: How do you predict the future of allogeneic organ transplantation? What is our ultimate goal?
Bartlett Griffiths: The goal is to achieve freedom of human organ transplantation (Organs for Everyone) while reducing costs. I think we can finally get there after a career of one or two scientists.
This will require passionate investment from people, companies and governments alike. In many Western countries, if a company believes it can not only benefit people by making a product, but also make money doing so, they will devote more time and energy to a specific product. These genetically modified organs are considered drugs by regulatory agencies, and it takes a great deal of effort and a lot of money to develop such a complex drug, so there has to be a market for this product.
I hope that the human passion for profit will motivate companies and governments to invest in this as a priority and important project that is not only profitable, but also saves lives. This is a process that is relevant to human needs and is a must for allogeneic organ transplants.
NK: What is your main research now? Is it related to allogeneic organ transplantation?
Bartlett Griffiths: Yes, we are currently working to validate the research results in order to move forward with pig heart transplants for multiple patients in pairs of different medical centers, which will take quite a while. I have developed and marketed a portable artificial lung and am interested in artificial organs.
NK: How is the artificial heart developing now?
Bartlett Griffiths: There are many new prototypes in development and some artificial hearts in use, and I first used the artificial heart Jarvik dating back to 1985. We need extremely good artificial hearts so that patients don't have to be drug dependent after surgery. But as anyone who works in the biomechanics field knows, this is as big a challenge as allogeneic organ transplantation.
NK: Do you also collaborate with Chinese doctors?
Bartlett Griffiths: During my career, there have been many Chinese doctors who have come here to study organ transplantation, and I have great respect for these young doctors. They are very bright and work very hard. I hope to continue to work closely with my Chinese friends on scientific research in the future.
Xinjing News reporter Hou Wu Ting Yao Yuan
Edited by Zhang Lei, Proofread by Wu Xingfa