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The International Xenotransplantation Association is deeply saddened by the recent passing of Prof. Bob Elliott, and Dr. John S. Najarian.

Emeritus Professor Sir Robert Bartlett Elliott, MBBS, MD, FRACP, KNZM 1934 - 2020
Professor Sir Robert Elliott, died peacefully at his home in Auckland, New Zealand on 21 August 2020. The International Xenotransplantation Association is deeply saddened by the recent passing of Prof. Bob Elliott.

Prof. Elliott was a truly brilliant world-renowned medical scientist, who dedicated his life and career for more than 60 years to develop treatments for cystic fibrosis, diabetes and to advance children’s health research. Prof. Elliott pioneered the clinical application of porcine islet cells for type 1 diabetes, leading international efforts to bring islet xenotransplantation to the bed-side.

Prof. Elliott was recently appointed to the New Zealand honorary order of merit of Knight for his contributions to the medical field.

We send our sincerest condolences to his wife, Lady Betsy, their five children and 11 grandchildren.

Dr. John S. Najarian, MD, Professor of Surgery 1927 - 2020

Dr. John S. Najarian passed away on August 31, 2020 in Stillwater, Minnesota, USA, preceded in death by his wife Mignette and his son Paul.

Dr. Najarian is one of the fathers of organ transplantation and distinguished mentor to the most accomplished transplant surgeons in the world. His contributions in the field of thoracic surgery, transplantation surgery and transplant immunology are countless as his long-life commitment to promote innovation in transplantation, including xenotransplantation.

Dr. Najarian will be remembered for his excellence in performance, his strong personality, his ability to overcome every obstacle, and his determination.

Our deepest sympathy to his sons Jon, Dave and Pete, his grandchildren and great grandchildren as well as to his colleagues and fellows at the University of Minnesota.

The Coronavirus pandemic

A brief summary of what we know about animal infection by COVID-19

It is relevant to xenotransplantation researchers to know whether animals may be infected by COVID-19. In light of the World Health Organization upgrading SARS-CoV-2 infection to the status of a global pandemic, Xenotransplantation, the official journal of the International Xenotransplantation Association, has recently published ‘Update on possible animal sources for COVID-19 in humans.’ This commentary by Tanja Opriessnig and Yao-Wei Huang is a follow-up to their previous, ‘Coronavirus disease 2019 (COVID-19) outbreak: could pigs be vectors for human infections?’ Their latest article summarizes the outcomes of SARS-COV-2 infection studies and documented naturally acquired infections in different species of animals.

They show evidence that animal species in the Mustelidae, Felidae, and Canidae families are susceptible to the virus and experimentally animal-to-animal (feline) transmission has occurred. Often, clinical signs of infection are not observed in animals. Although more study is warranted, animal-to-human infection and natural animal-to-animal transmission have not yet been observed. Importantly, none of the species considered susceptible to the SARS-CoV-2 are currently used for xenotransplantation. Pigs do not seem to be directly affected by the virus.

Literature on COVID-19 in animals is scarce, however, the works by these authors provide some valuable data for consideration.

Coronavirus disease 2019 (Covid-19) outbreak: Could pigs be vectors for human infections?
Update on possible animal sources for Covid-19 in humans.

Virtual TTS 2020

If 2020 has taught us anything it has made us more comfortable meeting and discussing business online. Due to concerns about COVID-19 and the difficulty in planning a large-scale meeting in such uncertain times, The Transplantation Society has decided to go virtual.

The new TTS2020 Virtual Congress will be a multi-disciplinary program featuring 250 presentations including plenaries, state of the art symposia, workshops and best oral abstracts sessions allowing participants to come together to learn the most up to date science and clinical practices and to share valuable academic research findings.

An integrated WebAPP solution offers ease of use and minimizes the creation of multiple accounts and platforms. The TTS will run three time blocks consisting of five hours of programing every day in a way that ensures that each participant, regardless of geographical location will have access to 5 hours of sessions in the morning and an additional 5 hours in the afternoon/evening. Recordings of each session will also be posted immediately following the session to help make sure that participants don’t miss anything. Please follow this link here to find the appropriate times to view each session in your time zone.

Please visit this link to read about Xenotransplantation programs here

  • Workshops will be presented on topics of interest to xenotransplantation including :
  • (1)Design of XenoTx clinical trials (#201, Day 1),
    (2) What is the ideal pig for XenoTx (#276, Day 2),The Xeno-Prize will be presented at the end of session #276 (Day 2).
    (3) Regulation of XenoTx (#341, Day 3).
  • (4)Experts will present State Of The Art updates for Recent Breakthroughs in Xenogeneic Tissue and Organ Transplantation (#462, Day 4).
  • (5)Abstracts on Xenotransplantation will be presented on Day 2 and 4 (#283, #384).
    • Despite the virtual reality of TTS2020, there will be plenty of opportunities for networking. Virtual networking rooms will be running concurrently with live sessions to allow participants to engage in discussions with peers from around the world on topics of interest. Speakers will be available to answer questions after most sessions.

      TTS has pulled out all of the stops in their effort to provide a satisfying and rewarding experience for everyone. Members registration fee is $150 ($75 for members from emerging economy nations).Registration for Students, Fellows, Trainees as well as Allied Healthcare Professionals is free. See here for more details.

New XenoTransplantation Podcasts and Webinar Coming

The IXA is in the planning stages of launching a podcast dedicated to topics of interest in the xenotransplantation community as well new series of webinars. We are therefore soliciting feedback from our members on topics that they would like to see included in this project. Suggestions can be emailed to Suzanne.Landis@tts.org

We thank you for your support and suggestions as we strive to provide our members with interesting and informative content a format that we hope can supplement our normal channels of communication.

A Reflection on the dark days of Xenotransplantation.

Wisdom for these challenging times from Pioneers in Xenotransplantation

This year has been a difficult one due to the worldwide COVID-19 pandemic. As always, our first thoughts are for the health of the patients, but the longer the disease remains uncontrolled, the more that people may begin to become anxious about their future in a changing post-COVID-19 world. This may include members of our own organization who may have concerns about unknown challenges to their own research and to the field of xenotransplantation. While none of us have likely faced anything quite like current times, the field of xenotransplantation has experienced many ups and downs and is still moving forward.

In order to illuminate several of these prior challenges, we asked several of our respected senior members if they would share some of the personal experiences from their “dark days,” that will hopefully remind us that we are not alone in our endeavors. Prof. Anthony D’Apice (Victoria, Australia), Dr. David K.C. Cooper (Birmingham, Alabama, USA) Prof. Ian F.C. McKenzie (and Mauro S. Sandrin) (Melbourne, Australia), Prof. Bruno Reichart (Munich, Germany), and Prof. Jean-Paul Soulillou (Nantes, France) have graciously responded to our invitation to share their thoughts with us. Due to space limitations, we will only be able to summarize their responses here, however, links will be provided to their complete responses and we hope that all of our readers will take the time to read the full works that are certainly quite interesting on their own merits.

Prof. Ian McKenzie

When considering the “dark days” for xenotransplantation, Prof. McKenzie points to a general frustration with the slow pace at which xenotransplantation advances toward clinical application. He recognizes that previous medical breakthroughs such as early attempts at allotransplants done in the 1950s were certainly facilitated by fewer theoretical objections and a willingness to try something new in order to save lives. His belief is that a bolder “carpe diem” attitude is beneficial to the advancement of medicine including xenotransplantation.

He cites several perhaps missed opportunities in which surgeons could have pushed the envelope (while still maintaining the necessary safety profile) including (1) the possibility to test pig islets in volunteer diabetic patients after success in nonhuman primates, with the drawback being the need for immunosuppression in place of the need for insulin, and (2) attaching normal pig kidneys to human arteriovenous shunts which resulted in HAR as expected instead of testing GKO pig kidneys to see what would happen.

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Our experiences of the “Dark Days” of Xenotransplantation

Ian F.C. McKenzie and Mauro S Sandrin

The University of Melbourne, Department of Surgery, Austin Health, Heidelberg, Victoria 3084, Australia

The impact of the current COVID-19 pandemic is having on xenotransplantation research, or research in general, in unprecedented. Here in Australia many laboratories have had to shut down for some periods of time, as only essential work was allowed.

We are not virologists, so other than showing that CD46 acts as a receptor for the measles virus, we were just observers for the PERV and BSE stories. The field is fortunate that the cow was not the species of choice for human xenotransplantation, otherwise it may have stopped the field indefinitely. The first examples of “mad cows disease” occurred in the mid 1980’s, and “infection” to humans in the early 1990’s. Yet, research quickly identified the agent, and measures put in place to stop further spread.

PERV is another chapter in the history of xenotransplantation. When it was shown that, in vitro at least, the PERV could infect human cells, the opponents of xenotransplantation believed that if the field was to progress to human trials it would bring a global pandemic, similar to what we now see. In an opinion article, we suggested that if PERV was to be such a problem, then we should have seen it already. Unfortunately, the fear of PERV was one of the reasons for a “moratorium” on xenotransplantation trials. Most in the field remained optimistic that ways to prevent this cataclysmic pandemic, and continued with their research. Indeed they were right, using CRISPR every copy of PERV can be removed from the pig genome. We were impressed with the boldness of the German group, who injected huge amounts of PERV into monkeys- it was harmless! Is a bit more boldness is needed today?

Another potential set back result for the field, was trying to modify Gal expression in pigs. We were among the first to show that Gal was the major target for human antibodies causing Hyperacute Rejection-HAR. But, what to do about lowering/ ablating Gal from pig tissues to decrease/avoid HAR? Gene Knockouts could be done in the 129 strain of mice due to multiple embryonic stem cell lines derived from this strain. It was suggested that 129 mice could be unique, due to the high incidence of spontaneous testicular teratomas in this strain. These ES cells that could be grown in vitro, modified and then used to produce viable mice. Several groups tried to isolated pig ES cells to no avail. We didn't have the expertise to try this in pigs- thus tried several other approaches. Firstly, we tried the glycosyltransferases to compete with the galactoslytransferase, then galactosidases, enzymes which cleaves Gal from the next sugar in the chain- leaving N-acetylgalactosamine exposed. We used these to produce low Gal cells in vitro,& in transgenic mice , Gal was significantly reduced , in our in vivo model of HAR, graft rejection was delayed, but not to such an extent to be of practical value. It was only with the advent of animal cloning, starting with Dolly the sheep, that the field again went forward.

The thing is our frustration with the relative SLOW PACE that clinical research is moving now - just as well the first allotransplants were done in the 1950s, where there were fewer theoretical objections to trying something new and potentially life saving. We give several examples: (1) our CD46 Pig Islets grafted into immunosuppressed diabetic monkeys; --monkeys were sacrificed at 3 month intervals--the last at 15 months; none were diabetic or required insulin, and all were healthy until sacrificed. This may be the FIRST example of both surviving and functional pig tissue in primates. Surely this could have then been tried in volunteer diabetic patients; the only drawback being a requirement for immunosuppression--used widely in humans for a variety of conditions. Secondly - in the early 1990s, Swedish scientists attached normal pig kidneys to human AV shunts (in situ for haemodialysis) and observed HAR - as expected. Surely GKO pig kidneys could have been used in patients to see what happened? If the kidney did not undergo HAR & produced urine, a lot could have been learned. If it failed - back to the drawing board! Such studies could easily have been organized with due monitoring of side effects (one of the Swedish patients had an anaphylactic reaction-easily treated) and care to avoid infection. Currently, we hear that Ig-ve pigs have been produced with most of the Human Ig genes inserted. Hopefully such HuIg pigs would also be Galo/o to avoid their antibodies being neutralized in vivo in humans. Immunising these pigs with COVID-19 virus would lead to a polyclonal antibody to use, passively, in patients (better than multiple Mabs) - while we await a vaccine, or the trials of infusing sever COVID-19 patiens with serum form individuals who were COVID-19 infected and recovered. (Yes, we know that pigs will have a different ”repertoire” of genes to humans—but—so what at this difficult time? ie time for a bit of boldness!).

However bleak the future looks at the present, we are encouraged that it has been in similar situations before, and always managed to find a solution. We are also encouraged by the new generation of researchers that now take up the challenges.


Prof. Anthony D'Apice

Prof. D’Apice also discusses quite heavily the slow nature of the advance toward the clinic. He mentions the hubris and naiveté of the earlier days which, perhaps led to false expectations that had long ramifications for xenotransplantation, only to be met by one problem after another to be solved before inching closer to the goal.

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Thank you for asking me to be part of your project on thoughts from the ancient modern history of xenotransplantation. Before I start, I ask your forgiveness for what are sure to be inaccuracies in my recall of detail and timing of events and my sketchy knowledge of events since my retirement 10 years ago.

I became involved in the late 80’s early 90’s when I moved from managing a clinical renal transplant service to a Clinical Immunology Department and wanted to continue my research interest in transplantation but without patients. At that time xeno was largely a surgical endeavour involving primates and it was unable to make any meaningful progress despite several hubristic surgeons who were willing, nay enthusiastic, to actually transplant a few unfortunate patients. (Think here of the litany of setbacks to progress of the field: #1: early surgical hubris).

David White, then of Cambridge, made the first really meaningful advance by showing that the complement cascade regulator Decay Accelerating Factor or DAF, could inhibit various in vitro models of hyperacute rejection (HAR) in the pig-human combination. To my mind this was beginning the modern era of xeno research. David and co went on to generate DAF transgenics and showed some inhibition of HAR and early graft survival. He was so enthusiastic that he stood on the stage at the Rome Transplantation Society meeting and called for a move to the clinic (#2: early scientific hubris). Despite the Pope who came to the meeting and addressed us in the hot sun, inter alia supporting xeno, there was no enthusiasm for immediate clinical application because the preclinical data did not support it. On its own, inhibition of the complement cascade was not sufficient because xenoantibodies continued to cause havoc.

Initially two scientific groups tackled antibody. David Cooper’s and our group showed by different routes that Gal was the main target. However, Uri Galili in a completely separate literature had already shown that Gal was the major target of human anti-pig antibodies. This prompted a series of efforts to remove the Gal target. The main effort was to inactivate the a1,3 galactosyltransferase gene in the pig. The other from Ian McKenzie’s group was to compete for the enzyme’s substrate using transgenic expression of human H-transferase. This was at least partially and often very effective but the appeal of elimination was greater. In those days, gene KO was performed in embryonic stem cells which were then used to generate hybrid blastocysts and finally hybrid animals which could then be bred on to become full KO animals. The only problem was that pig ES cells did not exist and we spent several years unsuccessfully trying to generate them. It was only when Dolly the cloned sheep came along that a technique that worked in pigs was found and there was a race to produce GalKO pigs. Our group won the patent race but not the actual race to first on the ground and within a couple of years at least 5 groups had made GalKO pigs. This was the second major advance toward clinical xenotransplantation. The GalKO and complement regulator transgenics were soon interbred and hyperacute rejection was overcome.

The next and overlapping era was that of the companies, the likes of Sandoz, Baxter and so on who had an interest in either immunosuppression or dialysis and so a position to protect. Their hope was a rapid translation to the clinic and / or to protect existing stakes such as dialysis, and they invested heavily in the various groups. The companies were very rough bedfellows and we were naïve virgins (setback #3). However, when the hope (or threat) of rapid clinical exploitation faded, they lost interest and the survivors went back to academic funding sore but experienced.

The cause of this fading of hope was two-fold, one from each side of the equation that needed solution for clinical application to be realistic. First, efficacy had to be shown. While there were plenty of signs of progress and indicators of imminent success in preclinical models, it was like reading a horror story. With each new page there was a new barrier, a new failure and new problem that required another genetic modification for solution. This is still the problem today with the two major clinical applications that were the main focus at that time; renal and cardiac transplantation – both solid organs. The focus was yet to seriously turn to pancreatic islet cells. The companies probably could have coped with this but when the other side of the equation raised its head, the bell started to toll. Safety had been discussed widely, pigs were dirty but could be cleaned up and isolated in expensive barrier facilities and the companies threw money at the problem and built them. But then came the stain that could not (at that time) be scrubbed clean: porcine endogenous retrovirus (setback #4). The horror was compounded by the fact that it was a retrovirus (think AIDS) and that one of the most prominent medical (and xeno) researchers of the time, Fritz Bach of Harvard, rose up to his full height and declared xenotransplantation to be dead (setback 4.1 – God had spoken, even the Pope’s prior blessing was now null and void). This was met with incredulity by xeno researchers many of the most prominent of whom were his friends and colleagues at Harvard Medical School. Bach’s intervention was denounced as treachery (and nest fouling) and he was until his death persona non grata to many around him. The companies were faced with efficacy still needing more money and an unknown amount more time and now a seeming insoluble problem with safety. They backed out of funding but still held tight to their grips on our IP via our patents…..just in case we were able to make something work. We bound up our wounds, took antibiotics and slowly recovered, finding some dignity and sufficient dollars in old fashioned academic funding. Interestingly the (continuing) progress of xeno to the clinic has been so slow that all the primary patents that these companies coveted so much are all now time expired, like me.

When I retired 10 years ago, PERV was the only significant known barrier to safety of xeno that could not be managed. At that time, and correct me if I’m out of date, as far as I know there is still no direct evidence of a human being infected with PERV let alone it causing any illness. So, all the concern is based on a theoretical possibility. However, I understand that a US company has edited out all the PERV sequences along with Gal and other transferases and inserted many complement and other regulators. This holds great promise for xeno. However, a minor word against premature adulation (potential setback #5). Building a stable pig herd for clinical use from a founder can be very difficult because of inbreeding issues, as hybrid vigour and fecundity suffer. Old-fashioned pig husbandry is still relevant.

I wish you all good luck and patience in what I hope are the last stages (of still indeterminate duration) before clinical application of xeno is a reality. The virtues in xeno are patience, constancy, self-reliance, doggedness, resilience, avoidance of hubris (and companies), a healthy dose of cynicism, self-deprecation, humility, humour and excellent science to justify academic funding. If anyone has these virtues, I have yet to meet her.


Dr. David K.C Cooper

Dr. Cooper addresses the difficulties in sustaining xenotransplantation research in face of inconsistent or non-existent funding. Organizations that provided much of the funding during the early boom period for xenotransplantation quickly exited the field when results were not what they expected and concerns about PERV exploded. With a little patience, more realistic investments might have moved xenotransplantation forward much more rapidly and these companies could begin reaping the rewards of their expenditures. While xenotransplantation research is no cash cow, the NIH NIAD has provided valuable support. These “small steps” have been key to keep xenotransplant research alive in several labs.

One thing that all of our correspondents agreed on the concern over PERV transmission to humans that almost ended any hope for clinical xenotransplantation and most likely contributed to private funding disappearing. As. Prof D’Apice and others have pointed out, even 20 some years later; there is still no conclusive evidence of PERV transmission to humans in nature, making the delays due to a more theoretical than actual concern. In any case, the potential threat of PERV can now also be addressed by genetic engineering of the pigs.

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Because of the fear in some people’s minds that the COVID pandemic will permanently halt progress in xenotransplantation research due to concerns that a pig virus will be transferred to a human recipient of an organ or cell xenograft, I have been asked to comment on what episodes caused me worry or concern during the past more than 35 years of involvement in this field of research.

Let me state immediately that, although the shutdown associated with the COVID pandemic has certainly slowed my own group’s progress towards the clinic, I do not have any concerns that it will permanently prohibit clinical xenotransplantation. My reasons for believing this were published recently in a letter to the editor of ‘Xenotransplantation’, written in collaboration with Michael Knoll and Rita Bottino (Knoll 2020). Similarly, none of the previous ‘scares’ relating to potential infection, e.g., PERV, MERS, SARS, etc., shook my belief that xenotransplantation would go ahead as soon as we had solved the immunological problems that face us.

What has been of much more concern to me over the years has been the difficulty in obtaining sufficient funding for the expensive studies necessary for us to move forward. In the early days of xenotransplantation research, it was even more difficult than it is today to persuade the funding agencies to support xenotransplantation research. A grant application would be reviewed without major criticisms by a reviewer, but he/she would end their critique by asking, ‘But is it ever going to happen?’ and it would not be funded. They were correct, of course, to ask this question – it certainly will not happen if there is no financial support. The reviewer was obviously someone with either no vision or, more likely, a quite different vision for the future.

Nevertheless, one or two research groups managed to obtain considerable financial support from major companies. For example, in the naïve belief that a pig that expressed a single human complement-regulatory protein, CD55 (DAF), combined with cyclosporine therapy, would solve all of the problems and allow us to proceed immediately to clinical trials, Novartis reputedly invested hundreds of millions of dollars into the work of the UK biotech company, Imutran. Clearly, not enough enquiry had been made into the state of the science before this investment was made, suggesting that some business executives should not have been in the high positions they held in the pharmaceutical company.

Imutran’s first transgenic pig was a major step forward, and if Novartis has backed the company with perhaps $10 million per year for a decade or more, steady progress would have been made by Imutran’s excellent team of scientists, and Novartis might now be close to reaping the financial rewards of its modest investment.

When the Novartis executives realized they had been overly-optimistic, coupled with their unjustified fear of PERV, they shutdown Imutran, and killed most of the remaining transgenic pigs – in my opinion, a second foolish business decision, compounding the first.

Similarly, at Tom Starzl’s urging, the University of Pittsburgh Medical Center (UPMC), the company that owns many of the hospitals in the Pittsburgh area, purchased the US pig biotech company, Revivicor, in 2004. When progress was slower than they had been led to anticipate, they withdrew their support precipitately. Revivicor was only days away from closure when saved by United Therapeutics in 2011.

Just as with Novartis, if UPMC had been patient enough to invest longer-term, it would today be in a position to soon dominate the field of transplantation. Given the immense wealth of both Novartis and UPMC, the necessary annual investments would have been ‘peanuts’ to them.

Fortunately, in 2005, the US NIH’s National Institute of Allergy and Infectious Diseases (NIAID) decided to support xenotransplantation research, enabling several groups to continue to make progress, which has been life-saving for the field.

I was never seduced by the lure of alternative technologies that were introduced during the past 30 years. For example, several gifted researchers were lured away from xenotransplantation by the perceived potential of stem cell technology. I was immensely skeptical that we would be able to produce a functioning kidney, heart, or liver from stem cells, at least not in my lifetime. With pigs, we already had organs that we knew would likely function well in humans. To achieve similar success from a stem cell seemed to me like the height of optimism. I had the same response to regenerative medicine, where we were promised that the decellularization of an unacceptable human organ or a pig organ, and its recellularization with cells from the potential specific recipient of the organ was going to be achievable. To me, this seemed unlikely within the next 50 years. And so, after careful consideration, and an unshakeable belief in the huge potential of xenotransplantation, it was easy for me to resist the attractions of a different field of research.

The ‘lows’ faced by the crises of funding were offset by the ‘highs’ experienced by the advances that have taken place over many years, e.g., the ever-improving techniques of genetic-engineering, the identification of the pig antigens against which humans have natural preformed antibodies, the introduction of agents that block the CD40/CD154 costimulation pathway, the identification and resolution of the dysfunctional coagulation and inflammatory responses that result from the presence of a pig graft, and, particularly, by the milestones achieved – the first islet transplant to maintain normoglycemia in a diabetic monkey for more than a year, the first pig kidney to function for more than 3 months, and then for 6 months, and even a year, the first heterotopic heart to function for a year, and the first orthotopic heart to function for 6 months. These highlights kept us believing in ultimate success.

There have been many disappointments, of course. Some of the genetic manipulations have been detrimental to the pig or have not had the anticipated effect on graft survival. At times, novel immunosuppressive regimens have proved inadequate. Some of these failures have been associated with our own lack of knowledge or forethought. Although some mistakes could possibly have been avoided by more careful planning, others were just part of a learning curve.

I once asked Norman Shumway, the major pioneer in the field of heart allotransplantation, whether he ever considered abandoning his research. He replied, “Not really. There was always just enough success - just enough gratification, if you will - that you could see that it probably would ultimately work and, if everybody kept working, we might get someplace.” That is exactly how I have felt about xenotransplantation.

However, Shumway worked in the laboratory for less than a decade before he was able to move into the clinic. We have had to struggle for very much longer, and still we are not quite ready to initiate a clinical trial. Nevertheless, it has been a very interesting and exciting experience, and I remain certain we will soon get there.

“We are at our very best, and we are happiest, when we are fully engaged in work we enjoy on the journey toward the goal we’ve established for ourselves.” Earl Nightingale.

Reference

Knoll MF, Cooper DKC, Bottino R. How the COVID-19 pandemic may impact public support for clinical xenotransplantation in the United States. Xenotransplantation. 2020; Jun 28:e12623.


Prof. Jean Paul Soulillou

While COVID-19 may bring more attention to zoonotic animal viruses among the general population, it is something that xenotransplantation science has been aware of for a long time. As several of our correspondents have pointed out, past pandemics have resulted from uncontrolled arenas quite unlike laboratory science.

Prof. Soulillou provides interesting insights on how strategies designed for xenotransplantation may lead to therapeutic options that can mitigate some of the most devastating consequences of COVID-19 on patient health.

Prof. Soulillou also commented that the pandemic has demonstrated an extremely active policy of regulatory offices at different levels in an attempt to contain the virus.

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In a recent book on Xenotransplantation edited by Pr. D Cooper (Recollections of Pioneers in Xenotransplantation Research), I was invited to write a chapter on our (modest) contribution in this field. This invitation gives me the opportunity to take some distance to the daily “battle field” of research in xenotransplantation, decades after my first apparition -using “Xenotransplantation” as a key word- on PubMed, to portrait what could be the actual place of xenotransplantation in clinic in the future. In my contribution entitled “A journey in xenotransplantation science, from Mélies illumination to medical wisdom”, despite the recent preclinical achievement in preclinical primate models and all amazing possible progresses offered by new technologies (Perv free donors, reduction of pig tissue immunogenicity, chimeric animals hosting human tissues, etc.), I confessed I still had difficulties to envision xenotransplantation of vascularized organs to enter the clinic for replacing allograft long term purposes, mostly due to the tremendous immunological barrier that xenotransplantation is facing. Rather, I suggested that more attention could be paid to the less mediatic approach of using animal engineered tissues (as “biological” heart valves) or animal molecules (as it has been the case for decades for insulin and more recently for monoclonal or polyclonal antibodies) now widely used in clinic. Moreover, the success of such approach initially based on a pragmatic behavior, now benefits of the developments of the xenotransplantation science mentioned above.

The COVID-19 pandemic of course questions researchers engaged in the field of xenotransplantation. The major concern, actually inherent to the topic itself, is the safety issue regarding animal derived viral (Perv) or molecular (“Mad cow”) risks, a concern that has actually triggered a schism in our community, particularly following Fritz Bach ethical warning on the risk of introduction of xenotransplantation in the clinic. A major benefit of this crisis has been the extremely active policy of regulatory offices of states and academic institutions (and particularly of IXA) facing this potential risks. In this respect, decades long discipline of all the research community working on xenotransplantation has been remarkable. Interestingly, in the same time, the research efforts spurred by xenotransplantation challenge itself – such as for the progress in the genetic engineering of large animals, have been able in few years to solve the major identified alarm that triggered the debate of “ethic in xenotransplantation”: the risk related to Perv.

However, the COVID-19 pandemic, as past pandemics of severe outbreaks from animal viruses, occurred in uncontrolled arena which differ from the arena of laboratories working on “xenotransplantation science”. Moreover, the perspective of “soft xenotransplantation” I defended in the book edited by D. Cooper is highlighted by observations directly issued from research in the field of “xenotransplantation science” and which may provide powerful tools to combat COVID-19 disease. As an example IgGs anti- CoV-2 Spike able to neutralize interaction of CoV-2 with their cellular ACE2 receptor present in COVID-19 convalescent plasma are a promising therapeutic tool to prevent severe COVID-19 disease. Interestingly, whereas a large scale production of such neutralizing anti CoV-2 human antibodies may be challenging, animals engineered for producing low immunogenicity polyclonal IgGs (as done by alteration of genes coding for the synthesis of aGal or Neu5Gc xeno antigens in pigs, or by introduction of genes encoding human IgG in the bovine genome) can be utilized to prepare large amounts of neutralizing polyclonal antibodies for passive therapy of the disease. Moreover, we have recently shown that disparate evolution constraints have resulted in a lack of physical and functional interaction between pig IgGs and human cellular Fc-Receptors (1). This absence of pig IgG binding to human Fc-R should prevent the risk of CD-16 stimulation of patient lung macrophages by pig anti-CoV IgGs at a critical stage of the disease which, in the context of a passive humoral therapy, would represent a serious safety hazard. Another example of “xenotransplantation science” derived research is a monoclonal inhibiting the C5a component resulting from the human complement activation cascade which may also decrease the uncontrolled inflammation of the innate immune response in COVID-19 disease. Thus, facing the devastating consequences of the COVID-19 pandemic on human health, economy, social disparities, research institutions and in fact almost all components of our societies, “xenotransplantation science” may modestly offer opportunities to prevent or combat the severe forms of the disease using targeted strategies. Furthermore the pandemic may also contribute to curve the future of xenotransplantation toward more “soft” clinical applications.


Prof. Bruno Reichart

As example of this more modern crisis, Prof. Reichart has provided us with guidance on how to design, validate and implement the experimental protocols that are now followed in his lab due to the COVID-19 pandemic that has temporarily curtailed the work of many of us. These guidelines, which received approval from the local authorities, demonstrate that addressing the problems appropriately, and satisfactorily, is essential to provide a safe environment and limit downtime.

Despite the slow pace and the starts and stops, it appears that clinical trials may finally be on the horizon, demonstrating that the many challenges that we face can be overcome with perseverance, even today.

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Preclinical cardiac orthotopic xenotransplantation experiments during the COVID19-pandemic: hygienic measures

  • Preprocedural testing
  • The entire staff is tested twice for SARS-CoV2 RNA in the nasopharynx: The first tests are done two days before initiating the immunosuppressive pretreatment (day -7). Should any person proves positive, the whole experiment will be halted. The second tests are done two days before cardiac xenotransplantation. Should at this time somebody proves positive for SARS-CoV2, this person will be excluded.

  • Teams
  • Excluding the day of transplantation, we have strictly divided our staff in two fully functional teams. Each team consists of one anesthesiologist, one veterinarian with two years of experience in baboon-studies and one additional scientific staff member with varying experience. The two teams rotate on a daily basis: While one attends to the animal’s postsurgical medical treatment and wellbeing, the other takes care of processing samples etc. Contacts between the teams are avoided. The whole team may switch shifts, but team members may not switch from one team to another.

    In case of an emergency, one team can be supported by an additional anesthesiologist or surgeon, provided the person wears full protective equipment (ffp2-masks, overall gear, gloves and eye protection).

    To exclude the infectious risk to other animals within the facility, animal care keepers are not allowed to the intensive care unit and the cages. The team members of the respective shifts take care of the cleaning also. The animal care keepers provide for supplies and prepare new cages outside the ICU.

  • Infection-protocol
  • In case of an assumed infection, both teams are tested for Sars-CoV2. The entire team working with the infected person will be quarantined until testing results are obtained (usually within 24 hours); meanwhile, the other team tends for the animal. Both teams are tested again after five days.

    Elisabeth Neumann, Julia Radan, Maren Mokelke, Ines Buttgereit, Rongrui Na, Paolo Brenner, Jan-Michael Abicht, Matthias Längin, Bruno Reichart.


We wish to thank our invitees who sent their contributions, living proof that dark days teach new lessons, and that a little sense of humor may be the key to look at the future with optimism.

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Address

International Xenotransplantation Association
C/O The Transplantation Society
International Headquarters
505 Boulevard René-Lévesque Ouest
Suite 1401
Montréal, QC, H2Z 1Y7
Canada