Alejandro Rossano
Director General
Grupo Médico Rossano
/
Expert Contributor

Humanized Organs: The New Hope in Transplants

By Alejandro Rossano | Mon, 11/29/2021 - 10:43

"Doctor, when would it be possible for me to get a compatible organ donor?" At my medical office, this is the obligatory and most frequent question from patients with kidney failure and cirrhosis, diseases that are currently among the leading causes of death in Mexico. "I may never get a transplant" is one of the answers they give themselves. Just in Mexico and the US, over 17,000 and 90,000 people, respectively, are waiting for a kidney transplant.

A bright light of hope shines with the recent news of an experimental procedure in which a "humanized" pig kidney transplanted  into  a  patient  (potential  organ  donor) in  New  York  City functioned correctly for up to 54 hours without immediate immune rejection.

Tissue engineering, genetic reorientation of nonhuman donors for transplantation purposes, xenotransplantation and regenerative medicine are steadily setting milestones in the field of replacing organs damaged by various diseases. It is estimated that 10 percent of the world population is affected to some degree by kidney failure, where diabetes mellitus is the No. 1 cause.

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Figure 1: Personal archive photograph. Human Kidney prepared for transplantation.

Attempts to adapt organs from different animal species to humans are not new and we can recall several precedents of high impact on society, such as “Dolly,” the cloned sheep, in 1997. On the other hand, genetic mapping and its codification determined a whole new era of knowledge of the human genome with the subsequent beneficial effect of putting at our disposal personalized medicine based on specific risks according to the genetic conformation of each individual.

Less than a year after the US Food and Drug Administration (FDA) in December 2020 authorized the first intentional genomic alteration in a group of domestic pigs for both feeding potential and for therapeutic purposes, medicine witnessed the worldwide impact from the “humanized” pig kidney news that opened a plausible road toward transplants between porcine species and humans.

Xenotransplants, from the Greek xenos meaning foreign, are transplants of organs among different species, for instance between pigs and humans. To avoid a negative response from the recipient's immune system, various genetic modifications can be performed on the cells of the donor animal. For example, a gene that adds sugars to proteins in pig cell membranes can be inactivated. Humans do not possess this gene, which is why human cell membranes do not possess those sugars. By removing such genes from the cells of the donor pig, the human body will believe that the newly inserted cells are human.

The pig can also undergo additional genetic modifications for them to express human genes that codify proteins with immunomodulatory capacity and which are capable of preventing rejection. The search for alternatives to increase the number of organs for transplantation includes new strategies that involve decellularization and recellularization of organs.

Decellularization involves the elimination of all the cells of an organ, preserving its structure and later repopulating it with cells derived from the patient who is getting the transplant, thus building a new “personalized” organ. The immune system of each person has the  ability  to recognize alien molecules; therefore,  at  the time of a transplant, multiple molecules are categorized as "foreign" and are capable of inducing a response in the recipient.

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Figure 2: Personal archive photograph Bench surgery performed by a transplant surgeon.

Ideally, with decellularization and recellularization, the possibility of rejection would be eliminated as well as the need to administer immunosuppressive drugs, whose function is to reduce the ability of the immune system to recognize a new organ as foreign and reject it. Although animals are a potential source of high-quality living cells and organs readily available for transplantation, the practice has also created an ethical controversy over many years, whereof legislation has already been enacted. In 2004, the World Health Assembly adopted a resolution calling for “xenotransplantations to be done only if they are subject to national regulatory control and effective surveillance mechanisms supervised by the corresponding health authorities.”

Recent advances in xenotransplantation, particularly those based on the research on pigs, could make it possible to carry out more testing. Considerable efforts have been made to improve efficiency and minimize risks. However, more studies are required before the several benefits of xenotransplantation can be exploited.

 

Where are we now and where are we heading? This is what we ask ourselves most often. The figures are  surprising  by themselves: according to the Global Observatory on Donation and Transplantation, 100,097 kidney transplants were performed in 2019 around the world. A glance at the mapping of transplant surgery reveals that the distribution of this clinical practice is very uneven. In countries where economic resources suffice and technology is available, such surgeries are almost routine.

On the other hand, in those countries where neither economic resources nor technology  are  plentiful,  these  transplants  are  scarce.  In many other countries,  this advanced surgical procedures remains out of reach.

The truth is that 60 years have  passed since the first  successful kidney transplant and throughout these years  transplant  surgery, as  we have just seen, has evolved dramatically. There are several lines of investigation in the fascinating world of transplants, such as the Kidney Project, which is developing an engineered implantable artificial kidney.

We shall remain mindful and collaborate in the related legislative, economical, clinical and ethical matters, and take into consideration the high impact such topics will have on society. What are the next steps in basic and clinical transplant research? What other animal species will be helpful for organ and tissue transplantation? What other humanized organs are suitable for transplantation? These and other questions are ahead of passionate and motivated transplant physicians, transplant surgeons, health companies, pharmaceutical industries and universities.

 

References

  • Hillebrandt, K.H., Everwien, H., Haep, N., Keshi, E., Pratschke, J. and Sauer,
  • I.M. (2019), Strategies based on organ decellularization and recellularization. Transpl Int, 32: 571-585. https://doi.org/10.1111/tri.13462
  • Dolgin, E. First GM pigs for allergies. Could xenotransplants be next ?. Nat Biotechnol 39, 397-400 (2021). https://doi.org/10.1038/s41587-021-00885-9
  • Sykes, M., & Sachs, D. H. (2019). Transplanting organs from pigs to humans. Science immunology, 4 (41). https://doi.org/10.1126/sciimmunol.aau6298
  • Roberts, M. (2021, octubre 21). rS surgeons test pig kidney transplant in a human.
  • BBC. https://www.bbc.com/news/health-58993696
  • Carla K. Jonhson AP Medical Writer. (2021, octubre 20). Pig-to-human transplants come a step closer with new test. ABC News. https://abcnews.go.com/Health/wireStory/pig-human-transplants-step-closer-test- 80675644
Photo by:   Alejandro Rossano