There is a worldwide shortage of human organs for transplantation
however, with sufficient advances in technology and our improved understanding of genetics
it might be possible to end this shortage with organ transplantations from other species.
Xenotransplantation is the transfer of living cells, tissues and/or organs between species
In January of 2022, surgeon Bartley Griffith performed an experimental xenotransplantation procedure on Patient David Bennett
He said to me two very important things He said I don't wanna die and he said if I do
Maybe you will learn something to help others
Bennett is a fifty seven year old man with end stage heart faliure.
He was on a cardiopulmonary bypass for a while, and was too sick to be put on the transplant waiting list
Given that he otherwise faced certain death, the researchers got permission from the FDA to give Bennett a pig heart.
Your first reaction is probably “Why did they choose a pig heart? Why not a chimpanzee?”
“Since we are much more genetically related to chimpanzees wouldn’t that be a better fit?”
Well it turns out that no, it would not be a fit. Quite literally in fact
you see in 1964 James Hardy, the man who carried out the first human lung transplant, thought the same thing.
He too had a patient who would not be eligible for a human heart transplant due to his condition
and obtained approval to transplant a chimpanzee heart into this patient
After the surgery the heart failed in only a few hours.
The chimpanzee heart was simply not large enough to support the circulation of the much larger human body.
Well what about another non human primate species?
side from running into the same problem of size,
there are other considerations if we were to scale our xenotransplantation operation up to a national or even global scale
If we were to compare non human primates and pigs
we would look at which specie is more suitable for experiments.
First, chimpanzees and many other non human primate s are currently Endangered and are facing the threat of extinction.
Pigs are easier to breed when compared to apes. Pig pregnancies are shorter, they have more offspring
And the offspring reach adulthood much faster
As for the organs, pig organs are of adequate size for human transplantation
and we already have a lot of experience with genetic engineering pig cells.
This makes pigs much more reliable when it comes to xenotransplantations and research.
All that is not to say there are no differences between our genome and pigs genomes
The differences between our immunological makeup is the biggest challenge we face currently
The pigs used for David Bennet's surgery are not regular pigs
in fact, they are pigs with 10 gene edits
Using CRISPR, Scientists edited a total of 10 genes
4 of which were eliminated from the pig's genome, while 6 human genes were added to the pig's genome
To understand this subject better, lets look into which genes were knocked out and which genes were knocked in, to make this surgery feasible
Obvious genes for scientists to start with are the genes that may cause Hyperacute organ rejection, starting with GGTA1
This gene produces the major xenoantigen involved in HAR is galactose-α1,3-galactose (α-Gal)
This enzyme is found in most mammals, including pigs, but not in humans and other primates.
Thus if the human immune system recognizes these glycoproteins on the surface of any cells, the immune system starts hyperacture rejection and attacks the cells
Along with this gene, two other carbohydrate antigens were eliminated by knockout of the CMAH and Beta-4-Gal genes of the pig.
The fourth and last gene that knocked out, is the growth hormone receptor gene
any of the pigs who are genetically modified for xenotransplantation have rapid and organ growth.
This highlights the growth potential of the organs, even post xenotransplantation, which may impair the function of the organs long term.
Since growth hormone is the major stimulator for organ growth, scientists deleted its receptor to reduce the size of pigs organs.
This allows researchers to obtain perfectly sized organs for xenotransplantation.
Now let's take a look at the genes that were added to the pig's genome
Scientists mainly focused on adding genes that can help prevent both hyperacute, and long term rejection types.
The first two knock-in genes are human CD55 and human CD46. These genes mainly serve to complement inhibitor genes
Simply explained, they trick the recipient (human) immune system into thinking the organ is a human organ with all the necessary surface signals.
This prevents blood clots in the arteries by eliminating the possibility of antibody binding and natural killer cells adhesion.
The second two knock in genes are human thrombomodulin (TBM), and human endothelial C receptor (EPCR).
These genes have shown benefits in preventing thrombotic microangiopathy, which are microscopic blood clots.
While the pig DNA does contain TBM, it does not bind well enough to human thrombin, making this addition necessary for successful xenotransplantations.
The final two knock-in genes are human heme oxygenase-1 (HO1) and human CD47.
These are immunomodulatory genes that serve to reduce inflammation in the xenograft and reduce phagocytosis by human macrophages.
CD47 is able to suppress the activation of T cells and macrophages that may attack the organ cells, while HO1 has strong anti-apoptotic and anti-inflammatory effects.
After all the gene edits, there was one more issue that must be addressed,
which is the fear of transferring, possibly fatal, porcine endogenous retroviruses from pigs to humans.
through herd husbandry, the porcine endogenous retrovirus C (PERV-C) has been bred out of the pigs, helping to prevent the chance of PERV transmission to human organ recipients.
Further, the animals are grown in pathogen free facilities do not pose risk to humans
and the pigs are also ested every three months to ensure that they are PERVC free
Thus. The pigs used for David Bennet’s surgery were deemed to be safe from retroviruses
Given all the gene edits, and the procedures that went into producing this pig heart and the xenotransplantation
Doctors are comfortable that they are ahead of any possible rejections as of now
Over all, all these edits have produced crispr pigs, that are retrovirus free.
As seen in david bennets surgery, these pigs can provide organs crucial for patients survival
The current success of xenotransplantation can provide hope for individuals in need of organs transplants
Today, approximately 17 people die each day while waiting for an organ transplant.
That’s 6,205 people each year,
and many more die because they're ineligible to be placed on the list itself.
However, with the possibility of harvesting organs from animals, and not being constrained with waiting for human organs, we can eliminate this number.