Muhammad Mohiuddin is at the center of xenotransplantation research, which involves grafting animal organs into dying patients.
In 1984, American surgeon Leonard Lee Bailey transplanted a baboon heart into a baby dying from a congenital heart disease. Baby Fae, as the infant is famously known, lived for 20 days after the surgical procedure. The operation itself was successful despite the baby's body rejecting the primate heart.
In the intervening decades, the process of grafting an animal organ into a human body has become relatively more manageable in part due to advances in the field of xenotransplantation. The remaining challenge involves keeping that organ functioning for a long duration of time.
This barrier to successful xenotransplantations dogged scientists for years. That changed with a US experiment in 2014 in which a pig heart that was attached to a baboon’s abdomen survived for almost three years.
A baboon’s genetic makeup is similar to that of a human. The consensus thinking is that what works on the monkey, can work on the man.
The scientist behind that landmark experiment is Dr. Muhammad Mansoor Mohiuddin, a Pakistani-born doctor and the director of the Cardiac Xenotransplantation Programme at the University of Maryland School of Medicine. Dr. Mohiuddin has spent the past 30 years trying to figure out how to increase the chances of survival for terminal patients in need of a heart transplant.
He told TRT World in a recent interview,“Just in the United States, 150,000 people are waiting for different organ transplants. Unfortunately, many of them will die waiting because there’s no alternative available.”
“Our idea is to somehow find that alternative.”
A human body has its own inbuilt fighting mechanism - the immune system - which helps ward off bacteria and viruses.
Nature has designed our bodies to trigger antibodies when attacked by intruders such as pathogens or foreign tissue – regardless of whether it comes from another human or an animal.
The trick to making organ transplants work is to tame the immune response just enough so the human body recognises and accepts a donor organ as one of its own. However, if the immune system is suppressed a bit too much, the organ recipient becomes susceptible to infections.
With the introduction of gene-editing tools such as CRISPR, scientists can erase certain pig genes that a human body typically resists.
Gal, a sugar molecule found in porcine blood cells, is one such barrier that is no longer present in pigs that have been genetically engineered for research purposes.
During experiments, these genetic modifications have extended the duration of viability of pig organs in monkeys. Where once these organs only lasted a few minutes, they can now last for months. This constitutes a major scientific feat since the first such trial was conducted more than 50 years ago.
Still, organs from these genetically modified pigs cannot be grafted into another primate without a heavy dose of immunosuppressant drugs.
Mohiuddin and his colleagues found a way around this problem in their experiments on baboons.
“Most of the immunosuppressant drugs used in transplantation are not targeted towards a specific pathway,” he said. “They are generalizing suppression just like cancer drugs; you give a drug and it suppresses immune response throughout the body.”
Think of a pathway as a signal, which provokes antibodies to spring into action.
With a targeted drug regimen using a specific antibody, Mohiuddin’s team was able to prolong the survival of a pig’s heart in a baboon. This neutralizing antibody, which suppresses CD40, a molecule found on the surface of pig cells, did wonders.
“What this (anti-CD40) antibody does is it only suppresses a pathway that activates T-cells and B-cells. So by suppressing that we were able to suppress the rejection,” Mohiuddin said.
Oncologists describe T-cells and B-cells as the “special ops” of our bodies, which are deployed when other cells fail to subdue a pathogen. Eliminate T-cells and B-cells completely and the body won’t be able to fight off more severe diseases.
Mohiuddin’s drug blocks activation of these cells, plus it prevents B-cells from secreting antibodies that destroy the graft. But it does eliminate these vital cells from the body.
“Whereas if you used generalized immunosuppression, as used during human-to-human organ transplants, over a period of time the immunity of the recipient is gone and they are susceptible to many infections and other diseases.”
So close yet so far
For more than 100 years, scientists have tried to save human lives and limbs using animal organs and tissues with varying degrees of success.
During World War I, doctors gave sheep’s blood to injured soldiers. In the early 1920s, a Russian surgeon, Serge Voronoff, grafted pieces of baboon testicles in impotent men (among them an elderly, senile man who reportedly regained his vigour), and pig skin was applied to ulcers and burns in the 1960s.
The first truly scientific attempt at xenotransplantation was made in 1963 when American surgeon Keith Reemtsma carried out 13 kidney transplants using chimpanzees as donors. The longest a human patient lived with such a donor pair of kidneys was 9 months.
The 1960s was remarkable because in that decade the first successful human-to-human transplants of liver, lung and pancreas took place. Success could only be measured in days as most recipients died due to lack of immunosuppressant drugs.
But those procedures underscored a shortage of human donor organs, which mostly came from corpses.
James D. Hardy, an American surgeon, who performed the first successful human-to-human lung transplant, was prompted by shortage of donor organs to use those of animals.
He tried to implant a chimpanzee's heart into a man, but the heart stopped functioning immediately as it was not large enough to support human blood circulation.
In the subsequent years, more effective immunosuppressant drugs and gene editing tools, which have helped narrow the genetic difference between pig and human organs, have raised hopes.
Yet researchers still have a long way to go before they can successfully replace a human heart or kidney with an animal organ.
When people ask Mohiuddin how long it will take for xenotransplantation to become routine practice, he gives the onion as an example.
“Once you peel off one layer, you see another layer. So the learning process never stops.”
Modern techniques such as the CRISPR CAS9 gene editing tool have allowed scientists to alter the genes of pigs in order to harvest organs.
The pigs that Mohiuddin uses for his research have ten edited genes. Four of them are pig “knockouts,” which means 4 pig genes have been removed. The remaining six are “transhuman” - genes from humans that have been added to the pig's.
“We don’t want to change that pig into a human. We want to do minimal changes that would be enough for the heart not to go through rejection,” he said.
Mohiuddin said he does not need 10 gene modifications in a pig to perform a heart transplant. But the company that supplies him with genetically modified pigs wants to use the animal as a source for multiple organs, and hence needs more genetic modifications.
He said the idea is to transplant a pig heart into a human using mild immunosuppressant drugs including the anti-CD40 antibody.
“So the first goal is to keep this pig heart (viable) long enough that a human heart becomes available for transplant. But if a pig heart works fine then there’s no reason to take it out,” he said.
Mohiuddin moved to the US in the early 1990s after graduating from the Dow University of Health Sciences in Karachi. A practicing Muslim, he believes it’s okay to use pig organs if it helps save human life.
Some Islamic scholars say it is prohibited to use pig for organ transplants. However, almost all research in the field of xenotransplantation is now carried out using pigs. Researchers say pigs are a preferred choice because they grow fast and the size of their organs is similar to that of humans.
Most non-human primates are classified as endangered species. Animal rights activists have long protested against using chimpanzees and baboons for such experiments.
Another big concern is that using animal organs can unleash a deadly zoonotic disease such as coronavirus or HIV AIDS, the latter of which reportedly spread to humans from apes.
For his part, Mohiuddin is confident he can successfully transplant a pig heart into a human and make it work without being rejected for a significant period of time.
His team is in initial talks with the US Food and Drug Administration, a federal health regulator, to seek permission to perform the procedure on a human. It’s a long process as the FDA requires many scientific studies and strong evidence before giving the go-ahead for human experiments.
“I myself don’t want to do something that could harm humans,” Mohiuddin said.
“I want to be careful. I don't want to waste 30 years of my work by just putting the heart in and later finding out that it’s not working.”