The news of a man getting a pig’s heart took the cardiology world by surprise. We had been hearing about xenotransplant (transplantation between different species) for a while now, but it was relegated to snide talk, rather than anything realistically achievable. In the die-hard (no pun intended) xenotransplant world, however, scientists have achieved a slow but definite progression of the science that led to the unique surgery.
So, how did the seemingly impossible come to fruition?
The heart is essentially a pump and, like any pump, it needs a supply of fuel and electricity to function. It is self-sufficient—there is an intrinsic pacemaker to generate electricity and wiring that conducts the electricity to different areas of the heart. The fuel supply is through tubes called arteries, which supply the blood through which the heart generates energy to function. Any abnormalities of the electrical system, or of the fuel supply, causes the heart muscle to dysfunction—a condition commonly referred to as heart failure.
There are also diseases that affect the heart muscle directly, and any malfunction of the valves (doors that separate the chambers) can cause a pressure load, causing it to weaken and result in a similar condition. The end result is decreased pump function and a reduced output, which affects the rest of the body. Every intervention done on the heart is essentially to preserve the pump function.
In the initial stages of heart failure, medications to improve the pump function generally work well. Pacemakers to control electrical issues, and stents and bypass surgery to improve the blood flow to the heart, helps keep the pump going. Unfortunately, sometimes because of either delayed treatment or progression of the underlying condition, the pump function continues to deteriorate, causing a condition called end-stage heart failure. This is the space where technology has made a huge impact in the past five years. From devices that stimulate the nerve supply of the heart to make it a more efficient pump, to a partial mechanical heart—a pump that is called a left ventricular assisted device (LVAD)—to a total mechanical heart.
The mechanical takeover because of organ shortage has gone from a temporary approach (LVADs were used as a bridge to heart transplant) to what is known as destination therapy, or a permanent approach instead of heart transplant. The LVAD is a mechanical pump that is inserted into the chest and takes over the function of the left side of the heart, which is responsible for pumping blood to the rest of the body. The device is powered by a driveline that comes out of the body and can be connected to power. There is also a battery pack that lasts 17 hours, making patients ambulatory. These patients do not have a pulse or the usual blood pressure (we love to watch the reaction of medical students and new nurses come running out of the room), as these pumps provide a continuous flow, unlike the pulsatile heart. Ironically the continuous pumps have been found more durable than the pulsatile pumps.
The survival for patients with an LVAD is about 70 per cent two years out. The good part of the mechanical pumps is that they are inert and patients do not have to be immunosuppressed, the bad part is they tend to clot off and lifelong blood thinners are the tradeoff. The total mechanical heart has not been as promising, and is still a bridge or a temporary solution, for patients awaiting a complete heart transplantation.
Dr Christiaan Barnard and his team performed the first human-to-human transplant in Cape Town on December 3, 1967.
In what is arguably the biggest covered medical event in history, Dr Christiaan Barnard and his team performed the first human-to-human transplant in Cape Town on December 3, 1967. The patient survived for only 18 days, but the first step to the journey in transplantation was taken. With his rugged good looks, Barnard soon became an international celebrity and got a whole generation interested in cardiology. He built on the animal lab transplant research at Stanford University and was able to overcome the ethical issues about declaring patients brain dead. (There was a disagreement in the US about when a patient was truly dead. District attorneys in the US had threatened to arrest surgeons who harvested organs from “brain dead” patients.)
Today, cardiac transplantation is standard of care. There are 250 transplant centres in the US alone. There are two issues with transplantation. The first is procuring the heart from the donor and transplanting it before there is damage to the donor heart. The second is managing the rejecting response of the receiving body. The heart can be used for approximately four hours after it is explanted, cooled and placed in a solution, before irreversible injury sets in, and the immune response to the donor heart is suppressed by using immunosuppressive medicines. Since 2000, the median survival with heart transplant has been 12 years.
The limited donor heart availability has led researchers to pursue xenotransplantation, which would potentially give us an unlimited supply of organs. The problems with xenotransplant have been combating the immunity differences in different species, different blood groups and, of course, different infections. We have pretty much tried all possible animals, including apes, monkeys and baboons, but due to ethical concerns, availability, expense, slow breeding and infectious issues, we settled on the pig. Not just any pig, but a genetically modified pig. In 2016, researchers were able to delete all 62 copies of pig genes that code for porcine endogenous retrovirus by a process called CRISPR-based gene editing. There is only one company in the world, Revivicor, that breeds these pigs in a facility near Birmingham, Alabama. The pig heart used in this transplant had three genes that trigger attacks from the human immune system knocked out. They also added six human genes that help the body accept the organ by promoting normal blood clotting and preventing blood vessel damage. A final 10th modification prevents the size of the pig heart from growing.
These models have been tested by transplanting the pig’s heart into baboons- with survival two years out. Each baboon experiment costs approximately $5,00,000. Researchers are unclear on whether all these modifications are needed in pig to human transplants. In addition to the gene modifications, the patient is given a super strong immunosuppressant—an experimental antibody drug called KPL-404—which shuts down production of antibodies completely by binding to a receptor called CD40. The team from Maryland also used a novel nutrient solution to preserve the pig heart after it was harvested. The solution was developed by a Lund University surgeon, Stig Steen, and is composed of water, hormones such as adrenaline and cortisol and—get this—dissolved cocaine. The last ingredient as expected posed some legal issues to the team.
The US Food and Drug Administration granted humanitarian exemption for this one patient. The result of the surgery so far has been positive, though these are early days. While the unlimited supply of organs from animals seems to be an exciting concept (we are talking about other organs, too, such as kidney, liver and lungs), the ethical and regulatory steps still need to be in place. We may be opening a whole new can of worms with new infections that could mutate and transmit to the general population and a whole new set of cancers, not to mention the creation of a new genetically modified species to suit our needs.
We really don’t know what the future of xenotransplant is, but it does offer a ray of hope to the terminally ill. The advancement of science to the extent of altering another species is always fraught with risk, as we have come to painfully realise with the gain of function virology research. While these two areas are completely different, the fact remains that we are messing around with the natural order of things—something that, at the very least, needs a robust public debate.
While there has been a significant evolution on the mechanical aspect of heart failure treatment, the machines do not mimic the action of the heart, not to mention the mobility aspect for a patient. Apart from the immunosuppression, heart transplant patients live a normal life. There are a limited number of donors and healthy hearts available for transplantation. I have been called in the middle of the night to do an angiogram on a brain-dead patient, when there is a question of donor heart viability. There is a section on our license that qualifies us for donors in the event of a heart transplant.
Despite this, there is a huge shortage of donors, given the number of patients with end-stage heart disease. If (and it is a big if) we can use hearts from pigs, the supply of hearts could be potentially unlimited. Patients who are otherwise deemed borderline can be considered for heart transplantation and a second shot at life.
The human heart, apart from being a pump, is also responsible for secreting hormones that help regulate the functioning of the circulation. Whether a pig heart, albeit genetically modified, will be able to perform these functions in a human milieu is uncertain. The fact that the FDA green-lighted the first transplant is a sign that there has been extensive discussion about an upcoming clinical trial. These decisions do not happen overnight in a vacuum.
In an ideal world, we will be able to overcome the infectious and immunological barriers of xenotransplantation and there will be an endless supply of organs-hearts, kidneys and possibly lungs. But we don’t live in an ideal world, do we?