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Organ transplantation is one of the coolest things to happen in medicine, and is incredibly important for patients. The idea of taking a faulty body part out and replacing it with a healthy version has been around for centuries. of course, you can’t just chop and sew organs without some understanding of science.

So the road to the first successful transplant was full of challenges, discoveries, and a whole lot of work — especially related to tricking the recipient’s immune system. As early as the 2nd century CE, you can find stories of leg, nose, and even heart transplants across the globe. From what we know of the technology and medical understanding of the time, the patients probably didn’t have great outcomes.

But that’s just a guess. Historians don’t have much concrete evidence because these early attempts weren’t well-documented. That changed in the late 16th century, though, with the Italian surgeon Gaspare Tagliacozzi.

He performed skin grafts, taking skin from one area of the body and transplanting it onto another. And he got especially good at reconstructing noses. There were a lot more sword fighting accidents back then….

I’ll leave it at that. As he developed surgical skills, he made sure to document everything. In 1597, he published an illustrated book with a title that roughly translates to “On the Surgery of Mutilation by Grafting.” Besides showcasing his techniques, these records may have been some of the first to hint at the science behind skin graft rejection — when the recipient’s immune system attacks the newly transplanted tissue.

In particular, Tagliacozzi noticed that tissue from the patient’s own body was generally rejected less than allografts, or tissue from other people’s bodies. He attributed this to “the force and power of individuality,” which we now understand as individual immune systems. For the next few centuries, not much happened in the field of transplantation.

But then, two technologies set the stage for bigger breakthroughs. The first was anesthesia — anything that interacts with the brain and blocks the sensation of pain. Some anesthetics had been used for dubious recreation for centuries.

But the first ones that were widely used in medicine hit the scene in the early 1800s. Early anesthetics were chemicals that patients inhaled. Like nitrous oxide, which you may know as laughing gas, or diethyl ether.

These chemicals gave surgeons more chances to practice. Because, I can imagine more patients will choose surgery when it didn’t feel like someone’s cutting you open with a knife. The other big innovation was antiseptic surgery, which was formally documented by the British surgeon Joseph Lister in 1867.

Around that time, microbiology was gaining more traction. Lister credited Louis Pasteur’s work with microbes as his inspiration in attacking germs. Early antiseptic surgery involved hand-washing and sterilizing wound dressings, instruments, and operating rooms with the microbe-killing carbolic acid.

These techniques let surgeons operate with a smaller risk of infection, which led to less people dying. With clean, painless surgery available, doctors started attempting more simple transplants. Their main goals were to make healing times faster and increase long-term survival.

For instance, skin grafts had been performed for a long time and became a more popular treatment in the mid-1800s. They could be used to cover up amputations or burns, prevent infection in larger injuries, or even repair sagging eyelids. But it’s not just cutting and pasting.

Skin is responsible for a lot of things, from temperature regulation to preventing infection. So surgeons had to consider factors like blood supply, nerves, and sweat glands. They ended up experimenting with skin from different body parts of patients, but also skin from dead bodies.

Around this time, doctors also became interested in transplanting other body parts like the cornea, the clear tissue that helps protect the front of the eye and focus light. The first few surgeries involved xenografts, or body parts taken from other species — especially pigs. The cornea doesn’t have a blood supply, so doctors could just lay the pig cornea on a human eye like a contact lens, suture it up, and let it heal.

Early transplants were far from perfect, though. A lot of people’s bodies were rejecting the foreign tissues, breaking down and absorbing them. But all these experiments were steps toward more complicated surgeries.

In the late 1800s, the Swiss physician Emil Theodor Kocher operated on hundreds of patients with goiters, which are swollen thyroid glands. His strategy was just to cut into the neck and completely remove the thyroid. But he noticed that afterward, patients developed a condition that we now call hypothyroidism.

The thyroid gland produces some of the hormones that run your metabolism. So when it’s removed, there are symptoms like sluggishness and trouble regulating your body temperature. To try and fix that, in 1883, Kocher transplanted thyroid tissue back into a patient.

Which may count as the first organ transplant! This led to more attempts to replace deficient hormone-producing glands with working ones, especially thyroid transplants. But, over time, these allografts eventually failed.

And as surgeons experimented with more organs, they ran into trickier problems. For instance, they learned that it was crucial to hook up a patient’s blood supply to keep newly transplanted organs alive with oxygen and nutrients. In the early 20th century, the French surgeon Alexis Carrel invented new techniques for anastomosis, or suturing two tubes together.

In this case, blood vessels. In fact, he got so good at it that he successfully transplanted many different organs — even hearts — between dogs! And they stayed alive… at least for a little while.

In all of his surgeries, he noticed that allografts and xenografts always failed given enough time. And, as you’ve probably gathered by now, that was an ongoing problem. As transplantation became more accepted in the medical community, rejection became the biggest challenge.

Scientists offered a bunch of explanations. Like, maybe rejection had to do with different nutrients or proteins in different bodies. And doctors tried a bunch of fixes, like soaking the donor organ in the recipient’s blood.

But as metal as that sounds, it didn’t do anything. Over the course of all these experiments, they did noticed something: animals that were battling some kind of infection during transplants usually had better results. They figured that the host’s immune system was too busy dealing with the illness to deal with the transplanted organ.

So researchers started weakening animal immune systems on purpose before transplantation. This technique is called immunosuppression. Initially, scientists tried radiation, certain drugs, or even removing the spleen — an organ that filters blood and makes white blood cells, which are key for immune responses.

Unfortunately, radiation was the only effective immunosuppression treatment. Doctors hoped it would make rejection less likely, but it was way too dangerous for clinical use. So progress stalled as scientists tried to nail down how the immune system worked.

By the early 1900s, a few researchers stumbled upon a discovery. They knew that if a patient got a from skin graft from a donor, it would usually be rejected after a few days. But if they took tissue from the same donor and grafted it to the same patient again, it was rejected much faster.

This pointed to some kind of adaptive immune response that they called the second set phenomenon. They didn’t really know what to do with this information yet, but it helped them understand how the human body recognizes foreign stuff with antibodies. Around this same time, a British biologist named Peter Medawar made some discoveries too.

Supposedly, while Medawar was at a cocktail party, a colleague asked him if you could tell different types of twin cows apart. And Medawar said that skin grafts between two fraternal twin cows would be rejected, but two identical twins wouldn’t. It was an important distinction.

Identical twins develop from one sperm and one egg cell, and may share a placenta. While fraternal twins are made from two separate sperm and egg cells, with separate placentas. Now, they ended up actually testing this experiment.

And what they found was surprising: most skin grafts between twins worked, even fraternal twins! Which isn’t what they expected. A few years earlier, research had shown that fraternal twin cows shared blood and other cells while developing in the uterus.

And as adults, their bodies made two types of red blood cells instead of just one. With that discovery on top of their own, Medawar and his colleagues realized that twin cows were probably making multiple types of immune cells too — which is why they weren’t rejecting skin grafts from their twins. Basically, the cows’ bodies didn’t recognize their twin’s cells as foreign, because of how their immune systems developed.

Then, these researchers attempted to cause the same phenomenon in mice. The team took spleen cells from a donor mouse, then injected those cells into mouse fetuses. If those babies grew up, skin grafts from the donor mouse weren’t rejected.

After all this time, they had proven that it was possible for a host to accept an allograft. Even though we couldn’t necessarily apply this technique to humans. Now, skin was one thing, but a fully functioning organ would be more difficult.

And a perfect storm of factors made one organ the ideal candidate to test in humans: the kidney. Back in the early 1900s, we didn’t have many effective treatments for end stage kidney disease, so taking a shot at transplantation seemed like the best option. In 1933, a doctor performed the first ever human-to-human kidney transplant.

But the kidney came from a 6-hour-old cadaver. And the transplant patient died less than 22 hours later. This probably because of a blood type mismatch and damage that had been done to the kidney from ischemia, a lack of blood supply.

Then in 1954, an American doctor named Joseph Murray had the opportunity to use a patient’s identical twin as a kidney donor. Similar to the cow and mouse studies, he was able to bypass the issue of rejection because their immune systems were a pretty straightforward match. This 1954 event is usually credited as the first successful organ transplant in humans.

And the recipient went on to live for another 8 years, which is significant! Really, though, this surgery mostly reinforced what scientists knew. Researchers continued to study histological compatibility, finding matches for organ donors and recipients based on aspects of their immune system.

And there were still plenty of kinks to work out to get to modern organ transplants. For instance, researchers developed immunosuppressant drugs to treat patients before surgery and as a method of anti-rejection in the long term. Healthcare teams also had to figure out how to get organs to patients.

They developed cold storage chains to try to preserve organs for as long as possible, because ischemia gets to work quickly. But figuring out where to get organs sparked many ethical dilemmas. Now, entire systems and committees are dedicated to figuring it all out.

Maybe someday, we could even make our own organs using stem cell technology. So we still have a lot more work to do when it comes to organ transplants. Now, while organ transplants are incredibly tricky, taking care of houseplants isn’t a piece of cake either!

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