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From bioprinting to growing organs in non-human animals, doctors and scientists are looking at different ways to make organ transplants a less challenging procedure.

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Let’s all take a second to appreciate how amazing organ transplants are. Because of centuries of knowledge, doctors can reuse organs between different bodies.

This can save people’s lives, and hopefully give them more time to do all kinds of things — like pet dogs, and eat burritos, and watch SciShow! But as amazing as transplantation is, it’s a complicated medical procedure and there are still some big challenges. And scientists aren’t just troubleshooting how to put an organ from Person A into the body of Person B.

They’re looking at different ways to grow organs basically from scratch, or even to use non-human animals in medicine! Organ transplantation is usually a last resort. Doctors will typically recommend treatments like medications, lifestyle changes, or therapies first.

That’s partly due to the technical challenges of transplants, like finding an organ match in a short amount of time. Matching is different for each organ, but it usually involves finding someone with a compatible blood type, similar body size, or similar markers on their cells called human leukocyte antigens. Plus, there’s the shortage of organ donors.

These are people who choose to give up spare organs, like a kidney or a chunk of liver, when they’re alive — or other organs if they pass away. The decision behind who gets each donated organ varies from case to case. But even after you’ve found a potential match, the transplant itself is really time-sensitive.

Once an organ isn’t hooked up to a blood supply anymore, the tissue dies pretty quickly. Since it isn’t being supplied with oxygen, the cells can’t carry out their regular functions and switch over to anaerobic processes that don’t use oxygen. This messes things up inside the cells, resulting in an overload of metabolic byproducts, acidity, and eventually cell death.

When they’re kept cold, organ death takes anywhere from 4-6 hours for a heart or lung, all the way up to a day and a half for kidneys. But even if this stunt works, and surgeons send their patient home with a new organ, that person still has a lifetime of treatments ahead of them. After all, that transplanted organ is big clump of foreign stuff.

So even with the best tissue and blood type matching, doctors still need to consider rejection. That’s when the recipient’s immune system attacks the new organ like it’s a microbe that would make them sick. Surgeons have been dealing with rejection of otherwise life-saving organs since the earliest days of organ transplants.

But a problem they keep running into is delayed failure, even if there’s initial acceptance. When bodies do the same thing with transplanted organs, it’s often because of antibody-mediated rejection, or AMR. There are a few different possibilities for why this happens, and they’re specific to each kind of organ.

The point is, AMR is still a serious issue that’s not well understood even now. To try and prevent this kind of rejection, doctors prescribe patients a combination of immunosuppressants, a category of drugs that dampen the strength of your immune system. This treatment will usually feature a drug that blocks the effects of calcineurin, a protein that that helps activate the T-cells in your immune system.

Plus, there are typically a few other drugs, including a corticosteroid to control inflammation. The idea behind immunosuppressants is that if your body is going to see a new kidney as a threat, it’s better to downgrade your immune system than to reject the organ. Unfortunately, this also makes it easier for the organ recipient to get sick.

Germs that would be an inconvenience to people with normal immune systems can be lethal for patients on immunosuppressants. And taking these heavy-hitting drugs is a big lifestyle change that requires patients to really stick to their medication regimens. Even one day of forgetting to take your meds on time can increase the chance of

rejecting that new organ.

And nobody’s perfect. Various estimates report that over 20% of late kidney transplant failures are because of problems with taking immunosuppressants. So that continues to be a challenge.

Plus, it’s deceptively difficult to transplant some organs like intestines, since they react with such a strong immune response. And fine-tuning the dosage of immunosuppressants is tricky. Now, all this comes into play when you use fully grown organs from other humans.

So if a healthcare team could somehow get organs that weren’t so incompatible with patients’ immune systems, they’d be able to help more people. And that’s where tissue engineering comes in, the process of making organs in the lab. For this, scientists got some inspiration from developmental biology.

Because when you’re an embryo, you have to make organs out of basically nothing. To start, you just have a handful of cells with instructions for what to build in the form of DNA. Based on those instructions, they divide and specialize into different cells that make up everything from your colored irises to the correct number of kidneys.

That process is called differentiation. And the cells that have the potential to develop into other cell types are called stem cells. Scientists are experimenting with a few different varieties these days.

For instance, you might have heard of embryonic stem cells, which are the ones in a developing embryo. They’re pluripotent, meaning they can differentiate into pretty much any kind of cell, which is really useful for tissue engineering. But experiments that involve creating embryonic stem cells have raised some ethical debates, as you might imagine.

So scientists have found a way to modify stem cells found in adults, like the ones found in blood, bone marrow, or other sources. They genetically reprogram these cells to mimic embryonic stem cells. And these engineered creations are called induced pluripotent stem cells, or iPSCs.

The hope is that we’ll be able to mold iPSCs into new organs, which means surgeons wouldn’t necessarily have to wait for a donor and rejection could be minimized. But you can’t just grow a bunch of nephron cells in a dish, hope they become a kidney, and stick that blob into someone’s body. Organs are complicated and have carefully organized tissues — and a few different cell types each!

So engineering them means creating the correct molecular environment and a structure so everything grows in the right place. Scientists induce differentiation in iPSCs by mimicking the chemical conditions in human bodies and during development. For instance, if they expose those cells to the right series of growth factors, they can grow into cardiac cells or liver cells.

Now, the differentiated cells still need something to grab onto in order to become organ-shaped. To provide that structure, scientists use scaffolds. Unfortunately, you can’t just pick up a liver scaffold at your local hardware store.

So in many cases, scientists make scaffolds from the organs from deceased donors. They decellularize these organs by flushing them out with a powerful detergent. The same system that delivered blood to the organ is used to kill off its living cells.

All that remains after this process is the extracellular matrix, a meshwork of fibrous proteins and other molecules that the cells can build around. This kind of decellularization and reseeding technology has been tested in simpler organs that act as containers or transport tubes, like tracheas. There have even been some successful trachea transplants that helped patients, although others have had more serious complications.

But this procedure is still being tested with many different organs in research labs. With many organs, though, plugging the right kind of cell into the right spot on a scaffold is tricky. So researchers are also looking into 3D printing organs, also known as bioprinting, which shows some promise.

Instead of filling up a printer with black ink or a thermoplastic filament, they load one up with the different molecular components you need to make an organ. There are lots of different techniques that scientists are developing. But in general, they suspend cells and pieces of the extracellular matrix in liquids or gels, to make the printing more manageable.

The goal is to build scaffolds and then deposit cells to try and grow whole organs. And we’re still in the early stages of successful experiments. But any organ will fail if it doesn’t get hooked up to a blood supply.

So researchers are also working on ways to create tiny blood vessels that can get to all the nooks and crannies of a large organ. In 2017, for example, a team from the University of California San Diego used a new technique to 3D-print microvasculature in tissue chunks. And when that tissue was implanted in the backs of mice, the blood vessels successfully integrated.

So if we’re starting to be able to print scaffolds for organs and blood vessels, the research is moving in a promising direction. Now, there’s another, stranger-sounding line of research to try and catch up with the demand for transplants: by growing a whole organ in an non-human animal and giving it to a human recipient. This idea of xenotransplantation, or transplanting organs between different species, isn’t a new concept.

For instance, someone’s tricuspid valve in their heart may allow too much backflow of blood. So doctors can take a heart valve from a pig, wash it with cleaning solutions, and implant it into a recipient who can get a few years out of it. In that case, the chemicals remove enough cells and chemical markers so that the new host’s immune system doesn’t attack it too strongly.

Xenotransplants of small bits, like heart valves, have already happened for decades. And they’re just the beginning. These days, researchers are looking into using whole organs from pigs in transplantation.

Some pig organs, especially their kidneys, are already about the right size for human recipients. But understandably, there are a lot of hurdles. Like, besides immunological rejection, we also have to worry about straight-up infection.

All pigs have DNA from a virus in their genome called porcine endogenous retrovirus. This means their cells churn out viruses that can infect human cells… which is obviously a problem, because we don’t want new organs to make patients more sick. So researchers have been trying to use gene editing techniques like CRISPR to inactivate the DNA that codes for this retrovirus.

That would hopefully make xenotransplants safer — although they’re still a long way down the road. Because even if we could inactivate the virus, these organs would still be a ways from a perfect match. So scientists are also looking into combining cells from two organisms into what are called chimeras.

The organisms could be two genetically distinct members of the same species, or different. But before you get too worried, we’re not talking about Frankenstein’s monster-style half human, half pig hybrids. In 2010, researchers tried to create mouse-rat chimeras to fix a defective organ with a kind of genetic band-aid.

Basically, if the genes from one organism weren’t coding for something essential, they wanted to see whether the second organism’s genes would cover for it. In one experiment, they took some mouse embryos that lacked a functional gene called Pdx1, which is required for pancreas development. Then, they injected each embryo with induced pluripotent stem cells from rats.

The mice with the broken gene wouldn’t normally develop a healthy pancreas, but in this experiment, they did! The pancreas was derived from the injected rat stem cells, and even worked to produce insulin. Fast forward to 2017, and a team of researchers has successfully made human-pig chimeras — but not nearly to the same degree as those mouse-rat chimeras.

They tried injecting pig embryos with human induced pluripotent stem cells, which proved to be difficult for a couple reasons. For one, human DNA and pig DNA are less similar than the DNA of rats and mice. Plus, both organisms have different developmental schedules.

Human embryos develop in 9 months while pigs take closer to 4 months, so these stem cells develop naturally at different rates. When the researchers did get the timing sort of figured out, they implanted the chimeric pig embryos into live pigs and let them develop for three to four weeks before euthanizing them for analysis. In the end, the human-pig chimeras had some human cells in developing muscle cells and precursors for other organs.

But not very many of them grew to a typical size, and most of the cells were still pig. So, needless to say, we’re still a long ways off from growing whole tissues or functional organs and successful xenotransplants. Even though we’re making progress in a lot of different directions, the demand for transplantable organs is still rising as our lifespans increase.

And while successes in the lab are cool, all these technologies need to be safe and scalable to actually start chipping away at the waiting list. Hopefully, though, we’re on our way to saving more lives. Thanks for watching this episode of SciShow and learning about the cutting-edge developments of medicine with us.

And thanks especially to our patrons on Patreon, because we wouldn’t be able to make these videos without their support. If you’re excited about science education and want to join our community, you can go to [ ♪ OUTRO ].