Lab 056: The Right Match: Organ Transplants

I don't know if I told you about this show. It's called Raised by Wolves, but the second season of it just came out. It's Raised by Wolves too. Is it a movie, No, it's a series, okay, But it's basically living in three thy ninety nine. Okay, it's very different. And it really made me think, like, all the stuff that they're doing in that show, I'm like.

Could this really be possible? What are they doing?

They're using like droid robot things, but they look like people and they're able to do all these biological functions. And it reminded me of where we saw that pig heart transplant story a couple weeks ago.

Do you remember? Yes, I do remember.

And that kind of blew me away because I remember back in the day when they put the ear on the back of the rat and that.

Was really big. Yes, that was in all the textbooks.

Yes, But putting a pig heart into Homo sapien rte I was like, Man, we are really making leaps and bounds in our lifetime.

I thought Raised by Wolves was three thousand ninety nine, but maybe it's twenty ninety nine.

Maybe it's close with it, And I.

Thought, welcome to dop Labs, a weekly podcast that mixes hardcore science, pop culture, and a healthy does of friendship.

T T.

I know I mentioned that I saw a pig heart transplant and that it feels like we are living in the year three thousand, that sci fi is upon us.

But I feel like.

I'm really blown away, Like how do we get here with all these new transplants and all of this technology. That wasn't the only one I saw. That's only one I can remember right now. I think we got to get to the bottom of it.

Absolutely.

This week we're talking about organ transplants specifically. We really want to know more about the process of getting approved for a transplant and how transplants actually work. Let's get into the recitation, So let's start with what we know.

I feel like everything that I know about transplants is based off of what I've seen in movies in television.

I think that's fine, is it.

I think that's an okay starting point because then we can figure it out. Well now I feel empowered. I think one of the things that I think I know is that getting a transplant is not as easy as saying that I need this new organ. There is a process you have to see a number of doctors and then be put on a list.

I think considering that list.

Sometimes getting a transplant is easy, though some people get it from family members. But some people can't match with their family members. So I don't know a lot about the matching process. I know sometimes it's easy, or you know, if you have family members who match with you. But I got to save this for the next section because I don't know how you match.

One of the things that I know is that not all transplants are created equal, and so getting a heart transplant and getting a kidney transplant are two very different beasts.

The other thing I know is that there are a lot of rumors about transplants and the medical system. I think one of the most damaging things that has happened when it comes to organ transplants is the myth and rumor that went around that if you put that you were an organ donor on your driver's license, that the paramedics wouldn't try to save you.

Do you remember this?

Yes, I remember this, and I hate to say it frihim, but I was actually one of those people who believed it for a little while.

That's all right, you were not alone but it is just that it's a myth, you know. I'm looking at this page from penn Medicine, so the University of Pennsylvania, the Perlman School of Medicine, and they're saying that you would have to be in the hospital on a ventilator and then pronounce dead in order to donate your organs. So it's not even that your organs are harvested if you're in a car accident, you know what I mean.

I've never heard that one, but I can understand why people would think.

That because it's an additional process right.

Absolutely, And the medical care system it feels like a black box. Sometimes you go to the doctor or you have to rush to the hospital, and next thing you know, you have this huge bill and you don't know where these charges came from. You don't know how you're going to pay for it. So I can definitely understand where that confusion comes from.

So what do we want to know though?

What I want to know is how do they determine whether or not somebody is able to receive a transplant? Because I know, I mean, I don't know a lot about this stuff, but I see on TV that there are some folks who, you know, they get a transplant and their body rejects it or something like that. I know, what are the criteria that doctors are looking for to determine whether or not someone is able to get a transplant?

Yes?

And along those same lines, are those criteria the reason the waiting lists are so long? Why are there ninety thousand people waiting for a kidney but then a little over ten thousand four other organs? Is it related to the difficulty of replacing the organ, the surgery, the tools that are required, the costs. I'm just curious about, like why the lists are so long and were they always this long? Or is this like a backup from you know, delays in our medical system.

Right, that's a good question.

I think Another thing that we're both curious about is because we always are interested in it, and that is new technology. So what is the new technology and innovations in transplant sciences?

Yeah, I'm sure they're not doing it the way they always used to. Now they can't be.

Everything I know about how transplants work is pretty much based on John Q.

You remember that movie.

Yes, that's all I know, and I know I don't know if it was accurate, but that's what I feel like.

I know Denzel was young in that movie. So young, Denzil. I'm expecting some changes.

That age is a let's jump into the dissection.

Yep, but its absolute. Our guest for today's lab is doctor Dave low Hi.

My name is Dave low and I work for Thermo Fisher Scientific and I am head of research and development in our transplant diagnostics business.

Thermo Fisher is a supplier of laboratory equipment and supplies. Me and Zekiah know them very well from all of our years in the lab. Their transplant diagnostics business focuses on developing and producing products with applications in both the clinical and the research side of organ transplants.

Doctor Lowe's specialty is in histo compatibility, which is a word that isn't typically used, so we asked to to explain what it means.

It's a hell of a mouthful, isn't it.

If you've ever watched a medical drama on TV and somebody needs a transplant and they run around and they say, Okay, we've got a match. Then that's kind of the histo compatibility bit right there.

Histo Compatibility means tissue matching, that the tissues of different individuals will be compatible. And by compatible, we mean that fusing tissues from two different people, so your donor and your recipient won't trigger a reaction from the immune system.

I think it's important for people to remember when we talk about tissues. Tissues are just superstructures of cells. We can think about individual cells, but tissues are just a conglomerate of individual cells, and so at a cell to cell level, if those cells are not going to be compatible, then definitely those tissues aren't going to be compatible. And the thing that brings those tissues the nutrients that they need in the oxygen that they need to stay alive,

Doctor Lowe's laboratory essentially develops and provides the tools that labs use to figure out how risky a transplant would be for each patient and how easy it would be to get them a transplant.

So histel compatibility has multiple components, and one way that we already think about compatibility is in blood type, so ABO and then AB and O can be positive or negative. Blood type compatibility is certainly important for transplants, but there's a lot more to it with transplants. Compatibility or being a match is really framed in the context of the HLA system or human leukocyte antigens, and that's all about tissue matching.

When we have people told about getting a match or not being a match, we're really talking about these specific antigens and what they are are proteins that are present on pretty much all of our cells and tissues, but they're highly diverse. Some of them are very common, and some of them are incredibly rare. So if a patient is unfortunate enough to have an incredibly rare tissue type, it's going to be much more difficult to get that patient donor.

Another main factor in histo compatibility is antibodies, and we've talked a lot about antibodies before in various different contexts. Most recently we talked about it in Lab forty seven when we explore the immune system, and in that context we talked about antibodies really being these protectors to shield our bodies from invaders and foreign particles. That's generally a good thing, but in the context of transplantation and histo compatibility, antibodies can be a huge problem.

Oh no, everything I thought I knew out the window.

They're part of your immune system and they can trigger symptoms. We would generally categorize a sickness that's just your immune system responding, right, So if you have a lot of antibodies, they can recognize a lot of different things. That means they might recognize your donor tissue and give you a pretty bad reaction.

So they're like, I, I this was not here before. Yes, that is not us attack.

Yeah, you know what this reminds me of what in the matrix were like the mister Smith agents, like they're checking constantly for your signature.

Yes, yes, this is so good.

And so if you come back in like the same doors, like they're constantly looking for you, Like they were constantly looking for NEO in the matrix, that specific part of the matrix scared meat. That was terrifying, mister Smith, always in the same spots, just constantly looking for you.

It was like a horror film.

But that sounds exactly like what's happening in our immune system.

Like those antibodies are.

Just like right, But really it's great for your body if you have a FORID invader, a low level of virus, or a low level of bacteria, mister Smith, and mune system is constantly looking, constantly finding them, reading those green little characters scrolling down through your blood system. Okay, it's great to have antibodies looking for things on the surface of a bacterial cell or things on the surface of

And your antigens are defenseless essentially.

Yeah, they're just things that they don't recognize. They say, hey, this is not part of the code.

So the antigens, they can't even do the matrix thing that neo.

Yeah, they can't do the Sierra.

You know, Sierra was able to go back like that to do the neo and yeah, she's the only one.

Those antigens are not doing that. Bruh. I remember trying to do that in high school. I was close. Really, I was.

A different human being back then, not so different, just a different mobility.

That's one thing that we find is on our transplant waiting lists, the more antibodies you have, the harder it is for you to get a transplant, and usually that means you will wait longer.

So why would somebody have more antibodies than someone else. How do we even get the antibodies? We ask doctor Low how people who are on the waiting list for a transplant got so many antibodies that made them have to be on the waiting list for so long. Doctor Low says that there are three main ways.

And the first is if you have a previous transplant, and quite often our patients when they have these previous transplants, they will form antibodies against some of those la and then the antibodies persist basically almost for the rest of that patient's life. So if you're then faced with a patient who has antibodies to HALA, all it does is it further reduces the number of potential donors for that patient.

So if you have a previous transplant, remember that's cells that make up multiple different structures and that forms a tissue. That previous transplant will have antigens from the donor, and so your body, naturally, your immune system will make antibodies to that transplant. So now you have the antibodies that you already had that were part of your immune system, plus a new subset that have developed in response to

So is there a critical mass of antibodies where once it gets to that amount that your body automatically starts to react.

I think that's a very good question. TT It is, I think two things. So it is volume of antibody and type of antibody. So you could have a variety of different types of antibodies, but if some of them are lower in number, it's less likely that you will have a strong immune reaction. Okay, does that make sense.

Yeah, that makes sense. The next problem that some patients may run into that will cause them to have more antibodies, which makes it difficult for them to receive a transplant, is if they've had a blood transfusion.

A lot of transplant patients get transfused quite a lot, and if there are cells in the transfused units that express HLA that is different, then there's a possibility in that way they can form antibodies as well.

So a transfusion is having blood from a donor and putting it into a recipient. You know, and when we think about blood, you may just think, oh, red liquid, but it's not. It has cells in it, and those cells have antigens on their surface. So if I am a recipient and I initially didn't have antibodies that would react to those antigens that are on the surface of those cells. In my transfusion, there are components of my immune system that will recognize those antigens and begin to

Another way that folks can acquire antibodies that might keep them from being able to receive an organ transplant is a really tricky reason, and that is because your antibody profile can expand through giving birth.

That sounds really wild, right, yes, but basically you have to think of when a baby is.

Born magical times.

Yeah, if a baby is born, the baby is not your clone, so it's gonna have half the genetic information from the other parent. And if that genetic signature causes the baby to express antigens that the birthing parent doesn't already have. As soon as that parents given birth, their skin, their womb, all of that is in contact with new antigens. We talk about that, right, And so then that immune system is like, hey, here's some foreign particles I've never seen.

This wasn't with me.

Before, and so at that moment, the birthing parents immune system makes antibodies to those antigens that are on the baby that came from the father that don't match with the birth and parents antigens that they already had. Now let's go back to early genetics. We know that when a parent birth's a child, it is not a clone. The other thing we know is that siblings are not clones. So every time there's a new birth, there's a new possibility of the birthing parent generating antibodies in response.

To the baby.

So let's say you are a parent of three, you've birthed three children. You are going up for a kidney transplant and they may say, have you ever had a blood transfusion? No, have you ever had a previous transplant? No, have you ever had kids? And it's like, whoa, And you know your antibody profile could be off the charts because I've been exposed.

That's so tough. Wow, it was really tricky, you know.

So if you think about that, that feels like that can really increase your antibody profile. Now here's the good news. This only happens about thirty percent of the time. So only thirty percent of the time do we see this type of antibody response after birth.

But it's good to know. Yeah, it's good to know about that. Is this something that.

We should be testing ourselves for or getting tested.

For or is that like not until it's time to have a transplant.

Okay, So we've talked about three main ways someone can get antibodies that makes it harder for them to match with a donor, like previous transplants, blood transfusion, and giving birth. But doctor Low told us about an even more unusual case.

A patient many years ago who came for transplant and it was a male. He was a really big guy actually, and he'd never had a previous transplant, and he'd never had a transfusion either, so we were really confused because he had a ton of anti so we were trying to work out where he could have got these from.

I think these are things they don't tell you on Fight Club.

Tyler Durton didn't say this so after the tissue type has been identified correctly in the antibodies confirm, the last step in checking a patient for histo compatibility is a cross match.

You would get material from the donor, so you would get cells and tissue, and you would test for reactivity from your patient and if it's positive, then that usually means you don't go ahead. So I would often be performing these cross matches, and it usually turned out to be at three am, because often transplantation happens when you can when you have the donor. The cross match is absolutely crucial.

Okay, So it seems like initially we're just looking at small things like the antibodies. Now we're pulling clumps of sales so tissues and saying, all right, are y'all gonna play well together? On paper, you look good together, but are y'all gonna play well together? And that cross match is where things can really start to look up.

Right.

The question is, you know, are you two gonna play well together? And so I think a cross match physically putting those tissues together is so important because if somebody made a mistake at the early stages of the antibody panel, or if there's something that wasn't detected. If you were to move forward with that transplant and they are not a good match, instantly the body will reject it, like

Okay, let's take a quick break and when we get back, we'll get into another important part of organ transplants with doctor Low, and that's immunosuppression. We're back and we've been talking with doctor Dave Low all about organ transplants and how important the PROSS match is to make sure tissues will be compatible in an organ transplant.

And I think that really gets us to the importance of another component of transplants, and that's immunosuppression. When a transplanted organ is rejected by the body, it's because of.

A really strong immune response. And this is the worst case scenario.

So when you have that antibody response that sort of floats onto that organ, the downstream effects of that antibody there are many different ways that that could lead to tissue damage.

One of them is complement activation.

So those antibodies bind to that target if you like that that foreign kidney or heart, whatever it may.

Be, and they kind of group together and.

They start this insane immunological cascade. They recruit lots of other proteins, and it ultimately forms a complex called the membrane attack complex, which basically just pumps holes in the tissues.

And even though there's all of this testing that we talked about earlier for histocompatibility, most patients who end up receiving a transplant are not fully matched. They're compatible, but there is some degree of mismatching, which is usually okay.

So we need to dampen down any potential immune response to help to make sure that that kidney or heart doesn't reject. But the immune system usually finds a way, so quite often the iminosuppression that is administered is really there to prevent the patient's T cells. The T cells are the kind of conductor of the immune response, so a lot of the iminosuppression is tailored to targeting those cells, and that enables you to transplant safely. It is effective in preventing the organ being rejected.

And something I didn't realize is that once you receive a transplant, immunal suppression can be a lifelong commitment. Most patients continue on immunosuppressants for their whole lives.

The holy grail is to achieve what we would term tolerance. So if you can get to a point where you can remove yourself from all help, so all your imminosuppression is taken away and your immune system is tolerant of that graph, that's extremely difficult to achieve.

Once you receive a transplant. Immuno suppression is a lifelong commitment and there's a lot that comes along with that. You're taking a ton of medicine, and when you're taking that medicine, that means it can make you more susceptible because you're suppressing your immune system. It means it can make you more susceptible to colds, It can make you more susceptible to getting really sick from exposures that wouldn't disturb most people. So it changes your quality of life.

Yeah, it's not intentional, it's o.

Can you imagine missing one pill in your routine and then having these things that you also can't see. We know, just human behavior, we delay things we can't see. We don't put as much importance on things that we can't see, and so it may not feel like there's going to be a media action, but that immune system is quick.

And we see there's a lot of studies that have shown that actually sort of stopping taking the immuno suppression really a leading cause of transplant failure, especially in younger people. I think that's something to sort of consider, is that a lot of the imminosuppressive drugs out there, they're quite powerful, and they have a number of side effects that could be seen as quite undesirable, you know, like excess weight being gained and hair growth and things like that.

This whole process might seem like a lot and it is. It used to take weeks to determine histo compatibility, but doctor Lowe was telling us that their technology has improved and what used to take weeks can now be done in a matter of hours, and.

In those cases where it's a deceased donor, you've usually got much less time because as soon as the organ is retrieved from the donor and placed on ice, then the clock is ticking. We have this thing called cold ischemic time, which is used to describe the number of hours that the organ is placed on ice before we can implant into the recipient. So part of what we do is to make these tests as rapid as we possibly.

Both of those points, doctor Lomay, are really important. That timeframe for determining compatibility and the ability to leverage more deceased donors, those are both really important because the demand for organ transplants is still very high.

Right According to orgondonor dot gov, over one hundred thousand people are currently on the National Transplant Waiting List, and.

The bulk of these folks are waiting for kidney transplants. Currently, there are ninety thousand candidates on the kidney transplant list.

And the statistic that really got me is that every day in the US, seventeen people die waiting for an organ transplant.

And so when you consider all of this, you know, we talked earlier in the dissection about compatibility and how that can be one of the biggest obstacles to getting a transplant. But we both wanted to know if that was the major cause of the long waiting list that we're seeing, or if there's like some other issue that we've seen in other places, like you know, specific types of demand for different organs.

I think supplying demand is a good way to put it. You know, the number of people waiting on list, generally speaking, they outnumber the number of available organs. And then there are the reasons that we've talked about why some patients may wait longer than others. So the patients with a lot of antibodies, they're going to struggle to get a donor from the waiting list, so they're waiting for deceased donors.

So quite often it could be family members, a brother, a.

Sister, mother, father, child, the people on the transplant weight list, you know, maybe they don't have a potential live donor.

These challenges of supply not meeting the demand mean that scientists and doctors have to think a little more creatively about different ways to get patients transplanted successfully.

So when I talked before about a lot of patients on the list have a lot of antibodies and disproportionately high numbers of female patients that you have to get a little bit creative and how are you going to get patients like this to have a transplant? And there are things you can do that I think they're really quite clever.

One is pared donation.

So you know, you might have a patient and they might have a lot of antibodies and their wife or sister or brother is willing to donate, but because of the antibodies, they're not compatible. So what often happens is

In its simplest form, they.

Literally just swap donors and then everybody gets what they need and if the patient is willing to accept a risk, you can do some more high risk transplants where you have a donor and they've got antibodies against them, but you use that donor anyway, and what you can do is you can do what's called desensitization therapy. So we

But once again it's really important to note that for procedure like plasma poresis, they are removing all the antibodies, which, as we know from Lab forty seven, means a much much weaker immune system.

That's one of the downsides is you're going to remove antibodies that kind of the patient needs.

There's antibodies that protect you.

Against bacteria, virus, whatever it might be, so you kind of run the risk of leaving your patient a little bit extra vulnerable and then you're going to give them amino suppression as well, so you can be double vulnerable.

This is such a great point, and this is part of why it's so important that those patients who've received transplants have regular monitoring. For example, doctors may want to periodically screen patients to make sure that they aren't developing anybodies that might reject the transplanted organ, whether it's regular clinic visits or new technology that allows patients to take these samples at home. Being a transplant recipient is really a lifelong commitment, and in order to make this lifelong.

Commitment more bearable.

There's a lot of technological advances that scientists are trying to pour into so that it makes that commitment of a burden. So we ask doctor Low about some of the advances in transplant technology.

There's been great advances over the last few years as we've gone from sort of the cells right through to various PCR techniques and now we're onto next generation sequencing and that gives you that deep level of understanding of the tissues so that we can have more information we can match to a higher and higher level. And this is amazing, and now we're trying to say, Okay, we can do it. But a lot of the time, some of these workflows take two or three days, so it's

Is that you know, there's lots of.

Us working on getting that deep level of resolution as quickly as possible.

So it's kind of a race, you know, where everyone's working on it.

So tt we consider it like that that we saw about the pig heart transplant. The recipient recently passed away. Yeah, I saw that, But they're also.

Saying they don't know what the cause is.

And one thing that we do know is when you have those types of transplants that you're taking a lot of them, you know, suppressant, so it could be anything. Right, This was really groundbreaking technology, but it was kind of a one off.

Right, Yeah, I think it's a really great start when we're thinking about the future of organ transplant And so we asked doctor Low what does he feel as possible in the coming years. Is this the future of transplant technology?

Yeah?

I mean I don't know if I'll be anything like accurate. I guess we could meet in ten years or something and see. But xeno transplantation, so using an organ from another species is it's been around for quite a long time. There's been a number of high profile cases that have

So I'll be really interested to see how these transplants go longer term.

I think there's a lot we need to learn about how that immune response to that pig organ differs from a human and what challenges we might have. I know that in these cases, these recipients are extremely heavily immunosuppressed, so it's not easy. I think there's a long way to go and there's going to need to be a lot of large human trials.

Immunology is everywhere.

Yeah, I don't know much about immunology, but I feel a lot smarter after all of this, and I feel like the future looks bright for organ transplant science.

I think it's really exciting, Like you said, it's bright, But I also am cautious. I think a lot of times we have the technology moving and it's divorced of this social context, And so I'm like, what does it mean for transplant technology? You know, as we start thinking about this new tech and until it's readily available for everybody,

Yeah, but I feel excited about it.

Like you said, what was it the ear on the back of the mouse, it's time to update the textbook photos. That's right, it's the genetically altered pig heart. Now, what's your one thing?

Tt my one thing this week?

Is a Dope Labs live show that is happening on April fourteenth at the Boston Museum of Science. We did a live show in Minnesota and so many people were like, oh, man.

I wish I'd known, I would have come out to see you. So now you know. Tickets are free ninety nine.

You can come April fourteenth at the Boston Museum of Science at seven pm. There'll be a link in the show notes so that you can reserve your ticket.

My one thing this week is this citizen science project. I don't know if you remember the earthquake back in Haiti and what we consider seismology and how do we track all of these events. There's a system called Raspberry Shake, which are these small computers that allow you to track

It's kind of cool. That's it for Lab fifty six.

Call us at two zero two five six seven seven zero two eight and tell us what you thought, or you can give us an idea for a lab you think we should do. Either way, we love hearing from you. That's two zero two five six seven seven zero two eight.

And don't forget there's so much more for you to dig into on our website. There will be a cheat cheet there for today's lab and additional links and resources in the show notes. Plus, you can sign up for our newsletter, so check it out at Dope Last podcast dot com special thanks to today's guest expert, doctor Dave Low.

You can find more information about Davelow's work with organ transplantation on LinkedIn at one Lambda Incorporated.

You can find us on Twitter and Instagram at Dope Labs Podcast.

And TT's on Twitter and Instagram at d R Underscore t Sho, and you can find Zakia at z said So.

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