This Podcast Will Kill You - Ep 59 Thalidomide: Justice Delayed, Justice Denied

Episode Date: September 29, 2020

The story of thalidomide is often employed as a cautionary tale - why testing a drug’s safety during pregnancy is crucial or why it’s important to choose the right animal models. Or it’s framed as a success story for drug repurposing or regulation. But those tellings often gloss over the darker lesson of thalidomide: that for some companies, the bottom line is more important than human life. This week, we explore all elements of this infamous drug. We start by examining what we know about how thalidomide causes the severe congenital malformations it’s associated with, and then we dive into the deep, dark history of the drug, complete with a full cast of villains and heroes. Finally, we discuss thalidomide’s controversial comeback as a treatment for myeloma and complications of leprosy. Get out your angry hats for this one, people, because you’ll find yourself asking along with us, “why are humans the way we are?” See omnystudio.com/listener for privacy information.

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Terms and conditions apply. Visit blueapron.com slash terms for more information. I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Letby, we unpack the story of an unimaginable tragedy that gripped the UK in 2023. But what if we didn't get the whole story? Evidence has been made to fit. The moment you look at the whole picture, the case collapsed. What if the truth was disguised by a story we chose to book?

Oh, my God, I think she might be innocent. Listen to Doubt, the case of Lucy Letby, on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. This is Special Agent Regal, Special Agent Bradley Hall. In 2018, the FBI took down a ring of spies working for China's Ministry of State Security, one of the most mysterious intelligence agencies in the world. The Sixth Bureau podcast is a story of the inner workings of the MSS and how one man's ambition and mistakes opened its fault of secrets. Listen to the sixth bureau on the Iheart radio app, Apple podcasts, or wherever you get your podcasts. I was born in a body very different to my brother and sister.

The only difference was that with me, my mom took one tablet in the early stages of pregnancy, and that one tablet sealed my fate in life. Can you just imagine the delivery room? Instead of the usual, congratulations, you have a beautiful bouncing baby girl. There would have been absolute hushed silence and gasps of horror as I was born. I was whisked away into a corner of the room and mom never saw me for three days because the doctors decided that I was too grossly deformed for her to love me. These doctors didn't know my mom, who is the most wonderful woman in the world, and knowing what she went through with me breaks my heart. She lives with so much guilt for taking that one tablet. How did the drug affect me? For starters, I have no arms. I have three little

fingers attached to a little hand that basically comes out of the side of my shoulders. There was also heaps of internal damage done to my heart and lungs, which has resulted in numerous open heart operations, and I still have more in the pipeline. My childhood was, of course, very different to any other child. I didn't walk until I was nearly seven, and then I had to be carried everywhere until I had major heart surgery when I was 12. Although they repaired my heart, I still get extremely tired very quickly. I can't walk far and I can't walk up hills as I get breathless, so I never knew the joy of running and skipping. The bullying has been horrid to say the least, and that's not just by other kids who are bad enough, but by adults who are just as bad, if not worse. I have had doctors look down

on me and say I am worthless, and that I would never amount to anything. I have had doctors poking and probing my body like a lab rat because my body is so different, with no compassion. With no compassion as to how they were treating me. One doctor told me, I would never have friends, because who would want to be friends with someone with no arms? It also amazes me how people think they have the right to say the most horrid things to me when I'm out in public. It's no wonder that there are days, even weeks, where I do not leave the safety of my house. The pain in my body is horrendous and extremely debilitating. I need knee and hip replacements, but have been told that I can't have them as mechanical ones don't bend the way I need my body to bend, just so that I can eat

and drink. Feet weren't meant to be hands, but that is exactly how I must do everything, since I have no arms, thanks to thalidomide. Can you imagine getting dressed and eating or cleaning your teeth with your feet every day? It is no wonder my body is falling apart, thanks to thalidomide. God, Aaron. Yeah, I know. That was Trish's story first. from the thalidomide group Australia.com. It was excerpts from her story. And I'll post a link to where you can read her full story along with other people's stories

who have been affected by thalidomide. So, yeah. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. So you've probably figured out by now that today we're talking about thalidomide. We are indeed.

A little different type of episode for us. It's not a disease per se that we're talking about, but rather a drug. Yeah. I guess the only other one like this that we've done is aspirin. But this is going to be a very different story than aspirin. Wait a second. We did something else that was weird that wasn't a crossover. Lead?

Lead, that's the one. This is not that. This is not that. No, no. Yeah. Although this is heartbreaking, as you heard and as you will continue to hear. Yeah. Yeah.

So, all right. Well, we have a piece of business to take care of Erin. I do. It is quarantini time. It is. On the dot. What are we drinking this week? This week we're drinking David and Goliath.

Yes, we are. And it is named David and Goliath, as you will find out later in the episode, because of all of the epic struggles to bring the dangers of thalidomide to light and how it's been basically like one fight after another. Yeah. And, you know, with some triumphs in there. But yeah. Yeah. And so, Aaron, what's in David and Goliath? Yes.

Yes. It has Lemoncello. Yum. Homemade. I would like to brag. A gin and some time simple syrup. Fabulous. Yeah.

Love it. And we will post the full recipe for the quarantini as well as the non-alcoholic placebo rita on all of our social media channels as well as our website. This Podcast Will Kill You.com. Yes. Well, any other business that we need to attend to, Aaron? The usual, you know, we have merch. Check it out.

This podcast Will Kill You. We have a goodreads list. You can also find that on the books tab on our website. And we also have a bookshop affiliate program. So you can find all the books that we talk about on the podcast through those links. Perfect. Well, shall we dive right in into what's going to be a very depressing episode? I think that we should. Let's take a quick break first, I think. Dinner shows up every night, whether you're prepared for it or not. And with blue, Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients so there's no meal planning and no extra grocery trip. There, assemble and bake meals take about five minutes of hands-on prep. Just spread the pre-chopped ingredients on a sheet pan, put it in the oven, and that's it. And if there's truly no time to cook,

dish by Blue Apron meals are fully prepared. Just heat them in the oven or microwave, and dinner is ready. And here's the exciting news. Blue Apron no longer requires a subscription. You can order meals when you want them and skip when you don't without adding another recurring charge. Order now at Blue Apron.com. Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and conditions apply. Visit blueapron.com slash terms for more information. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief.

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In 2023, a story gripped the UK, evoking horror and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict, a villain, a nurse named Lucy Leppie. Lucy Letby has been found guilty. But what if we didn't get the whole story? moment you look at the whole picture, the case collapses.

I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Letby, we follow the evidence and hear from the people that lived it, to ask what really happened when the world decided who Lucy Lettby was. No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the British establishment of this is wrong. Listen to Doubt, the case of Lucy Letby, on the Iheart Radio app, Apple Podcast. or wherever you get your podcasts. So thalidomide, which is a synthetic derivative of glutamate or glutamate

or glutamic acid. So thalidomide is a drug. Aaron, you're going to talk about kind of what it used to be prescribed for and in the history. And I'm going to talk about what we use it for today. Spoiler alert, it's still out there. But what I want to focus on for the biology section is just what the effects are when it's used. in pregnancy, since that's kind of the majority of the history of this drug. Am I right? Yeah, yeah. It's a huge part of it. Right. So thalidomide is what's called a teratogen, which means it's a drug or a substance that when it's ingested or used during pregnancy, it results in congenital defects or

malformations in the developing embryo or fetus. Okay. So to talk briefly about something that I love to talk about and think about embryologic development. In all animals, not just in humans, there's a very distinct pattern of embryologic development that has been extremely well studied. So we know all of the steps, like from two cells to four cells to eight cells, etc. We know the steps of development, especially in humans, like down to the days. Okay. Like what's going to develop in what order? Yeah, it's actually kind of incredible the amount of detailed information that we have on that. It's so cool. If you want some real detail, I found a great website. It's called like Embryology.com or something. It's an Australian website and it has pictures of like every single stage. It's very cool.

Whoa. Yeah. So in humans, the first eight weeks of development post-fertilization, which in pregnancy we call 10 weeks gestational age, that is the embryologic phase of development. At the end of this phase, so eight weeks post-fertilization, 90% of the anatomical structures that an adult human has have formed. Wow. Isn't that incredible? Yeah, that's wild. It's so cool. So any substances that have an effect on the developing embryo this early in the process can result in really significant effects down. stream. Right. Versus drugs that might have an effect later in pregnancy when most of the structures are already developed. Mm-hmm. Mm-hmm. Okay. All right. So that's sort of the brief overview. So the syndrome that thalidomide causes, if ingested during pregnancy, is called

thalidomide embryopathy. That's like the Google term, if you want to find it. It just means a pathogenesis in the embryo due to thalidomide. Okay. Okay. So there are a huge range of effects that thalidomide can have. Some of them, I think, are very characteristic. Like you might already have in your head an image. I know you do, Aaron, because you've been researching this. But listeners, you might have an image in your mind when you hear the word thalidomide. But there's a massive range anywhere from very, very severe to minimal effects.

And this does make it really difficult to know. know if the syndrome that you're seeing is from thalidomide or from something else. Yep. Yeah. So we'll talk about kind of what the most common ones are and what the ones that are very much associated with thalidomide and not really associated with other things and kind of focus on those. So thalidomide often induces what's called fokomilia, which was a new term for me, actually.

That was a new term for me too. Yeah. So Focomelia is a shortening of the limbs that's usually most prominent in the proximal, which means like your upper arm bones and upper leg bones compared to your distal, like your forearms or your calves or whatever. So you can end up with either very, very short limbs or you can have just like the hand bones and feet bones that are more directly attached to the shoulder. or hip girdle. And that would be

Focomelia. Or you can end up with complete loss of limbs, which is called amelia. But what's bizarre is that thalidomide can also be associated with like polydactyl, which means having extra digits. I have like you can feel the questions coming up and I'm just suppressing them. So I'm going to just let you finish. Okay. Great. Because I don't know

if I'm going to add the answers to your question there, but I'm going to try really hard. Okay. One of the things, though, that sets thalidomide embryopathy apart from other genetic causes of shortened or missing limbs, and I think this is, again, very interesting, is that the shoulder, so if you look at the shoulder, it tends to be very pointed. And this is because the clavicle tends to be a bit longer, and where the clavicle attaches to your scapula, that's called the acromeo-clavicular joint. So that joint tends to be very prominent in cases of thalidomide embryopathy. Interesting.

Whereas some genetic causes of shortened or loss of limbs, that shoulder tends to be more sloped rather than pointed. Are you going to tell me why this happens? Why there's a difference? What's the function? Come on. I don't know that I'm going to, quite honestly, really. It's not really. Okay.

Anyways, moving on. Okay, now those are the biggest characteristic typical symptoms. Okay, focomelia, amelia, this prominent shoulder joint. When limbs are affected, it tends to be the what's called preaxial, which is your thumb side and your big toe side. Those sides of your hands and feet are affected before your post-axial, so your pinky finger and little toe side of your limbs. Okay.

So does that mean like you would be more likely to have your pinky finger and your ring finger intact and not have the first three fingers? Yeah. So it means that you wouldn't have your pinky and ring finger affected without also having your thumb affected. Gotcha. So like it affects that first in the case of thalidomide embryopathy, which is different than some other causes of limb defects. The other thing about thalidomide embryopathy that sets it apart from some other causes is that it's almost always bilateral, if not perfectly bilateral, like absolutely equal shortening of limbs, at least mostly bilateral. So you're not going to have complete unilateral effects, okay? And this, Aaron, I know your question is always why. This makes sense, okay? because this is something that's affecting a developing embryo and embryos develop symmetrically.

And this is a toxic insult to that developing embryo. So it's not going to preferentially affect one side or the other. Gotcha. Ha! At least I had one. All right. And the other thing about thalidomide is that the upper limbs are affected before the lower limbs. So the same way that the thumb is affected before the pinkies, you won't have loss of portions of your lower legs without all.

also having loss of portions of your upper limbs. Oh, okay. Okay. Do you ask me why, Aaron, ask me why? Why? Aaron, why? Okay, we don't fully know, but here's a hypothesis. Thalidomide, as it turns out, has a very narrow range in which it has effects. Between 20 and 36 days post-fertilization is the window in which thalidomide exerts especially its most severe effects. Right. So that would be... Okay. That would be days 34 to 50 after a last menstrual period. So gestational age five to seven weeks, okay? Which is very early. It's very early. It also happens to coincide with what is often the peak of morning sickness, which is like weeks four to 12.

All of these are very pertinent details to the history. I know it. And it also is when the limb buds are forming. And the upper limb buds begin to form around day 26 post-fertilization, and the lower limb buds start to form one to two days later. Okay. And limbs grow from proximal, so from like humorous to distal to your hands. So depending on exactly what day you would have taken thalidomide and how long your exposure is, your downstream effects. are going to vary. A shorter or earlier exposure might only affect one small portion, like just your humorous bilaterally, versus prolonged exposure, which could then go on to affect the distal arm and the leg and the distal leg. Gotcha. Okay. Now, limbs are not the only thing that can be

affected in thalidomide. Thilidomide can also cause eye damage and ear damage, including with It's called microphthalmia, which means small eyes, or complete loss of eyes and ophthalmos. It can cause absence or reduction of the ear. And again, this is going to most often be bilateral, so on both ears. It can cause cleft lip or cleft palate. It can cause issues with the developing vertebrae. It can cause damage to nerves, which can cause things like eye palsy, so where you can't move your eyes properly because the nerves.

to your eyes have been damaged. And of course, it can affect literally any of the developing internal organs as well. So your heart, your GI tract, your kidneys, you name it. Okay. Right. So that's a lot of things, right? Yeah. Which makes sense. I warned you, right? You're affecting an early, very, very early stage of development. Okay. But of course, the biggest question that we try to answer is why or how. Like how does this happen? Why? Did this these specific things happen. Mm-hmm. Honestly, we don't know.

Still? Still? I thought there were at least hypotheses. I read a few of them. There's always hypotheses, Aaron, but that doesn't mean we know, okay? I know, but are there good hypotheses? Yes. There are three, okay?

There are three good hypotheses that have the most support. Okay. One of them is the inhibition of angiogenesis, and this is something that we know that thalidomide does because it's part of why we use it as a drug in other contexts today. So what does that mean? Angiogenesis is the process of blood vessel formation. So thalidomide is known to disrupt the formation of blood vessels. And it's not a far stretch to see how this disruption in the development of blood vessels to your arms would then cause a disruption in the growth of those arms in an embryo. But then that leads to a question, why does it affect the limbs so much more often

than internal organs? Does it? Who knows? Because it definitely has large effects on internal organs as well. And your limbs are a lot more visible. So you see those effects more than you might see some effects on internal organs. But there's also some evidence that, and this is getting very nitty-gritty detail, but the blood vessels developing in the limbs of an embryo lack smooth muscle at that particular stage in development when it is susceptible to thalidomide. And that seems to be what allows thalidomide to have an effect. So vessels that have smooth muscle are more resistant to thalidomide. And how does that vary among internal organs at that stage? Like, are there some that have more smooth muscle or less?

Yeah. Most of the internal organs have smooth muscle on their vessels as embryos, like during that stage of development, whereas the limbs are what don't. Right. But is there any variation within those organs within the internal organs? Great question. Probably. I don't know the answer to that. Okay.

Here's another question. Gosh. Here it comes. Maybe it's jumping the gun. But how long does the Lidomize? stay in your body and like why that that window is so narrow still like yeah yeah i don't get it it's a very good question so the half-life of thalidomide is actually very short it's like five to seven hours okay so that means that it's pretty rapidly excreted from your body all right um and the question as to why is it

only that particular window is a really good one a lot of studies have shown in in rats which i'm sure you'll talk about are not a great model, and also in humans' earlier exposure, so before 20 days, often results in spontaneous pregnancy loss. Okay. So then the effects... So you wouldn't even know necessarily. Exactly. The effects have been so dramatic that the, that embryo is no longer viable. Whereas after that period of 36 days post-fertilization, it's not clear what the effects are in humans. in rats, later exposure can induce brain damage in the fetal rat. Okay. But whether that happens with thalidomide, it's not at least clear from what we know about humans.

That makes sense. Okay, but that is all just angiogenesis. So that's just one hypothesis here. We have a couple more. But luckily, they're shorter because they're not as interesting or they're not as easy to explain at least. So another hypothesis is that thalidomide induces the creation of free radicals. We've talked a lot about radical reactive oxygen species. Yeah. So thalidomide does that. And so it's thought that that production can then cause damage that results in what we see.

Not a ton more detail I can give you beyond that. And then the third one I'm going to give you even less detail on because it's beyond my scope of being able to. to explain, but we know a few of the molecular targets that thalidomide interacts with. So the specific genes that thalidomide seems to have an interaction with. These are seriblon and S-A-L-L-4. What's very interesting is that there is a genetic disorder associated with mutations in the gene S-A-L-L-4 that result in really similar phenotypes. So really similar limb defects that we see in thalidomide. But this is a genetic disorder, like a hereditary disorder. So it's like that's kind of an appealing hypothesis in that way that maybe thalidomide is interacting with this gene somehow, which is turning something on, turning something off that's causing these limb defects. Does that gene have an impact on angiogenesis?

Good question. Not that we know of. Okay. Yeah. So that's a really good question because we know that philidamide has all these effects downstream, right? It has effects on nerves. It has effects on cartilage. It has effects on all these different things. But the real question is like what's the first, like what is the first disruption that results in all these downstream effects? And that is what we don't fully understand yet. Mm-hmm. Yeah. A lot to take in. Yeah. This is a lot, right? And it's depressing. Yeah. That's what I have for you. I'm not going to talk about what we use thalidomide for today until the current event section. Okay, good. I'll talk a little bit about it. Hopefully you'll right into it. I bet you will. So, Erin, where did we come up with this drug? What the heck? We've already kind of alluded. It was used in pregnancy. Tell me why. Tell me all about it. I want to know everything. Oh, man. Let's take a short break first. Okay. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working, working,

hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps

them soft and smooth no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit o'Keefscom slash this podcast and code this podcast at checkout. In 23, a story gripped the UK, evoking horror

and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict? A villain. A nurse named Lucy Letby.

Lucy Letby has been found guilty. But what if we didn't get the whole story? The moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, doubt the case of Lucy Lettby, we follow the evidence and hear from the people that lived it. To ask what really happened when the world decided who Lucy Lettby was. No voicing of any skepticism or doubt.

It'll cause so much harm at every single level of the British establishment of this is wrong. Listen to Doubt, the case of Lucy Lettby on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. China's Ministry of State Security is one of the most mysterious and powerful spy agencies in the world. But in 2017, the FBI got inside. This is Special Agent Regal, Special Agent Bradley Hall. This MSS officer has no idea the U.S. government is on to him. But the FBI has his chats, texts, emails, even his personal diary. Hear how they got it on the Sixth Bureau podcast.

I now have several terabytes of an MSS officer, no doubt, no question, of his life. And that's a unicorn. No one had ever seen anything like that. It was unbelievable. This is a story of the inner workings of the MSS and how one man's ambition and mistakes opened its fault of secrets. Listen to the Sixth Bureau on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. I think most people have heard of thalidomide before and its association with congenital defects.

And the story that I remember learning in college was brief, like in the 1916. 60s, a drug was developed that ended up causing these really severe congenital abnormalities. And when that link was discovered, it was pulled from the market. Right. That's the story we heard. Yeah. And it was used, I think, as like a teaching moment of how a medication can have enormous unforeseen side effects and to represent just how far we've come in terms of our policies for drug regulation and safety, almost like a cautionary tale about the price of progress. Yeah, and animal studies. I remember learning it in the context of animal studies.

Mm-hmm. That's a huge component to this. Yeah. But as it turns out, the story of thalidomide is much, much deeper than that. It always is, Aaron. And I just have to say that, you know, like, we've been doing this podcast for three years now. We're going on their fourth year. Yeah. And you'd think that after reading about all of the various accounts of horrible, unethical things that people do, I would cease to be shocked at some point. Oh, no, Aaron.

But no. So with that to set the tone, let's get started. I'm sorry. Okay. All right. Take a deep breath in. Let's begin with an origin story. That of Kemi Grunenthal, the company that created the litamide.

Grunenthal, I'm just shortening it to that from the first. point on. Okay. I was created in West Germany in 1946. The year after World War II ended. Hmm. And who better to staff a pharmaceutical company than a bunch of convicted mass murderers and war criminals. Oh, oh, like the, uh, Nuremberg.

Yeah, basically it was like Nuremberg was like a job fair. Yeah, hiring. It was like a hiring fair. Turns out. Yeah. Cool. Great. Awesome.

Mm-hmm. So convicted of mass murder, slavery, and crimes against humanity at the Nuremberg trials, Nazi Otto Ambrose actually ended up as the chair of Grunenthal's supervisory board and oversaw the production of thalidomide. I already hate this story, Erin. I know. It's really, it's all downhill from here. Great. Mm-hmm. But it's important to know. I feel like this is such an important story and it's been so underreported throughout its history.

We've shortened it to this very tight little narrative, and I was shocked to read about all of the stuff that's like beneath the surface. So with that. So before Otto Ambrose landed this position at Grunenthal, he had worked on chemical weapons and nerve agents. He had used slave labor from those imprisoned at Auschwitz and was also involved at having another concentration camp built that was closer for convenience for his work. After serving three years of his eight-year sentence, he was granted clemency by the U.S., he promptly landed that position at Grunenthal. Great. Another war criminal and murderer that found a job at Grunenthal was Heinz Baumkotter, an SS doctor at a concentration camp outside Berlin, where he would oversee executions, pick out people for gas chamber, and double heavily in medicalized torture using injections, explosives, and chemicals. He, too, was convicted of these crimes and was actually sentenced to life, but was let out in eight years and immediately found a job at Grunenthal as a salesperson.

And those weren't the only ones. There was also Ernst Gunther Schenk, another SS doctor, and Martin Stemler, a Nazi who wrote copious amounts on how German people were racially superior. And he actually ended up head of Grunenthal's pathology department. And in general, you know, it should be said. Grunintal was no special case of hiring Nazi war criminals. In general, they actually found work pretty easily after their conviction, including in the U.S., for instance, on research projects. But the question is, what role did these Nazis play in the development and promotion of thalidomide? Right. And for the names that I've already listed, it actually doesn't seem like they played

much of a very active role, perhaps in sales or the general overseeing of the development. but there's one more name that I haven't yet mentioned. Okay. And that's Heinrich Mukder. Also, I'm sorry if I'm horribly mispronouncing all of these names, all of them. You mean you don't speak German? I do not. And I probably should consult someone who speaks German to talk about these names.

But, well, here we are. During World War II, Mukder worked in Poland as the deputy head of the incident. for virus and typhus research, where he was involved in countless instances of medicalized torture. After the war, he fled Poland and the criminal charges that he faced there, and immediately was given a job at Grunenthal, and not just any job, but the director of research and development. He was also promised a percentage of sales in addition to his salary, sales which would later include thalidomide. Thalidomide would make Mukder incredibly wealthy. In 1961, which, spoiler, was the last year that it was sold,

Mukder's bonus was 22 times his actual salary. What? Mm-hmm. Okay. So why did I spend so much time just now on the Nazi backgrounds of the people working or running the show at Grunenthal? Why, Aaron? It's because later on, I know that you'll be asking whether literally or rhetorically, just like I did, how could this happen? How could a company be so without morals? And when a company is comprised of people who are accustomed to a complete disregard for humanity and human life, as well as a culture of extreme respect for authority, you basically have a recipe for criminal negligence. Not, I should know, that it takes Nazis to be greedy or amoral or to put the bottom line above human lives.

But in this case, I do think it's an important part of the background. So now let's get to the medical context in which the litamide was developed and introduced. Okay. So throughout the first half of the 20th century, the use of barbiturates had steadily risen, especially in Europe, North America, and Australia. And with this rise also came recognition of the dangers that barbiturates, carry, such as addiction, overdose, and respiratory system suppression. And the growing awareness of this meant that the market was ripe for a safer alternative, especially when it came to sleep aids. So when Grunenthal doctors on the hunt for a new antibiotic stumbled upon thalidomide, whose structure

closely resembled that of barbiturates, they were hopeful it might act as a sedative and hypnotic. The next step was simply to test it out. Rats were supposedly given doses of the drug and observed for sleepiness as compared to non-drugged rats. And the scientist came to the conclusion that, yes, this drug did have a sedative effect, which is interesting considering that no sleep was actually observed in the animals and no one was able to replicate the experiments. What? So it has something to do with something called a jiggle case.

and I'm not going to go into it, but basically it measures the amount of, like, jiggle that the rats or, like, movement that the rats would make. And less movement, they think they figured translated into a more sedative effect. Right. So the rats just weren't moving around, but they weren't necessarily sleeping. Yeah. And it doesn't really hold up. No one could ever replicate it. So there's no telling what really went on. Additional experiments continued testing the safety of the drug. And the company gave it an A-plus-plus. Apparently, there was no amount of drug that they could give the rats that would kill them. Okay, that we just know is false because you can kill a rat with water, okay?

Uh-huh. I know. I know. But just because you don't instantly die from the drug doesn't mean that there won't be short or long-term side effects. Right. And crucially, no studies were conducted on the safety of the drug in pregnant animals. Mm-hmm. Remember that. So rather than test animals, pregnant or not, for side effects, best to move on right to humans, right? Naturally.

And since we know that the company makeup at the time was at least in part Nazi, why not resort to what's familiar, e.g. medicalized torture. So for example, 40 developmentally disabled children were given doses of thalidomide, up to 20 times that of the recommended dose for an adult, all without the parents. knowledge. Of course. Two of the children died, and one lost their sight. The doctor in charge of this, Dr. Lang, said there's no way that the death were attributable to thalidomide. Oh, my. Uh-huh. And hidden among all of these glowing reports of the super safe and effective new sedative, some warning bells were going off. One doctor who had been given samples of the drug discontinued use because there appeared to be nerve damage after extended use, and another because it caused slight constipation in his patients, which I really appreciate. He's just like,

some people can't poop. You're a little backed up. And his justification for this was that, like, you know what, this is not a life-saving drug. This is not an essential drug. This is simply like an above and beyond. And if it's causing discomfort, then there's no need to give it. Can I, ask you again what year this was that like the already doctors had access to this drug? So in 1954 is when thalidomide was discovered or developed. In a 1957 it was released for public consumption. Okay. Wow. So within three years. Yeah. Yeah. Which is very fast. Yeah. In today's standards. Right. And so at this point, the scientists at Grunenthal still weren't sure how the drug actually worked on a molecular level, which it seems like we still don't truly know.

still aren't, so can't fault him for that one single tiny thing. Nor did they know how long it stayed in the body. But none of this slowed the enthusiasm for the drug. And thalidomide was launched in Germany in October of 1957 under the name Contrigan, with hundreds of thousands of ads and letters directed towards doctors and pharmacists. Wow. Its biggest selling point was its absolute safety, A-toxicity. And this hype machine worked far outside the German borders as well.

The pharmaceutical companies all over the world fought to license this wonder drug for sale in their country. So one of these companies was Distillers Biochemical, which was an offshoot of distillers, which sold some of the most recognizable liquor brands around the world. It was based in the UK. And Distillers won the bid to sell the lytamide under the brand name Distavol in the UK, and then, also in Australia, the year later, 1959, opting to have Grunenthal continue producing the drug while they would just package it and sell it under their name. Advertising for thalidomide under any of its brand names almost solely consisted of assurances of its absolute safety.

And sorry, at this point, it's marketed just as a sedative that is safer than barbiturates. Yes, so it began just to be... So that was how it was promoted to doctors. And then doctors sort of prescribed it for any manner of like sleep aid, sedative for people of varying age. It just became sort of this like cure-all type of drug. And it also was not prescription. It was over the counter. Oh.

Oh. Okay. I didn't know that. Okay. Mm-hmm. Yeah. So one ad that is very unsettling in light of all that would have. And all we know now showed a small child on a stool rummaging through the medicine cabinet.

It was a picture of him. And this kid has in his hands an unlabeled bottle with the implication that there's about to be a horrible overdose of some drug. But then the ad makes it clear that it's actually distavall with the quote, this child's life may depend on the safety of distavall. Oh, that's bad. Is that not? That's bad. A horrible.

But because it was at least superficially safer than barbiturates, a point that sales rep were urged to hammer on over and over again, it really grew in popularity. In some places, sales of thalidomide were second only to aspirin. Wow, which like already we've talked about the problems there. We've talked about how popular aspirin was and some of the problems with aspirin. Wow, though. Wow. Second to aspirin. And by 1960, it was the best-selling sleeping pill in Germany. Wow. A liquid form was advertised as being a great sedative for children.

Why are you sedating your children? Stop it. And it gets worse because it had the nickname Cinema Juice or the babysitter. Because parents could just drug their kids with thalidomide and go off to the movies and not have to worry about them. Oh, my God. not drug your child to sleep. Oh my goodness. Cinema juice. Yeah. Oh, so despite being hailed as this incredibly safe drug, reports of some side effects of the litemide started to trickle in. Shocker. Not of congenital defects or stillbirths or miscarriages, but rather peripheral nerve

damage. Yeah. Doctors began to bring these reports to Grunitol, and in response, Grunenthal did not pull the drug from the market, nor did they further investigate these claims or run any additional experiments to see what might be going on. Rather, they lied, they denied, and they spied. Ooh. Grunenthal hired a PI to follow around the doctors that made these complaints because they were convinced that a rival pharmaceutical company, such as Bayer, was behind it all. Wow. There's absolutely no truth to this, by the way. thalidomide does cause nerve damage.

Yeah, that's like the number one side effect that causes it to be discontinued in use today. Mm-hmm. And this PI even followed the victims of nerve damage to see whether they would seek compensation. And he gathered dirt on both patients and doctors involved in these reports. Wow. Uh-huh. When one Grunenthal rep went to sell more thalidomide to a psychiatric wing in a hospital, he heard no reports of nerve damage, and he attributed this to a lack of reporting, writing in a letter to his bosses,

quote, maybe the idiots are happy when there's tingling. Uh-huh. And another employee won up this despicable remark by suggesting that thalidomide be combined with other ingredients so that the nerve damage could be blamed. on those compounds instead. What? Uh-huh. This is real. This really happened.

So then they're like, yeah, sure, whatever. It causes nerve damage, but let, like, that doesn't eat. Oh, my God, Aaron. I know. I know. Just breathe. You have to just practice, like, focus on your breathing during this. I don't know if I can do that.

You're just going to hear like a, from the background of this whole episode. No one's going to want to listen. Yeah. Yes. So while internally, Grunitol began to more closely watch this drug, they at no point made any public announcement regarding it, fighting any pressure to put a warning on the bottle or make it prescription only. And Grunenthal wasn't the only one to be receiving these reports either. Distillers, the licensee in the UK and Australia, had learned of potential nerve damage and immediately slapped a warning label on its packaging. They asked Grunitol about the nerve damage, and they were assured that it was only in very rare cases, and they cleared up quickly. Also not true.

Some nerve damage was permanent, if not like the majority of it. But then another concern came to light. Distillers had been developing a liquid version of thalidomide similar to the cinnamon juice that Grunitol had made, and they were in the process of running some preliminary tests using animals, rats, I think in particular, when some disturbing results came to light. The animals were dying at like not very high doses. Uh-oh. And apparently the liquid was much more toxic than the pill form. And so these claims of extreme safety were unfounded.

And that's the one you're giving to babies. So you could go watch a movie. And the company brought their concerns and these results to Grunital, who assured them that they had run similar tests, but no animals had died, suggesting that it might be due to a difference in sensitivities between German and English mice. That, what? Come on. I know.

I know. So this logic, if you can even call it that. You cannot. Shaky, to begin with, it completely falls apart with the first published report of nerve damage in connection with the Lidamide titled is thalidomide to blame? And written by Scottish Dr. Leslie Florence, published in the British Medical Journal in December of 1960. Immediately following this publication, tons of doctors wrote to Florence saying that they had seen the same thing in their patients. And his letter was a pivotal moment in the history of thalidomide, because it not only created the momentum that would increase

scrutiny of the super safe drug, but it also played a huge role in one of the biggest triumphs of drug regulation or oversight. At this time, early 1961, thalidomide was a big hit in the countries where its production was licensed, but there was still one big untapped market, the United States. Grunital had been working with its U.S. licensee for over a year to try to get the drug on the market in the U.S. In anticipation of the eventual approval, they had stockpile thalidamide, and they were basically all ready to go, except for one thing. FDA approval. FDA medical officer and MD PhD, I believe, Francis Oldham Kelsey,

whoop-whoop, had raised a list of questions and concerns about the drug, and none of the answers that she was ever given, made her any more assured in the safety of the litemide. And the hopeful licensee company, Richardson Merrill, was not used to not getting their way. And so they essentially harassed her. They complained to her boss to try to get someone else on the case. And they made like over 50 contacts to her, which was like highly against regulation. There wasn't supposed to be any contact between like the medical officer and the drug company. They weren't even supposed to know who she was. like her name, but her boss gave them not only her name, but her phone number, which is bizarre.

So anyway, so Kelsey was already feeling super suspicious of the company's demands when in early 1961 she stumbled across Leslie Florence's article about the litamide and nerve damage, something that the U.S. licensee rep had failed to mention. So she called a meeting to basically call them out. out. She was like, all right, let's have a meeting. So is there something you're not telling me? And they're like, no, no, everything's great. Like, this drug is the best thing that's ever been invented. And she's like, what about this paper? And they're like, oh, no, it's nothing. Like, that's not, that's just whatever, whatever, you know. And she was like, okay, here's a list of

questions that I need thorough answers for, scientifically supported. Among these questions were, what were the long-term side effects, how and when did nerve damage occur, what levels led to overdose, and the new one, which hadn't really been asked that much before, was, was the litamide safe during pregnancy? Yeah. For more than six months, the company continued to fight for the license in the U.S., but still, Kelsey held her ground. she felt that their answers were not satisfactory. The drug would remain off the shelves in the U.S. And when it was finally revealed that the Lidamide greatly harmed the fetus if taken during pregnancy,

Frances Kelsey's role in preventing its licensing in the U.S. earned her great fame. However, there is a dark side to this story in the U.S. Even though thalidomide was never officially for sale here, millions of samples were sent out across the U.S. by the hopeful licensee Richardson Merrill. To do this, they exploited some loopholes to get the drug into the hands of doctors all over the U.S. in promotional events masquerading as clinical trials. Over 2.5 million pills were handed out to more than 1,200 doctors, which gave them to around 20,000 people.

Wow. Richardson Merrill rep Dr. Pogue, I think that's how you say it, ghost wrote an article under the name of a Cincinnati GP and submitted it to the American Journal of Obstetrics and Gynaecology stating how wonderfully the drug worked and how safe it was for the fetus or newborn. But no studies had actually been done.

But it got published anyway. This GP, by the way, was no stranger to this practice of putting his name on an article that he didn't write. And he continually denied any wrongdoing in this. Wow. Four months passed after the news of the link between thalidomide and congenital defects before Richardson Merrill finally told the doctors involved in these quote-unquote studies to stop their research and return all the remaining samples.

Four months after it had been pulled from German markets. Four months after it had been pulled from German markets? When the extent of their deceit and for shady behavior. behavior. I mean, that's like not an adequate adjective. When it was discovered, the FDA pushed for Richardson-Marrell to face criminal charges, which, of course, they didn't. Okay, so I wanted to tell that part about the U.S. in one big chunk, so I skipped ahead a little bit. So now let's backtrack to before the link between thalidomide and congenital abnormalities was uncovered. Yeah, like more detail, please.

Yeah. So, okay, so alongside its success as an extremely popular sleeping, aid, the litemide was also freely handed out as a treatment for morning sickness, uncontrolled vomiting in pregnancy, and just general anxiety for pregnant people. Because you know those hysterical pregnant people. The hysterical pregnant people. In some instances, it was specifically advertised for those uses. In one distillers brochure, they claimed that, quote, it is with absolute safety that distavall can be administered to pregnant or breastfeeding women without any adverse effects on the mother or the child. The reports of nerve damage associated with the drug led to it starting to require a

prescription in some countries, and it also prompted additional questions about the safety of the drug, especially as it related to pregnancy. Grunenthal, of course, was quick to dismiss and mislead any and all inquiries. For instance, when one pharmacist wrote to the company in November 1960 on the suspicion that the drug had caused birth defects in one of his patients, they replied immediately. Dear Mr. Pharmacist, based on all observations and findings on hand to date, in particular from gynecological departments, we can negate any causal connection. To date, not a single indication exists at all to suggest that a human or animal, irrespective of age, could suffer any form of liver damage through Contrigan. We therefore feel safe in assuming that the liver damage diagnosed shortly after the birth of the baby you are referring to is not to be connected with the mother's contragen use.

They didn't ask questions about the mother. They didn't investigate these claims further or ask a hospital about any increase in congenital malformations. They just denied. They asked an OB to use the drug and report on its findings. This doc gave the lytamide exclusively to breastfeeding mothers. He refused to give it to pregnant people and reported that it appeared safe to both mother and baby. Bits and pieces of his report were misleadingly used in an advertising letter that Grunenthal sent to German doctors. Quote, Dear doctor, during pregnancy and lactation, the female organism is subject to particular stresses.

The female organism, I know. What? Gross. It's disgusting. Okay. I'll continue. Sleeplessness, inner unrest, and tiredness are recurring complaints. Inner unrest? Does that mean like, what does that mean? I'm going to lose it. I know. This is definitely the most rage-inducing episode like we've had a very long time. It is therefore often necessary to prescribe a sedative and hypnotic, which is harmless to mother and baby. When the OB doc saw this letter, he was appalled by how they had misconstrued his words to indicate that the drug had also been tested to be safe and pregnant people.

I don't know if he took issue with the female organism or inner unrest part. He probably didn't, quite honestly. He was an OB in the 50s. Yeah. I don't know. Maybe he did. Who knows? I shouldn't assume. We'll never know. I think that's the bottom line. In February

1961, a pharmaceutical firm reached out to Grunenthal to ask whether there were any data on the safety of the drug for fetuses because they wanted to develop it as a potential way to prevent miscarriages. I know. Oh, dear. Horrifying. Grunenthal responded that they had never done any experiments, but they could prove useful, even though there's been nothing so far to make them doubt its absolute safety. They never took it upon themselves to run the experiments and to look directly at the link, ever.

When a Finnish doctor asked them three straightforward direct questions. One, does thalidomide cross the placenta? Answer, not known. Two, can thalidomide have a damaging effect on the fetus? Answer, improbable. Three, in what part of the body is thalidomide broken down? Answer, probably by the liver. What?

Yeah. They just made things up and then didn't even answer. I know. It's not even the liver. This was in July of 1961. So the drug had been out for four years at this point and had been developed seven years earlier. They had ample opportunity to do all. kinds of studies. And not to mention that they had received reports of a possible link between thalidomide

and congenital defects as early as August 1958. That's like a year after it was out. Right, which, yeah. Just as with the peripheral nerve damage, though, while their outward position was deny, internally, Grunenthal began looking into the matter. Fears and alerts continued to pile up during 1961. By the summer, Grunital employees refused to take the drug because of the side effects, and Mukder himself said he would not prescribe it if he were a doctor. He was like, I would not prescribe this drug. It's not safe. But we're going to keep selling it. The company's own lawyers were like, wow, you didn't do any experiments. There's no way that the insurance company is going to cover you. Don't go to trial, just settle. You're screwed.

What would it take for there to be some oversight, some looking into these claims? Well, one thing's for sure. It wasn't going to be done by Grunitol. The two main people involved in uncovering the link between thalidomide and congenital defects were an Australian OB named William McBride and a German doctor named Vidukind. I hope that's right, Lens. Oh, gosh. McBride is typically credited as the first person to recognize that the litemide was at the root of an epidemic of congenital abnormalities, although later he would face his own controversy when it was real that he had fabricated some of his research results and he would be stripped of his medical license. Why are all these humans? I know. I know. So he had also been giving his patients the litemide. at the request of distillers.

And when he delivered three babies in short succession that all had severe congenital defects, some very similar to one another, he immediately suspected that something specific was causing these. And eventually, though not as soon as you might think, he landed on thalidomide, and he brought his suspicions to the sales rep, who passed on his concerns, which were dismissed as having no basis in fact. This was in June of 1961. McBride took it upon himself to see if he could induce some of these congenital abnormalities in an animal experiment involving guinea pigs and mice, but he didn't use a control group and didn't compare doses. He simply looked for malformations similar to the ones that he had observed in humans, and he didn't find any.

And so a seed of doubt was planted. This is what happens if you don't have a lot of training and research study design. Mm-hmm, mm-hmm. Yeah, very true. Yeah. And still, though, for months, he continued to run these experiments and to ask distillers to look into the matter and even to pull the drug until additional testing was done. That's a very reasonable request. It is. But they didn't listen. They didn't take him up on that. And over in Germany, around the same time that McBride was developing his own suspicions about thalidomide lens Vitovied.

lens was beginning to notice an unusual increase in congenital defects when a man whose wife and sister both gave birth to babies with very similar congenital abnormalities. And that's weird. Your wife and your sister, no, maybe it's not that weird. Well, so at first she was like, is it genetic? Is it something with that? But then as the head of a children's clinic at Hamburg University, he recognized that these were not only like probably not linked to genetics, but that they were incredibly rare. These were ones that you would see every, like, I don't know how many years. Exactly.

But two in short succession was like red flag, something's going on. Yeah. Yeah. And so he was like, okay, I want to see whether there's a common factor between this. And in his research, he learned that there were several more children that had been born with the same deformities, like in his area. And then he was like, okay, now it's time for. like full-on detective work.

So he launched this investigation, calling doctors around the country and digging through medical reports and newspapers. By his estimate, in the last couple of years, there were 200 times more congenital defects than usual. Whoa. Can you imagine tallying those numbers with, like, the dawning horror? Oh, my. Yeah. he was convinced that there was a single element that was causing this. He thought maybe detergent, maybe something else, nuclear fallout,

maybe some sort of other like face lotion was one of the things, I think. But eventually he landed on thalidomide after asking detailed drug histories of the mothers that he interviewed. He brought this evidence to Grunital and asked that thalidomide be withdrawn from sale. The company was like, all right, yeah, yeah, sure, we can talk about it. And he was like, that's not good enough. So he sent an express letter that declared that he thought it was irresponsible to, quote, wait for the strict scientific proof. I consider it necessary to withdraw the drug immediately from the market until its innocuousness as a teradogenic agent in man is proved with certainty. Reasonable.

Very. Like the most basic of reasonable. And so he forced them to have a meeting with him. And in the meeting, they simply tried to discredit his research and then later threatened him with legal action. Irony of all ironies, Gruninatal then appeared to try to start a smear campaign against Lens by saying, isn't this the son of the Nazi eugenicist Fritz Lens? What? Oh my.

What? What? But Lenz wouldn't let it drop. Even when faced with Lenz's detective work and reports from distillers of six babies who died from complications after their mother took thalidomide, they refused to stop sales. They said, we'll let the doctors know what Lenz thinks of thalidomide, but that's it. But then a newspaper article appeared that shared Lenz's findings and said that a popular sleeping pill, not naming thalitomide outright, or Contergan was responsible for a huge increase in birth defects. And that was the final straw for Grunitol and thalidomide. So it took a newspaper article.

Like it took public opinion essentially. Yes. Yes. It would finally be withdrawn from the market on November 26, 1961, which was 11 days after Lenz first brought his findings to the company. But they had known about it before then. Let's not make that mistake. Of course. Not to mention the nerve damage. Yeah.

So despite these enormous revelations, the media was a bit slow to pick up the story outside of Germany, in part because the involved companies discouraged local coverage. And distillers had to approach to Grunenthal to be like, hey, this guy McBride is saying that thalidomide might be causing congenital defects. Do you know anything about this? And Grunitol replying, oh, yeah, yeah. we're pulling the drug from the market. What? So should we do that too? Like, yeah, you should do that.

And I should note that although thalidomide was pulled from the shelves in Germany in November in 1961, in many other countries, it remained on the shelves for months after this connection had been made. Jeez. Some companies said, oh, you know, we'll sell what we've got and then we'll pretend like we ran out of stock. What? Literally, it continued in some places. I think Japan, it was sold for months and months and months after. Like, just absolutely, I can't wrap my brain around this.

I can't either. I literally, I mean, it's because the bottom line is money, right? Right. Mm-hmm. That's it. Okay. Yeah. This is a very disheartening episode. I'm sorry. Yeah, it really is. So, but, you know, even when the dangers of the drug began to come to light, Grunenthal didn't acknowledge their wrongdoing. Instead, they promised to fight for thalidomide, quote, to the last with all measures. Within a few days of pulling the drug from the market, they started working on their legal defense strategy, knowing that many legal battles lay ahead of them. In 1967, nine Grunenthal executives faced criminal charges, including negligent.

homicide in Germany. And if you thought you couldn't be any more disgusted by this company, I'm sorry to say that you were wrong. Oh, God, Aaron. I know, because I'm about to tell you some of their defense strategies. Number one, they insisted that there was no evidence that the litamide caused nerve damage or fetal malformations, finding doctors who would actually support that claim. Number two, that even Even if the litemide caused these supposed defects, a fetus has no legal rights in Germany, so it wasn't against the law to damage a fetus. I'm sorry. Okay.

Uh-huh. Number three, there were many other compounds that were far more likely to be responsible, including detergents, nuclear fallout, and television rays. Yep, that was television rays. Number four, that the thalidomide actually helped save those babies who would otherwise have not. survived. Okay, that just literally doesn't make any sense. Mm-hmm. They were like, oh, well, they would have, they would have, like, either died or been stillborn or miscarried or whatever, but the thalidomide actually allowed them to survive with those fetal malformations.

That... Mm-hmm. And number five, the most appalling. That the congenital defects were actually caused by the mothers themselves in botched abortion attempts. Yeah. This was one of their defense strategies. I wrote down a few adjectives and then I ran out like deplorable, disgusting, despicable. Like, I don't know what else.

There aren't words. I don't have any words. There aren't words. What? There's no way that this company would not be held accountable for their actions, right? Ugh. Wrong. Wrong.

The trial dragged on and on and on. And after three years of tedious proceedings, the trial ended with basically a slap on the wrist for Grunetol and German law forbade them from being further prosecuted. For decades, they admitted no wrongdoing, even at times playing the victim. How this unforeseeable tragedy has haunted the Wirtz family who still owns Grunital, which is still an operating company, by the way, for years. Erin. I know. This is a tough one. Yeah, it really is.

According to CBC, an estimated 24,000 babies worldwide were born with thalidomide-induced malformations, with an additional 123,000 stillbirths and miscarriages. Wow. And those are conservative estimates. Yeah. The story of the legal battles for compensation for those babies, now adults affected by thalidomites, is an entire podcast in and of itself, not just an episode. And while I won't go into a ton of detail, I will, of course, recommend further reading.

The long and short of it is that any sort of justice has either been long delayed or denied entirely. It has been an upward battle every step of the way with incredible obstacles. For example, in England, there was a press gag for. years. So the story of distillers and thalidomide could not be written about for years and years and years. Yeah, it's really interesting. How can you even do that? So there's a whole documentary that I'll recommend that goes into it in great detail. It's called attacking the devil. What? Yeah. It has to do with not biasing a court case essentially by public opinion or whatever. Because it was still in a court case or something? But like once that court case starts, then it's a press gag until it's over.

But that gag, that press gag, prevented the public support that may have led to more accountability and actually adequate compensation rather than like the extremely, I mean, shockingly paltry pensions that they received. And since then there's been a lot more like struggle and fight. I mean, the story is ongoing. I think this is another big ass point. of it. But also, you know, in in this, of course, just like the name of our quarantini suggests, there are a lot of incredible people that have stood up against these pharmaceutical companies and saying, you know what, no, like, you will be held accountable. You're going to, like, help us at the very least, we can't, we can't get the lives that we could have had back, but you're going

to help us, like, live as comfortably as possible. You know, that's, and I think that's, yeah. So, There are still people continuing this fight today. In August 2012, Grunenthal's chief executive, Harold Stock, gave the first and only public apology, if it can be called that, on behalf of the company at the unveiling of a statue of a victim of thalidomide. Quote, we ask that you regard our long silence as a sign of the silent shock that your fate has caused us. What? Mm-hmm. Are you, that's not even close to an apology. No. No.

Before I wrap up with the story of thalidomide's comeback, I want to address one line of defense that was used by both Grunenthal and distillers to absolve them of any guilt. Why? It's just going to make me angrier. I know. I know. And this line of defense, well, so it's important because this line of defense has been misused in the narrative of thalidomide that is. often told. So the story of thalidomide often places the drug at the center of drug testing reform, particularly in ensuring a drug safety during pregnancy. Yes. And to be fair, the enormous media attention given to the thalidomide tragedy did bring increased scrutiny to drug testing and awareness and regulation and about how what might be safe for a pregnant person might not be safe for a fetus. But the whole, oh, we didn't test the drug in pregnant animals because it just

wasn't done at the time. And, you know, at the time, no one knew that a drug could affect the fetus and not the mother. Like, that doesn't fly one little bit. So let's not, let's not pretend like that's what's going on because when the lytamide was developed, there were plenty of drug companies that were testing their drugs on pregnant animals to ensure its safety. in the fetus because people had long observed that some drugs may be toxic to a fetus, but not the person carrying the fetus. Okay. And here's another thing, Aaron, because I feel like when I learned this story, it wasn't this story.

It was, what I remember was that it was like, oh, we even tested it in some animal models, but in a lot of mammalian animals that we often use for testing, drug testing, it doesn't cause those effects in the fetus. So they're like, we just didn't know. And so it's like the importance of using the correct animal model. That's the context that I remember learning the thalidomide story is like choosing the quote, correct animal model for doing these studies in. But like this is so far, so far beyond that. Oh, it's so far beyond that. And also like I do think that is, is part of it, like that was sort of something that brought to light the fact that, you know, it further illustrated differences between some mammal species and humans and how you can't

necessarily make a connection between those. Yeah. But thalidomide still does affect rats during pregnancy. Yes, but it doesn't cause the same defects that we see. So like there isn't a good mammalian model for the limb defects that we see in mammals. So I think there actually were some pregnant rats included in some of the studies, and there was note taken of the fact that there was an overall reduced litter size, which should be a red flag, first of all.

And secondly, the rats were found to have resorption scars on their uterus, which happens when a fetus develops and then dies or doesn't make it to birth. Right. So there were red flags, even if there weren't the exact, like, congenital abnormalities that were seen in humans. But then after the link between congenital defects and thalidomide came to light, a researcher at distillers was like, okay, we need to do some studies to see whether this is like happening in animal models, you know, realizing like, oh, we should have done this a long time ago. And he tested the drug on rabbits and voila, like it was very similar to what they were seeing in humans. Like

there were congenital defects. It was some New Zealand white rabbit or something like that species. Okay. So anyway, that defense, like all of their defenses, does not hold any water. All right. The final section, Aaron, come back. So when thalidomide was pulled off the market in 1961, its mechanism of action was still unknown. And I wrote that not knowing that we still don't know it. I mean, we know a lot more.

Yeah. Yeah, yeah. Yeah. But some researchers were starting to ponder what it. it might be. Early experiments weren't showing much promise. But then in 1964, a physician at a leprosy clinic was desperate to help one of his patients who had severe painful boils, E&L, if you remember what that stands for. Oh, do I? What is it? I do, but listeners don't probably. It's erythema, no dosum, leprosum. Yeah. Yeah. So hugely painful,

horrible boils. They're so painful and so uncomfortable that you can't sleep, you can't eat, they don't heal, like it's horrific. And so he realized he had some leftover thalidomide that he hadn't thrown out yet and was like, you know what, here take some of these, maybe they'll help you sleep. And not only did the person actually get some sleep, but their boils healed. Like they healed, which was almost unheard of. Yeah. And so then that That one person turned into a study of, like, many more, and it was found to be extremely successful in treating ENL. Yeah. So why this worked to help people with leprosy wouldn't become clear until 1991?

And then thalidomide would be in the headlines again. At this time, the HIV-AIDS pandemic was in full swing, and there was still no widely accepted treatment for the virus. Enter thalidomide, which acted to reduce TNF alpha to. tumor necrosis factor alpha, the cytokine found at high levels in people who are HIV positive. The litamide, because it was banned in the U.S., was actually being smuggled into the country. Wow. And so the FDA decided to revisit this banned drug and ultimately decided to legalize it, which is a very short sentence, but not a fast or easy decision. It was like a lot of contentious, you know, debate going on.

And even after its legalization, the amplified side effects in people with HIV or AIDS who already had weakened immune systems meant that its popularity didn't last long for that. But it was found to be helpful in people with multiple myeloma. So, Aaron, earlier you asked me if this episode is going to have any bright spots. So honestly, those are the only ones that I can really think of. I think there are like thousands of lessons to be learned. from the story of the litemide. But I think one of them is that, like, I feel like we tell this story a lot to kind of in a way

reassure ourselves that, you know, we've grown so much, we're doing so much better now. And I think that's valid in many ways we are. But it still very much scares me the whole bottom line over a human life. And I don't think that aspect has gone away at all, especially in light of like American health care and just how disgustingly abysmal it is in terms of like insurance companies, pharmaceutical companies, hospitals, like just this vicious cycle. I think another thing that concerns me is that the lessons that I feel like I have been taught from the thalidomide story in classes that I have taken are not the lessons that I am taking away from this discussion with you.

Yeah. So that is concerning to me. I agree. Well, Erin, what's going on with solitamide today? I don't know how else to end this really depressing history section. Do we even want to talk about it? I think we do. It's going to be, okay, let's take a quick break.

Okay. So like you mentioned, Aaron, thalidomide hasn't disappeared. And I have written in my notes that that's actually a good thing. And it is a good thing because it's a very useful drug, as it turns out, for a number of disorders. But now, after you told me this story in my pit of my stomach, I'm like, do you know what? It just means that the drug companies are still making money off of this drug. You know? Like, don't worry, we found another use for it.

That's what drug companies do with every drug. They're like, oh, gabapendon doesn't work great as a seizure med, but hey, it works. for peripheral neuropathy, woo-hoo! You know? Right. Okay, sorry. Anyways, let's talk about it. And I also want to clarify something. So in the biology section, when I was talking about how we don't fully understand the mechanisms of thalidomide, that is true, but it's more true for the mechanisms of thalidomide embryopathy than it is true for the mechanisms of thalidomide not in the fetus, if that makes sense. Yeah, okay.

So the part about the inhibition of angiogenesis, we know that that's what thalidomide does. What we don't know is exactly how that causes the congenital defects. Gotcha. And like you mentioned, thalidomide is an inhibitor of TNF alpha, tumor necrosis factor alpha. So those are kind of two of the biggest ways

that we know that thalidomide works in the ways that we use it like in adults and children that are not pregnant. Okay. Mm-hmm. So what do we use it for today? It's been studied at least peripherally in a really wide range of conditions, but there are a few conditions that it's like really more commonly used for and like more associated with today. So we'll kind of just like run through them all and then focus a little bit on the two or three biggest ones. Okay? Mm-hmm. So it has been used for the treatment of Crohn's disease, which I think is fascinating.

Interesting. How does that work? I don't know. Okay. But what's even more interesting is that I found a paper that it's, it was used in children with Crohn's disease that were also infected with tuberculosis. So you can't use other like forms of therapy in those kids because it would increase the tuberculosis load.

Oh, because it would be immunization. immunosuppressive stuff. Right. Yeah. Interesting. So, yeah, super interesting. It's not super well studied in Crohn's in general, and it's not like a first-line therapy, but in refractory Crohn's, it has been used. It's also used to treat graft versus host disease, which is what happens when you get a bone marrow transplant and the donor marrow starts attacking the recipient's own cells, which is a really common complication. of bone marrow transplantation. Okay, don't ask me how that works, because I'll explain it in a minute.

Okay. And then two of the kind of most common uses are the ones that you mentioned, Aaron, multiple myeloma and leprosy. Okay. And specifically, erythema, no dosum, leprosum. That's not actually leprosy, but it's an autoimmune reaction to infection with microbacterium lepray. So multiple myeloma is a type of blood cancer that specifically affects your plasma cells, which are like the mature form of B cells. Okay, check our vaccines episode if you want more.

Okay. So your plasma cells normally make antibodies. So it's like how on earth can this treat a blood cancer essentially? It doesn't make sense. Well, it turns out that multiple myeloma is associated like, most cancers with an increase in angiogenesis. Okay. And so the effect that thalidomide has on a couple of specific growth factors that are

associated with angiogenesis, fibroblast growth factor, and vascular endothelial growth factor, so FGF and VEGF, as well as its effects on TNF alpha, those things all combined are how it has its effects on a multiple myeloma, which is associated with an increase in angiogenesis. Now, a logical question you might ask me, Erin, is can this be used in any cancer? You're just preempting all of my questions, Erin. Yeah. The answer is it has been studied in a number of other cancers, but it's not as well studied. And I think what it boils down to is that for a lot of other cancers, we have better treatments. Whereas multiple myeloma is something that before this, we really didn't have anything.

So thylenmide was kind of like revolutionary in that way. And graft versus host, it's kind of the same thing, right? So it's inhibiting those cytokines associated with the inflammatory response. Right. So yeah. And then erythoma, no dosem, leprosum. Again, this is an immune-mediated react. to infection with the bacteria. So by suppressing that inflammation, somehow thalidomide works

really well to treat that disorder. Now, do you want some depression to end this depressing episode? I mean, I think I can guess what it is. Yeah. Okay. So the congenital effects of thalidomide are not gone. No. I couldn't find sort of exact numbers on what the epidemiology is worldwide. In most countries, thalidomide is very tightly regulated because of its effects, its teratogenic effects. So it's only given, you know, it's given under, like in the U.S., it's called the Class X drug, which means it's completely 100% absolutely contraindicated in pregnancy.

Generally, class X drugs, if you are a, person of reproductive age, you generally have to ensure that you're not going to become pregnant if you're going to use this drug. And so there's like a lot of regulation with that. Gotcha. Okay. And this is not just people with uteruses, actually, because the lidomide can be transmitted in the semen as well. So it's, I was wondering if you were going to bring that up. Yeah. So it's anyone of reproductive age. It's obviously most severe if you are a person with a uterus who becomes pregnant while you're using it, but it's anyone of reproductive age because it can be transmitted in the semen as well. But one place that there is some good data on kind of

the numbers of babies that are being born with psilidomide exposure today is Brazil. And that's largely because, first of all, there's groups that are actively studying it and doing active surveillance for it, but also because leprosy is common in Brazil compared to a lot of other countries. So I think I saw there are about 24,000 cases of multibacillard leprosy, which is the kind that is associated with this erythema nodosum that are diagnosed annually in Brazil. And so this study was looking at what the birth rate of thalidomide embryopathy was. And they found that in the period from 2000 to 2008, that rate has actually increased compared to the previous decades. So it's now 3.1 per 10,000 live births compared to about 1.9 per 10,000 live births from

1982 to 1999. What's going on? It's not clear. And this study really couldn't get a good handle on it. Thalidomide is tightly regulated in Brazil, but, you know, leprosy is also still a problem there. And so the study also reported that med sharing might also be contributing. So if we're not getting a handle on who exactly is taking thalidomide. And if people also, the other thing is that leprosy tends to happen in very rural areas and very remote areas where people might not have as much knowledge about thalidomide. Mm-hmm. Mm-hmm.

But the other thing is that the history that you told, Aaron, is not in the distant past. No. And I think that's another thing that, you know, when we learned about thalidomide in school, multiple times, you know, they show these black and white pictures and it makes it seem like this was so long ago. But it wasn't. This was like our parents' generation, right? Yeah, absolutely. And so babies that were born with anomalies or congenital defects due to thalidomite exposure are now adults living with these effects. And there are thousands of them. them across the globe. I think the estimate I saw was about 3,000 people living from like that

1960s cohort of thalidomide exposure. And there are a number of support groups. I think the internet has been wonderful for this and that people have been able to find other survivors and kind of connect with them. And there are a ton of different support networks and things across the globe in every different country where there are thalidomide survivors. And so now these are adults that are living with these quality of life issues. And there is a really interesting paper that came out last year that kind of specifically looked at this in UK thalidomide survivors. So we'll definitely link to that on the website as well. Awesome. Yeah. So I think that's really important to remember. This is this is not history. This is like it's still happening. Yeah, it is absolutely.

Shall we cite our sources so that people can do more reading and learn even more about this horrible tragedy? Absolutely. But actually, you know what I realized is that throughout that super long history section, there's one thing that I completely forgot to mention or touch on, which is etymology. But not of thalidomide, because we've talked about that. It's just like a shortening of its super long chemical name, but of teratogen. Erin, do you know what teratogen the origin is? Oh my gosh, no.

And I've never even thought about it. Yeah. I didn't realize it until I think I was reading one of these accounts, right? It was in a documentary. And it surprises me that it is still used because let me tell you. So the word teratology had been around since the 1800s, meaning like basically any sort of irregularity during any developmental process. So whether it was like in the womb or during puberty, not just humans, but also plants or whatever. But Teratogen was coined really only or started to be used really only in 1959.

But both of these share the same root, which is from the Greek tarato, meaning marvel or monster. What? And so literally Teratogen has monster in the name. Yeah. But I mean, and I would assume Jen is like, like it generates it or something. Right, right, right. So it's generating monsters. Wow.

That's awful. Isn't that horrible? We need a new word. I mean, I feel, you know, it's a word that right now it's so deeply, you know, embedded in medical literature and education. But it's kind of like, wow. Yeah. Yeah. I don't know.

I don't know what else to say about that. but I was dismayed to find that out. Wow. I am never going to forget that, Erin. Yeah, good. Wow. You're welcome. So, yeah, anyway, back to sources.

I read a few books for this. Medicine by Trent Stevens and Rock Brinner from 2009. And finally, Silent Shock, the men behind the thalidomide scandal and an Australian family's Long Road to Justice by Michael Magazanek. That was from 2015. And then finally, there's a documentary called Attacking the Devil. And that follows pretty closely the Suffer the Children's story. So more about the fight to get UK families justice from distillers.

And yeah. And so in addition to the firsthand account that I read, as I mentioned, there are many other personal stories on that website. And I'll post a link to that. But also, as I was doing the research for this episode, I also found that the Welcome Library did an oral history project for people who have been affected by thalidomide. And they have excerpts from the interviews on their sound. cloud account and also just more information on their website. So I'll post a link to those sources as well. Excellent. And I had a number of different articles, both about sort of the congenital effects of thalidomide as well as what we use thalidomide for today in terms of treatment. We'll post the full list of all of our sources for this episode. And you can find them from every single episode on our website. This podcast will kill you.com under the episodes tab. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. And thank you to you, listeners. This was a pretty depressing episode, but we think it's a pretty

important topic. So we really appreciate you sticking with us and making it through this episode. Absolutely. We hope you got something out of it. Yeah. Yeah. Okay. Well, Well, with that, wash your hands. You filthy animals. This is Special Agent Regal, Special Agent Bradley Hall. In 2018, the FBI took down a ring of spies working for China's Ministry of State Security, one of the most mysterious intelligence agencies in the world. The Sixth Bureau podcast is a story of the inner workings of the MSS and how one man's ambition and mistakes opened its fault of secrets.

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