The Devil in the Details: Chapter Three

The Devil in the Details: Chapter Three

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‍Katie Hafner: The fall of 1961 was a happening time.

President John F. Kennedy: Time for this great nation to take a leading role in space achievement…

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Katie Hafner:  There was a glamorous young couple in the White House with a president hell bent on going to the moon. The civil rights movement was gaining momentum. 

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James Farmer: The ride had become a symbol of the fight against segregation not only in southern bus terminals but everywhere.

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Katie Hafner: The swinging sixties were just revving up. Bob Dylan gave his first concert at Carnegie Hall and Brian Epstein heard the Beatles for the first time in Liverpool, England. 

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In Germany and elsewhere around the world , a sedative called thalidomide  had been selling like mad for several years. Chemie-Grünenthal, the manufacturer of that sedative, was profiting wildly.  

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But there was a pocket of people in a world of hurt. 

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I’m Katie Hafner, and this is the third chapter of The Devil in the Details, a special series from Lost Women of Science. In this episode, we explore the proverbial shit hitting the proverbial fan.

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Katie Hafner: In the fall of 1961 in the United States, Dr. Frances Kelsey continued to stall the application for thalidomide, much to the frustration of the manufacturer, William S. Merrell.  

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At the same time, in Europe, women by the thousands had given birth to children severely injured while in the womb. 

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And several doctors had taken notice. 

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Most notably, Widukind Lenz, the skeptical pediatrician, had been investigating for several months. He and Karl Schulte-Hillen, the father of one of these babies, were talking to   as many affected families as they could find.  

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But there was no obvious culprit. 

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Then, on November 11, the story began to shift. That day, Widukind had gone to meet a family, this time on his own. They were the parents of a girl born without arms. The mother mentioned she had taken Contergan, Grünenthal’s thalidomide-based sedative. 

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The following day, Widukind visited another family. As usual, he introduced himself and explained that he was trying to figure out what was causing these strange births. And for the second time in as many days, Contergan came up. The father told Widukind plainly he thought Contergan was the cause.

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Okay, Contergan had come up before, but it had never been at the top of Widukind’s list. Maybe because many of the families he’d interviewed did not mention Contergan. Or maybe he too had been influenced by the company’s bold safety claims.

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But two days in a row? This time, Widukind paid attention. He asked the father, what made him suspect Contergan? The father said he’d read that these tablets could cause nerve damage. (bBy then, the news about peripheral neuritis had reached the popular press.)

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After the meeting, Widukind called up Karl and he asked him this: Had his wife, Linde, taken Contergan during her pregnancy with Jan? Karl wasn’t sure. He’d have to find out.

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Katie Hafner: While Widukind Lenz was investigating in Germany, over in the United States, Frances Kelsey was still jousting with Merrell’s liaison, Joseph Murray.

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And if she was feeling the heat…well, Frances, in typical Frances “dare-me-to-raise-my-voice”  fashion, didn’t let on. 

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Katie Hafner: Yes. That’s all you’re gonna get out of the stoic Frances Kelsey.

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So, in the fall of 1961, Frances wasn’t letting Joseph Murray get to her. She wasn’t going to rush this product through if the application was incomplete. But Murray was DONE waiting.

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A full year had passed since the company had first submitted its application for Kevadon, Merrell’s thalidomide drug. And with another holiday season looming and visions of pill bottles dancing in the heads of Merrell’s executives— Murray decided to call in the big guns. 

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He brought a group of clinical investigators to the FDA to talk about their experiences with Kevadon. They were physicians and some professors who were consulting for the company or working in some capacity under contract.

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The idea was to show Frances that credentialed doctors and researchers backed Merrell’s claims about Kevadon, and put more pressure on the FDA to bring the drug to market quickly.

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But as pro-Kevadon as these hand-picked attendees were, some of them asked questions about Kevadon.

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Questions Frances had been asking for months.

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And one of her questions was about the safety of this drug in pregnancy. 

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Katie Hafner: Frances happened to know quite a bit about how drugs could affect embryos… Because during World War II, Frances and her future husband, Ellis, worked in Eugene Geiling’s lab investigating new antimalarial treatments. It was part of a nationwide effort to treat soldiers fighting in malaria zones.

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Trent Stephens: It put her in a unique, an absolutely unique position in my opinion.

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Katie Hafner: Trent Stephens is the co-author of “Dark Remedy,” a book about the history of thalidomide. He’s also a developmental biologist, who’s studied thalidomide’s effects on embryos. And he says that during her time in Geiling’s lab, Frances got to work with quinine—a well-known antimalarial medication. She and Ellis Kelsey were testing how rabbits broke it down in their livers. And that included pregnant rabbits.

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Trent Stephens: One of the things they learned during their research on quinine is that it passes the so-called placental barrier. 

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Katie Hafner: In quinine’s case, Frances was fascinated to discover that rabbits in utero processed quinine very differently than adult rabbits did.

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Adult rabbit livers are very good at breaking down quinine. Which is important because if your body doesn’t break down a drug, it can accumulate in your system beyond what’s safe. 

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And it turned out that fetal rabbits cannot break down quinine at all.

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Katie Hafner: So Frances Kelsey knew that just because a drug didn’t seem to hurt an adult, that didn’t mean it wouldn’t hurt a developing embryo. In fact, during her own pregnancies, she was very careful about taking ANY drugs.

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And actually, around the time Frances joined the FDA, there was a growing understanding of this: children, babies, and fetuses aren’t just adults in miniature. Their bodies work differently. So you can’t assume that because a drug is safe for an adult, it will be safe at other stages of development. So even though in the fall of 1961, Frances knew nothing about what was happening in Europe, she asked Merrell about safety during pregnancy. And it wasn’t the first time. She’d asked about it a few months earlier too, and she didn’t get a satisfactory answer.

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Now, Merrell did have some evidence about the use of thalidomide in pregnancy. The company told Frances they weren’t aware of any problems—but the company only tried it out in late pregnancy.

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Frances didn’t think that was good enough. The FDA needed to know what happened if thalidomide was taken throughout pregnancy. And she was right to insist on that. As we know now, thalidomide is most damaging when taken in the first few weeks. But Merrell refused to conduct such a study, of course, conducting another study would mean yet another delay in getting this drug to market. But Merrell did agree to add a warning to its labels indicating that thalidomide’s effects on pregnancy were not known.

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Still, Frances Kelsey was not ready to approve the drug. And that should have been enough to keep Americans safe, right? The drug wasn’t for sale in the US.

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But here’s the problem: while Merrell and the FDA went back and forth about labeling and studies and paperwork, hundreds of pregnant women were already taking thalidomide in the United States. Some had brought it back from overseas. But many of them got thalidomide from their doctors. Because Merrell had distributed Kevadon, its thalidomide pill, across the United States, without any FDA approval or oversight… And back then, that was completely legal.

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Gwen Riechmann: The dogs are going to, this is going to take a moment. Sorry. 

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Elah Feder: It’s okay. I think- I think it’s inevitable the pets are going to feature in this.

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Katie Hafner: Gwen Riechmann lives in Cincinnati with a menagerie of pets.

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Gwen Riechmann: I have two Shelties. and two cats.

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Katie Hafner: Elah, our senior producer, called Gwen up on Zoom a few months ago. Gwen closed the door to keep the pets out, but some were insisting on joining anyway.

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Gwen Riechmann: Um, that sounds like Arwen. The small female who's making all the noise at the moment. She has to say something about everything.

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Katie Hafner: Gwen is in her early 60s now, and she’s a thalidomide survivor. She was born in Cincinnati in May 1962. And pay attention to that date. May 1962, at least a year after Frances Kelsey first asked Merrell for evidence that thalidomide was safe to take during pregnancy.

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Gwen Riechmann: I was born with phocomelia of both arms, which means my arms are short and misshapen. One arm is eight inches. The other arm is 12 inches in length. And both feet are clubbed, meaning they literally look like golf clubs. 

Katie Hafner: Until she was about five, Gwen could walk and play tee ball with her brothers in the backyard by moving around on her knees. But later, surgery that was meant to help her actually made it harder for her to walk, and she started using a wheelchair. Gwen says that when she was growing up, her parents encouraged her to be as independent as possible, and in general, took a “tough love” approach to raising a child with a disability.

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Gwen Riechmann: For instance, if I tried to get them to do something like go get something for me that my parents knew I could do, my parents would say, are you handicapped or something? Go do it yourself. 

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Katie Hafner: Gwen says she didn’t ask her parents a lot of questions about her disability because it was clear they didn’t want to talk about it. So, for years, she assumed her phocomelia was genetic. There are, in fact, very rare genetic conditions that cause phocomelia—the shortening of the limbs. But Gwen’s condition wasn’t genetic.

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Gwen Riechmann: I didn't actually hear the word thalidomide until I was like 7th, 8th grade. 

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Katie Hafner: Gwen went to a public school for kids with physical disabilities. And, like at most schools, around middle school, the teachers split up the boys and the girls to talk about sex education.

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Gwen Riechmann: And they said if anybody wants to, find out if you could pass your disability on to a baby we'll be happy to talk to you. And so when I came home that night, mom said, “So how did it go?”

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Katie Hafner: So Gwen told her mom about the baby conversation, and she said she didn’t have a lot of questions for the nurse because she already knew her condition was genetic.

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Gwen Riechmann: And my mom said, well, that's not actually the case. And I said, well, what is it then? And that's when she said, it's from a drug called thalidomide that I was given when I was pregnant with you. And that was it. Conversation over.

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Katie Hafner: Gwen eventually learned that her mom had been given thalidomide sometime around October, 1961, during her first weeks of pregnancy. 

In October, 1961, Kevadon was, of course, not for sale in the United States. Frances Kelsey hadn’t approved the drug. But just because the drug wasn’t approved, didn’t mean the company couldn't distribute it in “clinical trials.”

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Now, when I use the phrase “clinical trials,” you might be imagining a rigorous, placebo-controlled study, with patients systematically recruited, and symptoms carefully tracked on clipboards. 

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Well, that’s not how things worked back then.

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Drug companies didn’t actually need approval from the FDA to conduct a clinical trial. All they had to do was turn in whatever results they had come up with when they submitted the drug to the FDA for approval. Okay, we don't know for sure, but theoretically, for instance, they could ask, you know, a hundred, a thousand, ten people. Gee, how do you feel on this drug? And somebody could say, Oh, yeah, pretty darn good. …

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But what Merrell had done to come up with its results…. Well…it almost defies belief.

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Katie Hafner: In 1958, after Merrell first got the license from Grünenthal to sell thalidomide, the company got busy recruiting doctors to test the drug. Merrrell was based out of Cincinnati, and one of those doctors was a Cincinnati obstetrician named Ray Nulsen. He just happened to be a friend of Merrell’s director of clinical research, Raymond Pogge. And I think the Nulsen/Pogge story tells you everything you need to know about these so-called clinical trials.

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Nulsen treated a few hundred pregnant women each year, and Pogge asked Nulsen to try out thalidomide with these patients to help calm their nerves at night. In June 1961, Nulsen published a paper in the American Journal of Obstetrics and Gynecology titled 

 “Trial of thalidomide in insomnia associated with the third trimester”. The paper had a very upbeat conclusion: thalidomide was a safe and effective sleeping agent for use in late pregnancy.

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But here’s what would eventually come out: Ray Nulsen didn’t actually write that paper. Later on, in a legal deposition he admitted that Raymond Pogge, his buddy at Merrell, had written the whole thing. The lawyer doing the deposition asked him, how about all the papers cited in that article? Did you read those? Nope. Okay, so what about all the data—do you have copies of the reports you sent to Merrell?

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Nulsen said, no, it was all verbal and he explained it was quote “by telephone, or it may have been that we had lunch together, or it may have been when we played golf.”

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Dr. Ray Nulsen… was the doctor who treated Gwen Riechmann’s mom.

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Gwen Riechmann: she did say that she had only taken one dose of the thalidomide that she was given.

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Katie Hafner: But that one pill was enough. 

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Neil Vargesson: There are studies going back to1990s, early 1990s that suggest just one tablet  is enough to cause damage to the embryo.

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Katie Hafner: Neil Vargesson is a professor of developmental biology at the University of Aberdeen in Scotland. He’s done extensive research on thalidomide’s effects. We now know that one of the main ways that thalidomide harms embryos is by blocking angiogenesis, the development of blood vessels.

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Neil Vargesson: It's the action of the drug on the blood vessels that's causing the damage. And as you destroy the blood vessels, you then get cells dying off. And it does it in a time dependent way.

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Katie Hafner: So if an embryo is exposed to thalidomide when the arms are forming, the blood vessels feeding those tissues will die and the arms won’t grow. Same with the ears, the heart, the brain…

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Neil Vargesson: It's as simple as that. You've got to remember that, oads of things are forming at that point. It's not like the limbs form, and then the ears form and then the nose forms.Now, they're all forming at the same time. So that's why many survivors have got multiple damages and no two survivors look the same. They all look unique because it was depending on when their mum took the medicine. 

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Katie Hafner: There’s a critical two-week window for the kind of harm typically associated with thalidomide, and that window starts roughly three weeks  after fertilization. When thalidomide is taken in that window, you can find effects on arms, legs, hearts… all the symptoms we’ve mentioned before. But harm isn’t restricted to that two-week window.

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Neil Vargesson: if you took the drug before the so-called time sensitive window, you'd end up in a miscarriage because you can imagine all the blood vessels will be destroyed.

There will be no blood vessels, so there's no embryo. And if you took it after the so-called time sensitive window, you might not see damage to limbs. But you would see internal organ damage and possibly brain damage as well. 

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Katie Hafner: In October 1961, when Gwen Riechmann’s mother took that pill early in her pregnancy, she wouldn’t have known any of this. Her doctor wouldn’t have known either. At the time there were, at most, suspicions about thalidomide. But it was only a few weeks later, across the Atlantic, that Widukind Lenz had two fateful interviews with two families in Germany, both naming the same suspect: Contergan. So after years of women taking this damn drug, Finally Widukind Lenz was about to set things in motion 

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And here’s how it all unfolded. In November of 1961, after months of investigating these mysterious births, aggrieved father, Karl Schulte-Hillen, and dogged pediatrician, Widukind Lenz, had gumshoed their way to a prime suspect: Contergan. 

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Here’s author Jennifer Vanderbes again:

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Jennifer Vanderbes: The tough part of this story is that once Karl realizes it's this drug, he has to go back and ask his wife if she took it.

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Katie Hafner: At first Linde Schulte-Hillen couldn’t remember even taking Contergan—the German version of thalidomide. But then a memory surfaced. A year earlier, when Linde was only one month pregnant, her father had died. The family had traveled to attend his funeral. It was a stressful time, nerves were frayed, and at the end of the day, the whole family took a sedative, including Linde who was pregnant.

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Jennifer Vanderbes: She took one or two and that, in the first trimester of pregnancy early on, immediately affected Jan in his development.

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Katie Hafner: On November 15, 1961 Widukind called Grünenthal. He reached a man named Heinrich Mückter. We could dedicate an entire episode to just this guy. But the important thing to know right now is that he wasn’t just any Grünenthal employee. He was the company’s chief science officer, and he had played a key early role in thalidomide, and he got a cut of every package of thalidomide sold.

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Widukind told Muckter that Grünenthal needed to take the drug off the market immediately, and the next day, he put that request in writing. And he did not mince words. He wrote in his letter that simply waiting for proof that the drug was harmless was indefensible. This drug should not be sold until it was conclusively shown to be SAFE.

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And then, that weekend, Widukind attended a pediatricians’ conference. And during a session about the uptick in phocomelia cases being seen around the country, he stood up. Widukind said that he had identified a substance that might be to blame. He couldn’t yet prove that it was the cause of these injuries, but it was conceivable, and so as a citizen he could no longer remain silent.   

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Jennifer Vanderbes: He didn't want to name the drug, but he says there is a drug. We're pretty sure it's causing this epidemic of phocomelia.

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Katie Hafner: And he made an urgent plea–right there in public–that the unnamed “substance” be withdrawn from the market immediately. He warned that each month's delay meant dozens more babies would be harmed.

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Early the following week, Grünenthal sent three representatives to meet with Widukind Lenz in person. He was ready to present his case, but he wanted witnesses present for this conversation, and so in the afternoon of November 20th, they met along with three representatives from the Hamburg University clinics and four from the Hamburg health authorities.

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It was, by all accounts, a tense meeting. Grünenthal wanted Widukind to hand over all of his materials. But some of that was confidential patient information, and some was property of the Hamburg clinic, and it wasn’t his to hand over. The Grünenthal side said if he didn’t turn the material over to them, then any delay in action would be his fault. He said he’d consult with a lawyer and the group would reconvene the next morning.

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The following morning, he gave them copies of his redacted notes. Now Grünenthal tightened the screws. The representatives said there would be legal ramifications if Widukind made false accusations against the company. And Widukind asked  them flat out— would they guarantee they would not use the material he presented in lawsuit against him? No, they said, they couldn’t guarantee it.

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So They scheduled another meeting for later in the week Friday, November 24th, this time in Dusseldorf with representatives of the regional health ministry. Widukind later described being repeatedly interrupted by the Grünenthal’s representatives as he tried to present his evidence, but this time, he took an even firmer stand. No, he said, he couldn’t say the case was definitively proven, but the evidence was overwhelming and there could be no reasonable doubt.

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Katie Hafner: I want to take a minute – or maybe a minute and half - to talk about this man, Widukind Lenz. Here you have the son of a Nazi, and not just some run-of-the-mill Nazi… Fritz Lenz, let me remind you, was a prominent eugenics specialist who endorsed racial cleansing even before Hitler. And he believed that disabled people should be sterilized – i.e. forcibly prevented from reproducing. Fritz Lenz was still very much alive and espousing his eugenic theories when his son took on Chemie Grünenthal, in the name of every single infant severely disabled at the hands of bad medicine.

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Like his father, Widukind later became a geneticist. But not only did this apple fall far from the tree, it rolled as far away as possible. I can only imagine the courage it must have taken for the younger Dr. Lenz to do what he did in 1961, still not even a generation removed from the Third Reich.

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Like Frances Kelsey, Widukind Lenz was no grandstander. The two people hadn’t met each other, of course. From what we can tell from the scant bit of audio we’ve heard, Widukind was soft-spoken but self-assured. And like Frances, he came across as …. maybe a little dry… a thorough dot-all-your-i’s-and-cross-all-your-t’s person.

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Katie Hafner: So you can imagine the level tones he must have used when meeting with Grünenthal’s representatives. In the end, the Grünenthal people did agree to add a label warning not to use Contergan during pregnancy. 

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But then they left, and Widukind kept talking to the government people. This time, without  the Grünenthal crew in the room, Widukind presented his materials more fully. And it was decided - a warning label was not enough. Quietly withdrawing the drug from the market would not be enough. No, as one doctor at the meeting put it, “It must disappear out of the last drawer in every house," The word had to get out. The state Ministry of the Interior would immediately send cables to local health departments telling them to stop the sale of thalidomide and contact other state governments to warn them as well.

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Then things really exploded. Someone who’d heard Widukind’s speech at that pediatrician’s conference had gone to the press and on Sunday, November 26, the newspaper, Welt am Sonntag published a story that shocked the public. The headline: “Birth defects due to pills?”  

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Jennifer Vanderbes: Grünenthal completely loses its mind in panic the second they realize that the game is up.

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Katie Hafner: Within a few hours of the publication of that story, Grünenthal announced that it was removing  Contergan from circulation until questions about phocomelia were resolved.

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And the next day, Grünenthal sent out warnings to doctors and pharmacies but they didn’t say this was a potentially dangerous drug that they were withdrawing to keep the public safe. Listen to this wording from a message they sent to the West German Federal Medical Association. As Grünenthal explained it, the decision came quote “because press reports have undermined the basis of scientific discussion.”

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But the pressure continued to mount. The West German Ministry of Health put out an urgent warning to women, telling them the pill suspected in these births was thalidomide. And urging them: DO NOT TAKE THIS DRUG.

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One other thing that happened—Grünenthal had to alert all the companies it had licensed this drug to. And so, on November 29th, William S. Merrell received a cable from Grünenthal letting the American company know that there might be an issue with thalidomide–a possible association with injured babies—they were withdrawing it from the German market. The next day, Joseph Murray called the FDA. He had some disquieting news.

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Katie Hafner: Next time on The Devil in the Details…

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Sherri Chessen: “My doctor said, the abortion has been canceled. They don't know who it is, but the county attorney knows that someone here in Arizona is going to have an abortion and they will do a citizen's arrest.”

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Katie Hafner: Elah Feder was senior producer for this episode, and Deborah Unger was senior managing producer. Sarah Wyman was producer. Our associate producer is Mila Rahim. Sophia Levin and Eva McCullough provided research support.

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Our music was composed by Lizzy Younan - except for the very first piece of music you heard in this episode, which is called “Brit Pop,” by Scott Holmes Music. 

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We had fact checking help from Lexi Atiya. Alexa Lim edited the audio. Morgane Fouse mastered this episode. Lisk Feng created the art for the season and Lily Whear did the art design.

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Thank you, as always, to my co-executive producer, Amy Scharf, and to Eowyn Burtner, our program manager. Thanks also to Jeff DelViscio at our publishing partner, Scientific American. We're distributed by PRX.

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Funding for Lost Women of Science comes in part by the Alfred P. Sloan Foundation and the Anne Wojcicki Foundation. 

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For a transcript of this episode or to learn more about Frances Kelsey, please go to our website, lostwomenofscience.org and do not forget to hit that all-important omnipresent donate button.

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See you next week!