Podcast: The blindsiding history of retinol

 

C&EN’s award-winning podcast Inflection Point leans on our 100-year archive to trace headline topics in science today back to their disparate and surprising roots. In each episode, we explore three lesser-known moments in science history that ultimately led us to current-day breakthroughs. With help from expert C&EN reporters, this show examines how discoveries from our past have shaped our present and will change our future.

In this episode, hosts David Anderson and Gina Vitale travel as far back as ancient Egypt to unearth the wide-ranging uses of retinol. They also bring in C&EN reporter Craig Bettenhausen to discuss why retinol is such a powerhouse molecule for skin care, and they hear from a contraceptives researcher about how an early candidate for a birth control pill for men affected the retinol pathway.

Subscribe to Inflection Point now on Apple Podcasts, Spotify, or wherever you get your podcasts.

The following is a transcript of the episode. Interviews have been edited for length and clarity.

David Anderson: So, Gina.

Gina Vitale: Yes, David.

David: Do you know where we are right now?

Gina: Well, it’s very hot. A lot of sand.

David: Yeah. Well, I’ll spoil it for you. We’re in Egypt.

Gina: Egypt. OK. And my phone is not exactly working, so I’m guessing we’re pretty far back in time?

David: They haven’t invented cell-phone towers yet, so no service out here. I guess I should have said earlier: ancient Egypt, 1500 BCE.

Gina: David, what are we doing here? Why did you bring us to ancient Egypt?

David: OK. Well, we are here standing in front of the pyramids to discover the little-known origins behind a molecule that I think you might recognize: retinol. Ever heard of it?

Gina: Retinol?

David: Yeah, retinol.

Gina: Like the skin-care antiaging treatment, retinol?

David: That’s the one, but its uses go way beyond skin. It’s a pretty important molecule since, well, I don’t know.

Gina: Since ancient Egypt?

David: All right. Now you’re getting it.

Gina: OK.

David: But buckle up because this adventure, it takes some twists and turns.

Gina: Some twists and turns?

David: Later in this episode, we’re going to visit a prison in 1951 to learn the dark and sinister origins of retinol as a skin-care cream.

Gina: OK. Not looking forward to that. But we’re also going to explain how retinol works for skin care and explain the difference between the different types of retinol.

David: And also later in the episode, we’re going to go to 1959 and see how retinol and parasitic worms helped lead to a potential new kind of birth control for men.

Gina: Right. We’ll explain how retinol plays a surprising and important role in many different parts of the body, like the eyes and the reproductive system.

David: Sounds like we’ve got a killer ep loaded up, GV. Are you ready?

Gina: Oh, boy. Yeah, I’m ready.

David: Then let’s go back in time.

Gina: This is Inflection Point.

David: Spanning a century of reporting from C&EN, this podcast traces discoveries from our past—

Gina: —to how they shape our present—

David: —and will change our future.

Gina: I’m Gina Vitale.

David: And I’m David Anderson.

Gina: So today you and me are going back in time to trace the disparate and surprising roots of retinol.

David: Exactly.

Gina: And the first one is in ancient Egypt?

David: Right here in ancient Egypt.

Gina: OK.

David: Now, I think we’ll try to make it over to this ridge here.

Gina: Hold on, David, let’s just take a second here and explain what retinol is.

David: Fair enough.

Gina: Right? For the people who might not know? So in the pop culture right now, I’m thinking of TikTok videos—

[Voices that sound like they’re from social media videos say, “If you’re new to using retinol…” and “You should be using a retinoid…”]

Gina: Instagram Reels. Retinol is talked about a lot as a skin-care ingredient. You will find all kinds of influencers—

[A voice that sounds like it’s from a social media video says, “If you haven’t started using a retinol yet, this is your sign.”]

Gina: —and even dermatologists—

[A voice that sounds like it’s from a social media video says, “I’m a dermatologist.”]

Gina: —talking about how retinol can prevent wrinkles, improve the appearance of skin, reduce acne, give someone a “glow.”

David: Right. I think it’s safe to say that retinol is dominating the skin-care conversation right now, but it didn’t start that way.

Gina: What do you mean?

David: Well, the earliest use of retinol, as far as I can figure, wasn’t for skin at all. Let’s turn our attention back to the scene at hand. Do you see that guy over there roasting something gross over a fire?

Gina: Yeah, that does look gross. What is that?

David: It’s ox liver.

Gina: OK, David. I’m going to get out in front of this right now. I am not eating ox liver.

David: OK.

Gina: Seriously, dude, there is not a chance. You have made me do some weird stuff on this show. I see that guy coming over here. There is a 0% chance.

David: OK.

Gina: David, I’ll leave this podcast right now.

David: Just let me cut in real quick. You always assume the worst.

Gina: I swear to God, David.

David: And I have to tell you, you don’t have to eat the ox liver, all right? OK?

Gina: OK.

David: Just relax.

Gina: OK. I feel like I had an outburst there. I apologize.

David: Well, apology accepted.

Gina: Please go on. What is going to happen with the ox liver?

David: You rub it on your eyes.

Gina: I have to what?

David: Yeah, this will make perfect sense. You have to—

Gina: David.

David: Yes?

Gina: David, I’m out. I’m not going to do this.

David: Not really a team player.

Gina: Are you going to rub it on your eyeballs?

David: Of course. You said this fellow, trundling over here with this ox liver, can you imagine how sad he’s going to be when he gets here and we go, “No, I think this is gross. I don’t want ox liver on my eyes. I’m from the 21st century”? OK. Back to the subject at hand. Records suggest that ancient Egyptians rubbed roasted ox liver in the eyes of people experiencing night blindness.

Gina: Oh, man.

David: And they’re not even the only civilization to do this. Multiple cultures have done variations of this: the Egyptians, as we’ve just seen, the Babylonians, the Greeks have also done this. A lot of cultures, a lot of people.

Gina: And peer pressure, David, is not going to work on me.

David: Each of these ancient civilizations zeroed in on some kind of liver as a cure for night blindness.

Gina: Interesting.

David: Some applied it directly to the eyes like here in Egypt with the ox. Others would eat it. In ancient Greece, they ate cow liver. Liver happens to have a lot of retinol.

Gina: Look, it’s not my personal taste, but it does scientifically make some sense that liver would help with night blindness.

David: Right.

Gina: So, in our eyes, we have molecules called photopigments. Photopigments help us see. More specifically, they absorb light, which sets off a chain of chemical reactions and ultimately results in an electrical signal to the brain. That signal is what allows you to quote-unquote see.

David: So photopigments basically take in the light and start the process of converting that into an image that my brain can interpret. It all starts with these photopigments.

Gina: Exactly. And there is one particular photopigment called rhodopsin that allows us to see at night. Can you guess what our bodies make rhodopsin from?

David: It’s retinol, right?

Gina: Exactly. Right.

David: OK, perfect.

Gina: We need retinol to make the photopigment, which allows us to see at night. So it makes sense that by feeding or otherwise applying liver rich in retinol—

David: They get creative with that.

Gina: Exactly. Applying liver rich in retinol to someone experiencing night blindness, it could help make it better. In fact, retinol is part of a group of compounds called retinoids, and retinoids get their name directly from their connection to, as you might guess, the retina.

David: OK. So that’s why this liver method existed across cultures: because it really did work.

Gina: Probably. Now, even though it may have worked, people didn’t really know what retinol was for a while. We understand a lot more about it now.

David: “We understand a lot more about it now.” Who’s this “we,” Gina? Do you have a mouse in your pocket?

Gina: Maybe I understand more about it. Let’s go through it together.

David: OK.

Gina: So retinol is actually one molecule in a family of related molecules, which are all kind of relevant in this episode.

David: OK. And these are retinoids, right? Like you mentioned earlier?

Gina: Right.

David: What makes something a retinoid?

Gina: Good question. Basically, retinoids are a group of structurally similar compounds that are all derived in some way from vitamin A. The terminology here gets a little tricky. Some people use the term retinol interchangeably with vitamin A, and some people use vitamin A as an umbrella term to refer to several different related compounds. To simplify things for the sake of this podcast, when we say vitamin A, we’re going to mean retinol, and vice versa.

David: OK, got it. So vitamin A equals retinol, and retinoids are a particular group of structurally-similar chemicals.

Gina: Yes. And as we mentioned before, a lot of people will probably recognize retinol and other retinoids from skin-care and antiaging products. They’re really having a moment right now.

David: You’re telling me. I can’t go three TikToks without getting some sort of influencer trying to sell me a retinol product.

Gina: I know.

David: Gina, it is making me kind of insecure. Do you see this? Do you see these on my forehead, these wrinkles, These lines, right?

Gina: Oh, no.

David: They are there, right? I mean, you can, clear as day, anyone could see it.

Gina: No, you don’t have wrinkles, David.

David: OK. Give it a second look. I mean, one more.

Gina: I have to really get in there?

David: They’re there. There’s wrinkles.

Gina: I think that you have ageless skin, David, but if you were worried about how your skin is aging, you could consider taking a retinol.

David: Right. OK. Let’s drill in on this. How does a retinol help?

Gina: So in a few ways, actually. It can reduce the appearance of fine lines and wrinkles, which seems like maybe that’s on your mind. It can also help with hyperpigmentation on your skin like dark spots. It can also help with acne by preventing your pores from getting clogged.

David: That sounds kind of like a Swiss Army knife of skin care.

Gina: Yeah.

David: How does it do all that?

Gina: Yeah, great question. So, in the body, retinol actually gets transformed into other retinoids. First, retinol gets converted to a very similar compound called retinaldehyde or retinal.

David: OK. So in the body, retinol, spelled R-E-T-I-N-O-L, gets turned into this slightly different thing. The O turns into an A, R-E-T-I-N-A-L, retinal?

Gina: Right. It’s a little confusing, but yes. Then the retinal, A-L, gets converted into retinoic acid. Retinoic acid is actually the key active chemical here that is responsible for the antiaging effects. For instance, retinoic acid stimulates our skin to make collagen. It also inhibits some enzymes that break down collagen. It also thickens the epidermis, which is the outer layer of skin, and increases the turnover of dead skin cells. This all leads to our skin looking more even and healthier and younger.

David: Right. More even, healthier, younger. I mean, is that why your skin is always looking so good? Glowing, radiant, like a woman from a Gustav Klimt painting?

Gina: Well, that’s very flattering, and I think that in this particular context, this is just the warm glow of the Egyptian sun.

David: Golden hour, they say.

Gina: But I do use a retinol every night.

David: OK. I’ve been meaning to ask you about that. I want to get into the retinol game.

Gina: Welcome.

David: I don’t know if you could tell. I do quite a good job of hiding it, to be honest, but I am a little bit nervous about some of these wrinkles that I have on my face that have been appearing in recent years.

Gina: Yeah, I was starting to get that impression earlier, that you might have some anxiety there.

David: Like I said, I hide it very well. But when I go to the drugstore or even open up my Instagram, I’m kind of overwhelmed by the options. There are literally thousands.

Gina: Sure.

David: So what’s the difference between all these kinds of retinoids?

Gina: Yeah. So remember how we talked about retinol getting converted to different retinoids in the body?

David: Yeah.

Gina: Some of these products contain retinoids that are further along in that pathway than others. So I take retinol. That undergoes two conversions in the body to become retinoic acid, the active chemical. So retinol is one of the gentler options.

David: OK. It’s at the starting point of that pathway, that process.

Gina: Yes. Got it. So some people take products with retinal, A-L, which is the next step in the conversion pathway. Because this is only one step away from the active chemical, it’s a little stronger than retinol, O-L.

David: Got it. OK. So that next step in the pathway, retinal, does that work better than the first step, retinol?

Gina: It’s more potent. For some people, that works better. For some people, that’s a little harsh on their skin.

David: Got it. OK. We’ve got retinol. That’s the first step on the pathway. Retinal, that’s the second step on the pathway. I remember there was a third step. Is there some sort of cream that is just retinoic acid?

Gina: Exactly. The most-potent options are products with retinoic acid. That’s the ultimate active chemical. For instance, you might recognize the brand name Accutane. That’s a prescription-only treatment for severe acne, and that contains a form of retinoic acid.

David: They’re really strong stuff, right?

Gina: Right. And we should also say there are differences in concentration, too, in a lot of these products that can also really affect the potency.

David: OK. So which one would you suggest for me, GV? Money is no object. I want to look like I am 19 for the next 50 years. I think that shouldn’t be that hard.

Gina: I would suggest—

David: Your voice kind of went up a little bit.

Gina: Oh, did it?

David: Are you a little skeptical?

Gina: I would suggest that you talk to your dermatologist because everybody’s skin is different. And I would maybe not get your hopes up about looking 19.

David: I guess that’s a little ridiculous. Maybe 20 then.

Gina: Oh, boy.

David: All right. Fine, I will do my skin-care journey on my own time, perhaps with someone who is more receptive to my ideas. But thanks to you, I do have a much better understanding of how retinoids work and all the different kinds there are out there.

Gina: You’re very welcome, David.

David: But when should people start taking it back to my goal of looking 20? Would it have helped if I took it way back then?

Craig Bettenhausen: Except for the medical applications, it is a purely aesthetic choice.

David: That voice sounds very familiar to me.

Craig: Hey, David and Gina, happy to be back again.

Gina: Yeah, that’s Craig Bettenhausen. He appeared in our first ever Inflection Point episode.

Craig: I’m a senior editor, a business reporter at Chemical & Engineering News, and one of my several areas is personal care and cosmetics.

David: OK, Craig, give it to me straight. Is it already too late for me to take retinol this far into my “chopped unc” era?

Craig: So part of the answer is, “You don’t ever need these things. You’re a beautiful person,” whatever. But when you start to see the visible signs of aging, so for a lot of people that’s in their mid-30s, say they start to see some of these effects, it depends on how well you take care of your skin and what your standards are.

David: In my 30s, huh? OK. Close enough. Maybe it’s not too late for me after all.

Gina: That’s good. I’m glad we’ve narrowly avoided a total vanity-fueled meltdown from you.

David: Just by the skin of our teeth, GV. Yeah. We’ll see how the rest of the episode goes, but back to the retinol timeline. We haven’t really talked about what happened in the time between using retinol to treat night blindness and using it on skin.

Gina: That’s true. I’m actually not really sure how we figured out that retinol could make our skin look better.

David: That’s where my little history part comes in. Let’s go back to 1951.[Inflection point sound effect: digital blips and tape-rewinding whir]

Gina: OK. Using my powers of deduction here, it looks like we’re in a prison.

David: Yeah.

Gina: I’m guessing this is your prison inflection point that you mentioned. What are we doing here exactly?

David: I will get to that, but before I do, I do want to give a genuine content warning. I’m sure you can tell from our surroundings here that this is a kind of gloomy inflection point. The story involves some really unethical treatment of people incarcerated here, but I do think this is an important story when it comes to retinol.

Gina: Right. Part of having a science history show should be acknowledging when science has done wrong.

David: And in this case, it has done quite a bit wrong.

Gina: OK, lay it on me.

David: So this story concerns a drug called tretinoin. It’s a retinoid that is prescription strength.

Gina: Right. Tretinoin contains a form of retinoic acid, which, as we discussed before, is the most potent retinoid in the pathway.

David: Right.

Gina: It’s the active chemical, so it’s pretty powerful stuff.

David: Yeah. Even in moderate doses, it can still cause a lot of side effects—rashes; dry, irritated skin; burning sensation; itching or stinging sensations—a lot of uncomfortable stuff.

Gina: Yikes. Though, to be clear, this does not happen to everyone who uses it, but I definitely get why tretinoin is a prescription-only cream.

David: So tretinoin was approved by the US Food and Drug Administration in 1971, and it’s still sold under the brand name Retin-A, but before it got approved, it had to be tested.

Gina: Oh no, David. Please don’t tell me that’s why we’re at this prison.

David: Sadly, yes. Actually, according to the New York Times, up until the ’70s, 90% of all pharmaceutical products were tested on incarcerated people. Testing for tretinoin was done here, among many other tests that involved hundreds of people spanning decades, right here between these very walls, and much of it was very, very—how should I put this?—morally reprehensible

Gina: Yeah, I think “morally reprehensible” is good.

David: So, between 1951 and 1974, a team of researchers led by dermatologist Albert Kligman ran many experiments here. They had contracts with chemical companies like Dow, pharma giants like Johnson & Johnson, and even the United States Army.

Gina: OK. We’ll have to circle back to some of those things, but for now, let’s get back to the retinol thread. You mentioned Kligman was testing tretinoin.

David: Right. And yes, there were a ton of terrible experiments which we don’t have time to get into. There’s just too many. For the whole story, anyone curious should check out the book Acres of Skin by Allen M. Hornblum. That was the book that really broke the story open to a wide audience for the first time. But back to tretinoin. Remember when I said that even a moderate dose can have pretty painful side effects?

Gina: Yeah.

David: A common dose for tretinoin is a concentration of 0.025%.

Gina: OK.

David: Dr. Kligman was using a 1% concentration.

Gina: Hold on, hold on—1%?

David: Not zero-point anything: 1%. Yeah.

Gina: That’s 40 times a common dose we now use for a prescription retinoid?

David: Yeah, exactly 40 times. According to Acres of Skin, Kligman told Philadelphia magazine, “I damn near killed people before I could see a real benefit. Every one of them got sick.” And if you think he said those words with contrition or regret, hold on to your hat.

Gina: Oh, man, this is dark.

David: Of his experiments at Holmesburg [Prison], he also said, “Things were simpler then. Informed consent was unheard of. No one asked me what I was doing. It was a wonderful time.”

Gina: Oh, that is nauseating. That is absolutely horrible. So this person, through doing these sadistic experiments, found out that retinoids could be used in skin care?

David: Well, as you mentioned, retinoids can help reduce acne and wrinkles on your skin. It was Kligman who discovered that one retinoid in particular, tretinoin, was very effective. He and Johnson & Johnson patented the drug for commercial use, and like we mentioned, it’s still on the market to this very day.

Gina: That is a bleak inflection point for the history of retinol.

David: Yeah.

Gina: And you said Kligman was involved in other experiments at this prison too?

David: Unfortunately, a lot of them. One contract Kligman had with Dow involved placing microscopic amounts of dioxin on incarcerated peoples’ skin, between—

Gina: Sorry, dioxin? Isn’t that Agent Orange?

David: The very same. Yeah. Kligman was asked to apply between 0.2 and 16 μg to peoples’ skin.

Gina: That is unbelievable.

David: It really does sound painful and cruel already. But get this, Kligman delivered hundreds of times that dose. So instead of 0.02 or 16 μg, he would place 7,500 μg of this stuff on peoples’ skin.

Gina: OK. Just doing some math again, that’s 486 times the maximum dose Dow asked him to test?

David: Yes. Yeah. And Dow claims that they were taken completely by surprise by Kligman’s methods. They ended their contract with him, and in the book Acres of Skin, a Dow employee at the time says the data Kligman gave them was totally unusable.

Gina: Wow.

David: Meanwhile, the men who were being tested were left with painful lesions and blisters on their skin.

Gina: I’m speechless. This is some very dark history.

David: It’s beyond the pale. Yeah, it’s so ridiculous. And people were paid such paltry sums to participate in these tests. In all my research, I couldn’t find a single instance of anyone getting more than $25 per experiment.

Gina: Absolutely unreal. Now that this story has come to light, has anyone received real compensation? Not that any of this was OK. We condemn this in the strongest possible terms. But did anyone receive more than $25 for what they had to go through?

David: By and large, survivors and their families are still seeking restitution. There have been lawsuits over the years. The only successful case that I could find was from 1984. Leodus Jones reached a $40,000 settlement with the city of Philadelphia.

Gina: Wow. Seems like not nearly enough.

David: Right. As for Kligman, he made millions of dollars from his patent on tretinoin, much of which he donated to his longtime employer, the University of Pennsylvania. In 2021, the university issued an apology to survivors and their families. A year later, the city of Philadelphia made a similar apology, though neither offered any financial reparations. Kligman died in 2010.

[Somber music]

Gina: So I think we’ve learned so far that retinol can impact the body in a lot of different ways.

David: Right. It seems like retinol can play a role in every single part of your body. Retinol can affect how your eyes see at night. Retinol can affect how your skin looks. Retinol can help your wounds heal.

Gina: Wait, did you say it can help your wounds heal?

David: Mm-hmm.

Craig: Because part of what retinol and retinoic acid, what all these are doing is stimulating the process by which the skin refreshes itself from underneath. So your skin is constantly making new skin cells that are moving their way outward.

David: Wow. So with retinol, I can stop skin aging, I can heal wounds. Gina, I’m going to live forever.

Gina: OK. Well, not so fast. David, I can see what you’re Googling, and I don’t think it would be wise to buy a rocket-powered skateboard.

David: I’m invincible, GV.

Gina: OK.

David: And besides, it looks like they’re sold out.

Gina: Oh, thank God.

David: Anyway, it is kind of funny that an ancient treatment for blindness ended up having so many uses.

Gina: It’s a versatile molecule. For instance, did you know that retinoids play a huge role in fertility? There’s even birth control treatments being developed for men that involve retinoids.

David: Right, the male birth control pills. I guess it’s time for my parasitic worm inflection point.

Gina: David, I know you consider yourself something of a feminist, but calling men “parasitic worms” is a little much.

David: OK. Well, I am forever and always a girl’s girl, but this worm thing actually has to do with real literal parasitic worms. Let’s go back to 1959.

[Inflection point sound effect: digital blips and tape-rewinding whir]

Gina: OK. So parasitic worms have something to do with a type of male birth control that relies on the retinol pathway.

David: Yeah. I mean, they play a small, but very pivotal, role. So in 1959, scientists were researching a drug and a few others like it to treat worms in people.

Gina: OK.

David: They started by testing it on rats, and it didn’t work.

Gina: OK. Off to a good start.

David: Well, it didn’t work at treating worms, but the drug was doing something. Scientists noticed that rats in the experiment had stopped reproducing.

Gina: OK, I’m starting to see where this is going. Go on.

David: So once they stopped giving the rats the deworming drug, [the rats] actually went back to reproducing like normal. So the drug was temporarily stifling the male rats’ fertility, and all with seemingly no side effects.

Gina: So this worm drug that actually didn’t treat parasitic worms was actually an effective birth control medication?

David: Yeah, as far as rats go. Next they needed to do human trials. And as we learned from my earlier inflection point, back then, and up until the ’70s, they mostly did those trials on incarcerated people.

Gina: Oh, man, I really hope this inflection point isn’t as dark as the last one.

David: You can relax a little. While testing new drugs on incarcerated people is obviously not ethical in any form, as far as I can tell, this was not an overtly diabolical experiment like the tests that we talked about earlier.

Gina: OK, good to know.

David: So in 1959, they tested this drug on these people, and it kind of seemed like a success. The drug worked the same way that it did in rats and no one reported any major side effects. At first.

Gina: This story sounds kind of familiar to me. So anyway, they give the drugs to the men. and then what?

David: Well, according to a few accounts, these prison trials went off without a hitch, no problems at all. It was just that when the drug was tested on people outside of those prison walls, they realized that you can’t drink alcohol while you’re taking this medicine. It would cause all sorts of nasty side effects—vomiting, shortness of breath, headaches, blurred vision—which obviously could be a major problem.

Gina: Wait a minute. I do know this story, but that’s not the version of the story that I’ve heard.

David: What do you mean?

John Amory: This is a story.

Gina: That’s John Amory. He’s a contraceptive researcher at the University of Washington, and I talked to him back in 2022 for a story that I was writing on birth control for men. And I remember him telling me that his mentor’s mentor, so his grand-mentor, I guess, Al Paulsen, was one of the researchers in this prison study.

John: So they were testing on prisoners here in Washington State, and they were testing their sperm counts. Sperm counts come down; guys feel fine.

David: OK. That sounds a lot like what I was just saying.

Gina: Just wait.

John Amory: And then one day, I talked to Al Paulsen about this before he died, this guy said to them, “You’re never going to sell this to men.” And they were like, “Why?” And he said, “You can’t drink when you take it.” And they’re like, “How can you drink? You’re a prisoner.” And they thought, like, he drank some cleaning fluid and got sick or something. He pulls out this bottle of Jack Daniels that somebody had smuggled in for him. And sure enough, he was right.

David: You are full of surprises, Gina. That is amazing.

Gina: Right? One smuggled bottle of booze dashed the dreams of an otherwise promising birth control for men.

David: Well, at least now we kind of know the science behind it. The reason the pill reacts so violently with alcohol is because this pill basically inhibits—

Gina: –inhibits an enzyme called aldehyde dehydrogenase, which our liver uses to metabolize alcohol.

David: Great. OK. So you also already know this part?

Gina: I do, yes. When people were taking the drug, their body couldn’t process alcohol normally. That’s where retinol comes in. The enzyme that helps us metabolize alcohol also helps us convert retinol to its ultimate active form, retinoic acid, and men need retinoic acid to make sperm.

David: But it wasn’t until 2011 that scientists, one of whom was John Amory, finally figured out that’s how the drug was working as a contraceptive. It was not only preventing the enzyme from helping people metabolize alcohol, which is why they had all those crazy side effects, but it was also preventing retinol from getting converted to its later form, which men need to make sperm.

Gina: So they finally figure out the mechanism of the drug, but even knowing that, they were still stuck with the same problem. If this pill targets that enzyme, which is involved in both the retinol pathway and alcohol metabolism, that means you can’t drink while taking the pill, which, kind of a nonstarter.

David: But at least this is an important step in figuring out how to influence male fertility, right? Once drug makers had this proof of concept of targeting the retinol pathway, they had something that they could work towards.

Gina: Right. So in the ’50s, scientists make this birth control pill for men but don’t know how it works and can’t sell it as a drug without really sickening anyone who has a cocktail.

David: Yeah. I’m kind of a mai tai type of person myself, little tiki style.

Gina: And then in 2011, they figure out what makes it work, but they’re still stuck with this alcohol problem.

David: So fast-forward to now, and we have a new birth control pill in development for men, YCT-529. It’s the first nonhormonal birth control pill for men to enter clinical trials.

Gina: Yeah, this was also part of my reporting. The new pill that you’re talking about is developed by a company called YourChoice [Therapeutics]. This pill also targets the retinol pathway in male fertility, just in a different way than that drug candidate from the ’50s.

David: Right. As you mentioned before, when it enters the body, retinol gets converted into retinoic acid, part of that pathway that you were referring to.

Gina: So you were listening.

David: Yeah, sometimes.

Gina: In the reproductive pathway, retinoic acid binds to a receptor called retinoic acid receptor α. Very catchy. I know. When it binds to this receptor, it sets off a chain of events that ultimately allows the body to make sperm. Now, the way that YourChoice’s drug works is by also binding to that same receptor, retinoic acid receptor α. Because the drug binds to it, retinoic acid can’t bind to it, and in theory, you could take this pill and have as many mai tais as you want.

David: OK. It’s a pretty strong drink, GV.

Gina: All right. Anyway, this drug candidate is also neat because, unlike some other birth controls in development for men, it isn’t based on hormones. But before we get people too excited about it, we should say this drug is still in clinical trials. So we don’t know, necessarily, how it’s going to affect all the other parts of the body yet. And even if it succeeds in those trials, it’d be a while before it actually came out on the market.

David: Boy, if only this drug was administered via your eyes like a big piece of liver, then this episode could really come full circle.

Gina: David, I’m getting sick again.

David: OK. Getting myself back on track here. It is exciting that this molecule that I thought of as an Instagram antiaging thing is actually relevant to a potentially cutting-edge medicine of the future.

Gina: It’s true. Retinol works in so many different and incredible ways. There’s even some evidence that retinoids can be used to help treat cancer.

David: What can’t it do? That’s amazing.

Gina: Yeah, right?

David: I kind of feel bad about just using retinol on my face.

Gina: Yeah. Well, it seems like there’s plenty of them to go around.

David: I guess that’s true. No shortage of ox livers, at least not that I know of.

Gina: Really stuck on the liver thing. I don’t think we get them from ox livers anymore, David.

David: Oh, sure. But I like to be [an] all-natural, organic kind of a guy, so I just get myself an ox and get some liver from it.

Gina: You know you’d have to kill the ox to get the liver, right?

David: Well, I hadn’t thought that far ahead.

Gina: Oh, David.

David: OK. What if I took just a little bit, surgical style, and sewed the little fellow back?

Gina: Come on, David. You’re going to do surgery on an ox because you’re nervous about going to the Sephora?

David: OK. Well, I’m coming clean. It is a mess to go into a Sephora.

Gina: OK, here it is.

David: First of all, there are way too many options. It’s so overwhelming. The lighting in there is so harsh. It’s like a dentist’s office.

Gina: Look, David, we can go together. We’ll find the right option for you. It’ll be great.

David: OK. Well, first I might need a mai tai to loosen up.

Gina: OK.

David: While I rustle us up some drinks, I want to tell listeners about the next episode.

Gina: Right. We’re going to explain everything about carbon capture and carbon removal.

David: Carbon capture, carbon removal. OK, what’s the difference?

Gina: I promise I’ll explain everything.

David: Sure.

Gina: How does it work? Does it work? All the fascinating new technologies, sucking CO₂ out of the air in the water.

David: Right, that reminds me. Gina, did you know that the first carbon dioxide scrubber was invented 150 years ago by a feminist submarine builder?

Gina: A kindred spirit of yours, I’m sure.

David: Yeah, well.

Gina: We’ll also cover the carbon credits that fund many of these efforts. Are they working? Are they a scam? Do we understand them at all?

David: We could also visit the first carbon-offset project site, in Guatemala. I think 1988, if my memory serves.

Gina: Sure. We could do that too.

David: Oh, and Gina, you know the whole reason that we know about how carbon dioxide affects our atmosphere is thanks to a scientist who was trying to measure the temperature of the moon?

Gina: Oh, brother. You know what, bartender? Make mine a double.

Gina: Inflection Point is a podcast project from Chemical & Engineering News.

David: Chemical & Engineering News is the official news outlet of the American Chemical Society.

Gina: Music by Kirk Ohnstad, Jeremy Barr, David Anderson, and Shutterstock.

David: Written, produced, and hosted by Gina Vitale and David Anderson.

Gina: Our audio producer is Jeremy Barr.

David: Our fact-checker is Michelle Boucher.

Gina: Email us at [email protected].

David: Thanks for listening!