Unlike a broken bone or clogged artery, a brain that goes awry due to disease or injury—or even an errant molecule—causes weird and unpredictable changes in personality.
Hear some of the bizarre tales of tiny particles that alter behavior from neurologist Sara Manning Peskin, author of “A Molecule Away From Madness.”
Plus… how parasites hijack animal brains, sometimes turning a host into a zombie in their quest to reproduce.
Phil Stieg: Hello, I’d like to welcome Dr. Sara Manning Peskin, a neuroscientist and assistant professor of Clinical Neurology at the University of Pennsylvania. Today we are here to discuss her recent book “A Molecule Away From Madness” in which she describes how some of the very molecules that allow us to exist can also sabotage our minds. Sara, thank you for being here with us today.
Sara Manning Peskin: Thanks so much for having me.
Phil Stieg: So tell me, why did you write in capital letters “this” book? What was the motivating factor?
Sara Manning Peskin: I think for the most part, I was thinking of what actually drives the day to day experience in clinic, of seeing people whose minds change. And we all sort of have this idea that you could have a broken leg, you could have heart failure, you could have liver cancer, but your identity is essentially unchangeable that’s part of you. And what I found in residency, and then as I started off after, is that that’s actually not the case.
And we sort of depend on this idea that our identity is unchangeable and it’s controllable. I’ve always been “quiet” or I’ve always been someone who loves the outdoors or something like that, but actually those things can be thrown on their heads and even with just a single molecule.
Phil Stieg: In the book, you refer to the concept of molecules hijacking the brain. What do you mean by that?
Sara Manning Peskin: So what I wanted to capture is the way that these particular molecules essentially hijack identity and personality. One of the stories they tell us is about a guy who was this extremely successful entrepreneur, and he owned tons of different companies. And then he eventually started building a company that sold wine, and it became this multimillion dollar Goliath. And then suddenly he actually was working with his son at the time, and then he started basically being kind of cold to his son. He used to hug his son when they would come to work, and he didn’t really seem interested.
And then he started being really disinhibited. So if he wanted to buy something, he would buy multiple of them. So there would be, like, tons of DVDs that sprout out of the mailbox, and his wife would sort of be like, “why did you purchase so many of the same DVDs”? And he really had no insight. And he started having trouble at work where there was a meeting early on where they had said they gave him a list of finances for February. And he said, well, where’s the 29th and 30th?
And this was a guy who was just highly, highly functional. He started having these personality problems, and everyone said, maybe it’s related to back pain and maybe it’s related to ADD or something else. And eventually he ends up with a neurologist who says, this isn’t related to any of that stuff. This is from a single molecule, and this is a diagnosis we know. It’s something called frontotemporal dementia. And your family history raises some concern that this is actually from a genetic mutation. And so those are the types of stories I wanted to sort of capture this. What is it like when you go from that process of saying something big and confusing is happening in the real world, and actually, there’s a microscopic molecular explanation for it.
Phil Stieg: Briefly, you talk about rebel proteins. What is a prion?
Sara Manning Peskin: So prion was this term that was coined by Stanley Prusiner, and it’s a combination of the word protein and infection. And it was this huge, groundbreaking idea in science that came about in the it was based on this disease of kuru. So kuru was a condition that affected what’s called the Fore tribe. It was a tribe in the highlands of Papua New Guinea, and in the 50s, there was a public health worker that started observing people with the disease, and it tended to affect women and children, and it would cause them to very quickly lose their language, lose their balance, and they would shake and they would laugh uncontrollably, and then they would die within a year. So it was this very aggressive disease.
And the guy who first sort of started publicizing it ended up sending off slides of brain slices of people who died of the disease. And he found colleagues who said, well, maybe these diseases are related. And so they ended up figuring out that all these conditions kuru, another condition Creutzfeldt-Jakob, and then another disease that affects sheep called Scrapie, they’re all sort of called these spongiform encephalopathies, and it’s named after the way they look under a slide because it looks like a sponge. It looks like parts of the brain have just melted away.
Basically these diseases behave like infectious diseases, but there’s no bacteria, there’s no virus, there’s no parasite, there’s no fungus. Nobody could figure out why these diseases look infectious when there’s no infectious agent. And what Stanley Prusiner basically figured out is that there is no virus or fungus or parasites or bacteria that’s causing these diseases.
The infectious agent is actually a protein which is much, much smaller, and a protein can’t multiply and divide. So it makes no sense for how it could cause an infection. But it turns out that if you have proteins that unfold, then there are other proteins nearby that will also unfold. And the best analogy, was basically a room full of mousetraps, where if one of the mousetraps goes off, they all go off. And it turned out, with kuru, that the reason why this disease was spreading and looking like an infectious disease was that the Fore tribe practiced what’s called endocannibalism, so they would eat their own after they passed away. And as part of the practice, the women would eat the brains, and that’s where these infectious proteins were. And then they would take the leftovers and give it to their children. And so that’s why it had that sort of epidemiologic signature
Phil Stieg: And why you use the term rebel protein, I guess, right?
Sara Manning Peskin: Exactly, because we all have it. We’re all sitting around with this protein. It’s just in some people this happens, and in some cases, in rare cases, it’s related to genetics, but in most cases it’s totally sporadic and we just have no clue why one person develops it and most other people don’t.
Phil Stieg: You know, one of the diseases you talked about that I thought was incredibly creative, just in terms of solving it, was the story about this Mike Bellow, this big strapping guy who is well, it’s a cute love story that kind of goes sour, but then comes back. So, it’s got all the right mixings. Briefly kind of go through Mike Bellow.
Sara Manning Peskin: Yeah. So he was a guy who grew up in rural Pennsylvania riding motorcycles and going to high school with this woman who he always had a crush on, but they never quite got together. And they both went off and married other people. And then eventually they both got separated and met in the general store in their hometown and started going out again. The relationship developed and eventually Mike Bells decided he’s going to propose to this woman. He gets a ring, and then things start to change.
So his personality starts to change. He was always kind of an easy going, friendly guy. His partner sort of describes him as like he’d be just as happy at a bar at a black tie event. He’s just sort of a nice person to be around. And that starts to change. So they go on vacation with friends, and he basically puts his beach chair into the sand at the other end of the beach. He doesn’t seem to want to talk to people. He doesn’t make eye contact. He starts drinking heavily, which took his girlfriend by surprise.
And then one day she comes home and she finds he’s like on his motorcycle in the yard, saying that she might have been a spider in his window. So sort of mixing things that don’t make sense. And it gets sort of worse and worse and worse. Then eventually they go on this vacation where he was going to propose, and instead he basically punches a wall through the hotel room. So he gets very, very aggressive to the point where she has to sleep in a separate room. And at that point, she sort of says, we have to get some help, this is extreme.
So he gets admitted to the hospital and he starts having these incredible contractions of the body, almost like tetanus. The disease actually works in the same way as tetanus, where it’s just these incredibly forceful muscular contractions. And they’re so bad that he’s actually worried he’s not going to be able to breathe. And he nearly bites his own tongue off. He can’t control them. So he ends up getting a breathing tube. He gets a feeding tube, and he’s hospitalized like that for months
And eventually he ends up at another hospital with someone who happens to recognize what’s going on. And he’s one of the few experts in this sort of relatively rare disease. And this physician basically says, “I know what this is, this is autoimmune encephalitis we actually have a treatment for this.”
It turned out that what was happening was that the mechanism that the body uses to relax relies on our ability to sense certain neurotransmitter emitters, which are these little molecules that help nerves communicate with each other and communicate with muscles. The one that helps the body to relax in Mike Bellow’s body, that one, he was basically not able to sense it, so basically he could never relax.
So what we do normally, you lie down at night and you rest your head on the pillow, you relax. He couldn’t do that. It was happening both at a muscular level and also at a sort of an agitation level, that was part of the personality change.
It turns out it was actually an autoimmune problem. So it’s a set of diseases where your body inadvertently makes antibodies that attack yourself. So you actually treat it by suppressing the immune system. And once they started doing that, he actually got better, and he was totally cured.
Phil Stieg: So that falls within the autoimmune disorders, right?
Sara Manning Peskin: Exactly, and these are a set of disorders that were discovered sort of in 2006, 2007, so they’re pretty recent.
Phil Stieg: That’s a fascinating story because the body’s making an antibody against itself, but then there’s another disease where we can actually inflict pain on ourselves. And that’s the fascinating story by Korsakov. Not so much the disease, but the trials and tribulations that he had in proving that he actually found a disease.
Sara Manning Peskin: Korsakov was this Russian psychiatrist living in the 1800’s and at the time, people knew about this condition called multiple neuritis, where people basically, their limbs would get really weak, and they would not be able to move, and nobody knew what caused it.
But Korsakov eventually met this guy who was a writer, and like lots of writers, he was sort of filled with some angst, and he sort of soothed it by drinking. And he essentially started having some difficulty with memory. And his friends brought him into the hospital and said he doesn’t seem to remember the things that we told him yesterday, whereas a week or two weeks before, he’d been totally fine. So, it was this very rapid change, and Korsakov starts examining this guy, and it turns out he examines, like, a normal person at first. He could make an argument, he could play a game, so he seems completely normal. But when Korsakov comes back a day later, the guy has no clue that they’ve met before. So basically, he cannot create new memories. And it’s this remarkable alteration of memory that Korsakov ends up writing up. And he basically says, look, no one’s really described this change in psychiatry almost, this dramatic change in his ability to remember things.
Nobody figures out what’s going on for a long time. And eventually it comes down to the same disease actually affecting lots of people in the Dutch army. So you’d have people who were totally healthy, and then they get shipped off, and then six weeks later, they’re totally weak and losing their memories. And now that it’s a problem in the army, lots of people care about it and it starts getting attention.
Phil Stieg: It’s ok if they kill each other, but they can’t die on the job.
Sara Manning Peskin: They can’t die before. So this guy starts trying to study it, and he’s working in this laboratory where there’s some chickens that are in a coop nearby. Ultimately the stuff that the guy is studying is totally failing. He’s not really making any progress, but he starts to notice that there’s these chickens nearby who start suffering from what looks like the same disease as these Dutch troops. And the chickens basically, they start keeling over and dying. Their wings stop flapping.
So this researcher, he basically says, oh, maybe I should look at the chickens instead of looking at what I think is going to work. And sure enough, as he’s trying to figure out what’s going on with the chickens, a few weeks later, they basically get better out of nowhere. And he has no idea what happens, but he suddenly says, maybe it has to do with something that they’re eating.
So he goes to the cook who’s the one who feeds the chickens, and the cook says, look, a few weeks ago this person came and said that we’re going to start giving polished rice, so white rice to the chickens when it’s left over. But then I came in and said, we can’t give fancy rice to the chickens. You have to give them the brown rice. And so it turned out the chickens got sick when they started eating white rice, and as soon as they switched back to brown rice, they did fine.
So this researcher very astutely figured out that this disease was caused by something that was in the shell of rice that you basically take off when you polish it from brown to white rice. And he basically figures out that this disease is caused by a deficiency in thymine, which is vitamin B-1.
Phil Stieg: So isn’t it amazing to you, the serendipity that’s involved in science? Number one, this person actually recollects what Korsakov was describing, recognizes that it’s in chickens. The chickens happen to be on the same base as the Dutch soldiers.
Sara Manning Peskin: Right and you have this obstinate cook on the same base who sort of is the catalyst for all of it. But there’s stories of that throughout science. There’s like this idea of for penicillin, that the guy was on vacation and then suddenly, “ta-da” there’s the world’s first effective antibiotic.
Part of it also is just not having blinders on. Being able to see when something promising pops up that you didn’t expect – being able to follow it.
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Narrator: For some species of parasites, hijacking their host animal’s brains is their ticket to survival. From protozoa and fungi to worms and wasps, these parasites turn their hosts into mind-controlled zombies that serve one purpose: to help the parasite reproduce.
Excerpt from “The Last of Us”
“If you don’t think there’s hope for the world, why bother going on?”Narrator: In the HBO series The Last of Us, a fungus called cordyceps infects and controls humans. It has a real-world inspiration: a fungus known as Ophiocordyceps, which preys on ants and other arthropods. Ophiocordyceps controls ants by releasing bioactive compounds that short-circuit the ant’s nervous system, giving the fungus direct control over the ant’s muscles.
Once infected, an ant will abandon its colony and climb a tall plant, where it bites down on a branch and hangs on until it dies—perfectly positioned for the fungus to sprout and release its spores.
Mind-manipulating horsehair worms, such as Gordius robustus, drive their cricket hosts in a different direction: toward a watery grave. Crickets typically avoid water. But an infected cricket is compelled to find water and jump in. The hairworm wriggles out and swims off to find a mate, while the cricket is left behind to drown.
Hairworms infuse their cricket hosts with neurotransmitters—chemicals that send signals between neurons. Researchers suspect this tweaks the cricket’s attraction to light, drawing it toward the water’s reflective surface.
Even mammals are susceptible to parasitic mind control. The single-celled Toxoplasma gondii reproduces only in the digestive tract of domestic cats and other felines. It can spread to other animals that come into contact with cat poop, and it’s these intermediate hosts that become Toxoplasma’s puppets.
Curiously, when rodents are infected, they seem to lose their fear of cats. This makes them more likely to be caught and eaten, sending Toxoplasma back into the guts of its preferred feline host. In this game of cat and mouse, the winner is … the parasite.
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Phil Stieg: So in the book, you refer to four types of molecules, or you characterize four types of molecules that hijack the brain. What are the terms that you use?
Sara Manning Peskin: So I talk about them as mutants, rebels, invaders, and evaders. And mutants are these diseases that are caused by mutations in DNA. The rebels are caused by proteins that have become rebellious. So if we think of DNA as basically the instructions for being a human, proteins are actually the workhorses of how we actually stay alive. And we think that they’re going to help us, and most of the time they do, but sometimes they can turn against us.
And then there were invaders. These are small molecules, so they’re much smaller than DNA, much smaller than proteins, and they’re not endogenous to us. So it’s things that we actually are exposed to or that we ingest, things like medications. And these are things that are sort of foreign molecules that come into our systems, get into our brains, and cause problems.
And the last was evader. So these are things that are also small molecules, but we really need them to function normally, and we encounter a problem when we don’t have enough of them.
Phil Stieg: I’ve got to tell you that I’m a Lincoln-phile and there isn’t a Lincoln book that I don’t buy and try to read. And I was particularly surprised by “blue mass” and your invader that you talk about. So tell me why blue mass is a problem and how it explains some of Lincoln’s mood affective disorders.
Sara Manning Peskin: Yes. So I will say this is all still in the realm of conjecture, but there’s a well known infectious disease doctor named Norbert Hirschhorn who was reading Gore Vidal’s novel, Lincoln. And there’s this part about the pharmacist referencing giving Lincoln blue mass.
At the time, blue mass was relatively commonly prescribed in Lincoln’s era. And there’s some question of whether he used it for constipation or for depression because it was indicated for lots and lots of different things. But when Hirschhorn started to look at other sources, there’s actually a lot of evidence that Lincoln did take blue mass. The most convincing one is from a colleague of his who quotes Lincoln, and basically says that Lincoln told him he stopped using blue mass soon after he was elected to the presidency, because he realized it was making him “cross.” And so it’s a great description of one of the most famous people in history having a medication side effect.
The main ingredient in blue mass was actually mercury, which was thought to be a wonderful healer at the time. Now we know better.
But essentially the idea was that we think of Lincoln as being stoic and thoughtful and calm. But actually, there’s these accounts from before he was elected president where he acts incredibly rashly. There’s a story of him working on his final case, and he’s presenting this case to the judge, and the judge makes a ruling he doesn’t like, and he basically jumps over the judge’s bench and essentially attacks him. So it’s these really dramatic scenes.
There’s another one from one of the Lincoln-Douglas debates where Lincoln gets angry that he’s being accused of not supporting the troops. And he literally takes someone from the stage, drags them forward and like, nearly strangles them to the point where his bodyguards have to step in and pull his fingers from around this guy’s neck.
There are these examples of Lincoln not acting very Lincoln like, at least in the image that we have. And Hirschhorn’s idea is that maybe that’s actually from mercury toxicity. Maybe these are examples of this incredible president actually behaving completely differently because of a medication side effect.
Phil Stieg: It’s interesting because in that era, also, people took mercury for the treatment of syphilis. So you would have expected more people to have this toxicity and also these affective mood swings. But it doesn’t seem to be the case. So that’s why I think it’s interesting. It’s great conversation, so hopefully we’ve given some people some dinner conversation.
Sara Manning Peskin: The nice thing about it, is it can’t be proven or disproven (laughs).
Phil Stieg: Dr. Sarah Manning Peskin, thank you so much for taking us through your book, a Molecule Away From Madness, and how our brains can be affected by a change in a simple molecule within them. It’s been a fascinating story about disease, but also the history of medicine. Thank you so much for spending time with us.
Sara Manning Peskin: Oh, thanks. It was such fun to talk with you.