The Story of the Family that Couldn't Sleep
IRA FLATOW, host:
This is TALK OF THE NATION: SCIENCE FRIDAY. I am Ira Flatow.
A bit later in the hour, a mathematical mystery. But first up, a medical mystery. A new book tells the tale of an Italian family suffering from a rare and deadly disease called fatal familial insomnia. Just like it says, it's insomnia, an illness that literally kills its victim by robbing them of the ability to sleep. They die of exhaustion. You know how you say I'm just so tired I could die. These people actually die of exhaustion.
The disease is linked by the new science of prions to outbreaks of the neurological disease kuru in Papua New Guinea in the 1950s, and mad cow disease in the UK in the last decade. So we're going to start this hour by talking about the family that could not sleep and the strange protein called the prion. And if you'd like to join our discussion, our number is 1-800-989-8255, 1-800-989-TALK.
D.T. Max is a science writer and the author of The Family That Couldn't Sleep: A Medical Mystery. He's written for The New York Times and the New Yorker, and he joins us today from our NPR studios in Washington. Welcome to the program.
Mr. D.T. MAX (Author, The Family That Couldn't Sleep): Thanks very much.
FLATOW: This sounds like a really unusual disease. They really die because they can't sleep.
Mr. MAX: That's essentially right. It's a disease, fatal familial insomnia. The name sort of puts it all on the table. It's a progressive, inherited condition, characterized by eventually a total insomnia - leading within about nine months time to death.
FLATOW: So you're awake - you're dying when you're awake because you can't sleep?
Mr. MAX: Yeah, I think that's one way to look at it. We don't really know. One of the reasons I was drawn to this project to begin with is really the question of why we sleep. And in fact, we still don't really know why we sleep. But paradoxically, we know we have to sleep.
And in the case of this family - much for the same reasons that we have this paradox I've just laid out - this family cannot sleep and they ultimately die - and therefore we believe they die from a lack of sleep. There are other causative problems. They lose the ability to regulate their autonomic systems - their sweating, and their pupils become these tiny little pinpricks. I mean many things happen to them. It's almost a kind of a plane crash of a disease, and yet they have a complete insomnia that's clearly one of the key symptoms and one of the causes of the death.
FLATOW: And you say this is probably the worst disease in the world because of people suffering from it are aware they're awake, about what's happening to them.
Mr. MAX: That's right. I mean I would always be reluctant to rank diseases in terms of horribleness, but I think a case certainly could be made that this disease in many ways - one, because of this insomnia - and anyone who's ever, you know, suffered insomnia knows just how dreadful a condition it is...
FLATOW: Right, right.
Mr. MAX: ...even if the insomnia is simply worries about work tomorrow.
Mr. MAX: You stay awake and the clock ticks and the clock ticks. But while this disease has much in common with Alzheimer's in terms of some of the things going on physiologically in the brain, what makes it quite different from Alzheimer's is that you - is that many, many of the sufferers of the disease have the ability to understand exactly what's going on. And even to be in, you know, routine verbal contact with their loved ones at the end, even though they've had this extraordinary insomnia.
FLATOW: You say there are about 40 families in the world known to have this disease.
Mr. MAX: Yeah, that would be a bit of a guess. We have 40 families based on the genomes that we know, and we can extrapolate from that that probably there would be maybe around 200 families worldwide. And I would emphasize that these - this disease, which is a mutation, of course - that these 200 families would all have developed the mutation probably separately.
FLATOW: Hmm. And you trace - it's interesting - in the book you trace the disease through several generations of an Italian family. One of the most memorable cases was a man named Silvano. Tell us about him.
Mr. MAX: Well, Silvano was a member of the family in the 1980s. And Silvano - the disease as far as I could trace it back - and I had the assistance of the family in digging through records.
In Italy, records are kept - these sorts of records are still kept in the parish houses of the churches, because the Catholic church was once responsible for recording births and deaths. And so the way they would assemble - the family would assemble information on its ancestors was, you know, you'd have to go into the church, and you'd have to ask for the records. But in Italy, records aren't really freely available. So there's a figure in the book named Ignazio - who's a young doctor who marries into the family and who - Ignazio's very much responsible for helping to solve the mystery of fatal familial insomnia.
Ignazio was an organist. He was an ardent Catholic in the Italian fashion, which means that he really - as he used to love to say to me - I believe because it's absurd.
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Mr. MAX: So Ignazio is also an avid organist and very talented. And Ignazio would go into the church and he would ask the priest could he go and, you know, play the organ. And the priest would say sure, and Ignazio would play for a little while, and then the priest would get bored and go back into the parish house. You know, in Italy, priests have really quite nice parish houses, and they have someone who looks after them, so it's kind of its own life.
And then when Ignazio noticed that the priest was no longer listening, he would sneak down into the basement where the parish records were taken - were kept - and he would take photographs of anyone who had the same last name as his wife's family.
So with his help, I was able to trace the disease back to the 1760s, in all probability to a doctor, fascinatingly enough, who probably - I doubt he was the first member of the family, but he might well have been. You know, it could also have gone back further. But when you get before the Napoleonic era, you pretty much lose records in Italy because of the devastation of the Napoleonic Wars.
In any event, fast-forward to Silvano; we're in the 1980s. And, you know, Italy had become very rich in the period from the end of the Second World War to the 1980s, and Silvano was very much a product of the new Italy. He was a stunningly handsome man who loved to go out at night. I don't think I've ever seen a picture of Silvano not wearing a tuxedo.
So this was a man who, from the way I look at things, would probably not have been well-equipped to deal with a devastating disease, just because he was, again, to my mind, a man who very much judged by exteriors. He was a very external man. But he was also the head of the family - which in Italy is a very potent post - and he had just watched two of his sisters die from this unnamed, familial disease of which clearly had an important insomnia component.
So Silvano, in his heart, always knew, I think, that he would get the disease. And one thing we haven't mentioned that we should, is that the disease strikes in your 50s. So you get - one reason the disease doesn't burn itself out, the way of many severe genetic mutations, is because you live long enough to reproduce...
Mr. MAX: ...so it foils that mechanism, so to say, by which most diseases are - most really virulent genetic diseases are eliminated.
Silvano one day, in the Italian style, was dancing with his mother. And in Italy, you know, young bachelors are always dancing with their mothers, even today. And so he noticed he was sweating, which he knew from his experience with sisters was the first sign of the disease. And so Silvano understood what was happening. He'd always really known, I think, that he was going to get the disease. And then he went and looked in the mirror and he saw that his pupils had become these tiny pinpricks, and he knew for sure what was happening.
And rather than just say, OK, I'm going to give up, I'm going to die, he really decided that he was going to throw everything he had, all of his strength, into trying to understand what was killing his family. And so he went to a neurological institute in Bologna, with the help of Ignazio - this young man who had married into the family - and he basically said to them - he sat down with a young neurologist who really just graduated from, you know, graduated shortly before and had done his neurology residency.
And the neurologists will tell me, you know, what seems to be the problem? And so Silvano says - you know, this is obviously taking place in Italian - he says I know how I'm going to die. It's exactly the way that my father died and my two sisters have died, and I can give you all the details.
And the neurologist was stunned, because you know, neurologists are trained in the art of euphemism. They don't really have much to offer, but they do their best. And so the neurologist said, you know, please, please, sir, you know, we have cures, we have palliatives. And Silvano said - he said, cut the nonsense, I assume when I'm gone you'll want the brain. That was Silvano. He was able to confront what was going to happen with great courage. And through the experience, through the extensive EEGs that were taken of his brain - because really nobody had done a proper EEG before on any of these people. EEGs were traditionally done in little snapshots. You know, what the family - what you needed to diagnose this family was to leave in an EEG in place for an hour, and then you would see that the brainwaves looked like nothing we had in the literature.
And you know, Silvano eventually, he died, and - but what had been learned from him, that this disease - that insomnia wasn't just a byproduct of this disease, but a key component of the disease. We really owe this to Silvano, although, you know, at that point there was still much, much left to be discovered about the disease. But it was the first step. It was the first step beyond saying we have a familial encephalitis, which was the typical diagnosis, you know...
Mr. MAX: Or in other eras, for instance, we had - they were believed to have Vonaconomo(ph) syndrome in the teens, when everyone had Vonaconomo syndrome. I mean they would take on...
Mr. MAX: Sorry.
FLATOW: Yeah, but what you learned through this was that this was actually connected to mad cow disease, which I found, you know, quite interesting.
Mr. MAX: It's extraordinarily strange. It's like having two people pop up in the same room you didn't know knew each other. It is connected to mad cow, and in fact very, very closely connected to mad cow, because in the period after Silvano's death, Ignazio kept digging and he kept finding other sufferers - cousins, second cousins, third cousins.
This family had been decimated by fatal familial insomnia, and they weren't in touch in the way most Italian families are in touch. And Ignazio - again, it was his wife Leezy(ph) who was actually, you know, related to these people, was able to put together this family tree of extraordinary early death and misdiagnosis.
Eventually, two other members of the family came down with the disease, and they came down with a slightly different version of the disease. And when neurologists looked at their version, they were able to see on their EEGs that their brainwaves looked rather like the brain waves of a disease called Creutzfeldt-Jakob disease, or CJD. And CJD, as was known at the time - we're now in the mid-'90s - is a prion disease. It's in fact what you get when you consume infected beef and come down with the human version of mad cow disease.
FLATOW: Right, right. Very interesting story, because I want to get into this whole prion connection, and what a fascinating world of medicine we're in when we talk about prions and how spooky and strange they are. And in the time we have left - we're going to go take a break - let's get back and talk about that, because as you mentioned, Jakob-Creutzfeldt disease and prion diseases, they're all connected, right?
Mr. MAX: That's right. That's exactly right.
FLATOW: What makes a prion different than, you know, a regular protein?
Mr. MAX: Well, a prion is a protein. This is the strange thing about the prion, is - the prion is a regular protein, encoded for by a regular gene in the body, which when misformed takes on the properties of a virus and in fact takes on some properties viruses don't have, because people can just come down with prion diseases sporadically.
There are in fact - and this is extremely rare but it does happen - there are people in the United States who just suddenly come down with fatal insomnia, although they don't have any other family members who have it and they wouldn't pass it on in their genes if they reproduced.
FLATOW: All right. We're going to take - we'll come back and talk about how a protein - which is not a virus, it's not a bacteria, it has no DNA - how does it become infectious and carry a disease from one person to another, or one animal or some organism to another? So this is a medical mystery. We'll talk more about it with my guest, D.T. Max, author of The Family That Couldn't Sleep. Stay with us. We'll be right back after this short break.
I'm Ira Flatow. This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News.
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FLATOW: You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. We're talking this hour with D.T. Max, author of The Family That Couldn't Sleep: A Medical Mystery. It's out this fall from Random House.
Tell us about the prions. I gave them a big - I mean they are mysterious and strange, and we hardly know very much about them, and how do they spread diseases?
Mr. MAX: I think the strangest thing in all of nature, and indeed the final proof that prions exist - we can get to that in a minute - has not really been achieved. But the basic theory of the prions goes something like this. Proteins are normally - normally assume a single state, which is to say when proteins are manufactured in the body, they're manufactured mostly as ribbons, and then they curl up, kind of like kinky hair into a form which is useful for whatever function they happen to serve in the cell.
Now, most proteins can be forced into different forms if you try hard enough. Say with heat - you can deform a protein. But it will not have - it will tend to spring back to its original form to maintain its function.
Now, what's odd about prions, although not unique, is that the prion - which as I say is a perfectly normal protein whose function we don't know - but given the fact that you can find prions right across mammalian and even below that in terms of development - you find prions even in certain - in frogs - it must perform some function or it would not, according to the sort of rules of evolution, have been so well-conserved across all these species.
So whatever this prion does, weirdly, unusually, and I think sort of unfortunately, as it turns out, this prion can assume a second stable state, a misformed but stable state. And this - and the quality of this stable state that's so of devastating is that the prion in turn is able to cause adjoining prions to also assume the misformed state. What you get is in effect a chain reaction.
One way to think about it is a little bit what happens with salt crystals, where if you - you can have a single salt crystal as the nucleation point, and then as other salt crystals precipitate, they'll form around that salt crystal - or indeed they'll also form around bits of dirt. I don't know if you've ever done this experiment in high school, if you were a high school science wizard. But this is the kind of thing kids are always doing in high school.
So essentially it's a kind of a seed-crystal phenomenon, where the first misformed prion functions as a seed crystal, and then adjoining prions misform around it.
Now, what's really remarkable about this fact is that it allows for infection without nucleic acid, as you point out. Now, the idea that a protein could cause an infection, for any ordinary biologist, is complete heresy. It's essentially saying that, you know, you saw a dead man walking. I mean it's just not possible. Proteins are not alive, and we all know based partially on observation and partially on sort of Darwinian theory that only living things or things with nucleic acid are interested or have reason to create infections, because infection is a way for a virus or a bacteria to replicate.
Well, the prion has no reason to replicate because it's not alive, and yet it too can form, as the theory goes, it too can cause an infection. So for instance, in mad cow disease you have an infected cow, you eat some of that beef, some of the infectious-formed prions go into your digestive system. Eventually, through ways we don't really understand, they work their way up to your brain, where they begin to convert adjoining prions into the infectious form.
Unfortunately, infectious prions are not really very useful for bodily functions. In fact, for reasons, again, we don't quite understand, they inhibit or destroy them, and as a result, you get a disease. But you - but at no point do you have a nucleic acid.
Mr. MAX: At no point do you have replication through nucleic acid.
FLATOW: And what's also fascinating about these prions is how indestructible they are.
Mr. MAX: They are really extraordinary. A prion - the only really reliable way to kill a prion is with bleach. You can't kill it with heat. You can't kill it with radiation. Formalin actually makes prions more virulent.
I once went to - well, there's a domestic prion disease in the wild in the United States called chronic wasting disease that affects deer and elk. And I once went to one of these stations where they were hauling in deer during a shooting season in Wisconsin, attempting to kind of limit the damage that these - you know, that this spread of this chronic waste disease in the wild was extraordinary. And they were trying to kill some of the carriers - which turned out to be a fruitless effort, but it was fun for a lot of the hunters because they removed the limits on the number of deer that they...
FLATOW: The hunt?
Mr. MAX: Yeah, so they would - but - so they would bring in, you know, dozens of deer. And anyway, they - what was going on was so strange. And nobody could really understand the risks, but every so often - and the place stank. It was an open-air trailer out in the woods, and you could smell it for miles away, and there were all these deer. I mean it felt like nature was out of control. There were these deer with their tongues hanging out after they had had their heads cut off, and the bodies were being thrown away, because even though the hunters could take the body home, subject to some sort of protein analysis to see if the deer had been infected, no one wanted to.
And anyway, they would - every so often this guy, you know, in a hat that said Chronic Wasting Disease Response Team would come by and splash this extraordinarily harsh bleach over everything. And I thought to myself, this is what it takes. I mean this is, you know - you can't use any other method. You can't use any conventional antibacterial or antiviral method to control this disease.
And I think that's why, although prion diseases are quite rare, ordinarily, they have the ability to kind of swell up in these incredible epidemics and epizootics. I think you see that with mad cow disease in England, where I think 800,000 cattle had to be destroyed or died from mad cow disease, and then 150 humans to date have gotten it from - probably from consuming the infected beef.
FLATOW: Hmm. And so how did you get the connection, or how did they connect the familial insomnia - that it was, you know, to a prion, that it was a prion?
Mr. MAX: Well, basically the way they did it essentially was, okay, they had the information from the brainwaves, which was to say that Creutzfeldt-Jakob disease, CJD, as it's more often called, had a very similar EEG signature to the familial disease of this Italian family.
And then, you know, at this point we're in the 1990s, and some very good scientists - among them Stanley Prusiner, who the Nobel Prize in 1997 - had been able to find the gene for the healthy prion. You know, it was an ordinary gene. They had found it. Using the technology of the time, it was possible to find the genes. And then they were fairly, in short order, fairly able to find the mutation on the gene which corresponded to fatal familial insomnia.
So after this 200-year-long mystery, the disease, you know, took its place as one of a number of inherited prion diseases, because prions can also, you know, as I say, prions - we've talked about infection, we've talked about them occurring sporadically, but of course they also can be passed on.
Now, what's particularly devastating about the inherited form of the disease is, of course, that the prions misform on a vast scale in the body probably more or less simultaneously when you reach a certain age. So it's a far - it's a sense a farm harsher - again, I hate to rank diseases, but the prion diseases, the inherited form, is the most - I think the harshest, the most destructive and overwhelming.
FLATOW: So are you a believer in the prion idea?
Mr. MAX: Well, that's a very relevant question, because it does almost become kind of like - when you get into this world - you know, and I spent about four or five years working on this book - you really are asked whether you're, you know, dry or wet. Everybody's got a strong opinion, and then there's a kind of middle group who are agnostic, who do the work on prions because they know that the protein must be important in the disease, without absolutely knowing that the protein is, you know, is the disease.
I would say, you know - and as a writer, as a journalist, you're not in there doing the experiments. You know, you're able to read the papers. You're able to look at the protein gels as they're reproduced, you know, usually fairly poorly in the off-prints that you get a hold of. So I believe that the science is pretty sound. I would be more - I would be more far more surprised to find that prions were aided by some sort of quasi-nucleic acid not yet found, not yet understood, than that in fact the theory, you know, probably with some slight, slight fiddling on the edges for just why this happens, you know, some slight adjustment to allow for the fact that it just seems a little bit kind of out of the blue - I would think that would be far more likely.
And in fact, we've even - researchers have even found another disease which spreads the same way. One of the amyloidoses, one of the infectious amyloidoses, can actually be injected into mice and cause amyloidoses. So prions are not absolutely alone in having this ability. You know, and the amyloidoses, again, would not be - would be a disease without a nucleic acid.
FLATOW: Right. I have one question left for you before we have to say goodbye, and that is what about this Italian family? What is happening with them?
Mr. MAX: Well, I think - you know, I think for them, as I try to draw out in the book, the process of coming to terms with this disease has been a long-term one, beginning really with Silvano in the '80s and then going through the '90s when they got a name for the disease and a genetic test, and into the zero-zeroes or whatever decade we're in.
The family has now joined forces with a very sophisticated group in Milan, a proteomics group - really the foremost organization of its sort in Milan - and interestingly, although there are right now a couple of cures - I shouldn't say cures - there are a couple of palliatives that seem to work fairly well for prion diseases, the best known one being Pentosan, which is actually an ordinary drug that's usually given for bladder infection but which has shown great promise in a young man who got the infectious form of mad cow disease from eating infected beef and lives in Belfast who's now been alive for four or five years with a prion infection.
The family didn't choose to go that way. For one thing, these drugs usually have very strong side effects. In the cast of Pentosan, you need a shunt placed in your brain because the drug is too big to get through the blood brain/barrier. And I don't know if it's because they're Italian or because they're just making a good decision or because they are closer to this Milan group, but they've chosen instead to sort of give themselves to some very basic research on what causes prion infections, you know, without, let's say, looking for a quick fix.
And a quick fix is very much on their minds because, you know, if the disease routinely strikes in your 40s or 50s, there are a number of members of the families now in their 30s and 40s that must surely be getting up and looking in the mirror and saying, you know, do I look different today?
FLATOW: Fascinating story, D.T. I want to thank you for taking time to talk about it.
Mr. MAX: Thank you.
FLATOW: And I wish you good luck.
Mr. MAX: Thanks.
FLATOW: D.T. Max, author of very interesting book, The Family That Couldn't Sleep. D.T. Max. I highly recommend it. Thanks again. He's a science writer in Alexandria, Virginia.
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