Dr. Dennis Drayna — Genetics of Stuttering and Communication Disorders
Dr. Dennis Drayna is a human geneticist who has identified mutations in several genes that cause communications disorders, particularly stuttering, using family- and population-based genetic methods. Dr. Drayna's team studies the biochemical and cellular effects of these mutations and how they may cause specific neuronal pathologies. With so much to cover, we divided this episode into two parts. Here, in Part 1, we discuss Dr. Drayna’s research into the genetics of stuttering. In Part 2, to follow, we continue to explore stuttering research and delve into Dr. Drayna’s perspectives about research and research training at the NIH, as well as his lab’s ground-breaking work on how genetic variation affects the sense of taste and how population-specific genetic factors can influence preference for menthol in cigarettes, a common flavor additive that is particularly popular among African American smokers.
Dennis Drayna, Ph.D., is a Senior Investigator in the Section on Systems Biology of Communication Disorders at NIH's National Institute on Deafness and Other Communication Disorders (NIDCD). Learn more about Dr. Drayna and his research at https://irp.nih.gov/pi/dennis-drayna
>> Hello, Dr. Drayna. It's great to meet you. Thanks for joining us on the podcast today. How's it going?
>> It's going very well, thanks. It's a real pleasure to be here.
>> Cool. So, before we get into the science and the research that you do, I'm told that you used to be a prominent rock and ice climber and have done many famous climbs from the Yosemite Valley to Europe to the Himalayas. So, what attracted you to explore such an extreme endeavor?
>> Well, it's always exciting. It's great exercise. And it tends to take you to exotic places. So it, it has a lot to offer.
>> What, do you have any favorite climbs or scariest climbs?
[ Laughter ]
>> Well, there were a few that were memorable. My favorite climb? Probably the Salathé Wall of El Capitan in Yosemite. It's, it's enormous. It's very, now very historic and famous. And it has a lot of really great climbing all on one giant route.
>> Yeah, is that one of those where you, you sleep overnight? Does it take multiple days?
>> Oh, yeah. Yeah. Of course, in this day and age, people do it a lot faster than we did it years ago. But yeah, it, it was a, when we did it. It was, it was a five-day effort.
>> How'd you sleep up there?
>> Pretty well, actually. Some places to sleep are comfortable. Some places are less comfortable. But you're usually pretty tired at the end of the day and have no problem falling asleep.
>> Is there anything about climbing that challenges your, your brain in ways that might be similar to science?
>> I always like to note that climbing involves getting your muscles in shape and getting your brain equally in shape. It's really a separate process for each. And it, it takes a while to get the right kind of attitude to be able to do what you need to do without freaking out, basically. A lot of people think that climbers like to climb big things because they're not afraid of heights. But, actually, that's not true. We're all afraid of heights. But it involves getting your brain into shape to be able to do what you need to do when you're out there. So, it's very challenging in a lot of ways. And it's something that is in some ways similar to being a scientist, I think. Because science, you bring yourself to intellectual challenges really. Just like climbers are attracted to technically difficult climbs, scientists tend to be attracted to intellectually difficult problems. And I think willingness to just strike out and try it is a common feature that makes for success in both climbing and science.
>> Yeah, and you've been very successful in your scientific career. And one of the things that you're focused on now is trying to figure out the causes of stuttering, I believe? Could you maybe explain a little bit about what is stuttering, and what causes it?
>> I'd be glad to. It's a very puzzling disorder. It's common. It is more debilitating than most people think. Before I got to know about stuttering, I thought of it as something that must be a minor inconvenience to those who have it. In reality, the many people who have it feel like it's been a major, major detriment in their life. I mean, they feel that it has harmed their employment. It's harmed their personal relationships. It's harmed everything they do. Everyone they interact with has been impacted by this disorder. And the disorder itself has enough puzzling features that it's not, there's no obvious explanation for what's amiss in this disorder. To give you an example. A joke I learned from the stuttering community is that no one stutters when they talk to their dog. And it turns out, this is largely true. And so you ask yourself, what kind of a neurologic disorder is this? It really doesn't have obvious parallels across the spectrum of other neurological disorders. But there's some, there are some aspects to the disorder that maybe give us hints about what might be wrong. But the real path that was open to us was the realization, that comes from work done by many people in many places, that the disorder has a very substantial genetic underpinning to it. And since I'm a human geneticist, it seemed like something good to see if we could make some progress, using genetic approaches, which is what we've done.
>> Correct me if I'm wrong, but I believe maybe eight or so years ago, your group was the first to discover any gene that was associated with stuttering? Is that close to being correct?
>> That's pretty correct, yeah. We've now found four causative genes. It's clear there are more to be found. There might be a lot more to be found. It's a little hard to tell at this stage. But I think what is clear is that you can find these genes, and when you find them, they have told us fairly remarkable things about the origins of the disorder that were really completely unsuspected before. So, it's been in that sense a pretty big success. Of course, our long-term goals are to translate a better understanding of the disorder to better treatments and therapies for the disorder. So that's something for the future. But at the moment, we have been making some progress on understanding the causes using genetic approaches.
>> So, you said you or your team has uncovered four genes that cause stuttering — are they always present in any given person stuttering? Or do they cause different types of stuttering in different people?
>> So, the numbers so far are as follows. We can find a mutation in one of these genes in about 20% of people who stutter. So, you can sort of take the optimist's view or the pessimist's view. The optimist's view is that in what are called complex genetic disorders. That is disorders like stuttering. They cluster in families but don't follow simple rules of inheritance like traditional medical genetic disorders. Things like hemophilia or cystic fibrosis: they follow simple rules of inheritance in families. Complex disorders cluster in families, but they don't follow any rules, and so that makes the underlying genes harder to find. But for complex disorders, explaining 20% is a pretty substantial fraction. So that's the optimist's view. The pessimist's view is we have 80% left to go. And[CB( so we don't know what the remaining genes code for. We don't know what areas they'll point us to in terms of subsequent biological, what we call functional research as opposed to genetic research. What are the functions of these genes? And how are they amiss in stuttering? We don't know where that other 80% will take us. But we do know that the first 20% are all of a piece. And it's really a tremendous surprise to us. And I think to other people who've been interested interest his disorder. All of the genes that we found so far affect what we call intracellular trafficking. That is moving things around inside the cell. Now the fundamental machinery of this business was discovered by a number of people that received the Nobel Prize for doing this. Jim Rothman and Randy Schekman and Thomas Sudhof were awarded the Nobel Prize in 2013 for the discovery of this fundamental mechanism within cells. And all of the mutations we've found in stuttering to date are genes that encode the machinery of this process. [DS(
>> And is this lysosome related?
>> Well, it is. So there are a number of compartments in the cell. Lysosomes are one of them. They are related in turn to things called endosomes: ‘endo’ meaning inside; ‘some’, ‘soma’, meaning body. It's a body inside the cell. And these different bodies or compartments inside the cells perform various functions. The lysosome is sort of the cell's recycling bin. It takes things apart so the cell can reuse them. But some of the other genes we found, in fact, control endosomes, endosomal trafficking. So, the genes we found to date control basically the traffic, that is, where things go in this system. What determines where things need to go? Well, there is the lysosomal targeting system, which is encoded by the first genes we found. There are the adaptor proteins, which survey the contents of endosomes and decide where those endosomes need to go, based on what they're carrying. Okay? So, all of the genes we have found to date interact with each other. Their products all interact with each other, both naturally in the cell, what we call in vivo, as well as in a test tube, what we call in vitro. So, it's a great surprise. No one ever suspected deficits in moving things around inside the cell was what was fundamentally causative in stuttering. But it looks like that is what causes one chunk, one fraction of cases of stuttering. But the question remains, how, how does a deficit of moving things around in a cell lead to a speech disorder, and no other problems in the people who have these mutations? So that is of course a very large and very challenging project in itself. And that's [DS( much of what we've been doing for the past four years has been focused on.
>> So, is it a genetic mutation that you've identified? Or is it a missing gene? What is it that you've identified in those four genes?
>> Right, so that touches on actually a really important point in this whole business, which is that there are mutations in genes. These genes are not a surprise to the medical genetics community. [DS( Mutations in these genes have been known for decades to be associated with rare, devastating metabolic diseases of children, rare medical genetic disorders that are frequently fatal in young childhood. These are tragic disorders. So, we were very much taken aback when we began to find all these people who have mutations in the same genes. And we thought to ourselves, "Could it be that maybe these disorders aren't so rare, and that in fact there's lots of very mild cases walking around? And the only manifestation they have is just a little speech problem," right? So, we brought these people, quite a few of them, into the NIH Clinical Center, where we have the advantage of some of the greatest experts in the world already waiting for us [DS( and looked at everything and found no symptoms of these rare medical genetic disorders whatsoever. And that's actually not a surprise. These are perfectly high-functioning individuals, you know they're, they're college graduates. They're employed in good jobs. They have great relationships. You know, all of them are perfectly normal. They're athletic, perfectly normal in every way we can see, except for this little speech disorder. And some of that, some of that difference might be due, probably, to the kinds of mutations. The children with the rare medical genetic disorders have complete loss of functions. They have deletions or what is sometimes called stop codons. The gene is actually truncated by a mutation, so only a piece of the gene product is made. The mutations found in stuttering are much milder, and we've shown they're much milder by laboratory studies on enzyme function. The people with the rare medical genetic disorders have zero percent activity or maybe a few percent activity of these enzymes. The people who stutter, the mutations we find in stuttering have maybe as, as a generalization, maybe half their activity. Maybe 50%? So it's just a mild decrease in the function of these enzymes that somehow modestly interrupts the flow of where things are supposed to go inside cells. That produces some very specific neurologic problem that just affects the neurons that are involved in the production of speech. And I want to make clear that [DS( stuttering is a very partial deficit in speech. I don't even like calling stuttering a speech disorder, because there's so much about the speech of these people that's perfectly normal. They don't have problems with memory, what we might call word finding. They don't have problems with grammar. They don't have problems with syntax. They don't have intelligibility problems. They don't have a, a, an articulation disorder like a lisp. They know exactly what they want to say. They just can't say it at the rate they would like to. So, rather than being a speech disorder, I think of it more as a disorder in the voluntary control of speech that can otherwise be really quite normal.
>> So when someone stutters, what is actually happening?
>> Well, we know that there, we all have this, something[CB( sometimes referred to as an internal voice. Professionally it's known as subvocal speech, right? The people who stutter have perfectly normal subvocal speech. They know, they, they know right what they want to say, but they come to a problem where the speech articulation and the breathing is supposed to be coordinated, and you're supposed to make this nice free flow of what they had in mind, right — so-called fluency. And it fails. And it produces something called a block. And people who stutter, they can feel a block coming. They can see it.
>> That's interesting.
>> Oh yeah, they know one is coming.
>> Like how far ahead?
>> Oh, it can be, you know, they can feel it coming several words in advance. And they develop typically many reactions, often as a very young child, they develop reactions to this. So, they'll start to repeat, "I, I, I, I, I, I went to the store." Right? Or they'll develop a, a prolongation. "I--I--I went to the store." Right? And these things tend to be efforts to overcome this inability to proceed with their speech as they have planned. Okay?
>> So that's a conscious thing that they're doing?
>> Oftentimes it's not. Oftentimes these coping mechanisms and the sometimes profound anxiety that accompanies an approaching block are often developed about the time stuttering's developed, which is really quite young. These people can be three years old. I mean, they don't even remember speaking without stuttering. Some of these people, right? And so, a lot of their, the development of their coping mechanisms and, and their development of their speech, such as it now is, is kind of lost to their memory. Right? They've always had it. It's been that way always. So, in some senses, it, it, it looks like it almost could be like Parkinsonism. So, Parkinson's disease is, one of the hallmark features is something called a tardive dyskinesia. So, when a person is walking, they begin to walk, but they can't pick up that foot and move it, you know? So, they have a, a dyskinesia, a failure of movement. And it's tardive, it's slower than, than the person would like. That's a little reminiscent of what's wrong with the speech in people who stutter. But it's clear that stuttering is not a form of Parkinsonism. And, and it is, it's a completely separate neurologic phenomenon. Parkinsonism affects many symptoms, it affects many systems in the body. Stuttering is just speech.
>> Is Parkinsonism, is that related to lysosomes or meta--metabolic disorders?
>> Well, funny you should ask. It turns out I have a colleague in the Porter Neuroscience Center who works in the Genome Institute, Dr. Ellen Sidransky, who has recently found that people, a surprising number of people who have a rare inherited genetic lysosomal disorder called Gaucher's disease, actually, a lot of those people, actually their, their first symptom is Parkinsonism. So, this is a newly-recognized symptom of previous, what was previously thought of as a somewhat rare lysosomal genetic disease. So, there are some connections beginning to be made. And in general, disorders of moving things around inside cells, trafficking disorders, are now coming to be recognized in many areas of neurology. It was thought originally that these sorts of disorders were only in very rare disorders, things that I had never heard of: Perry syndrome, Hermansky-Pudlak syndrome, Niemann-Pick Type C. But now it looks like disorders in trafficking are perhaps important in much more common neurologic disorders including things like perhaps Alzheimer's disease or Huntington disease. So, it's an emerging concept in clinical neurology, and I think the fact that stuttering looks like it's in the same group, mechanistically speaking, is an important advance. I think not necessarily--not just for the field of stuttering, but for people who stutter. Because to be honest, their disorder doesn't get the same kind of respect that medical conditions often get. Right? It's frequently viewed as some sort of psychological condition, you know? Or some sort of social phobia because, of course, it only happens when you're talking to other people, right? But that's almost certainly not what it is. It's, it's probably, to be perfectly honest, it's probably simpler than that. It, it's a deficit in some particular set of cells in the brain that are probably uniquely involved in speech because there are no other deficits in the people who have these mutations.
>> And it sounds like, at least going by the joke that people who stutter don't stutter when they talk to their dog, does that mean that there's some kind of social component to it? Like there's a reaction in their, in their brain to speaking to a person that sets this up?
>> Absolutely. This is a, it's a major component of the disorder. The social anxiety that accompanies it can be debilitating. And in fact, it's oftentimes the most debilitating feature of the disorder. It's not so much their inability to communicate. But it's their social anxiety that comes from the fact that they know they're going to have problems.
>> Yeah, I can imagine.
>> Yeah, yeah, yeah.
>> What kind of treatments are there for people who stutter?
>> Well, at the moment, the disorder is treated by speech/language pathologists. So, speech/language pathologists are a very highly skilled group of people. They're very well trained, and they have a very, in my opinion, a very fine eye for subtleties of speech and communication. The problem is treatments for stuttering, are, they're not as successful as we would all hope. It's considered one of the most difficult speech disorders to treat within the speech/language pathology profession. And sometimes you can get good clinical outcomes for a while, but then the patient regresses back to stuttering. So effective long-term cures of stuttering are considered the exception rather than the rule. And part of the uphill battle that speech/language pathologists fight is, to some degree, they're working empirically. They have very good knowledge of speech and the components of speech and the mechanisms of speech. But since we don't know, haven't known the causes of the disorder, it's been very difficult to make a treatment that is based on an understanding of the causes. Their treatments are largely empirical. And some of them are effective. But the disorder remains, just a chronically difficult condition to work with in the clinical world of speech/language pathology.
>> Yeah, I guess. I mean, there's a, so there's some kind of a deficit there that's probably really hard to overcome with practice and training. I guess, is one of your goals to maybe eventually set things up towards, like, a gene therapy type of treatment? Or a pharmaceutical-type of treatment that can address the intracellular trafficking?
>> Having come to the NIH from the pharmaceutical industry--[chuckles] right? I like to point out that if you can give the pharmaceutical industry the right target, they can find a drug. They're very good at this, right? We, the Nobel Prize-winners Brown and Goldstein just gave us the rate-limiting step in cholesterol biosynthesis, an enzyme known as HMG-CoA reductase. And the pharmaceutical industry, with that target in hand, gave us statins. Right? Okay, so the pharmaceutical industry works at the level of molecules. Molecules and cells. And I should, to be perfectly fair, of course, point out that other people are doing research on other facets of stuttering. For instance, neuro imaging has long been a popular area of inquiry for stuttering. But genetic approaches give us the opportunity to go straight to molecules. And that's the level at which the pharmaceutical industry operates. So, we're always hopeful. Developing pharmaceutical or gene therapy treatments for stuttering, of course, is a formidable challenge, and it's because of the costs and the length of time that's required to develop any new drug, much less a new gene therapy. Right? And it's treatments for stuttering are not often reimbursable by health insurance in the current system. It's a very sad situation, at least in the United States. It's different in other countries of the world. But in the United States, it's not.
So, the economic factors in developing something like a pharmaceutical for stuttering are substantial hurdles. It costs billions of dollars to develop a new drug. And, of course, if a pharmaceutical company is going to do that, it needs the promise of a financial reward at the end so. But you know, many of the greatest successes in the pharmaceutical industry have been surprises.
>> Like what?
>> So benzodiazepines like Librium and valium, they were developed as high blood pressure drugs, anti-hypertensives. And they failed the clinical trial to lower blood pressure. But all the people who were in the study who were on drug as opposed to placebo reported feeling much more relaxed. [Laughter] So it was realized that it, subsequently found uses as so-called anxiolytic, an antianxiety drug, but it was never designed as such. It was designed as a blood pressure drug. And so the pharmaceutical industry actually has seen a lot of these, amazingly enough. And the concept of drug repurposing is one that we're always hopeful for, because of course much of the cost of developing a drug is early studies like toxicology, safety studies, things like that — metabolism, drug metabolism studies. And for any drug that's already been through those, well then a large amount of that cost has already been paid. So, one could imagine some sort of repurposing, and there are many people who do have an eye out for drugs that could actually be repurposed for stuttering when they were originally developed for something else.
>> Yeah, and your role is not really, I don't believe, to look for treatments. You're building sort of a foundation of basic knowledge about what gives rise to stuttering disorders and sort of generate the information, the knowledge that will someday lead to hopefully better treatments. And this is the type of research that, as you kind of described, a pharmaceutical company's probably not going to undertake the type of research that you're doing because it's so far removed from any profit. And so that's why you work in the NIH now. You have an opportunity to do that kind of work.
>> That's what the NIH is for. We're here to understand basic biological mechanisms, both in healthy systems and in disordered systems like disease, and to provide that basic knowledge that then serves as a foundation for everybody else who wants to use that knowledge to develop drugs. And the NIH of course has an enormous track record of doing just that. The example of HMG-CoA reductase and statins — well, it was NIH funding of very basic research on how cholesterol is synthesized in the cells of the body that ultimately led to that discovery. And the pharmaceutical industry took it from there.
>> And as you mentioned, I believe you used to own or run a pharmaceutical company. And then you sold it, I believe and then eventually came to work here at the NIH. Why did you decide to make such a change from being in private industry to public research?
>> Yes, well. Just to make things clear. It wouldn't be fair to say I owned that company.
>> A number of very far-sighted and very I think talented investors, successful investors, provided the funding to do that. And it was a wonderful experience, and we did discover something very important. We discovered the most common disease gene in Europeans which happens to be the only medical genetic disease for which there's a safe, cheap, and fully effective therapy. The disease is called hereditary hemochromatosis. And not only is all the disease due to one gene in Caucasians, more or less, but more than 90% of it is due to a single mutation in that gene. And since it's an iron overload disorder, and since there's a simple treatment, so you just have people donate blood, and it removes iron, and it completely normalizes their health status.
>> Oh wow! So, they don't even have to take a drug?
>> So, they don't even have to take a drug. And they completely relieve themselves of a disease that's fatal. It's a fatal disease.
>> It kills people in middle age. And it's still vastly under recognized. But it's, the challenge is finding these people. Right? And since all, most of it is just a single mutation, well then of course there you have it. You, you have an easy way, a cheap way to screen large numbers of people to find people who are now at risk that you can intervene early, right? Before the iron begins to accumulate and damage all their organs, and so that was a big success. But that company is sort of I would say, at that stage, the company was going to change. And I was looking for a change. And I was interested in things that were more basic research, as opposed to applied research or translational research. And there are precious few places where you can go work on difficult problems right out of the starting gate, because people, most universities are funded by the extramural program of the NIH. And that funding is a process that takes time. So, if you have a wonderful idea and you have gathered all the materials you need to do the research, well, first you submit a grant. Then often you revise the grant. Then the grant goes to council, then it gets funded, right? And you're now the better part of a year out. Well here at the NIH, we go to work at the lab bench that afternoon. Right?
>> Yeah, and you can switch the next day.
>> And you can switch the next day. So that's one of the many features of research here at the NIH that made it attractive to somebody like me, who was more of a mid-career person, and allowed me to start doing work basically the day I got here. That and the other features of the NIH that make it unique, that are really essentially impossible to replicate elsewhere.
>> What are some of those features that really make this a unique environment for you to do this kind of research?
>> There are a lot of them. The first is the breadth and the depth of the research enterprise at the NIH. There are some thousand principle investigators here[DS( , and that's a lot of horsepower. But more importantly, let me tell you in practical terms what that means. You don't know where your research is going to lead you tomorrow, but one thing you can be pretty sure of is that it's going to lead you into some place you didn't expect. And when you're at the NIH, remarkably, no matter where your research seems to lead, there is a world expert in it here. And you can just walk across campus and find somebody who is, you know, they have everything. [Laughs] They have everything up and running, including an incredible knowledge base of that field. And the administrative hurdles to establishing collaborations are virtually nonexistent here.
>> You just, I like to say that the administrative requirements for establishing a collaboration across different institutes or something like that consists of a phone call.
>> And then you can work together.
>> Exactly. What do you think about this? So that's the first thing is the personnel that's available here. And the breadth and the depth of the scientific horsepower.
>> So, there's a thousand PI's you said?
>> A thousand PI's.
>> And then there's probably like 6000 trainees [DS( or something?
>> Something like that. The NIH is not a degree-granting institution. But we nevertheless train lots and lots and lots of talented students. Especially postdocs. A lot of the heavy lifting around here is done by postdoctoral fellows. And the NIH has good ones. It's, they have a system for easily getting postdocs here and giving them the resources and the infrastructure they need to just focus on their work. And so, the NIH is filled with very productive postdocs. But then, especially important is that Clinical Center. There isn't anything else like the Clinical Center. I mean yes, it's the largest hospital devoted exclusively to research in the world. But that really kind of understates what it is. It's filled with people, the most remarkable people. These people are clinicians. They are more than specialists, they're sub-specialists. They are both clinical and scientific experts in a particular area of health and disease. And, in my experience, they're just the greatest group of people to work with. They have familiarity and comfort working with people in basic research labs like me. And that, I'll tell you, is a rare and precious commodity that you don't find very easily elsewhere. Oftentimes clinical people and basic laboratory research people operate in two very different worlds. And that's not the case at this place. It's, and I have found it, really, I think: My clinical colleagues, I think in retrospect, have provided a lot of the most satisfying interactions I've had here. Of course, science, laboratory science, has that intellectual excitement to it. But eventually, the rubber hits the road, right? And it hits the road with humans, with humans who have a problem. And we have here the ability to look into those problems that's really unparalleled. There's really nothing else like it. And I never cease to be pleasantly surprised at who I run into that's helped us do that.
>> Very cool. And yeah, there must be, I'd imagine more than a thousand staff and researchers in that building. There's probably many more than that. I don't know. Do you have any idea how many researchers are in the Clinical Center?
>> I don't. It's 200 and a few beds. I think it's just over 200 beds[DS( . Many people who work in that building also have labs or space elsewhere. So, it's not completely defined by location, right? But the important thing is infrastructure, you know? It's a, it's a fully functioning tertiary care sub-specialty hospital. And I'll tell you a story, give you an example. So, one of our big unusual stuttering families. So, we study genetics of stuttering. And we spent a lot of that effort on rare, very large families with many cases of stuttering, because there's probably some gene that has a very big effect on stuttering floating through that family. Okay? Right. So, we found an enormous family in Cameroon, in West Africa.
>> Oh, wow.
>> Oh, yeah! It was, it was a remarkable experience.
>> How did you find them?
>> Well, that was an interesting story in itself. So, what happened was, there was for a long time something called the Stuttering Home Page that sponsored an online symposium, sort of a research symposium. And the way it worked was, they would ask experts in the field to write up little sections about their particular area of stuttering, clinical research, something, you know neurological, and post it, and they would open it up on the internet. And anyone in the world could log in and ask questions and everyone could see the questions. And then the author of the presentation could write answers. And everyone in the world could see that. It was very cool. I was not a formal participant. But in the middle of it—so it lasts for a couple of days—and in the middle of it I got an email saying. "We have a question from someone who appears to be in Africa. And it has to with something that looks like maybe you could answer. So, could you please do it?" And I said sure. So, the email was simple. Gave his name. He said, "I'm from Cameroon in West Africa. My father was a chief. He had three wives. I have 21 full and half siblings. Okay? And all of us stutter. But in addition, we have lots and lots of cousins and aunts and uncles and nieces and nephews. Many of them stutter as well. And is it possible that there could be something genetic going on here?" And so.
Now I have to reel you back 15 years. Okay? So just take yourself back ten or 15 years ago. And I'll tell you that my very first reaction was that this was a subtle and sophisticated version of the Nigerian email scam. [Laughter]
>> Oh yeah, trying to trick you into doing something?
>> Right. But then I started communicating with this person, and it was clear not only were their bona fides completely above board, but that this was obviously a very high-functioning group of people. The fellow who contacted me initially, wrote in, was an attorney. His elder brother is superintendent of schools. And so actually it was in a very casual discussion with Francis Collins, I said, "Francis, I found this family." And he said, "Go over and take a look. Just go." I said, "Francis, I'm not a neurologist." He said, "Don't worry about that." He said, "If there's something obvious, you'll be able to tell." Meaning that if they had some gross neurologic disorder or something else wrong with them, you might get a hint of it. So, I went over there and had met a very dignified group of people. Very high-functioning, as I say. And there was, other than a very nasty stutter, there was nothing else wrong with these people. But to make sure, we brought this fellow, what we call our proband, sometimes known as the index case to the Clinical Center. And we gave him the big workup. And what happened, they couldn't find anything. But somebody who had a malaria protocol said, "You know he has covert malaria. We found it." And they said, "Would it be okay if we enrolled him in our protocol? Because we think we can cure him." So, I talked to him. I said, "Well, what do you think?" He said sure. So that's the way the Clinical Center works. People are on the lookout for ways they can help our research subjects. So, it was a complete fluke to find this. And only the NIH had this kind of research protocol on malaria. So, malaria is not a big problem in the United States. You know, it's kind of an unmet, major unmet medical need in lots of poor places in the world. But it's not such a major problem in the United States. But we had a protocol on it here. And by gosh, they just checked him. Right? Just in passing, they checked him, and they found that they could cure him. And in fact, they sent him home cured of malaria.
>> Oh, that's great!
>> It was great! Yeah, needless to say, the family was all ready to come after that. They all wanted to come. And in the end, we brought a lot of them here over time. Quite a few of them have come.
>> And what did you learn from this family about stuttering?
>> Well, this was the family that allowed us to find the gene, the fourth gene. The one that surveys what's inside endosomes. And directs them to where they're supposed to go. And I know you haven't asked about this, but I'm going to volunteer another anecdote.
>> Yeah, please!
>> In the category of only at the NIH. Okay? So, this was very head-scratching. We found this mutation, and it was clear that this thing was the cause of the disorder. In one very large branch of this huge family, okay? But we'd never heard of this thing. It's what's called an adaptor protein, okay? And adaptor proteins, what they do is they survey the contents of these endosomes, and then they adapt with things outside the endosome in the rest of the cell so that they can direct them where they need to go, right? That's why they're called adaptors. So, we found this thing, and I thought, "What is going on?" So I mentioned this to someone, and then somebody said, "Well, have you talked to the person upstairs?" I said who? They said, "Juan Bonifacino." So, Juan Bonifacino, who is arguably one of the NIH's most distinguished cell biologists, his office is directly one floor above mine. He's the guy who discovered adaptor proteins.
>> Oh, wow!
>> And so, I took our data up to Juan, the great gentleman that he is, and he looked at it carefully. He looked at it, and he looked at it. And then he handed it back to me. And he said, "We have everything you need. We have the assays, we have the antibodies, we have everything you need." So, it was really, I can't imagine another institution that would have this kind of ready-made collaborator, you know, 20 feet away from my desk. Right? So, the Porter Neuroscience Center is I think fulfilling its dream of putting people from different institutes together who are all interested in neuroscience. So, that was a tremendous stroke of luck. And, as I say, only at NIH.
>> Yeah. So, you found these genes, and they do certain things in the body. And you see that defects in these genes cause certain things with these adaptor proteins. And intracellular trafficking. But you don't quite know how that leads to stuttering, I believe. You don't quite have that answer. So how do you, how do you go about figuring out that these genes are the actual cause of stuttering when there's a big gap there, kind of in the middle of that information?
>> There's a huge gap. And it becomes a big challenge. We just sort of dove into it. You know I don't think anyone could be further from neuropathologist than I am. But that.--.
>> A medical geneticist? Is that how you'd describe yourself?
>> I'm a human geneticist. I'm, a medical geneticist usually refers to someone with clinical training. Right? A physician. So I'm kind of a basic research human geneticist. Okay.
Right, so that, that very question. How do you connect, you know a defect in a gene to a speech disorder led us to kind of jump off the deep end of the pool. So to speak. And do again something that would, I don't think it would be fundable in the extramural program of the NIH. I could be wrong, but I, having served on study section myself. I can say that this would be viewed as a longshot. But we decided we'd try to make an animal model. Which is a long shot because animals don't talk. Yeah. [Laughter] But if you, if you in fact think of stuttering not as a speech disorder. But in a, a, a deficit in vocalization. Well, mice have extremely rich vocalization. A lot of it is ultrasonic and we can't hear it. And so in fact it's been, it's been slow to be characterized. But it's clear that it's what we call context-specific. They make all sorts of different sounds, noises. And some are specific to some circumstances and others are specific to other circumstances. And it's known that these things can be under genetic control. That is different strains of mice, different laboratory strains, have different types of calls. And they seem to be kind of innate, okay? So if you just take the genes we found. And you just knock them out in the mouse. They get these rare human medical genetic disorders, severe disorders. And the little mice just die. So you can't really test anything. So what you have to do, is you have to engineer the human stuttering mutations. That just sort of loss of half of function, right? These, just these, what we call missense mutations, right? You have to engineer those into the mouse gene. Okay? So you have to put in the human mutations. And then you have to start looking very, very carefully at the vocalization of these mice, okay? So we've done that. And it turns out there's nothing wrong with these mice in almost everything we look at. They grow normally, they develop normally. Their behaviors seem to be normal. Everything seems to be normal about their vocalization with one exception. They have gaps in their vocalization. They have little pauses that aren't supposed to be there. And in fact, and so these are not human judgements. This is if you take the vocalizations of the mouse. Because we can't hear them of course. They're ultrasonic. But you can record them with special microphones, and you can give that, those what are called spectra. Those, those auditory signals to a computer. And ask them to make judgements about what, what's there, okay? Lots of things that the computer looks at aren't any different from normal. But there are, but it finds gaps in the mouse vocalization. There are more gaps, and the gaps are longer.
>> Compared to like a wild-type mouse?
>> Compared to a wild-type normal mouse. Actually to their wild-type litter mate.
>> Oh, so brothers and sisters without the--.
>> Well they have the same in utero environment. The same birth environment, the same everything, okay? Alright. So if you give the speech of humans who carry those mutations. Give a recording, now that, that's we can hear, right? But the computer doesn't care, right? It, it'll take the information just fine. So you give the human speech information to the same computer program, and it finds the exact same problem. Okay? So this is really, we don't, you know we, we really are hesitant to say that this mouse stutters. Because of course mice don't talk. But this mice clearly has a problem with the voluntary control of the flow of its, of its vocalizations. And in that respect, it's really the first animal model of any human communication disorder. Any speech disorder.
>> Oh wow, very interesting.
>> That reflects, that, there are other animal models. But they don't recreate the salient features of the human disorder. They have a bunch of other problems, often, okay? Compared to what the human has. Okay? So, so that's very exciting. But what, why do you do that? I mean, it's like a parlor trick, right? To see if you can affect the vocalization of a mouse. So why do we want to do that? Well, now you have all of the techniques and technologies and tools available for studies in the mouse. That could never be applied to a human, right? You can't go in and do a biopsy of the brain of a human who stutters, right? But we can, we can look at the brains of these mice in exquisite detail. We can look at all the tissues of these mice in tremendous detail. And so we're doing it. And we're beginning to find some very specific and very surprising differences. And the research is kind of ongoing. So, I think we're probably not quite ready for primetime to talk about details at this point.
>> Sure, yeah. Maybe in the future, though..
>> But, but we [DS( are writing papers as fast as we can write. And we are hopeful that these discoveries will be really a significant advance. In our understanding of what's wrong—what are the cellular and structural problems at the cellular level in the brains that are associated with this deficit? Call it what you will in mice. We call it stuttering in humans. So that, that could be very exciting, I think. To finally get at what we would call the neuropathology. Of a disorder that's otherwise kind of intractable, okay? It's, and puzzling. It, it's such a, it's such an odd disorder. And I think the stuttering community has been very patient about this. They've been very, I think welcoming.[DS(
>> It’s very difficult if you're a member of the stuttering community because treatment has, has been so problematic. And many things have been brought to the stuttering community over the years as potential cures or treatments. And there was a lot of initial enthusiasm. And one by one they have not panned out maybe as they had initially hoped. And so I think the stuttering community is always careful. But they've been very welcoming and enthusiastic about what we do. And of course, we're incredibly indebted to the community. Because we study genetics, human genetics. You can't do human genetics without humans, right? So the participation of the stuttering community and some of these unusual big families has been an enormous benefit to our research. And we can't thank them enough.
>> Are you always recruiting people? Or are you currently recruiting people to come in who have stuttering? Or, or maybe who don't have stuttering? How can people find out how to participate in your research?
>> We are recruiting. We have different goals for recruitment for different aspects, different parts of our research. But we're recruiting subjects. When the field of genetics is a field of numbers. And bigger numbers are always better. So we're, we're always recruiting and looking for subjects. Many stuttering support organizations have been very instrumental in helping us do that. The Stuttering Foundation and the National Stuttering Association have helped a lot in our recruitment efforts which we hope to, hope to continue to press forward on.