>> rose: welcome to our program. tonight, a special edition the charlie rose brain series, year two. in our eighth episode, we consider parkinson's disease and huntington's disease. >> this is a profound insight, which allows us to think that there may be a uniifying theme connecting these disorders, and perhaps allowing us to get a completely new therapeutic approach to this, that if we could solve any one of them in a fundamental way, we would revolutionize neurology. >> rose: episode eight of the charlie rose brain series two. the charlie rose brain series is about the most scientific journey of our time. understanding the brain. it's a series made possible by a grant from the simons

foundation. their mission is to advance the frontiers of research in basic sciences and mathematics.

captioning sponsored by rose communications from our studios in new york city, this is charlie rose. >> rose: tonight, we. our exploration into our magnificent brain with a look at disorders of movement. they're associated with changes in the brain cells that help us move. these changes can affect the speed, quality, and ease of movement. the two disorders we will focus on are parkinson's disease, and

huntington's disease. parkinson's disease was first described in 1817 by the british physician, james parkinson. approximately one million people in the united states alone are afflicted. parkinson's' onset is typically subtle and commonly developed between 55 and 85. its features include tremors, difficulty moving, slowness of moving and muscular stiffness. it results when cells in the part of the brain that produce dopamine fail and deteriorate. there is currently no cure for parkinson's disease. huntington's is more complex than parkinson's. it is a hereditary nur lodgal disorder first described by james huntington. those affiliated typically see the signs in early middle age. the symptoms develop gradually

over time causing a progressive degeneration of cells in the brain and slowly impairs a person's ability to walk, think, and talk. there is currently no cure. tonight i am joined by two people who deeply understand parkinson's and huntington's. sam posey is a retired race car driver and television commentator for abc sports. he has had parkinson's disease for 18-year-old. they will each share their personal experiences and insight into their conditions. also joining me, a remarkable group of scientists, stanley fahn. he is a professor and director of the center for parkinson's disease and other movement disorders at columbia university medical center. anne young is a professor at harvard medical school. stanley prusiner from the university of california, san francisco. and once again my cohost is

dr. eric kandel, a nobel laureate at columbia university and a howard hughes medical investigator. >> we can discuss parkinson's and huntington's disease two gedenrative diesels that affect movement. what is interesting about these disorders is the history. if we consider autism, which is a program we did recently, that was discovered 60 years ago. we've had beautiful, detailed, insightful descriptions of parkinson's disease huntington's disease that go back over 150 years. james parkinson's, in 1817, described six families who had what he called shaking palsy. the symptoms are a tremored rest. an abnormal posture and muscular weakness. this description was so detailed and so excellent, that physicians soon were able to

characterize the disease and see exactly what parkinson's was, and they renamed the disease from shaking palsy to parkinson's disease. it was a long time before we began to understand what some of the mechanisms underlying the disease was. it was only around 1960 we dan to realize the disease is caused by fact that there's a death of dopa meanic neurons. dopamine is a modulatory system in the brain that affects the i haveatium, a key structure involved in motor coordination. we now know a lot of the treatments available for it are based upon this initial deep insight. huntington's disease was discovered 50 years later, about 1870. george huntington, a columbia-trained physician, very astute, had the insight, looking at families in long island, that it was a hereditary disease that

he encountered children also affected motor movement. and the defining features of that were that it was genetic, hereditary disease, number one. that, number two, there were involuntary movementes, and number three, it went beyond the motor system to also affect cognition and sometimes alterations in personality. the clinical picture alone suggests this disease goes beyond the striatium. it involves the cerebral cortex, hip campus, a structure involved in memory storage. and sometimes hypothalamus, as well as the cerebellum. progress in this disease also is very, very slow. it wasn't really until about 1968 that one began to make progress in it, and this owes a great debt to the hereditary disease foundation which milton wexler founded. milton wexler was a very

well-known psychoanalyst living in los angeles whose wife had huntington's disease. so he started a foundation with a double purpose in mind. one is to get resources to do basic science, and the other was to try to direct the science in a productive way. and since this was a hereditary disease, the key idea was to try to define the gene that was responsible for huntington's disease. this was in the easterly years of trying to do gene sequencing and gene cloning, so this was a very daring effort. in 1983, they were able to localize the gene for huntington's disease to chromosome 4, to the very tip of the chromosome. an international consortium of gene hunters formed, and in 1993, they iced and sequenced the gene. that was an enormous advance because with the gene, they could pop it into mice and flies, and into worms, and study

mechanisms of pathogen sis, how the gene does its harm. they learned an enormous amount about this. moreover, as they began to look at these disorders, they realized that in addition to the clinical similarity, they both affect motor systems and they both share certain anatomical features in common. there also is an interesting similarity in the way the proteins that are involved in the disease become abnormal. they realized this is a protein-folding disorder, and it belonged to a larger family of protein-folding disorders which were pioneered by stan pewsener. he described a disease many years before that as a disease involving protein misfolding and we realize, alzheimer's disease, that you and i talked about, frontal temporal dementia, in addition to parkinson's disease and huntington's disease, are

protein-folding disorders. what does that mean? that means the protein can exist in two confirmations. one is the normal confirmations in which it does its normal function, but flips into the abnormal and forms aggregates. these bundles of proteins are pe toxic. they kill cells. they're released by the cells, taken up by other cells, and in term, these aggregates kill the cells that take them up. this is a way of propagating the disease, extending it throughout different parts of the nervous system. this is a profound insight which allows us to think that there may be a uniifying theme connecting these disorders, and perhaps, allowing us to get a completely new therapeutic aproposal to this. so we're going to have a really terrific opportunity to discuss this because not only do we have, as you pointed out, sam and allen here, who have the disease, but they brought their physicians with them.

so stanley prusiner is a pioneer in parkinson's disease, and anne young is a pioneer in huntington's disease. and stan has been thinking about protein-folding disorders for much of his academic career. >> parkinson's is of disease is the second most common yo neurodegenerative we have. hopalm add ali and many others, like michael j. fox, the disease. the most common symptom people recognize is the tremor, and the tremors are usually in the fingers. in addition to tremor, there is the stiffness of muscles, what neurologists called rigidity. but probably the most important first symptom is slowness of movement and decreased amp

liitude of movement, difficulty getting out of a chair, swinging an arm when they walk, their writing-- their handwriting becomes small and slow. they may have trouble shaving. and the tremor, of course, interferes, too. but it's the slowness of movement that gets them. but the disease doesn't stop there. those are the early features. eventually, a person's posture changes and becomes flexed. so they have stooped posture. in fact, people recognize of stooped posture of many people with parkinson's. and walking is involved. they begin to have a shuffle of their walking. their balance becomes impaired. if they lean over too far to one side they can fall. so falling becomes a problem, in more advanced parkinson's disease. and a particular problem is-- which not everything gets-- is freezing of gait. their feet stick to the ground. often it happens when they're turning. this leads to falls.

parkinson's', again, is a little nuclear in that it tend to start on one side of the body but eventually goes to the other side. >> rose: sam posey, tell us what it's like for to you experience parkinson's and how you first noticed it and how it progressed for you. >> well, i'll tell you, it was like being ambushed. i was just turning 50, and everything was going incredibly well in my life. i had a great job with abc sports, and suddenly, out of nowhere, comes this tremor, and stanley just described it. in my case, it was the wrist. there was no hiding it from abc, and i lost my job within a few months. but it progressed so slowly, that it was a strange sort of dichotomy because here's this thing, no known cure, everything-- everywhere i looked, it looked like a nightmare. but as i said, it progressed so slowly, that now, 18 years in, i can still describe it largely as an inconvenience. it's a hell of an inconvenience.

i mean, i can't do buttons. i can't change light bulbs. but it's-- >> race cars? >> well, driving is-- driving and painting have been the saving grace for me because something about driving, all of the parkinson symptoms vanish when i'm around my racing car. >> fantastic. >> rose: what does that say? the basal ganglia where disease is affecting is bypassing you and you're working out of the cerebral cortex. just like in sleep. parkinson's goes away in sleep. i think the basal ganglia is not being used in those times. who he's driving, he's concentrating and focusing, he has to use his cortex. >> rose: you also sought psychological human, didn't you, sam? >> i can. a friend of mine said you should get a psychiatrist immediately and i did. he stepped up to the plate and has been fantastic for me ever

since. the point to having a psychiatrist-- well, another member of the team. i look at this as a racing team. stanley is not-- there's no demeaning. he's the chief mechanic. ( laughter ). >> that's an honor. believe me. >> but my psychiatrist was-- the original purpose was-- because there would be things that would drive me crazy about this disease, that it would be just better not to be taking out on my family. >> rose: what about longevity? >> well, this, of course, is something that scares me to death, the eternal silences. and whether that will be hastened by all this or what, i don't know. i mean, right now i'm, as i said earlier, 68, and feeling terrific. my general practitioner said, "you're in great shape, except you have parkinson's." ( laughter ) so i don't know. >> rose: let me have stanley add to the history we were talking about. >> the history of parkinson's

disease is fascinating. you mentioned it was 1817 when james parkinson described it. it took another 100 years, basically before we knew anything more about parkinson's and that was in 1912 and 1917, two important papers on the pathology of parkinson came out. in 1912, certain neurons were in the brain of people who died of parkinson's disease. in 1917, a russian, who was a medical student in paris, studied parkinson brains and he wrote his paper describing the substabsifying rapart of the basal ganglia was involved in parkinson's. if you look on the left, you see a dark band on each side of the midbrain. this dark band is called the substandpointia nigrim.

there is decreased pigment. if you look on the right half you see a parkinson's brain, and there is decreased pigment, and if you look under the microscope, you see cell loss in the suwstantia nigra. he called it louie body. if you look at the graphic, you see a nucleus in the cell, and just below that and a little bit to the right is inclusion called the louie body. it is found within the sighto plasm of the cell and is the hallmark of the disease. the next part of the interesting picture of understanding parkinson's disease took about 40 years. carlson actually discovered dopamine in the brain. he found high concentrations. he was very much interested in what we call moano amines, and seratonin is one, norepinephrines and dopamine. he was interested in what caused drug-induced parkinson's from

resurring. resuring is a drug from india, and caused people and animals to become parksonian. nobody knew how it worked, but early investigators found a decrease in seratonin. he wondered if it increased dopamine. he gave it to animals and it showed an increase of dopamine as well as seratonin. he took rabbits, made the rabbits listless. they droopped, they couldn't move. their ears dropped down. and then he injected the precursor for seratonin, nothing happened. he injected the precursorror dopamine, l-dopa, and bingo, the animals woke up. carlson recognized this as a very important and came up with the hypothesis that dopamine is somehow involved in parkinson's disease. eventually he won the nobell prize the same year eric won it. >> rose: anne young, tell bus huntington's. >> huntington's is a little different than parkinson's but

starts insidiously like parkinson's. it begins in midlife, usually after people have had their families, but it can start as early as age two or as late as in the 90s. >> rose: as late as the 90s. >> yes, i've seen a person 94 with early huntington's disease. and the disease starts out with little personality changes, perhaps some changes in cognition, and little flick-like movements of the fingers and toes that people term dance. as they move along in the course of the disease, those movements get really quite severe, and people lose their fine-motor coordination, and eventually, actually, need to have else to care. they can't speak. they can't swallow. can't walk. it's a long illness that takes

place over 15 to 25 years. with alan and his family, alan inherited the huntington gene from-- here he is the red square is depicted as alan. it's red because he has huntington's disease. and his mother, the red circle, also had it. and she passed it on to him. and her mother, his grandmother -- >> rose: there's a clear genetic basis. >> in huntington's disease, it's a clear, inherited disease, passed from one generation to the next in what we call a dominant fashion. >> rose: let me town alan. give us the sort of real-life experience with living with huntington's. >> yes, i've been-- i've been very fortunate that i don't have as much motion disorder as a lot of people with huntington's disease do, so i still ride a bike 20 miles on monday and 30

miles on wednesday. and try to exercise every day. i thought i was free. my mother got it in her 40s, so when i turned 50 we celebrated. we built a house on martha's vineyard, and we were really on the way, and all of a sudden, at 59, i developed symptoms. >> rose: what were the symptoms, tremor and things we described? the symptoms were mostly insomnia for me. >> rose: really? >> i could not sleep. >> rose: and other symptoms? >> i then also had some tremor, and a lot of movement, where i was crossing -- >> rose: you were 59, though? >> yes. >> rose: did you seek help in the same way sam did? >> di. because of the family history, we thought of huntington's disease, and so i tried to get the test done, and i went to my doctor, who said, "no, you don't

have huntington's disease. you're too old." ( laughter ) >> rose: he said you're too old. >> i said, "no, no, i think i have huntington's disease." so i finally kinessed him to do the test. i tried to-- i paid for a test myself, and sent it off, and they never did the test on me because i wasn't approved by a doctor. even though i was a doctor, they wouldn't accept me as a person to authorize it. >> rose: how are you today? >> i'm doing really well. i think the creatine has really happened me. i started taking creatine when i was 60 or so, and i think that has really made a difference in my progression. >> rose: as we did with stanley and parkinson's, give me a sense of the history. >> well, as eric mentioned earlier, huntington's disease, i think some of the major breaknews huntington's disease have been through advocacy and philanthropy, actually, from the

hereditary disease foundation and other foundations, and one of the important things is that, that was organizing the effort of all the scientists to work together, which was really unique to bring people to bear on this problem. and huntington's, we all have a huntington's gene, all of us do. there is a portion of the gene that gets bigger in huntington's disease. and that expansion gives you the disease. so what happens in huntington's disease is that the code is altered, the genetic code. now the code of the genes is-- our whole genetic code is made up of an instruction manual basically, and four letters is the alphabet of the code. and then there are three-letter words that are made up of this

code, and each three-letter word codes for an amino acid and a protein. what happens in huntington's disease is that one code, cag, gets repeated again and again in a portion of the gene. now, we all have in the portion of the gene cag repeated multiple times. but what that results in, each cag results in a glutamine in the ultimate protein. so every time you have a cag, you get a glutamine. and in most of us, those glutamines are functioning in the protein. but what happens in huntington's is that gets expanded, and when the number of glutamines gets expanded in the protein, that confers a toxic property to it. and that causes cell death, and aggregation. so what happens with

huntington's disease is that if you inherit more than 39 of those cags, you will get huntington's, and alan got it at 59. >> rose: so if you're more than 39 you are at high risk and you will definitely get it. >> you will definitely get it if you live long enough. if you inherit fewer than 35-- just think, there's only four difference there-- if you inherit less than 35, you will never get it. >> rose: no risk. >> what's wonderful about the insight it turns out this is not unique to huntington's. >> that's right. >> cag repeats in other diseases as well. >> exactly. so it turns out after this was discovered there are maybe 10 diseases that have this cag expansion. they all affect it the nervous system, curiously, and they all cause neurodegenerative disease. so we think this toxic portion of these glutamines in the protein is bad for you. and you have the nucleus of the

cell, the protein is made, and the protein in the cell body, in the sight on plasm outside the nucleus is processed, it's cleaved in two, and the pieces that are generated from that, then accumulate in the cell if you have the huntington protein. it would be expand repeats. as you can see that in the process of the cell, as well as in the nucleus. and that causes disrupted cell function, and cell death. and we know now enough about the process that i think we can make a difference in treatments for the disease. >> rose: stanley, help us understand the mechanism behind these disorders. >> so the mechanism, we believe now, behind these disorders, really begins with studies of a very rare neurologic disease.

about one in a million people get the disease. you can describe it as alzheimer's disease on fast forward. so the brain degenerates from the first symptoms until death within three to six months, whereas in alzheimer's disease, you get a profound dementia, but it takes 10 years. and we're talking about even slower problems with parkinson's and huntington's. i was looking for a virus that caused the disease because fourize before i began these studies, the disease had been transmitted into monkies and apes at the n.i.h. and i kept looking and looking, and there was no virus. there was no genetic material of life, d.n.a. and rn, there was only protein. and as i began to investigate this further and further-- first identifying the protein way large number of colleagues

helping me-- then it became clear that the protein was change its shape. it's quite clear now that different proteins cause different disease. we've00 hearing about parkinson's disease. we've00 hearing about huntington's disease. and you see this little chart in which there are six different degenerative neurologic diseases. each one has a different protein, but in each case, we now believe that the protein is changing its shape or confirmitation, as scientists talk about it, and in some cases, smaller pieces of the protein become very important. what happens is when the protein adopts the preon form, and you see that after the red arrow, that preon form feeds back. it grabs the normal form of the protein and makes another preon form, and more and more of the normal precursors converted into preons.

and eventually, the cell gets to be very unhappy. the neurons don't function properly. and the way the brain tries to deal with this is to make fibers, long fibers. and these fibers eventually end up coalescing into what we call plaques in alzheimer's disease on the very left, into tangles in the second one, and we see that in alzheimer's disease. we see it in football players who take their lives-- recently, junior seau is an example of this. we see it in soldiers. that's just beginning to be appreciated. what's often called posttraumatic stress disorder. some number of these people-- and we don't know how many-- have chronic traumatic encephalopathy, or c.t.e., like the football players. and then you see the next one is a louie body. this one is inside the cell, just like the tangle. and then on the very last panel,

we see a nuclear inclusion, that everywhere dark-brown dot in the cell in the upper left, right inside the nucleus. that represents an aggregate of the huntington's protein with an expanded cag repeat, or polyglutamine sequence. so we're now beginning to get an entirely new appreciation for what's happening. and one of the things that has come from this generalization where-- there's data being accumulated by investigators working on each of these diseases to argue that they're all preon diseases. we see this self-propagating altered shape. the altered protein, the preon form aggregates. forms as incluls p collusion bodies in the nucleus, in

parkinson's, nuke lein. and it forms the louie bodies we talked about. it has huge implications how we develop therapeutics. >> it also points out how this disease propagates. these toxic aggregates are taken up by normal cells and the normal cells essentially become infected, if you will, and they ultimately sie. this is an extremely profound, uniifying insight that just really crystallize out in the last few years with the detail we now understand it. >> rose: sam, when you look at the scientific discoveries, how have they benefitted patients? >> well, of course, i've been so lucky. i mean, i feel as if stanley has been able to roll a carpet out in front of me. as it gets worse, the treme gets better and better. but my own approach has been--

woody allen once was asked what he believed in and i believe they were looking for religious expwrs he said,"i believe in the powers of distraction," and i've pursued that russialy. ( laughter ) because i any on with my painting and my racing and everything else and i get up in the morning as somebody that doesn't have parkinson's. i'm surprised at things that i can't do, but they still fall in the category of inconvenience, as i said earlier. >> what do those paintings look like? >> the first one is of a hotel in florida. i made that in my mid-40s. it's part of a group of landscapes i made them. if we look at the next ones. the last two are very recent. talking about going from out of doors where people swarmed around you to the seclusion of a studio. it's interesting for me to trace a little bit the developments of parkinson's and see how they interact with the paintings.

i mean, there are times when i can hardly paint at all my hands are shaking so badly and i have to give it up. and then there are other times that are almost clairvoyant. there's a strange relationship between parkinson's and creativity. >> what is interesting that you said about you getting into the car and feeling completely normal when you drive, chuck close, was with him when he had alzheimer's disease, and he said he would walk around, and his memory would be defective. he walked into the studio and he was like a different person. he continued to paint until almost the end of his career when he had vpsed alzheimer's. >> you look at we'd guthrie. he was incredibly creative. many people with huntington's are incredibly creative and have done lots of interesting things. >> rose: stanley, let's come back and talk about some of the approaches to parkinson's. start with the farmicological. >> i mentioned carlson

discovered dopamine and came up with a hypothesis. the next step was to find out how does one follow up with treatment? one of the things you can see in the graphic is the dopamine was found to be found in the cells of the su bstantia nigra. and now we can measure in life, and if you have an f-dopa pet scan, this measures essentially f-dopamine in the brain---- it d it lights up the nerves in the brain. and this is a normal brain lit up with the-- where the red is. as parkinson's starts to develop, you get a mild degree of parkinson's symptoms, and you get a mild loss of the pet scan uptake and see the posterior part of the basal ganglia gets affected first. we see more advancement of

modern disease and in more advanced disease you get almost a complete loss of the dope peen content. we can see in a living person. and i think sam had a pet scan and saw he had deficiency of dopamine at that time. >> yeah, the technician said, "here, would you like to look at this thing?" he pointed to a normal brain and then he pointed to mine, and the shock of seeing that your brain doesn't look normal is profound. and i mean it's really abnormal. one of those lobes is there and the other one just wasn't. and i must admit that was part of the early phase of depression and the shock of getting the disease and everything. it really overwhelms you at first. and one of the things i think i feared the most, which i don't think has happened, was the loss of identity. you feel that this disease is going to attack you as a person. of somehow and disrupt the core of your values and your sense of yourself.

and that-- looking at that pet scan seemed to threaten that tremendously. >> rose: that reminds me, eric of a friend of mine who you know who was suffering from a terribly terminal brain disease, and he said to me once, you know, "i don't feel like i was the person i was." he saw himself as a different personality because of this. >> what we have, fortunately for sam and many other people with parkinson's disease, is a good treatment. l-dopa is now the gold standard of treatment. after cave itch found the decreases in the brain of dopamine, many nurrologists tried to give l-dopa as a treatment. we know today you need high dosedoses and long-term treatmet for several weeks before you can get better. the person who was able to find that was george kochitch. in 1967, george kochitch found a way to do it.

he was a physician working at brookhaven national laboratory in long island, and he started to bring patients into the hospital and give them small doses of dopa and build the buildup gradually over time. this was a revolution in treatment in neurology. they got out of the wheelchair. they walked and could do all kind of things. >> rose: what about deep brain stimulation? >> deep brain stimulation came into being because people already knew from prior surgical experiments that they can target a certain region of the brain and reverse are reverse some of the symptoms. a neurosurgeon in france decided instead of a lesion in the brain, let's to stimulation of the brain. with the stimulus electrode put into the target, they can-- this

is what they call inhibit the overactivity and reverse the symptoms. >> rose: anne, how about huntington? >> well, huntington's is, as you know, is more complicated than parkinson's. and i think the first thing that scientists began to do after parkinson's and dopamine was discovered was let's look at other diseases. so they looked for the missing chemical and doesn't find it. right now, our therapies are really gauged on the basis of what we think the protein is doing in the cell. none of our therapies can reverse it. and none of our therapies can slow it down as yet. but we can in animals. so, for instance, we know now that we can make animal models of huntington's disease, and

actually, not only stop it, but we can actually reverse some of the symptoms of it. so we think we'll be able to do this in humans. and we have therapies that we're trailing in humans. one of the things that's important to realize that's different about huntington's than parkinson's-- and this is in large part due to work with the hereditary disease foundation, and the daughter of wexler is at risk of huntington, because her mother had it, is devoted to finding the gene and the therapy for the disease. and once the gene was found, the hereditary disease foundation has been working on new therapies for the disease. we think that we can alter the progress of the disease in people at risk. we now know we can test people--

unlike parkinson's, we can test for huntington's disease to see who inhotterred the gene and think about starting people in therapy before the symptoms even begin. so alan, for instance, we put him on a therapy called creatine, which is an energy booster. it improves energy function in the brain, and he's been taking massive doses of it. you started at-- at one point you got up into 30 grams a day. >> i'm still taking it at a lower dorse at 12 grams a day, and that seems to be doing fine. >> he has had a marvelous career as an extraordinary physician, treating children who have bone cancer, developing more kinds of therapeutic trials by combining different therapies and a marvelous career which unfortunately he was not able to

continue but he still advising the dana farbener boston as to how to think about these things. what is wonderful about these two characters is they've got severe disease but they're functioning amazingly well and continuing to contribute to society. if painting is considered a contribution to society. we'll have to discuss that over a glass of wine. >> one thing i've learned through the years is how incredibly helpful people are. i am very reliant now on people for help of all kinds, from doing butons up to all sorts of things. and i mean, just coming to the studio this afternoon, i started to fall right on lexington avenue, and a big, strong man picked me up. i mean, dusted me off, and sent me on my way. ( laughter ) it's just remarkable how generous of spirit people are. i've been in airports and have hands shaking too much to get my wallet out of my pocket, you know-- >> there was a pickpocket. >> exactly, exactly.

( laughter ). >> you always have to worry about that. >> rose: let me turn to stanley, and then we'll have a general discussion and talk about some of the general treatment strategies for protein confirmational disorders. >> so i think the important thing to realize in all these diseases is we have therapies but they're symptomatic therapies, and that's what l-dopa is, as stanley made it so clear. the underlying disease process marches on. as eric said it marches by accumulating preons that spread to neighboring cells and more and more spread occurs and it's true of all these diseases we've talked about-- parkinson'sa disease, alzheimer's, chronic dramatic encephalopathy talzheimer's, als, motor neuron disease, and huntington's disease. so we've got to get at these proteins that are turning into

preons and stop them. i've marked three possible intervention points. so one is that we decrease the normal precursor-- protein. the second one is that we interfere with the change in shape from the normal precursor to the preon form. and number three is that we increase the clerps of the preon form that we get rid of it. and we get to a point when the level of the preon form is low enough. we don't have to get it to zero but we need to get if down fairly far in some people, and then at that point, the normal clearance mechanisms take over in the brain. we can think about this in a very different way than we did initially one is i think the therapies can work for a few weeks or a few months. they can be short term. they don't need to be years, and if we have to go back and

re-treat somebody, that's fine. so you spoke about-- anne spoke about the diagnosis of huntington's disease and having a genetic test for this. i think in all these disease we're going to need very good imaging techniques, and we saw this with stanley's demonstration of what goes on in the parkinson's disease in the flora dopa scan. we need to be able to follow these proteins. we have to look at the precursor form. we have to look at the preons when they're small aggregates and then look at the large aggregates, the fibers. so this is a very important new approach, and really the whole spectrum of degenerative nur lodge diseases. >> we're at an absolute turning point. one of the interesting things that emarriages is why do these

diseases occur with able? one possible belief was as you indicated, the aggregated self-perpetuating form develops, but as people age, the clearing mechanism capable of getting rid of it pay very well weaken. and if we can find out the nature of the clearing mechanisms we might be able to reap force them, just like your strength being restored by creatinine. we're getting inside into a whole family of disorders, that if we could solve any one in a fundamental way we could revolutionize neurology. if we could find a way of getting rid of the aggregates-- either preventing them from forming or allowing them to form but enhancing the system that gets rid of it -- >> rose: we're looking at a revolution. >> reverse it. >> rose: can reverse it? >> in animals we can reverse it.

we should beab to look at it in humans. i think if you look at end-stage disease, i think not. but in moderate stages, there are six cells, but they're not dead. and we can rescue them. >> rose: connect all of them, all the things we've talked about so far, anne and stanley and all of you. what's possible in terms of the future, reversing the diseases of the brain that we've discussed? >> i think what we need to do is identify the markers that tell us whether somebody's going to get the disease. so you any to your local doctor, quiet a little test, and it will stay you may be at risk for huntington'huntington's diseaser parkinson. and you're started on i a program of therapy. if you are at risch for that disease, that therapy will take place over the rest of your lifetime, to reverse of symptoms. ththe huntington gene started te

genome project. >> to me you could develop a methodology, here is a extreme-- we haven't the foggiest notification, and sequence the gene and see if the cga exists and it is a profound. i can say a lot of this is due to molecular biology has revolutionize the medicine. these are, normalitily difficult programs. >> and gene huntington has been

applied parkinson's. we have 18 different genes that can cause parkinson's. with now that is found in many other parts of the brain. it starts in the lower part of the brain stem and progresses up over time. the dark brownt very bottom of the slide is the medulla, and that's where the alphus nucleus aggregate accumulates, and it goes up to the pons, and up to the cortex. you get other symptoms, and it's because of the spread of the louie nurrites-- that's what they're called-- you anytime symptoms of parkinson's. >> rose: are you optimistic? >> i'm very optimistic, but this is very difficult. i think it's difficult for several reasons. one is, as eric said, not a single disease has been cured

yet. we don't have a simple road map. on the other hand, there are self factors that make it very difficult, and the first factor is called the blood-brain barrier. this is the barrier from getting things in the blood into the brain. only small molecules can get into the brain. so it limits the sizes of our medicines that we'll be able to develop. we have to be very clever about knepg something that is very small. we are also beginning to learn with the insights that all of these are preon diseases, that we're going to have to get thyself medicines all over the brain. so just trying to put them in one signee place is not going to be good enough. on the other hand, as you saw with the pet scan, i think it's going to give us when we develop develop the right proibs -- or reporters, as they're called-- for each of the different

preons. for each disease there's a different protein turning into a preon and we can begin to measure the preon forms, the aggregated forms. when we can do that, we can diagnose the disease, like anne was talking about, very, very early, before there are symptoms. you can mca diwith you're 50 years old and you go get a physical exam and lie down on the pet scanner and we can can look at all the proteins simultaneously. and we can see which ones turn into preons-- it could be one, it could be two-- that will inform us what medicine to give to stimulate clearance and cut downtown precursor level and cut down the conversion. medicine will work at all these different point. when we're able to do that, we'll be able to stop the disease in, i think, three or

four weeks. not months, not years. but to be sure, we'll than rescan of people six months later or a year later and if they need more medication, we'll do that. i see a day when this happens but it's a long way unless we get more push and get this done. >> also, one of the things we know in huntington disease-- and we should be able to apply it in other diseases-- is we can actually clip the gene, the messenger r.n.a. for the gene. so you can tearing the actual huntington gene with these little trick pieces of rn. it comes in and it binds to the jean that you're worried about and the body says, whoa, that shouldn't happen. if come the scissors and clip the gene and target it distributely. so you could turn the gene for

the disease off like a silver bullet. they're planning human trial to do this in the next couple years. we'll see what works. >> rose: i always like to ask this question and i think some of you have answered it, what is the one question you most want to see answers, sam? >> i want to know what the hell is causing this so i can come out in the open and fight it. ( laughter ) it's been a shadowing adversary for so long. >> rose: well, the joy of this conversation is there are a lot of very good people in search of that as you know. >> absolutely, the sape thing that sam wants, not only the cause but how can we stop the disease from getting worse. gl. >> my dream in all of this is that we are able to develop therapeutics over the next few years, and early diagnostic tests that we can stop these diseases and which are only growing in nabs people age. >> rose: live longer. >> yes. >> rose: are you hopeful? >> i'm very hopeful.

>> rose: very hopeful. alan? >> i would like to see a cure for my grandchildren and my daughters before they get symptoms, if they have,disease. havehuntington's disease. >> i'd like to cure everybody with all these disease. if i could contribute to some of that, i'd love that, but i want to see the cures, and it's not just in our country. but it's all over the world. these are just horrible illnesses. and we need to take them to everybody. >> rose: eric? >> my hope as a psychiatrist, incompetent though i am as a psychiatrist, i wish we had the insight into psychiatric disorders that we have into these neurodegenerative disease. this is a remarkable set of insights. the fact we can't cure it is tragic, but the progress in the last 50 years has been spectacular. and my hope is in the next 50 years, we'll have, you and i 50 years from now, will be meeting to discuss psychiatric disorders.

>> rose: you and i will look different. ( laughter ) let me conclude by saying a couple of things. nobody one, i'm so deeply honored to have people here who are both living with disease and in hot pursuit of disease, with a sure commitment that with the overwhelming desire to find answers and to make them applicable to disease, they are in one of, i think, one of the great journeys of life. and people like those who sit with me today, you know, offer and for those of you thinking about how you can make a difference, science is a place you can make a difference. science is a place where you can take vastly expanding tools and go in search of some of the most interesting questions with some of the most extraordinary consequences. so i thank each of you for coming here to share these insights and these experiences and i think we're all better for

that and we understand that the great possibilities of understanding about this brain of ours and what its implications for both disease and health are. so thank you for joining us. we will see you next time. but before we go, i always ask eric to tell us what's next? >> you told me you wanted to do multiple sclerosis next, so that's what we're going to do. this is a different disease, also a degenerative disease of the brain and we have very good insights and very good treatments. we're going to have very good session next time. >> rose: thank you, to each of you. great to see you. and thank you, for joining us. for this episode of our brain series 2. see you next time.