xfdhe THE-CHARLIE-ROSE-SHOW-01
<Show: THE CHARLIE ROSE SHOW>
<Date: August 15, 2012>
<Time: 23:00:00>
<Tran: 081501cb.111>
<Type: SHOW>
<Head: Charlie Rose Brain Series, Year 2, Episode 4 - Part 2>
<Sect: News; Domestic>
<Byline: CHARLIE ROSE>
<Guest: Eric Kandel, Scott Small, David M. Holtzman, Alison Goate, Bruce
Miller, Marc Tessier-Lavigne>
<High: Exploration of the human brain looking at two of its most
devastating diseases: Alzheimer`s disease and frontotemporal dementia; the
central hallmark of Alzheimer`s disease is loss of memory, frontotemporal
dementia on the other hand is characterized by behavior and language
dysfunction.>
<Spec: Science; Brain; Diseases; Alois Alzheimer; Arnold Pick; Health and
Medicine; Drugs; Alzheimer`s Disease; Frontotemporal Dementia; Government>
<Time: 23:00>
MARC TESSIER-LAVIGNE, ROCKEFELLER UNIVERSITY: Right so the -- maybe I can talk about the progress in identifying drugs for Alzheimer`s.
CHARLIE ROSE: Exactly, exactly.
MARC TESSIER-LAVIGNE: Which there are most advance but then you know later in the conversation perhaps we can come back to frontotemporal dementia and other things. There are of course a few drugs that are already approved for the treatment of Alzheimer`s but they provide a modest benefit.
They work by boosting the function of nerve cells that remain, so they can provide some benefits in terms of brain function but it`s usually temporary because they don`t target the underlying cause, the nerve cells continue to die, the brain continues to deteriorate. So while they can help some patients, somewhat they don`t make a big dent in the disease. And what we need of course are drugs that slow or block the progression of the disease by targeting the underlying mechanism.
Now unfortunately, several drugs that attempted to do that have failed and none has so far been successful but what many are pinning their hopes on are drugs that target the central amyloid cascades that Alison and David discussed.
And more specifically that A-beta peptide the one that aggregates and forms plaque based on the assumption that A-beta or maybe small aggregates are bad actors that drive the disease and that have to be stopped.
Now it`s taken a long time to develop drugs for the target A-beta. Drug discovery, of course, is inherently a lengthy, costly and risky business. What you can see here is that on average it takes about 14 or 15 years and about a billion dollars to make a drug and the attrition is just massive.
So when you start with about two dozen projects trying to make drug candidates only about a dozen drug candidates will come from that. Only about nine of them turn out to be safe enough to enter human clinical trials and only one -- only one of nine will make it all the way through to approval with the others failing either because they proved to be unsafe or because they just don`t work.
In the case of Alzheimer`s disease there`s a further hurdle which is that there`s a protective barrier that prevents most drugs from entering the brain, so you have to get around that as well. And so it`s taken a long time to make drugs for A Beta. A Beta was discovered over two decades ago. It took almost a decade for people to figure out an approach that could enable us to get access to the A Beta in the brain. But the good news is that applying that approach there`re now about half a dozen drugs in clinical trials, some of them in late-stage clinical trials, some of them have already shown that they can reduce the amount of plaque in the brains of Alzheimer`s patients and in this calendar year in 2012 we should see the clinical results for at least one of them, with others giving results in subsequent years.
CHARLIE ROSE: And if those clinical trials are satisfactory what would be the result? I mean what -- how will it --
MARC TESSIER-LAVIGNE: The result would be a slowing of cognitive decline.
CHARLIE ROSE: So it`s not like you can reduce the impact already of the decline and of the erosion or destruction or - -
ERIK KANDEL: A lot of that is due to loss of neuro-cells. You can`t get those cells again.
CHARLIE ROSE: You can`t get them back. Can`t you grow them back? Elasticity or regeneration or anything like that.
ERIK KANDEL: There is some limited regeneration of nerve cells but not in most regions of the brain -- not in most regions of the brain.
MARC TESSIER-LAVIGNE: That`s right.
ERIK KANDEL: But excuse me, Marc. There`s another hopeful sign which you should mention before and that is we`re also improving techniques for detecting the disease earlier so the combination of new insights into how to intervene therapeutically and getting at the disease earlier through better imaging, through better ways of having markers in the blood.
MARC TESSIER-LAVIGNE: I think that`s a very important point, Erik. I think one of the scientists biggest concern with the ongoing trails is that they are in patients that are already symptomatic. But as David mentioned earlier, those patients have had the disease progressing in the brains for years and many are arguing that we should be doing the trials in patients who are pre-symptomatic based on the use of new bio-markers that may lead to detect the disease even before the symptoms appear. And David is a world expert on this and perhaps could comment on it.
CHARLIE ROSE: David.
DAVID M. HOLTZMAN: I think if you think of Alzheimer`s it`s a little bit like cardiovascular disease. We know that the plaques that build up in the heart that block the arteries take many years to build up and some of the most effective treatments now to prevent a heart or a stroke is to take medications that lower cholesterol. You get your cholesterol checked.
Well, we now have markers for Alzheimer`s disease that tell you that the changes of Alzheimer`s are occurring in the brain while you`re still cognitively ok. And so in applying those, some of them were imaging. Some of them are checking the fluid in either the blood or what`s worked the best is our spinal fluid. We can really tell that somebody is likely going to develop Alzheimer`s disease in the next few years.
And I think if things like that are applied in clinical trials maybe we`ll actually be able to give things to actually delay or even prevent the disease. And I think that`s where the big hope is.
CHARLIE ROSE: So then if you`re able -- successful in doing that, you`ll be able to see it maybe after it`s into five into development or ten years into development.
DAVID M. HOLTZMAN: That`s exactly right.
(CROSSTALK)
DAVID M. HOLTZMAN: That`s exactly right. There`s good evidence we can do that now.
CHARLIE ROSE: So what`s necessary to advance that hope.
DAVID M. HOLTZMAN: In theory, it`s straightforward. You enrol a lot of normal people of a certain age and you assess these biomarkers and then you put them on a treatment or placebo you see if it delays the disease. The problem is it takes many years for somebody to progress.
Even if they are going to develop the disease it might take three, four, five, six years and so it`s going to be very expensive to do these trials and how even a single pharmaceutical company it might be very difficult for them to do that. And so we may need to come up with new models maybe public-private partnerships or other new ways to be able to enable us to get a treatment. I think that really is the way to go, though.
MARC TESSIER-LAVIGNE: Or find surrogate markers so that you go early before symptoms appear and you give the drug and you measure outcome not based on the development of Alzheimer`s disease per se but on some further progression, pre-symptomatic progression of the disease.
DAVID M. HOLTZMAN: Just like cholesterol in your blood; you give a drug and you see if it gets lower. That would -- this same type of thing could occur in Alzheimer`s disease.
CHARLIE ROSE: Let`s move it over to where you are.
BRUCE MILLER: The frontotemporal dementia I think has given us some incredible exciting genes. One of them is called progranulin and we`ve learned that people of about five percent with frontotemporal dementia carry this gene. It produces something called haploinsufficiency which just means we don`t get enough progranulin from the bad gene.
So this becomes I think one of the most plausible areas to treat something. All you have to do is figure out a drug that will either increase the amount of progranulin in the blood and brain or figure out a way of delivering this protein. And so I think it becomes one of the simplest neuro-degenerative diseases and we`re already beginning to think about treat trials with drugs that we think will elevate the progranulin levels in the blood and brain.
CHARLIE ROSE: Talk about a bit about sort of the creativity in the left side of damage there and what that tells us?
BRUCE MILLER: Yes. So 1996 I started to notice that some of my patients all had progressive aphasia. They hit the left frontal part of the brain or the left temporal lobe. There was a small percentage who suddenly in the setting of this progressive language disorder began to show visual creativity.
And this is I think a fascinating story about the brain. It tells us that we have circuits and we turn one off and we may actually be turning other circuits on. And I think in some of these patience there is actually increased activity in the posterior parts of the brain on the right side that are involved with creating art.
I`d like to, you know, talk a little bit about Anne Adams, who I think was our most extraordinary story --
CHARLIE ROSE: I love this story.
BRUCE MILLER: Anne and her husband both scientists, he was a mathematician and Anne was a biologist who studied the epithelium of the ovary under the cell and suddenly decided that she didn`t want to work in science and she began to create art. And what Anne did initially was some static pictures. She hadn`t used the paint brush very much. But then I think her work built and it became more visually beautiful.
CHARLIE ROSE: She became obsessive about this. I mean she -- all she wanted to do was go to the art studio and look at Ravel and whatever -- I`d forgotten who it was but -- it just -- that was her life --
BRUCE MILLER: Exactly.
CHARLIE ROSE: -- which is extraordinary. So a scientist who becomes more committed to art than she could ever have imagined.
BRUCE MILLER: Yes. Her whole life became art and painting.
CHARLIE ROSE: Because it moved to a different section of her brain.
BRUCE MILLER: We think so. We got a picture of Anne`s brain before she ever developed her language disorder and we saw that already she was showing loss of tissue and this is -- she had loss of tissue initially in the left part of the brain involved with producing speech and a larger right posterior parietal area which we think was involved with this burst of visual creativity. Sadly the burst of visual creativity was really the beginning of the frontotemporal dementia.
So I wanted to talk about the picture of Anne`s which she used -- she punned -- she said unraveling "Bolero" and what she attempted to do was capture in a visual way what a "Bolero" does and "Bolero" was a very rhythmic, repetitive, compulsive piece very similar I think to the way Anne approached the art.
CHARLIE ROSE: She did it note by note.
BRUCE MILLER: She did it note by not. She took this 340 meter piece that is highly repetitive with a progressive crescendo. And she began initially with the beginnings of this and showed in a snaky fashion how the crescendo builds. If the note is longer that means that "Bolero" was producing a louder note. If it was wider they played the note longer.
And then what you see here is the sudden change in key which Anne Adams was fascinated by. So suddenly we`ve gone from these dull blue and brown keys to this gaudy florescent pink and orange which is the beginning of the crescendo and the stop of the music.
And so, Anne had done something that we have called transmodal association; she associated sound, rhythm, auditory processes with a visual picture.
CHARLIE ROSE: But the sad thing is this is the beginning of the onset and these implications.
(CROSSTALK)
BRUCE MILLER: Absolutely. And the amazing thing for us, we don`t think it`s a coincidence that Ravel himself seven years before he produced "Bolero" was beginning to have problems with writing and he developed progressive aphasia we think identical to Anne`s. Seven years before Anne was diagnosed with progressive aphasia, she produces a wonderful piece. Of course, neither of them knew about the other.
CHARLIE ROSE: Let me tie up Alison with this idea of not only the genetic disorder with some kind of environmental impact.
Uf1: Right. Yes. So, as you probably (INAUDIBLE) the well-described example of how environment can play a role relates to the most common risk factor for Alzheimer`s disease which is a particular form of a protein called Apolipoprotein E or APOE for short. This protein comes in three forms and two, three and four, bizarrely not one and the three is the most common form that has no -- it`s neutral in terms of risk.
The APOE 4 form of this protein increases our risk for developing Alzheimer`s disease and E2 will decrease one`s risk for Alzheimer`s disease. And what has been observed is that if you have head injury with loss of consciousness, if you have an E-4 form of the protein your outcome is much worse than if you have one of the other forms of the protein. So this is an example of where an environmental factor, head injury, can have a different impact on your risk for disease depending on your underlying genes.
And it`s really quite a substantial increase in risk so people who have the APOE-4 form of the protein and have a head injury can have a 15 to 20-fold increase in risk of developing Alzheimer`s disease. And obviously --
(CROSSTALK)
CHARLIE ROSE: Go ahead.
ALISON GOATE: I was going to say this has a big impact when you think about the sports that people play where you`ve contact sports where you --
CHARLIE ROSE: Concussions seeming to be on the rise.
ALISON GOATE: Exactly. That`s right. I mean I think that this is -- has significant public health issues when you think about the number of people who are obviously at risk. Putting themselves at risk for developing Alzheimer`s disease or other dementias as a result.
CHARLIE ROSE: Before I open this up to broader questions. Talk to me about drugs and what we`ve learned in a sense and the fact that if in fact the drug fails does not mean that it was -- that there`re not lessons to the learned.
MARC TESSIER-LAVIGNE: That`s right. So the -- I mean we`ve already discussed how even the ongoing trials right now to target this A Beta peptide, if they fail, is it because the theory was incorrect as Erik pointed out -- this is a theory. Or is it because we intervened too late and the horse already left the barn and closing the door won`t keep it in.
So through these trials we will see effects on amyloid. We`ll see whether there`s behavioral improvement and improvement in cognition. We`ll be able to learn, you know, how good our theory is and I think that`s one thing that`s going to happen over the next several years.
At the same time, there`s a -- as we target one specific mechanism there, I think it`s very important that we continue to target other mechanisms. One of the great lessons of drug discovery is it`s rarely the case that by hitting one you can get all the benefits you want, that you can get a magic bullet.
Typically you need combinations of drugs, hitting different aspects of the mechanism. And I think a very important area in neuro-degeneration is understanding, once the disease is initiated with factors like A Beta or progranulin, how does the death get executed? What are the executioners of the nerve cell death? It`s thought that tau protein that we`ve heard about earlier is involved in this. So drugs against tau are being made and developed and I think as we learn more about that we`ll get more entry (ph) points for drug development that can work in a complementary fashion to the other drugs.
CHARLIE ROSE: And so when we look at the concentration of tau what do we find in terms of the (INAUDIBLE)
MARC TESSIER-LAVIGNE: Well, we see it increasing as in spinal fluid for example, it increases over time as the disease progresses. Tau is interesting because it`s in those tangles that David talked about initially, neurofibrillary tangles in Alzheimer`s disease. It increases in the spinal fluid. And you may have noticed on Alison`s genetic chart in frontotemporal dementia, it`s a causal being when it`s mutated. You get frontotemporal dementia and that points at one additional thing. These execution pathways may actually be a (INAUDIBLE) to get drugs across dementias because they may start for different reasons but they may converge down to the same point.
So a drug that targets tau may be useful both for Alzheimer`s disease and potentially frontal temporal dementia.
CHARLIE ROSE: Let`s broaden this out and talk about the cost of this. In other words, I mean there`s huge societal cost.
ERIK KANDEL: Enormous. One forgets and this is one of the things that Marc pointed out, the costs are true for cancer as well. It takes a long time to bring a drug to market. The reason the cost is so enormous here is because this is an epidemic. There are so many people who suffer from it.
CHARLIE ROSE: Because people are living to be over-age.
ERIK KANDEL: When I was a medical student this was not talked about. This is a disease of the last 50 years because people are really living a significant amount longer and therefore dramatic increase in --
CHARLIE ROSE: So when you were a medical student there was no discussion of Alzheimer`s?
ERIK KANDEL: Practically not.
DAVID M. HOLTZMAN: Me neither.
MARC TESSIER-LAVIGNE: Interesting in terms of societal cost currently the Alzheimer`s Association reports that the cost to society today in the United States alone is about $280 billion a year and that`s where money changes hands primarily through nursing care. And it doesn`t involve in- kind care from families. It`s estimated, as David said, there`s going to be a tripling of the population by 50 years which estimated the cost to the nation in today`s dollars will be a trillion dollars a year.
A trillion dollars a year; we`re trying to squeeze a trillion dollars out for the next decade. It shows you that the magnitude of the potential economic impact, not to mention the human toll from the disease.
ERIK KANDEL: I think the country`s beginning to realize this requires a national effort. And the government`s actively becoming involved in it. There are now plans that by certain dates hopefully there will be significant progress on this.
CHARLIE ROSE: One of the great questions for government in the 21st century is the cost of health care as a percentage of GDP and how to make a more effective and more efficient health care treatment and delivery of health care.
ERIK KANDEL: Right. What`s fascinating about Mel Goods, he`s such an amazing guy. First of all he reminds me a little bit of President Reagan who also came public with it realizing that it`s not going to do much good for him perhaps but people will know what an important disease it is. Mel Goods` company was involved, it`s the first company trying to develop a drug for Alzheimer`s disease.
CHARLIE ROSE: Right. I always thought that Reagan`s decision and the eloquence of what he said about Alzheimer`s and the way he said it was one of the significant contributions that he made.
ERIK KANDEL: Absolutely.
CHARLIE ROSE: Bringing attention with the prestige of the office and brining attention and recognition and --
ERIK KANDEL: Not being embarrassed.
ALISON GOATE: Yes. Taking the stigma away from the disease.
ERIK KANDEL: Yes. This is a disease. This is not bad behavior.
CHARLIE ROSE: Exactly right. Go ahead.
BRUCE MILLER: I was going to say one of the real tragedies now is that we had a spokesperson at that time. We don`t really have a spokesperson at the moment for Alzheimer`s disease and suddenly we have these incredibly powerful biological approaches that we think are poised to make a difference for our society and we are not getting the NIH funding.
CHARLIE ROSE: So you`re worried that there`s opportunity that we may miss the chance to activate.
BRUCE MILLER: Exactly.
We finally have the discoveries now we really need to act and just get treatments that are effective. We`re right at the point to do it.
CHARLIE ROSE: And the need is so large that only government can provide or primarily can provide the kind of resources necessary?
(CROSSTALK)
DAVID M. HOLTZMAN: That`s true, although -- there probably has to be more than -- more things than that as well.
ERIK KANDEL: Yes. The government has to be involved it`s of such large size. And what is tragic is that with the cutback in government spending, research is being hit particularly hard. We are fortunate that people like the Lauders are interested in Alzheimer`s disease and actually that`s where Mel Goods spoke and drawing people`s attention to it. So private philanthropy stepping in an important way but it can never substitute for what the government can do.
CHARLIE ROSE: Yes. I still don`t -- I`m not clear because I mean, we hear all the time that we should all be doing things to make our brain more active. I`m not sure that I understand what is the hard empirical evidence of doing that?
ERIK KANDEL: If you keep your mind active and actually being in good health, keeping blood pressure under control, keeping diabetes under control. These are protective factors against age-related memory loss. So age-related memory loss is something we can actively do something about. This is a question of getting the word out.
CHARLIE ROSE: As we have made very clear here and everyone knows that more and more you meet people that have in some way been connected to either some kind of dementia or whether it`s Alzheimer`s itself. We are where here in terms of the research and the possible breakthroughs in the near term? Let`s take them all.
DAVID M. HOLTZMAN: I think we really understand a lot, not everything about what underlies the disease. And we are at a point where new treatments that are being developed now are in people for the first time that really attack the mechanism. And we`re probably going to have to also treat earlier and that`s where there`s real hope to really delay or prevent the disease. And that should happen in the upcoming 10, 15 years.
ERIK KANDEL: Could you summarize some of the markers that are available --
DAVID M. HOLTZMAN: Some of the markers for the disease include being able to image amyloid in the brain of a living person --
CHARLIE ROSE: Right. Right.
DAVID M. HOLTZMAN: You can also see markers not only in amyloid --
CHARLIE ROSE: So we can do that now.
DAVID M. HOLTZMAN: We can do that now. We can also in the spinal fluid detect whether the brain is beginning to degenerate by measuring proteins like tau that Marc had mentioned.
CHARLIE ROSE: Right. Right.
DAVID M. HOLTZMAN: And combining these things together you can really detect roughly when somebody`s likely going to develop the disease.
MARC TESSIER-LAVIGNE: I think it`s worth pointing out that the progress has been very exciting in terms of the basic science and even more exciting seeing it move towards the clinic with these experimental drugs. There are still many, many things we don`t know. For example, how it is that the nerve cells are actually dying which if we knew it would enable the next generation of drugs. So while we move forward with the current drugs that are in the clinic, that are going to mature in the coming years and the coming decade, we also have to keep at it to get additional drug targets.
CHARLIE ROSE: We do not know why the nerve cells are dying? We know they`re dying, we don`t know why.
MARC TESSIER-LAVIGNE: It depends on the why. In terms of the why, they`re dying because of the triggers at the top, whether it`s progranulin, A Beta, other things. We don`t understand how it is that the nerve cells get dismantled. What`s the program of suicide inside the nerve cells at the biochemical level? If we knew that we could try to intervene and block it.
CHARLIE ROSE: And how far away do you think we are from that? Just to ask you a kind of locker room question.
MARC TESSIER-LAVIGNE: You never want to make predictions in science but if I have to make one, I think we`re poised to make a lot of progress in the coming years because a lot of insight into how cells die have arisen over the past two decades that are converging on an understanding a nerve cell.
CHARLIE ROSE: Erik.
ERIK KANDEL: He makes a very good point which we`ve made repeatedly here. The brain is a marvelous organ and we like to think that we understand it completely. We`re extremely far from doing that. It`s obvious.
(CROSSTALK)
ERIK KANDEL: And this is even more true in terms of treatment. These are extremely difficult problems and it`s going to take a long time to really tackle them. But one has to realize that molecular biology wasn`t applied to the brain until 1980. The imaging techniques, when we are house officers (ph), x-rays, the most primitive techniques of visualizing and you didn`t really visualize the brain you visualize the vascular tree. You visualize the bones. You didn`t visualize the actual brain and so brain imaging, CAT scanning and MRI came along, 30 years.
CHARLIE ROSE: I`m always struck though no matter how sophisticated the science and the biochemistry, and whatever it is, it`s always ripe with fundamentals, very basic fundamentals, unless you understand why the nerve cells are doing that you can`t even go to understand how to address the issue.
So let me do something we always do here and with sort of interesting kind of results and we may have been on it with you and let me ask this question of what`s the most important question you`d like to see answered?
MARC TESSIER-LAVIGNE: The most important question I`d like to see answered is how it is that the nerve cells die in these diseases.
DAVID M. HOLTZMAN: I really want to know if you treat the disease with these really attractive mechanism-based therapies whether you can delay the disease.
CHARLIE ROSE: Whether you can delay it?
DAVID M. HOLTZMAN: Delay the onset of the disease which would be effectively preventing it.
CHARLIE ROSE: And you`re optimistic that we will --
DAVID M. HOLTZMAN: I`m very optimistic.
CHARLIE ROSE: In the near term?
DAVID M. HOLTZMAN: I think in the next 10 to 20 years, I think we`ll have --
CHARLIE ROSE: Bruce, your turn.
BRUCE MILLER: I spent 30 years working on diagnosis and I don`t want to work on that. I think we`re good at it now. I want to spend the rest of my time showing that we can treat frontotemporal dementia. And I`m very optimistic.
CHARLIE ROSE: Today?
BRUCE MILLER: Today. I think that this is going to be like cancer. We`re not going to treat all cancer at the same time; we`re going to pick off different sub-types of frontotemporal dementia, Alzheimer`s disease, one by one. And I think with progranulin and the tau-related problems of FTD I think we really are making some headway.
ALISON GOATE: Yes, I would agree with Dave and I think that maybe a combination of knowing our genetic background and genetic respecters in combination with these biomarkers is really going to be something that will allow us to identify people who are at most at risk at the earliest possible times to allow these treatments to be used to prevent disease rather than to be curing the disease.