Many people don’t understand exactly what stem cells are, they imagine stem cells are cells that will go into the body and rebuild it, make it new again. I don’t see that happening so quickly in MS because MS affects so many different regions, and it isn’t easy to do something like that.
The other aspect of stem cells that people don’t understand, it isn’t in the news as much, is that you can take – a stem cell is a very primitive cell. So you can take a primitive cell and you can differentiate it so it becomes an oligodendricite, or a neuron or some part of the nervous system, and using that cell you can find out what signals could help stimulate growth of the nervous system. So the stem cell could be used to find new drugs without the stem cells themselves being the drug. And that’s very important, and I see that happening before stem cells being given to people and rebuilding their myelin in their brain.
There are very clear research priorities, so I’ll talk about them. So one of them is that we know that if you suppress the immune system, you can decrease inflammation and attacks. And one of the priorities now is to find new drugs that will do it without side effects, or that can be given orally. So that’s one major research area. Better drugs to suppress attacks that can be given orally, with less side effects.
Another major research priority is the progressive forms of the disease. We really don’t have good drugs for those, so that research is focused on understanding what is progressive disease.
And we’re getting some clues, there’s different things going on in that stage. And once we can understand what’s going on in that stage, and we have some clues already, then we can target new therapies.
Classic biomarkers – like measuring blood pressure, that’s a biomarker, it tells you how the vascular system is working. Cholesterol – testing cholesterol is a biomarker.
The same thing is true for MS. And the biggest biomarker is the MRI scan. And the first drug that was approved for MS, which is betaseron, which was approved by the FDA in the early 90s, the only way the panel really approved it is they had the biomarker, which is the MRI, and they really saw things were changing.
So, what are the biomarkers of the future, and what are we working on? I think that one of the biggest biomarkers that we don’t have is a blood test for MS. And we’ve been working for years on this, and I think we’re beginning to make some headway, maybe even breakthroughs. We just published a paper that with serum, just simple serum, in the simple tube of blood that you can take, we can pick up patterns in the blood that will tell us whether someone has MS, what stage of disease they are, and so we’re very excited about that.
There’s 3 definitions of a cure as far as MS is concerned.
One is to stop the progression of the disease. Someone comes down with the disease, and you stop it from going further. So a young man or woman has an attack, blindness in the eye, or numbness, or difficulty walking. They recover from that, you give them a treatment, and they never have another attack again.
Cure number two, is that somebody has damage to the nervous system and you repair that damage. So that somebody can’t walk very well because of damage, and you treat them with, whether it’s stem cells or new chemicals or whatever, it repairs the nervous system, and they walk again.
So the third cure is prevention. And that would mean taking populations, vaccinating them or giving them something and so they never come down with MS. And that’s kind of the ultimate cure. For the first time actually we’re beginning to think of experiments where we can begin testing this. Where we would take people at risk and give them a certain treatment or certain vaccine and see whether it prevents the disease.
Number one is going to come first, there’s no question, stopping the disease in its tracks, or stopping it from progressing. And I think there’s people that we’re curing now, I have patients who started with the disease, and we put on treatment or whatever, had it for a number of years, and are doing great. So I think that there are people today who are being, in quotes, ‘cured.’
There certainly are approaches that have garnered a lot of interest in the research community to actually come in and inject, for instance, pieces of messenger RNA or DNA into the brain to try to change the amount of mutant protein there is and that would involve actual injections into the brain of what we call interfering RNA or anti-sense RNA and that would then actually cut the genes function off directly.
There are a number of companies that have started to make genetic compounds that can interact with the mutant protein and stop it in its tracks and they are planning clinical trials and I believe that we’ll have clinical trials within the next 5-10 years of these agents that stop the gene from being expressed.
There are new treatments that are being tested in individuals. These are treatments that affect energy metabolism and boost the energy metabolism in the body and in the brain and these are being looked at to see whether they will delay the onset of the disease or slow the progression of the disease. And those are being tried now in people who are at risk for the disorder, so they have not started to show the symptoms, but they are people that we know have the gene for the disease. So we can follow those people prospectively to see whether they actually get the disease when predicted or whether it takes them longer to get to that point.
So we have genetic models of Huntington’s disease in mice and rats. Now there are actually sheep that have Huntington’s disease and primates that have Huntington’s disease. We can look at these drugs in those models and they seem to work and now the issue is will that translate into human treatment and those trials have begun and are in progress and they’re double blind so we don’t know who is getting the therapy and whether it’s working yet or not, but there’s some very interesting pieces of information coming out of some of the studies.
So the current therapies are virtually all aimed at symptoms of the disease. So if you get depressed you treat it with anti-depressants and they work. If you are psychotic and have difficulty putting yourself and your world and understanding where you are in the world, hallucinate or other things we use anti-psychotics and that helps. People become very irritable and there are medicines for those symptoms as well, but now doctors are starting to find a number of agents that we’re looking at in clinical trials that will affect more than just the symptoms of the disease, the overt symptoms of the disease, but actually try to find something that will change the beginning brain changes and then the progression of the disease.
The gene was first localized in 1983 and it was actually the mutation itself, the abnormality in the gene, was identified in 1993 and it’s been 15-16 years since then and an incredible amount of research has been done to understand what this gene does. It is a completely novel gene. It wasn’t as if some enzyme or some protein that we all had been studying for years turned out to be the thing that had the mutation in it. It was completely novel and that is not an easy problem to solve.
Many researchers have been working on it in yeast and fruit flies and C. elegans and various small non-mammalian species all the way up through humans and doing the work from bench to bedside trying to find out new ways of therapies for the illness.
I think we have as much chance of finding a cure for this disease as we do of any of the neurodegenerative diseases because we can identify who is going to get it. So we can identify people who have the gene, but haven’t started to show the symptoms and we could potentially start our therapy early on before those symptoms have even started to cause any change in the person’s brain and then cut it off.
As part of my residency program, I actually saw one or two people with Huntington’s disease. I was fascinated by how the brain works and could cause a disorder, a genetic disorder to cause this abnormal movement, abnormal personality. I wanted to be able to figure out how the brain changed in the disorder in such a way to cause these symptoms.
There’s huge momentum, the research in Huntington’s disease. When I started out in this field back in 1978 we knew virtually nothing about the disorder except that it was a clinical disorder causing all of these problems and now we have the gene, we know the proteins that it hangs out with, we know what abnormalities happen within the cell. And if you look at the number of researchers actually working on Huntington’s disease over the past 15 years since the gene mutation was identified it’s gone up exponentially.
We have strategies and approaches to getting therapies for the illness that I think will actually be effective. The patients don’t see it yet because those therapies haven’t actually been implemented in man, but we see it from a scientific standpoint because in the laboratory we can change the course of the disease. So we know it’s possible to do and now it’s a matter of translating that into getting into humans.
So stem cell research I think is a very exciting area in ALS. There’s really two goals that people are thinking about for stem cells.
One is just using stem cells to provide a nurturing environment for motor neurons, to help them survive, and the second to help to regrow motor neurons.
The second one is a little farther away, but there are a lot of laboratories in Massachusetts and California and a couple of other places in the United States are really going after stem cell research for ALS.
There’s also a couple of groups moving forward towards getting into people. I think it will be in our first people in 2009, the first phase one study. I think that the field is going to move in small steps on this one because it is new and it is high risk. There can be a gap of two to three years, if not longer from when you’re in your phase one safety to your efficacy trial. I think the speed will depend on the safety profile. If it’s not that risky or if the safety profile looks okay, I think they’ll move fast at the efficacy trial.
The other stem cell challenge is which kind of stem cell and whether you need to administer anything else with the stem cell and again there’s a lot of basic science work on that but pushing more complicated things into people is going to take a little bit of time.
There is a lot of research going on now to try to find biomarkers for ALS. And they can be useful in many ways. One is to help us diagnose illness sooner, so at the moment it takes about fourteen months on average from the time the person has their first symptom to when they’re told definitively they have ALS. That’s a long window for someone to be in uncertainty, and also it’s probably a window where some of our therapies might be more beneficial if we could get them to people sooner. So a biomarker might help with getting the diagnosis sooner. It also would help with understanding the disease better, and lastly as a way perhaps to allow us to test drugs in a more efficient, quick way.
So the challenges for biomarker again are funding, to get an organization willing to support a repository of samples, and then the other is enrolling people and characterizing them clinically well and getting the right type of samples. But there’s great interest in doing it. At the moment there’s a lot of groups doing it but the field could benefit from a more comprehensive, kind of collaborative effort to bank a lot of samples from tissue to blood to spinal cord.
There are a lot of challenges to testing treatments in people with ALS. It’s a rare illness which is very variable between people, so some people with the illness have a course of ten years, some less than one and many in the middle of that range, and because of that variability when we want to test a new treatment in people with ALS to see if it works, we often need to enroll hundreds of people and follow them for at least a year, if not longer, and that’s challenging when there’s a rare illness. One of the ways the community has gone around to handle that challenge is by forming a very collaborative consortium called the Northeast ALS Consortium, of sites that work together to do trials.
The other challenge is funding. It’s hard times for everybody in funding but for a rare illness there aren’t a lot of pharmaceutical companies developing treatments for ALS. The government is for the most part at this time one of the major funding agencies for clinical trials in ALS but they have a mandate to treat lots of illnesses, not just ALS, so we depend on philanthropy and other sources.
There’s kind of two priorities, I think. One is to try and better understand the cause because if we understand the cause better we’re more likely to get better therapeutic targets. So there is a lot of research looking at what genes might be responsible for causing ALS as well as what pathways might not be working right in people with ALS.
Some of the most exciting work has come out of the genetic work and that’s because the genes kind of give you a clue as to what might be causing the motor neurons to die, and there’s at the moment about five different genetic changes that have been associated with ALS and there’s probably many more coming out soon. There’s animal models, Petri dish models of the disease that give scientists tools to study the illness and screen therapies, and then there’s what we do in people. There’s a lot of clinical trials in people with ALS that look very promising.
I think there is one particular promising approach in a small subset of people with ALS called, it is called familial ALS, and these are genetic approaches to turn down the gene mutation we know is causing the illness. I think that area is likely to be the most fruitful soonest. We’re involved in one of those studies which is with a drug called an anti-sense oligonucleotide that can shut down this particular mutant protein in familial ALS, and that’s a treatment that’s right on target, we know that that mutation causes the illness and if you get rid of that protein you can prolong life.
So there’s what we call the sporadic type, that’s when there’s no family history of ALS, and then there’s the familial type. The familial type is about ten percent of people with ALS and then sporadic is everybody else. And when you see someone clinically if you don’t take a family history, the two forms look the same. So at the moment the field is largely treating people the same way. It’s only now that there’s going to be some targeted therapies just for people who have the type that runs in the family, because in some of those we know the gene cause and we know how to get rid of that genetic problem. For the ninety percent of people who don’t have it in their family there’s lots of other treatment options and both forms are really high priority for research. The reason people focus so much on the genetic form is because it’s an easier target as far as trying to understand what processes might cause the disease, but it gives insight into the sporadic form as well.
I got interested in ALS when I was a neurology resident, and when I realized that the science for the illness was exploding, yet there were really no therapies that were being developed for ALS, and that it was really an area that was really ripe for someone to come along and try to translate those scientific advances into meaningful treatments for people with ALS.
The illness is one of the most devastating ones that exists. It’s an illness that consumes the patient, consumes their family. Yet I’m always amazed when I meet people and their families, how strong patients are and how they, in spite of this physical, demanding illness, still maintain hope and a good quality of life.
I think we’re if, one assumes maybe a hundred steps to the cure, that we’re maybe at thirty steps there, and that the speed of development is quite fast in ALS.
People say there’s no therapies but there actually are some. We don’t have the cure, something that stops it, but we have one treatment that slows down the illness and we have lots of symptomatic treatments that also prolong life, and improve quality of life and those treatments weren’t there fifteen years ago.
I think this is an incredible time in ALS research. When I started in 1994 there were almost no clinical trials going on and now there are nation – internationally at least ten phase three efficacy trials. That’s amazing for a rare illness.
MS is a complex disease, there’s no question about it, and it’s heterogeneous which means that different people are affected differently.
There are different stages of the disease, there’s the relapsing stage and the more progressive stage. The relapsing stage means that people have attacks, and they recover. So that’s what a relapse is, that they – something happens to them, and then they get better. They have weakness in an arm and then it gets better, they lose vision in an eye, and then the vision returns. And MS begins as a relapsing, remitting disease. People have an attack, they recover, another attack, they recover.
The second stage of the disease is called the progressive stage – and there there are no attacks. The patients just slowly get worse. So they have slowly more trouble walking or carrying out other functions.
In these two different stages of the disease, usually the relapsing stage comes first, and that leads to the progressive stage. And one of the big questions is why do people shift? How can we predict who’s going to shift? Can we have drugs for the progressive stage? Because we only have drugs for the relapsing stage – probably because it’s earlier and it’s easier to treat. And a very big question is that if we totally shut off the relapsing stage, will nobody get progressive disease? So that’s a goal.
So the first question is why I chose this specialty. I actually chose it when I was a resident studying medicine. And it stemmed from two things. Number one, I saw a man in the hospital who had MS. And he had two kids the same ages as my kids. And so I identified with him, so there was this emotional connection to the disease. And the second was that the science connected to understanding the disease was very interesting to me. And at that time it was the immune system and viruses. So the thing that drew me to MS initially was a connection with someone who had MS who was like me, and then as I learned about it I became very, very intrigued by the science.
MS is a complex disease, there’s no question about it, and it’s heterogeneous which means that different people are affected differently. So that different people may respond differently to certain therapies. And I think that the research that’s being done, which I’m very excited about, and I think people who have MS should take a certain hope from that, is that people are really working on all the different stages. I don’t think there’s one or two parts of MS that are being neglected.
I’m optimistic about MS for two reasons. One – we really understand the disease better, in ways we never understood it before, and number 2, we have drugs that work. Because we have drugs that work, even though they’re imperfect, it means we know the pathway, and those two things give me a lot of optimism.
My interest in cell repair is it has grown after years of research in which I have seen how you can actually in an adult living brain, in a mature brain, find ways in which new cells can be put back in minute – we put them basically in a millionth of a liter, a microliter, maybe the finest little drop on your fingertip and those cells can grow like seeds – a little bit like seeds in a garden – to reconnect the brain. What was so remarkable to us that did this scientific work was that the adult brain which we thought of as fixed and fairly mutable could form new connections. And no matter what immature cell we put in, these cells would find ways of hooking up with the older brain if you will and create functional transmission. This became then my main interest and I realized that if we could translate that kind of science to medicine we may be able to help patients and indeed we have some remarkable success as well as remarkable failures which is kind of typical for new technology. But it is my belief that this kind of innovation can really bring change to medicine and neurology in the future.
So Parkinson’s disease is perhaps the lead disease for the new treatments in neurological sciences because it has this very localized brain degeneration, at least the degeneration that gives the signs and the symptoms of the disease. It has been the first disease that has been approached by cell therapy and cell repair. It is also a disease that has been approached by gene therapy. There are currently two trials that are fairly active in the United States using genetic means of introducing substances to the brain.
It is actually perhaps the detective in all of us that drives many scientists to look for causes and indeed this has been very helpful to understand why a person gets Parkinson’s disease.
But the particular research that I am very excited about is the research that drives towards new treatments. We may find ways of transforming the treatment of Parkinson’s disease by treating people early. There may be ways in which we can pick up ways of reducing the incidence of Parkinson’s disease and genetic risk factors now help us to perhaps find personalized medicine in such a way that if you are at risk there may be a treatment for you.
On the other hand, once a person has Parkinson’s disease, which is millions of people, I believe there is going to be a way beyond drug therapy and that’s now one way of the so-called regenerative medicine. We work on stem cells. Stem cells can provide new cells even from the patient’s own cells. We develop them from skin that may in the future be able to replace the cells that have died or are dysfunctional.
So stem cells fit into the overall strategy for Parkinson’s disease in two ways. One, it is a way to obtain the nerve cells that we transplant into patients that in small clinical trials have shown dramatic and beneficial effects. Although it is a new technology; I believe it is one that will be perfected over the next decades, and really revolutionize the opportunity. The other way we use stem cells in Parkinson’s disease research is to produce them in a dish maybe even from patients themselves and look at ways in which we can protect the cells. It becomes a research tool in pharmacology.
There are basically two ways of treating Parkinson’s disease. One is the drug treatments. They help patients with the symptoms for quite a long time.
When the drugs stop working, between 10 to 15 years sometimes, after the first use of drugs, there are surgical options. One of the most commonly used today is called deep brain stimulation. That involves putting down electrodes into the brain in the part of the brain that controls movement. By turning on the electrodes – a little bit like a pacemaker, in fact it is made by the same type of technology – the brain will actually function better and now be able to initiate movements better and have less side effects because you can take less drugs. Those are the two major treatments available today. What I hope will be available in the future are drugs that also prevent further degeneration of the brain but also replace some of the cells and what we call synapses, the connections of the brain, so that they can function better.
The causes of Parkinson’s disease range from very small influences in genetic risk factors. By that I mean family. They can be dominant. They can go for generations as a risk that increases the risk for Parkinson’s disease. So Parkinson’s disease definitely has a genetic component but it may be that 20 percent of the cases we see in the clinic are from pure genetic components. We believe that about 70 to 80 percent of the patients have had some kind of influence on their brain over a lifetime that triggers them to precipitate the disease.
The other most important risk on the other end of the spectrum is age. All cells age and particularly ones that die in Parkinson’s disease – the dopaminergic cells – are particularly vulnerable to that age process. Between these two genetic, extremes and aging, are multiple – are many, many factors including environmental toxins. We know that pesticides can influence the rate at which the population gets Parkinson’s disease. We also know that simple conditions such as inflammation and we are also now studying inflammation of the brain, at a low grade, a little bit like we study heart disease, as a risk factor for having Parkinson’s develop over a lifetime.
When I started medical school I was very interested in science and one of my first opportunities to do science was in a laboratory that was interested in brain repair. And in studying brain repair there were animal models of Parkinson’s disease and I realized quite quickly that perhaps it was the best model for the kind of neurological diseases that I saw or knew about. And the excitement about being able to actually restore function in a disease as devastating as Parkinson’s disease became very exciting for me. And we started as a small team working on a very new idea. Which was that you actually could take new brain cells and put them into old brains and actually improve function. And having seen the experiments work over and over again it became a very strong desire for me to try to get patients the same kind of success.
I am very hopeful that we can deal with many of the neurodegenerative diseases. And I am most hopeful about Parkinson’s disease because at least we understand what happens to the brain in a somewhat limited way during a lifetime. So I believe that there may be ways in the future in which we can both prevent the disease, retard its progression, or even replace the cells that have degenerated and create a functional benefit to the patient so that they are not so hampered or in fact very much helped from their previous disease.
Even 20 years ago there was not any brain surgery for many of these diseases including Parkinson’s disease. There are thousands, literally 50 to 100,000 patients, who have been helped by deep brain stimulation today and I believe this heralds a future era in which many more patients will be helped by a variety of techniques. From drugs, preventive treatments, gene therapy, cell therapy or reparative therapy.
We believe that the disease starts years before clinical symptoms are recognizable. So years before a patient comes to me in the clinic and says, gee my memory is not so good, we think that the disease has really been going on and chipping away at their brain function. How do you tell whether or not that’s been happening before there are symptoms? And the answer to that is in the broadest sense something called biomarkers and this means a blood test – something like cholesterol for heart disease.
Well there’s active research going on in laboratories here at Harvard and around the world, looking for those markers that might show up in the blood beforehand. There’s already markers in the spinal fluid that seem as if they can predict development of dementia two, three, maybe even as much as 5 years before the clinical symptoms happen. There’s neuroimaging, MRI scans, and a special kind of scan called a PET scan using something called Pittsburgh Compound B as the marker, that seem again to anticipate the problems that patients are going to have.
And so if we can identify people who 2 or 3 or 5 years from now will develop symptoms, that’s a reasonable point to try to intervene. And that’s one of the things that I think is most exciting about where we are today compared to where the field as a whole was, even two years ago.
There’s a remarkable ability of the brain to recover, if only the lesions that are happening to the brain can be slowed down or stopped. And so we really feel as if we could get a handle on the underlying damage that’s being caused to neurons can be ablated that some recovery would indeed be possible, even in those individuals who have had severe problems.
Now we model the disease using something that called transgenic mice. So mice that have been created in the laboratory that develop something that’s very, very similar to Alzheimer’s disease. And those mice, if we can halt the process of degeneration, the mice which have become impaired on a variety of cognitive tests, so literally, the mice can’t find the cheese. And yet if you stop the process, even though there’s been a lot of damage done to the brain already, the mice actually improve on the behavioral tests – they’re able to go back, not to where they were when they were young, in that baseline, but they improve substantially. And there’s no reason to think that the mouse brain is wired any differently than a human brain. That really gives us hope that if we can halt the progression of the disease, that some recovery of function would be possible.
Right now in the United States there’s several different medications that are available for Alzheimer’s disease. They’re medications that without doubt help patients. There’s been clear data in the literature that say that if you have a group of patients who take these medicines, or a group of patients who don’t take the medicines, then on average the individuals who take the medicines do a little bit better. That means they score a little bit better on neuropsychological testing. That means their memory’s a wee bit better if you give them formal tests. But if you ask those patients’ families or those patients’ doctors, well, are they different, are they better? – for the most part the families don’t notice the difference. For the most part the doctors don’t notice a difference. And so these are very subtle effects.
And they’re important, and we certainly prescribe these drugs, they slow down the disease, some individuals have a great response and really do a lot better. But on average, it’s not as if we prescribe the drugs – it’s not like penicillin, where if somebody’s sick, you give them a medicine, they feel better. If anything we prescribe these medications in the hope that over time they’ll do worse less quickly.
Twenty years ago, Alzheimer’s disease was considered to be a rare illness, there were just a handful of labs around the country studying Alzheimer’s disease. And with increasing understanding of the genetics of Alzheimer’s disease, and frankly an increased understanding of how devastating Alzheimer’s disease will be to the population and to the country, more and more researchers, and more and more drug companies, and more and more academics, not only in the United States but around the world, have been drawn to study this problem.
So on the one hand, there’s a lot of research going on, there’s a lot of drugs now reaching phase 1 and phase 2 and even some into phase 3 clinical trials, and so that kind of progress is heartening. On the other hand, we don’t have a cure. On the other hand, we don’t have treatments that truly slow the disease down yet. And until we’ve succeeded in accomplishing those goals, we really don’t have enough research.
There’s no doubt that Alzheimer’s disease is an epidemic. As people get older – and age is the first risk factor for Alzheimer’s disease – their likelihood to get Alzheimer’s disease goes up and up and up. By the time you get to be in your mid-80s to 90, the chances are about 50% that somebody gets Alzheimer’s disease. And so the more people who live to old age, the more chance is they’re going to get Alzheimer’s disease. Right now about six million people in the country have Alzheimer’s disease. If we look forward about a decade, that number is going to more than double. And it’s already devastating, it’s already economically and socially – and even more than that, just the devastation that is causes to the patients and their families is awful, and to increase that by twice – there aren’t enough nursing home beds, there aren’t enough people to care for those individuals. We really have to do something about this.
There’s a lot of neurological diseases which are devastating, but as you go through your medical training there are certain individuals and certain causes that really just call to you as an individual, and Alzheimer’s disease is one of those, a disease that just devastates people’s memory, a disease that takes away the individual’s sense of self. And does so over the course of years, you can almost watch their abilities melt away over time. And figuring out what causes that in the first place and hopefully how to stop it I think is really an exciting thing to be able to make a contribution towards.
In animal models now we have ways of dissolving the plaques, those are the lesions in the brain that Alzheimer described, and yet we can get rid of them in animal models. And in fact there is some early, early, early data that some of those therapies also can get rid of plaques in patients with Alzheimer’s disease.
Now, will that be enough to cure the disease? We don’t know yet, but it sure feels optimistic to know that we can actually reverse the lesions that are in the brain. Is that going to be enough? We don’t know. Maybe we have to stop them from forming in the first place. Maybe there are secondary things that we also have to do. But it sure feels like it’s a step in the right direction.
The same thing with neurofibrillary tangles. We’ve now reached a point in the laboratory where mice that develop neurofibrillary tangles, we can reverse those lesions. Can we turn that into something that’s effective in people? Well, I don’t know. But it’s just 4 or 5 years ago that the whole notion of being able to reverse a plaque, or being able to reverse a tangle, was thought to maybe be impossible. Now we know it’s not impossible. We don’t know if it’ll work, but that’s the kind of thing that gives us optimism, it gives us enthusiasm to move forward with new therapies.
So one of the things that I am most excited about that the center has pioneered really among academic medical centers around the world, is direct access to drug discovery. What do I mean by that? Big pharma does drug discovery every day, but they need to have a very strong economic incentive to do that of course and the shareholders in those companies need to be rewarded in our system. Here, at the Harvard NeuroDiscovery Center, we take that profit motive out of the picture and we can work on diseases that are sometimes called orphan diseases like Huntington’s like Lou Gehrig’s disease and frankly even Parkinson's although it’s quite common has elements of being an orphan disease still. We don’t have a breakthrough drug that will treat all Parkinson’s. The drug discovery center allows academic scientists like myself to go physically to a very well outfitted plant in Cambridge, right across the river from where we are now and get the experience of people who worked at companies like Merck or DuPont or Sepracor or other companies like that who actually know how to discover drugs which we academic scientists have very little experience with.
So when we looked around our community, frankly, we didn’t see what we needed so what we did was we went out to the biotechnology industry and the pharmaceutical industry and we hired some really terrific people from industry and we said, what we’re looking for here is the best of both worlds. We want the imagination, the flexibility. And the fact we don’t have to concentrate on profit, we want to take that from academia, from the university and the hospital setting, but we want to balance it with that real clear focus and efficiency that will come from the commercial sector. This idea that when you’ve identified a problem, when you’ve set your sites on a particular target, you really can be focused and go straight for that target. So we wanted the best of both worlds and that’s what we built into the drug discovery laboratory here within the center. So that’s a group of 14 people, full time people. They’re not individually looking to create their own labs or to build up their own groups. They’re working as a team and it’s I think probably unique in the US. We don’t know of another drug discovery center set up like this.
So we are standing on the shoulders of giants in the science community and we can see much farther than we ever did and the discoveries are coming fast and furious. That’s why a collaborative center is needed right now. We want to build on the momentum and we want to solve problems that are devastating to the human population. Why do we need to do this now? Because we’re all getting gray hair and the fact is that so many of the terrible; diseases we study are related to time on the planet. How long has a person been there? So we want to treat diseases of middle and late life with the best knowledge of how the brain works and we have those two elements now. We have a population that has a great medical need and we have hot science that is falling all over itself making new discoveries.
Well I think it’s important to recognize the burden of disease created by these conditions. It’s estimated that as our population ages and in the case of Alzheimer’s disease we go from what is now estimated to be 4.5, four and a half million people effected to as many as 10 or 15 million affected within the next 20 to 30 years. The burden of disease here is in the multiple hundreds of billions of dollars of expense for the care of the patient and for the families who have to divert resources to take care of their loved ones. So all of this places great priority on our finding solutions that can be applied to the disease burden of our society and to the families whose lives are so interrupted and in many cases destroyed by these conditions.
So the funding for the center is really quite unusual. Most of our colleagues get most of their money from the federal government or from state government funding and we get important and critical funds from these sources as well. But the majority of our funding, about 70 percent at the moment comes from individuals and foundations who have recognized that we are trying to do something a little different, that we are pushing our necks out there and that we are trying to change the model. These are individuals who have looked at us, have compared us, have done their due diligence and have decided this is a place worth putting their dollars.
And we work together planning the most efficient and effective way to use the resources that we’ve been able to put together. And I think it’s important to recognize that the resources that we have identified are applied almost entirely back into the research mission. Our administrative costs are very low. We’re efficient in the way we manage the structure of research and we’re able to put almost every dollar back into where it belongs which is trying to work with our patients and our doctors in solving these problems.
To do cutting edge biomedical research is very expensive. The tools are expensive. We spent a lot of our money on salaries for very gifted people who actually don’t get individually paid that much. They could get more money if they were in industry or purely in private practice. So the costs are high and the way that we fund that is that we first try to find the informed donor who is really upset and concerned about at brain degenerative disease or maybe more or than one and who wants to see his or her dollars used efficiently and effectively without unnecessary competition and overhead. That’s what we do well.
I think we put together a collaborative effort with the best people who are committed to alleviating human suffering from disease and the people who we have working with us in the Center both within the Harvard Medical School and it’s hospital access and those we collaborate with around the world, all are dedicated to the notion that science and discovery, NeuroDiscovery, will lead us to answers that our patients will benefit from in the short term rather than the long term.
The reason that we think we’re just the right recipient of philanthropic donations is because we work together and we can use the money wisely and directly to further the research of a number of scientists simultaneously. So rather then asking the informed donor to put their money into one basket only, one egg into one basket, we have many eggs in one basket, we have many shots on goal for therapeutic advances. We think the reason this works the best is number 1, we like to say that we’re among get smartest centers around the world in doing this kind of work and we work in a rarefied and spectacular atmosphere intellectually, but number 2, we apply almost every penny of a dollar directly to research so we’re lean and mean in terms of our structure, our overhead.
What you should consider in making that decision, I want to spend my money wisely, what do you actually mean? Do you mean you want to make progress towards developing ways of treating patients? Do you mean you want to do it efficiently? Do you mean that you have a particular interest and a focus on certain diseases? Now if the answer to that is yes, I’m interested in neurodegenerative diseases – One or more of them; yes, I like the idea of not having to select an individual group but supporting a community who really work well together and yes, I like the idea of pushing research through to the point where it has implications for patients where it starts pushing towards new treatments, new diagnostic tools. If that’s your answer, then I think we have a good story to tell you. And I think that’s probably the most significant point for many donors is, it will be a very efficient, targeted focused use of your funds.
So the hallmark of neuro-degeneration in humans is this gradual, inexorable loss of certain brain cells, not all brain cells so in one disease, memory cells go out – that would be Alzheimer’s – in another disease, cells important for the smoothness of movement go out, that would be Parkinson’s. In another disease, cells that allow the muscles to move properly would go out and that’s ALS. So the common theme is selective breakdown of cells before their time, before they’re supposed to die out.
We think the mechanisms by which these diseases cause those losses of neurons are common mechanisms which when looked at together will give clues that we wouldn’t find if we were isolated and separating them one from the other.
It’s such an important question. It’s one we get a great deal for good reason. I mean, I think the first thing to say is none of us can really predict in the short term or in the medium term when new treatments, when cures, when preventative treatments are going to come through. It’s just too complicated to make that kind of very specific prediction. However, I think if you go into this community and you ask people who’ve been working on this part of biomedical research for a couple of decades or a decade or more, you are going to hear a common theme and that is: that over the last 10 to 15 years, we have learned a significant amount of cause behind these diseases. We’ve learned what causes them at a very basic level. We’ve learned some terrific basic biology that seems to underlie these diseases and once you have that basic understanding you suddenly have the capacity to look ahead and say okay, how do I take advantage of that, how do I translate that basic discovery into something that really will work for a patient in five or 10 years.
Basic science that lies behind the work that our researchers are doing has led us to understanding the mechanisms of these disorders. Some of them are genetic. When you find mutational in a gene, it helps you understand what the actual process by which the disease leads to the symptoms and the deterioration that the patient experiences. These brought together give us clues about points in the process that we can take on for therapeutic targets and that’s all happened since 1995 I would say.
So Alzheimer’s’ in many ways is sort of a flagship disease for efforts that this center is making. It’s very common, it’s devastating, It’s enormously expensive, but just in the last 7 years, since the Harvard NeuroDiscovery Center began, we have the advent of a number of clinical trials that believe it to not have reached phase 3, the final phase of clinical testing and so there is a real hope that in the year 2008 hopefully certainly by 2009, there will be some trial results announced. So in Alzheimer’s, in Parkinson’s, in MS in particular, the therapeutic opportunities are right in front of us and in some cases have already been delivered. So it’s not just a matter of hopeless brain diseases.
The idea was to bring together investigators from different fields, who are working toward understanding the nature of these conditions and to help them work together in collaborative mode so that they can learn new things from each other. The whole point of this is to take this kind of work in a translational way, which means to move from ideas that tell us about the mechanisms of the disorders to actual therapies that would become treatments for the patients who have them.
So what I think the Harvard NeuroDiscovery Center does best is to bring scientists, physicians out of their silos and get them to talk about common problems and common opportunities.
Everyone these days in biomedical research is talking in about collaboration. It’s become a real buzzword. We wanted to take it a step further and we wanted to say, how do you put together a program where you actually identify the challenges and the problems through a collaborative effort and then you assemble the right groups to take on that challenge through a collaborative effort and then you actually implement and do the science and do the work collaboratively.
So we have over 600 members and they come from a whole variety of places and backgrounds and skill sets. So we have investigators from all the major teaching hospitals in Boston. We have them from Harvard University and the Medical school. We also have another ring of collaborators from beyond the Harvard System.
So the center is really quite a large organization. I would venture to say that it may be the largest concentration of brain scientists really working together anywhere in the world. The essence of this center is cooperation and collaboration and we haven’t had enough of that in science. I hear donors sometimes say, you know, I don’t know if to give to you or to give to another university in another school here or overseas. And the answer is here, we have a community that actually doesn’t just collaborate among many, many gifted Harvard Medical School affiliated scientists, 600 and growing, but to many other institutions. We have wonderful agreements with 15 or 20 other groups around the country, around the worlds and we are very much a collaborative fraternity.
It’s more than just us. It’s important to recognize that our collaborations in these conditions reach allover the world. We have collaborations locally with MIT, with the other universities in the area. We have collaborations with Cambridge University in England, with the UCSF in California, and so our work is not just local. It is taking advantage of the world of science out there that allows these discoveries to bring the most promise to the work we’re doing together.
We’re in a better position today than we ever have been in terms of making a serious impact on these diseases. We can’t tell you precisely when that will be, but we know that every day, every week, every month, every year, we’re making progress and that leaves me very optimistic.
We’ve been able to identify for each of these disorders key metabolic steps that we think may explain why nerve cells deteriorate and die and cause of symptoms. We have a laboratory of drug discovery, which has taken clues from these specific mechanisms of deterioration or degeneration, and are applying tests with known drugs and some that are from panels of drugs that have not been widely used yet in patients, and are testing them in what we call biological models of disease.
So in the area I know the most about, Alzheimer’s, the progress has been enormous and I’d like to attribute some of that progress in my own research to what the Harvard NeuroDiscovery Center has provided for us. Tremendous core facilities to do things that individuals, scientific labs like mine wouldn’t be able to afford to do, or have the wherewithal to do. So the reason, that I feel that we can boldly predict that some of these diseases will gradually ease off, is because in the example of Alzheimer’s we are where we need to be. We are in the advanced stages of clinical trials.
The Harvard NeuroDiscovery Center has a first priority to bring together people to collaborate around research that will direct us toward cures for the neurological disorders that we associate with degenerative changes in the brain. Alzheimer’s disease, Parkinson’s disease, ALS, or Lou Gehrig’s disease, multiple sclerosis, and other conditions like that.
The idea was I guess threefold. One is, we’re going to focus on these diseases. There’s a big need for these diseases, these neurodegenerative diseases. Secondly, we’re going to do it in a very collaborative and open way. Unfortunately, that’s not the typical pattern in academia so there was a real challenge there. And then finally, this idea of translation – take basic discoveries and move them towards the stage where they’ll be useful for a patient. So that translational emphasis, that collaborative emphasis, and that focus on disease. That’s just a terrific opportunity for all of us.
I think what‘s unique about the Harvard NeuroDiscovery Center is that it takes scientists out of their silos. A silo is the appropriate word for how we live our lives, we scientists, and I’m one of them. And that is, we focus on these little molecules or particular abnormalities and it’s hard for us to connect to each other the Center really challenges us and helps us connect in many different ways.
If you had asked me that 15 years ago, I would’ve said, I’m not sure. Today, I think there is, and the reason for that is that the basic science that lies behind the work that our researchers are doing has led us to understanding the mechanisms of these disorders. And today every condition that we are working on shows promise for the development of new strategies that are based upon scientific facts that we simply didn’t have 15 or 20 years ago.
So the reason I am hopeful is because we know a huge amount. The Center here at Harvard has helped us create that knowledge in a very dramatic way. And we’re applying that in clinical trials. Indeed, the center actually helps sponsor clinical trials.
You know 15, 20 years ago, we were scrambling around in the dark. We’re not in the dark anymore, we don’t have all the lights on, but we’ve got enough light shining on this problem that there is a great deal of hope. Now, in biomedical research, luck always comes in. You know, Mother Nature’s tricky and it’s a fool who tries to predict how she’ll behave, but having said that, there’s a great deal of hope in this community.
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Preview of the HBO series, The Alzheimer's Project, takes a close look at groundbreaking discoveries made by leading scientists as well as effects of this disease on those wih Alzheimer's and their families.
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Richard M. Cohen, Harvard NeuroDiscovery Center council member and best-selling author of Blindsided: Lifting a Life Above Illness and Strong at the Broken Places, recently interviewed five renown Harvard neurologists: Drs. Brad Hyman, Ole Isacson, Howard Weiner, Merit Cudkowicz, and Anne Young. These exerpts reveal why they chose their medical specialties and reasons for optimistic research outlooks. See Video Library for full length videos.
HNDC council member Richard M. Cohen makes the case for better communication between the research community and the public.
View collaboration piece
June 2009
Singer/songwriter Eric Lowen, other ALS patients and supporters together sing Lowen's poignant song: Learning to Fall
May 17, 2009
ALS: Fighting for a Last Chance at Life.
New York Times
May 7, 2009
National MS Society newsletter features HNDC and Intl. MS Genetics Consortium project.
National MS Society - Research News
May 5, 2009
HNDC co-founder Dr. Joseph Martin comments on the need for a new approach to primary care.
Boston Globe
April 15, 2009
Cautious optimism surrounding early drug candidate in Alzheimer’s.
BBC News
Important clue toward neuronal selectivity of Huntington’s disease.
MSNBC
Access science paper
June 29, 2009
New Approaches to Neurological Pain: Planning for the Future.
October 2008 summary report. (To request a hard copy, please
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June 29, 2009
P.P. Pandolfi, MD, presents in the Harvard Catalyst Colloquium Series on "Discovery in Translational Medicine" from 4:30-5:30pm in the TMEC Amphitheater, HMS.
For more information: Harvard Catalyst
©2009 by the President and Fellows of Harvard College