Ole Isacson: Development of New Therapies for Parkinson's Disease

So I'm Professor Ol Isaacson, and I work at Harvard Medical School. I'm a neuroscientist primarily, but I've also been trained in the basics of medicine. So that is my combined background.

Parkinson's Disease is a so-called neurodegenerative disease. That means that the cells don't die right away when you're born, or they don't die in, in one fell swoop. But typically it's a disease that's associated with age.

You can get it when you're young, but typically it's something that occurs midlife or late in life. And it also means, although that's not defined, that it's a select group of cells in the brain that die. So actually, even though the disease may actually affect the number of the cells in your body, it's a few select neurons.

In fact, a neuron called the dopamine neurons in the mid brain, so the middle of, or the basal part of the brain that die. So in your brain or my brain, we typically have about a million or so dopamine neurons on each side of the brain when we're born. And we may lose them over time, but if we lose more than, say, 70 or 80%of the cells or their connections or their health, then the brain can't compensate anymore for this loss.

So it's, it's really a redundancy to begin with. But when you lose those cells, you get this typical science of, of rigidity, tremor and lack of movement That is typical of Parkinson's disease. Parkinson's disease is a neurological disease that actually has pharmacological treatments in the evolution of the treatments, which received a Nobel Prize from the work of orbit, Colson and others.

They found that they could substitute for the transmitter produced by the dopamine neuro by something called l-dopa. L-DOPA is a substance that a patient can take that's gets taken up by mainly the surviving dopamine cells. It gets decarboxylated into the active form dopamine and then released in the part of the brain where these cells normally send their projections or axons and terminals.

So L-DOPA has been in, in practice for, for many years, and it's a well-known drug. The problem with the drug is that even though it works initially, for example, in the movie called Awakenings, it was well described and the patients may develop increased or extra abnormal movements that we call dyskinesia. So that is a big problem with use of l-dopa.

Additional drugs are dopamine agonist. They are act and look like actually in some cases like substitutes for dopamine. The patients can take them and they sometimes reach the brain insufficient concentrations that it helps the patients to move.

Interestingly, the most helpful drug to the patient is this pro drug, the l-dopa, which then gets made into the regular dopamine. So that's the mainstay of treatments at the end of the patient's, we should say, towards the end of the effectiveness of l-dopa, the when the cells are degenerating and more of them are dead, the patients can also get surgical help. And there's one, one treatment called deep brain stimulation, which sounds like a, a interesting thing.

It's basically electrodes placed in a, in a part of the brain that relieves some of the symptoms of Parkinson's disease. It doesn't substitute for dopamine, but it actually primarily reduces the side effects from l-dopa, so that's called DBS and a few patients, a few percent of the patients can receive that treatment. Since The discovery of Pharmacological means, most neurologists and scientists thought that all you needed to do was to come up with what we call a better dopamine agonist.

It's a little bit like, you know, perhaps the analogy is trying to find a better mouse trap. What I believe the most promising development in the field is really not in pharmacology, but rather in cell biology. So the development of an understanding of the so-called growth factors, including BDNF, brain derived neurotrophic factor, we see in the same family as the classic neuro nerve growth factor NGF.

And lately variants working on other growth factor receptors such as GDNF, glial derived neurotrophy factors are actually potentially gonna reach the patients in a major way. For example, initially there was a clinical trial in which GDNF was introduced in the brain by pumps that turned out to be somewhat problematic, more than the technicality than in the biology. It's difficult to get this peptide into the brain, so you actually have to implant or, or, or give it in such a way.

Small clinical trials that are currently underway actually use gene therapy as a way of, of providing GDNF to the brain, or in this case actually an analog of it called nurturing. But in that way, you actually put in a vector, a small viral vectors that puts the gene back into the brain that produces the trophy factor. And these are some of the more promising leads towards activating the remaining cells or protecting them from further degeneration.

The growth factors sometimes work in the neurotransmission between the cells. So that's an unexplored territory that I think is very interesting. The other big event in Parkinson's disease, and perhaps in all of neurology, was the work on neural transplantation that started in the early eighties and got into clinical trials in the nineties and mid nineties of last century.

And that revolutionized the way we think about treatments, even though it is not the treatment that we offer to patients, it illustrated that you actually could put in, in this case, fetal growing neurons back into an aged or adult brain. And those neurons were able to release dopamine instead of the drug that was given by, by the pharmacological substance. And in many cases could repair the system to such an extent that animal models and in some cases, patients improved over a long time.

This has been one of my major efforts in my research career, and it's been a very rewarding one in the sense that the basic science demonstrate how plastic the brain is, how adaptive it can be, and it's really not just a pump producing cell or a cell just producing dopamine, but frequently we see how these cells integrate into what we call a neural circuitry and really influence brain function. So I think that's one of the most promising development, although at this stage, I would call it very preliminary and, and it requires a lot of Work to develop further. My Work focused very early on and like others on trying to understand why the dopamine cell died, a number of laboratory has worked on the genetics on Parkinson's disease.

For example, over the last 10 to 15 years, we've discovered a number of genes, maybe a dozen or so that are associated with familial or even, you know, associated with the risk of developing Parkinson's disease. That has helped us see what potential, you know, factors can influence Parkinson's disease. I took a particular interest in the difference between cell types.

So I asked myself if most of the brain is intact in Parkinson's disease, even in genetic Parkinson's disease, where the gene can be expressed throughout the body, what made those cells that got sick so special? So that's known in the field as a field of selective vulnerability. So lately, for example, you may know that we have used genetic techniques or genomic techniques by, for example, studying dopamine neurons that are in the brain looking very similar.

Some of them will die in the disease and others won't. And we have studied the gene expression in these two different populations of cells and tried to develop a profile that describes them in terms of their molecular biology. Indeed, we found that there were approximately 40 to 50 genes that were expressed differently in cell types that were very sensitive to Parkinson's disease versus those that were very resilient.

We then used that information to try to understand the molecular pathways that we then could try to mimic actually to try to protect the cell that lack the pathway or try to block a pathway that seemed to make the cell more sensitive to the disease. So this is an example of my recent work in which we really try to use the molecular techniques or the genomic techniques to understand a cell disease process, or actually in this case, to develop Therapeutics. Well, it's a, It's, it's a very important question you ask, and it's, it is one that, that there isn't actually a simple answer, but I'll try to give you my perspective on it.

I think the main thing you learn as a scientist that many obstacles are real, it is in the conception of an experiment that you sometimes can see an elegant solution that leads to a very clear answer. But in biology, perhaps more than in, in maybe engineering, the biological problems are so complex at times that even though you have a clear experimental plan, in the end you end into both technical and biological problems that are more difficult to solve than you've idealized in your question. So I think actually most of the time many scientists ask the right questions in their experiments.

They frequently find that they are, have real problems, real obstacles, that they, there's nobody's fault basically, that this research takes a longer time. So, however, in in some extent it's also an intellectual problem and a problem of of approach. For example, I illustrated or told you earlier that in Parkinson's disease, the success of pharmacology early on in the sixties made everybody believe that all we needed to do was to find a better receptor agonist.

As we now know that it wasn't really that simple. We needed to understand how a cell ages, what is its identity. And as I mentioned, our interest in trying to understand why some cells are so resilient or resistant, whether others are so vulnerable and that makes the disease happen.

And so in my mind, I think some of the translation from research to, in my case medicine, is the difference in understanding pharmacology in this case and cell biology. So sometimes it's a transition or a translation or a growth of a field that needs to happen before it gets applied. So for example, I mentioned to you the genome revolution.

We now just don't study the effects of bad genes, the disease provoking genes, but also how to create cellular health by understanding how a cell adapts very well to a toxin and that can give us new leads to therapies. In terms of cell transplantation, we're currently working on stem cells, but stem cells is a completely new field of biology that requires a lot of work to understand the very basics of, you know, how to make a cell from a stem cell that we want to use. In our case, it would be a dopamine cell that we can implant into the brain and not just any dopamine cell.

It would have been a specific one that we know is the important one for making the right connections in the brain. So it is a very difficult thing to do in practice. There is one more important thing perhaps to mention, and it also has to do with attitude and, and traditions.

And I, I dare to say that typically clinicians will have a different approach than scientists. They have a very good approach in that they focus on patients and therapies, but sometimes because of their perhaps less, less training or perhaps less availability to, to see the recent data, they're typically, and perhaps for a good reason, more conservative, they typically will see more the risk than the benefit of a new procedure. And they provide a little bit of an impedance at times to developing very rapidly new ideas.

On the other hand, there's also a problem with scientists. Scientists typically will not translate their own findings perhaps, or think of the endpoint as the patient. They get fascinated and it's very easy to get fascinated by intellectual problems, and they typically stop before they provide something very useful to clinical medicine.

So I think perhaps a certain amount of arrogance on the part of the scientist can also block this very important translation to the patient. And on the other hand, clinicians too can provide a sort of conservative view that also stops or, or reduces the scientists ability to reach the patient. And not to mention politics, as we all know, stem cell biology is now become a political problem, which basically freezes down or cools down all the development that I just mentioned.

Well, it's a very difficult thing to say, you know, the, the, the joke is, you know, it would be easier to live in the universe next door. The reality is, I think that the scientific methodology from the Renaissance to today has basically been the same thing. We build experimental models and we use the tools available to us to find an answer.

So I think the academic structure that we have now in, in science, whether it's done in industry or done in academia, is actually quite similar. I do feel, and I think the effort that, for example, NIH or patient related groups now called translational science is sort of, even though most people don't know what, how to describe translational science, it is a genuine effort to try to understand if we can make science and medicine meet in a practical way. And I think there are many obstacles to that, mainly traditional, for example, in promotions of staff or in the way we look at publications, even to get a publication in, in a, what we call a more an a journal with higher impact.

The old values of what is brilliant work versus practical work is confusing the idea perhaps between what's really brilliant, a brilliant therapeutic discovery versus a brilliant insight perhaps about, you know, a fundamental phenomenon in basic science. So all of these things, those traditional values sometimes help us, sometimes impede us. So I think it's, it's a mixed, mixed situation.

But I think essentially the answer is that the current academic structures I see it is, is excellent because it does train us in scientific methodology. And whether you're working inside an industry or in a clinic or in a basic science lab, we have to understand the basic values of science, how we are objective, how we develop and understand our data and how we report them. And those are the tools that we have available for all Of us.

I feel What really drives me is trying to understand what's beyond pharmacology. I'm very intrigued by the way, and the techniques that are available for us today to look at the, both the outside and the inside of the cell and how it interacts. So it's a form of, we call it neurobiology in, in, in, in the nervous system, but it's a form of cell biology and particularly our understanding of organelles and morphological what's sometimes called compartments of the cell.

For example, in neuroscience and neurology, I think that one of the major discoveries still will lie in cell cell communication. And one of the major specializations of nerve cells obviously are terminals or synapses. I believe a number of the diseases of the nervous system essentially is a breakdown in the communication or the structural integration between cells, synapses, and that that precedes the cell death and degeneration that we see by years, maybe even decades.

So understanding those concepts that that rule, the very basic physiology and function of the nervous system drives my thinking also for therapeutics. Beyond that, I am also learning, for example, that when a nerve cell dies or a set of nerve cell dies, there's also a cellular inflammatory reaction, which is one aspect that what we call the progression of the disease. So even though one can study the isolated cell as a component of the nervous system, when it dies, we get disease.

I'm also very interested in how the field is developing an understanding of the progression of the disease. And sometimes there may be some overlap between Parkinson's disease to some extent Alzheimer's disease and a LS and Huntington's disease in those kind of progressive changes. In other words, I think that by understanding the progression of the disease, we may find common ways of, of maybe limiting some of the damage that's occurring due to these progressive damage Scenarios.

Well, the Difference between the genetic diseases and what we call idiopathic, which means maybe not such a well known cause. I actually think that the difference in the progression of new therapies is very similar. As, as you may know, the expectation was that the genomic revolution would give us easy answers.

I think definitively we've learned that when developed therapies, understanding the basic biology, cell biology or pathology is as important as understanding genetics. Whereas the genetics gives us a lot of leads. It typically requires the standard hard work of testing one therapy or therapeutic idea against the other before we actually empirically find the answer.

Usually in clinical trials. So in Huntington's disease, for example, we know it's an autosomal dominant disease. We know the gene since 1983 or 19, early 1990s.

We know exactly what the protein looks like and how it's mutated. And when that finding was made, people said enthusiastically, well, there we have it, now we have a treatment. Turns out in 2007 that we still don't have a treatment for hunting disease.

And it illustrates the difficulty of believing that simply a genetic change can predict what the treatment is. In fact, sometimes the ingenuity, perhaps in understanding a therapeutic solution will rest on understanding some of the genetics, but the two are not necessarily linked. Well, the, the truth is, I would do the same thing I'm doing now as a very active scientist.

You know, I enjoy working with a problem, a scientific problem, and trying to find an experimental method to solve the problem. So I would probably do the same thing I'm doing now and hopefully with more funding. But I think the advice one could give to a young scientist is again, that it's really an apprenticeship.

Being a scientist is perhaps not the most glamorous monetary type of work, at least in the beginning of, of, of, as a scientist. But it requires an apprenticeship. And by that it means that you have to find a good mentor or a good laboratory or good teachers to teach you about the scientific methodology.

So if I was a postdoc, I would look for a very productive laboratory where I would feel that I could learn from interacting with other scientists. And that interaction, of course, has many aspects. The two major ones are the intellectual part and also the, the methods, the techniques available.

Obviously if you find a new way of looking, say at the nervous system, but with better techniques, you have an immediate advantage to explore new territories where people, fields or people would investigate new fields at the same time, I believe that most scientists need to understand, or young scientists, that a lot of science is still done by thinking by the mind. So I would try to find a mentor that could teach me a way to think effectively about how to solve a research problem, and in that way save me from doing a lot of extra work in a sense because the, the intellectual part of, of science is also very important and to some extent underestimated. Sometimes you can throw a lot of money, as we say on a problem, or you can try to think it through.

And I think both of these things are very important. But basically I think that one should follow an important problem. Whatever that inspiration is for you to go into science, it'll probably drive you for a very long time.

So if you happen to know that you have a very strong drive for a particular field of science, it'll usually, in my experience, sustain scientists for a long time, maybe decades, to try to resolve and understand a certain biological process or if the importance is in medicine to attach their career to a certain disease problem or so on. And that typically can drive both the creative thinking and, you know, the, the wish to pursue and feel that the work is very meaningful. So training is important.

Mentorship, identifying a research problem that is really interesting, whether it be clinical or basic or both, and then pursue it with an understanding that it requires a lot of hard work to keep up with trends and developments, but also to learn how to think like a scientist and, and be very critical, yet objective about data. And, you know, honest, important and understanding the kind of integrity that's important to the scientific process.