What prompted your initial interest in studying Parkinson’s disease?

I went to school in Canada, and then came to the U.S. to do my residency. This was in the post-levodopa era and I had the opportunity to work with many of the prominent leaders in the field of Parkinson’s disease at that time. I got interested largely because of their influence.

One of the interesting things about Parkinson’s disease is that it’s one of the first diseases that had a therapy, one effective for millions of patients, that was rationally designed based on laboratory findings. You have to understand how important this can be to medical students. In the early days of the 20^th century, going right on up to the mid-century and even to this day, most drugs we have that help patients are discovered by serendipity. Someone in the forest notices this plant and realizes it makes your heart work better and then it’s later realized that the plant contains digitalis. That was the traditional pathway for drug development.

“One of the interesting things about Parkinson’s disease is that it’s one of the first diseases that had a therapy, one effective for millions of patients, that was rationally designed based on laboratory findings.”

In terms of really novel therapies for an otherwise untreatable disease, the introduction of levodopa for Parkinson’s disease was really one of those remarkable advances that occur very rarely in biology. What that means to a young student, and what it meant to me, is that it is conceivable you can go into a laboratory and through your work and effort you can develop a treatment that can help people who have this affliction. It’s a very inspiring concept for a young person starting out in a career in medicine.

  When did you personally have this revelation?

I suppose it was while I was a resident in the 1970s at Columbia. I was working with people who did much of the original research on levodopa, and who had the opportunity to see the effect of this drug. For those who weren’t there, it’s hard to imagine. A Parkinson’s patient could suddenly be restored to functioning to such a great degree by levodopa that it appeared truly miraculous. If you’ve ever seen the movie Awakenings, it was actually like that. The movie really did not overstate that phenomenon and the degree of awe that it inspired. Someone who had previously been frozen in a chair could now get up and walk. That kind of thing actually occurred, and that got me started being interested in Parkinson’s disease.

  How would you describe your research philosophy over the years?

Well, I am a clinician by training and I still see patients with Parkinson’s. But I have also been interested in the laboratory research and in trying to understand the clinical problems in basic science terms. The third part of my life in this field is that I have been interested in translational aspects: particularly, running clinical trials that allow for a new therapy in the lab to be tested to see if it works in human patients. That combination of basic and clinical research is what I do, and I’m particularly interested in the experimental therapeutics.

Toward that end, I have been sort of eclectic in my career in that I have looked at a variety of different approaches to treating this disease. For instance, I did probably the first major, double-blind multi-center trial of dopamine agonists in Parkinson’s disease. I also headed what may have been the first major, double-blind fetal nigral transplant trial in Parkinson’s disease. I have done many studies looking at neuro-protection.

  What was the context of your highly-cited 1999 review in Annual Reviews of Neuroscience (Olanow CW and Tatton WG, "Etiology and pathogenesis of Parkinson’s disease," 22:123-44, 1999)?

That was an invited review and the idea was to focus primarily on the potential cause of Parkinson’s disease. That is still, of course, one of the major questions we have to answer. Maybe I can it explain as follows: even with the therapies we have—levodopa, in particular—we still have limitations in our ability to treat the disease. Those limitations include the side-effects you get from levodopa—what are called motor complications, and they include the emergence of features that don’t respond to levodopa. We call these non-dopaminergic features and they include things like dementia, falling, and freezing. Much of my work has been in the basic science of understanding why those problems exist and the clinical aspects of figuring out how to treat and prevent them. So the Annual Reviews of Neuroscience review looked at the pathogenesis and etiology of Parkinson’s disease—what’s the cause and why do cells die?

  Why do you think it’s been so influential over the years?

One reason is that the review was written and published at a very critical point in time. It was just before the genetic revolution and so it really represented the state of the art of why cells die, everything we knew up until the genetic revolution. It’s funny because I have just written another major review on this topic, which is basically what happened between now and then, encompassing this genetic revolution.

  So what’s happened between then and now?

What’s happened since then is we have now discovered at least six different gene mutations that are involved in causing Parkinson’s disease or a Parkinson’s disease-like syndrome and that can now be used to understand why cells degenerate and die in this disorder. Once you know certain gene mutations cause cell death and lead to Parkinson’s disease, you have reason to believe that the same defects might also apply to all the sporadic cases. A small percentage of Parkinson’s disease cases are genetic, but the huge majority are sporadic.

  What do you call a "small percentage?"

Perhaps five percent are familial; the rest are sporadic. So once we had that genetic information, even though these genetic cases are rare, we now have a signal as to what might be going on in all cases. For me at least, that has pointed to the idea that protein misfolding is at the heart of the disease; that there is an accumulation of abnormal proteins that can not be satisfactorily cleared by what is called the proteasome.

  Was this a popular theory when you wrote your 1999 review, or is it a newer idea?

I would say that it was not popular at the time, but I put it into that review, mentioning it then as something we were beginning to investigate. Subsequent to that review, people began to talk more about protein misfolding and we were able to show, indeed, that in Parkinson’s disease there is damage to the proteasome, which is the mechanism that clears proteins. We were also able to argue that the genes that had caused Parkinson’s disease all had the potential to impair this protein clearance function.

The proteasome is like a giant protease. A protease will degrade a protein at a certain point. A proteasome contains multiple catalytic enzymes that can basically chop down any proteins into their constituent parts. It’s the way to degrade proteins and prevent them from aggregating in the cell, because that aggregation, in turn, can disrupt cell function and cause the cell to die. That’s now our hypothesis for what’s happening in Parkinson’s disease.

  What are you pursuing at the moment in your research?

Several things. Remember I told you that I work in the lab and in the clinic. In the lab, we are busy trying to see if there are any mechanisms that can enhance protein degradation in a condition like Parkinson’s disease. There are a few strategies one can use to accomplish this and prevent cell death, at least in the laboratory. The next question will be whether we can translate these into human patients, by testing these agents in clinical trials.

We have done some very exciting clinical trials to try to help patients, but most of them have failed. The latest one, and probably the most exciting, involves a gene therapy study where we’re using a gene delivery system to treat patients with trophic factors. These are factors that enhance the survival of dopaminergic cells to prevent degeneration and enhance regeneration or restoration.

So we have a three-phased approach here. We’re looking in a laboratory to see why cells are degenerating in Parkinson’s disease and how we can stop it. We’re looking to see how we can translate these rational-based therapies to the clinic to find out if they will slow down Parkinson’s disease. And the third phase is one we have also had considerable success with, dealing with the motor complications I told you about.

Levodopa is still the best drug therapy we have, but it has limited utility because maybe 50 to 80 percent of patients develop these motor complications. These are a wearing off of the effect, so that it doesn’t last long, or involuntary movements called dyskinesia. We believe they occur because levodopa is not being properly administered physiologically. We believe if we can accomplish that administration in a more appropriately physiological manner, that will lead to enhanced benefit. And we now believe that we have data to support that notion.

In short, we’re trying to figure out the cause of Parkinson’s disease, we’re trying to figure out how to block that cause and translate those findings into clinical trials, and we’re trying to find better ways to use levodopa so it doesn’t cause motor complications.

  Of the half-dozen genes discovered so far, are any definitively not involved with protein clearing or misfolding?

It’s hypothetical. You can argue than none of them have been proven to be involved in protein clearing and that some are more likely to be involved than others. So, for example, the protein alpha synuclein is prone to misfold and aggregate and so you can argue that if alpha synuclein causes Parkinson’s disease, one way it probably does so is by aggregating in the cell and causing proteolytic stress. We have too much misfolded protein, we can’t clear it. That would be a rational hypothesis for how alpha synuclein causes this disease.

Another mutation is in a gene called parkin, and this codes for a protein that actually acts as what’s called a ubiquitin ligase. Ubiquitin ligase attaches ubiquitin to misfolded proteins to signal for their proteasomal destruction. So if the enzyme that’s attaching ubiquitin to the protein is mutant, it may not attach it correctly and therefore the protein may not be able to be properly cleared. That’s a pretty rational explanation for why parkin mutations might cause cell death by way of this proteasomal problem.

  Is excess ubiquitin found in Lewy bodies?

There are marked increases in staining of ubiquitin in Lewy bodies and throughout axons of Parkinson’s disease. So, yes, this also suggests these proteins have been tagged for clearance but that clearance hasn’t happened. Having said that, in all fairness, I should point out that there are alternate explanations for this disease and I am focusing specifically on the proteasome story. We still don’t know for sure that it’s right. Other areas that still attract a lot of attention are mitochondrial disorders and oxidative stress.

  If you lived in an ideal world and had an unlimited source of funding, what one experiment would you do to improve our understanding of Parkinson’s disease or our knowledge of how to treat it?

I am going to give you a different kind of answer to that question. I believe if there was an institute devoted to the cure of Parkinson’s disease, one that had the necessary funding, it would allow us to move forward at a considerably faster rate than what we are currently achieving. And that’s what I would do with the funding.

Such an institute could assure that there are sufficient numbers of good laboratories working together and that their work could be integrated. It would insure that all the missing pieces were covered, so that you are not in a situation as we are today, where the universities don’t like to do high-throughput work and the drug companies don’t like to do high-risk basic science and the basic scientists don’t have access to the medical chemists and don’t understand how to do toxicology studies, etc.

Such an institute would also have a clinical arm, because you need patients for clinical trials and biological materials and so on. If I had unlimited funds I would change the model. I would create a single institution that puts all these pieces together, that would allow for different people with different theories to work together, to pool their skills, and fill in all the missing pieces. I think that would expedite our advance.

  What message would you like convey to the public about Parkinson’s disease and the ongoing Parkinson’s research?

The important thing the public needs to know is that there are very dedicated, very devoted researchers who are focusing on Parkinson’s disease and working with great enthusiasm, great purpose, and considerable success. But I would also tell the public that, even so, progress doesn’t happen overnight. And it doesn’t happen just because a politician tells us that stem cells will be the cure for Parkinson’s disease. It doesn’t mean the politician knows what he’s talking about and it doesn’t mean that stem cells will be a cure or even provide an appreciable benefit.

The public needs to be educated on this disease so they can make rational decisions. They should not participate in experiments that do not have a rational scientific basis—such as giving stem cells in China—but they can help the pursuit by giving money to appropriate sources, such as the Michael J. Fox Foundation. And they can help research by participating in clinical trials.

I would further urge the public to avoid wild experimental therapies, surgeries, or procedures. And, indeed, I would urge them to do the opposite, to take the risk of accepting a placebo in a double-blind clinical trial. Because the only way we will eventually learn the truth about this disease and how best to treat and prevent it is if people participate in these kinds of truly scientific trials.

That’s my message: retain hope, be proud of the research community, and continue to support good research. Don’t act out of desperation and don’t act without thinking and caution.

As for my own research, I would say that we will continue to act along the same path we have followed to date. I truly believe the problem of motor complications in Parkinson’s disease will be resolved within the next half-dozen years. I believe we will make great strides in better understanding why cells die in Parkinson’s disease and developing targets and even drugs to prevent it. The biggest challenge facing us is developing the skills to do clinical trials that allow us to demonstrate this and take advantage of all this great basic science research.

C. Warren Olanow, M.D.
Department of Neurology
Mount Sinai School of Medicine
New York, NY, USA

Dr. C. Warren Olanow's most-cited paper with 388 cites to date: Olanow CW and Tatton WG, "Etiology and pathogensis of Parkinson's disease," Annu. Rev. Neurosci. 22: 123-44, 1999. Source: Essential Science Indicators