Putting together the Parkinson’s puzzle: An interview with Dr. J. William Langston

In 1982, six people in California fell into a completely frozen state—they were unable to move, unable to speak and unable to explain what had happened.

One of these patients came into the care of Dr. J. William Langston, who eventually linked the condition—which bore an eerie resemblance to advanced Parkinson’s disease—to a bad batch of synthetic heroin. Further analysis showed that the drug contained MPTP, a toxin that selectively destroyed the part of the patients’ brains responsible for producing dopamine, a neurotransmitter that is critical for voluntary movement. Although treatment with L-dopa, (which turns into dopamine in the brain) can mitigate Parkinson’s symptoms and helped unfreeze the patients, some still suffered with debilitating symptoms throughout their lives.

What followed was a revolution in Parkinson’s research, fueled by MPTP as a new tool for studying the disease, and a quest to help six people who lost so much.

Dr. Langston played an integral role in the care of these patients throughout the years and in subsequent research, becoming an internationally recognized leader in the Parkinson’s field along the way and establishing the Parkinson’s Institute and Clinical Center in Sunnyvale, California. We recently chatted with him about the “Frozen Addicts” case, his groundbreaking work and where he sees Parkinson’s research and treatment going in the future. You also can hear Dr. Langston speak during Grand Challenges in Parkinson’s Disease, which will be held Sept. 27–28, 2017 at Van Andel Research Institute, where he will receive the 2017 Jay Van Andel Award for Outstanding Achievement in Parkinson’s Research.

Q: Looking back on 1982 all the way through today, how would you describe the impact of the “Frozen Addicts” case?

Dr. Langston: It’s been huge, really. For example, at the time there were no good models for the disease and, of course, the MPTP model gave us that tool. It’s been very important for testing new drugs and looking for new therapies to help us control the disease.

Secondly, it opened new research avenues to help us understand the factors in the brain that cause dopamine cells to selectively die. A key finding was that a metabolite of MPTP—MPP—was found to inhibit mitochondria function. This was very important because mitochondria are the “energy factories” for cells and without energy, the cells die. We now know that PD patients have similar problems with cellular metabolism, which opens new avenues of research aimed at finding better treatments for the disease.

Lastly, discovery of MPTP lead to renaissance research on environmental toxins that could cause PD. Interestingly, genetic factors have been found that make individuals more susceptible to certain toxins. For some people, exposure to an environmental factor doesn’t do much to impact risk of Parkinson’s but for others who have certain genetic predispositions, it can tip the scale toward neurodegeneration. It’s teaching us a lot about gene-environment interactions.

Q: As a physician and a scientist, please describe the importance of translational research.

Dr. Langston: When we founded the Parkinson’s Institute, it was my vision that you can’t do science alone in a lab or in an ivory tower, as they say about medical schools. You have to be able to apply what you learn to real patients. So we came up with three programmatic rings of care and research—day-to-day patient care, clinical research and basic research in the lab. It’s where those three rings overlap in the middle that you get this incredibly powerful science. You would be surprised how many times a clinical observation actually gives you a lead in the lab.

It’s just amazing what patients will tell you and then a bell will go off. Almost every day, you get new hypotheses from patients you see in the clinic. That’s one reason why I have a real commitment to both sides of the coin—basic and clinical work. I see patients every day—if you don’t stay close, you can get off track.

Q: In your view, what are one or two of the most exciting and promising things happening right now in Parkinson’s research?

Dr. Langston: One, I think there has been a complete revolution in the understanding of what Parkinson’s is and that’s amazing because here we are 200 years after James Parkinson’s original Essay on the Shaking Palsy. It turns out the disease is totally different than we thought before—it involves multiple systems and we have now identified a key protein, alpha-synuclein, that accumulates in many areas of the brain, the spinal cord and the peripheral nervous system. That’s huge for so many reasons. In the old days, a person would come into the clinic and complain about constipation or difficulty sleeping and they would be told to see their primary care physician. Now that we know those symptoms are related to Parkinson’s, they stick with the movement disorders specialists, who are really becoming the general practitioners for people with PD.

Understanding the involvement of these other systems is important because many of the non-motor symptoms show up years before diagnosis. I saw a patient yesterday whose sense of smell went out 20 years before he was diagnosed with Parkinson’s. If we can pick these precursor symptoms up early, before too much damage has been done, it opens the way for much earlier treatment, once we find drugs that slow or stop the disease.

The other big one is that I think for the first time, we have a leading target in what we think causes Parkinson’s—the protein alpha-synuclein. If you look at other neurodegenerative diseases, it seems like they all have their own protein that’s involved—something goes wrong with a protein and it wreaks havoc on the nervous system over time. When we look at parkinsonian brains, we see that the neurites that run out of the cells are full of alpha-synuclein. We now have a protein target that we didn’t have before. Alpha-synuclein was an absolute game-changer. While it came from studies of a rare genetic form of the disease, we now know it is present in all PD patients whether they have sporadic or genetic forms of the disease, once again proving the old adage that rare genetic forms of a disease are often highly informative for the much more common sporadic disease.

Q: What do you think the next 10 years of Parkinson’s disease research and treatment looks like?

Dr. Langston: This is my vision and my dream. Two things have to happen—we have to find ways to pick up the disease much earlier and we have to have disease-modifying drugs.

First, we need a kit or a battery of diagnostic tests that can detect the disease much earlier. One example is loss of smell, which can be knocked out by a lot of things—smoking, trauma, et cetera. But, if you take someone’s medical history who is over 50, and they have a loss or reduction in sense of smell, a history of REM sleep disorders and GI issues, it raises a high degree of suspicion that they may have early, early Parkinson’s. There are other early signs such as sympathetic denervation of the heart. If we can get these added to a standard physical exam after age 50, we may be able to screen the general population and catch the disease early.

Second, if one or more of [the ongoing clinical trials] comes to fruition and we get a disease-modifying therapy and if we can in fact catch the disease before it manifests, we could actually have secondary prevention.

It’s like a puzzle. You usually start with the corners and build in. I think that’s where we are—we have the corners and we’re building in. You can’t rush science, but that being said, I’m excited that we could be close to a seismic change in how we treat the disease and what we can do for patients.

 

Dr. Langston will receive the 2017 Jay Van Andel Award for Outstanding Parkinson’s Disease Research during Grand Challenges in Parkinson’s Disease Sept. 27 –28, 2017 at Van Andel Research Institute in Grand Rapids, Mich. For more information on Grand Challenges and to register, please click here.