Prof. Kordower is Professor of Aging and Neurological Sciences at Rush University Medical Center and a Professor of Parkinson’s disease at the Van Andel Institute in Grand Rapids. He has published landmark papers in the area of cell replacement strategies, including the first demonstration that fetal dopaminergic grafts can survive, innervate, and form synapses in patients with PD. He published the lead article in Science demonstrating that gene delivery of the trophic factor GDNF can prevent the emergence of motor symptoms and nigrostriatal degeneration in a pre-clinical model of PD. He also was the first to demonstrate that gene delivery of trophic factors can obviate neurodegenerative processes in nonhuman primate models of Huntington’s disease and Alzheimer’s disease.
The following has been paraphrased from an interview with Prof. Jeffrey H. Kordower on November 22nd, 2017.
(Full audio version)
Medical science seems to work by isolating one factor at a time and tweaking each to measure its effects. For diseases which come about from some unknown combination between multiple factors, as most seem to believe is the case for neurodegenerative diseases, is medical science capable of properly studying and intervening in these diseases?
Yes I think it is. The brain has specific functions in different places. With PD we used to think it was just a dopamine disorder or just a movement disorder. We now believe there are many non-motor features of PD whose pathology lies outside the dopamine system. We are starting to attack those symptoms and trying to figure out what brain regions are involved in them.
You are correct, for most there are probably genetic and environmental factors involved. But even so, the changes in the brain remain similar, for the most part. We get loss of dopamine in the cells, loss of dopamine in the striatum, and alpha-synuclein positive cells and fibers throughout the brain. Where they are and in what dosage determines those other features. So though there are multiple initial triggers we see common pathways involved.
Young people tend to have a tremor predominant PD, older people tend to have postural instability and gait disorder, some people get dementia or depression, but the disease is fairly similar across the board with similar symptomatic features that we can target.
The primary goal of most research today is to get published in an esteemed journal and to secure funding for more research, what can be done to shift this towards understanding disease and developing treatments?
I’m not sure I agree with that supposition. Certainly, getting funding for research is on everyone’s mind, but the way to do that is to be successful in establishing important scientific findings and to understand and develop therapies. When I meet my colleagues we don’t talk about what grants we are writing, we talk about our findings. I think most people are genuine about wanting to help people. Also, if you are not doing important science you are not getting into those publications.
What aspects of the system hold back good research?
The level of funding is holding back great research. It has been established by the NIH that for every dollar that gets spent 1.7 dollars gets back to the community, so it’s a tremendous investment. Yet, the amount of money available is quite limited. President Trump has said he is going to further diminish funding to the NIH by 20%. Also, this new tax bill is going to tax graduate students for the waived stipends they get for getting in to graduate school. This is going to significantly decrease the number of graduate students. These will be catastrophic to the science community.
Other catastrophes are also on the horizon. It was just estimated in a new paper that the number of people with PD by 2040 will be 14.6 million. The number with Alzheimer’s by 2020 will be 25 million. This is going to economically destroy our countries.
Is there too much hype surrounding genome wide association studies? (source)
I don’t think so, it tells you when things are different at a very high statistical level. The probability value is incredibly high, meaning we can be very confidant that what we are seeing in these studies is real. We are able to discard those factors that are only modestly changing from those that are having a significant effect. So, I think they have been quite helpful.
One of the biggest barriers to brain research is getting good models of the human brain. Where do you see the best new models of human brains coming from?
One of the most important findings in the last 5-10 years is that most neurodegenerative diseases are believed to be protein misfolding diseases. For reasons that we are trying to understand, these normal proteins misfold and become toxic and then seem to spread throughout the brain in a manner similar to, though not the same, as a prion disease. So what we can do now in a variety of diseases is take these misfolded proteins and put them into animals brain models and get them to spread similar to how they spread in the human brain. We also now have much better delivery mechanisms that enable us to deliver these misfolding proteins into the brain and interrogate different neuronal symptoms to better predict therapeutic success.
Why do you say that PD is not a prion disease?
Because it can’t spread from person to person. The biology in the brain is very similar. What happens is that a normal protein becomes misfolded and then a seed from that misfolding gets out of the cell and into another cell which starts to over produce the misfolded protein which is how a prion works. But a prion can also spread from person to person like mad cow disease and that has not been shown in Parkinson’s disease outside of a lab.
Science history is littered with stories of times when a consensus built around a certain topic only for us to later realize that we were looking at it incorrectly all along. How do we know we are not making the same mistake today with alpha-synuclein.
For me the biggest piece of data was the study by Andy singleton at the NIH who discovered a family that had duplication and triplication of the alpha-synuclein gene. The family made too much of this protein and got Parkinson’s disease. Dosage also matters as people with these alpha-synuclein triplications also got dementia. This demonstrates how alpha-synuclein is central this disease. Also the fact that alpha-synuclein is the major constituent of Lewy bodies further showed that it was integral in patients with PD.
Is there any way to meaningful measure and treat environmental exposure to toxins and pollutants that one has built up over a lifetime and that can cause PD?
We know from experimental studies that toxins can cause PD in a lab. The question is does this apply to the real world. Some people with very little exposure to toxins get the disease and some people who are heavily exposed to toxins don’t get it. So the premise is difficult to prove. Also it is hard to measure the amount of exposure that someone has.
You’ve looked at a lot of brains from people who had PD, how much difference was there between them and could you tell definitively just by looking at a brain whether someone had PD and which symptoms they had?
Well there are imaging techniques that are quite sensitive, such as DAT scans and fluorodopa scans. Though it wouldn’t be practical to do them in everyone because they are quite expensive but people with PD do have a characteristic pattern of loss of binding of fluorodopa.
There are other types of imaging measures lead by a great scientist named David Eidelberg who is putting a collection of imaging findings together and creating a Parkinson’s phenotype. This is giving us better ways to define the disease.
If you were just starting your career in PD, what field of research would you go into?
In terms of cures, I am for testing everything that modifies synuclein. I often say, synuclein now, synuclein forever. There are other pathways and genetic markers to address that are important, but I am a translational neuroscientist, I like doing things that are close to the clinic. It’s rare for anyone to see what they are doing in the lab tested in the clinic and I’ve had a chance to do that several times. So I would do just what I’m doing.