Spotlighting Parkinson’s Disease Awareness month, NYSCF Investigator Dr. Aiqun Li shares the latest in NYSCF’s Parkinson’s research, why he started his career in science, and the promise stem cells hold for Parkinson’s patients around the world.
Q: What research are you currently conducting in Parkinson’s disease?
A: At the NYSCF research institute, I am currently using patient-specific stem cells to understand Parkinson’s disease (PD). Because PD mainly affects the dopamine-producing neurons in the midbrain of patients, we are interested in recreating these neurons in a petri dish for our research. I am proud to say that we have worked out ways to generate dopamine-producing neurons from sporadic PD patients, familial cases, and healthy individuals. This unprecedented technological innovation allows us to search for PD-relevant changes by comparing neurons from these different groups. I am hoping that these efforts will one day translate into new drug development and clinical interventions.
Our recent work, published as the cover story of Cell Reports in November 2014, reveals differences between a pair of identical twins, both with a glucocerebrosidase (GBA) genetic mutation that is associated with an increased risk of PD, but only one twin developed PD symptoms. We were able to create dopamine-producing neurons from the stem cells derived from the twins. We found that the neurons of both twins produced less dopamine than normal; however, the twin with PD had even lower levels of dopamine because he had higher amounts of monoamine oxidase-B (MAO-B), an enzyme that breaks down dopamine. This finding identifies a potential strategy for developing combination therapies, targeting both GBA and MAO-B, for Parkinson’s disease.
Q: What does your research mean for PD patients?
A: PD is the second most common neurodegenerative disease, and there are about a million people affected in the United States. It is an irreversible disease that is characterized by a loss of dopamine-producing neurons. One of the diagnostic shortcomings in PD is that the onset of the disease is not easily detected—tremors, one of the common symptoms, are not apparent until a patient loses 40-70% of their dopamine-producing neurons. In late-stage PD, the disease and related clinical problems become more difficult to manage. Although not much is known about the underlying mechanisms behind disease onset and progression, it has been attributed to a combination of genetic and environmental risk factors.
Our research using stem cell technology serves as a valuable tool to evaluate how genetic and environmental risk factors contribute to PD at the cellular level. Our recent study of twins carrying GBA1 mutation, one affected and one unaffected with PD, provided a prime example to evaluate and dissect the genetic and non-genetic contributions to the development of PD.
We believe that our stem cell research could lead to methods for early diagnosis, prevention, and to a path for discovering new drugs to treat PD.
Q: Why did you choose to pursue stem cell research?
A: Though toxin-induced and genetically modified animal models of PD are close to human, they cannot recapitulate the complexity of human PD. Studying living human nerve cells was once thought to be impossible. Now, we pursue stem cell research because neurons created from human stem cells offer the opportunity to make the impossible a reality, giving us new insights into human PD.
As a matter of fact, this importance of stem cell research is widely recognized in the scientific community. Patient-specific stem cells not only have the potential to give rise to many different cell types individually, but collectively they also represent a broad overview over the population of patients. These cells offer an unprecedented research opportunity as a large-scale model to understand the mechanism behind many diseases and to develop and test new drugs.
Q: What led to your career in science?
A: I was encouraged to be a scientist by parents and teachers, even in my early childhood. I was always interested in life science, because there are many unanswered questions about the fundamental principles of life.
In 1995, I fortunately became a student in Nanjing Medical University where I learned about diseases. During my medical training, I realized that there was a critical need to study the fundamental mechanisms behind the diseases we were learning about. I decided to pursue my Master’s degree and PhD degree at the Chinese Academy of Sciences, studying the molecular and cellular mechanisms of PD - the second most common neurodegenerative disease. After my postdoctoral training program at Weill Cornell Medical College, I joined the NYSCF team in 2011, focusing on using patient-specific stem cells to understand PD.
Q: What promise do stem cells hold for PD patients?
A: We at the NYSCF Research Institute, together with many other scientists around the world, believe that stem cell research holds the most promise for finding a cure for Parkinson’s patients. The well-known dopamine reduction in PD patients is due to a loss of dopamine-producing neurons. The existing gold standard treatment of L-DOPA therapy and surgical deep brain stimulation (DBS) can relieve the symptoms or slow down the progression of PD; however, there is no known cure.
Future patient-specific, stem cell-based, personalized treatment provides hope for desperate PD patients by creating the opportunity to figure out new and more effective therapeutic approaches for each individual patient, or even stopping their disease progression completely.
Even more remarkable is the fact that neurons created from stem cells can function equally well as the authentic dopamine-producing neurons. In the long run, stem cell transplantation to replace the damaged neurons in patients could provide a cure for PD. Excitingly, a number of stem cell engraftments have shown conceptual promise in animal studies.
Q: What is the most exciting development in PD research today?
A: Today, there are many exciting advancements in PD research, including genetic intervention, bone marrow transplantation and delivery of growth factors. However, in my opinion, the model of ‘Parkinson’s-in-a-dish’ using patient-specific stem cells is the most exciting development right now. Accumulating evidence has shown that stem cell research holds the most promise for finding a cure for PD patients.
Using stem cell technology, scientists are also developing an approach to create ‘mini brains’ that may mimic the real brain functions. The 3D arrangements of neural tissue–closer to native brain than 2D tissue culture–will open up a more efficient avenue to conduct PD research.
Q: What other approaches are you taking towards curing PD?
A: To date, mutations in GBA1 or LRRK2 (leucine-rich repeat kinase 2) genes are the most common genetic risk factors for PD. Investigating the genetic forms of PD may reveal a molecular mechanism–for example, the impaired cellular disposal system–that may also be implicated in more common sporadic forms of PD. Moreover, CRISPR/Cas9 system–a powerful new genome editing technology–enables us to precisely manipulate GBA1 and LRRK2 genes. Using this technology recently, we have introduced mutations into normal stem cells and corrected the natural mutations in stem cells from patients. Through work on the genetic manipulation, we are trying to answer the critical questions of how mutations in GBA1 or LRRK2 lead to abnormalities in PD.