Dr. Richard Hickman 2018 HDSA Human Biology Project Fellow
Columbia University Irving Medical Center
Mentors: Ai Yamamoto, PhD, Jean-Paul Vonsattel, MD, Karen Marder, MD, MPH
What initially inspired you to enter into HD Research, and, since entering the field, what experiences have brought you to your current point in your career?
I became interested in diseases of the brain while studying medicine in the UK. The lectures and tutorials I received there left a longstanding impression and a desire to better understand neurodegenerative diseases. Why should a brain that was previously functioning well for forty or more years suddenly appear to decline? Why do certain brain regions seem more affected than others? Why do we not have good treatments to adequately stop these conditions?
It seemed to me that the best way to understand the disease would be to directly study the brain tissues and neuropathology appeared to be the best specialty to do that. After receiving some post-graduate research training in neuropathology in Oxford, UK, I moved to New York to pursue pathology and neuropathology subspecialty training, the latter of which I did at Columbia University in New York. This is a clinical specialty that provides diagnoses from patients’ tissue or fluid samples and include cancer diagnoses, as well as post-mortem diagnoses from autopsy. Columbia houses a world-renowned brain bank that was at the time directed by Jean-Paul Vonsattel, who is also an expert in the neuropathology of HD.
What I found appealing to study HD was that we already know the principal cause of the disease, the mutant Huntingtin gene, whereas a lot of other neurodegenerative conditions are less clearly defined, like Alzheimer disease. During the second year of my fellowship, I learned methods of brain banking (carefully collecting specific areas of brain tissue for researchers) as well as being able to diagnose different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, frontotemporal lobar dementia etc. These tissues were obtained from generous patients/ families who had arranged for their brains to be donated for research after death. After my fellowship, I stayed on staff to continue my research studies in HD and work with the other research groups/Alzheimer Disease Research Center.
In layman’s terms, please tell us some highlights about your HDSA-funded project. What is the potential impact of your project on the field of HD research and/or clinical outcomes for persons with HD?
One of the principal goals of the grant was to bank brain tissue and carefully document the severity of HD and other conditions in the brains that were received for the HD research community. Brain banking is inherently expensive and requires 7 days a week of dedication from staff, not just the neuropathologist. The funding from the HDSA enabled brains to be banked and provide anatomically-precise samples to be collected and stored for the HD research community. These donations will help scientists understand the human disease better for many years ahead.
By carefully studying these brains and those previously examined in the brain bank we made several critical observations that hadn’t been recognized before, probably because one requires a large cohort. One was that in HD, there seem to be more frequent developmental changes that occur early in life and persist in HD brains than in non-HD brains in the brain bank- notably very small malformations (https://link.springer.com/article/10.1007%2Fs00401-021-02269-4). By themselves, they are unlikely to be causing symptoms, but they point to developmental problems in nerve cell migration when the HTT gene is abnormally expanded (i.e. mutated). More work on developmental problems are appearing in other neurodegenerative diseases and if they further contribute to degeneration many decades later, it may mean treatments should start before symptom onset (https://www.nature.com/articles/s41582-021-00595-5) .
One advantage with working in a brain bank is that you interact and work with numerous researchers in related fields. In a study led by Dr. Bryan Traynor at the NIH, the team there had noticed that in patients with clinically diagnosed amyotrophic lateral sclerosis (ALS), about 1 in 1000 had the mutant Huntingtin gene (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864894/). This frequency of the mutant Huntingtin gene was far higher than that of healthy controls. In the postmortem ALS brains of their cohort, the brains showed the same pathologic inclusions/aggregates that are seen in HD despite not having any visible evidence of HD. In a separate study, we also noticed that ALS pathology seems to be unusually overrepresented in HD brains (about 0.8%) in contrast to the frequency of ALS in the general population (about 0.005%) (https://link.springer.com/article/10.1007%2Fs00401-021-02385-1). So, looking from these different perspectives, it seems that the expanded Huntingtin gene may also be a rare possible cause of ALS. More research is needed to establish this finding but if true, there is the possibility that upcoming treatments targeting Huntingtin in HD may also help these rare patients with ALS.
We have another study that is nearing completion that look at the distribution of Huntingtin protein aggregates in the HD brain and how they relate to Huntingtin expansion. Although we have learnt a lot of the neuropathology of HD, we still do not fully appreciate the distribution of where these protein inclusions are in the brain, why they appear more frequently in certain areas and not in others, and whether they are a cause or consequence of the disease process.
What do you like most about your work or the HD research field, and what is your biggest challenge?
Early on, I was captivated by the energy and commitment of the HD community to study and improve treatments for HD. The generosity of the HD families for their gifts to research, the coordinators who work tirelessly to make brain donations happen at any times of the day, and the support of foundations who invest in young people to do research (HDSA and HDF) makes the HD research field feel like a shared endeavor where everyone is striving toward the same goals. To be able to study the human condition directly under a microscope as a neuropathologist is a privilege and an opportunity that not many scientists have.
I think the major challenges relate to better understanding the disease process in patients and how to slow and/or halt the disease. Although much has been learned from HD mouse models, the disease is inextricably human and so research using carefully characterized brains is critical to better understand the disease processes happening in people with HD.
What are your biggest goals as you move forward in your career, or major areas of interest for future research?
I recently moved to Memorial Sloan Kettering Cancer Center to pursue molecular genetic pathology, a field that is rapidly expanding in cancer. It relies on the integration of the pathologic findings of patient tissues in addition to genetic sequencing. The field of cancer has witnessed remarkable advances through therapies that target specific genetic mutations in cancer and many such patients are living longer now than before because of this work. While continuing to publish studies on HD from Columbia and with those that I have active collaborations with, I hope to learn and apply these sequencing technologies to better understand HD and other human diseases.
When you’re not working on HD research, what do you do for fun?
Right now with the pandemic, learning Hungarian (which gives my Hungarian wife a source of amusement with my horrendous pronunciations!), playing badminton (another source of laughter), and watching film.
What has the grant support from HDSA meant to you?
The generous HDSA grant funding has enabled many more donated brains from individuals who have died from HD to be banked and diagnosed so that they can be studied by many others in the HD research community. It’s also provided me with time and funding to study the disease and work with many investigators across the country and outside to make discoveries that otherwise would not have been possible for me.
Thank you all for your generous support and your willingness to take a chance to sponsor me as someone new to the field.
