Meet Paul Marcogliese of Baylor College of Medicine (BCM) and the Jan and Dan Duncan Neurological Institute. He is a postdoctoral associate in HHMI Investigator Hugo Bellen’s lab within the Department of Molecular and Human Genetics of BCM. Paul was on campus for the tenth Neurodegenerative Diseases: Biology & Therapeutics meeting where he presented a poster entitled: “Loss-of-function variants in IRF2BPL are associated with neurological phenotypes”.

What are your research interests? What are you working on?
I am interested in the use of model organisms, particularly the fruit fly, to functionally assess candidate disease causing genes in human neurological disease; specifically, unraveling the molecular and cellular pathogenic mechanisms driving neuronal cell death in two movement disorders: IRF2BPL-linked neuroregression and Parkinson’s disease.

How did you decide to make this the focus of your research?
We are in the era of genomic sequencing that is progressing towards what has been called ‘personalized or precision medicine’. However, the identification of disease causing variants (even with access to large control databases) can be a challenge in light of the amount of natural genetic variation and variation of unknown significance. To bridge this gap, we can use genetically tractable model organisms, like the fruit fly, to help the human genetics diagnosis effort. Humanization strategies in model organisms that allow the functional assessment of a candidate disease variant and compare it to the human reference gene can support disease diagnosis and shed insight on biology. Added to this, the brain and its related disorders still remain a substantial challenge to understand. I feel that model organisms can be used in identifying and unraveling the function of genes causing these disorders. This will also lead to the identification of therapeutic targets thus helping both patients and families.

How did your scientific journey begin?
It has been an interesting journey for me. After completing a BA in criminology at 23 years old, I went to adult high school to complete 3 science credits that I initially avoided. This was due to an increasing interest in science primarily through understanding the evolutionary mechanisms underlying the diversity of life. Then, while completing a BSc in forensics, I was fortunate to work in the lab of David Park at the University of Ottawa studying animal models of Parkinson’s disease. It was here where my love of the scientific process really developed and what led me to conducting my doctoral studies in the Park lab. Not only did I work on mouse and fly models of Parkinson’s disease, but I met inspiring patients.

Now that I am a postdoc in the Bellen lab, I get to be part a large collaborative effort: the Undiagnosed Diseases Network (UDN). The UDN employs next-generation sequencing and model organism studies to help diagnose individuals with rare, undefined diseases. Our newly discovered human disease gene, IRF2BPL (Marcogliese et al., AJHG, 2018), which we originally deposited to bioRxiv has led to meeting a handful of patient families that inspire me to determine a more mechanistic understanding of the gene/disease in hopes of potential therapy.

Was there something specific about Neurodegenerative Diseases: Biology & Therapeutics meeting that drew you to attend?
I have kept a high interest in the role of glia in the pathogenesis of neurodegenerative disorders. There was a substantial portion of the meeting focused on this topic. Additionally, as part of a team studying rare diseases, it was important for me to be able to present our recent work identifying IRF2BPL-linked neuroregression to this audience. While the audience may be focused on more common neurodegenerative diseases, their input and advice on tackling novel diseases/genes will only help.

What is your key takeaway from the meeting?
Not all neurons are the same and there is differential susceptibility across neurodegenerative diseases. Additionally, glial cells -- specifically microglia -- are clearly critical players in neurodegenerative disease development and progression. Hence, from a therapeutic standpoint, there are multiple cell types and potential targets to ameliorate or slow disease progression.

What did you pick up or learn from the meeting that you plan to apply to your work?
The Bellen lab excels at model organism work in vivo, but the CSH meeting has allowed me to make collaborative connections with experts in the iPSC field that could allow us to translate our findings to human cells.

If someone curious in attending a future iteration of this meeting asked you for feedback or advice on it, what would you tell him/her?
I would tell them it was a great experience. The two main reasons why I enjoy CSHL meetings are that the topics are focused enough to attract major players in the field to attend, and there is a substantial discussion of unpublished and novel ideas in the field.

What do you like most about your time at CSHL?
CSHL is located on a beautiful campus. The smaller size of the meeting allows for an intimate atmosphere where everyone is very approachable and inclusive. It not only builds networks but also friendships.

Thank you to Paul for being this week's featured visitor. To meet other featured scientists - and discover the wide range of science that takes part in a CSHL meeting or course - go here.