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Faculty Spotlight: Simon Gregory, PhD

Friday, March 17, 2017
Simon Gregory DREAMS

Simon Gregory, PhD, is the subject of this week’s faculty spotlight. The new addition to our faculty talks to us about his upcoming Cell article which builds on a decade of research to broaden our understanding of the genetics of multiple sclerosis, proving a reviewer wrong and other joys of research, and  immersing himself in Duke sports after an education that spanned three continents.

Your current work involves understanding the complex molecular and genetic processes which lead to conditions like multiple sclerosis, autism, and cardiovascular disease, each of which themselves are complicated, with many causes and influencing factors. How did you get interested in this area? What do you enjoy most about this work?

Before coming to Duke, I worked on the Human Genome Project for 10 years, which gave me the opportunity to collaborate with many investigators whose data pointed towards their gene of interest residing on chromosome 1. Although these collaborations and the HGP itself were immensely satisfying, I wanted to drive my own disease research. At Duke, I joined existing projects on autism, CVD and multiple sclerosis (MS) and, for the latter, was asked to write an aim for the renewal of a grant held by a collaborator.

My aim, labeled by a reviewer as a fishing expedition that was unlikely to succeed, proposed intersecting publicly available genetic and transcriptomic data in humans and animal models of MS to identify a series of candidate genes for targeted genetic analysis. So, what do I find enjoyable? Using a generalist approach to gene discovery, making a significant finding, publishing it in Nature Genetics and proving my reviewer 100% wrong! In addition to continuing these same approaches in MS, autism, and CVS I’ve tried to incorporate novel technologies, such as single cell sequencing, which plays to my generalist background and allows for exciting unbiased discovery of disease mechanisms.

Gregory team
Gregory celebrates the Cell publication with the rest of his lab team.

You’re a senior author of a forthcoming article in Cell in which you describe a RNA helicase, different variants of which can increase or decrease risk for multiple sclerosis. How does this study improve our overall knowledge of multiple sclerosis?
Our Cell paper is the culmination of more than 10 years’ hard work in which Mariano Garcia-Blanco (formerly of Duke, now at the University of Texas, Medical Branch) and I have tried to understand the functional implication of the SNP from our Nature Genetics publication. Given that we had shown that the SNP plays a role in alternative splicing and membrane/soluble ratios of IL7R, we hypothesized that the genes regulating IL7R splicing may themselves also be associated with MS – and this is exactly what we have shown.

We identified a complex epistatic interaction at a genetic and functional level in which the effects of a splicing gene (DDX39B) are only seen in the context of the MS associated SNP in IL7R. This may not seem significant. However, in identifying DDX39B as a new MS risk gene we highlight the importance of splicing in MS, and establish common mechanisms between MS, rheumatoid arthritis and type-1 diabetes as soluble IL7R is elevated and DDX39B is also genetically associated with these diseases.

Ten years ago, you helped identify the first gene outside of the major histocompatibility complex to be associated with multiple sclerosis. Besides your most recent study in Cell, how has our knowledge of multiple sclerosis changes since then? How much of a role does genetics play in the development of multiple sclerosis?

Genetics studies have undergone a sea change in the period following our 2007 publication. The era of genome-wide association studies has pretty much come and gone; the International MS Genetics Consortium will soon publish their final GWAS paper associating ~200 common SNPs from immune pathway genes/loci with MS.

We are now in the era of rare-variant discovery from exome and whole genome sequencing, this means that we’re now looking at a disease burden of rare variants within a set of pathways or genes that are associated with disease. Recognizing that I can’t easily compete in the genetic arena, my own MS research has branched out into animal models to understand the effect of soluble IL7R and MS (with Mariano), while developing an expansive biospecimen collection as part of the MURDOCK study in which we’re developing biomarkers of chronic disease. However, the burgeoning MS community here at Duke is the reason we established DREAMS. For example, the environment at Duke allowed me form a new collaboration with long time MS researcher Mari Shinohara, PhD, and Eric Benner, MD, PhD, who is new to the field to explore a novel drug that might regulate immune response and remyelination.

What is your role within DREAMS? How does this kind of multidisciplinary group help advance research for multiple sclerosis?
Although we have an extraordinarily rich MS research community at Duke we needed to coalesce this groundswell of basic and clinical research around its own entity. To that end, Chris Eckstein, MD, and I direct the Duke Center for Research in Autoimmunity and MS (DREAMS). DREAMS aims to raise awareness of each other’s AI and MS research, to provide a forum for the sharing of ideas and data, and to develop new collaborations/opportunities to increase Duke’s research footprint in these areas. Dr. O’Brien generously provided 3 x $20k pilot research awards to kick start these efforts and lead to larger formally funded grants in the future.

How do you see our understanding of multiple sclerosis changing over the next 10 to 20 years?
In the last decade, we’ve seen significant advances in the development of new drugs for relapsing remitting MS. However the field, and the drugs that will follow, are rightly focusing on progressive types of disease. In this realm, it will take more than just genetics, gene expression, or epigenetic approaches to identify biomarkers or risk factors of progression, it will require multi-modal datasets that also integrate e.g. metabolomic and imaging modalities to identify such signatures of progression. Either way, funding for these approaches (and science in general) will continue to be very challenging to obtain. Thus far, we’ve been very fortunately to have the backing of Duke and philanthropists, such as the Herman Stone Family Fund, to allow us to keep pursuing these high risk high reward avenues prior to obtaining NIH/Foundation funding for identifying mechanisms/signatures/cures of MS.

You earned your bachelor’s degree in Australia, your PhD in the United Kingdom and you’ve spent the last several years working in the United States. How do the academic environments of these countries compare? What’s the biggest difference you noticed between these three environments?

I left Australia pretty much straight after obtaining my undergraduate degree, telling my parents that I’d probably back within six months – that was 26 years ago! Having ‘grown up’ in my academic career in the UK and US I’ve been lucky to meet and collaborate with some fantastic scientists. Insightful science isn’t the prerogative of a nation or culture but rather the individuals within them. I’ve tried to work with smart people who are collaborative, generous in their mentoring, and who have prepared minds. All this, however counts for nothing without science taking place in the context of opportunity. Duke has been a fantastic environment in which I can find a clinical or basic science expert who is willing to help me make that next step in my science, and where possible I’ve tried to ‘pay back’ that same ethos when I’m approached.

What passions or hobbies do you have outside of the Department?
Take an Australian out of their country and they’ll find a sport to immerse themselves. Duke sport is a passion, I’ve spent many an hour shouting at my TV for basketball (men and women’s) and football; my eldest daughter, Olivia, runs for the Blue Devil Track and Field club and my youngest daughter, Isabella, has just started a new season of soccer at the Durham School of the Arts where they both attend – handily across the road from my lab. Having ruptured my ACL 12 months ago my time playing pick-up soccer has probably passed so Deb (my wife) and I spend lots of time in the garden planning for the new season… perhaps I’ll give soccer one more try.

Gregory Cape Cod
Gregory and his wife Deb relax during a visit to Cape Cod.