Please describe the research questions of your lab.
I am an instructor of medicine at the Channing Division of Network Medicine (CDNM) at Brigham and Women’s Hospital and an Associate Epidemiologist at Harvard Medical School. The main focus of the CDNM is to use an integrated, network-based, systems biology-driven approach to define the etiology of complex diseases and to develop new treatments and preventative strategies for such diseases. In particular, most researchers are working to better understand the genetic and environmental determinants of asthma and chronic obstructive pulmonary disease (COPD), and to utilize this information to better define these conditions and identify clinically translatable therapeutic targets.
What genetics/genomics techniques do you utilize in your lab?
The majority of my work focusses on metabolomics, i.e. the profiling of all the small molecules that represent the downstream products of the chemical reactions and processes governing the properties of a biological system. To me this is the most exciting of all the omics technologies, as it informs on the upstream genetic and environmental factors, as well as the interactions between, them that lead to a given phenotype. While at the same time representing the ‘ome closest to phenotype in the central biological dogma. This unique position makes metabolomics particularly amenable to the development of biomarkers, whilst also providing insight into etiology and pathophysiology.
Describe a key technique/assay/instrument utilized in your lab, and what novel insights does it bring to your research question?
One of the things I am most excited about currently is leveraging metabolomic data to derive clinically and biologically meaningful endotypes of asthma. Asthma, like many complex chronic diseases, is highly heterogenous in terms of etiology and clinical manifestation, and this has hindered the development of effective therapeutics. My research is based around the idea that we can improve clinical management by identifying subgroups of asthma patients whose disease is driven by the same molecular mechanisms, and target treatments towards these subgroups, rather than using a “one size fits all approach”.
My K-award from the NHLBI is aimed at deriving endotypes, that is subtypes defined by a distinct functional or pathobiological mechanism, of asthma based on metabolomic profile. Then comparing the clinical and phenotypic features of these ‘metabo-endotypes’, as well as investigating their upstream genetic drivers. We are utilizing a number of novel statistical techniques in order to derive and explore these metabo-endotypes, and are our results so far are really exciting!
At what point in your life did you decide you wanted to be a scientist/physician?
I actually wanted to be a dentist growing up! In the UK, where I am from, you start Dental School straight out of high school. However, I partied a little too hard in my high school years and didn’t get the grades to take up my place in dental school…... Instead I got a place to do Biology at the University of Warwick, and it turned out to be the best thing that ever happened to me. My undergraduate degree cemented my interest in science and specifically molecular epidemiology, which led to my masters, my PhD, and finally the opportunity to move to Boston to take up a postdoctoral fellowship at the Harvard TH Chan School of Public Health.
In your opinion, what is one of the most important discoveries in the field of respiratory illness/disease/function that was dependent on genomics or similar techniques?
From a personal point of view, the discovery of the 17q21 locus, and in particular ORMDL3 within this locus, as a key locus for childhood asthma, has shaped much of my work. A lot of my metabolomics research has focused on the role of sphingolipids within asthma, so the knowledge that ORMDL3, which is a key sphingolipid biosynthesis regulator, is a validated asthma gene allows me to bring a really compelling targeted, pathway-based integrative-omic approach to my work. I think ultimately the best understanding of any complex system will be achieved through integrating multiple omic technologies.
Briefly, describe your favorite publication involving genomics/omics that you were involved with in general-audience terms.
I think the publication I have been most excited about to date is a study within the Vitamin D Antenatal Asthma Reduction Trial, where we got to work with some of our favorite collaborators from the COPSAC study in Denmark. Both VDAART and COPSAC were aimed at determining whether supplementation with Vitamin D throughout pregnancy reduces the risk of asthma in offspring. Intriguingly, what both studies showed is that prenatal vitamin D supplementation can reduced asthma risk, but it doesn’t work for everybody. The results of some preliminary metabolomics analyses indicated that sphingolipids may be involved in this relationship and this led us to explore functional variants influencing the expression of ORMDL3, which as I mentioned above encodes a key enzyme regulating sphingolipid biosynthesis. By integrating metabolomic, genetic and epidemiological data from the clinical trial, we were able to determine that vitamin D supplementation increases de novo sphingolipid synthesis which is protective against the development of asthma. However, in children with the high-risk genotype at rs1293623, ORMDL3 is overexpressed leading to the inhibition of de novo sphingolipid synthesis, so that supplementation with vitamin D is ineffective at reducing asthma risk. I think, these findings have some really fascinating implications for the field of precision disease prevention (PMID: 31439681)
What is your favorite aspect of ATS?
My favorite thing about the ATS is the potential to meet with, learn from and discuss ideas with others working in the field, be it at the yearly meeting, one of the smaller ATS sponsored meetings, or virtually via the different social media options. As wonderful as my lab is, I think it is always so helpful to get expert opinions from researchers working in other labs around the USA and internationally, and ATS provides that!
How could your research assist scientists and clinicians in other assemblies at ATS?
I think that metabolomics (as with some other notable omics, such as proteomics and the microbiome) is pretty underrepresented at the ATS, which I think is a real shame, as it has so much to offer. Not just to people working directly in metabolomics, but also to those working in genetics for example, as I mentioned I really think integrative omics is the future. And crucially, I think metabolomics can be most useful to those who have never even considered adding an omics element to their work. I think they will be pleasantly surprised by the deeper insights into their research area metabolomics can provide. I’m always happy to talk about metabolomics to anybody who is interested!
Would you be open to collaborations with GG and/or non-GG scientists and clinicians? Do you have any potential lab openings currently or in the near future?
Absolutely, we are always looking for new collaborators! As in all omics, validation is key so we are always searching for collaborations with other researchers with metabolomic data. We do currently have an opening in our lab to work with myself and Dr. Jessica Lasky-Su on some really exciting integrative metabolomic projects, so please get in touch if you are interested in working at the Channing Division of Network Medicine!
Please include your email address or lab website to share with potential collaborators!
hprke@channing.harvard.edu
https://www.brighamandwomens.org/research/departments/channing-division-of-network-medicine/overview
@RachelSkelly4
