Our laboratory is motivated by two of the most humbling yet fascinating challenges in medicine:
1) Why is it that patients with seemingly identical risk factors demonstrate such wide variety in disease manifestations and outcomes?
2) How do we create a classification system that reflects underlying disease pathophysiology rather than one that captures superficial phenotypic similarity?
Our interest in these problems is pragmatic - we want solutions that will change clinical practice rather than simply add to a list of published work. But we also need a system which we can approach scientifically so that we can actually derive some conclusions. As a result, we have focused upon a human disease with a strong genetic basis - the inherited cardiomyopathies - that should allow ready modeling and at the same time adequately reflect these two challenges. In genetics, the terms variable expressivity and incomplete penetrance are often used to describe problem (1) - namely that patients with identical genetic mutations demonstrate such wide variation in disease severity. I am constantly reminded of this situation in the clinic, where a 90 year old mother might share the same pathogenic mutation as her 20 year old son, who needed a heart transplant. Problem (2) is the basic challenge of “precision medicine”, namely the need to describe superficially similar disease processes (in this case, conditions which cause big, week hearts) in a way that reflects prognostically and therapeutically more homogeneous subtypes.
So these are the problems - what are the tools? Our lab uses a mixture of patient samples, genetic models (predominantly in zebrafish, but recently in mouse), unbiased genomic/epigenetic profiling, quantitative imaging, and statistical/machine learning to advance our goals. We have actively embraced CRISPR/Cas9 technologies for genetic modifications. We also believe that environmental perturbations including drugs are essential to elicit subtler phenotypes that may be missed upon baseline assessment. Our interests have taken us in some expected places, such as investigating the role of cardiac autoimmunity in disease expressivity, and looking at single cell sequencing. We are fortunate to be in a rich scientific environment, which allows us to pursue these problems using a variety of scientific approaches, and yet still perform at a high level.