The overarching goal of our research
is to understand the intersection of common and rare disease genetics to uncover the genetic architecture
and molecular mechanisms of human disease. We take a conceptually innovative approach to our research,
bridging genomics and classic genetics, integrating informatic, molecular, translational, and clinical approaches,
to investigate our hypotheses and perform our work.
.
Our lab has a particular focus on disorders affecting the primary cilium, but our science is guided by genetic discovery
and we are excited to tackle interesting questions agnostic of organ system or disease pathogenesis.

I. The Primary Cilium and Common Disease

Obesity, kidney failure, diabetes, hepatic fibrosis – each of these diseases remains a major public health burden despite billions of dollars spent on their treatment and research every year. For patients with rare syndromic genetic disorders affecting the primary cilium the dysfunction of this single organelle can produce all these diseases in a single person. By studying the primary cilium, can we discover new molecular mechanisms of disease pathogenesis and identify novel therapeutic targets for common diseases of huge public health burden?

Found on nearly every human cell type, the primary cilium is a small, non-motile projection of the cell’s apical surface that acts as an antenna for the reception and integration of signals from the extracellular environment. A number of rare syndromic genetic disorders, termed ciliopathies, are known to result from perturbation of any of the ~300 genes critical to ciliary function. The pathologies characteristic of the ciliopathies include extreme risk of common diseases like kidney disease, diabetes, obesity, and hepatic fibrosis, which are caused by deficits in cell signaling pathways dependent on the cilium for normal function. Evidence now suggests that many signaling pathways with critical roles in common complex diseases pathogenesis (PDGF, TGFβ , SHH, Insulin) are dependent on the ciliary localization of their cognate receptors for appropriate downstream signaling.

Previous work in our lab has found that common genetic variants affecting ciliary gene expression are associated with markers of diabetes, liver function, and kidney health in the general population, with different sets of ciliary genes conveying increased risk for different diseases. This suggests that there exist distinct molecular mechanisms, each involved in different aspects of ciliary signaling/function, that play a role in the risk for common diseases like obesity and diabetes. However, despite these findings and despite the many links between ciliary signaling and pathways important to common disease pathogenesis, the cilium’s contribution to the development of common disease remains largely unexplored.

How do genetic variants in ciliary genes affect common complex disease pathogenesis? We have a number of ongoing wet and dry lab projects, detailed below, focused on understanding (1) the association between ciliary genetic variants and human disease in large patient biobanks, (2) the molecular mechanisms underlying the cilium's role in common complex disease in basic cell models, and (3) the reciprocal role of different common disease states on ciliary gene expression and the structure and function of the cilium in animal models of chronic disease.

1. Identifying variants in ciliary genes that increase risk for common complex disease

Our lab is working to characterize associations between common and rare ciliary genetic variants and numerous patient phenotypes in large medical biobanks using a combination of informatic approaches. With thousands of phenotypes derived from the electronic health record linked to individual-level genotyping array and exome sequencing data, we can discover previously unknown disease associations for ciliary genes and validate our findings in cell models. Phenome wide association studies (PheWAS) are ongoing, investigating the effects of both rare and common ciliary genetic variants on patient phenotypes, with many projects available for graduate students and postdocs in this space.

2. Differentiating the ciliary genes required for different disease-associated signaling pathways

We now know that receptors for signaling pathways involved in common complex disease pathogenesis, including insulin, PDGF, and TGFβ, must be specifically imported into the cilium to affect appropriate signal transduction upon stimulation. However, we know little about the molecular mechanisms by which this process is regulated, we do not know if specific subsets of ciliary genes are required for signaling through different pathways, and we do not understand how genetic variants affecting the cilium perturb these processes to increase disease risk. We have numerous projects avaialble in this space, using diverse wet lab techniques (engineered reporter cell lines, signaling assays, immunoblotting/ELISAs, live cell imaging) to understand these processes and discover novel therapeutic targets.

3. Comparing the effects of different chronic disease states on cilium structure and function

While it is clear that dysfunction of the priamry cilium can have a profound impact on human health, little is known about the reciprocal effects of different common disease states on cilium structure and function. Recent studies and preliminary results from our lab have identified significant differences in ciliary gene expression between diabetic and non-diabetic mice and humans, suggesting that secondary defects in cilium function can result from common disease states. However, how these secondary changes interact with an individual's underlying genetics to exacerbate, or perhaps ameliorate, the symptoms of disease is unknown. Projects are available in this space, using RNAseq and microscopy to discover and define secondary changes in cilium function in animal models of common disease and in human tissues.

II. Genetic Variation and Disease on the Population Level

With the advent of larger and larger population-level biobanks linked to genetic data and the electronic health record, and with the development of more robust artifical intelegence approaches and more powerful statistical models, we have the opportunity to ask questions about the genetic architecture of human disease in ways never before possible. Our lab is actively exploring ways of integrating rare and common genetic variants to make fundamtental discoveries that begin to explain how our genes affect our health.

Our lab has shown that "rare" genetic disorders are actually much more common than previously thought, and often obscured by complex genetic paradigms such as somatic mosaicism, reduced penentrance, and unexpected pleiotropy. We have undertaken collaborative projects to begin to understand how burdens of rare deletarious variants in individual genes can influence a person's risk for disease, ranging from cardiomyopathy to COVID-19. We will continue to apply these approaches to further our knowledge of the rare genetic variant contribution to human disease phenotypes across the genome and phenome. There are projects available in this area for students, clinicians, and postdocs, with the diseases and genes to be investigated tailored to each person's interests.

But the big challenge that remains to be answered is this: can we integrate data on all of an individual's genetic variants -- both common and rare -- with our knowledge of gene pathways and interaction networks to more robustly predict each person's risk for disease? Can we use such a model to more precisely target our medications and interventions and make fundamental discoveries about the pathways involved in disease pathogenesis? We are working on AI-driven methods to do exactly this. We have many projects ongoing in this area, well-suited to scientists with computational and informatic interests and experience.

How "rare" are rare genetic syndromes, and do all rare disorder patients present with the same phenotype? How do rare and common generic variatns interact to influence a person's risk for disease? Can we develop AI-driven apprpaches to begin to integrate all of an individual's genetic variation with gene interaction networks to more accuratly predict risk for disease?

III. Genetics and Medicine:

Disparities, Implementation, and the Unknown

It seems inevitable that over the next decade genomic data will become an integral component of each patient's medical record. Healthcare systems are investing heavily in Genetic and Precision Medicine initiatives that stand to fundamentally change the practice of medicine. But while there is immense promise in the implementation of these approaches, there are many important questions and hurdles that must be overcome to ensure the equitable, effective, and economic implementation of genomic data in healthcare. Which patients will undergo genetic testing? Who will analyze and review the results? How can we harness this data to ensure that the right patient gets the right treatment at the right time?

Our lab, and others, has been working to understand how genetic data is currenlty being incorprated into clinical medicine so that we can prepare for and anticipate both the remarkable advances and major pitfalls that will come with these new technologies. Our data show very clearly that the current system amplifies and propagates race- and socioeconomic-status-based inequalities, and our findings highlight major failings in our ability to identify patients who would benfit from genetic testing. Using the data derived from the electronic health record and from the deidentified genetic information available through the Penn Medicine BioBank, we can begin to identify and address these issues. We have many projects ongoing in this area, working to identify and address the hurdles that must be overcome to ensure the equitable roll out of Precision and Genetic Medicine initiatives, and working to design and implement new approaches that will bring precision medicine to fruition in a fair, equitable, and economic way.

Which patients undergo genetic testing; and which patients are disproportionatly excluded? What resuts do we obtain, and how can we use this data to improve patient care? These are all questions we are working to answer in the Drivas lab.

The goal of our research
is to understand the intersection
of common and rare disease genetics
to uncover the genetic architecture
and molecular mechanisms of
human disease.
.
We take a conceptually innovative
approach to our research, bridging
genomics and classic genetics,
integrating informatic, molecular,
translational, and clinical approaches,
to investigate our hypotheses and
perform our work.
.
Our lab has a particular focus on
disorders affecting the primary cilium,
but our science is guided by genetic
discovery and we are excited to tackle
interesting questions agnostic of
organ system or disease pathogenesis.

Obesity, kidney failure, diabetes, hepatic fibrosis – each of these diseases remains a major public health burden despite billions of dollars spent on their treatment and research every year. For patients with rare syndromic genetic disorders affecting the primary cilium the dysfunction of this single organelle can produce all these diseases in a single person. By studying the primary cilium, can we discover new molecular mechanisms of disease pathogenesis and identify novel therapeutic targets for common diseases of huge public health burden?

Found on nearly every human cell type, the primary cilium is a small, non-motile projection of the cell’s apical surface that acts as an antenna for the reception and integration of signals from the extracellular environment. A number of rare syndromic genetic disorders, termed ciliopathies, are known to result from perturbation of any of the ~300 genes critical to ciliary function. The pathologies characteristic of the ciliopathies include extreme risk of common diseases like kidney disease, diabetes, obesity, and hepatic fibrosis, which are caused by deficits in cell signaling pathways dependent on the cilium for normal function. Evidence now suggests that many signaling pathways with critical roles common complex diseases pathogenesis (PDGF, TGFβ , SHH, Insulin) are dependent on the ciliary localization of their cognate receptors for appropriate downstream signaling.

Previous work in our lab has found that common genetic variants affecting ciliary gene expression are associated with markers of diabetes, liver function, and kidney health in the general population, with different sets of ciliary genes conveying increased risk for different diseases. This suggests that there exist distinct molecular mechanisms, each involved in different aspects of ciliary signaling/function, that play a role in the risk for common diseases like obesity and diabetes. However, despite these findigfindings and despite the many links between ciliary signaling and pathways important to common disease pathogenesis, the cilium’s contribution to the devellopment of common disease remains largely unexplored.

I. The Primary Cilium and Common Disease

1. Identifying variants in ciliary genes that increase risk for common complex disease

We are working to characterize associations between common and rare ciliary genetic variants and numerous patient phenotypes in large medical biobanks using a combination of informatic approaches. With thousands of phenotypes derived from the electronic health record linked to individual-level genotying array and exome sequencing data, we can discover previously unknown disease associations for ciliary genes and validate our findings in cell models. Phenome wide association studies (PheWAS) are ongoing, investigating the effects of both rare and common ciliary genetic variants on patient phenotypes, with many projects available for graduate students and postdocs in this space.

2. Differentiating the ciliary genes required for different disease-associated signaling pathway


We now know that receptors for signaling pathways involved in common complex disease pathogenesis, including insulin, PDGF, and TGFβ, must be specifically imported into the cilium to affect appropriate signal transduction upon stimulation. However, we know little about the molecular mechanisms by which this process is regulated, we do not know if specific subsets of ciliary genes are required for signaling through different pathways, and we do not understand how genetic variants affecting the cilium perturb these processes to increase disease risk. We have numerous projects avaialble in this space, using diverse wet lab techniques (engineered reporter cell lines, signaling assays, immunoblotting/ELISAs, live cell imaging) to understand these processes and discover novel therapeutic targets.

3. Comparing the effects of different chronic disease states on cilium structure and function



While it is clear that dysfunction of the priamry cilium can have a profound impact on human health, little is known about the reciprocal effects of different common disease states on cilium structure and function. Recent studies and preliminary results from our lab have identified significant differences in ciliary gene expression between diabetic and non-diabetic mice and humans, suggesting that secondary defects in cilium function can result from common disease states. However, how these secondary changes interact with an individual's underlying genetics to exacerbate, or perhaps ameliorate, the symptoms of disease is unknown. Projects are available in this space, using RNAseq and microscopy to discover and define secondary changes in cilium function in animal models of common disease and human tissues.

With the advent of larger and larger population-level biobanks linked to genetic data and the electronic health record, and with the development of more robust artifical intelegence approaches and more powerful statistical models, we have the opportunity to ask questions about the genetic architecture of human disease in ways never before possible. Our lab is actively exploring ways of integrating rare and common genetic variants to make fundamtental discoveries that begin to explain how our genes affect our health.

Our lab has shown that "rare" genetic disorders are actually much more common than previously thought, and often obscured by complex genetic paradigms such as somatic mosaicism, reduced penentrance, and unexpected pleiotropy. We have undertaken collaborative projects to begin to understand how burdens of rare deletarious variants in individual genes can influence a person's risk for disease, ranging from cardiomyopathy to COVID-19. We will continue to apply these approaches to further our knowledge of the rare genetic variant contribution to human disease phenotypes across the genome and phenome. There are projects available in this area for students, clinicians, and postdocs, with the diseases and genes to be investigated tailored to each person's interests.

But the big challenge that remains to be answered is this: can we integrate data on all of an individual's genetic variants -- both common and rare -- with our knowledge of gene pathways and interaction networks to more robustly predict each person's risk for disease? Can we use such a model to more precisely target our medications and interventions and make fundamental discoveries about the pathways involved in disease pathogenesis? We are working on AI-driven methods to do exactly this. We have many projects ongoing in this area, well-suited to scientists with computational and informatic interests and experience.

II. Genetic Variation and Disease on the Population Level

III. Genetics and Medicine:

Disparities, Implementation, and the Unknown

It seems inevitable that over the next decade genomic data will become an integral component of each patient's medical record. Healthcare systems are investing heavily in Genetic and Precision Medicine initiatives that stand to fundamentally change the practice of medicine. But while there is immense promise in the implementation of these approaches, there are many important questions and hurdles that must be overcome to ensure the equitable, effective, and economic implementation of genomic data in healthcare. Which patients will undergo genetic testing? Who will analyze and review the results? How can we harness this data to ensure that the right patient gets the right treatment at the right time?

Our lab, and others, has been working to understand how genetic data is currenlty being incorprated into clinical medicine so that we can prepare for and anticipate both the remarkable advances and major pitfalls that will come with these new technologies. Our data show very clearly that the current system amplifies and propagates race- and socioeconomic-status-based inequalities, and our findings highlight major failings in our ability to identify patients who would benfit from genetic testing. Using the data derived from the electronic health record and from the deidentified genetic information available through the Penn Medicine BioBank, we can begin to identify and address these issues. We have many projects ongoing in this area, working to identify and address the hurdles that must be overcome to ensure the equitable roll out of Precision and Genetic Medicine initiatives, and working to design and implement new approaches that will bring precision medicine to fruition in a fair, equitable, and economic way.