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Steinmetz Group

Systems genetics and precision health

The Steinmetz group develops experimental approaches to read, edit and write entire genomes across scales. By applying these technologies, members of the lab aim at understanding the genetic basis of complex phenotypes, the mechanisms of gene regulation and RNA splicing, and the molecular systems underpinning disease.

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Previous and current research

One of the most daunting obstacles in biomedicine is the complex nature of most phenotypes (including cancer, diabetes, heart disease and several rare diseases) due to epistatic interactions between multiple genetic variants and environmental influences. Our research is directed at understanding such complex traits, by developing novel genomic approaches to study the molecular processes linking genotype to phenotype, to identify the causal underlying factors, and to quantify their contributions. Our projects are mainly in the following areas:

Quantitative genetics: We apply functional genomics technologies to dissect the genetic and environmental interactions that underlie complex, multifactorial phenotypes. Using high-throughput genome editing screens and methods for massively paralleled readouts, we are studying the consequences of genetic variation, learning to predict phenotype from genotype, and define intervention points that can be targeted to modulate phenotypes of interest.

Precision health: Using eukaryotic model systems of different complexity – from yeast to mouse and human – we characterize the genetic and cellular processes affected in diseases and explore potential therapeutic strategies (Figure 1). We apply genomics technologies to patient-derived cells and mouse models of several disorders including DCM, cancer, and different types of immune diseases. We also develop point-of-care biosensors that monitor an individual’s health and facilitate early disease diagnosis and intervention, even before symptoms set in.

Synthetic biology: Novel DNA synthesis methods and synthetic biology tools allow us to generate entirely new designer genomes from scratch. We are using the first eukaryotic synthetic genome, Sc2.0, to learn how to write the code of life, to rearrange genomes on demand, or to generate organisms with novel traits. This will ultimately allow us to better understand genome architecture, transcriptional mechanisms, and nothing less than life’s basic organizing principles.

Genomics technologies: We have pioneered genomics technologies that are now standard in the field, including novel CRISPR/Cas9 precision genome editing tools (Figure 2), single-cell RNA-sequencing methods (Figure 3), multiomics readouts from single cells, or bulk RNA-seq methods with isoform specificity. We developed these methods or improved their efficiencies and throughput, to scale with the complexity of eukaryotic genomes and phenotypes.

Future projects and goals

Our aim is to transform the way we approach biomedical research, eventually by assigning a function to every nucleotide in the human genome. Along the way, we continually innovate and improve novel genomics technologies, enabling us to achieve our goals faster, more accurately, and more efficiently. For example, we will develop novel tools for precision genome editing, increase the scale and complexity of functional genomics screens, learn how to write genomes with unique traits from scratch, and apply long-read sequencing methods to understand disease mechanisms. Ultimately, we are working towards an era in which we can predict phenotypic traits from genetic and environmental information alone. Achieving this ambitious goal would have far-reaching implications, from facilitating precision medicine for everyone, and to predicting how natural populations will respond to changing environments.

Interested in working with us? Please check out our job opportunities pages.

Links:

Life Science Alliance (Directed by Lars Steinmetz)

Steinmetz lab at Stanford University

ERC INVESTIGATOR


Figure 1: Understanding, treating and preventing human diseases using powerful systems genetics approaches on cell culture and animal models (Briganti et al. Cell Rep, 2020; Zhu et al. Nat Comm, 2021)
Figure 2: Precision genome editing with MAGESTIC potentially allows saturation editing of entire eukaryotic genomes (Roy et al. Nat Biotech, 2018)


Figure 3: Functional genomics screens using CRISPR and single-cell readouts to characterize thousands of genomic loci in the blink of an eye (Schraivogel et al. Nat Meth, 2020)

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