Our body contains hundreds of different cell types with specific developmental histories or lineages. In addition, these cells can acquire different states in development and disease.All these cell types are defined by the pathways they use. We are interested in cell identity, and how cells transition from one type to another. In this context, we study genetic dependencies of cells in different identities of health and disease as well as the transitions between.
We use forward genetic screens to learn about lineage maintenance, lineage transition, and the underlying genetic and epigenetic programs. These have an impact on development, regeneration, and diseases such as cancer. To account for the heterogeneity in cell identities we develop new genetic screening paradigms such as improved sgRNA designs, temporal control of CRISPR/Cas9, and single cell-based readouts. Our expertise in high throughput genetics has also enabled us to contribute to the scientific response to the current pandemic as we sequence SARS-CoV-2 samples for clinical diagnostics.
We are fascinated by using unbiased genetic screens to unravel biologic dependencies of biological processes. We think a data-driven approach to research facilitates discovery. Assumptions can limit our questions and insight – let biology tell the story. We like to use large scale, high-throughput methods to generate data that form a complete picture or answer to a particular question. For that we need to adapt technology to account for biological challenges such as heterogeneity.
Pooled genetic screens empowered by the revolution in next generation sequencing represent an extremely informative approach to ask unbiased questions in biology. While cellular heterogeneity and cell identities are of great interest biologically, they confound genetic screens by introducing noise. We have set out the goal to develop genetic screening further in order to ask questions in more rewarding yet more challenging contexts.
Changes in cell identity require time, involve several intermediate steps, and are often inefficient. While this fact prevents identity change towards pathogenic states, it also represents a hurdle e.g. for regenerative processes. We want to identify the genetic hierarchies governing these transitions positively or negatively, to gain further understanding of cell type control as well as to establish a handle to modulate them.
With our advanced screening technologies, we contribute to make more challenging model systems such as organoids and in vivo settings accessible for high-throughput genetic analyses, in particular pooled genetic screens. We use these new technologies to ask questions such as: Which genes and pathways control cell identity change? Which gene is a cancer specific dependency? Which genes are required in vitro versus in vivo? For that we have generated state of the art CRISPR libraries that we use for our projects as well as in collaboration.
Our expertise in high-throughput genomics is able to solve challenges also generated by Covid-19. Our contribution to the pandemic by supplying sequences of the spike gene for 10-50% of all Austrian patients has led to important measures for the Austrian management in response to Covid-19.
Elling, U., Penninger, JM. (2014). Genome wide functional genetics in haploid cells. FEBS Lett. 588(15):2415-21
Wirnsberger, G., Zwolanek, F., Stadlmann, J., Tortola, L., Liu, SW., Perlot, T., Järvinen, P., Dürnberger, G., Kozieradzki, I., Sarao, R., De Martino, A., Boztug, K., Mechtler, K., Kuchler, K., Klein, C., Elling, U., Penninger, JM. (2014). Jagunal homolog 1 is a critical regulator of neutrophil function in fungal host defense. Nat Genet. 46(9):1028-33
Elling, U., Taubenschmid, J., Wirnsberger, G., O'Malley, R., Demers, SP., Vanhaelen, Q., Shukalyuk, AI., Schmauss, G., Schramek, D., Schnuetgen, F., von Melchner, H., Ecker, JR., Stanford, WL., Zuber, J., Stark, A., Penninger, JM. (2011). Forward and reverse genetics through derivation of haploid mouse embryonic stem cells. Cell Stem Cell. 9(6):563-74