Izsvák Lab

CV of  Zsuzsanna Izsvák

Zsuzsanna Izsvák received her PhD in 1993 from the Hungarian Academy of Sciences in Budapest, Hungary. After a postdoctoral period at the University of Minnesota, St. Paul, USA, she returned to Europe. She held a long-term fellowship from EMBO and worked at the Netherlands Cancer Institute in Amsterdam between 1997 and 1999. She joined the Max-Delbrück-Center for Molecular Medicine in Berlin in 1999. In 2004, her research was evaluated by the European Science Foundation (ESF) as “strategically important” for Europe and was awarded by the European Young Investigator Award (EURYI) in 2004. In 2004 she has established her own research group, “Mobile DNA“, at the Max-Delbrück-Center in Berlin. Between 2009-2011 she was a guest professor at the Medical University of Debrecen, in Hungary. In 2011 she was entitled to the title of D.Sc of the Hungarian Academy of Sciences. From 2011 she has a permanent group leader position at the Max-Delbrück-Center in Berlin. In 2012, her proposal has been selected for funding by the European Research Council (ERC Advanced).

Main research domains

Transposable elements, recombination, gene therapy, genome manipulation, non-viral gene delivery, gene targeting, stress response, cancer, embryonic stem cells, endogenous retroviruses, retrotransposon, domestication, co-option, host-transposon interaction, regenerative medicine.

Scientific Publications

97 publications in reviewed journals, >6700 citations; h-index 39 – 8 book chapters – 11 patent applications – 78 invited speaker lectures in International meetings and seminars,
https://scholar.google.de/citations?hl=de&user=7z1VOhEAAAAJ&view_op=list_wo

Positions and Honors

1987 - TMB fellowship – Hungarian Academy of Sciences

1996 - Long Term EMBO fellow

2004 - European Young Investigator Award, EURYI (European Science Foundation, ESF)

2004 - Present- Group Leader, Max Delbrück Center for Molecular Medicine, Berlin, Germany

2009 - 2011 - Guest Professor of the Medical University of Debrecen, Hungary

2009 - SB100X, ‘Highlight of the Year’, 2009  European Society of Gene and Cell Therapy, ESGCT

2009 - ‘Molecule of the Year’, 2009;

2012 - ERC Advanced (European Research Council)

2015 - Research Highlight, MDC (a)

2015 - Research Highlight, MDC (b)

2015 - Best Publication of the Year, 2015 German Stem Cell Network (GSCN)

 
Committee, advisory boards, advisory groups

• Mobile DNA
• Mobile Genetic Elements
• Gene (pending)
• Guest editor of a special issue in Seminars in Cancer Biology, “Repetitive elements and genome instability” – containing 8 articles
• European Science Foundation – reviewer
• Advisor of the Danish Council for Strategic Research
• International Mentor, Szent-Györgyi International Mentor Program
• Dennis Gabor Gesellschaft, founder

Scientific Leadership Profile

Transposable elements (TEs) are discrete segments of DNA that have the distinctive ability to move from one genetic location to another in a genome. Although, large fractions of genomes can be composed of TE-derived sequences (~45% of the human genome), the vast majority of these elements are not essential to the host cell. TEs accumulate inactivating mutations over evolutionary time to give rise to a fraction of the genome often called “junk DNA”.
 
In an attempt to turn this “junk” into treasure, Zsuzsanna has utilized TEs to understand how these elements shape(d) the genomes. She has delineated several molecular mechanisms of how TEs piggyback basic cellular mechanisms, and still maintain a coexistence with their host^1-6. Her pioneering work, the resurrection of an ancient, inactivated transposon, Sleeping Beauty (SB)⁷ not only represents the first DNA-based transposon ever shown to be active in cells of vertebrates, but the first functional gene ever reconstructed from inactive, ancient genetic material, for which an active, naturally occurring copy either does not exist or has not yet been isolated. In addition to SB, her lab has succeeded in identifying and/or resurrecting several, previously undefined transposable elements from vertebrate genomes^8-10. A course of studies generated valuable model systems to study recombination mechanism as well as transposon-host interactions in higher eukaryotes^1-4,11, which was possible only in bacteria and in lower metazoa before. Her research significantly extended our understanding of the principal molecular processes involved in cellular responses to DNA transposition.
 
Molecular reconstruction of SB represents also a milestone in genome engineering in vertebrate species, in which genome manipulation was hitherto not possible. Indeed, the SB system has been developed into a technology platform for vertebrate genetics with application areas including gene therapy, transgenesis, functional annotation of cancer genomes and germline mutagenesis for gene discovery. These efforts revolutionised genomic manipulations in vertebrate species. Her team has contributed to establish transposon-based genetic strategies on several fronts:^12-37: (i) Her laboratory played a leading role in developing a knockout technology in the rat model that lacked such a technology before^17,38,39(ii) Her team has established transposon-mediated transgenic technology in various model organisms, including Ciona intestinalis²⁶, rodents^29,35, rabbits³³ and pigs^19,34 for biomedical research and for biotechnology; (iii) A strategy to combine lentiviral and transposon insertional mutagenesis enabled genetically track human tumours and identify novel tumor repressors³⁶; (iv) In parallel, she established the transposon-based, non-viral gene transfer vector technology for therapeutic use. Using a combination of molecular evolution and high throughput mutagenesis approaches, her laboratory has developed a hyperactive SB transposase called SB100X, the first non-viral gene delivery system capable of highly efficient gene delivery in primary stem cells^17,40-42. This achievement was recognized with the title “Molecule of the Year” in 2009; for the first time in the history of the title the award went to European scientists. The SB00X system has been adopted as a non-viral, integrating vector, providing a safer alternative to retro/lentiviruses. The SB100X system has particularly favorable attributes for stable, long-term expression in various cell types, including primary and stem cells^17,41,43 of therapeutic potential³⁷. Translating her experience accumulated in transposable element research proved to be fruitful in establishing novel strategies to address yet unsolved challenges in genome engineering, stem cell research and therapy. These include, generating iPSCs³⁰, targeting transposon integration into a desired genomic locus^24,25,44 or generating hybrid virus/transposon systems that merge desirable features of the transposon with various viruses^31,32,45-47. She is actively participating in promoting clinical translation of the SB100X system with the mission of establishing both efficacy and safety of transposon protocols for future gene and cell therapy applications³⁷. As a result of these efforts, the SB100X system is used in numerous pre-clinical studies, and the first in-man clinical trial has been successfully conducted in the USA (MD Anderson, USA). In Europe two SB100X-based Phase 1 clinical trials are supported by the European Union and the Berliner Institute of Health (BIH) to treat age-related macular degeneration (AMD)²³ and cancer, respectively.
 
In addition to DNA-transposons, she has a fundamental contribution to our understanding the genomic impact of retroelements and endogenous retroviruses (ERVs) in vertebrates11,48,49. Participating in a gibbon genome consortium, her team described a propensity of a retrotransposon (LAVA) to insert and alter transcription of chromosome segregation genes, pointing to TEs as a major creative force in the evolution50.
 
Her recent work has established that much of the circuitry regulating pluripotency in human pluripotent stem cells (hPSCs) is primate/human specific, controlled by an endogenous retrovirus, HERVH51. HERVH has been co-opted for this cellular function and the HERVH-based regulatory network helps to understand why embryonic stem cells are genuinely different between mouse and human. Using HERVH as a reporter it was possible to discover human naïve-like stem cells that are generally present in human embryonic stem cell cultures. The HERVH system could be a powerful tool for enabling optimisation of naïve-like hPSC culture conditions. This work has major ramifications for understanding how humans develop and for new technologies to provide cures for many diseases.  It also leaves an unexplained evolutionary enigma. As the HERVH-based regulatory network does not exist in mice, we cannot expect the human naïve to have the same defining features as murine naïve cells. Her team suggests that the human naïve cells should be compared to human inner cell mass (ICM) instead of mouse naïve cells.
 
In summary, Zsuzsanna Izsvák is a pioneer on the field of TE research in vertebrates. Her focus is to understand the basic mechanism of transposition and the interplay between TEs and host cells in mammals. Her team integrates basic knowledge with technologies that are revolutionizing genomic manipulations in vertebrate species, including gene therapy, transgenesis, cancer research and functional genomics. The other objective of her research is to investigate the impact of TE-derived activities on the vertebrate genome. To model how a vertebrate-specific transposon senses and responds to cellular signals of the host organism, she studies molecular interactions of transposons with host cellular mechanisms. Her studies highlights evolutionary processes that seem to “recycle” the inactive TEs, co-opt them for novel cellular function, and argue against the dogma that views them exclusively as parasites or “junk” DNA.