I grew up in Stockholm, Sweden. After attending 4 years of college studies in the USA, I landed a graduate student position in the lab of Professor Gunnar Ahnström at Stockholm University in Sweden. My thesis was entitled “The role of chromatin in the induction and repair of DNA damage”. I performed my postdoctoral work, in the laboratory of Dr. Phil Hanawalt at Stanford University, where I developed a new technique that uses the ability of psoralen to “sense” torsional tension in DNA to probe for “unconstrained DNA torsional tension” in the genomes of living cells. In 1994, my family and I moved to Ann Arbor where I became Assistant Professor in the Department of Radiation Oncology at the University of Michigan Medical School where I have been ever since. My early work identified blockage of transcription as a major trigger of p53 and apoptosis after DNA damage. To map transcription genome-wide and to investigate the effect of DNA damage on ongoing transcription we developed Bru-seq, which is based on bromouridine labeling of nascent RNA followed by immunocapturing and deep sequencing of the Bru-labeled RNA. We were fortunate to be invited to ENCODE3 to develop these techniques and to ENCODE4 where we now participate as a mapping center. We recently developed Precision KLIPP Therapy as a universal and specific cancer-targeting approach and are working on bringing it to the clinic.
Our lab has been a member of and funded by the ENCODE Consortium since 2012. During ENCODE III we were one of the “Technology development groups” developing our nascent RNA Bru-seq techniques and during ENCODE IV we are one of 8 “Mapping Centers” where we are using our Bru-seq technique to profile the transcriptional and post-transcriptional profiles across many cell types as well as assessing co-transcriptional splicing and mapping active enhancer elements genome-wide. This is a very computational focused project working with big data sets across multiple cell lines. One of the projects are exploring the immediate transcriptional response following exposure to ionizing radiation across 16 cell lines, many of them cancer cell lines. This study should yield important novel insights about how cell re-program their transcriptome to respond ionizing radiation and could lead to the identification of new pathways for radiosensitization.
2) RNA Exosome
In this project we are exploring the quality control mechanisms that cells use to purge the transcriptome of certain RNA species such as enhancer RNA (eRNA) and aberrantly spliced transcripts. The RNA exosome degradation complex is the focus and we are performing studies using cell lines where we can induce rapid degradation of key components of the RNA exosome using auxin. Our hypothesis is that the RNA exosome may be an impactful cancer therapy target. In collaboration with Nouri Neamati and his lab, we have set up a high throughput screening assay and we have screened >80,000 small molecules and are currently performing validation studies of our preliminary positive hits from the screen. The long-term goal is to test the lead compounds for their anti-cancer activities in mouse models and potentially in clinical trials.
3) Precision targeting of cancer with CRISPR
The innovation of this CRISPR approach is that it targets cancer-specific chromosome rearrangement junctions (CRJ), common to almost all tumors. We have called this approach “Precision KLIPP therapy” and it is based on the use of a “split” enzyme approach consisting of inactivated dCas9 fused to the endonuclease Fok1 (Fok1-dCas9). To activate the Fok1 endonucleases, two Fok1 proteins need to homodimerize; this will occur by using CRJ-targeting guide RNAs to nucleate two Fok1-dCas9 complexes at the CRJ, leading to the specific induction of DNA double strand breaks (DSBs). We have obtained strong proof-of-concept for good efficacy of this approach in cell systems and are now developing lipid nanoparticles to deliver the CRISPR reagents to tumors in vivo. After obtaining in vivo data supporting a tumor inhibiting activity, we intend to set up clinical trials initially for bladder cancer and subsequently for other tumors. The long-term goal is to develop personalized KLIPP Therapy based on whole genome sequence information from patient’s tumors and to rapidly synthesize CRISPR reagents, package them in lipid nanoparticles and provide this medicine to individual patients.
Research Opportunities for Rotating Students
- First Generation College Student
- First Generation U.S. Citizen