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Michal Zimmermann and his efforts to improve cancer drug efficacy

2018-07-19

Michal was born and raised in the Czech Republic and completed his PhD at Rockefeller University in New York. He has been working in Dan Durocher’s Lab for the past four years as a post-doctoral fellow. During his PhD he studied telomeres, the structures found at the end of chromosomes to protect them from being cut back during cell replication and becoming damaged. This ties directly into his work in the Durocher Lab which is one reason why Michal decided to work at the LTRI. He read papers from the lab and saw connections between the two. The Durocher lab focuses on how cells repair DNA following damage. If mutations or breaks DNA are not properly repaired, the integrity of the genome is lost which can lead to cancer. Each of our billions of cells sustains damage up to 70,000 times every day so the cellular systems designed to detect and repair such damage must be incredibly efficient and effective.

Michal Zimmermann
Michal Zimmermann

Michal recently completed a study as lead author, along with collaborators at the Institute of Genetics and Molecular Medicine at the University of Edinburgh. He and the team looked at an enzyme termed poly(ADP-ribose) polymerase (PARP) which helps to repair single-stranded breaks in DNA. Along with PARP, the BRCA1 and BRCA2 proteins are also important in repairing DNA damage. The BRCA1/2 proteins use an error-free method to repair breaks called homologous recombination (HR) which is done using by pairing identical molecule of DNA from a second chromosome to ensure it is repaired with the correct nucleotide sequences through exchanging strands of the DNA. Mutations in either of BRCA1/2 leads to errors in the repair which can promote breast and ovarian cancer. When PARP is inhibited, it cannot repair DNA breaks, but rather stays bound (‘trapped’) at the breaks, which creates a bulky obstacle to DNA replication. This leads to damaged DNA that BRCA1/2 tumor are unable to repair and therefore lose viability. An advantage of this treatment is that PARP inhibition does not affect normal cells as they don’t replicate as often as cancer cells and it doesn’t affect those with non-mutated BRCA1/2 as these proteins are still able to undergo HR mediated repair. In the new study the team identified 73 genes that when mutated significantly increased sensitivity to PARP inhibition, which then increases cancer cell death. As a result of this work, the team not only increased understanding of the processes affecting PARP-mediated DNA damage repair but also uncovered potential new mutations that may help to expand the use of PARP inhibitors beyond BRCA1/2. In particular, they found that mutations in an enzyme called RNase H2 cause PARP inhibitor sensitivity independently of BRCA1/2. RNase H2 removes bits of RNA that are often mistakenly incorporated into DNA during DNA replication. When RNase H2 is inactive, these pieces of RNA are processed in a manner that engages PARP and increases toxic PARP trapping after PARP inhibition, leading to cell death. This finding prompts to explore whether PARP inhibitors could be used against cancers with mutations in RNase H2, such as some cases of chronic lymphocytic leukemia and metastatic prostate cancer.

Michal describes himself as nerdy yet curious which helps to motivate him within the lab. He also enjoys solving puzzles and relishes the possibility of being able to discover something that nobody else has seen before. Outside of the lab you can find Michal listening to music, playing the guitar and going to shows. When working in a lab there can be many challenges or setbacks. Michal tries to keep a positive mindset by not taking the failures personally and uses running, another one of his hobbies, as an outlet to clear his mind, so the next day he can try again.

Michal enjoys working with other trainees in the lab and having the ability to bounce ideas off of each other. He finds it very stimulating and motivating when an experiment works and the moment he enjoys most is when he sees results for the first time. The main challenge that Michal has had throughout his studies was during his undergrad when he was trying to figure out where he wanted to go within sciences. One piece of advice Michal has to those wishing to pursue a career in sciences is to read widely within and on the periphery of your field and then new questions and answers should naturally start coming to you. This will help to guide where you want to go.

Michal’s overreaching goal is to contribute to either human health or knowledge in a tangible way. Michal has recently accepted a position working for a pharmaceutical company where he can pursue his dream of developing better treatments for disease.

 

Ref.: https://www.nature.com/articles/s41586-018-0291-z

 

By Sophie Lily Polan

          
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