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CRISPR: An Interview with the Director of the Leibniz Institute for Molecular Pharmacology (FMP)

5/8/2017

By: Julia John-Scheder

CRISPR: An Interview with the Director of the Leibniz Institute for Molecular Pharmacology (FMP)

The German Center for Research and Innovation (GCRI) conducted an interview with Prof. Dr. Volker Haucke, a biochemist, cell biologist and the director of the Leibniz Institute for Molecular Pharmacology (FMP). The FMP conducts basic research in Molecular Pharmacology with the goal of identifying novel bioactive molecules and characterizing their interactions with their biological targets in cells or organisms. The Haucke laboratory’s primary focus is the dissection of the molecular mechanisms of endocytosis and endolysosomal membrane dynamics and its role in cell signaling and neurotransmission.

Prof. Dr. Haucke is also a professor of Molecular Pharmacology at the Freie Universität Berlin and a faculty member at the Charité - Universitätsmedizin Berlin. We asked Prof. Dr. Haucke about his research involving the gene-editing technology CRISPR/Cas9 future developments in this area, as well as concerns about the misuse of the CRISPR tool.

When and how did you first hear/read about the CRISPR/Cas9 technology? How has it changed your work life?

The system was discovered back in 2011/ 2012, largely by the work of Emmanuelle Charpentier, who, at the time was at the Umeå University and is now in Berlin, as well as Jennifer Doudna from UC Berkeley. It became more widely known in 2013 when Feng Zhang from the Broad Institute successfully applied the system to genome engineer eukaryotic cells and was named one of the breakthrough discoveries by both Nature and Science magazine. My own lab, like many others, started to use the CRISPR/Cas9 technology soon after, as it allows us to genome engineer cells on a hitherto unknown time scale at the cellular level. The implications for our own work have been multifold: We are now capable of knocking out genes to produce mutant cell lines, if all works well, in a matter of weeks. These cells often have replaced the use of RNA interference, which may result in incomplete loss of gene expression and, hence, hypomorphic phenotypes. Of particular value has been the insertion of fluorescent protein tags that allow us to visualize proteins in action in real cells when expressed from their endogenous locus. This opens up many possibilities for cell biology to study proteins for which antibodies are unavailable or to determine exact protein copy numbers in a cell or even a subcellular compartment such as an endocytic vesicle.

What research involving the CRISPR technology are you working on now?

We use CRISPR/Cas9 for a variety of applications although we do not exclusively rely on the technology. We study membrane dynamics in endocytosis and the endolysosomal system, and its relationship to signaling and development, for example in the nervous system. In one project we use genome-engineered cells to determine how many copies of a given protein are present when an endocytic vesicles forms at the cell's surrounding membrane. This for the first time allows us to get a quantitative understanding of these uptake processes that also many viruses and bacteria hijack to get access to the cell interior. In a current project we have studied a hitherto poorly understood lipid kinase and its role in nutrient signaling at organelles called lysosomes that can monitor and respond to nutrient status. CRISPR/Cas9 allows us to tag the endogenous enzyme with a fluorescent protein and now we can see the enzyme moving within the cell. Finally, we are using genome-wide approaches to identify new factors involved in macropinocytic uptake of molecules in antigen-presenting immune cells. All of these exciting studies would be much more complicated, if not impossible, without CRISPR/Cas9.

What kind of developments might we see down the road?

In plant biotechnology, CRISPR holds great promise when it comes to any kind of modification, because it now allows the precise re-engineering of the plant genome rather than transgenes that may have side effects due to the way they are inserted. In fact, we are much closer to what nature does to change genes; it’s just that we can do this nearly at will now. For human therapies, it offers the potential to correct a mutation in a specific gene and thereby allows for a true cure for rare diseases, if side effects can be avoided and specificity is guaranteed. A more immediate impact is on the development of tailored models for human disease, e.g. by CRISPR-based genome engineering of mice, fish etc. or stem cell-based systems to study development.

What are your concerns about the misuse of the CRISPR tool?

Any technology can be misused and, hence, science needs to take the lead in discussing these issues openly with the general public and with politicians. In the case of genome-engineering there will be ethical issues when it comes to its application in humans that require public debate, for example regarding the use of patient-derived stem cells vs. embryonic stem cells.

What does the public need to know?

As always in basic science, it takes a while until the limits and caveats of new technology become overt. In the case of genome engineering such concerns pertain to the specificity of the genomic alteration as well as to possible side effects of Cas9 or related "scissors" that cut the DNA. Though times are exciting, it certainly is good to remain somewhat cautious regarding possible risk. Moreover, one needs to see whether all that can be done really will also find the financial resources it needs to develop specific therapies. In that sense, public funding for basic science is more important than it ever was as we have to rely on facts and data - with no alternative.

Read about German innovations in CRISPR here.

Here is a video from our CRISPR Event, Applications of CRISPR Technologies in Research and Industry from March 30th, 2017: