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After a postdoc spent exploring the first phase of the cell cycle, Manuel Kaulich was recruited as a group leader at Goethe-Universität Frankfurt am Main in December 2015. His lab’s first paper, published in eLife in March, describes a new technology that allows researchers to produce high quality reagents for use in gene-editing experiments.
Most people stopped asking me after my first year of college because I can’t stop talking about my work! In short, we apply genetic screening systems and aim to understand how cells become cancerous and drug resistant.
In 2013, while I was a postdoc, I met Ivan Dikic at the cell cycle conference at the Salk institute and we had great fun discussing science. A year later he asked me if I ever thought about my future, because they had an open position and could really use my expertise in Frankfurt. I applied and he invited me to visit, and it was a fantastic day. I gave a 45 minute job talk, and the audience was so interested in my research that I spent another two hours answering questions. Shortly after my visit the committee in Frankfurt offered the position to me.
The toughest thing was to identify my own weaknesses and compensate for them by bringing the missing expertise to the lab. For me, that meant recruiting computational engineers and bioinformaticians. Another challenge was that, coming from the US, I had no network in Germany and didn’t know anything about the German funding system. What I needed was strategic mentoring, which I think is extremely critical for young group leaders. Ivan is amazing for this task – he cares for early-career scientists in the department by giving advice and introducing them to research networks and people. I learnt a lot from him about how to strategically position myself and my lab in order to become successful.
The first independent data was the most rewarding moment in my scientific life so far. What we did was extremely risky – we decided to first establish a new technology to then follow our biological questions. But it was extremely rewarding when it worked, and it generated so much enthusiasm and motivation for everyone in the lab. All of our projects are based on this technology now.
We established a method to generate ‘libraries’ of gRNAs used in CRISPR gene-editing experiments that is rapid and does not involve conventional cloning. These libraries are used to generate pools of virus particles that can precisely induce gene editing events in cells, allowing researchers to perform screens to investigate how this change affects the activity of a particular gene. Our new technology is a robust alternative to existing methods because the quality of the final library stays at a constant high level, no matter how many gRNAs the library contains.
One of the students in the lab wanted to make a small focused CRISPR library. We tried to make it using most of the methods that were reported to work, but we failed miserably. The quality of the library was just terrible. I didn’t know if that was normal, because there is not much literature about it. But when we analysed other libraries, we realised that quality is a general problem.
At the time, I shared an office with Andreas Ernst, who uses directed evolution and phage display to develop inhibitors based on ubiquitin and ubiquitin-like proteins. One day, when we talked about our different technologies, the idea emerged to apply the Kunkel mutagenesis method established in his lab to solve the problem we were encountering. My lab then went on to combine it with the CRISPR/Cas technology and it worked immediately. We were surprised that nobody had ever tried this.
I gave talks about the data at two meetings, before it had been published. At each meeting I was approached by a different editor of the same journal, and they asked us to submit the paper to them. When we submitted, it was immediately sent out for review. Two reviewers were fairly positive: constructive criticism, but everything doable. But the other two were destructive and it was really difficult to explain those comments to the graduate students who had done the work. I felt the editor could have taken a stronger stand and indicated to the reviewers that what they’d written wasn’t a detailed and factual review, it was just putting a paper down.
We took the comments as a challenge, and we worked on revisions for another half a year. We transferred the paper to another journal at the same publisher, and they sent it to the same reviewers as before. The first two reviewers thought the paper was fine with minor changes, but the other two said no, and the paper was rejected. I wanted to argue with the reviewers, but Ivan advised me to submit to another journal. We decided to send the paper to eLife, which provided a constructive, fast and factual review process. We were asked for some experimental and textual changes, and after one round of revision the paper was accepted.
I wish there could be more transparency and open discussions among reviewers to reach a consensus, similar to what eLife does. Also, sometimes one can observe differences in handling manuscripts for younger scientists when compared to established scientists. Part of it I understand because established scientists have proven that they deserve the trust. Nevertheless, this is a credit that can be misused, and it also makes it harder for younger PIs to enter the field.
When we have smaller moments of celebration we go to the Trinkhalle, these little kiosks where people stand and drink their beer. But I have a French wife and her father likes good wine and champagne. He always stocks our fridge, so I took one of the really good bottles to the lab and said OK, this is a proper celebration.
So far, we have only published that the technology works if you are screening for effects on a single gene. But we are advanced in demonstrating that this technology works robustly for gRNA combinations, where multiple genes are examined simultaneously. There is currently no technology in the field that can robustly do this. Spoiler alert – it’s really impressive.
We’ve taken a little detour in technology development, and now we are coming back to applying our technologies to biological questions. If you have a unique technology you have a strategic advantage because you can ask questions nobody else can ask. There are some crazy ideas: people now think about multiplexing the entire human genome, though from a technological point of view we are not there yet.
We have almost too many. A year and a half ago it had reached a point that students in the lab were complaining because they couldn’t work on their own projects, they were only providing reagents for other people. Ivan and I discussed this matter and soon after we established the Frankfurt CRISPR/Cas Screening Facility (FCSC) that supports our academic collaborations. In addition, together with the Goethe University we have founded a start-up company that provides reagents to everyone in the international community.
Be curious, be ambitious. During the first two years of having your own lab you enjoy incredible freedom to test new ideas and turn them into something that people will associate with you. Take a calculated risk; it can be career making.
2019–present: Chief Scientific Officer, Vivlion GmbH
2016–present: Head, Frankfurt CRISPR/Cas9 Screening Center (FCSC), Goethe University Frankfurt, Germany
2015–present: Group Leader, Goethe University Frankfurt, Germany
2011–2015: Postdoc, University of California, San Diego, USA
2009–2011: PhD, Biocenter Basel, Basel, Switzerland
2006–2009: PhD, MPI of Biochemistry, Martinsried, Germany
2004–2006: MSc, University of Lübeck, Germany
2001–2004: BSc, University of Lübeck, Germany