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Marc Bickle: A Quest for Cell Culture Relevance

Marc Bickle, Ph.D., is fascinated with cell culture and its link to life sciences. He is also obsessed with data quantification. His interests led him from researching worms to yeast to high-content screening and beyond.

 

"A common thread through my career has been that I was always interested in life and was highly suspicious about cell culture," says Bickle, an SLAS2015 Short Course Instructor, a board member for the SLAS Europe Council, and a Journal of Biomolecular Screening (JBS) Editorial Board member, JBS special issue guest editor and author. "I understood that many fundamental processes could be studied in cell culture systems, but I found that their relevance to life was limited."

His quest for relevance eventually led Bickle to his current position as the head of the Technology Development Studio (TDS) of the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany. TDS is an open-access screening facility specializing in high-content screening (HCS) of RNAi and chemical libraries. Using open source software to allow its clients to recreate analytical workflows in their own laboratories, TDS provides assay development toward high-throughput screening (HTS) applications and HCS services.

"When I started at the TDS in 2008, cell culture, particularly HeLa cells, were prominent," Bickle continues. "This luckily coincided with a general shift toward more complex systems using 3D mixed cell cultures, primary cells or stem cells." These advances, according to Bickle, will considerably improve the drug discovery process as it allows for screening in physiologically relevant assay systems and will improve the predictability of screens.

He observes that cell culture has not had an exciting history apart from its beginnings, where establishing the techniques were a massive challenge, but now the future is teaming with possibilities. "I am pleased that we also run screens on small organisms, since they are true free living organisms, even though they are grown and bred in the laboratory." Bickle's work at TDS has helped him connect with people from many different backgrounds and who possess a variety of goals. "I believe this has broadened my horizon and given me great professional experience by helping me to tackle various issues efficiently," he shares.

Another avenue broadening his professional experience is membership in SLAS. "SLAS is a great community for networking with peers. Discussions, exchange of information and comparison of methods are very important in the rapidly evolving field of HCS," says Bickle, who joins Hakim Djaballah, Ph.D., of Institut Pasteur Korea in Seongnam, South Korea, and Lorenz M. Mayr, Ph.D., of AstraZeneca in Alderley Park, UK, as guest editors for the 2015 JBS special issue, Screening by RNAi and Precise Genome Editing Technologies.

"RNAi technology has had a tumultuous past," Bickle says. "It first generated a lot of enthusiasm promising to introduce genetic approaches to mammalian cell culture to find new targets and as a therapeutic agent. That enthusiasm was quickly damped by the discovery of off-target effects and publication of irreproducibility of similar screens in various laboratories." He explains that now interest is coming back to the technology because scientists have learned to handle some aspects of off-target effects and have had some recent success in using RNAi for therapeutics.

"Genome editing is the new kid on the block and with that comes great expectations," Bickle continues. "Now is a good time to review and discuss what has been accomplished to date."

The JBS guest editor post is Bickle's second major role as a new member of the JBS Editorial Board. The first was an opportunity to represent SLAS, JBS and the Journal of Laboratory Automation (JALA) at the European Laboratory Robotics Interest Group's (ELRIG) Drug Discovery 2014 conference. Bickle presented an SLAS Authors Workshop, entitled "How to Get Your Work Published" in which he reviewed what editors want, what they don't want and how reviewers evaluate manuscripts – something with which he is intently familiar as the JBS special issue comes together. Bickle also served as chair of the phenotypic discovery and cellular imaging presentations at the event.

Another opportunity to share knowledge is Bickle's turn as an SLAS2015 Short Course instructor. He will join Eberhard Krausz in leading "High Content Screening: Instrumentation, Assay Development, Screening, Image and Data Analysis" on Sunday, February 8, 2015. During the session, which he also presented in September at the ELRIG conference, Bickle will discuss aspects of image processing and multi-parametric analysis and introduce participants to the open source software tools he uses at TDS.

"I hope to show people the principles of image analysis and especially convey the message that image analysis starts at the bench," says Bickle. "It is a common problem for analysts: they receive data that is not adequate for analysis, because controls are missing, sampling is too small or the type of data is wrong for the problem at hand. If biologists understand the analytical pipelines (both for images and their features) they can design their experiments better."

In the statistical analysis part of the course, Bickle will communicate the interesting relationship of multiple parameters, which he recommends others should investigate thoroughly, and will show how to represent such data in order for scientists to gain an intuitive understanding of phenotypic profiles.

"A passion of mine in biology is the quantification of data. I was not always like this, especially when I started in the lab," Bickle explains. "Computational tools were limited and required scripting skills I did not have. My image analysis was limited to looking down the microscope, seeing how many clear phenotypes I could find and then having colleagues come to the microscope, count 100 objects and classify them in the phenotypic classes I had determined previously. Still these were not computational methods and suffered from human limitations, especially my own."

When he joined a biotech company in France, Bickle developed HTS where qualitative observations were simply not enough. "I started using Excel more seriously and over the years have used more sophisticated tools and learned scripting, he says. "This has radically changed my approach to biology and I have become somewhat of a maniac of quantification."

Bickle finds that understanding all steps of screening is beneficial for the quality of the output. "I think you should never stop learning and should always embrace new challenges that arise in your career even if they are daunting. It helps maintain interest in the job," he says.

Inspired by the Cell

Bickle's intense interest in biology dates back to high school when he first encountered the Jacques Monod model of transcription, translation and cell biology of eukaryotic cells – all of which sparked Bickle's imagination.

"I was always interested in physics and mathematics, but was unsure about my future career. These few lessons about cell and molecular biology set me on fire," he says, adding that in an ironic twist, his teacher hated molecular biology and only taught the minimum that was required for the curriculum. This did not hold back the eager student.

Bickle's journey continued at The Biozentrum, University of Basel in Switzerland where he eventually earned his Ph.D. While there, he studied the immunosuppressive drug Rapamycin, and helped identify its mode of action. He then went to the Medical Research Council's (MRC) Laboratory of Molecular Biology (LMB) in Cambridge, U.K., to study the genetics of behavior in Caenorhabditis elegans (C. Elegans), and later participated in the creation of Aptanomics, a drug discovery Biotech in Lyon, France, where he set up several yeast two-hybrid screening systems.

Throughout his transition from studies to professional work, Bickle says that a great obstacle was the lack of IT people or statisticians with whom to collaborate. "This meant that we had to learn everything from scratch using online material, books and we had lots of internal discussions," he says. "When I started working in HCS, the entire field was looking for methods to deal with multi-parametric data, compare phenotype amplitude and measure distance between phenotypes. Many of these problems now have well established solutions, but at the time they were a challenge. Having no analyst when I arrived in the TDS made our progress harder."

This obstacle, however, turned into a team builder. The lack of IT and statisticians forced all members of the facility to collaborate to acquire skills. "This had two main advantages," he explains. "One, having to work out the methods, learning to code and do the math helped to forge a closely knit team, and two, since all scientists of the facility were able to carry out all the steps of screening – assay development, screening, image analysis, statistics – our time to develop and run screens was considerably shortened and the quality increased."

A further obstacle Bickle discovered were the issues surrounding proprietary software used in HCS. "As an academic screening center, funds are limited and paying yearly fees for several licenses of image analysis or statistic software was not on the table," Bickle comments. "Vendor software closed clients in with their proprietary formats instead of opening up and allowing users to share and contribute. As a consequence, the users ended up using expensive software that often do not fulfill their requirements and whose output is difficult to share. Luckily, plenty of open source software exists to go around those constraints."

Supporting New Initiatives

Bringing his collaborative efforts to the SLAS Europe Council is Bickle's next exciting opportunity. He was one of two new members elected to the Council for three-year terms that begin in January 2015. Bickle, who has been active in SLAS Europe since its beginning in 2012, hopes to use his background in an academic screening facility to bridge partnerships between academia and industry on the Council.

"I am excited by this new multidisciplinary era and will facilitate the exchange of knowledge between the fields," says Bickle, who added that many factors, from the sequencing of the human genome to advances in computer sciences, have profoundly changed the way biological science is conducted. "These new technologies require that experts in different fields come together to bring those changes to bear in the drug discovery world."

In a similar consortium, Bickle also represents TDS in a new initiative called Core for Life (C4L), an alliance of core facilities in six institutes across the Europe Union that pool resources to buy state-of-the-art equipment and share the tools as soon as they become available. "The association is young and the various workgroups are developing areas where collaboration will be most beneficial," says Bickle, who serves on the Technology Work Group for screening. "One of the aims is to exchange protocols, share reagents and be able to share workloads during periods of high demand," comments Bickle. "We hope to promote the model of running facilities in this way and foster exchange between the various platforms." He credits his collaborative experiences within SLAS as supporting his interactions in C4L.

Core facility management and aligning cooperative opportunities are an up-and-coming career path in the laboratory profession, Bickle says. "There's no managerial school to measure performance of a core facility. You need experts to run those platforms. It would be great to explore this in an SLAS special interest group."

Time to Recharge

This busy schedule runs Bickle right out of the lab most days for a mid-day jog. The avid triathlete often takes a lunchtime run in a nearby forest to clear his head.

"Since I am sitting most of the day at the computer, it gives me a nice break during the day and an opportunity to get some air," he comments. After work, he spends time with his sons, ages 8 and 11. "We discuss their day and they tell me their news, such as the latest things happening with Pokémon and soccer," continues Bickle. In the midst of a busy family life, he also makes time to play his baroque recorders and teaches Karate and Kobudo. Once the kids are in bed, however, it's time to train once again.

"Most days I train in the evening at a gym, martial arts school or swimming pool. I find that sports allow me to attain a good equilibrium in my life," says Bickle. Although he typically participates in two triathlon events each year, he was sidelined for a bit in 2014 with a knee injury, but managed to run in a marathon in May 2014 near Dresden. "Luckily, I do not have a television and so still have time for family, music and reading!"

December 8, 2014