How did you get interested in Medicinal Chemistry and Chemical Biology?
I was intrigued by the question which structural features make small molecules bioactive and relevant to biology? We then devised new principles and concepts for bioactive compound design (inspired by natural product structures, i.e. classes of compounds that are biologically relevant by definition), developed the corresponding synthesis programs (including new enantioselective catalysis methods), evaluated the new compounds in unbiased phenotypic assays, identified and validated the targets, and finally explored the most promising compounds in disease-relevant settings. This continuum of investigations defines chemical biology research leading straight into medicinal chemistry.
Where and when did you obtain your PhD diploma?
I graduated from the University of Mainz in 1985. My thesis focussed on the development of new protecting group strategies for glycopeptide synthesis. Working in the group of Horst Kunz, I introduced the allyl ester into glycoconjugate synthesis. Afterwards, I did my Post Doc with George Whitesides at Harvard University in 1985-1986.
Where are you currently working and what is your current position?
I jointly hold positions as Director of the Department of Chemical Biology at the Max-Planck-Institute of Molecular Physiology in Dortmund and as Full Professor of Biochemistry in the Faculty of Chemistry and Chemical Biology at TU Dortmund.
My work requires being a scientist and researcher, teacher, mentor, manager, advisor, consultant, company founder, ….. (as holds for many, if not all of my peer group).
What are your current research interests?
The underlying question described above has been a consistent motivation for my group. We are a team of organic chemists, biochemists, biologists and computer scientists which fuse these disciplines into chemical biology research. We develop new concepts for bioactive compound design (now integrating underlying principles of chemical evolution), synthesize these compounds, including the development of new methods, e.g. in enantioselective catalysis, investigate the resulting compound collections in target-agnostic phenotypic and morphological cellular assays and then identify the cellular targets and modes of actions of the new bioactive compounds, and if these are related to human disease we advance them into drug discovery. This multidisciplinary program has given rise to a “Chemical Evolution of Natural Product Structure”, and “Pseudo-Natural Products” now in preclinical investigation.
What do you like best about your work?
The freedom to work on what interests me most, and the singular moments of discovery and insight.
What kind of skills does your work require?
Most important is the ability to repeatedly generate good ideas, see underlying principles behind data sets and derive new concepts and principles from them which will then guide future research. But people skills and the ability to motivate come next. In science being a good communicator is of high importance. And, finally, a certain degree of robustness, both mental and physical, is required. Personally, for long-time success, I try to consistently operate at 95% of my maximal capacity (which requires that the 100% threshold has been identified), which leaves sufficient bandwidth to go beyond 100% on short notice and whenever required.
How many PhD students and postdocs do you currently supervise? Are you currently looking for a new PhD student or a postdoc?
Currently, we are a group of ca. 25 students, Post Docs, Senior Scientists and associates. Applications by excellent Post Doc candidates are always welcome. Since I will adopt Emeritus status in the coming years, I do not accept Ph. D. students in my group anymore.
How would you describe yourself as a supervisor?
Good science needs the air of freedom to explore own ideas and to be creative, and I leave my students and Post Docs the required room. Certainly, I am demanding, and all members of my group work hard. But I will always welcome a good beer on a Friday afternoon and a barbecue on the terrace adjacent to the lab. The social atmosphere in a group is of high importance.
What are the features of a successful PhD student or postdoc?
Be rich in creative ideas, boldly tackle them, work hard to reach your goals and differentiate the doable from the unreachable. In other words: inspiration, motivation, transpiration.
What would you like to ask from other medicinal chemists?
Don´t be dogmatic (dogma never helps), and don´t be shy to embrace new developments and new fields. After all, the ultimate goal is to cure diseases. The patient does not care whether this is achieved by a small molecule, a peptide, a protein or a nucleic acid vaccine. These are all chemical entities, hence their discovery and development needs medicinal chemists.
Have you experienced any unfair situations during your scientific career? How would you advise scientists facing similar situations?
At times reviews (for instance of papers and applications, or by company-internal Boards) are perceived unfair, but I cannot say that I faced such an outcome too often. In my experience, taking such situations easy and not being too annoyed (of course, there is annoyance; nobody wants to be rejected) helps. Take out emotions, sleep over it once, and then react, tomorrow will be a new day. You win a few, you lose a few … let´s continue.
What do you consider your greatest achievement in your scientific career?
I consider the discovery of general concepts to guide organic synthesis for chemical biology and medicinal chemistry, as the work that will have widest and long-lasting impact. We progressed from natural products and Biology-Oriented Synthesis to Pseudo-Natural Products and a chemical evolution of natural product structure.
Which of your papers are you most proud of and why?
The concepts have been developed and proven in a series of papers. They are detailed in three Concept articles in Nature Chemistry (2020), Angewandte Chemie Int. Ed. (2021) and the Journal of the American Chemical Society (2022). The original Biology-Oriented Synthesis idea was developed in three papers in the Proceedings of the National Academy of Sciences in 2004-6, and the Pseudo-Natural Product principle was first described in a Nature Chemistry paper in 2018.
What is the most embarrassing thing you have done in the lab while doing experiments, e.g. explosions?
In the introductory organic chemistry lab course, I managed to explode a small flask I held in my hand. Fortunately, there were no serious consequences. This experience taught me to be cautious, and I never had to face such an accident again.
What are your recommendations for a book, podcast, website, blog, YouTube channel or film?
For Medicinal Chemists I recommend “The Billion Dollar Molecule” and its congener “The Antidote” (both by Barry Worth). This case-study showcases the rise of the Biotech era in the few square meters around Kendall Square, Cambridge, Ma since the mid-eighties. It is entertaining to read (you will know the main characters), and gives an insight into the early days of the Biotech Industry. Those who know Kendall Square in 1986 and 35 years later may have good stories to tell at dinner.
Which scientist do you admire the most and why?
I am fascinated by Justus von Liebig and Emil Fischer. Liebig is considered the Founder of Organic Chemistry and of Agricultural Chemistry and worked on Physiology as well. Fischer raised Organic Chemistry to unprecedented heights (beautifully showcases for instance in his first total syntheses of carbohydrates), and his research ranged from amino acids and saccharides through heterocycles and peptides to proteins and enzymes. He proposed the “lock and key” principle.
Which field of medicinal chemistry do you consider the most promising for the future?
Among the therapeutic areas I note a rising interest and promise in targeting immunological disorders, and I have shifted much of my own interest there. In terms of targets, modulation of RNAs and of transcription factors hold a lot of promise. We will have to be open to different chemical modalities.
What would you expect to be the next major breakthrough in medicinal chemistry?
We will learn how to systematically identify and develop small molecules that will not inhibit or activate their targets, but that will induce modulation of their activity by different mechanisms and modes of action. Induced target degradation is a first example for this generation of drug discovery programs.
