A Pioneer of Directed Evolution in Catalysis: Manfred T. Reetz (1943‐2026)

Manfred T. Reetz (Figure 1), one of the most influential and creative figures in modern catalysis, passed away on April 23, 2026.

FIGURE 1.

Manfred T. Reetz after receiving the Biotrans Award (2017, Budapest) one of his numerous awards (including Leibniz‐, Karl‐Ziegler‐, ACS Arthur C. Cope‐, Tetrahedron‐, Otto Hahn‐, and Ryoji Noyory Prize).

His scientific work, spanning more than five decades, is remarkable for its breadth, originality and enduring impact. From fundamental contributions to organometallic chemistry to the conceptual and methodological foundations of directed evolution of enzymes, Reetz shaped the way chemists think today about catalysis. His work bridged disciplines that were once considered separate including synthetic organic chemistry, computational/theoretical chemistry, molecular biology, enzymology, bioinformatics and statistics, ultimately helping to establish biocatalysis as a central tool in chemical synthesis and biotechnology.

Manfred T. Reetz was born 1943 in Jelenia Góra (formerly: Hirschberg) and studied chemistry at Washington University in St. Louis and the University of Michigan. He obtained his doctorate from the University of Göttingen under the supervision of Ulrich Schöllkopf (1967–1969). Following postdoctoral work with Reinhard W. Hoffmann, he began his independent career in Marburg in the early 1970s.

In his first scientific period, Reetz established himself as a leading figure in organic and organometallic chemistry. He introduced the concept of dyotropic rearrangements, providing a new class of symmetry‐allowed transformations to synthetic chemistry. His work on organotitanium chemistry and Lewis acid catalysis solved longstanding challenges, such as the α‐tertiary alkylation of carbonyl compounds and enabled new strategies for stereoselective synthesis. Importantly, many of these studies were accompanied by quantum chemical investigations, reflecting his early appreciation of the synergy between experiment and theory.

By 1991, when he moved to the Max‐Planck‐Institut für Kohlenforschung in Mülheim an der Ruhr (Germany) as Director, Reetz had published about 200 papers and was widely recognised as a leading organic chemist. He played a decisive role in reshaping the institute, establishing a structure centred on multiple independent catalysis departments. This transformation required considerable vision and determination and has had a lasting impact on the institute's scientific profile. Many in such a position might have chosen to consolidate their standing and turn their attention primarily to science policy and representational duties; Manfred Reetz, however, was not one to shy away from new scientific adventures.

In fact, the most profound turning point in Reetz's career came in the mid‐1990s, when he entered the field of biocatalysis. In the early 1990s biocatalysis was valued mainly for highly selective transformations such as kinetic resolutions, but it remained limited by narrow substrate scope and the lack of effective enzyme engineering tools. As a result, it was seen as a specialised complement to traditional catalysis rather than a general strategy for organic synthesis. At a time when directed evolution was primarily associated with improving enzyme stability, Reetz recognised its potential as a tool for controlling stereoselectivity in organic synthesis. This insight, both simple and revolutionary, marked the beginning of a new era. He demonstrated that iterative cycles of mutagenesis and screening could be used to evolve enzymes with tailored selectivity, thereby introducing a powerful and general strategy for catalyst development.

The early successes of his group, notably with lipases as enantioselective kinetic resolution catalysts, provided the first convincing demonstrations that enzyme stereoselectivity could be systematically improved by laboratory evolution. However, Reetz's most enduring contribution lies not in individual examples, but in the development of a comprehensive methodological framework. He pioneered the use of saturation mutagenesis at active‐site or highly flexible residues, thereby introducing the Combinatorial Active‐site Saturation Test (CAST) and the B‐Factor Iterative Test (B‐FIT) methods for the engineering of enzyme selectivity and stability, respectively (Figure 2). He also introduced the concept of Iterative Saturation Mutagenesis (ISM) as a systematic approach to exploring protein sequence space in a cost‐effective way, which has been used not only for the CAST and B‐FIT methods, but also for any protein property including activity, binding, allostery, etc. These concepts transformed directed evolution from an empirical technique into a rationally guided methodology.

FIGURE 2.

Directed evolution of improved enzymes by exploring Reetz’ iterative saturation mutagenesis.

A central challenge in directed evolution is the vastness of sequence space, which renders exhaustive screening impossible. Reetz addressed this “numbers problem” through elegant and practical solutions, including the use of reduced amino acid alphabets and statistical tools to optimise library design. His work demonstrated that careful experimental design could dramatically reduce screening effort while maintaining high success rates. In doing so, he laid the foundations for efficient enzyme engineering strategies that are now widely used across academia and industry.

Equally important were his conceptual contributions. Reetz was among the first to recognise the importance of nonadditive, or epistatic, mutational effects in protein evolution. Through systematic deconvolution studies, his group demonstrated that beneficial mutations often act cooperatively, challenging simplistic interpretations of evolutionary pathways. He coined the term “learning from directed evolution” to describe the use of evolved systems as a means of gaining mechanistic insight, and he consistently combined experimental work with computational studies to uncover the molecular origins of catalytic performance.

Reetz also played a key role in integrating computational methods into enzyme engineering. Collaborations with leading theoreticians enabled detailed quantum mechanical and molecular dynamics studies of evolved enzymes, providing unprecedented insight into catalytic mechanisms. In later years, his work anticipated and demonstrated current trends by incorporating machine learning and data‐driven approaches into directed evolution, further enhancing efficiency and predictive power.

Reetz's contributions have been recognised by numerous prestigious national and international awards, reflecting his standing in the global scientific community. Yet, perhaps his greatest legacy lies in the transformation of biocatalysis into a mature and widely applicable discipline By providing chemists with tools to tailor enzymes for specific synthetic tasks, he fundamentally expanded the repertoire of catalysis.

Beyond his scientific achievements, Manfred Reetz was an exceptional mentor and educator. He created an intellectually stimulating and open research environment, encouraging his co‐workers to pursue independent ideas while maintaining rigorous scientific standards. He emphasised the importance of critical thinking, clarity in scientific communication and ethical responsibility in research. Many of his former students and postdoctoral fellows have gone on to successful careers, carrying forward his influence in academia and industry. His continued support for his co‐workers, often long after they had left his group, is remembered with deep gratitude.

Manfred Reetz shaped the field of catalysis in a way that few scientists have done. His ability to connect disciplines, to identify fundamental challenges and to develop elegant solutions was extraordinary. Equally memorable are his intellectual generosity, his openness to unconventional ideas and his enthusiasm for science. He will be remembered and missed not only as a pioneering scientist, but also as an inspiring mentor and a deeply thoughtful colleague.