Charles Weissmann was a giant of 20th century science who created much of the bedrock of modern molecular biology. His discoveries have shaped entire disciplines—molecular biology, immunology, and neurodegeneration—yet he carried his brilliance with humility and good humor. His thinking was defined by precision, intellectual honesty, and a refusal to accept vague explanations. Those who collaborated with him quickly learned that his expectations were high, not out of severity, but out of respect for the scientific enterprise.

 

What made Charles exceptional was not only the originality of his discoveries but also the generosity with which he shared his insight, his time, and his wisdom. He cultivated talent, he challenged assumptions, and he inspired the people around him to think more clearly and to aspire higher. His laboratory was a place where rigor and enthusiasm coexisted, and where scientific ideas were treated with seriousness, curiosity, trepidation and joy.

 

One of Charles Weissmann’s earliest and most enduring contributions was his role in the conceptual and experimental foundations of site-directed mutagenesis—the idea that one could introduce defined, intentional changes into a gene and thereby interrogate biological function with molecular precision. At a time when genetics was still largely descriptive and mutations were mostly accidents of nature or the result of relatively crude chemical or radiation treatments, Charles helped pioneer a radically different approach: rational genetic surgery. By deliberately altering specific nucleotides in cloned DNA and observing the resulting phenotypic consequences, he enabled biology to move from correlation to causation. What distinguished Charles’s contribution was not only technical ingenuity but intellectual clarity. This way of thinking became a hallmark of his scientific style and influenced generations of molecular biologists.

 

The second chapter of Charles Weissmann’s scientific life unfolded at the interface of molecular biology, immunology, and medicine: the cloning of interferon. Before this work, interferon had been identified by Zurich virologist Jean Lindenmann in 1957 as an almost mythical substance—known primarily as a biological activity, detected indirectly through antiviral effects, present in vanishingly small quantities, and resistant to classical biochemical purification. Its therapeutic promise was enormous, but its molecular nature remained elusive.

 

Charles recognized that recombinant DNA technology offered a way forward. By cloning interferon genes, he transformed an abstract biological phenomenon into a defined molecular entity. This achievement required extraordinary technical courage at a time when cloning mammalian genes was still pioneering, difficult, and uncertain. 

The consequences were immediate and far-reaching. Interferon could now be produced in sufficient quantities, characterized structurally, and studied mechanistically. What had once been a biological curiosity became one of the first true biopharmaceuticals, ushering in the era of recombinant protein therapeutics. This achievement led to the creation of Biogen in 1978, one of the world's foremost biotech companies co-founded by Charles. Yet even here, Charles’s impact extended beyond the immediate result. The interferon work demonstrated—perhaps more clearly than any earlier example—that molecular biology could serve as a bridge between fundamental discovery and clinical application. It helped legitimize biotechnology as a scientific and medical enterprise, not merely a commercial one. For Charles, cloning interferon was not the end of inquiry, but the beginning of deeper questions about gene regulation, host defense, and immune signaling—questions that continue to shape immunology today.

 

The third chapter of Charles Weissmann’s career is arguably the most intellectually courageous: his decisive role in establishing the protein-only hypothesis of prions.

When the idea emerged that infectious agents could exist without nucleic acids, it challenged one of biology’s most sacred principles. Many dismissed it outright. Others accepted it too readily. Charles did neither. Instead, he approached the problem with disciplined skepticism and experimental rigor. He understood that extraordinary claims require not belief, but rigorous experiments. Through genetic manipulation of the prion protein gene, transgenic models, and carefully controlled infectivity studies, Charles provided the clearest and most convincing evidence that prion propagation depends on host-encoded protein and not on hidden nucleic acids. By showing that prion infectivity could be abolished or restored by manipulating the prion protein itself, he helped settle a debate that had divided the field for years. This work expanded the conceptual boundaries of biology by revealing that information can be encoded not only in sequence, but in conformation—a principle now recognized as central to many neurodegenerative diseases, from prion diseases to other protein misfolding disorders.

 

I first met Charles Weissmann in 1988, when I was a young resident at the Institute of Neuropathology of the University of Zurich. His laboratory had just identified the gene encoding the prion protein, and I attended a research seminar in which he reviewed the state of prion biology at that time. Just then, Mario Capecchi and Oliver Smithies had introduced the revolutionary technology of gene targeting in mice, making it possible to ablate any chosen gene from the mouse genome. While I was listening to Charles, it occurred to me that “knocking out” the prion protein gene might provide the ultimate proof of its necessity for prion replication. At the end of his seminar I asked him whether this experiment might be feasible. Charles immediately lit up, said that this was exactly what he was planning to do, and invited me to join his laboratory to carry out the work.

I was deeply tempted, but I had already committed to a postdoctoral position in Erwin Wagner’s laboratory in Vienna, and for the next three years I lost contact with Charles. In 1992, I was offered a position as an attending physician in neuropathology at the University Hospital of Zurich. A few months before taking up the post, I met Charles again by chance at a meeting in Berlin and told him that I would soon be returning to Zurich. On 1 July 1992, my very first day back at the University of Zurich, I arrived to find a barrage of fax pages—email did not yet exist in our daily lives—waiting for me from Charles’s secretary. They all contained the same message: Where was I, and could I start working with him on the prion biology project as soon as possible? Needless to say, I felt tremendously honored and flattered that a scientist of the stature of Charles Weissmann would be interested in engaging my help. 

 

When I came back to Zurich as “Oberarzt” (attending physician) after my postdoctoral stint in Vienna, I was 31 years old and I felt that I was insufficiently prepared to build and lead a scientific laboratory. For one thing, my knowledge of molecular biology was insufficient; secondly, I knew that I did not possess the maturity and mental balance necessary to successfully advise and promote co-workers who would only marginally younger than me. I therefore literally attached myself to Charles, hoping that he would take me under his wings and help me develop as a scientist and more generally as a considerate and fair manager of my nascent laboratory. Charles accepted this onerous task with amazing generosity, and he effectively served as a teacher of science and of life to me for the following 20 years.During this period I can say that I learned everything I know from Charles.

The legendary Weissmann Laboratory Meetings were held every Saturday morning at 9AM, a tradition that was much appreciated at the time (but would be unconceivable in today’s world of work–life balance). The meetings were accompanied by a generous breakfast and extended until noon. While everyone else went home to spend their free time or be with their families, Charles regularly invited me to a late discussion in his office, which was adorned with a sign saying “WARNING: DO NOT ENTER THIS ROOM WITHOUT POSITIVE AND NEGATIVE CONTROLS”. Afterwards, he would take me for a handful of spaghetti in his favorite restaurant Commercio near Stadelhofen Train Station, where we dissected scientific projects and concocted possible new research adventures. During this period, Charles was a mentor in science and also in life for me. Not only did he continuously give me advice about decisions in my laboratory, but also when difficult situations happened to me. The continuous guidance he dispensed helped me maintain my mental balance in times of difficulty, but above all to develop a satisfying and professional trajectory.

 

A defining measure of a scientist is not only the discoveries they make but the people they shape. Charles Weissmann created a school of thought—an intellectual lineage that continues to influence modern biology through the scientists he trained. Among the most prominent is Tada Taniguchi, who carried forward Weissmann’s mechanistic rigor into immunology. Taniguchi’s discoveries in cytokine regulation, interferon signaling, and innate immunity have shaped the foundations of modern immunology. Walter Schaffner, another alumnus of Weissmann’s environment, became a pioneer of eukaryotic gene regulation. His discovery of transcriptional enhancers revolutionized molecular genetics and opened new horizons in genomics. Shige Nagata extended Weissmann’s intellectual legacy into cell biology and immunology. His identification of the Fas–Fas ligand system was a landmark discovery that transformed our understanding of apoptosis and immune homeostasis. In the prion field, Bruno Oesch played a central role in defining the molecular basis of prion biology. His work provided essential tools and led to a hugely successful company that played a pivotal role in protecting Europe from the threat of Mad Cow Disease. Koni Basler, who became one of the world’s leading developmental biologists, demonstrates the extraordinary breadth of Weissmann’s influence. Basler’s groundbreaking work in Wnt/Wingless signaling and developmental patterning reflects the same conceptual clarity and genetic discipline that were characteristic of Weissmann’s laboratory. Among Charles’s distinguished scientific disciples was Michel Aguet, whose work on interferon receptors and antiviral signaling carried forward Weissmann’s insistence on mechanistic clarity and genetic rigor, and whose leadership of the Swiss Institute for Cancer Research helped shape modern immunology. Another notable of Charles’ postdocs was Dick Flavell, an English molecular biologist and immunologist who went on to become Sterling Professor of Immunobiology at Yale. Flavell’s use of gene-targeted and transgenic mice to probe innate and adaptive immunity reflects the deep experimental discipline he absorbed during his time in Charles’s laboratory. 

Charles reminded me many times that the important legacy of a scientist is not the number of papers they publish or the number of citations they accumulate, but rather how they are remembered by their trainees. He used to joke that the effective lifetime of a scientific paper is about three years, whereas the future lifetime of a trainee is 30–50 years. And for that reason, it is obvious that the second is much more important than the first.

 

In this sense, although Charles has left us physically, he lives on in the memory and gratitude of the entire school of scientists he created. His influence endures not only in those he trained directly, but also in the next generation of scientific grandsons and granddaughters who honor and continue his legacy of curiosity, scientific enthusiasm, integrity, and clarity.