Charles Weissmann: another new challenge

Charles Weissmann’s new office, squeezed into the corner of a London laboratory, seems in every sense too small for him. An imposing physical presence, his intellect also dominates the space with the kind of energy that can scarcely veil its impatience. Weissmann, best known today for his contributions to the molecular biology of prion diseases such as scrapie and BSE, came to work at Imperial College School of Medicine at St Mary’s in March, at the invitation of Britain’s Medical Research Council. He had just retired from the University of Zurich in his native Switzerland, as director of the Institute of Molecular Biology which he founded 32 years ago. He is almost 68 but you could mistake him for a man 15 years younger. Perhaps this is because, by his own admission, he likes to challenge himself. Not many people in their late sixties would give up a lifestyle that includes weekend skiing for the noise and frustration of London, but Weissmann is relishing the change. He had, in any case, vowed not to stay in his former department in a different role. “It is very disturbing for a successor to have his predecessor hanging around, trying to be a sort of éminence grise,” he explains, grinning briefly at the thought. Originally, the MRC had wanted him to set up a new group in Cambridge. But he did not want to find himself in competition with John Collinge, head of the neurogenetics group at Imperial College, so he opted to join Collinge’s group instead. Weissmann’s fascination with the spongiform encephalopathies began when he heard Stanley Prusiner talk on the subject in Perth, Australia, in 1982. Since then, his contributions have been critical. In particular, he and his colleagues cloned the gene that encodes the prion protein, PrP, in 1985 and then, between 1990 and 1992, made knockout mice lacking functional PrP genes and showed that these animals were resistant to scrapie infection and incapable of propagating the scrapie agent. Then, in 1995, Weissmann showed that, when PrP genes were put back into the animals, they became susceptible to infection again. These experiments went a long way towards convincing sceptics of the seriousness of the controversial ‘protein-only hypothesis’: the idea that a protein without nucleic acids could be an infectious agent. But Weissmann is far from complacent. He is quick to emphasize his respect for a number of heavyweight researchers who reject the hypothesis and fall into the other camp, believing that a virus-like entity, sometimes called a virino, must be the causal agent. Even for those who agree with him that prions are central to infection, he warns, there are still unanswered questions. For example, there is a growing consensus that the prion protein must be accompanied by some other protein or chaperone molecule in the process of infection — but, as yet, no one knows what it is. One key challenge, Weissmann says, is to generate measurable prion infectivity in vitro. Former colleagues are not surprised at Weissmann’s unwillingness to rest on his laurels. “Charles is an incredibly rigorous person,” says Richard Flavell at Yale University. “He is almost obsessive about making sure that he is right.” Flavell first worked with Weissmann as a postdoc in the early 1970s, when they interacted on an almost daily basis for a year and a half, which might have been too intense for many people. “Charles is a very strong personality and doesn’t tolerate fools readily.” Yet, although Weissmann could be harsh on his students, he always had a keen sense of humour, says Flavell, and the two got on well and continued to collaborate for years afterwards. But for others, such as Esteban Domingo, now at the Universidad Autónoma de Madrid, it was a case of developing what he calls “adaptive strategies to survive under the domination of Charles.” Domingo says he learnt from fellow postdocs how to show Weissmann his intense involvement in his research, for example by adopting expressions of intense joy if an experiment worked, and deep sadness if it did not. If he has a reputation for driving students hard, he also dislikes the slower reaches of molecular biology. Heidi Diggelmann, now at the University of Lausanne, worked in Weissmann’s lab in the late 1960s, studying avian retroviruses. She says he found retroviral research too slow. “Experiments with bacteriophages corresponded better to his impatient temperament.” Weissmann, born into a Jewish family, was still a child when his father, fearing a Nazi invasion of Switzerland, took the household to Rio de Janeiro in 1941. Five years later they returned to Switzerland but in the meantime Charles had Magazine R625