Max Birnstiel 1933-2014: Gene pioneer.

Max Birnstiel, who died in November, was a pioneer of molecular biology and a creator of European scientific institutions. Born in Brazil in 1933, his family moved back to their native Switzerland when he was 5 years old, and he completed his education there. When he asked his teachers how he should best train to be a biologist, the counterintuitive answer was that he should study biophysical chemistry. He never regretted his decision to follow this unconventional path, which, coupled with his deep interest in the natural world, guided his approach to research. After obtaining his doctorate in botany with Albert Frey-Wyssling at the Eidgenössische Technische Hochschule in Zurich, Max moved to Caltech to train with James Bonner. Here he was impressed by the egalitarian nature of the Caltech research community and was exposed to some of the 20th century’s great biologists, including Pauling, Beadle, Dulbecco, and Delbruck. Other important influences were also acquired in California. It was here that Max was amongst the first to use the revolutionary technique of RNA/DNA hybridization to show that the genes encoding the RNA components of the eukaryotic ribosome are multicopy. Conrad Waddington subsequently recruited Max to the new Medical Research Council Epigenetics Research Group in Edinburgh. To Waddington, epigenetics was the study of the way the phenotype was determined by the genotype, and he felt that the only way to get at this was to understand how genes work at the molecular level. The problem was that chromosomal DNA in those days, before restriction enzymes, PCR, or cloning, was almost impossible to analyze. Despite the monotonous homogeneity of the genome, Max realized that physical methods might separate out some genes if they were abundant enough and had a sufficiently atypical composition of bases. The ribosomal RNA genes of the South African frog/toad Xenopus laevis with their high copy number and C+G molar content fitted the bill. On his arrival in Edinburgh, Max was provided with a prefabricated hut containing a Spinco Model E analytical ultracentrifuge. With his colleague Hugh Wallace, Max went searching for the high-density satellite and succeeded in purifying the ribosomal RNA genes to homogeneity by repeated rounds of isopycnic ultracentrifugation. This was the first time a single gene had been purified, predating the isolation of the bacterial lac operon gene—sometimes hailed as the first gene isolation—by 3 years. In a series of papers in the late 1960s both from Max’s group and from Don Brown’s laboratory at the Carnegie Institution in Baltimore, it was elegantly demonstrated that the genes for 18S and 28S ribosomal RNAs are clustered in headto-tail tandem arrays. Their conclusions were beautifully verified by the electron micrographs of Xenopus ribosomal RNA gene transcription in progress produced by Oscar Miller in 1969. Here were rows of ribosomal RNA genes, each carrying many growing RNA polymers like a chain of Christmas trees. Other repetitive genes were subsequently purified. These included the genes coding for 5S ribosomal RNA in Don Brown’s laboratory and those encoding histone mRNAs by Max’s research group. With the advent of recombinant DNA cloning and PCR, however, genome analysis was revolutionized, and physical methods for isolating genes became obsolete. Max moved to Zurich in 1972 where he used the new methods to study the histone genes. Here his laboratory continued to make important contributions to our understanding of the concept of a eukaryotic gene and of transcriptional activation by RNA polymerase II. Amongst other discoveries, he identified a specific DNA sequence which acted as an upstream enhancer of histone gene activity and which he named the “Modulator.” As chair of one of two geographically separate Institutes for Molecular Biology set up in Zurich (the other chaired by Charles Weissmann), it was only a matter of time before Max once again became restless. This time he looked for a challenge of a different kind. Genentech and Boehringer Ingelheim approached him to create a new basic research