8th Rodney Porter Memorial Lecture

Prof. Sir Edwin M. Southern, FRS
(Emeritus Professor, formerly Whitley Professor of Biochemistry, Department of Biochemistry, Oxford)

EMS joined Peter Walker in the MRC Mammalian Genome Unit, Edinburgh, in 1967 and initiated some of the earliest DNA sequencing with an analysis of satellite DNAs from guinea pig (1) and mouse (2,3). These studies led to theories, still accepted, of the structure and evolutionary origins of the tandemly repeated sequences and set the scene for the debate on the existence of non-coding sequences in the genomes of the higher eukaryotes (1). The studies of satellite DNAs required development of new methods of analysis. EMS was the first to introduce the use of type II restriction endonucleases to study the structure of sequences from eukaryotic DNAs (2,4).

With Peter Ford, EMS showed that the 5s RNAs of ovaries and somatic cells of Xenopus laevis differed in sequence (5), an observation which led to the discovery of the internal promoters of RNA polymerase III. An attempt to isolate the genes coding for the two types of RNA produced the method of detecting specific sequences among restriction fragments by molecular hybridization (6), which subsequently became known as the "Southern blot" and found many applications. It permitted studies of gene structure. EMS used it in studies of the structure of ribosomal (7,8) and histone genes. With Adrian Bird, he developed a method to characterize methylation patterns in eukaryotic DNA, which, as Bird went on to show, are important for gene regulation in vertebrates. The method formed the basis of Jeffrey's DNA fingerprinting technique and was used to isolate the genes for a number of inherited diseases and to create the first genetic maps of the human genome.

EMS set up the first project to map the human genome using molecular methods in the MRC Clinical and Population Cytogenetics Unit in 1979 (7). Technical innovations he developed in response to the need to analyse sequences on the large scale required by such projects include: methods for accurate sizing of restriction fragments by gel electrophoresis (9); automated methods for reading DNA sequences from sequencing gels (10); a new method for the separation of large DNA fragments by crossed-field gel electrophoresis, based on a theory of how DNA fragments move through gels under the influence of an electric field (11). In 1985, he moved to Oxford to take up the Whitley Professorship of Biochemistry. In 1988, he introduced methods of analysis using oligonucleotide arrays or "DNA chips", which are used to analyse DNA sequences by molecular hybridization on a large scale. He showed how large sets of oligonucleotides could be made on a glass surface by in situ synthesis in few steps by efficient combinatorial methods (12,13). The array method has been adopted by many laboratories for genotyping, resequencing and expression analysis. In addition to his genome studies his current interests include basic studies of hybridization behaviour of nucleic acids, particularly how the duplex formation is influenced by structure in the single strands (14-16). His group are also involved in the development of more effective antisense reagents for therapeutic applications and for use as knockdown reagents in the study of uncharacterized gene sequences (17,18).

Other research on methods for high throughput analysis of nucleic acids is carried out in Oxford Gene Technology, a company founded by EMS in 1996. EMS is the Chief Scientific Officer of OGT. EMS founded a research charity, Kirkhouse Trust, and an educational charity, formerly the EM Southern Trust, now the Edina Trust, using royalty income from licensing the microarray technology. The Kirkhouse Trust supports research and training on crop improvement in semi-arid regions of the developing world. EMS is chairman and a trustee. The Edina Trust supports educational projects which promote an interest in science in primary schools.

1. Southern EM. Base sequence and evolution of guinea-pig alpha-satellite DNA. Nature 1970;227(260):794-8.
2. Southern EM. Long range periodicities in mouse satellite DNA. J Mol Biol 1975;94(1):51-69.
3. Biro PA, Carr-Brown A, Southern EM, Walker PM. Partial sequence analysis of mouse satellite DNA evidence for short range periodicities. J Mol Biol 1975;94(1):71-86.
4. Southern EM, Roizes G. The action of a restriction endonuclease on higher organism DNA. Cold Spring Harb Symp Quant Biol 1974;38:429-33.
5. Ford PJ, Southern EM. Different sequences for 5S RNA in kidney cells and ovaries of Xenopus laevis. Nat New Biol 1973;241(105):7-12.
6. Southern EM. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 1975;98(3):503-17.
7. Southern EM. Application of DNA analysis to mapping the human genome. Cytogenet Cell Genet 1982;32(1-4):52-7.
8. Arnheim N, Southern EM. Heterogeneity of the ribosomal genes in mice and men. Cell 1977;11(2):363-70.
9. Southern EM. Measurement of DNA length by gel electrophoresis. Anal Biochem 1979;100(2):319-23.
10. Elder JK, Southern EM. Measurement of DNA length by gel electrophoresis II: Comparison of methods for relating mobility to fragment length. Anal Biochem 1983;128(1):227-31.
11. Southern EM, Anand R, Brown WR, Fletcher DS. A model for the separation of large DNA molecules by crossed field gel electrophoresis. Nucleic Acids Res 1987;15(15):5925-43.
12. Southern EM. Method and apparatus for analysing polynucleotide sequences. European Patent 373203B1 1988.
13. Southern EM, Maskos U, Elder JK. Analyzing and comparing nucleic acid sequences by hybridization to arrays of oligonucleotides: evaluation using experimental models. Genomics 1992;13(4):1008-17.
14. Sohail M, Akhtar S, Southern EM. The folding of large RNAs studied by hybridization to arrays of complementary oligonucleotides. Rna 1999;5(5):646-55.
15. Southern EM, Mir K, Shchepinov M. Molecular interactions on microarrays. Nature Genetics Suppl. 1999;21(1):5-9.
16. Mir KU, Southern EM. Determining the influence of structure on hybridization using oligonucleotide arrays. Nat Biotechnol 1999;17(8):788-92.
17. Milner N, Mir KU, Southern EM. Selecting effective antisense reagents on combinatorial oligonucleotide arrays [see comments]. Nat Biotechnol 1997;15(6):537-41.
18. Southern EM, Milner N, Mir KU. Discovering antisense reagents by hybridization of RNA to oligonucleotide arrays. Ciba Found Symp 1997;209:38-44.