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    14. The History of Biotechnology

    15. 1859 Charles Darwin publishes his book (On the Origin of Species by Means of Natural Selection). According to this book evolution is lifes motor. The interplay of mutation and selection endows living beings with optimized traits in order to survive. These principles are also valid for the so-called 'chemical evolution' of biomolecules and are being used in laboratories for in vitro optimizing of wanted qualities in molecules

    16. 1865 Gregor Mendel finds that independent 'factors' are responsible for the heredity of traits from one generation to the next according to a set of (Mendelian) priciples.

    17. 1869 Friedrich Miescher discovers an acidic substance in the nucleus of cells which he names 'nuclein'. By elemental analysis he finds 14 % nitrogen, 3 % phosphorus, and 2 % sulfur (from proteins). Since the substance cannot be cleaved by the proteolytic enzyme pepsin Miescher concludes that this substance is not a protein.

    18. 1879 Walther Flemming observes the separation of chromosomes during mitosis but fails to fully understand its meaning. He counts 24 pairs of chromosomes, a number which will be corrected to 23 later in 1956 by the Indonesian scientist Joe-Han Tijo.

    19. 1900 William Bateson introduces 'genetics' as a scientific discipline

    20. 1902 Walter Sutton observes in grasshoppers' cells that chromosomes carry the Mendelian 'factors of heredity', i.e. the genetic information.

    21. 1909 Wilhelm Johansen coins the terms 'gene', 'genotype', and 'phenotype' referring to Mendel's 'factors'. Archibald Garrod confirms the hereditary nature of four metabolic diseases. He publishes "Inborn Errors of Metabolism"

    22. 1910 Thomas Hunt Morgan's studies in the biology of Drosophila melanogaster confirm that certain traits are inherited sex-specifically. He also proves that some phenotypes result from several genes located on different chromosomes.

    23. 1927 Herman Muller finds that energetic radiation causes defects in the chromosomes, i.e. mutations.

    24. 1928 Fred Griffith demonstrates that material from killed bacteria of the pathogenic strain Streptococcus pneumoniae S ('smooth') is taken up from living ones of the non-pathogenic strain Streptococcus pneumoniae R ('rough') which are subsequently 'transformed' into the pathogenic S-strain.

    25. 1944 Oswald Theodore Avery, Colin McLeod, and Maclyn McCarty find by careful analysis of Griffith' experiments that desoxynucleic acid (DNA) is the carrier of the 'transforming principle'.

    26. 1945 Erwin Schrdinger proposes in his famous book 'What is life?' that genes must be 'aperiodic crystals' consisting of a succession of a small number of isomeric elements whose precise sequence constitutes the heredity code. Although these ideas do nothing to identify the responsible molecular structures, they attract many newcomers to the field.

    27. 1950 Erwin Chargaff observes the 1:1 ratio of the nucleic bases adenine/thymine and guanine/cytosine. This will be a decisive hint for Watson & Crick to the structure of the DNA molecule.

    28. 1952 Alfred Day Hershey's and Martha Chase's studies in bacteriophages prove that only the nucleic acids carry the genetic information; proteins are definitively excluded from playing this role.

    29. 1953 James D. Watson and Francis H. C. Crick elucidate the structure of the DNA molecule. It consists of two strands which are bound by hydrogen bonds bewtween opposite basepairs of adenine-thymine and cytosine-guanine. Their model is based on the results of many colleages, namely Rosalind Franklin who discovered the helical structure and the outward position of the phosphate-sugar backbone.

    30. 1955 Frederick Sanger finds a method to sequence proteins. With this he determines the sequence of the amino acids of insulin.

    31. 1956.. Arthur Kornberg reports the first in vitro synthesis of a DNA molecule.

    32. 1956 Joe Han Tijo and Albert Levan correct the number of the chromosome pairs in human cells to 23. Since the days of Walther Flemming 24 was believed to be the true number.

    33. 1959 T. Akiba, T. Koyama, Y. Isshiki, S. Kimua, T. Fukushima, T. Watanabe and T. Fukusawa describe the transfer of multiple resistance to antibiotics by bacterial plasmids. Plasmids turn out to be efficient vectors for trafficking genetic information between bacteria of different strains.

    34. 1960 Francois Jacob and Jaques Monod recognize the function of the messenger RNA (mRNA). They develop the operon model of gene regulation in procaryotes.

    35. 1961 Sydney Brenner and Francis Crick claim that every amino acid corresponds to a triplett of nucleotides, called 'codons'.

    36. 1962 John Gurdon claims to have reproduced frogs from the epithelium cells of Xenopus laevis. J. B. S. Haldane coins 'cloning' when describing these debated experiments.

    37. 1966 Mainly due to the work of Har Gobind Khorana the 'Genetic Code' is completely known.

    38. 1968 Werner Arber discovers enzymes, so-called nucleases, which digest DNA double strands from the ends.

    39. 1969 Jonathan Beckwith is the first to isolate a complete gene, in this case a gene from the bacterial sugar metabolism.

    40. 1970 Hamilton Smith discovers an enzyme (HindII) which specifically cleaves DNA double strands

    41. 1971 Paul Berg, Peter Loban, and Dale Kaiser find enzymes which attach short single strands to the blunt ends of double stranded DNA. The single strands consist of only one sort of nucleotides. Complementary single strands (sticky ends) allow the coupling of ds DNA fragments; the remaining gaps can be closed by the use of ligases.

    42. 1972 Janet Mertz and Ron Davis paste DNA fragments of different origin resulting from specific enzymatic restriction. They close the gaps using ligases and thus produce recombinant DNA.

    43. 1973 Stanley Cohen and Herbert Boyer paste enzymatically restricted DNA fragments into plasmids which have been cleaved by restriction enzymes. The resulting recombinant plasmids can serve as vectors for the transfer of foreign DNA into bacteria. These experiments are generally regarded as the beginning of the era of genetic engineering and modern biotechnology.

    44. 1975 The first conference on safety issues of the new technology is held at Asilomar in California.

    45. 1976 Herbert Boyer and Robert Swanson found Genentech the first biotech company.

    46. 1977 Walter Gilbert and Frederick Sanger independently develop two different methods for DNA sequencing.

    47. 1978 Walter Gilbert discovers that genes of eucaryotic organisms are composed of coding and non-coding parts. The non-coding sequences, named introns, are cut from the mRNA before translation leaving the coding exons as the source of information for protein synthesis.

    48. 1979 Thomas Cech and Sydney Altman discover the autocatalytic activity of some RNA molecules to cleave themselves at well defined positions. They coin 'ribozyme' for this type of RNA.

    49. 1980 Jozef Schell and Marc van Montagu transfer foreign DNA into plant cells by employing T-plasmids of Agrobacterium tumefaciens as vectors.

    50. 1981 The first patent for a genetically modified organism is granted to Ananda Chakrabarty of General Electric. It covers a P. aeruginosa strain which is equipped with genes of certain enzymes in order to metabolize crude oil.

    51. 1982 The U.S. Food and Drug Agency (FDA) approves recombinant insulin for marketing.

    52. 1984 Alec Jeffreys develops 'genetic fingerprinting' allowing the comparison of minute variations, the so-called restriction length fragment polymorphisms (RLFPs), in the genomes of two organsims.

    53. 1985 Karry Mullis develops the polymerase chain reaction (PCR). This powerful tool allows to copy and accumulate extremely low amounts of DNA from various sources until a level sufficient for analysis is reached.

    54. 1986 Neal First develops protocols for clonig cattle from bovine embryos by separating cells at early embryonic stages. These experiments resemble John Gurdons earlier attempts at the cloning of frogs. The first cloning of an adult animal will be reported in 1997 by Ian Wilmut who succeeds in cloning a sheep, Dolly.

    55. 1988 The first patent for a transgenic mammal is granted to Harvard's Philip Leder and Timothy Stewart. It refers to a mouse which is susceptible to tumors and serves as model organism for studies in cancer.

    56. 1990 French Anderson successfully tries the first somatic gene therapy of a human. Patient

    57. 1993 The German Genetic Engineering Act of 1990 is revised, i.e. many restrictions of the 1990 version are eased.

    58. 1994 Genetically modified tomatoes are on sale in the U.S. Cans containing puree from transgenic tomatoes are on the shelves of british supermarkets.

    59. 1995 The Institute for Genomic Research (TIGR) publishes the first complete sequence of the genome of a free-living organism, the bacterium Haemophilus influenzae

    60. 1996 The complete sequencing of the baker's yeast' genome is accomplished by close collaboration of laboratories in Europe, Japan, and the U.S. The Saccharomyces cervisiae genome ist the first eucaryotic genome completely sequenced.

    61. 1997 Ian Wilmut (right) visits Dolly (center) the first mammal cloned from an adult cell.

    62. 1998 Two research teams report embryonic stem cells differentiate to specialized tissue cells. The picture shows an early developmental stage, the blastocyst.

    63. 1999 Pluripotent stem cells from tissues can be reprogrammed to other cell types.

    64. 2000 There are 1300 biotech companies on each side of the Atlantic. About 400 are listed at stock exchanges.

    65. 2001 Less genes than expected The international Human Genome Project (HGP) and biotech company Celera Genomics publish their versions of the sequence of the human genome. The Celera team estimates the number of genes to range from 26,000 to 39,000, HGP scientist' estimate is between 30,000 and 40,000.

    66. 2001 RNA interference Thomas Tuschl is the first to demonstrate that RNA interference (RNAi) is also working with mammalian cells.

    67. 2002 Genomes of the malaria agent and its carrier sequenced Researchers of the Institute for Genomic Research (TIGR), the Sanger Institute (UK), and Stanford University publish the genomic sequence of Plasmodium falciparum and Plasmodium yoelii. The protozoa P. falciparum causes malaria. The genome of its carrier Anopheles gambiae is also sequenced and published.

    68. 2003 Genome of SARS virus sequenced Within three weeks after its discovery scientists of the Michael Smith Genome Sciences Centre in British Columbia (Vancouver, Canada) succeeded in sequencing the genome of the virus causing severe acute respiratory syndrome (SARS). The RNA virus remotely resembles corona virus species and contains roughly 30,000 genes.

    69. 2003 Germ cells from stem cells Karin Hbner and Hans Schler of the University of Pennnsylvania succeeded in generating oocytes from murine stem cells which were able to grow into further embryonic stages. The experiment demonstrates the potential of pluripotent stem cells to acquire totipotency via a germ line cell stage

    70. 2004 99.999% accuracy Three years after the publication of the first draft a far more precise version of the sequence of the human genome is published.

    71. 2004 Fatherless mouse Tomohiro Kono of the Tokyo University of Agriculture presented the first mouse which was obtained from oocytes only. His team combined the genomes of oocytes

    72. 2004