Thursday, January 11, 2018

A History of Genetic Engineering

Genetic engineering is normally taken to mean recombinant DNA technology -- the artificial addition, deletion or rearrangement of sequences of bases in DNA in order to alter the observable form and function of an organism. However, genetic engineering is sometimes referred to as biotechnology and biotechnologists have been quick to point out that mankind has been doing biotechnology ever since the first farmers some 10,000 years ago started to domesticate wild species by selecting seeds of wild plants for cultivation or selectively breeding wild animals. In this history, therefore, we include any artificial intervention in the reproductive process as well as some landmarks in the development of genetics which has made genetic engineering possible. This will include selection procedures old and new which could influence the genetic outcome of a reproductive event, gene therapy and diagnosis as well as cloning, vegetative reproduction and in vitro (test-tube) reproduction procedures.

circa 10,000 years ago
The beginnings of agriculture: selection of wild grasses and subsequent breeding in cultivation to form the precursors of modern staples such as wheat, rice and maize. A considerable practical knowledge was developed by breeders over the centuries and selection procedures often achieved from a single wild species a huge difference in form and function: e.g. the Great Dane and Chihuahua dog varieties from the wolf. Furthermore, 'unnatural' hybrids -- i.e. creating breeds across species barriers -- were made in ancient times. For instance the mule, a cross between a jackass or male donkey and a mare has been used as a pack animal in Europe for at least 3,000 years.

Francis Bacon foretells genetic engineering and terminator technology.

Charles Darwin published the first edition of The Origin of the Species which amongst other things gives extensive information on the knowledge of breeding at that time. 
Gregor Mendel's publication of his discoveries with the breeding of peas which became the foundation of modern genetics. MendelWeb - Origins of classical genetics.
Ernst Haeckel proposes that the cell nucleus is the bearer of an organism's heritable characteristics.
Friedrich Miescher discovers nuclein -- a major component of which is DNA -- in the cell nucleus.
Oscar Hertwig using microscopy observes sea urchin sperm entering the egg and the two nuclei fusing.
Birth of a rabbit from an embryo implanted in the uterus of a surrogate.
Hugo de Vries, Carl Correns & Erich von Tschermak rediscover Mendel's principles.
Walter Sutton & Theodor Boveri propose the chromosome theory of inheritance.
Archibald Garrod suggested from studies of alcaptonuria, a disease for which one symptom is the appearance of a black pigment in the urine, that a defective gene gave rise to a defective enzyme (a protein which is a biological catalyst in cell processes).
T. H. Morgan demonstrated that the chromosomes are the concrete entities which carry the genes. (Also Clavin Bridges, 1916)
A.H. Sturtevant constructed a genetic map.
H. J. Muller demonstrated that genetic mutation could be induced by X-rays.

Barbara McClintock and Harriet Creighton demonstrate direct physical recombination by examining maize chromosomes microscopically.
George Beadle and E. L. Tatum pinned a gene defect down to a single step in a biochemical pathway that would normally be carried out by an enzyme. They restored normal growth to a mutant micro-organism by adding the missing enzyme.
Oswald Avery demonstrates by experiments on transforming bacteria that of the three polymers in the cell nucleus: DNA, RNA and protein it is the DNA which carries the genetic information.
Development of a technique for freezing and storing bovine sperm.
Implantation of an embryo in a cow's uterus.
Birth of a calf by artificial insemination (AI).
Cloning of frog embryo cells.
In-vitro (in the test-tube) regeneration of plants.

James Watson and Francis Crick using X-ray diffraction data for the structure of the DNA molecule from Rosalind Franklin and Maurice Wilkins proposed the double helix structure of DNA.
Human artificial insemination used for first time.
Rabbit in vitro fertilisation (IVF).
Matthew Meselson and Franklin Stahl demonstrated the semi-conservative replication of DNA.
Sidney Brenner, Fran├žois Jacob & Matthew Meselson Discovered messenger RNA.
Cloning of differentiated (adult) toad cells.
Marshall Nirenberg & Har Gobind Khorana finished unravelling the genetic code.
late 1960s
Stewart Linn & Werner Arber discovered restriction enzymes in E. coli. These enzymes known as endonucleases 'cut' DNA at specific sites determined by the adjacent base sequences. Since then hundreds of these enzymes have been discovered in different micro-organisms and together they comprise one of the most important tools in the genetic engineer's toolbox. The property of restriction enzymes to create 'sticky ends' in the 'cut' DNA allows fragments of DNA of known properties and composition to be 'spliced' into the DNA 'chain'.
Plants regenerated from protoplasts (plant cells with cell wall removed).
Paul Berg made the first recombinant DNA in vitro.
Mouse born from an embryo which had been stored frozen.
Herbert Boyer & Stanley Cohen performed the first recombinant DNA cloning experiment using restriction enzymes discovered only a few years before to insert DNA into a plasmid and use the transgenic plasmid (a circular bacterial 'chromosome') to transform bacteria.
Calf born from an embryo which had been stored frozen.
Identification of the Ti plasmid used for genetically engineering plants.
February, the "Council of Asilomar", a conference in the USA at which the "molecular bishops" met to discuss how the newly discovered and potentially very dangerous recombinant DNA technology (genetic engineering) should proceed.
J. B. Gurdon and others: cloned frog keratinocytes (skin cells) survived to the tadpole stage.
Prenatal genetic diagnosis with the help of DNA.

Walter Gilbert and Frederick Sanger worked out methods to determine the sequence of bases in DNA.

Frederick Sanger determined the base sequence of an entire viral genome (f X174).
Phillip Sharp, Richard Roberts, and others discovered interruptions (introns) in genes.
Birth of Louise Brown (25th July) -- the first 'test-tube' baby born from in vitro fertilisation (IVF).
Twin lambs born through artificial embryo splitting.
First production of insulin through genetic engineering.
First transgenic (genetically modified) mouse.
Giant mouse produced by transferring growth hormone genes from a rat.
Calf born after IVF.
Kary Mullis, a biochemist invented the polymerasein reaction or polymerase chain reaction which is a technique enabling scientists to reproduce bits of DNA faster than ever before. (Mullis was awarded the Nobel Prize for this in 1993)

First transgenic plant (tobacco).
Richard Palmiter and Ralph Brinster placed the gene for human growth hormone in an early mouse embryo. The resulting adult was double the normal size.
Birth of a baby from an embryo which had been stored frozen.
Development of genetic fingerprinting, a technique that has greatly helped the police force in finding and identifying criminals.
Sheep-goat chimaera created, dubbed a 'geep'. Note patches of sheep's wool and goat's hair. (Original paper: Fehilly, C. B., S. M. Willadsen, and E. M. Tucker. 1984. Interspecific chimaerism between sheep and goat. Nature (Lond.) 307:634.)
First transgenic domestic animal, a pig.
First transgenic plant produced which was resistant against a definite insect species.
Cloning of embryo cells from sheep.
Transgenic mice produced whose milk had an artificially altered composition caused by the expression of genes coding for sheep beta-lactoglobulin and human alpha-1-antitrypsin.
A series of transgenic mice produced carrying human genes.
A transgenic plant produced resistant to a particular kind of herbicide.
Nancy Wexler, Michael Conneally and James Gusella located the Huntington disease gene on human chromosome 4.
First transgenic plant producing a pharmaceutical.
Transgenic maize (corn) produced.
First animal patented: the Harvard University 'oncomouse', a transgenic mouse genetically engineered to develop cancer.
Publication (Science 254: 1281-1288) of data about the 'Beltsville pig', a transgenic pig (named after the agricultural research station in Maryland USA) which suffered a range of pathological conditions because it had a gene for human growth hormone.
Lap-Chee Tsui, Francis Collins, and John Riordan found the gene that is responsible for cystic fibrosis.
Transgenic sheep 'Tracy' produced with the human gene for alpha-1-antitrypsin which is expressed in the milk. The intention is to harvest the alpha-1-antitrypsin for the treatment of human emphysema. Ian Wilmut and colleagues, Roslin Institute, Scotland.
James Watson and many others launched the Human Genome Project to map the entire human genome and ultimately to determine its base sequence.
Gene Pharming, Netherlands produce first transgenic bull, 'Herman'. (Herman was killed on 3 April 2004 having developed arthritis)
First gene therapy trials on humans.
First transgenic cows producing human lactoferrin in their milk (Gene Pharming, NL). The intention is to harvest the lactoferrin for the treatment of septicaemia.
Introduction into IVF procedures of intra-cytoplasmic sperm injection (ICSI).
Plant IVF -- maize (corn).
Transgenic tomatoes sold in the shops.
Walter Gehring and colleagues introduce expression of a single eye control gene in Drosophila melanogaster (fruit fly) antennae, thus producing compound eyes on the antennae, and show that the corresponding mouse eye control gene supports compound eye development in Drosophila in the same way. Gehring Lab Home.
June, Paris: birth of first baby produced by the fertilisation of an ovum (egg cell) with a spermatid (spermatozoa precursor) -- collaboration of Jacques Testart (INSERM) and Jan Tesarik (American Hospital, Paris).
In May, Duke University Medical Centre (USA) researchers transplanted hearts from genetically altered 'humanised' pigs into baboons.
Ian Wilmut and colleagues, Roslin Institute, Scotland announced the birth of a lamb (Dolly) cloned by nuclear transfer using an mammary cell from an adult sheep as nucleus donor and an enucleate ovum as recipient.
March 2, Beaverton, Oregon, USA: cloning of 2 monkeys by embryo splitting.
A transgenic tobacco variety producing haemoglobin, a human blood protein.
December, birth of the first transgenic cloned sheep, 'Polly'. Foetal cells were taken from Poll Dorset lambs, and the blood clotting factor IX gene inserted, cultured, tested to see they had which cells had taken up the gene and only those cells used for nuclear transfer cloning in the way Dolly was created.
March 3: 'Terminator technology' moved a step closer to the fields: US Patent No. 5,723,765, granted to Delta & Pine Land Co. an American cotton seed company and the U.S. Department of Agriculture (USDA) on a technique that genetically-disables a seed's capacity to germinate when planted again.
April, a UK supermarket chain bans use of GMOs in its products, a move which is over the following 18 months is followed by the other UK supermarket chains.
May, Roslin Institute, Scotland -- discovery of premature ageing of cells in Dolly the cloned sheep.
US scientist clones one of his own cells in a cow's egg.
December, Lee Bo-yon of Kyunghee University, South Korea claims to have been the first to carry out human cloning by nuclear transfer. The fusion product was last seen dividing into four cells before the operation was aborted.
September, first publicly reported patient death in a gene therapy trial caused by the gene therapy itself.
Monday 26 June: The leaders of the publicly sponsored Human Genome Project (HGP) and Craig Venter who leads the parallel private initiative of the company Celera Genomics announce completion of the first draft of the human genome.
First gene therapy successes: 
1) April, successful treatment of SCID in France

2) August, successful treatment of heart muscle blood supply using vascular endothelial growth factor gene by Jeffrey Isner and colleagues at Tufts University, Boston, USA
May, widespread contamination of the UK oilseed rape (canola) crop by GM oilseed rape contaminated seed imported from Canada by Advanta.
29 August: birth of Adam Nash, wrongly hailed in the press as world's first 'designer' baby. In fact he was born after IVF following which pre-implantation genetic diagnosis of the embryos was carried out to ensure that they did not carry the genes for Fanconi's anaemia, a disease suffered by his sister Molly. After his birth, his umbilical cells were used in the successful tissue transplantation treatment of his sister.
2 October: World's first germ-line genetically modified monkey (rhesus) born in Oregon USA.
2 October: Birth of first genetically modified primate, a rhesus monkey named ANDi (inserted DNA backwards) and containing a fluorescent marker gene from a jellyfish, at Oregon Regional Primate Research Centre, USA (news released on 12 January 2001). 224 eggs were injected with the gene. On fertilisation these yielded 40 viable embryos from which 5 pregnancies resulted. Of 3 monkeys born live tests show that only AND i carries the gene, although it is not being expressed.
200122 January: UK Parliament passes a regulation believed to allow the cloning of human embryos for the purposes of research into serious disease. Embryos may be experimented on only up to their 14th day of life.
11 February: Publication in the journals Nature and Science of the first draft of the human genome estimated to be between 26,000 and 40,000 genes.
5 May: World's first genetically modified humans. US scientists announce that babies have been born carrying the DNA of three parents: two women and a man. The babies were the result of ooplasmic transplantation -- effectively adding cytoplasm from a donor woman's egg to that surrounding the nucleus of an infertile woman's egg.
26 November: First human 'embryo' cloned. Advanced Cell Technologies USA used somatic adult cell nuclear transfer ('Dolly method') to create a clone which developed to six cells before dying.
14 February: News released of worlds first cloned cat. 
Seoul National University in South Korea: first human embryos created that were true clones of the sixteen women who provided the cells to make them.


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