Look at any website, book or magazine article concerning genetic engineering and it will tell you that, although

it seems in the public eye to be a recent development, it has actually been going on for thousands of years, indeed from when the first breeding programme was devised. The earliest known breeding programme was set up by Jacob in Genesis 30; he had an arrangement with his uncle that they would split their flock, Jacob getting the speckled, spotted and dark-coloured lambs with his uncle keeping the rest. Jacob set up peeled branches of poplar, almond and plane trees in front of the place where his uncles sheep mated, which he believed increased the chance of any lambs being born speckled, spotted or dark-coloured. He only did this when the strongest ewes were in heat, removing the branches when weaker ewes mated. This meant that Jacob got the strongest lambs, and became more prosperous than his uncle. [1] However, this is not the recombination of genes from different organisms into one organism in a way that would never occur naturally. This is not genetic engineering, but merely selective breeding. Selective breeding has been going on for thousands of years, and is alluded to in hundreds of texts, from the Bible to Shakespeare [2]. Actual genetic engineering became possible only with the discovery of Mendelian genetics. Before Gregor Mendel made his ground-breaking research into heredity, it was thought that when a male and a female mated, their characteristics blended like two different liquids to create a roughly-halfway point between them [3]. Mendel did extraordinarily insightful work into inheritance by breeding different pea plants together, described in his only paper still to be referred to, published in 1866 [*********1]. He bred a green pea-producing plant with a yellow peaproducing plant, and all of their offspring produced green peas [3]. However when he bred the offspring together, a quarter of all the next generation produced yellow peas. This effectively disproved the blending theory if this was the case all peas would be a nasty shade of beigebrown and showed that another explanation was possible, namely that heredity is affected by particulate factors, which can be dominant or recessive [3]. One factor is given from each parent, two recessive factors (called alleles) produce the recessive trait (in this case, producing yellow peas) but if there are one or more dominant alleles, the dominant trait will show up [3]. This is explained visually in the table below, which shows the results of second-generation breeding, and assessing the roundness of the peas.

[4]

Once particulate genetics had been established, the study of changing the characteristics of an organism became much easier. Instead of dealing with a soup of thousands of millions of ancestors genetic information, there are only two factors which can be manipulated. In 1970, restriction enzymes were discovered. These are enzymes which slice DNA at very specific points, meaning that they can be used to remove a gene which can then be introduced into a new cell [5]. This could have and still may revolutionise genetic engineering, but currently there is no tape to go with the scissors. Once the DNA has been cut, there needed to be an enzyme to put it back together again, in a different order. Theses enzymes are called ligases. Ligases join together strands of DNA, forming the bonds in the phosphate-deoxyribose backbone again [6].These were discovered in 1968 [6] but the problem was that ligases did not specify where in the DNA sequence the new sequence should be inserted. It was just inserted randomly and if it was inserted in the middle of another gene, it rendered that gene useless, raising the possibility of cancer [*********3]. Instead retroviruses were used. These are viruses which naturally incorporate their own genetic material into a host cell in order to get itself replicated. They convert their RNA into DNA in order for it to successfully function in the host cell DNA [*********4]. Retroviruses have enzymes called recombinases that recognise both the specific stretch of host DNA to be split, and the stretch of viral DNA to be spliced into [*********3]. The stretch of host DNA is sure to be an intron as any recombinases that splits a gene in half is going to cause the host cell to undergo apoptosis, which will cause the virus to die and be selected against. Attaching the new genetic material, in the form of RNA, to the RNA of the retroviruses ensure that the new genetic material is inserted in a safe and appropriate place. Alternatively, purified recombinase can be used. Recombinases seem to be the perfect solution to all the problems of genetic engineering, but there are some issues that are yet to be resolved when using them. Transgenic animals (i.e. animals into which genes from another species, or mutated versions of their own genes, have been deliberately introduced by genetic engineering [*******2[) have been being produced since 1974, when a mouse zygote was combined with DNA from the SV40 virus [7]. However I am only going to briefly talk about the most interesting and developmental ones here. The most widely-used transgenic organism is not an animal, but it has an effect on the 6% of the UKs population who have diabetes. The insulin-producing E. coli strain was first developed in 1978, and was made by inserting the human gene for the two polypeptide chains which make up natural insulin, into an ordinary . The bacteria then make the protein as they would make an ordinary protein themselves, and when the concentration of the polypeptide chains is high enough, they are filtered off and combined chemically to produce natural insulin [8] . In 1982, a mouse was produced that already had a gene for a protein called metallothionein (MT). A gene for the easily-measured enzyme thymidine kinase was attached to

the promoter for the MT gene. When cadmium, which usually promotes the production of MT, was introduced, thymidine kinase was also produced [9]. This was the first transgenic organism produced using enzymes, but it had no use, other than to prove that genetic engineering was possible in animals and, more importantly, mammals. Dolly the sheeps predecessor (that is, she was developed by the same two scientists) was sheep called Tracy. Tracy had been fitted with the human gene for alpha-1-antitrypsin (AAT) which while making her milk production extraordinary, also made it contain the AAT enzyme, used to treat cystic fibrosis, emphysema and other lung diseases. The only way to produce AAT before this was to extract it slowly and expensively from human blood plasma, which had the possibility of human infections [10]. This lead to the further possibility of producing proteins for medical use, and general human use, in animals, especially in animals milk. Dolly the sheep was the first animal cloned from an adult Dolly the cell, in 1996. Her predecessors Megan and Morag were clones of sheep each other, but they were formed by splitting an embryo, in the same way that identical twins are produced naturally [11]. A cell from the mammary gland of an adult sheep was taken, and the nucleus was extracted. This was then implanted into an enucleated (empty of genetic material) egg from a different ewe. These were combined and the hybrid zygote was given an electric shock to stimulate it to divide. Once it became a blastocyst, it was implanted in a surrogate ewe, and Dolly was born naturally [12]. Dolly was proved to be a generally normal sheep, and she produced several lambs [13]. Dolly had shorter telomeres than usual in sheep. Telomeres are structures that protect the ends of a cells chromosomes, and they are associated with aging, as the sheep grows older they wear down. Since all of Dollys cells came from a cell that had telomeres the length that would normally appear in a six-year-old sheep, it was suggested that she would age and die prematurely. In fact she died at the age of six, when she was expected to live until she was 11 or 12. She was euthanised because she had progressive lung cancer and arthritis. The particular form of lung cancer is a particular danger to sheep kept indoors, which Dolly was for security reasons, and other sheep in the flock had died of the same disease [14]. Therefore it is unclear whether she died early because of her telomeres, or because of chance. In 2000, two goats were produced which, it was hoped, when bred together would give rise to a kid that produced the protein that makes up spider silk in its milk. Spider silk is widely recognised as the toughest and strongest fibre around, but the temperament of the spiders themselves makes it impossible for it to be farmed the spiders will fight and its unfeasible to extract it from them against their will. These goats were designed to produce the protein for spider silk in their milk, which could then be extracted. This development also showed to the public that transgenic organisms were not a freakish mutant of half-one creature and halfanother, and that they are, behaviourally, totally normal [15].

In 2001, a rhesus macaque egg was modified to include a simple jellyfish gene, designed to make a cell molecule glow under a special microscope. This was introducing no new techniques, but it was the first primate to be genetically modified which, understandably, stimulated a slippery-slope debate, with people wondering how long it would take for GM humans to be made.GM mice had been used before to test drugs, with their immune systems modified to be more similar to humans and to be receptive to human diseases, but it was felt that the mouse immune system still had differences that caused problems which were too great to overcome, so the team created a monkey with a modified immune system. The reason for the glo-gene was to demonstrate that once a drug being developed was reaching its final stages, it could be tested on a GM monkey before humans because of the similar immune system and no risk of human mortality. The final aim was to produce monkeys that would be susceptible to human diseases such as Alzheimers, breast cancer or HIV/AIDS and so help in developing cures or vaccines [16]. In 2003 the first GM animals went on the market to the public. These were GloFish, fish that glow in the dark and sometimes just naturally. They were originally designed to be used as an instrument to detect the presence of pollutants in water supplies, but the decision was made to sell them to the public, and they have been patented by the company Yorktown Technologies. They are produced using genes from a variety of different species to make different colours. Fluorescent green was the first colour, using a gene from a jellyfish, but then more colours were introduced using genes from species including various types of coral. There are now five colours on the market [17]. The US Food and Drug Administration (FDA) said they found no reason to prohibit the sales of the fish as they did not affect any natural food chains, and were not intended to be eaten by people [18]. Since their introduction, there have been no ecological concerns expressed [17]. Current experimentation In 2009, the number of GM animals used in scientific procedures exceeded the number of nonGM animals used for the first time.