Transgenics

The word transgenic refers to the translocation or relocation of genetic material i.e. genes. A past, practical example of this was the translocation of genes taken from a human and inserted in to the genome of a female sheep. This is a form of genetic engineering, which is a term used to describe the skills which have been developed enabling molecular biologists to move genes from one chromosome to another. Genetic engineering involves locating a desirable gene, isolating it and then inserting it in to the genome of another organism. The proteins produced in response to the new piece of DNA by the new host cell will either have a useful effect in the host cell or may be harvested for use elsewhere.

The techniques used in genetic engineering are complex. Special enzymes called restriction endonucleases or restriction enzymes chop up DNA strands, cutting them at very specific sites. Other enzymes known as DNA ligases act as "genetic glue" and join pieces of DNA together. The required fragment of DNA cut from the chromosome of one organism is pasted in to another piece of DNA which will carry it into the host cell. Plasmids, the circular strands of DNA found in bacteria, are frequently used as these vectors. Once the plasmid is incorporated in to the host nucleus it becomes part of the new recombinant DNA of the engineered genome.

What can Transgenics do?

These techniques have made possible the creation of new genomes resulting in the production of altered organisms such as Polly. The foreign genetic material inserted in to Polly will produce proteins which are excreted mainly in the milk and can be separated and purified and can be given to humans. Therefore Polly can be looked at as a protein factory with its products being closely controlled.

Polly is also a cloned sheep, a copy of another sheep. A clone is a group of cells or organisms which are genetically identical and have all been produced from the same original cell. In the 1950s a carrot was produced by Frederick Steward from a single carrot phloem cell which was grown in a rich nutritive medium. For this to happen the original cell needs to have retained the capacity, present in the cells of an embryo, to go through all the stages of development. Since it produced a normal adult, none of the genes in the phloem cell must have been permanently switched off. A cell which is capable of being used in this way is known as totipotent.

What Benefits does this infer upon Society?

Cloning has two major uses. In horticulture, plants such as orchids are now almost always produced commercially by cloning. In research, it is of great value to have plants and animals to work on which are known to be genetically identical. Any differences in their development or behaviour can then reasonably be put down to the experimental variable. Cloning of plants is now commonplace and relatively easy. The cloning of animals is less straightforward, yet is possible as shown by Dolly and Polly. The cloning of humans however is a very long way off as most adult human cells are not totipotent.

Polly the Sheep

Polly was born in Edinburgh, courtesy of PPL Therapeutics in July 1997. She was a cloned sheep created using the same technique that PPL had used to make Dolly the first cloned animal, Polly had been genetically modified by having a human gene placed in her genome which would produce a protein in her milk called Factor IX. This protein can be extracted and given to people suffering with haemophilia B which is caused by a lack of Factor IX being produced within there bodies.

Treating Haemophilia

PPL Therapeutics is one of the worlds leading companies in the application of transgenic technology to the production of human proteins for therapeutic and nutritional use. The press release I received from them had this to say in March 1998.

PPL Therapeutics plc announces today that it has achieved an expression level of 300mg/l for human factor IX (FIX) protein in the milk of transgenic sheep. This is the first time this protein has been produced at commercial levels in the milk of transgenic animals. Factor IX is a human plasma protein essential for the blood clotting process. Deficiency of this protein is inherited as an X-linked trait resulting in haemophilia B in males with a frequency of 1 in 30,000. FIX has been shown to be effective in controlling bleeding in haemophilia B patients. In the UK, it is usually used therapeutically to treat bleeding episodes. However, it is becoming more common for young people diagnosed with haemophilia B to be started on preventative FIX treatment immediately.

Haemophilia is a severe sex linked trait in which one of the proteins need for the clotting of the blood is missing. The mutated gene is carried on the X-chromosome. The homozygous form is unlikely to arise since haemophiliac men rarely have offspring (don't often reach a reproductive age-if they do, will often choose not to reproduce), but if it does it is lethal when the affected female reaches puberty if not before.

Factor IX plays an essential role in blood coagulation and its deficiency results in haemophilia B (Christmas Disease). This disease is currently treated with FIX derived either from human plasma or from expensive cell culture technology. Recombinant FIX produced in sheep's milk will provide an alternative source available in large quantities at lower cost and free of the potential risks associated with human blood derived products such as AIDS and CJD.

What Controls are in place to Regulate all of this?

With new technology relating to transgenic animals increasing and finding favour in both biomedical research and biotechnology guidelines on ethics and use of the technology need to be instated. This has been done by the UK Advisory Committee on Genetic Manipulation (ACGM). The guidelines, which the committee hopes will set an example for other countries, are particularly concerned with the consequences of the deliberate or accidental release of transgenic animals in to the wild, and the hazards of using viral, and especially retroviral, vectors for transgenes i.e. the use of genetically modified viruses being introduced to new genes in animals.

ACGM, which will need advance notification of any plans to use viral vectors or to release transgenic animals. Among the considerations will be the precautions that have been planned to ensure containment. For large animals, ACGM takes the view that a well-fenced field is sufficient. This would apply to animals such as Dolly, Polly and Mr. Jefferson the genetically modified cow.

Their main intent is to establish a legally backed compulsion both to notify ACGM of the production and use of transgenic animals and to set up and operate local risk assessment committees at any establishment that carries out genetic manipulation. The guidelines advise that the "consumption of transgenic animals or their products by humans or animals would be subject to consideration by the Advisory Committee on Novel Foods and processes", which in turn seek advice from ACGM. This is another part of the guidelines which would effect Polly as she produces a protein which is given to humans and therefore stringent guidelines need to be enforced.

Who Owns a modified Gene in a Living Organism?
Who Owns the Organism?

Another issue which effects Polly is the questions raised concerning ownership of man-made life and if you can patent such a creation. Is it an invention or as some believe should it be treated as any other animal with no legal claims over it. How should something like this be treated.

Patent law treats genes and genetic engineering in the same way as any other invention. To be patentable in Europe an invention must be "new, not obvious, capable of industrial application and be patentable subject matter". To be considered new, an invention must add to the current state of knowledge. For instance a gene, in its natural state would not be new as it has existed since the beginning of life and has merely been discovered. An invention is not considered obvious if the inventive step of the patent would not have been clear to the average specialist in the field (hard to define). If the invention can be made or used in any kind of industry it will be considered capable of industrial application. Patentable subject matter is defined by exclusion, any discovery, scientific theory, variety of animal or plant and anything contrary to public order or morality are all none patentable subject matter.

The issue on the variety exclusion is whether a genetically engineered animal is a variety. Both the natural process of the animal and the genetic manipulation have produced it, so when is an animal considered man made? The U.S. position on this is better defined then in Europe, it states "The living character of inventions does not prevent them being patentable subject matter." Therefore in the U.S. at least, genetically engineered plants and animals are considered patentable subject matter.

Summary

Cloning combined with genetic manipulation is a huge landmark of scientific achievement. Along the scientific progress, I am glad to see that the moral and ethical advances has been able to keep up with science, as such proper safeguards have been implemented to help the progress of these new techniques. In turn this allows the benefits of these techniques to be realised with the production of new 'resources' to safely produce much needed medical drugs.

The only matter still to be finalised is the question of ownership, how far does this go? for me this is a much bigger question, if a gene is inserted in to you to repair a defect which you pass on to your offspring, does the company own your children?

Bibliography

  • PPL Therapeutics Ltd.
  • Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., Watson, J. D. (1994). Molecular Biology of the Cell. Garland Publishing Inc. ISBN : 0-8153-1620-8.
  • Stryer, L. (1995). Biochemistry 4th edition. W.H. Freeman and company Ltd. ISBN : 0-7167-2009-4.
  • Thomas, J. H., Gillham, B. (1989). Will's Biochemical Basis of Medicine (2nd Edition). Butterworth-Heinemann Ltd. ISBN : 0-756-06849-8.
  • Voet D., Voet J. G. (1990). Biochemistry, John Wiley and sons. ISBN 0-471-61769-5.

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