#trangenic

There has been a great deal written about genetically modified organisms (GMO) with particular focus on foods that we buy. Altering the genes of crops has been used to increase crop tolerance to pesticides allowing their use to increase yield, to increase resistance to insect pests and to increase nutrient value of the plants.

The main argument against GMOs is that making big leaps in modification of a plant or animal using genetic trickery may make unhealthy food or has unknown consequences although this seems not likely. But there is a side to GMOs that gets very little attention: the use of genetically modified organisms in medical research. It is hard to overstate the importance of such organisms to the discovery of life process or mechanisms of human disease.

The movement of genes from one organism to another at its most fundamental level is an important aspect of reproduction. This process ensures genetic diversity within a population and creates strength but also provides the template for adaptation. The fact that parental genes re-assort themselves during reproduction assures robustness of the offspring. It also allows for selection of desirable traits in plants and animals and from time immemorial man has exploited breeding to improve the agricultural aspects of domestic animals.

The genetic analysis of cancer gained a big boost in the 1960s and 1970s when it was learned how to swap genes between cells directly. This was done by forcing the cells to fuse and creating cells with an amalgam of chromosomes (and their genes) from the fusion partners. The behavior of the cells changed in a way that allowed the discovery of genes that promote cancer and other genes that inhibit cancer.

The age of molecular biology ushered in a period more than 40 years ago that allowed genes to be isolated directly from cells grown in a dish. Scientists then developed methods to put  many many copies of small stretches of DNA into other cells. These altered cells could be used for a wide variety of studies. The DNA managed to fit into existing chromosomes in the recipient cell. This process of incorporation of DNA into intact chromosomes is called integration. You will recall that in earlier posts we discussed the way that genes are organized and regulated in chromosomes and the newly acquired cells get the DNA in a way that allows them to function by producing RNA and ultimately proteins. This allowed the study of the function of individual genes in a convenient experimental setting.

Soon after scientists were encouraged to try and put foreign genes into animals. Remarkably this worked! The first attempts to do this were presented to the scientific community in the early 1980s. The approach was to use a teeny tiny needle to inject DNA containing the coding sequence of a gene, without any of regulatory machinery or proteins that normally package DNA, into the nuclear structure of a fertilized egg (where the chromosome are).

Recall from an earlier post that following fertilization the sperm enters the egg and develops into one of two pronuclei, which are small nuclear structures that will join together in order to combine the chromosomes, and thus the genes of the mother and the father in the offspring. Injecting DNA into a pronucleus is quite a feat since the target structure is about 20 microns (20 millionths of a meter or 0.0008 inches; 50 of them would fit on the head of a pin!). When injected, the foreign DNA integrates into the DNA of the egg. Once this occurs the regulatory machinery and normal proteins of the chromosomes surrounding the injected DNA take over or adopt the foreign gene which then begins to function in its new home.

The injected egg is transplanted into the uterus of a mouse and allowed to develop into a mouse that now has the foreign gene. This gene transcribes RNA and ultimately the protein it codes for is produced. Such animals are called transgenic and they have allowed the study of thousands and thousands of proteins and biological processes in impactful studies from diabetes to stroke to cancer and psychiatric disorders.

The insertion of a gene from jellyfish that makes a fluorescent protein, for example, has allowed many many studies of how cells move about during development, how proteins interact and how genes effect behavior. Transgenic animals are made from many species for specific purposes including zebrafish, rats and pigs. Transgenic pigs with green fluorescent protein are a critically important model of transplantation studies and may eventually lead to successful use of pig organs in humans!

There are other methods for moving foreign genes into organisms including the use of embryonic stem cells, viruses or even specialized bacteria used to make transgenic plants.

In the next few posts we will explore how transgenic animals have impacted our understanding of human disease and how to treat it along with brief discussion of alternate methods of their production.