Transgenics and Cancer -
The constellation Cancer (zastavki.com)
How GMOs Help Us Understand Human Disease
In the last post we discussed how animals could be produced with foreign genes for use in medical research. We will look at a few examples of how this technology has revolutionized many aspects of research into human disease.
We mentioned that a very early example of this technology began 50 years ago when it was discovered that by inducing two cells to fuse or join together their chromosomes and hence their genes were also combined. It was then learned that if the cells came from different species the chromosomes from one of the species would be preferentially but randomly lost as the cells grew and divided. That is to say fewer of one type of chromosome and hence its genes would eventually be present in the fused cells but any of the chromosomes from that species might be lost. This was exploited to do somatic cell genetics, the study of genes in isolated cells without breeding. When human cancer cells were fused with normal mouse cells, following the fusion the cells no longer behaved as cancer cells. After a time in culture, as the chromosomes of one of the types of fused cells were lost, the cancer-like behavior returned. In the case of human cancer cells fused to mouse cells it was the human chromosomes that were lost.
A red cell and a green cell fuse to form one cell with both nuclei, all the chromosomes and all the genes. Over time chromosomes from one of the original cells can be lost. (iskweb.co.jp)
The explanation is that there are genes on human chromosomes that suppress cancer, and if they are broken or absent the cells behave like cancer. When the chromosome containing those genes is added back following fusion with a normal cell, the fused cells behave as if they were not cancer. Once the chromosome containing the special genes is lost from the fused cells they once again behave as cancer. Thus these genes are called tumor suppressor genes. But is this true of cancer in intact animals? Do the genes behave in the same way with cancer in an animal or just with cancer ‘in a dish’? Answering this question was accomplished by putting DNA coding for mutated tumor suppressor genes into mice. In one example, transgenic animals were produced by inserting a tumor suppressor gene (a gene called p53) that was mutated or not functional. The transgenic mice were more susceptible to forming lung cancer after treatment with cancer causing chemicals than animals that did not have the mutated form. This worked even though the normal suppressor genes were still present in the transgenic animal. The normal tumor suppressor was overwhelmed by the mutated p53 and the result was cancer. So in this case the p53 tumor suppressor is like a brake stopping cancer and when the brake is broken and installed in the cell it develops cancer even though the normal, cancer suppressing gene of p53 is still there. This turns out to be important in the terrible childhood brain cancer medulloblastma.
Following work with cell fusion the investigation of how viruses can cause cancers in animals led to the discovery of a class of genes, known as oncogenes that cause cancer under special circumstances. Originally it was thought that the virus carried these genes as their own and inserted them into the animal’s genome. It is now known that the virus, when it invades a cell and takes over the cell’s genetic machinery, picks up genes that are normal in the cell and then in another cycle of infection inserts them into the animal’s genome in the wrong place where the genes escape normal controls. Without normal controls they can act as oncogenes, cancer causing genes. Genes that are normally not active in adults can become active either because a mutation prevents their regulation or because a piece of chromosome carrying the oncogene moves, or translocates to some other chromosomal location that keeps the gene active. It can then cause cancer.
The proof of the pudding for a cancer-causing gene is to insert it into an animal and determine if it results in cancer formation. For medulloblastoma the oncogene N-myc (MYCN) is a causative oncogene and by using GMOs we now know that N-myc can induce mutations in p53. So N-myc is the gas pedal and p53 is the brake. When the gas pedal (for cell division) is stuck down and the brake (tumor suppression) is broken the result is brain cancer. Our lab showed (with Dr. David Walterhouse) that in medullblasotma of children another important oncogenic pathway was interacting with p53, the Sonic Hedgehog/PTCH/GLI pathway discussed in an earlier post. We now know that GLI, a molecular switch that turns other genes on and off, competes with p53 for a rate-limiting co-factor (another part of these switches). When GLI wins the result is cancer.
So childhood cancers are a complex series of overlapping and interacting networks that can be worked out using GMOs. Once they are worked out therapeutic targets emerge and the pharmaceutical industry can develop drugs to attack those targets. Early testing of the utility of the drugs also occurs in the transgenic GMO models developed to identify the mechanism of cancer formation. They have contributed greatly to our understanding of cancer and to our ability to treat it.
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Originally published at lcresearchcenter.tumblr.com.