Chapter 10: Gene Expression and RegulationIssues in Biology |
From time to time, we hear reports of strange scientific experiments that make us wonder, "Why on earth would anyone want to do that?" One example occurred in 1995, when newspapers, magazines, and newscasts reported the existence of some very bizarre flies in Switzerland. Using genetic engineering techniques, Swiss researchers, led by Walter Gehring, had produced flies with additional eyes. Instead of the normal situation in which the fly has two eyes, each properly located on the side of the head, these genetic anomalies had eyes on their knees, their antennae, their wings, and other strange places. One fly had fourteen “eyes” located in various positions on its body! When people heard this report, they imagined stories of Frankenstein and other mad scientists of Western literature—who else would attempt such a feat? However, the real question the researchers were asking had nothing to do with creating a “visually-endowed” fly. Instead, it dealt with the most fundamental nature of how genes determine the structure of body parts in organisms. And the way they answered the question was elegant and straightforward.
During development of a multicellular organism, whether it is a fly or a human, specific genes must be turned on in a temporally programmed series. This hierarchy of gene expression enables cells to adopt their ultimate location, shape, and function within the developing organism. In the case of eye development, about 2,000 different genes must be “turned on” at the proper time and place for eyes to develop properly. Such genetic “pyramid schemes” underlie the formation of all tissues and organs in multicellular organisms. A good illustration of this process is to consider a complex array of dominoes, each poised to topple one or more other dominoes set up nearby. When one domino falls, a chain reaction occurs in which dozens or hundreds of other dominoes also fall, in a specified timing and order. When the whole event is over, the pattern of dominos that have fallen versus those that have been left standing depends on which initial domino was toppled.
In organisms, the first "dominoes" in a gene regulation pyramid are sometimes called master control genes. These genes encode proteins that bind to the control regions of other genes and turn them on (i.e., activate transcription). As a result, a second tier of genes is activated, many of which also activate expression of a third tier of genes. The process continues in a kind of genetic chain reaction until, ultimately, the set of proteins that are uniquely expressed in that particular cell is activated. For example, in red blood cells, hemoglobin must be produced since it carries oxygen and carbon dioxide. In eyes, the protein rhodopsin must be produced since it is the primary light receptor.
What are the master control genes that stimulate eye development? For such developmental questions, the fruit fly, Drosophila melanogaster, is a wonderful experimental organism. Mutant flies had been discovered that lack eyes altogether. The defective gene in these flies was identified and given the rather obvious name, “eyeless.” The eyeless gene was cloned and its DNA sequence was determined. Now, the fun began in earnest. There are massive databases on the World Wide Web in which researchers throughout the world deposit information about the sequences of the genes they have discovered. In fact, it is typically a requirement of the publishers of scientific journals that information about a gene’s sequence is placed in these amazing resources. The most common one is GenBank, a database managed by the U.S. National Center for Biotechnology Information. This information is an incredible boon to genetic research because it lets a researcher compare a gene sequence they are studying to that of ALL OTHER known genes on the planet. In many cases you can get clues about what your gene is doing by learning what it does in other organisms.
Here’s where Gehring’s group hit paydirt. They found other genes in the database that were similar to the eyeless gene of Drosophila. One is the Pax-6 gene from mice and the other is the aniridia gene from humans. Amazingly, both of these genes are involved in eye development. Mice with defects in the Pax-6 gene have small eyes and humans with defects in their aniridia gene lack an iris. This information suggested the possibility that development of eyes in vertebrates might be similar to the development of eyes in flies, even though the basic design of their eyes is different (vertebrates have a simple eye and flies have a compound eye). How can this hypothesis be tested?
The first step is to determine if eyeless itself is a master control gene. How can this idea be tested? In normal development, the eyeless gene is turned on only in cells that will become cells of the eye. If eyeless is truly a master control gene, turning it on in the wrong cells will produce eyes in the wrong places. This is exactly where the many-eyed flies came from. Using genetic engineering techniques, Gehring’s team produced flies in which they could turn on the eyeless gene in cells that would normally just produce legs or wings or antennae. In all these cases, the developmental fate of at least some of the cells was short-circuited. For example, instead of becoming wing cells as unusual, some of the wing cells that were expressing the eyeless gene became eye cells instead. This result clearly showed that eyeless is one of the master control genes needed for eye cell differentiation.
Now, they can test the idea further. They took the mouse Pax-6 gene and the human aniridia gene and expressed them in flies. These genes were also able to induce eyes in places that eyes don’t normally exist. Thus, these genes are likely to be master control genes for eye development as well.
So, other than revealing more about the principles of gene regulation and its relationship to development, why are these experiments interesting? One possibility is that, by manipulating gene expression in the retina, scientists may be able one day to restore sight to people with damaged retinas. Normally, these cells do not divide, so damage to the retina is irreversible. However, if it were possible to transplant cells and turn on the genetic program that will produce more retinal cells, some vision might be restored. So, the next time you hear about some apparent crazy experiments, perhaps you will delve deeper to find the real reason that the scientists devote their energy, as well as your tax dollars, to these studies.