What is a synthetic gene? In a manner of speaking all genes are synthetic. Currently accepted theories about gene origins usually describe how a new gene is added to an already existing string of genes. One of the spin-offs of the Human Genome Project has been the development of tools that allow manipulation of individual bases within a DNA molecule. We are at the point in the use of this technology where researchers can construct any sequence of base-pairs. This technology is constantly being refined with its ultimate goal being precise, targeted placement or such artificial gene segments. The time is not far off when you will be able to simply type out a sequence of base-pairs and an automated DNA synthesis machine will produce a string of DNA for you.
As our understanding of cell chemistry and ability to manipulate DNA improves, we see a growing use of terminology that many students find intimidating. The other day we were asked, 'What is a synthetic gene?' Trying to be helpful, we began to explain gene transplantation and they interrupted, saying, 'Not that old stuff, I'm asking about the new 'de novo' ('of new', or from scratch) gene synthesis.' We decided to start at the beginning and describe what is meant by synthetic genes, as well as some of the state-of-the-art techniques that are used to accomplish the placement of such synthetic or artificial genes within a living genome.
In a manner of speaking all genes are synthetic. There has been much speculation, notably by the biologist Richard Dawkins, about the origin of genes and our genetic structure. Currently accepted theories usually describe how a new gene is added to an already existing string of genes. This new gene confers some survival advantage to the organism and is therefore passed on to future generations. For instance, a new gene that increases melanin (a dark skin pigment) production in the skin may be very useful to people living under a tropical sun. A gene, such as the one that causes the 'Sickling' of red blood cells by altering the crystalline properties of our Hemoglobin molecules, may be beneficial if you are exposed to malaria but very detrimental if you live in an area of the world where malaria does not exist.
"New" genes may originate from other species (such as when a viral or bacterial gene becomes part of the human genome) or may be the product of random mutations of the existing DNA structure. As such they are synthetic; although naturally occurring. In this sense all existing genes must have at some time been "new."
Today we think of mutations as an alteration in the "normal" gene structure or sequence within a genome. A high energy particle released from a radioactive element may fly through a cell and collide (just like an asteroid colliding with the earth) with a strand of DNA. This collision fractures the DNA and leaves several pieces scattered about the cell. Internal cell repair mechanisms try to reassemble the DNA strand and usually succeed1. However, several base-pairs may wind up out of order or be altogether missing. This is a mutation. If this mutation interrupts the production of a protein critical to the life of the cell, the cell will die. Likewise, if this mutation causes some wide alteration in the chemistry of the organism, the entire organism may die (cancer is an example of this). If this mutation changes the structure of a protein and allows the organism to live, it may be passed on to future generations. For example, if the mutation caused a change in the shape of a plasma-borne protein to prevent that protein from crystallizing at low temperatures, the organism may find that it can survive colder and colder environments. Such an organism could move into a biome where food is more plentiful or competition less severe, increasing chances for the organism's survival.
With relatively simple laboratory procedures new genes (copies of genes from other species) can be spliced into the existing genome of a organism. Gene 'A' is excised (removed) and gene "B" is put in its place. With such maneuvers eggs of a red-eyed flies have been changed into eggs of blue-eyed flies. Although genes so implanted or exchanged have been referred to as artificial or synthetic genes, they are neither. They are naturally occurring genes moved into a new alien genome. Currently, this is a hot technology. All sorts of mixing and matching of genes are being tried to produce new and often unusual products. Researchers have implanted a gene that codes for the production of a plastic-like molecule (a polyester) from an insect into the genome of a normal cotton plant. The resulting plants produce cotton fibers (normally hollow) filled with a polyester resin. This is (jokingly) an example of a synthetic gene producing a synthetic fiber, naturally.
The correction of aberrant (malfunctioning) genes, or the restoration of gene function is one of the goals of molecular medicine. Many diseases caused by specific genes or small groups of genes may ultimately be cured by repairing the mutant genes. Sometimes inactivation of an abnormal gene may accomplish the same therapeutic effect as repairing that gene. By replacing only a few of the base-pairs within a gene, molecular biologists are able to nullify the effect of that gene. Such molecular medicine works well for genetic disorders that are passed on from generation to generation. Those diseases that arise spontaneously through mutation pose a 'moving target' for modern medicine. Without knowing which genes are involved or the structure of those genes, it becomes almost impossible to counteract their action.
One of the spin-offs of the Human Genome Project has been the development of tools that allow manipulation of individual bases within a DNA molecule. We are at the point in the use of this technology where researchers can construct any sequence of base-pairs2. This technology is constantly being refined with its ultimate goal being precise, targeted placement or such artificial gene segments. The time is not far off when you will be able to simply type out a sequence of base-pairs and an automated DNA synthesis machine will produce a string of DNA for you. Science fiction? There are companies now selling similar services and products. This is true 'de novo' synthesis, starting with raw elements (or in this case molecules) and composing specific base-pair sequences.
On the frontier of molecular biology is the production of base-pair sequences that code for completely unique compounds. Although the base-pairs on DNA have codons that ultimately, through the production of RNA, code for the placement of amino acids; some sequences of similar bases may code for other substances. An alteration in the usual four bases (A,T,C,G) to include some other compound may indeed a bit of DNA to code for the production of some non-protein compound. Non-protein compounds are common in the living world. Almost all such compounds are produced by proteins and protein-based cycles. We know that sequences of base-pairs on the DNA molecule get translated into sequences of amino acids that make up protein molecules. These protein molecules then catalyze the production of many other types of compounds. It is theoretically possible, and there is some evidence from the laboratory, that many non-protein compounds may be produced by reactions similar to those used by RNA to make proteins. If we can harness the production of any compound through a DNA-cycle type of reaction we may, ultimately, develop synthetic lifeforms capable of reproducing themselves and functioning as 'factories' to produce the compounds we need.
The usefulness of all this alchemy may escape you. However, many diseases result from the breakdown of our genetic structure. Some aspect of our biochemistry simply fails to respond to the stress placed upon it and a disease-state develops. Scientists have learned how to take a chromosome (containing genes suspected of causing disease) from a human being and place that chromosome into a simple animal or plant, such as a yeast cell. This permits detailed study of how that the genes on that chromosome function and allows us to study the progression of the disease without exposing humans to risky research procedures. An example of this is the construction of a yeast artificial chromosome (YAC) with a gene that causes Usher syndrome, an autosomal recessive deafness. The mapping of this gene and our ability to place it within living yeasts has enabled us to study the development of Usher-type deafness and perhaps find a way to alter its development. Artificial genes have been reported and are being used to study many of our biochemical processes, including the production of Hemoglobin, the oxygen bearing red pigment within our blood.
footnotes:
(1) If the gene is too far gone, the pieces will simply be digested and the molecules reused for other purposes.
(2) Remember, it is the sequence of base-pairs within DNA that makes up the genetic code, or blue print for the organism. Change the sequence of base-pairs and you are changing the blueprint.