PHARMING FOR FARMACEUTICALS
Pharming: it's not just another misspelled word! The term "pharming" comes from a combination of the words "farming" and "pharmaceuticals" - a melding of the most basic methods of agriculture with the most advanced biotechnology.
Gene pharming is a technology that scientists use to alter an animal's own DNA, or to splice in new DNA, called a transgene, from another species. In pharming, these genetically modified (transgenic) animals are mostly used to make human proteins that have medicinal value. The protein encoded by the transgene is secreted into the animal's milk, eggs or blood, and then collected and purified. Livestock such as cattle, sheep, goats, chickens, rabbits and pigs have already been modified in this way to produce several useful proteins and drugs.
How do you change an animal's DNA?
Producing a whole transgenic animal with the same new piece of DNA incorporated into every single cell may seem like a difficult feat. In reality, it is quite simple, because every animal begins as one cell that divides over and over again until the animal is fully developed. To ensure that every cell in an animal contains the same new piece of DNA, all a scientist needs to do is add the DNA to a single cell (such as a fertilized egg) before it starts dividing. This can be done by microinjecting the cell with a very fine needle. (View the animation to see how this is done.)
The injected embryos are then tested to see which ones have the transgene in their DNA. The ones that do are put in a surrogate mother's uterus to develop. A successful transgenic animal will produce the desired protein without damaging its own health and pass this ability on to its offspring.
Before the advent of cloning techniques, microinjection of fertilized eggs was the only method for producing transgenic livestock. Using this approach to produce a herd or flock of transgenic animals was a long and expensive process, though, because only a small number of animals end up with the transgene in their genome, and not all of these will pass on the transgene to their offspring. Cloning changes the face of pharming technology, however: when one suitable transgenic animal has been raised, it is then possible to produce an unlimited number of genetically identical animals quickly.
What types of products are made using transgenic technology?
The first successful products of genetic engineering were protein drugs like insulin, which is used to treat diabetes, and growth hormone. These proteins are made in large quantities by genetically engineered bacteria or yeast in large "bioreactors." Some drugs are also made in transgenic plants, such as tobacco.
Some human proteins that are used as drugs require biological modifications that only the cells of mammals, such as cows, goats and sheep, can provide. For these drugs, production in transgenic animals is a good option. Using farm animals for drug production has many advantages because they are reproducible, have flexible production and are easily maintained. They also have a great delivery method: just milk them.
Just milk them?
Sure. It's just about the best way to recover large quantities of a protein encoded by a transgene. More importantly, since the mammary gland and milk are not part of the main life support systems of the animal, there is not much risk of harm to the animal that's making the transgenic protein.
The challenge is to get the new transgene expressed only in the milk. To do this, scientists join the gene for the protein drug with a DNA signal, called a promoter, which is only active in the mammary gland. So the transgene, while present in every cell of the animal, is only active where the milk is made. Some examples of the drugs currently being tested are antithrombin III and tissue plasminogen activator to treat blood clots, erythropoietin for anemia, blood clotting factors VIII and IX for hemophilia, and alpha-1-antitrypsin for emphysema and cystic fibrosis.
Spiderman II: Spidergoat?
It sounds like a sequel to "Spiderman: The Movie" - Spidergoat! OK, maybe not, but it is a very interesting application of transgenics. The dragline form of spider silk is regarded as the strongest material known; it's 5 times stronger than steel and twice as strong as Kevlar. People have actually tried starting "spider farms" to harvest silk, but the spiders are too aggressive and territorial to live close together. They also like to eat each other.
Though the genes for dragline silk were isolated several years ago, attempts to produce it in bacterial and mammalian cell culture have failed. When the genes were put into a goat and expressed in the mammary glands, however, the animal produced silk proteins in its milk that could be spun into a fine thread with all the properties of spider-made silk. This can be used to make lighter, stronger bulletproof vests, thinner thread for surgery and stitches or indestructible clothes.
What's all the phuss?
Many people have moral and ethical concerns about the necessity of pharming. Are the ends able to justify the means? Are there other ways to get the same results?
Like other forms of animal research, pharming has the potential to cause suffering and harm to the animals involved. Because of the somewhat random nature of gene insertion of microinjected DNA, genes are not always expressed in the appropriate tissues or at appropriate levels. It is possible that a transgene would be activated in places other than the mammary gland, and the resulting protein may be toxic to the animal.
In addition, there is a chance that the transgene DNA, when microinjected into the fertilized egg, may insert itself into the genome in a way that disrupts the animal's normal gene function. If this happens, it can lead to birth defects, poor brain development, cancer, arthritis, diabetes or other health problems.
To try to avoid these random effects, scientists are using viruses to target where the genes are inserted. A type of virus called a "retrovirus" inserts its genetic material into the cell's genome in a predictable manner, targeting specific sequences that typically don't interrupt the normal functions of a cell.
The retrovirus approach leads to fewer problems with development, but it has raised concerns about the possibility of new viruses being created and spread when the transgene's viral components associate with naturally occurring viruses that may be present in an organism. An alternative to retroviruses is to develop more powerful screening methods to tell if the transgene is functioning properly in the embryo prior to implanting in the uterus.
Another concern is the number of failed attempts to get an acceptable transgenic animal. Typically, only 1% of injected eggs will result in a live birth containing the transgene, and not all of those animals will express the transgene in an acceptable manner. For many, the high cost, in both animal lives and money, of making a transgenic animal is not worth the possible benefits. However, others feel that the cost is justified by the human lives that could be saved by the drugs produced.
Some of the proteins currently being pharmed can be collected from donated human blood. However, the need is far greater than the supply, and there is also the possibility of unwanted contamination in any human blood-derived products. Each case needs to be weighed separately to compare the benefits and risks. For example, in the Spidergoat case, the spider silk would replace many common petroleum-based products that require toxic chemicals to produce.
There are always good and bad points to medical research. Can we justify causing some harm to cure greater suffering? Is the long-term result such that it justifies using animals to produce medically necessary proteins? What about those products that are not necessary but improve quality of life? There are many successes and failures that could argue for or against transgenic research, but it's up to each of us to decide how we think about it.
Funding for this feature was provided by the Educational Resources Development Council, University of Utah.
Author: David Gillespie
Find out more
Ethics, Morality, and Animal Biotechnology (PDF)
Cloning: Uses & Ethics
Science Briefs: GM Animals
Genetically Modified Foods and Organisms
Genetically Modified (GM) Animals
How about crop pharming?
Pharming is not just for animals. See an introduction to the genetically modified food debate with The New, Improved Garden?