Genetically Modified AnimalsScience & Technology — POSTED BY Joe Murray on July 28, 2010 at 11:16 am
UNLESS you live in Europe, your last meal probably contained genetically modified ingredients – 80 per cent of soya grown worldwide is now genetically engineered, for instance. Yet while modified plants are rapidly taking over the planet’s farms, the same cannot be said for GM animals. There’s the occasional flurry of reports about glowing rabbits or marmosets, but no one is yet eating beef from bioengineered bullocks.
From the NewScientist by Bob Holmes
The main reason is that the genetic engineering of animals – with the exception of mice – has been a slow, tedious process needing a lot of money and not a little luck. Behind the scenes, though, a quiet revolution has been taking place. Thanks to a set of new tricks and tools, modifying animals is becoming a lot easier and more precise. That is not only going to transform research, it could also transform the meat and eggs you eat and the milk you drink.
The first transgenic animals were produced by injecting DNA into eggs, implanting the eggs in animals and then waiting weeks or months to see if any offspring had incorporated the extra DNA. Often fewer than 1 in 100 had, making this a long, expensive process. “That’s just really inefficient,” says Scott Fahrenkrug, a geneticist at the University of Minnesota in St Paul.
In mice, geneticists found a way round this problem: producing cells with the desired modification first, before growing entire animals. The researchers alter the DNA in embryonic stem cells growing in a dish, then inject successfully modified cells into embryos. This yields chimeras with a mixture of cells that can be bred to produce mice in which all the cells are modified. It has become cheap and easy: there are now many millions of GM mice in labs worldwide, including extraordinary creations like the “supermouse” capable of running twice as far as normal, “brainbow” mice whose neurons light up in different colours and even mice that do not fear cats.
Saved by the clones
It is not yet possible to grow embryonic stem cells from other animals – except, since last year, rats – so this technique does not work for other species. However, improvements in cloning mean that for many species ordinary cells can be altered, and entire animals then produced by cloning cells with the desired modification.
At the same time, biologists have developed more efficient ways of adding DNA to cells, by hijacking natural genetic engineers such as viruses, and jumping genes capable of “copying and pasting” themselves. All these advances mean the effort and cost needed to produce GM animals has decreased a hundredfold, says Fahrenkrug.
Researchers are also developing far more precise ways of altering DNA, rather than relying on random insertion. One promising new tool is the zinc finger nuclease: a DNA-cutting enzyme attached to a “zinc finger” that can be customised to bind to specific DNA sequences. Zinc finger nucleases allow engineers to cut a cell’s DNA at a preselected spot. When the cell attempts to mend the cut, it often leaves out a few DNA letters or incorporates a few extra ones, so this method can be used to destroy, or knock out, specific genes.
“This will revolutionise genetic engineering of animals,” says Bruce Whitelaw, a geneticist at the Roslin Institute in Edinburgh, UK. “You can design your zinc finger to cut at a specific site in the genome, and it doesn’t matter what that genome is. It could be pig, sheep, dog, rat – it doesn’t matter.”
What’s more, in theory, if you also add a bit of DNA flanked by sequences matching those on either side of the cut, the cell should sometimes be tricked into repairing the cut by splicing in the added DNA – a process known as homologous repair. In other words, the extra DNA is added exactly where you want it. Rumour has it that researchers at the biotech company Sigma-Aldrich are the first to use zinc fingers to achieve this in animals.
The ability to easily and precisely modify animals will undoubtedly lead to huge pay-offs in research and medicine. Whether it will transform the animal products we consume is less clear.
The US Food and Drug Administration, which regulates GM animals, has yet to approve one for agricultural use. The first candidate, a fast-growing salmon, has been under review for more than a decade, in part because of fears it could affect wild populations. Such concerns would not apply to most farm animals or pets, and last year, the FDA appeared to be preparing the ground for commercial production of GM animals when it published guidance on the steps a company would have to take to obtain FDA approval. The European Union is working on a similar statement, but this is not expected to be finalised until 2012.
Ultimately, the adoption of GM farm animals may hinge on public opinion and the demand for the benefits they can offer. That demand may be felt most urgently in countries such as China, where meat consumption is skyrocketing. “I anticipate that genetically engineered livestock will be first used in China, Cuba and other places around the world, and then come to the US and Europe,” says James Murray, an animal geneticist at the University of California, Davis. “It’ll be the reverse of what you saw with the plants.”
So in 20 years’ time will GM animals be as widespread as their botanic counterparts are now? “Technologically, nothing is standing in our way,” says Fahrenkrug. “Really, the issue is coming down to: what are you going to make?” Some of the likeliest future developments are presented below.
Tasty meat, milk or eggs
Don’t expect a cow to walk up to your restaurant table and offer you a prime cut anytime soon. Nonetheless, genetically modified farm animals could provide us with more nutritious meat, milk and eggs, while causing fewer pollution problems and perhaps suffering less too.
Pigs whose muscles are enriched with omega-3s have already been created, and researchers are exploring similar options with milk. Meanwhile, a team at the University of Guelph in Ontario, Canada, has developed a pig that contains a gene for a bacterial enzyme that enables them to absorb more phosphorus from their feed. These “Enviropigs” excrete less than half as much phosphorus as ordinary pigs, thus reducing the pollution problem from intensively reared animals. The pigs have not yet been approved for human consumption, but China has begun importing them for testing. “They’re obviously very interested – they consume half of the world’s pork,” says Scott Fahrenkrug of the University of Minnesota. A similar effort under way in fish could reduce pollution from fish farms.
Animals could also be modified to reduce disease risk. Hematech of Sioux Falls, South Dakota, has created a cow that can’t get BSE because it lacks the protein that turns rogue and triggers mad cow disease. Other ideas being tried or considered include making pigs and chickens less susceptible to influenza, and chicken eggs that produce human antibodies to rotavirus, protecting people who eat the eggs against this common gastrointestinal pathogen.
Welfare could be improved, too. Cows have been modified to produce a compound that protects them against udder infections, for example. Engineering could also end the quick slaughter of half of all offspring of dairy cattle and laying hens, whose owners have little use for male animals. This could perhaps be done by inserting genes on a bull’s Y chromosome to cripple male-producing sperm. “The idea has been around for 15 years, but now the efficiency of making transgenics is so high that this problem will be solved within the next couple of years,” says Fahrenkrug, whose group is one of about 10 worldwide working on the issue.
Pets in all colours
The first genetically modified pet to go on sale was a medaka, or rice fish, with a green fluorescent jellyfish gene, launched in Taiwan in 2003. The “Night Pearl”, or TK-1, is sterilised before sale.
It was swiftly followed by the GloFish, a zebrafish with fluorescent genes from jellyfish or corals that has become a popular aquarium fish in the US and parts of Asia, with green, red and yellow versions available and more on the way. Like the medaka, it was a spin-off from scientific research. It is not approved in Australia, Canada, California or Europe, though there have been illegal imports. If released into the wild, it would only have a chance of surviving in tropical regions.
Several years ago, there was talk of genetically engineering cats and dogs that people would not be allergic to. That never happened, but new methods would make knocking out the relevant genes much easier if attempted today.
While there are valid reasons to be concerned about the welfare of GM pets, conventional breeding can also produce deformities, as seen in many dog breeds.
Genetic engineering is now a standard technique in the production of many protein-based drugs. Human insulin, for example, has long been produced by cultures of bacteria carrying the human insulin gene. Pharmaceutical companies are eager to turn animals into drug factories, too. That’s because animal cells alter many of their proteins by tacking on sugars and other “decorations”, an extra step that bacteria cannot perform. As a result, many proteins – most importantly, antibodies – work much better if they are made in animal cells.
One such animal-produced protein has already been approved for clinical use by the US Food and Drug Administration. An anticoagulant called antithrombin III is purified from the milk of genetically engineered goats created by GTC Biotherapeutics, a biotech company in Framingham, Massachusetts.
Many others are under development. The Dutch company Pharming has several products in the pipeline, including human lactoferrin produced in cow’s milk. This antimicrobial compound could be added to foods such as yoghurt. Open Monoclonal Technology of Palo Alto, California, has engineered rats to produce human antibodies. Its first product, an anti-cancer antibody for treating lymphoma, should be in clinical trials within two to three years. And Hematech of Sioux Falls, South Dakota, has produced cattle that it plans to use to make human antibodies to potential bioweapons such as anthrax and smallpox.
We have around 23,500 genes. What do they all do, and which gene variants contribute to common diseases? By disabling genes to see what happens, geneticists can work out what they do. Until recently, however, this was possible only in mice, which are not always the best animals to use. Now genes can be “knocked out” in an ever-growing range of animals.
At the Medical College of Wisconsin, Howard Jacob has used zinc finger nucleases to knock out 43 genes in rats associated with increased risk of high blood pressure or kidney disease. Once, knocking out even a single gene in rats would have been enough to earn someone a doctorate. “I’ve now done 43 PhD’s work in nine months,” says Jacob. He is now raising the resulting animals to see to what extent each gene contributes to disease risk.
The new techniques are being used to create animals that are a big improvement on the mouse “models” used to study human diseases today. “Not only is this low-hanging fruit, it is easier politically to deal with,” says Scott Fahrenkrug at the University of Minnesota. “Most people are OK with this kind of work. The bigger issues are the agricultural ones.”
For instance, Randall Prather’s team at the University of Missouri in Columbia has disabled the CFTR gene in pigs, which causes them to develop symptoms of cystic fibrosis. Using these pigs, the researchers have shown that the lung inflammation characteristic of the disease in humans develops as a result of bacterial infection (Science Translational Medicine, vol 2, p 29ra31). Earlier mouse models of cystic fibrosis had been unable to resolve this question, because mice lacking the CFTR gene do not develop lung disease.
Fahrenkrug’s team have created pigs with high cholesterol by deleting a protein that mops up LDL cholesterol. Since the heart and arteries of pigs are roughly the same size as those of humans, the modified pigs are a realistic testbed for stents and other devices to keep blocked arteries open.
Many people die waiting for organ transplants. Animals could provide an unlimited supply, if only the human immune system did not reject them. So geneticists have been working for years to create pigs whose organs lack the molecules that trigger rejection, such as alpha 1,3-galactosyltransferase. The race is gathering momentum.
Already, a team led by Heiner Niemann at the Institute of Farm Animal Genetics in Mariensee, Germany, has begun testing pig organs modified to be compatible with monkey immune systems. The aim is to get monkeys to survive for 180 days after the transplant – a milestone that would mean they could begin considering trials in humans. So far, however, they have fallen short of that goal. “Occasionally you get the 180 days, but not on a regular basis,” says Niemann.
Meanwhile, Scott Fahrenkrug of the University of Minnesota and his colleagues are working on another major barrier to pig-to-human transplantation: the presence of dormant viruses within the pig genome that could, in theory, reawaken and infect a human recipient. Fahrenkrug has added a gene for a human antiviral protein into pigs in the hope that it will suppress the viruses. If it works, the likely first application will be transplants of insulin-producing islet cells from pigs to humans. “This is personal issue for me,” says Fahrenkrug. “I have friend and family members that have died from the complications of diabetes.”
Bob Holmes is a consultant for New Scientist based in Edmonton, Canada
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