From lab-made cows to gene-altered goats
They look like normal black-and-white Holstein cows, a common sight in Western Iowa. But these cows are special: used not for their milk or meat, but for their blood. They’re plasma donors, and one day, the life they save may be your own.
The cows were genetically engineered by biotech company SAB Biotherapeutics to produce human antibodies, proteins that fight pathogens. These antibodies could one day treat infectious diseases like Ebola, influenza, and Zika — and their potential to address global outbreaks was recognized this summer by the World Health Organization.
USED NOT FOR THEIR MILK OR MEAT, BUT FOR THEIR BLOOD
SAB’s cattle are just the latest example of lab-made animals engineered to be drug factories. Last year, the US Food and Drug Administration approved a genetically modified chicken that makes a drug in its eggs to treat “lysosomal acid lipase deficiency” — a rare genetic condition that prevents the body from breaking down fatty molecules inside cells. In 2014, the FDA approved a drug collected from the milk of lab-made rabbits to treat hereditary angioedema, a genetic disease that causes body swelling and can be fatal. And in 2009, the FDA approved a genetically altered goat that can make a drug in its milk that prevents fatal blood clots.
These transgenic animals are promising because they could make drug-manufacturing cheaper in the long run. Once created, the animals can basically keep pumping out drugs at a low cost — the cost of maintaining chickens and goats in a farm. And now that new gene-editing techniques like CRISPR-Cas9 are making swapping and inserting genes easier than ever, creating new animals in the lab will be faster and cheaper. “I expect that we will see this progressing at light speed now,” says William Muir, a professor of animal sciences at Purdue University. “We know the technology, we know how to use it, and we’re just waiting for, how many applications can we use it for?”
Antibodies made by animals have been used before to treat diseases. In the 1890s, German bacteriologist Emil von Behring was the first one to use serum from animals like horses to treat diphtheria, an infection of the nose and throat that can be deadly. (He won the first Nobel Prize in Physiology or Medicine in 1901 for his discoveries.) But the human body recognizes these animal antibodies as foreign, which can make for severe allergic reactions. In SAB’s cows, their bovine antibody genes were turned off and replaced with the human version of those genes, so the cows can make fully human antibodies. “This is really just an extension of that technology that was discovered many many years ago, by being able to produce this human version in an animal,” says Eddie Sullivan, SAB’s president and CEO.
To create the antibodies, the cows are injected with a virus, for instance Ebola, that creates an immune response. After the cows have produced enough antibodies to that disease, their plasma is extracted three times per month, says Sullivan. The antibodies are then isolated from the plasma, purified, and made into a drug. “We are simply boosting a patient’s own immune system, using the natural proteins that we use in our bodies — these antibodies — to fight disease,” Sullivan says.
Transgenic animals have actually been used for a long time by pharmaceutical companies — usually to discover new antibodies that were then made into drugs. In the early 1990s, for example, mice were genetically engineered to produce human antibodies. This is how pharmaceutical companies discovered many new antibodies for use in drugs, says Robert Etches, the president and CEO of antibody discovery company Crystal Bioscience. That’s how Novartis’s Arzerra, marketed for a kind of bone cancer, was discovered, for instance.
But since then, the field has progressed slowly. Only a few animals that produce drugs in their eggs or milk — like the transgenic chicken made by Alexion Pharmaceuticals — have been approved by the FDA. The reasons, according to many in the field, are public concerns over genetically modified organisms (GMOs).
PUBLIC CONCERNS OVER GMOS HAVE MADE IT HARD TO ATTRACT INVESTMENT
The controversies in the US and Europe have made it hard to attract investment in the technology, says Sullivan. That’s because investors have qualms about funding “controversial” research, says Alison Van Eenennaam, an expert in animal genomics and biotechnology at the University of California, Davis. “The global furor has made investors wary,” she says. Animal welfare groups also oppose the practice. The Humane Society of the United States, an animal rights group, criticized the FDA’s approval of the first drug made by genetically altered goats in 2009. The organization also opposes SAB’s cows.
“We are of course in favor of developing safe and effective products and therapies, but we don’t think that investing in what is called ‘pharming’ is the best way to do it,” says Pascaline Clerc, the senior director of animal research issues at The Humane Society of the United States. “It kind of perpetuates the notion that they are disposable … that they’re a tool for human use.”
Here in the US, SAB’s Iowan cows are more the exception than the rule. Another barrier to adoption is that most US pharma companies already have sophisticated facilities for manufacturing drugs, which cost hundreds of millions of dollars to build, says Mark Westhusin, a professor at Texas A&M College of Veterinary Medicine. Existing companies may be reluctant to switch to so-called “pharming” since they’ve already sunk so much money into equipment. “If I’ve got a tractor that already works fine and I’m making a lot of money on it, why do I want to buy a new tractor, even though it’s more efficient?” says Westhusin.
There may be more potential in developing countries, though, Westhusin says. He’s developing genetically altered goats that can create an anti-malaria vaccine in their milk. Such goats could be a gold mine for African countries where the disease is widespread, but that can’t afford expensive facilities. Instead, the goats are cheap to keep and give a huge return for your bucks: one goat is estimated to produce 8 million doses of vaccine, Westhusin says. “It has tremendous potential.”
ONE GOAT CAN PRODUCE 8 MILLION DOSES OF VACCINE
The genetically altered cows are particularly valuable because they create polyclonal antibodies, antibodies that can attack bacteria, viruses, and even cancer cells in multiple areas. (Monoclonal antibodies, like AbbVie’s Humira, latch onto their targets in one area only and are incredibly expensive to produce.) Polyclonal antibodies are the natural way our bodies fight diseases, and they can only be produced by living animals. The cows also produce more antibodies than humans do — 30 to 60 liters of plasma per month versus about four liters per person. The antibodies extracted from that much plasma hold the potential of treating several hundred patients.
The cows’ antibodies are currently undergoing two clinical trials to determine if they’re safe. In one trial, set to enroll up to 70 people, the National Institutes of Health is testing the cow-derived drug to treat a respiratory disease that has no treatment called Middle Eastern respiratory syndrome (MERS). Another trial, conducted at Brigham and Women’s Hospital in Boston, has already enrolled a patient with a rare bacterial infection, with more patients to follow. Many more trials will have to be conducted before the antibodies hit the market — and that could take years. But for now the technology seems promising. “For polyclonal antibodies, this is a very interesting opportunity for the future,” says Van Eenennaam at UC Davis.
The trials suggest that these cows are serious business. Though there are certainly objections to creating drugs from genetically modified animals, many in the field believe the technology is only likely to become more popular: “I’m betting on it,” says Westhusin.