By Rick Weiss
Washington Post Staff Writer
Monday, January 1, 2007
Scientists said yesterday that they have used genetic engineering techniques to produce the first cattle that may be biologically incapable of getting mad cow disease.
The animals, which lack a gene that is crucial to the disease's progression, were not designed for use as food. They were created so that human pharmaceuticals can be made in their blood without the danger that those products might get contaminated with the infectious agent that causes mad cow.
That agent, a protein known as a prion (pronounced PREE-on), can cause a fatal human ailment, variant Creutzfeldt-Jakob disease, if it gets into the body.
More generally, scientists said, the animals will facilitate studies of prions, which are among the strangest of all known infectious agents because they do not contain any genetic material. Prions also cause scrapie in sheep and fatal wasting diseases in elk and minks.
In the future, experts said, similar techniques might be used to engineer animals with more nutritious meats -- though the Food and Drug Administration has said it will require engineered food animals to pass tests far more stringent than those it recently deemed adequate for clones.
"This is a seminal research paper," said Barbara Glenn, director for animal biotechnology at the Biotechnology Industry Organization, a Washington industry group that counts among its members Hematech, the Sioux Falls, S.D.-based company that created the gene-altered cattle.
"This shows the application of transgenics to improving livestock production and ultimately food production."
Prions, which are normal protein components of the brain, immune system and other tissues, cause disease only when they "go bad." For these long strands of protein, that means folding themselves into three-dimensional shapes that are slightly different from their conventional conformation.
Prions remain poorly understood, but experiments suggest that it takes just one bad one to ruin a brain. That's because a badly folded prion in the brain can strong-arm normal, nearby prions, turning good prions bad.
So, although prions are not able to replicate themselves the way bacteria and viruses do -- by creating new offspring -- they can amplify their numbers and spread disease as long as there are normal prions around to be recruited.
That recruitment requirement gave Hematech scientists an idea: Why not make prion-free cattle?
First, they cultivated a colony of cattle cells in a laboratory dish. Then they used a genetic engineering method to "knock out" just one gene inside each cell -- the gene that directs the production of prion proteins.
Finally, using cloning techniques, the team grew a dozen calves, each from one of those altered cells. Because the starter cell from which each animal was grown lacked the prion gene, so did all the daughter cells that ultimately constituted the animals' bodies.
Today, as far as scientists can tell, those 12 cattle are wholly lacking in prions.
The fact that they developed properly and remain healthy even as they approach their second birthdays has already answered one of the more contentious questions in prion biology: Can an animal live without its normal prions?
Experiments by various research teams have, over the years, suggested that normal prions might be crucial for such varied processes as blood formation and memory. But by every test the team has been able to administer, these cattle seem fine, said Juergen A. Richt of the Agriculture Department's National Animal Disease Center in Ames, Iowa, who has been studying them.
"Apparently it is not vital," Richt said. "By our analysis -- how do they eat, how is their heart rate, how is their immunological function -- they seem to be normal."
Richt emphasized, however, that the cattle are still young and may show signs of trouble as they age.
Next came the question of whether they are protected against mad cow disease, also known as bovine spongiform encephalopathy, or BSE. In one experiment, tissues from one of the animals' brains were grown in a culture dish and exposed to two different strains of infectious, mad cow prions. As expected, the bad prions did not propagate, according to a report in yesterday's online issue of the journal Nature Biotechnology.
A more definitive test -- injection of mad cow prions directly into the brains of living prion-free animals --is now underway. Because it can take two years or more for symptoms to appear (and even longer if prions are eaten, the usual mode of transmission), it will be another six months or so before the results will be known, said James M. Robl, Hematech's president and chief scientific officer.
Until December 2003, mad cow disease had never been found in American cattle. That made the pristine U.S. herd an ideal resource for companies that extract blood and other products from cattle for use in human pharmaceuticals.
Later, two other BSE-infected animals were identified, inspiring Robl and his teammates to develop prion-free cattle.
But policies enacted in recent years by the Agriculture Department have so reduced the risk of BSE in this country, Robl said (current estimates are that, at most, four to seven cases might be found if all 42 million head of U.S. cattle were to be tested) that it may not be necessary for Hematech to use prion-free cattle as it strives to make potent, disease-killing antibodies in cattle for use in humans with life-threatening infections.
"If BSE becomes an issue, we'll know we can make these knock-outs," Robl said. "So it's more insurance at this point."