By David N. Leff

Science Editor

Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.

Europe – especially Britain – can be hazardous to your health. But that threat may take its time, years to decades of incubation, before a neurologist diagnoses variant Creutzfeldt-Jakob disease (vCJD).

That’s the human form of mad cow disease – transmissible bovine spongiform encephalopathy (BSE). In recent years, some 4 million cattle in the British Isles have been slaughtered as a firewall against The spread of BSE, which had been detected in 180,000 animals. The fatal human and bovine infections are both prion diseases, inflicted by a mutant form of the PrP protein. (See BioWorld Today, March 22, 2001, p. 1.)

From 1994 to this year, 97 cases of human vCJD have been diagnosed in Britain – plus two in France and one in Ireland. Of that number, seven are still alive. So far, no confirmed cases of vCJD have emerged in the U.S.

On Thursday, an advisory panel to the U.S. FDA advised the agency to ban blood transfusions from any donor who spent five years or more in Europe since 1980, or three months or more in the UK from 1980 to 1996.

A paper in the current Proceedings of the National Academy of Sciences (PNAS), dated June 19, 2001, carries the title: “Genetic and environmental factors modify bovine spongiform encephalopathy incubation period in mice.” Its senior author is molecular geneticist Ian Jackson, at the Medical Research Council’s Western General Hospital in Edinburgh, Scotland.

Jackson and his co-authors injected virulent BSE, extracted from the brain of an infected cow, into the brains of 1,200 inbred mice. “We did a genetic cross,” he told BioWorld Today, “between the two inbred strains that we knew differed in their incubation period. In doing the cross, we segregated the progenitor genomes for the two original strains, with their offspring. So each offspring – and we had 1,200 of them – had a different combination of genes from these two parental strains.

“Then we measured the time it took for each of those animals to get the disease – and it varied. That’s what we expected because the two original strains differed by 100 days of incubation. We found new genetic factors that affect the incubation period [IP] of BSE when transmitted into mice. Also that there are environmental factors involved.

“We knew already,” Jackson continued, “that differences in an individual’s genotype – the gene that encodes the prion protein – apparently affect susceptibility to the disease, whether in mice or sheep or humans. We suspected that there would be additional genetic factors, because the two mouse strains that we studied have the same genes, yet they have a different incubation period. But we didn’t know how many of those genes there would be, and how big an effect each of them would confer.

“We found,” he went on, “that we could identify four new genes that affected the IP. They differed from the PrP gene that had been shown before to be involved. We also demonstrated that the age of the mouse at the time of infection has an effect, so that older mice at infection had a shorter IP. Also there appeared to be an effect of the age of the mother: Mice that were offspring of an older mother got the disease more quickly, and we can’t explain why that should be.”

Jackson pointed out, “We did the experiment the way we did – by using an extract from a cow’s brain that had BSE – because we were measuring what affected transmission of the disease between species. And that is of relevance to humans getting vCJD by eating beef from infected cattle.

“Looking at the underlying genes we detected in this experiment,” Jackson observed, “there certainly would be therapeutic and diagnostic implications. In diagnostics there may well be a means of identifying more or less at-risk individuals. And in terms of therapeutics,” he concluded, “understanding the underlying biological mechanisms by which prion diseases are transmitted may well open up drug targets revealed by those interactions.”

Why, At 1 Percent, Is Cloning Of Farm Animals So Inefficient? One Short Answer: Mismethylation

At 4 years of age and going strong, Dolly the sheep is a bellwether role model that cloning of higher life forms is a viable enterprise. Her advent has sparked efforts by laboratories worldwide to clone cattle, pigs and other domestic animals, by variations of cloning and nuclear transfer approaches. Nonetheless, the efficiency of such efforts stays stuck at around 1 percent.

Progeny that survive gestation frequently suffer from gross obesity, heart ailments, lung defects and other setbacks. One school of thought attributes this embryonic failure to aberrant methylation during gestation. This involves the phenomenon of genetic imprinting, where it seems to matter whether you derive both of your parental chromosomal copies from mother or father, or – as in the case of us all – one from each. Early on in development, the embryo seems to “perceive” whether or not it has inherited a copy of each chromosome from each parent. If it hasn’t, then abnormalities occur.

A paper in the June 2001 issue of Nature Medicine, by scientists at the Korea Research Institute of Bioscience and Biotechnology in Taejon, South Korea, is titled: “Aberrant methylation of donor genome in cloned bovine embryos.”

The co-authors studied a specific region of the genome in cells from cloned bovine embryos. They found, unexpectedly, that cells of the cloned blastocysts had methylation patterns resembling those of the donor cells, but also showed wide variation. This indicated that the early genome-wide reprogramming – erasure of the methylation – had gone awry.

Faulty imprinting is blamed for Beckwith-Wiedemann syndrome, a human genomic disorder with many symptoms reminiscent of those cloning stigmata.