David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
A quick fix toward a svelte figure ballooned the incidence of a potentially fatal lung disorder from one or two cases per million to 23 or 46. The appetite-suppressing product that wreaked this havoc was the notorious "fen-phen" combination of anorexigenic agents fenfluramine and phentermine.
FDA pulled fen-phen off the market in 1997, after finding that it inflicted primary pulmonary hypertension (PPH) on the myriad hapless women (and some men) who popped the toxic pills to combat obesity. One such PPH woman is the wife of clinical psychologist Armond Aserinsky, who founded Pulmonary Hypertension Central Inc., in Philadelphia, as a family support center for victims of the disease. (See BioWorld Today, June 1, 2000, p. 1.)
The banned drug combination acts as one of several trigger factors that jump-start PPH by upsetting the endothelial cells lining the lung's blood vessels, causing them to release cytokines and growth factors. The creeping onset of PPH is a pulmonary early-mid-life crisis marked by shortness of breath, skimpy oxygen in the blood and critical upsurge of arterial pressure in the lungs, due to obstruction of precapillaries.
These symptoms denote a parting of the ways between the air entering the lungs and the blood perfusing them. Once PPH is diagnosed, therapy usually features vasodilators - akin to treatment for asthma. But the disease progresses over two or three years to heart failure or sudden death. The only efficacious intervention of last resort is heart-lung or lung organ transplantation.
However, pulmonary hypertension existed long before fen-phen. Like breast cancer, it has hereditary (about 10 percent) and sporadic components, and a 5-to-1 preponderance of female victims. A paper in the September issue of Nature Genetics explores this genetic pattern in a paper titled: "Heterozygous germline mutations in BMPR2, encoding a TGF-b, cause familial primary pulmonary hypertension." Its Anglo-American co-authors belong to the International PPH Consortium.
The team set up a panel of eight PPH kindreds for candidate gene mutational analysis. The gene they fingered, on the long arm of chromosome 2, encodes bone morphogenic receptor type II (BMPR2), which belongs to the transforming growth factor-beta receptor family. In seven of the eight PPH-susceptible families studied, they encountered a variety of mutations - two frameshift, two nonsense, three missense.
One intriguing connection cited in the commentary (titled "Pulling apart pulmonary hypertension") accompanying the paper is that the complex vascular lesions in PPH "have been likened to the multifocal neoplasia formed in familial adenomatous coli - colorectal cancer."
Salmonella, Ace Food-Poisoning Bacterium, Colonizes Intestine, According To New Mouse Experiments
Salmonella has nothing to do with the fish by that moniker. The intestinal pathogen bears the name of its long-ago discoverer, American pathologist Daniel Salmon (1850-1914). One of the bacterium's numerous types, S. enteritidis (which has 2,000 antigenic variants) perpetrates fully 85 percent of the serious food poisoning occurring in the U.S. Fish aside, its fecal infection is passed on to humans by cats, dogs, ducks, hens, mice, rats - as well as pet turtles and contaminated marijuana.
So it's no wonder that bacteriologists would like to know more about just how Salmonella does what it does in the human gut. A research paper in the September 2000 issue of the journal Infection and Immunity reports the bug's devious mechanism, as well as current misconceptions. Its title: "Invasion genes are not required for Salmonella ernterica serovar [antigenic subtype] typhimurium to breach the intestinal epithelium: Evidence that Salmonella pathogenicity island 1 has alternative functions during infection." Its authors are a microbiologist and a molecular geneticist at Harvard Medical School, in Boston.
Their findings seem to contradict a decade-old understanding of how the germ launches its gut-wrenching invasion. Received wisdom says that to gain its foothold, S. enterica passes from the stomach into the small intestine, and invades the walls of its last 12-foot length, the ileum, which abuts on the large intestine - the colon. To break through that wall, the bacterium sends a bundle of genes from its single chromosome to express a set of proteins that take over the cytoskeletal structure of those epithelial cells.
Rebutting that common knowledge, the journal article reports, based on mouse experiments, that instead of penetrating the ileal wall, Salmonella settles down in situ and proceeds to colonize that gut. The co-authors infected mice with S. enterica lacking the bacterium's bundle of invasion genes. Amazingly, those gene-knockout microbes penetrated the rodents' intestinal wall as easily as wild-type typhimurium. The co-authors surmise that the bacterium lures its host's immune cells to the site of infection and kills them, leaving the way wide open to infection.
They conclude that "Understanding infection in mice could lead to new therapies and, possibly, vaccines for humans."
Prion Diseases Can't Cross From Species To Species? Don't Bet On It
Another widely accepted belief holds that transmission of prions - the cause of bovine spongiform encephalopathy (BSE), or mad cow disease - in cattle, and Creutzfeldt-Jakob disease (CJD) in humans - is barred by a "species barrier." This limitation on infection between mammalian species supposedly depends on the structural differences in prion proteins between infecting agent and host. But a paper in the Proceedings of the National Academy of Sciences (PNAS) dated Aug. 29, 2000, demonstrates that hamster prions presumed to be nonpathogenic for normal mice actually led to high prion levels in the brains of such mice - but without causing clinical disease. The article, by authors at the Imperial College of Medicine, London, carries the title: "Species-barrier-independent prion replication in apparently resistant species."
"These results," the paper states, "demonstrate the existence of subclinical forms of prion infection with important public health implications, both with respect to iatrogenic [treatment-caused] transmission from apparently healthy humans and dietary exposure to cattle . . . . The appearance of a novel human prion disease, variant CJD, in the U.K. from 1995 onward, and the experimental evidence that this disease is caused by the same prion strain as that causing BSE in cattle, has raised the possibility that a major epidemic of variant CJD will occur in the U.K. and other countries as a result of dietary or other exposure to BSE prions." (See BioWorld Today, July 28, 2000, p. 1.)
The PNAS paper concludes that "Current definitions of the species barrier . . . need to be fundamentally reassessed."