By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
It took 193 co-authors from 34 academic, commercial and government laboratories in eight countries to achieve the feat reported in Science's cover story, dated March 24, 2000 - namely, completing "The genome sequence of Drosophila melanogaster." The monumental 11-page paper's co-senior authors are J. Craig Venter, president of Celera Genomics, of Rockville, Md., and Gerald Rubin, leader of BDGP - the University of California's Berkeley Drosophila Genome Project
BDGP, jointly with EDGP, its European counterpart, constitute the public consortium engaged in sequencing the entire human genome in competition with Celera. (See BioWorld Today, April 7, 2000, p. 1)
The announcement in Science of the fruit fly's genome sequencing led off by observing that "The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans."
Ten pages later, it concluded: "The genome sequence and the set of 13,601 predicted genes presented here are considered Release 1. Both will evolve over time as additional sequence gaps are closed, annotations are improved, cDNAs are sequenced, and genes are functionally characterized.
"The diversity of predicted genes and gene products," it went on, "will serve as the raw material for continued experimental work aimed at unraveling the molecular mechanisms underlying development, aging and many other processes common to metazoans [multicellular animal organisms] for which Drosophila is such an excellent model."
On the eve of this published report, March 23, 2000, in Pittsburgh, 1,300 members attending the annual meeting of the Fly Biologists Association "found on their chairs [as reported by The New York Times] a gift from Celera, a CD-ROM of the genome sequence of their favorite organism." In acknowledgment, the association's president, Gary Karpen, of the Salk Institute in La Jolla, Calif., said, "We are about to be handed an incredible tool that many of us only dreamed about for many years."
This annotated sequence, the Science article pointed out, "will provide the foundation for a new era of sophisticated functional studies." Elsewhere in the paper it commented that, "Overall, the correspondence of Drosophila proteins involved in gene expression and metabolism to their human counterparts reaffirms that the fly represents a suitable experimental platform for the examination of human disease networks involved in replication, repair, translation and the metabolism of drugs and toxins."
And it noted: "We began whole-genome shotgun sequencing of Drosophila less than one year ago, with two major goals: (i) to test the strategy on a large and complex eukaryotic genome as a prelude to sequencing the human genome, and (ii) to provide a complete, high-quality genomic sequence to the Drosophila research community so as to advance research in this important model organism."
Two Sets Of Neurologists Show Why apoE4, But Not apoE3, Is An Alzheimer's Risk Factor
A pair of scientific journals, Nature and the Proceedings of the National Academy of Sciences (PNAS) climbed on the same bandwagon last month to probe how apoE4, a hallmark molecule of Alzheimer's disease, gets in its dirty work.
In Nature's issue dated Mar. 23, 2000, a research report by neurologists at the University of California/San Francisco bore the title: "Apolipoprotein E and cognitive performance." One week later, PNAS for March 29, 2000, published: "Apolipoprotein E isoform-dependant deposition and neuritic degeneration in a mouse model of Alzheimer's disease," reported by co-authors at Washington University in St. Louis, Mo.
The PNAS team showed - reportedly for the first time - that apoE directly fosters the development in the brain's hippocampus and neocortex - centers of memory and cognition, respectively - of amyloid-rich neuritic plaques, which are telltale postmortem markers of the disease. Moreover, they found that apoE4, the molecule's high-risk version, does far more damage to the affected neurons than does apoE3.
In vivo mouse studies showed that amyloid deposits alone did no damage, but in the presence of apoE the amyloid shaped up into fibrils, and plaques around the damaged neurons appeared. Moreover, mice that made both human amyloid-beta and human apoE4 had 10 times as many fibrillar deposits as those that made apoE3. This effect, productive of neurodegeneration, appeared to explain the main reason why apoE4, but not apoE3, is an Alzheimer's disease risk factor.
The co-authors also inserted the gene for human apoE3 or apoE4 into mice that made human amyloid but not murine apoE3. By 15 months of age, the hippocampi of many of these animals had amyloid-beta deposits and plaques with fibrils. But they found these deposits in 89 percent of the apoE4 cohort, compared with only 33 percent of the apoE3 mice. And some apoE4 - but no apoE3 - mice also had amyloid-beta build-up in the brain's neocortex.
"We believe it may be possible to alter the levels of apoE with drug therapy," proposed co-author Steven Paul, group vice president of discovery research and clinical investigation at Eli Lilly & Co., Indianapolis. "Such drugs should inhibit the deposition of amyloid-beta, prevent fibril formation and promote amyloid removal - which would have the potential to slow down and even prevent Alzheimer's disease."
Authors of the Nature paper found that transgenic mice carrying human apoE4 - but not those with apoE3 - had impaired memory, even though both had comparable levels of beta-amyloid in their brains. This cognitive finding, they suggested, "may explain why human apoE4 carriers are at greater risk of developing Alzheimer's than apoE3 carriers."
Autoimmune Muscle Weakness, Attributed To B-Cell Autoantibodies, May Involve T Cells Too
A droopy eyelid, or a pathologically weak handshake, may betray an autoimmune disease marked by muscle weakness, and named myasthenia gravis (MG). Mice, rats, rabbits and monkeys are susceptible to a clinical mimic of MG. The main autoimmune antigen targeted in MG is the nicotinic acetylcholine receptor. That immune targeting is presumed to be deployed mainly by autoantibodies that the immune system's B lymphocytes generate. However, new evidence implicates T cells as well, as reported in The Proceedings of the National Academy of Sciences (PNAS), dated Feb. 29, 2000. The article is titled: "Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice."