By David N. Leff
Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
So, naturalists observe, a flea
Hath smaller fleas that on him prey;
And these have smaller still to bite 'em;
And so proceed ad infinitum
These lines, penned a quarter-millennium ago by Jonathan Swift, may serve today to illustrate the struggle of lower life forms to wrest iron from their mammalian betters. From humans to bacteria to fungi, all oxygen-breathing creatures depend on a steady supply of iron in their diet. By that token, each erects metabolic safeguards to keep its iron stashes away from raiders.
A case in point is Candida albicans, a ubiquitous fungus that wreaks the itchy torment of candidiasis on humans, young and old, especially women. In 30 percent or so of people, the fungus maintains a benign stand-off with the body's immune system. But when those defenses fail - as in patients on chemotherapy or immunocompromised AIDS victims - systemic C. albicans infection can be fatal. Antifungal remedies are so drastic that they, too, may threaten life.
Just how the fungus goes about heisting its iron loot from its victim is a black box in which researchers at the Institute of Molecular and Cell Biology in Singapore have opened a crack. Their report in Science dated May 12, 2000, is titled: "A high-affinity iron permease essential for Candida albicans virulence." Permeases are enzymes that smuggle molecules in solution across cell-surface membranes - which is precisely where C. albicans cells adhere.
The Singapore scientists isolated a fungal gene, CaFTR1, which expressed a major iron permease. They showed in mice that this gene "was indeed essential for C. albicans to grow and to cause systemic infection in the host." The gene, they conclude, "represents a potential target for the development of anti-Candida therapies."
Osteoclasts - Bone-Building Cells - Travel To Construction Site On Foot, Via Podosomes
Osteoblasts and osteoclasts are the yin and yang of skeletal bone formation. The first lays down the matrix and minerals that comprise the bony substance; the second whittles them away. That constant tradeoff maintains the balance between too little and too much bone density. Osteoporosis happens when overactive osteoclast cells beat out osteoblast cells in this lifelong wash, which normally nets neither gain nor loss.
An osteoclast travels to its bone-diminishing work site on foot. That is, the sizeable, multinucleated cell perambulates on foot-like extensions called podosomes. Those cells can't get far if they lack a protein called gelsolin, which helps give podosomes their shape and rigidity. Mice lacking gelsolin grow thicker, stronger bones because of their osteoclasts' decreased mobility.
In the April 2000 Journal of Biological Chemistry, Keith Hruska, a nephrologist at Washington University in St. Louis, identifies factors that interact with gelsolin, so would make good inhibitors of osteoclast movement. His paper bears the title: "Rho-A is critical for osteoclast podosome organization, mobility and bone resorption."
Rho is a protein that stimulates a rare enzyme present at sites where podosomes develop. Hruska suggests that the specialized fat molecule it produces acts as a glue, connecting proteins that form the inner structure of podosomes.
He and his co-authors suggest that chemicals that inhibit gelsolin-associated proteins - such as the enzyme and Rho - might shut down osteoclast activity, and slow the progression of osteoporosis. It might also work against tumor cells that metastasize to new sites on podosomes.
Construction Of Largest Known RNA Virus Packs Surprises, Clues To Viral Pathogenesis
Biotechnologists in Spain have constructed a full-length, infectious coronavirus - a feat until now thought to be unachievable. Their report appears in the current Proceedings of the National Academy of Sciences (PNAS), dated May 9, 2000, under the title: "Engineering the largest RNA virus genome as an infectious bacterial artificial chromosome."
The 27-kilobase virion they synthesized at the Campus Universidad Autsnoma's National Center for Biotechnology in Madrid is "the longest viral RNA genome by far," according to a commentary accompanying their PNAS article. The virus they tackled is known as TGEV - transmissible gastroenteritis virus of swine - a strain that replicates exclusively in the respiratory tract of newborn piglets. Coronavirus also infects birds with bronchitis, mice with hepatitis, calves with diarrhea, and people with the common cold.
"A very surprising finding of this study," said the commentary - authored by molecular microbiologist Michael Lai at the University of Southern California in Los Angeles - "is that the coronaviral RNA, which is normally present only in the cytoplasm, is not spliced in the nucleus and is successfully exported as an intact molecule to the cytoplasm."
Substance P Mediates Depression, Anxiety, Stress - Plus Rewards Of Food, Opiates
Mice deprived of substance P, a brain neuropeptide, kick morphine addiction, but still get a kick from cocaine. An article in Nature dated May 11, 2000, probes this counterintuitive phenomenon. Its title: "Rewarding effects of opiates are absent in mice lacking the receptor for substance P." The paper reports research at University College, London, and Universidad Miguel Hernandez in Alicante, Spain.
Substance P's receptor is widely expressed in one area of the brain implicated in depression, anxiety and stress. Reformed drug addicts (and mice) who become stressed out are likely to relapse into their addiction.
The co-authors found other brain areas, notably the nucleus accumbens, which mediate reward-seeking motivation - as provided by food and opiates of abuse, such as morphine. The article confirms "a contention that the rewarding effects of cocaine may be mediated by brain mechanisms partially distinct from those involved in opiate reward."
The Nature paper's bottom line makes the point, "Stress responses can be attenuated by substance P receptor antagonists or by genetic disruption of the substance P receptor. Therefore, drugs that antagonize the actions of substance P may be powerful new tools in both the treatment of opiate drug addiction and the prevention of relapse into drug taking."