Notebook

ANTSY ANTIBIOTICS Humans didn't invent self-medication. Ants got into the act 50 million years ago. The attine ants are expert gardeners, cultivating edible fungi in subterranean "mushroom farms" on food harvested above ground. The most famous attines are the leaf cutters, whose superorganismlike colonies of several million ants are organized into functional castes led by a queen (B. Hölldobler and E.O. Wilson, Journey to the Ants, Harvard University Press, 1994). Their prodigious harvesting of leaves to feed the fungi, and the soil they turn over building the colony, are important in tropical ecosystem dynamics. But there's a fly in the ointment: Another fungus, called Escovopsis, parasitizes the farms. What's a poor ant queen to do? According to graduate student Cameron Currie and colleagues at the Smithsonian Tropical Research Institute, Panama, and the University of Toronto, Canada, like many a parent she insists on antibiotics (C.R. Currie et al., "Fungus-growing ants use antibiotic-producing bacteria to control garden parasites," Nature, 398:701-704, April 22, 1999). The researchers were surprised that fungus-farming ants carry crusty colonies of Streptomyces bacteria on their bodies. "We really had no idea what it might be, but thought it looked microbial in nature," says Currie. The widespread occurrence of the bacteria and their genus-specific location on the ants, indicate that the practice is ancient and highly evolved. Logic says it must also be functional, and indeed Streptomyces isolated from ants inhibited the parasitic Escovopsis but promoted growth of the farmed fungi. Currie thinks the bacteria nix the parasites with antibiotics, which isn't surprising--Streptomyces "belongs to a group of bacteria that are a well-known source for human antibiotics," including streptomycin and fungal-zapping nystatin. Streptomyces is a heretofore unrecognized member of a three-way mutualism including the ants and their fungal crop--a five-way interaction if you count the plants and the parasites. --Barry Palevitz FUNGUS MIMICS INSULIN An African fungus with no known indigenous use has yielded an ingredient of no known biological function that can activate insulin receptors (B. Zhang et al., "Discovery of small molecule insulin mimetic with antidiabetic activity in mice," Science, 284:974-7, May 7, 1999). In transgenic cell cultures and in mouse models, this action appears to be selective to the insulin receptor. "It is astounding, and it's a subject of active investigation," comments coauthor Gino Salituro, the chemist who isolated the ingredient for Merck Research Laboratories in Rahway, N.J. Structurally similar to quinone, and dubbed L-783,281, it comes from the fungus Pseudomassaria, found in the rainforest of the Democratic Republic of Congo. Merck researchers screened more than 50,000 nonpeptides, which aren't quickly degraded by digestive juices, as insulin and other proteins are. They sought a compound that could lead to a pill to replace the need for injection of insulin-dependent diabetes patients. It also might become a novel oral treatment for diabetics with insulin resistance, characterized by the failure of insulin and its receptors to bind. Discovered with the help of Merck researchers in Spain, the agent activates the PI3-K/Akt signaling pathway (see Hot Papers, p. 15), involved in many cellular processes and diseases. "But in this instance, we're only using it as a marker of insulin activation," warns lead author Bei Zhang. Senior author David E. Moller adds, "It's a very early-stage, lead compound. It's very unlikely to ever be a drug." --Steve Bunk FROG DEFORMITY Parasites, rather than pollution or ultraviolet (UV) rays, cause some frogs to sprout extra limbs, report two recent papers. One group experimentally induced extra limbs using trematodes, which are parasites (P.T.J. Johnson et al., "The effect of trematode infection on amphibian limb development and survivorship," Science, 284:802-4, April 30, 1999). Another team failed to find field evidence of retinoids such as vitamin A contributing to extra limbs (S.K. Sessions et al., "Morphological clues from multilegged frogs: are retinoids to blame?" Science, 284:800-2, April 30, 1999). "Together these two studies provide the most convincing evidence we have so far that multilegged amphibians are caused by trematodes," Stanley Sessions, professor of biology at Hartwick College in Oneonta, N.Y., writes in response to an E-mail query. Sessions first raised the trematode hypothesis in 1987. However, pollution and UV rays may still be responsible for other deformities, Tony Maciorowski, senior scientist at the Environmental Protection Agency, notes, adding that deformities may arise from a complex interaction of pollutants, parasites, and UV rays. "In the field you're probably getting some combination of those three. But in terms of one being predominant right now, or one being ruled out, I don't think that's anywhere near the case." Sessions comments that there is little evidence that retinoids or UV rays caused the deformations he and colleagues reported, but he admits they could play a role in others: "We cannot at this time say with confidence that trematodes explain all of the reported cases of missing limbs ... and I strongly doubt that they do." --Paul Smaglik AVIAN ORGASMS The male buffalo weaver stands out among birds in that it has a penis--and possibly enjoys orgasms. The solid rod of connective tissue is most definitely used in copulation, as researchers from the University of Sheffield, England, observed in the forests of Namibia. But it wasn't easy--the birds mate far from their nests, their private parts hidden in foliage and feathers. So the researchers replicated the act--which typically lasts 18 minutes--in the laboratory, giving males access to females as well as a taxidermist's model. The males didn't seem to tell the difference (M. Winterbottom et al., "A stimulatory phalloid organ in a weaver bird," Nature, 399:28, May 6, 1999). The organ rubbed rather than penetrated the female, and this activity seemed to climax with orgasm, at least for the male. "It is extremely difficult to tell whether another organism has had an orgasm. But the male bird shudders and clenches its feet, drawing the female toward it at the moment it ejaculates," reports Tim Birkhead, professor in the department of animal and plant sciences. Because semen was found in the female (or fake female) only after the males climaxed, the researchers tested the hypothesis that orgasm is a prerequisite for ejaculation. They allowed males to mount females, then rubbed the phalloid organs, which prompted the birds to ejaculate. It didn't work if the males had not mounted the females first, establishing that he needs a she (or a reasonable facsimile). Presumably, these rare avian orgasms offer some selective advantage, which might be related to the intense sperm competition characteristic of this species. "One possibility is that the protracted copulation stimulates both the male and the female, and the female then is more likely to retain or take up more of that male's sperm." --Ricki Lewis PERSISTENT VIRUS HIV may be more resistant to existing treatments than previously thought, according to three papers in the May issue of Nature Medicine. Even though aggressive retroviral therapy can reduce plasma virus to undetectable levels, CD4+ T cells serve as latent reservoirs for virus, according to Robert Siliciano and colleagues at Johns Hopkins University Medical School (D. Finzi et al., "Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy," Nature Medicine, 5:512-7, May 1999). Combination therapy can keep the virus at bay, but can't remove it completely. "New approaches will be needed to get rid of these cells," Siliciano comments. Louis Picker and colleagues at the University of Texas Southwestern Medical Center suggest the need for a new therapeutic approach consisting of early and aggressive treatment to protect T-helper cells from being inactivated during HIV-1 infection (C.J. Pitcher et al., "HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression," Nature Medicine, 5:518-25, May 1999). The team found that HIV-1-specific CD4+ T cells can be generated during active HIV-1 infection, and that these cells are not necessarily eliminated or suppressed by ongoing viral replication during acute infection. They also found significant loss of CD4+ helper memory with long-term (more than 47 weeks) combination therapy. Thus, early and repeated vaccination with HIV-1 determinants after combination therapy begins may be a way to retain HIV-1-specific CD4+ and CD8+ T cells to fight HIV-1 infection. Julie Overbaugh and colleagues at the Fred Hutchinson Cancer Research Center, Seattle, report the first experimental study to conclusively demonstrate that simian immunodeficiency virus (SIV) becomes more virulent during progression to AIDS in macaque monkeys (J.T. Kimata et al., "Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression," Nature Medicine, 5:535-41, May 1999). The late variants of virus demonstrated increased fitness for replication in the host compared to early virus from which they evolved. The question remains whether a similar phenomenon occurs with HIV and how relevant for HIV infection in humans the SIV monkey model is. --Nadia S. Halim ISCHEMIA AND ISOFORMS Vascular endothelial growth factor (VEGF) could be used to treat congestive heart failure, report a team from the University of Leuven in Belgium, led by Peter Carmeliet (P. Carmeliet, "Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factors VEGF164 and VEGF188, Nature Medicine, 5:495-502, May 1999). The researchers developed a mouse model to probe this mechanism. The gene for VEGF encodes at least three spliced isoforms: VEGF120, VEGF164, and VEGF188. Each differs in molecular mass and biological properties. The group generated mice that only express VEGF120 by removing exons 6 and 7, which encode the isoforms of 164 and 188 amino acids. Conventional transgene technology could not be used to develop an animal model because loss of a single VEGF allele results in embryonic lethality due to severe vascular defects. Those transgenic mice had impaired postnatal myocardial angiogenesis, resulting in heart attacks. They ultimately died of cardiac failure. The transgenic single-isoform model may be useful in studying the molecular mechanisms of the cardiac response to ischemia and for testing the angiogenic properties of other isoforms, Carmeliet notes. Gene therapy protocols now use VEGF120 or VEGF164 indiscriminately for improvement of ischemic heart and tissue disease. Whether the isoforms differ in specificity, potency, or quality for their role in angiogenesis in vivo is unclear. Interestingly, when the single-isoform, transgenic mice were ill, but not yet dying, cardiomyocytes survived ischemia exhibiting several features consistent with "hibernation," a phenomenon observed in human ischemic cardiomyopathy. --Nadia S. Halim AWARENESS NEURONS? Humans' extraordinarily high degree of self-awareness is one of the major characteristics that sets us apart from other animals. Yet difficult biological evidence for what gives rise to this rather mysterious trait has been difficult to come by. Recently, however, researchers at the California Institute of Technology uncovered a rare anatomical clue (E.A. Nimchinsky et al., "A neuronal morphologic type unique to humans and great apes," Proceedings of the National Academy of Sciences, 96:5268-73, April 27, 1999). A cluster of neurons found only in the brains of humans and other primates--28 different species were studied--appears to have some part in providing those species with varying degrees of self-control and self-awareness as well as with an enhanced capacity for solving tough problems. Nearly visible with the naked eye, these large, sausage-shaped neurons are located in the frontal lobe in a part of the cortex that wraps around the corpus callosum, the band of fibers uniting the cerebral hemispheres. Thought to be a relatively recent evolutionary acquisition, the neurons are more highly concentrated in humans than in any of our primate cousins. "I wouldn't want to say that these neurons are consciousness neurons, or self-awareness neurons," says coauthor John Allman, a professor of biology and psychobiology at the California Institute of Technology. "But I think that they do reflect a difference in circuitry between humans and our very close relatives .... [This area of the brain] seems to be where you have a sort of convergence of the intellect and the emotional life of the individual." Allman and his collaborators are now trying to identify the genes that encode these neurons so that they'll be able to study their effects more closely in transgenic animals. --Eugene Russo

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