Science Editor

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

Most proto-human (hominid) fossil remains have been discovered over the years in the Rift Valley of East Africa, and deposits in South Africa. The recovered skeletal finds and petrified footprints suggested these early bipeds lived 3 million to 4 million years ago.

This month an international team of human-fossil hunters announced they have unearthed (literally) a fragmentary human skull in the central African Republic of Chad - 2,500 kilometers (some 1,600 miles) distant, and twice as old, as the traditional East African origins of earliest mankind. Their cover story in Nature dated July 11, 2002, became a widespread media sensation. It lists 38 co-authors from five countries - most of them at the University of Poitiers in France and two Chadian paleontology centers. Their report is titled: "A new hominid from the Upper Miocene of Chad, central Africa."

The fossil skull "constitutes a new genus and species of hominid," the paper notes. It comprises a nearly complete cranium and two lower jaw fragments, plus three isolated teeth, all belonging to at least five individuals of the new species. These hominid remnants are mingled with more than 700 datable faunal fossils composed of aquatic and amphibious vertebrates - indicating a biochronological age close to 7 million years ago. They include 24 primitive mammals - carnivores, elephants, three-toed horses, giraffes, antelopes, hippopotamus, a very large wild boar, as well as rodents and monkeys.

The remote distance from the Rift Valley, and the great antiquity of the fossils, "suggest that the earliest members of the hominid clade [family tree] were more widely distributed than has been thought." The study also pointed out, "The divergence between the human and chimpanzee lineages was earlier than indicated by most molecular studies."

The discovery, found in the flat arid Djurab desert of northern Chad - bordering the southern Sahara - has received the scientific name Sahelanthropus tchadensis. However, the Chadian co-authors have nicknamed the skull "Touma ." This moniker designates children born close to the desert's dry season and signifies "hope of life" in the local Goran language.

Did Touma walk on four feet or two? With no leg bones to answer this key evolutionary question, the scientists point to the position where his spine enters his head as indicating, though not proving, that he could have been habitually bipedal. As for gender, his brow ridge is thicker than that of a male gorilla, so in all probability Touma was "he" rather than "she." His skull's cranial capacity, about 350 cubic centimeters, is similar to that of living chimpanzees. In side view, it measures just less than four inches.

As the now earliest-known hominid, the Nature co-authors propose, "Touma could be considered as the forerunner of all later hominids - that is, the ancestor of the human lineage."

Janus-Faced Signaling Molecules, Smad, H-ras, Induce Metastasis Suppression, Progression

Cancer development and metastasis is a multistep process. It involves local tumor growth, acquired mobility and invasion, followed by dissemination to distant sites. There it digs in and sets up secondary tumors. Increasing activation of the signaling molecules Smad2 and H-ras drives tumors through the different stages of becoming metastatic. The ability of a malignancy to metastasize is the major factor that determines patient mortality. So elucidating the molecular pathways essential for tumor metastasis is a high priority in cancer biology, as well as for small-molecule drug design.

A paper in the journal Nature Cell Biology, released online July 1, 2002, reports examination of this mechanism by research oncologists at the University of California at San Francisco and Onyx Pharmaceuticals, of Richmond, Calif. Their study bears the title: "Metastasis is driven by sequential elevation of H-ras and Smad2 levels."

Transforming growth factor b (TGFb), the co-authors point out, has been implicated in both tumor suppression and progression. Although it inhibits growth of early carcinomas, later in tumorigenesis, in cooperation with Ras, it can induce an epithelial-mesenchymal transition (EMT) toward an invasive, metastatic tumor phenotype. The mechanisms of these contradictory actions are unclear. "Our results," the paper observes, "provide a new view of Ras and Smad cooperating to promote tumor development by demonstrating that H-ras induces nuclear accumulation of phosphorylated Smad2 and consequent upregulation of Smad2-mediated transcription."

AVI BioPharma Reports Successful Trials Of Antisense That Blocks Enzyme's Breakdown Of Approved Drugs

Approximately 50 percent of all FDA-approved drugs are inadvertently broken down by a liver enzyme, cytochrome P450 3A4. By inhibiting such enzymes, one can potentially control the way drugs are metabolized by the body. AVI BioPharma, of Portland, Ore., has developed a proprietary antisense technology, NeuGene, which can inhibit this liver enzyme. In its cover story, the July issue of Drug Metabolism and Disposition reports a Phase I trial of NeuGene titled: "Phosphorodiamidate morpholino antisense oligomers inhibit expression of human cytochrome P450 3A4 and alter selected drug metabolism."

In the study, AVI scientists, using primary cultures of human liver from 11 individual donors, demonstrated the efficacy and specificity of their antisense inhibitor. In May, AVI expanded on this research through completion of a 96-patient trial showing that its antisense drug can change gene expression in humans. It inhibited expression of the offending enzyme by changing the metabolism of a test drug, BuSpar (Bristol-Myers Squibb Co., of New York). AVI is currently in the process of submitting the 96-patient study for peer review.

The company suggests that this approach also may be used to improve the pharmacokinetics of drugs coming off patents, thereby gaining new intellectual property life.