By David N. Leff

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

From domestic beers to Italian wines to Mexican tequila, every ethanolic potation sold in the U.S. must carry on its label - in capital but small letters - this word to the (not-so) wise:

GOVERNMENT WARNING: ACCORDING TO THE SURGEON-GENERAL, WOMEN SHOULD NOT DRINK ALCOHOLIC BEVERAGES DURING PREGNANCY BECAUSE OF RISK OF BIRTH DEFECTS.

The defects may range from hyperactivity and learning disabilities in childhood to depression or severe psychosis in adults. These psychiatric disorders are known collectively as fetal alcohol syndrome. (See BioWorld Today, July 8, 1997, p. 1.)

A report in the current issue of Science, dated Feb. 11, 2000, starts out by observing, "The deleterious effects of ethanol on the developing human brain are poorly understood." The article, titled "Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome," clears up some of this molecular mystery.

The co-authors - in Berlin, Tokyo and St. Louis - describe their in vivo experiments, in which high levels of ethanol, given to rats, killed off nerve cells in the animals' developing brains. In humans, that developmental period of vulnerability begins in the third gestational trimester - the sixth month of pregnancy - and continues until the infant's second birthday, or beyond.

During this neuronal growth period, called synaptogenesis, when brain cells hook up their myriad connections, "transient ethanol exposure," the paper states, "can delete millions of neurons from the developing brain. This can explain the reduced brain mass and neurobehavioral disturbances associated with human fetal alcohol syndrome [FAS]."

To be numerically precise, their pivotal rodent experiment counted an average of 12,567,726 degenerating neurons in the forebrains of 7-day-old rat pups that had imbibed alcohol dosages of 200 milligrams per deciliter of blood - about twice the legal intoxication limit in humans. This one-shot binge triggered the programmed cell-suicide process of apoptosis. In contrast, control pups - rendered abstemious by swigging saline instead of the good stuff - suffered less than one-tenth that neuronal mayhem - 1,008,195 cells.

These results suggest, the paper stated, that "if a pregnant mother imbibes alcoholic beverages for several hours in a single drinking episode, she could expose her third-trimester fetus to blood ethanol levels equivalent to those required to trigger apoptotic neurodegeneration in the immature rat brain lasting four hours or more."

The molecular basis of FAS, the co-authors explain, indicts two brain chemicals, NMDA glutamate receptor antagonists and GABA (gamma-aminobutyric acid) agonists. But many other licit and illicit agents besides ethanol implicate NMDA and GABA.

Drugs of abuse that block NMDA glutamate receptors include phencyclidine, known on the street as "angel dust"; the hallucinatory analgesic ketamine, or "special K"; and nitrous oxide, or laughing gas. Both of the latter agents are often employed as pediatric anesthetics. GABA receptor activators that are frequently abused include the benzodiazepines (Librium, Valium), barbiturates (tranquilizers) and the anesthetics isoflurane and propofol.

Depending on the timing of ethanol ingestion, the paper concludes, "different combinations of neuronal groups will be deleted, which signifies that this is a neurodevelopmental mechanism that can contribute to a wide spectrum of neuropsychiatric disturbances."

Herceptin Blocks Breast Cancers. So Does PEA3 Protein, Which Also Inhibited Ovarian Tumors

A recent wrinkle in anticancer drugs is Genentech Inc.'s Herceptin (approved in 1998), which targets metastatic breast tumors. It's a recombinant, DNA-derived, humanized antibody, which selectively binds to the human epidermal growth factor receptor 2 protein (HER-2). Herceptin acts by inhibiting proliferation of tumor cells that overexpress the HER-2/neu gene.

Now, cell biologists at the University of Texas M.D. Anderson Cancer Center in Houston report discovery of another protein with the potential to block tumors overexpressing that same HER-2/neu gene. That gene is activated when a transcription factor binds to its promoter region. This new activating protein is called PEA3. Its discovery is reported in the February 2000 issue of Nature Medicine, under the title: "The Ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis." It does so by curtailing the activity of the tumor oncogene promoter.

The Texans found that giving PEA3 to mice bearing human breast tumors prolonged their survival. Moreover, of animals with human ovarian cancer, 50 percent "survived without detectable tumors for longer than one year after treatment with liposomal PEA3." All control mice "died of tumor growth within six months."

Embryonic Stem Cells Are Way To Go For Added- Trait Transgenes, Faster, Better Transgenic Animals

Using embryonic stem cells (ESC) to clone mice at the Whitehead Institute for Biomedical Research in Cambridge, Mass., yielded record efficiency in the number of viable clones. Most clones die during or soon after gestation, for many reasons: donor's genetic makeup; cell-cycle stage of donor cell; inability of recipient egg cell to reprogram donor cell nucleus. In addition, the scientists showed for the first time that it's possible to modify the genetic material in embryonic cells before using them to clone new animals.

A study in the February issue of Nature Genetics suggests that genetic makeup of donor cells plays a key role in viability outcome. It's titled: "Generation of mice from wild-type and targeted ES cells by nuclear cloning." The co-authors inserted into an ESC a gene derived from the tetracycline antibody receptor, then transplanted this thus-modified transgene into an enucleated egg. Result: Tetley, a transgenic, cloned mouse, which now carries the tet sequence in its genome.

Making transgenic animals more efficiently is another payoff claimed for the new technology. "If we know which gene is mutated in a particular human disease," said the paper's lead author, "we can develop mouse models with the same mutation." Today, constructing a transgenic animal of a new strain is a cumbersome project that can take three to nine months. The co-authors indicate that using targeted ES cells will cut that time down by one third.