Most of the four million or more babies born alive in theU.S. each year manage to make it from fetus to neonate ataround 40 weeks' gestation. Those who leave the wombmuch before 25 weeks after conception are usuallymiscarriages.In between lies the third trimester of pregnancy. Infantsborn alive during this terminal phase of gestation arefrequently termed premature, because their bodies havenot developed sufficiently to take on the outer worldwithout medical help.In the U.S., seven to nine percent of all babies born towhite mothers are premature. Among black births, theratio of prematurity is twice as high."Preemies," as obstetricians and nurses call their fragilepre-term patients, are not just undersized andunderweight, but under-developed. Given expert care, agood 85 percent of them will survive their first fewfraught weeks post partum.The high-risk complications they must overcome centeron lungs and digestive tract. To make breathing possible,lungs must coat their alveolar surfaces with surfactant, adetergent-like substance than enables the alveoli to stayopen during respiration.Fetal lungs start secreting surfactant at 24 to 30 weeks ofpregnancy, so many preemies are born without it. RDA_ respiratory distress syndrome _ is one seriousconsequence.Because of their tiny size, premature infants weighingless than 3.3 pounds have a ratio of skin surface to weightthat dissipates body heat. To maintain a viabletemperature, and supply their immature lungs withoxygen, many preemies spend their first weeks of sololife in incubators, which pipe in needed O2. The catch isthat if the oxygen supplement is ever so slightlyexcessive, it can cause blinding retrolental fibroplasia _which replaces the sensory retina with an opaque fibrouscoating.Premature intestines cannot well digest and absorb food,which prevents growth. Moreover, the infant, thusweakened, can't muster the strength to suckle at thebreast, thus creating a vicous circle of inanition.Master Gene of Late-Pregnancy Fetal Development

Among the scientists now scrutinizing the third trimesterof fetal development and premature-infant pathology ismolecular geneticist Gretchen Darlington, at BaylorCollege of Medicine in Houston. Her point of departure isa highly strategic gene, c/ebpa, which encodes theprotein, C/EBPa.Observing that "this is a terrible field for acronyms,"Darlington told BioWorld Today that C/EBPa stands for"CCAAT-enhancer binding protein." She added,"CCAAT is the sequence in the DNA that this DNA-binding protein recognizes, and thereby enhances genetranscription."This gene resides on the long arm of chromosome 19, andexpresses its C/EBPa protein in a number of vital organs,notably liver, lungs, fat tissue, gut, brain and mammaryglands. Darlington's lab has raised colonies of knockoutmice deprived of their c/ebpa gene and its proteinproduct.She and her co-authors report their first experimentalresults, titled "Impaired Energy Homeostasis in C/EBPaKnockout Mice," in today's Science, dated August 25."There are some differences in the way rodents andhumans develop," Darlington said, "but with respect toglycogen storage, it's very similar. We would predict,"she added, "that the gene is activated late in humandevelopment, as it is late in rodent development."She observed that "in humans, the third trimester is theprimary time of glycogen storage in the liver, and fataccumulation in the adipose tissues." By the time of birth,she recalled, adipose deposition accounts for 15 to 16percent of the human infant's weight, "which is whybabies are chubby."This glycogen reserve provides glucose to the newborninfant in the hours before it begins to nurse. In contrast,she pointed out, "normal mice really don't start toaccumulate fat in adipose tissue until after birth."Hypoglycemia Fatal to Gene-Lacking Mice"In the mouse," she said, "the c/ebpa gene gets activatedin the liver around 17 days of gestation _ four daysbefore birth." Mice lacking the gene, Darlington reported,"at birth were indistinguishable from their normallittermates {but] did not store hepatic glycogen, and diedfrom hypoglycemia within eight hours after birth."(Glycogen, she noted, is the precursor of glucose, thebody's main source of energy.)During those few hours of apparently normal life, theScience paper added, "the mutant neonates had little orno milk in their stomachs, presumably from lack ofenergy to compete for nourishment."Subcutaneous glucose injections prolonged their life forup to 40 hours, but not beyond. At 32 hours, "the glucose-injected neonates had suckled and ingested milk [but]their livers failed to store the appropriate amounts ofglycogen.""We learned," Darlington said, "that the C/EBPa proteinhas a very specific and active role in the activation ofliver-specific genes, and that one of its important targetsis involved in glycogen storage. In the knockout mice, theprotein is not there to turn on the right genes at the righttime, and the animals don't accumulate glycogen.""The c/ebpa gene," Darlington said, "is expressed in veryhigh levels in adipose tissues, and presumably affectslipid storage in addition to glycogen storage."Next on the list of organ systems she and her lab willstudy for c/ebpa gene expression is the lung, specificallycells in the lung that have a role in surfactant production."The other avenue that we're pursuing is to understandwhat activates the gene itself," she said. "Ultimately, wehope that would help us to understand how we might up-regulate its expression in a premature infant, to turn on itsnormal genes by giving it the appropriate signals."Darlington suspects that "some of those signals will beregulated hormonally, and we would be able to deliversuch hormones to the particular tissue, certainly theliver."She notes in addition that "a very large group here atBaylor is interested in gene therapy. Conceivably, wecould actually deliver the c/ebpa gene itself, the DNA,and it would express for a period of time, enough to tidethe infant over until its own gene becomes activated." n

-- David N. Leff Science Editor

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