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Molecule that Destroys Normal Metabolism Found

A molecule once considered only involved in detecting and fighting viruses, now is found in mice when they overeat - destroying their normal metabolism by leading to insulin resistance and diabetes. These results are in a new study led by researchers at the Harvard School of Public Health (HSPH).

The research specifically links the immune system and metabolism, a pairing increasingly suspected in diseases that include — in addition to diabetes — heart disease, fatty liver, cancer, and stroke. Understanding how to regulate the molecule through targeted drugs or nutrients could eventually change the way these diseases are prevented and treated in humans. The study is published in the February 9th issue of the journal Cell.

“When mice eat a normal diet, this molecule called PKR is silent,” said senior author of the study Gökhan Hotamisligil, chair of the HSPH Department of Genetics and Complex Diseases. “However, if a cell containing PKR is bombarded with too many nutrients, PKR grabs other immune system molecules that respond to this food attack and organizes a firing squad to shoot down normal processes, leading to insulin resistance and metabolic dysfunction.”

The results provide compelling evidence that a process called “metaflammation” occurs in the body, said Hotamisligil, the James Stevens Simmons Professor of Genetics and Metabolism. Metaflammation is inflammation triggered by the metabolism of nutrients into energy. Previous studies by Hotamisligil had demonstrated inflammation in metabolic diseases such as obesity, type 2 diabetes, and heart disease in mice and humans.

“We know that nutrients can be detrimental in excess quantities or when they are in the wrong place at the wrong time,” Hotamisligil said. “But we don’t quite understand which paths they travel that result in harm and produce inflammation. PKR is a mechanism by which nutrients — necessary and beneficial under normal conditions — cause damage to cells and organs.”

The researchers used sets of mice in their experiments. One set of mice had PKR in their bodies, and the other set did not. The scientists then overfed a group of PKR-positive and PKR-negative mice high-fat, high-calorie diets. The overfed mice with PKR became obese and developed insulin resistance, while the overfed mice without PKR gained significantly less weight and did not develop insulin resistance, indicating that absence of PKR can alleviate harmful metabolic effects due to overeating in mice.

Now the researchers will turn their attention to identifying which nutrients cause the adverse effects. “One of the difficulties in understanding how our diet is integrated into disease risk is our inability to understand what specific component of a diet is actually regulating particular responses in humans,” said Hotamisligil. “So the discovery of this molecule actually gives us a very specific way to identify the harmful components of the diet.”

Results from those studies could be available within a couple of years, Hotamisligil predicted, after which human trials would be needed on potential drugs or nutrients that could regulate PKR.

This study was supported by a grant from the National Institutes of Health.

TUESDAY February 9---------News Archive
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UC Davis Study Confirms Link Between Advanced Maternal Age and Autism

Advanced paternal age is a risk only when the mother is younger.

Advanced maternal age is linked to a significantly elevated risk of having a child with autism, regardless of the father’s age, according to an exhaustive study of all births in California during the 1990s by UC Davis Health System researchers. Advanced paternal age is associated with elevated autism risk only when the father is older and the mother is under 30, the study found.

Published online today in the February issue of the journal Autism Research, the study, “Independent and Dependent Contributions of Advanced Maternal and Paternal Ages to Autism Risk,” is one of the largest population-based studies to quantify how each parent's age — separately and together — affects the risk of having a child with autism.

The study found that the incremental risk of having a child with autism increased by 18 percent — nearly one fifth — for every five-year increase in the mother’s age. A 40-year-old woman’s risk of having a child later diagnosed with autism was 50 percent greater than that of a woman between 25 and 29 years old.

Advanced parental age is a known risk factor for having a child with autism. However, previous research has shown contradictory results regarding whether it is the mother, the father or both who contribute most to the increased risk of autism. For example, one study reported that fathers over 40 were six times more likely than fathers under 30 to have a child with autism.

“This study challenges a current theory in autism epidemiology that identifies the father’s age as a key factor in increasing the risk of having a child with autism,” said Janie Shelton, the study’s lead author and a doctoral student in the UC Davis Department of Public Health Sciences. “It shows that while maternal age consistently increases the risk of autism, the father's age only contributes an increased risk when the father is older and the mother is under 30 years old. Among mothers over 30, increases in the father's age do not appear to further increase the risk of autism.”

Autism is a pervasive developmental disorder of deficits in social skills and communication, as well as repetitive and restricted behaviors, with onset occurring prior to age 3. Abnormal brain development, probably beginning in the womb, is known to be fundamental to the behaviors that characterize autism. Current estimates place the incidence of autism at between 1 in 100 and 1 in 110 children in the United States.

During the 1990s, the number of California women over 40 giving birth increased by more than 300 percent. But only about 5 percent of the 600-percent increase in the number of autism cases in the state can be attributed to women waiting longer to have children, the study suggests.

To conduct their investigation, the researchers obtained the electronic records for all births in California between Jan. 1, 1990 and Dec. 31, 1999. The records incorporated detailed demographic information, including the ages of both parents. To identify which children would develop autism, the researchers obtained electronic records identifying children born during the study period who later received an autism diagnosis from the state Department of Developmental Services. In this study autism was defined as a diagnosis of full-syndrome autism at a California Regional Center. With exclusions, the total size of the study sample was approximately 4.9 million births and 12,159 cases of autism.

For older mothers, the risk of having a child who later would be diagnosed with autism was apparent in every age group of fathers. When the father was older and the mother was under 30 — the child’s risk for developing autism also was elevated. For example, among births to mothers under 25, children fathered by a man over 40 were twice as likely to develop autism as those whose father was between 25 and 29. Among mothers over 30, the increased risk associated with older fathers dissipated, the study found.

The researchers note that understanding the relationship between increased parental age and autism risk is critical to understanding its biological causes. Earlier studies have observed that advanced maternal age is a risk factor for a variety of birth-related conditions, including infertility, early fetal loss, low birth-weight, chromosomal aberrations and congenital anomalies.

Irva Hertz-Picciotto, professor of public health sciences, a researcher at the UC Davis MIND Institute and the study's senior author, said the reason that having an older parent places a child at risk for autism is not known.

"We still need to figure out what it is about older parents that puts their children at greater risk for autism and other adverse outcomes, so that we can begin to design interventions," Hertz-Picciotto said.

One possible clue comes from a 2008 UC Davis study that found some mothers of children with autism had antibodies to fetal brain protein, while none of the mothers of typical children did. Advancing age has been associated with an increase in auto-antibody production. Further work investigating advancing age may be useful, the study authors said. They added that some persistent environmental chemicals accumulate in the body and also may have a role to play in autism, possibly contributing to the apparent effect of parental age.

The study also suggests that epigenetic changes over time “may enable an older parent to transfer a multitude of molecular functional alterations to a child ... thus epigenetics may be involved in the risks contributed by advancing parental age as a result of changes induced by stresses from environmental chemicals, co-morbidity or assistive reproductive therapy.”


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