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Stress Reaction May Be In Your Dad’s DNA, Study Finds

By Geoffrey Mohan, Los Angeles Times (TNS)

Stress in this generation could mean resilience in the next, a new study suggests.
Male mice subjected to unpredictable stressors produced offspring that showed more flexible coping strategies when under stress, according to a study published online Tuesday in the journal Nature Communications.

The secret might be hidden in a small change in how certain genes are regulated in the sperm of the father and in the brains of offspring, the study found.

Several studies have shown that stress in early life not only can affect the individual’s behavior and cognitive functions, but can affect the next generation. So researchers have been eager to find any trace of changes in DNA coding that might underlie their observations.

Before you pen a “thanks for the resilience” Father’s Day card, consider: The study involved mice, not humans. More important, even the seemingly more resilient mice had lots of negative behaviors — depression and anti-social tendencies among them.

“If we look at the whole behavior of these animals, the benefit is really a very small proportion of the effects,” said study co-author Isabelle Mansuy, a neuroscientist at the University of Zurich’s Brain Research Institute. “Most other effects are fairly negative, because the animals are depressed, are anti-social, and have cognitive impairment.”

Researchers tried to mimic the effects of erratic parenting and a stressful home environment. So they separated male mouse pups from their mothers for several hours a day over the first two weeks of life, during which time they were occasionally restrained or forced to swim for five minutes — all at unpredictable intervals.

The mice then matured in social groups of four or five unrelated mice of the same sex that had equally unpredictable childhoods. Then they were matched to females, producing pups of their own. Once the pups grew up, they were subjected to various mazes that test the ability to show goal-oriented and flexible behavior under stress.

Compared with a control group, the offspring of stressed dads showed less hesitation in exploring an arm of a maze. And when offered the choice of getting a drink of water immediately or waiting for sugared water, the offspring of stressed males tended to wait for the greater reward. They also were better at figuring out changed rules — rewards that were moved from one spot to another, or cues that were changed.

Numerous studies of the effects of stress implicate a loop in the brain’s limbic system, which mediates emotion and causes the release of the stress hormone cortisol. That chemical can amp up a feedback loop to the brain.

Much of this stress-related reaction in the brain is mediated, in part, by a mineralocorticoid receptor, or MR, in brain cells.

The study found small changes in regulatory DNA sequences near an MR gene in sperm cells of the stressed mice. Such changes in gene regulation in response to the environment are known as epigenetic processes. The study found epigenetic markers associated with a half-dozen genes in the brain cells in the hippocampus of the offspring of stressed male mice.

Together, these changes offer a hint at a possible path for passing the effects of stress from one generation to the next.

Soldiers may offer a prime example, Mansuy said. “Many soldiers are people from lower socioeconomic environments and many of them have been exposed to violence, to broken families and to bad conditions when they were young,” she said. “And many of these people are stress-resilient, and they also have some adaptive advantages when they are placed in a situation of danger or challenge. They have developed coping strategies perhaps that other people have not.”

Still, she noted, these enhanced resiliency behaviors were “the only benefit” observed among the mice.

Researchers have been trying to untangle the effects of genetics and family background in post-traumatic stress disorder among soldiers returning from war.

Photo via WikiCommons

‘Physician-Scientists’ Transform Health Care For Amish, Mennonite

By Amy Worden, The Philadelphia Inquirer

STRASBURG, Pa. — Weeks after his birth in 2001, Benjamin Glick was stricken with a mysterious illness.
He would vomit and pass out. He wouldn’t eat and lost weight. Over five agonizing months, his parents took him to 12 doctors at six hospitals in the Philadelphia area.
“He was fading out, we were going to lose him,” said his father, Amos Glick, who is Old Order Amish and runs a foundry in Chester County.
It took a clinic in a Lancaster County cornfield to save the boy.
Doctors at Children’s Hospital of Philadelphia sent the family to the Clinic for Special Children in Strasburg. For years, the site had been refining an unusual specialty: treating Amish and Mennonite children with rare genetic disorders.
Clinic doctors had seen similar symptoms in other children from the insular population they serve. They discovered Benjamin had a debilitating milk-protein allergy and fine-tuned his formula. Benjamin stabilized in a month.
There was no genetic diagnosis, but two of his siblings born later suffered similar symptoms. Together, their medical histories will provide a foundation for what may lead to a genetic link.
A big hospital likely would have treated each child individually, never making the connection to help those children and others, said Kevin Strauss, a pediatrician and the clinic’s medical director. The case was also meaningful for another reason.
“The modern American medical system,” he said, “didn’t have a place for them to go.”
In the 25 years since its founding, the clinic has transformed pediatric health care for an underserved population, turned diseases from death sentences into treatable conditions, and broken ground in genetics that could one day lead to cures for diseases that afflict the wider population.
The barn-like building, raised in a day by Amish and Mennonite craftsmen, has parking spots for horses and buggies out front, and dairy cows graze out back. Inside, 63-year-old pediatrician D. Holmes Morton and his team practice cutting-edge medicine.
Morton was a Children’s Hospital fellow in 1988 when he encountered a 6-year-old Amish boy with an undiagnosed disease that left him brain damaged and unable to use his limbs.
Doctors thought it was cerebral palsy. Morton, a specialist in biochemical genetics, identified Danny Lapp’s disease as glutaric aciduria type 1 (GA1), a metabolic disease that attacks the brain with sudden and catastrophic results.
At the time, there were only eight known cases.
The Lapp case changed Morton’s life and led to discoveries that have since saved many of the 2,500 patients he has seen. GA1 is one of more than 150 diseases or genetic mutations the clinic has identified that affect the Amish and Mennonites of Lancaster County — but that are not exclusive to them.
The county’s 60,000 Plain People, as they are called, descended from fewer than 100 settlers who came to Lancaster from Europe in the early 1700s. Centuries of intermarriage have increased the risk for developing many conditions.
For instance, Amish babies are 100 times more likely to have GA1 than other infants. At the same time, Morton said, diseases that strike the general population, such as cystic fibrosis and sickle cell disease, are nonexistent among the Plain People.
Before 1990, 90 percent of children suffering from GA1 had irreversible brain damage that left most of them severely disabled. Now, if caught early, those with the disease suffer no brain injury and, with vitamins and dietary restrictions, those the clinic treats have been able to live normal lives.
Vanessa Guimaraes’ 3-year-old daughter was diagnosed with GA1 during a newborn screening. Guimaraes, a native of Brazil living at the time in Hawaii, decided to move to Lancaster to be close to treatment.
“I thank God every day for the clinic,” she said.
Jan Bergen, chief operating officer at Lancaster General Hospital, said she was “awestruck” by the small clinic’s big results.
“They are unique in the world,” said Bergen, who works with the clinic on research.
Born in Fayetteville, W.Va., Morton was a high school dropout before, as he puts it, talking his way into Trinity College. Later, he was accepted at Harvard Medical School.
After Children’s Hospital, Morton decided he wanted to bring medicine to the people but found making inroads with the Amish and Mennonite difficult. A handful, mostly skeptics, came to his first meeting in 1988.
Last month, several thousand Plain People were on hand for a quilt auction to benefit the clinic. Morton rose to thank them for their help, gazing out over a sea of straw hats and prayer caps.
“I think of the clinic as a health care model,” he said in his office later.
In addition to seeing patients every day, clinic researchers publish three to five peer-reviewed papers a year and participate in 25 research projects with hospitals worldwide.
Strauss, the Harvard-trained medical director, said if he had taken a traditional path, he’d be spending his career in a large hospital lab “with mice and fruit flies.” He describes himself today as a physician-scientist, with patient care guiding him.
“We do research on whatever problem comes through the door,” he said.
Forty percent of the patients diagnosed have treatable — if not curable — conditions. Another 40 percent are partially treatable. The remaining 20 percent have terminal conditions.
Some leave with no diagnosis. That’s where Erik Puffenberger comes in.
On a recent afternoon, Puffenberger, a geneticist and the clinic’s lab director, sat hunched over vials of DNA in a basement lab.
When Morton founded the clinic, he said, he thought he might find 10 to 20 new diseases in his career. Puffenberger identifies five to 10 gene mutations a year.
A freezer contains 8,000 DNA samples from patients that Puffenberger says will provide the foundation for understanding as-yet-unidentified diseases.
He’s working on developing a quicker, cheaper test for Down syndrome among newborns. “Our patients have no insurance and they may be of limited means,” Puffenberger said.
With a staff of 14 and an annual budget of $2.6 million — one-third funded by quilt auctions, the rest by fees and donations — the clinic has been able to offer its largely uninsured patients services at a fraction of a hospital’s cost.
Morton, recipient of the Albert Schweitzer Prize for Humanitarianism and a MacArthur Foundation “genius grant,” is looking to the future. The clinic recently started a fellowship to cultivate the next generation of physician-scientists, and Morton is involved in building a clinic to serve the Amish population near State College.
The treatment Glick’s son Benjamin got 13 years ago made the difference for two of his other six children. Daughters Naomi and Katie, now 7 and 3, were diagnosed quickly and spared any suffering.
“What’s really inspiring to me is that these doctors and scientists could be working in fancy hospitals making six-figure incomes, but they have — as Dr. Puffenberger put it — chosen the road less traveled,” Glick said. “They are making a serious difference in families like ours in our local community and in Brazil and India and Canada from this little place in a cornfield.”

Photo via Wikicommons

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Can A Genetic Model Predict Next Year’s Flu Strain?

By Geoffrey Mohan, Los Angeles Times

LOS ANGELES — The seasonal flu has met its enemy, and it’s calculus.

A theoretical physicist and computational biologist analyzed the genetic code of thousands of strains of Influenza A that occurred over a 44-year period to create a model that accurately predicts which strain will prevail in the pitched evolutionary battle between human antibodies and the rapidly mutating virus.

Their method proved more accurate for selecting an appropriate vaccine than the current method used by public health officials, according to a report published online Wednesday in the journal Nature.

The researchers, from the University of Cologne in Germany and Columbia University, examined Influenza A/H3N2, a seasonal strain that causes thousands of deaths annually. They focused on the H part — short for hemagglutinin, a spike-shaped protein that seeks out sugars in human cells and binds to them, allowing the virus to inject its deadly code.

Human antibodies — naturally launched or gigged into action by vaccines — engage in a constant arms race with this wildly mutating protein, making flu vaccination season something of an educated guessing game. World health officials have been reasonably accurate in identifying which resistant strains are emerging as a new threat. But their method has a lot of uncertainty. A study in 2010, in fact, called several popular diagnostic methods “questionable.”

Inaccuracy also is at the heart of the survival for a virus, which shuffles its code enough to create variations that don’t show up on the radar of the human immune system.

“This is a really fast-evolving virus,” said study co-author Marta Luksza, a computational biologist at Columbia University. “Individual strains are very short-lived. Very, very rarely are there two identical strains. They mutate, they infect another individual. But they do share common mutations still.”

Luksza and co-author Michael Laessig estimated the frequency of these mutations in the viral RNA and factored in such variables as infection rates to come up with a model predicting a strain’s evolutionary fitness.

Since the researchers already knew the outcome of the evolutionary arms race from the record of flu strains from 1968 to 2012, they tested whether their model would have identified the fittest strains. It predicted the rise of the correct lineage in 93 percent of cases.

Perhaps more importantly, the model chose a more genetically matched strain than the one deployed as a vaccine.

Luksza cautioned that the study focused on one type of influenza. When they tested the model against an extinct H1N1 strain, results were less precise.

“In principle, there’s no reason why it shouldn’t be applicable to other strains,” Luksza said. But there may be complicating factors involved in the evolution of other strains that would have to be incorporated into the model, she added.

“I think our model could be used as guidance for the existing way of choosing vaccines,” Luksza said.

Photo: Mcfarlandmo via Flickr

Appetite Regulation Might Be Link Between Genetics And Environment, Study Says

By Mary MacVean, Los Angeles Times

Most anyone who’s ever tried to lose weight probably has wondered about appetite, perhaps wishing it to be less voracious. Scientists are looking at appetite and feelings of fullness as they try to figure out genetic connections to weight and what to do about the obesity epidemic.

Children now are growing into a higher body mass index than any previous generation, and that is “rooted in environments with easily available, cheap, palatable, energy-dense and intensively marketed foods,” researchers wrote this week in the Journal of the American Medical Association Pediatrics.

But there’s more to obesity than environment, the researchers say in two studies and an accompanying editorial, which look at aspects of childhood weight gain around appetite and satiety, or feeling full.

In one study, led by Jane Wardle, researchers from University College London looked at sets of twins to see what happened over the first 15 months of life based on response to cues regarding food such as smell or sight and on satiety.

In the other study, led by Clare Llewellyn, the researchers also looked at twins, this time with a mean age of 10, studying their satiety, food responsiveness and weight gain. Their results suggest that “low satiety response” is one way that genetic predisposition leads to weight gain “in an environment rich with food.”

These studies suggest that ability to feel full is a way that genetics can play a part in who becomes obese. And the use of twins meant that some factors could be ruled out, because they had the same environment.

“A heartier appetite in early infancy is associated with more rapid growth up to age 15 months,” the researchers wrote. Babies with bigger appetites could be more at risk and might be well targeted in strategies to prevent obesity, they said.

An editorial accompanying the studies, by Daniel Belsky of the Center for the Study of Aging and Human Development at Duke University Medical Center, suggests that the work could lead to the possibility of intervention before children become overweight rather than leave families with the difficult task of reducing weight and maintaining the loss.

“Findings suggest that a mother’s report of her child’s appetite may be informative in identifying children especially vulnerable to developing obesity,” Belsky wrote.

He also said that studies should be done to determine what the differences in appetite in childhood mean for adolescent and adult weights.

Photo: Wader via Flickr