A bit of family medical history with that turkey and gravy?

Is your Thanksgiving feast marred by awkward silences, backbiting comments or, worst of all, sports talk?

Your surgeon general, Dr. Regina M. Benjamin, prescribes the cure for these common holiday afflictions: why not take the opportunity presented by the family gathering to gorge on some of the clinical details of your family's medical history?

The resulting conversation will not only enliven any holiday table. It'll remind everyone that the grim reaper may be hiding in the gravy, that the heartburn they're about to experience might not be so benign, and that in addition to inflicting psychological wounds upon their children, parents bequeath a propensity to certain diseases as well.

Now there's no script for getting this conversation started. But here are a few possible icebreakers:

--I'm interested in understanding my family medical history better. But first, how do I know I'm actually related to you?

--Was Uncle Tommy always like that, or did some neurological disease ravage his brain?

--Why does Uncle Bill's frozen hand look like it's clutching a beer bottle? Could it be alcoholism?

--Was Aunt Zelda born male, or is that facial hair the result of hormone imbalance?

--Your face is very red. Are you angry I'm asking these questions, or do you suffer from dangerously high blood pressure?

    As you can see, there's no wrong way to jog memories and tap the flow of colorful family stories. And if you want to write down the health information you collect along the way, that might come in handy someday as well. You can create a "Family Health Portrait" by checking out this site.

 -- Melissa Healy 

Is a wonder pill necessarily wonderful for people with Down syndrome?

Scientists are hard at work developing a cure for the genetic disorder Down syndrome. But even if they succeed, nearly 60% of parents whose children have Down syndrome might take a pass.

In a survey conducted by researchers from the psychiatry department at the University of British Columbia in Vancouver, 27% of parents said they would not cure their children, and another 32% said they were unsure. Many parents expressed concern that a cure would change their child’s personality, said Angela Inglis, a genetic counselor who worked on the survey.

“Yes, it is a challenge, but your life will change in so many ways for the good, [but] you can’t imagine not having him,” said one parent who would decline a cure.

That feeling was not universal. Forty-one percent of parents said they would definitely treat their children for Down syndrome. Those parents said they were motivated by a desire to make their kids more independent and to give them more opportunities in life, Inglis said. She added that parents who had the hardest time caring for their children were the most inclined to seek a cure.

“It is very difficult, especially for the family dynamics,” one parent told researchers. “It changes our life because there is so much more stress and issues with a child with special needs. We often feel like giving up on life.”

Patients with Down syndrome have three copies of chromosome 21 instead of the usual two. In addition to the mental and physical symptoms, it can cause congenital heart disease, hearing problems, celiac disease, dementia and problems with the intestines, eyes, thyroid and skeleton. People with Down syndrome often live into their 50s, according to the National Institute of Child Health and Human Development.

About one in every 800 babies is born with the disorder. Pregnant women over the age of 35 are routinely offered prenatal screening for Down syndrome. Nearly two-thirds of parents surveyed said they thought prenatal testing for the disorder – through amniocentesis or chorionic villus sampling – was a “good thing,” and 60% said such testing should be available to pregnant women of any age.

The survey was conducted in Canada and included responses from 101 parents. No similar surveys have been taken in the U.S. The results were reported this week at the National Society of Genetic Counselors’ annual education conference in Atlanta.

The question about a cure might become less theoretical in the not-too-distant future.

In patients with Down syndrome, the brain loses its ability to make an important neurotransmitter called norepinephrine. But researchers from Stanford University and UC San Diego found that in genetically engineered mice that have a rodent version of the disease, injections of a drug called xamoterol returned the animals to normal function.

Once inside the mouse brains, xamoterol converted into norepinephrine and allowed the mice to build nests and complete cognitive tests just like regular animals, according to a study being published in Thursday’s edition of Science Translational Medicine. The drug kicked in within just a few hours, but its effects wore off quickly.

The researchers suggested that people with Down syndrome could be treated with Droxidopa, another drug that converts into norepinephrine in the brain. Droxidopa is currently taken by people for orthostatic hypotension in Asia, and it's in Phase 3 clinical trials in the U.S. now. It should be taken with a second drug called carbidopa that would keep it from converting to norepinephrine until it entered the brain, the researchers said.

-- Karen Kaplan

Photo: A recent survey presented parents whose children have Down syndrome with a dilemma: To cure or not to cure? Credit: Beth A. Keiser / Associated Press

Do these genes make my heart seem big? Study finds a gene for empathy

In the long-running nature-nurture debate over what makes us who we are, chalk up a new victory for nature.

A study published Monday in the Proceedings of the National Academy of Sciences has found a single coding variation in the human genome that appears responsible, at least in part, for individual variations in such personality and behavior traits as empathy and response to stress. 

The gene they looked at -- the OXTR gene -- carries the design and production blueprint for cells scattered throughout the heart, uterus, spinal cord and brain that serve as docking stations for a chemical called oxytocin.

Scientists have long known oxytocin as the chemical of bonding and nurture. Produced in the hypothalamus and pumped into both the brain and the bloodstream, oxytocin responds to warm human interaction and drives us to seek it out when our stores are low. It is thought to cause the letdown of milk in breastfeeding mothers, and to soar for many after lovemaking. At the same time, oxytocin appears to have a pronounced calming effect: people and mice alike seem to chill out when the chemical is puffed up their noses or pumped into their bloodstreams, even under conditions of stress.

These two qualities prompted research psychologists from Oregon State University and University of California Berkeley to ask themselves: If some people's genetic endowment made them richer in oxytocin receptors, might they not, by nature, be more attuned to others and more unflappable when under stress?

In the massively complex human genome, it's a daunting challenge to find a single site where a tiny variation in the code of inheritance might produce observable differences in behavior. Fortunately, the authors of the PNAS study had a few clues to guide them: Researchers had earlier found a site on the OXTR gene where certain variations brought with them a higher incidence of autism -- a disorder marked by impairments in social interaction and communication. Variations in this site also had been shown to predict how sensitively mothers responded to their offspring. Perhaps, they asked, coding variations at this same site would yield more subtle differences in a person's sociability and ability to withstand stress?

To make a long story short, they did. The researchers put 192 college students at UC Berkeley through a pair of experimental tests -- one that measured their ability to infer the emotional state of others from looking at their facial expressions and another that measured their jumpiness when warned that a loud blast of noise was imminent. The students also were asked to rate their own levels of empathy and ability to handle stressful situations.

The one in four subjects who inherited a variation in this allele called G/G were significantly better at accurately reading the emotions of others by observing their faces than were the remaining three-quarters of subjects, who had inherited either a pair of A's or an A and a G from their parents at this site. Compared to the three-fourths with A/A or A/G variations, the G/G individuals were also less likely to startle when blasted by a loud noise, or to become stressed at the prospect of such a noise. And by their own reports, the G/G subjects were mellower and more attuned to other people than were the A/As or A/Gs.

The group's findings would appear to strike a decisive blow for nature over nurture in shaping who we are and how we behave. In fact, subjects were asked to rate how nurturing their own parents were, and researchers found that a subject's genetic inheritance seemed a better predictor of his empathic disposition than did his mother and father's parenting styles.

But UC graduate student Laura R. Saslow, a co-author of the paper, cautioned that genetic inheritance -- nature -- is never the sole determinant of our personalities. While researchers will get closer to filling in the inborn components of our personalities, the environments in which we've been raised will always interact with our genetic inheritance and shape how it expresses itself, Saslow says.

"Really, both matter," says Saslow.

-- Melissa Healy

  

Gene therapy strengthens monkeys' muscles, may eventually work for human diseases

Injecting a gene into thigh muscles of a monkey's leg greatly increased muscle mass and strength, a finding that could have potential application in a variety of human diseases that involve muscular weakening, researchers reported this week in the new journal Science Translational Medicine. The effects have now persisted for as long as 15 months and no side effects have been apparent, according to the researchers from Ohio. Clinical trials in humans are expected to begin next year.

Researchers have long sought ways to boost muscle mass and tone. Androgen steroids and glucocorticosteroids are the most obvious approach, but both have long-term consequences that render them less than desirable. Many researchers have thus turned to gene therapy, but results have been mixed so far.

Physiologist H. Lee Sweeney of the University of Pennsylvania has been working with a gene that is the blueprint for a protein called insulin-like growth factor 1, or IGF-1. Sweeney injected the gene for IGF-1 into one back leg of rats and found that the muscles in that leg became as much as 30% bigger than those in the untreated leg, even without exercise. But Sweeney has since switched his studies to focus on a chemical called follistatin, which promises to be more useful.

Work on that chemical was pioneered by molecular biologist Se-Jin Lee of Johns Hopkins University, who had been studying another chemical called myostatin. Muscles in young animals continue to grow until they reach maturity, at which time the body begins producing myostatin, which blocks the growth process. Researchers have been looking for chemicals that would block the activity of myostatin, thus allowing the muscles to continue their growth. Lee discovered another naturally occurring chemical called follistatin that is the strongest blocker of myostatin activity known. Lee found that giving follistatin to mice caused them to bulk up substantially. Genetically engineering mice to produce extra amounts of follistatin and to not produce myostatin led to exceptionally muscular mice whose muscle fibers were more than double the size of normal mouse muscle fibers.

In the new study, Dr. Jerry R. Mendell, director of the gene therapy center at Nationwide Children's Hospital in Columbus, Ohio, and his colleagues inserted the gene for follistatin into a defanged cold virus, which they used to insert the gene into thigh muscles in the legs of healthy macaque monkeys. Eight weeks after the treatment, the monkeys' leg muscles were 15% bigger and as much as 78% stronger. The effects persisted for the full 15 months that the monkeys were studied and no obvious side effects were observed.

The treatment would not cure muscle diseases such as muscular dystrophy or amyotrophic lateral sclerosis, which are caused by genetic defects, Mendell said. But  it could strengthen the weakened muscles, allowing victims of those disorders to use them for longer periods.

The results in the monkeys should be sufficient to persuade the Food and Drug Administration to allow clinical trials of the technique in humans, Mendell said. He hopes to begin such studies by the middle of next year. The first patients will be people with inclusion body myositis, a rare condition that weakens the muscles of adults over the age of 50.

Mendell conceded that the therapy could be abused by athletes seeking to improve their muscle strength. But he noted that, if it is approved eventually, it will be closely regulated and will likely be very expensive. Athletes, he said, are more likely to stick to cheaper and more readily available steroids.

-- Thomas H. Maugh II

Photo: Gene therapy in the legs of monkeys like this macaque in Bangkok made the legs up to 78% stronger. Credit:  David Longstreath / Associated Press

Do these genes make me drive poorly?

Cracking the human genome is a dense and seemingly impenetrable undertaking, what with our 46 chromosomes, more than 30,000 genes and 3 billion base pairs: It's hard to imagine that some tiny variation embedded in the middle of all that code could actually predict something like who will have to retake driver's ed three or four times just to pass the driving test.

Well, it can. In fact, according to a new study by researchers at UCI, a tiny variant in the genetic code can help predict whether its owner will be a lousy driver. Their study is published in a recent issue of the journal Cerebral Cortex.

Seven in 10 of us carry genetic instructions to flood certain regions of the brain with a neurochemical called brain-derived neurotrophic factor  -- or BDNF -- when we're challenged to learn a new aerobics routine, land a plane or navigate a tricky patch of road. It seems to help us learn to do new things.

But 30% of humans have a small variant in their genetic code that results in the release of smaller doses of BDNF when they're trying to master a new skill that involves physical coordination. These people have brains that are smaller in some key regions. Researchers have observed that when people with this genetic variant suffer a stroke with loss of motor function, they recover more slowly and less completely than those without the variant.

Could it be, asked researchers in the lab of UCI neuroscientist Steven Cramer, that when it comes to learning new things, this 30% of humans is just not as fast on the uptake?

To see, Cramer's team ran a series of experiments culminating in the driving challenge: 22 subjects had the genetic code that ordered up lots of BDNF when it came time to learn a new trick; seven had the genetic variant that coded for the release of less BDNF. Earlier experiments had already shown that compared with the smaller group with the genetic variant, the brains of those in the large group responded to the challenge of a new physical task with stronger activity in many more regions.

In the driving challenge -- learning to steer down a simulated winding road without drifting off the center line -- the group with the genetic variant made 20% more errors than the larger group, were slower to learn and, when tested again four days later, forgot more of what they had learned than had their peers without the variant in the BDNF gene.

Cramer said his team was astonished that a single-nucleotide polymorphism -- sometimes called a SNP -- would seem to yield such distinct differences in actual everyday behavior. Whether it influences how we learn every new task or has a cumulative effect in shaping the brain, said Cramer, this tiny genetic variant is powerful.

"Next time someone cuts you off on the freeway, one could conjecture that this could be part of the problem," said Cramer in an interview. (He adds that this knowledge hasn't make him feel more kindly toward offending motorists though.)

--Melissa Healy

As genetic medicine races ahead, docs are left behind

Genetic tests that can help predict and refine a patient's response to drug therapy may be the first big thing in personalized medicine. But the vast majority of physicians don't know how to use them, a new survey finds.

Individual genetic variations can affect how a patient will respond to many antidepressants, pain medications, cardiovascular medicines and certain drugs that treat cancers and gastrointestinal ailments. In all, roughly one in four American patients take medications whose effectiveness could be tweaked or predicted by a pharmacogenetic test. And purveyors of genomic testing services and devices are rushing to provide tests for them all.

A survey of more than 10,000 U.S. physicians undertaken by the American Medical Assn. and the pharmacy benefits manager Medco Healthcare Solutions Inc. found that just more than  one in four had had any type of education in the use of genetic testing to guide medication decisions. And only 1 in 10  felt he or she had the necessary training and knowledge to put pharmacogenetic testing to good use in treating patients. Some 13% had ordered or recommended a genetic test for a patient in the last six months. But twice that many said they would do so in the next six months. 

Genes that regulate liver enzymes can have a particularly powerful influence on a patient's response to a medication. Scientists believe that one such enzyme may be responsible for governing the way patients respond to some 30% of all drugs used today. In oncology, a test can help predict if breast cancer patients will respond to the drug tamoxifen. And cancer drugs in the development pipeline are expected overwhelmingly to be administered with the guidance of genetic tests. Genetic tests also can help reduce unwanted side effects; the blood thinner warfarin, for instance, can cause blood clots or serious bleeds in some patients with an identified genetic variance, and physicians are increasingly testing those on a blood-thinning regimen in an effort reduce such risks.

"It's clear there's wide acceptance" on physicians' part for the role that genetic testing can play in guiding medication decisions, said Dr. Robert Epstein, Medco's chief medical officer, who briefed physicians and researchers on the survey at the annual meeting of the American Society for Human Genetics on Thursday. But the AMA and other groups must step up efforts to educate physicians in the use of these tests, added Epstein. "With the number of new drugs coming to market with a companion diagnostic, it's paramount that this education takes place."

--Melissa Healy

Gaucher disease linked to Parkinson's

People who carry the gene for a rare genetic problem known as Gaucher disease have at least five times the normal risk of developing Parkinson's disease, researchers reported today in the New England Journal of Medicine. Some clinicians had noticed an apparent link between the two conditions in the past, but a new international study of nearly 5,700 people is the first to show the magnitude of the risk. The finding suggests that the gene is one cause of the disease, but indicates that other factors must be operating as well because not all patients who have Gaucher also develop Parkinson's.

Gaucher disease, which afflicts an estimated 5,400 Americans, is caused by defects in the gene known as GBA, which serves as the blueprint for the production of an enzyme known as glucocerebrosidase. The enzyme breaks down a fatty substance called glucocerebroside which, when not disposed of, can harm the spleen, liver, lungs, bone marrow and, in some cases, the brain. People with two defective genes suffer from the disease, which comes in three distinct types. Lifespan may range from as little as 2 years to as many as 40 or 50.

People with only one defective gene do not suffer from symptoms and are said to be carriers. About one in 100 Americans carries the gene, but among certain groups, like Ashkenazi Jews, the incidence rises to one in 15. It was previously thought that the gene was harmless in such people, but the new results show that is not the case.

Dr. Ellen Sidransky of the National Human Genome Research Institute had been intrigued by an observed link between Gaucher and Parkinson's. To explore it, she organized a consortium of 64 researchers at 16 institutions worldwide--virtually every Gaucher researcher in the world. They studied two common GBA variants in 5,691 people with Parkinson's disease, including 780 Ashkenazi Jews, and compared them to 4,898 disease-free individuals, including 387 Ashkenazi Jews.

They found that 3.2% of the Parkinson's patients had at least one of the common variants, compared with only 0.6% of the healthy people, a five-fold increase. Among the Jews, 15.3% of those with Parkinson's carried the gene, compared with 3.4% of healthy Jews.

Five of the research centers sequenced the entire GBA gene in 1,642 non-Ashkenazi Parkinson's patients and 609 health non-Ashenazis, looking for other mutations. They found mutant genes in 7% of the patients, indicating that their risk of developing Parkinson's was 10 times normal.

The finding does not offer any new ideas about how to treat Parkinson's disease. Indeed, researchers are currently at a loss to explain the mechanism by which the defective gene increases the risk of Parkinsonism, which affects an estimated 3 million to 4 million Americans. But they hope that exploring the link will provide new information about how the disease develops and progresses.

-- Thomas H. Maugh II

Warning: DNA test results may not be as reliable as they appear

“Understanding of the genetic contribution to human disease is far from complete.”

This statement, by DNA decoder J. Craig Venter and three colleagues, is undeniably true. But it probably would come as a surprise to much of the general public.

A host of genetic testing companies have cropped up in recent years that offer to scan your DNA and calculate your risk of developing a host of diseases. It’s no wonder that customers are under the impression that their medical destiny can be read in their genes.

Venter – a key figure in the massive effort to sequence the human genome – and his colleagues have burst this bubble with a clever experiment, reported online today in the journal Nature.

They took DNA samples from five people and sent them to two prominent genetic testing companies in Silicon Valley, Navigenics Inc. of Foster City and 23andMe Inc. of Mountain View. Both companies sell testing kits online ($399 for 23andMe, $999 for Navigenics). Customers return their vials of saliva, and within a few weeks their test results are available over the Web.

If this were a perfect science, those five people would receive identical test results from both companies. And indeed, the predictions for breast cancer, celiac disease, multiple sclerosis and rheumatoid arthritis were in agreement in all five cases.

But for nine other diseases, at least one of the test subjects got conflicting results. In fact, with seven conditions – Crohn’s disease, heart attack, lupus, prostate cancer, restless leg syndrome and type 2 diabetes – at least half of the subjects got different answers from the two companies.

It wasn’t because the companies did a sloppy job of reading the DNA. Consumer testing companies typically scan 500,000 to 1 million genetic variants, and in this experiment more than 99.7% of those variants were read the same way by Navigenics and 23andMe.

Discrepancies arise in the way that different companies interpret those results. Researchers conduct genome-wide association studies to compare DNA samples from patients with particular diseases to DNA samples from healthy controls. Using powerful computers, they can pick out certain variants that are more likely to occur in people with a disease, as well as calculate the extra risk (or extra protection) that comes with each of the variants.

Both Navigenics and 23andMe rely on the same studies to assess their customers’ genetic risk. But they also use their own criteria for deciding how much weight those studies deserve.

They also emphasize different components of risk, Venter and his colleagues wrote. For instance, in calculating the chance that a particular customer will get a certain disease, 23andMe takes age into consideration, since the risk of many diseases goes up as you get older. On the other hand, Navigenics factors in the customer’s gender, since some conditions are more likely to affect men and others tend to strike women.

For some diseases, the genetics are clear. A single DNA marker has been shown to increase the risk of celiac disease by a factor of 7. Both companies recognize this, and so their results for this digestive disorder are in strong agreement. (Navigenics also includes seven additional markers that play a modest role, but their combined effect isn’t big enough to trump the effect of the one big marker.)

The situation is completely different for the skin condition psoriasis. One of the subjects was told by 23andMe that his or her chances of getting the disease were four times greater than for the general public. Navigenics agreed that the subject had an increased risk, but said it was only 25% higher.

The main reason for the discrepancy was 23andMe’s decision to rely on a DNA variant that nearly triples the risk of psoriasis, according to one study. But that study didn’t meet the scientific standards of Navigenics, so that particular variant isn’t part of the company’s risk model, Venter and colleagues said.

Even if all the results were in perfect agreement, it wouldn’t necessarily make the tests more reliable, the researchers said.

In the case of celiac disease, the DNA variants that have been identified so far are estimated to account for only 35% to 40% of the disorder’s genetic basis. (And that’s not even counting whatever environmental influences play a role.) A genetic scan today could give a customer a false sense of security if he or she happens to carry some disease variants that have not yet been discovered. There could also be customers whose risks are overstated because they have an unidentified DNA variant that greatly reduces their risk.

For these reasons and more, Venter and his colleagues can’t conclude which company’s test is more accurate. Instead, they emphasize that none of the consumer-oriented testing companies is as reliable as they appear.

-- Karen Kaplan

Photo: A research associate at Affymetrix Inc. examines genetic data from a saliva sample submitted by a Navigenics customer. Credit: Steve Yeater

Breastfeeding may benefit women with a family history of breast cancer

Women who have watched a mother, sibling or child battle breast cancer can become understandably preoccupied, if not obsessed, with trying to reduce their own risk of the disease. One possible way to do that? Breastfeed.

In a study published online today in the Archives of Internal Medicine, researchers at Brigham and Women's Hospital and Harvard Medical School analyzed information on 60,075 women who had given birth and who had provided information about, among many other things, their breastfeeding practices.

Earlier studies had hinted that breastfeeding might lower a woman's chance of developing the disease, but those results were far from conclusive.

This study seems somewhat clearer. It found that women who had a so-called first-degree relative with breast cancer were less likely to develop pre-menopausal breast cancer if they had ever breastfed. Duration of breastfeeding didn't affect risk, the study said, nor did whether the women supplemented with formula, nor did whether the women experienced a cessation of menstruation. Just the act of breastfeeding.

No such connection was found in women who didn't have a family history of breast cancer.
 
Here's a synopsis of the study; more on the risk factors for breast cancer, from the American Cancer Society; and a roundup of information on breastfeeding, from the National Institutes of Health's Medline Plus.

(As for the women in this study, if you hadn't guessed already, they were participants in the Nurses' Health Study. Some years ago, thousands upon thousands of nurses answered detailed questions about seemingly every health factor imaginable. Researchers have been mining their answers ever since, and the possible connections between health and lifestyle gleaned from those participants just keep coming.)

In this study, the researchers conclude: "The observed 59% reduction in risk compares favorably
with hormonal treatments such as tamoxifen for women at high risk for breast cancer. Moreover, breastfeeding is associated with multiple other health benefits for both mother and child. These data suggest that women with a family history of breast cancer should be strongly encouraged to breastfeed."

-- Tami Dennis

Photo: Los Angeles Times

Stanford professor sequences his own DNA

My how times change.

Twenty years ago, when the government began the Human Genome Initiative, researchers believed it would take 10 years,  $3 billion and thousands of scientists to determine the sequence of the 3 billion individual deoxyribonucleic acid bases that constitute a single individual's genetic complement or genome. That estimate proved to be conservative. A complete sequence was not announced until 2003 and the total cost is still unclear.

Since then, techniques for sequencing have improved dramatically. By last year, a complete human genome could be deciphered at a cost of only $250,000 and requiring only about 200 people.

Today, bioengineer Stephen Quake of Stanford University reports online in the journal Nature Biotechnology that he has sequenced his own genome at a cost of less than $50,000 and with the help of only two people. "This is the first demonstration that you don't need a genome center to sequence a human genome," he said. "It's really democratizing the fruits of the genome revolution and saying that anybody can play in this game."

Quake's becomes one of only about a dozen genomes that have been sequenced so far. Others whose genomes have been sequenced include J. Craig Venter, founder of Celera Genomics -- which played a significant role in the mapping of the human genome -- and James Watson, co-discoverer of the structure of DNA.

Stanford physicians are studying the genome -- and Quake -- to look for links between health and genetics.  The genome revealed that Quake carries a rare mutation for a heart disorder that has affected other members of his family. The good news, he said, is that he also has a gene that suggests he will respond well to cholesterol-lowering statin  drugs.

He also found he bears a gene that has sometimes been associated with increased disagreeability. "Of course, you don't need my genome to tell you that," he said. "My wife could have told you that, and certainly the dean could have as well."

-- Thomas H. Maugh II