stanford medicine




Bug food

Terry AllenUpfront

We are what we eat, but who are “we”? New, high-powered genomic analytical techniques have established that as many as 1,000 different single-celled species co-exist in relative harmony in every healthy human gut.

“What you eat is proving to be one of the major determinants of the components of your ‘inner self’ — that community of bacteria living in your intestine,” says Justin Sonnenburg, PhD, assistant professor of microbiology and immunology.

Each individual’s microbial ecosystem is different in its relative composition, with potential implications for our health. Disorders such as inflammatory bowel disease, colorectal cancer and even obesity have been linked to skewed intestinal microbe distributions.

Scientists hope that someday they will be able to manipulate microbial populations in the gut as a way to remedy disease and enhance health. One step toward this goal would be taking “genomic censuses” to categorize and count the components of each individual’s bacterial community and how they respond to interventions, such as changes in diet. That’s no small task, because the aggregate gene count of all the micro-organisms dwelling in a typical human gut outnumbers our own by a hundredfold.

In an animal study published June 25 in Cell, Sonnenburg and his colleagues showed that zeroing in on just a small set of bacterial genes allowed them to predict how bugs would respond to a diet change.

Their results set the stage for scaling up germ-free mice, who become living laboratories into which scientists can introduce, one by one, steadily increasing numbers of bacteria found in the human intestine, eventually enabling an understanding of the complex microbial superorganism that dwells inside each of us.

The team introduced two distinct species of bacteria, both known to abound in the human digestive tract, into mice that had been raised in a sterile environment. Then they fed the mice a diet rich in a particular complex carbohydrate that one bacterial species seemed genetically better equipped to digest. As predicted, that bacterial species became predominant in the mice’s intestines.

The results highlight the potential of the burgeoning new field of prebiotics, which (in contrast to probiotics — the eating of healthful bacterial organisms) involves adding substances to the diet that nourish the healthful micro-organisms.

The researchers caution that it will be a while before the results in this simple experimental system — two competing bacterial species — can be extrapolated to the real, human gut-dwelling microbial community. Since a more complex experimental system would be closer to the reality inside human intestines, they are introducing a greater diversity of human-associated bacteria. — Bruce Goldman


The study was funded in part by the National Institutes of Health.

IVF test

Terry AllenUpfront

Women who fail to become pregnant after undergoing in vitro fertilization treatment often grapple with deciding whether to try IVF again. The procedure carries hefty financial, physical and emotional costs, and there are no guarantees it will work.

Now a team of School of Medicine researchers has developed a model to predict the outcomes of a subsequent round of IVF for those women who have already gone through a cycle. The researchers found that their test, which uses clinical data from prior, failed treatments to provide more personalized predictions, is 1,000 times more accurate than the age-based guidelines currently used to counsel patients.

“Our findings show that the first IVF cycle can provide quantitative, customized prediction of the live birth probability in a subsequent cycle,” the researchers wrote in their paper. “This concept is radically different from the current paradigm, in which age is a major predictor.”

The study, published online July 19 in the Proceedings of the National Academy of Sciences, was led by Mylene Yao, MD, assistant professor of obstetrics and gynecology.

Each year, close to 100,000 IVF cycles are performed using a woman’s fresh eggs, and around 29 percent of the treatments result in live births. Physicians typically use age-based data, with adjustments based on other clinical factors, to counsel patients on the probability of success. But given all the variables at play, age may be misleading as a prognostic factor.

The team’s goal was to provide patients with more personalized predictions. They took data from 1,676 IVF cycles performed at Stanford Hospital & Clinics between 2003 and 2006 and identified 52 factors — such as patient age, levels of certain hormones, number and quality of eggs, and individual characteristics of each embryo — that influence a woman’s chance of having a baby. They then developed a computer model that sorted patients into subsets defined by similar clinical characteristics to predict live-birth probabilities in a subsequent round of IVF.

When testing their model with data from a separate set of more than 600 IVF treatments performed in 2007-08, the researchers determined that the model’s predictions were significantly different from the age-based predictions in 60 percent of patients. Interestingly, out of this group, more than half were assigned greater odds of having a baby than what age-related data indicated.

In further verifying the accuracy of their new method, they determined that their model predicted outcomes with 1,000 times more accuracy than the age-based guidelines widely used in clinics.

Yao notes that because it’s critical to have data from previous treatment, this model wouldn’t be able to predict chances of success for those embarking upon their first IVF. But she says having personalized, accurate prognostic information would be invaluable in helping patients decide whether to keep going. — Michelle L. Brandt


The study was funded by the National Institutes of Health and the Coulter Foundation Translational Research Program at Stanford University. Yao and co-author Wing Wong, PhD, professor of statistics and of health research and policy, have founded a company, Univfy, to develop and market prognostic tests to support clinical decision making in infertility. Stanford holds the patent on the test referenced in this study.

Antibody surprise

Antibodies — warrior proteins the immune system makes to defend the body against invading pathogens such as viruses and bacteria — have a gentler side nobody knew about until now: They function not only as soldiers but also as nurses.

“In an injured human brain or spinal cord, the degenerating myelin just sits there for the rest of the person’s lifetime. But after injury to, say, the sciatic nerve, the degenerating myelin is cleared within a week or less.”

And researchers at the School of Medicine now think antibodies’ absence in the central nervous system (the brain and spinal cord) might be a key reason nerve damage there doesn’t get naturally repaired in humans.

In a study conducted in mice, published online June 14 in Proceedings of the National Academy of Sciences, the Stanford scientists showed for the first time that antibodies are critical in repairing damage to the peripheral nervous system — nervous tissue that extends outside the brain and spinal cord, such as the sciatic nerve, where circulating antibodies have access. The study also shows that some, but not all, antibodies get the job done. Harnessing the unanticipated nurturing qualities of these proteins might lead to new ways of repairing damage from stroke or spinal-cord injury.

“Nobody has known why, but nerve cells in the central nervous system fail to regenerate after injury whereas those in the peripheral nervous system regenerate robustly,” says senior study author Ben Barres, MD, PhD, professor and chair of neurobiology.

His group was intrigued by one major difference between the two nervous systems: Antibodies have limited access to the brain and spinal cord (these organs are surrounded by an interface called the blood-brain barrier or, in the spinal cord, the blood-spinal cord barrier), while they have ready access to the peripheral nervous system.

Nerve cells convey electrochemical impulses over long distances by means of long, tubular projections called axons. These axons are typically wrapped in an insulating layer of a fatty substance called myelin.

“After nerve injury, the degenerating myelin downstream from the injury is rapidly cleared in the peripheral, but not the central, nervous system,” says Barres. “In an injured human brain or spinal cord, the degenerating myelin just sits there for the rest of the person’s lifetime. But after injury to, say, the sciatic nerve, the degenerating myelin is cleared within a week or less.”

The researchers wondered whether antibodies might play a role in that clearance. They obtained mutant laboratory mice that can’t make antibodies, and demonstrated that repair of injury to the sciatic nerve is substantially impeded, as is the removal of degenerating myelin downstream from the injury site. Simply injecting the injured mutant mice with antibodies from healthy, uninjured ones restored both myelin removal and sciatic-nerve repair capability in the mice.

While antibodies have been found to play a role in the disposal of aging red blood cells, this is the first time they’ve been implicated in injury repair, say the researchers. What’s more, they threw light on the way in which this happens: Antibodies grab onto the degenerating myelin downstream from the site of the nerve injury, tagging the myelin for clearance by immune cells called macrophages. — Bruce Goldman


The work was funded by the National Eye Institute, the Adelson Medical Research Foundation, the National Institutes of Health and the National Multiple Sclerosis Society.

Orphaned elders

The increase in aids deaths in sub-Saharan Africa has led to a burgeoning new category of neglected individuals — nearly a million orphaned elderly, or older adults living alone without the benefit of any caregivers, School of Medicine researchers have found.

“We find that AIDS has produced close to a million elderly people in sub-Saharan Africa who are living without the support of their sons, daughters or other younger adults.”

The researchers used existing data to develop the first estimates of the number of elders left without any adult support as a result of the AIDS epidemic, says Grant Miller, PhD, MPP, assistant professor of medicine.

“We find that AIDS has produced close to a million elderly people in sub-Saharan Africa who are living without the support of their sons, daughters or other younger adults. Many of them also live with young children under 10 years of age, creating households with a missing generation of adults,” says Miller, senior author of the study, which was published online June 16 in the British Medical Journal.

Miller says he and his colleagues were stunned to learn that no one had taken a systematic look at this group of needy individuals.

“It just blew me away,” he says. “We all know we have this problem with orphaned children. I wondered, do we have a similar problem with orphaned elderly? I searched a variety of publications and didn’t find a clear answer.”

The researchers used data from the Demographic and Health Survey, a USAID-funded database that provides standardized information on maternal/child health, HIV and other health indicators in low- and middle-income countries. The survey covered 123,000 individuals over age 60 living in 22 African countries between 1991 and 2006.

The scientists found a strong correlation between the rise in AIDS deaths in these countries and an increase in elderly individuals living alone. For every one-point increase in AIDS mortality, they found a 1.5 percent increase in elderly people left to manage on their own.

In the 22 countries, the estimates translated into 582,200 to 917,000 elderly people left unattended. About a third of them — or as many as 323,000 — were also caring for young children. These individuals were more likely to be women, uneducated, living in rural areas and poorer than their attended counterparts. The results suggest HIV/AIDS has had a disproportionate impact on elderly people of lower socioeconomic status.

Yet few African countries have public pension programs or formal systems for caring for elders; most rely on traditional family structures, now undercut by the strain of AIDS, to provide this service. The researchers say the study points to the importance of taking these needy elders into consideration when providing resources and planning programs.

“This is another component of the social consequences of HIV. So people in agencies who make resource allocation decisions need to consider this cost of HIV, and it’s a pretty important one,” Miller says. — Ruthann Richter


The study was funded by the National Institutes of Health.

Smoke signals

Terry AllenUpfront

Point-of-sale tobacco advertising works impressively well on teens — so well that federal regulators should consider barring such marketing efforts from convenience stores, gas stations and small groceries, says a School of Medicine researcher.

A study published in the August issue of Pediatrics led by Lisa Henriksen, PhD, senior research scientist at the Stanford Prevention Research Center, reports that teens’ exposure to cigarette advertising at retail outlets substantially increases the odds they will start smoking. According to the findings, students who visited these stores on a regular basis were at least twice as likely to try smoking as those who visited infrequently.

“The tobacco industry argues the purpose of advertising is to encourage smokers to switch brands, but this shows that advertising encourages teenagers to pick up a deadly habit,” says Henriksen, who has studied tobacco marketing for more than a decade.

Point-of-sale is the major form of marketing used for tobacco — representing 90 percent of the industry’s $12.5 billion marketing budget in 2006 — and the study suggests that further limits on such activity could affect long-term smoking habits.

Henriksen based the study on repeat surveys of 11- to 14-year-olds at three middle schools in Tracy, Calif., and assessments of cigarette advertisements at stores near the schools. The survey questioned students about smoking experience as well as how often they visited the types of stores with lots of cigarette ads — convenience stores, gas stations and small groceries — and was repeated, first at one year and then at 30 months.

Of the 2,110 students surveyed in 2003 when the study began, 1,681 reported never smoking. A survey of these non-smoking students a year later revealed 18 percent of these students had smoked over the year, at least one puff, and that smoking initiation was much more prevalent among those who had reported frequent visits to stores with the most cigarette ads.

Among the non-smokers who had reported visiting these stores at least twice a week, 29 percent took at least one puff in the study’s first year. Among those who rarely visited — less than twice a month — only 9 percent started smoking that year.

A survey 30 months after the study began found that by then 34 percent of those who had visited stores at least twice a week had tried smoking, and only 21 percent of those who had rarely visited had taken a puff.

When researchers adjusted for all the variables that affect tobacco use, they found a strong relationship between store visits and smoking initiation. A year after the survey, frequent shoppers (two or more visits a week) were more than twice as likely to have taken at least one puff than infrequent shoppers. Thirty months after the initial survey, the apparent influence of the store visits remained: Those who had reported frequent visits were 42 percent more likely than infrequent visitors to have tried smoking. — Rosanne Spector


The research was funded by the National Cancer Institute.







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