by Rob Mitchum

An advantage and disadvantage of hypothesis-free studies looking for genes associated with various traits or diseases is that they often point to genetic candidates that don’t make immediate sense. One example of this occurrence was the 2005 discovery of an association between the gene Glo1 and anxiety-like behaviors in mice. Previously, scientists knew Glo1’s protein product, glyoxylase 1, primarily as a enzyme involved in in glycolysis — the cellular digestion of glucose. Nobody had considered that glyoxylase 1 played a role in brain function, much less behavior, leading some to question the validity of the genetic association.

“When people discover a gene, they’re always most comfortable when they discover something they already knew,” said Abraham Palmer, assistant professor of human genetics at the University of Chicago Medicine. “The alarming thing here was there was a discovery of something that nobody knew, and therefore it seemed less likely to actually be correct.”

But Palmer’s laboratory continued chasing down the Glo1/anxiety connection, and their experiments paid off in the discovery of an entirely new mechanism for anxiety disorders. Their study, published today in the Journal of Clinical Investigation, also describes a previously unrecognized inhibitory neural factor, offers a promising new target for the treatment of anxiety disorders and other psychiatric symptoms, and suggests an intriguing connection between metabolism and neurobiology.

“What’s neat is that we started with exploratory, open-ended genetic studies in mice, and we’ve now gotten into some fundamental new physiology that nobody had appreciated or put together before,” Palmer said. “Now we’re starting to reap some of the fruit from those types of genetic studies to enrich our understanding of more classical aspects of biology.”

Lead author Margaret Distler, an MD/PhD student in the Pritzker School of Medicine, started her examination of the Glo1/anxiety link by testing it in a new way. In a 2009 paper, Palmer’s group hypothesized that mice with more copies of the Glo1 gene — a genetic phenomenon known as copy number variants — were more likely to show anxious behaviors. Distler tested this theory by inserting two, eight, or ten copies of the gene into mouse lines, and measuring their anxiety with various laboratory tests, including the open field test and the light-dark box test. As predicted, more Glo1 copies equated to more anxiety-like behavior, lending more evidence to the link.

“Animals transgenic for Glo1 had different levels of anxiety-like behavior, and more copies made them more anxious,” Palmer said. “We showed that Glo1 was causally related to anxiety-like behavior, rather than merely correlated.”

The next step was to figure out how Glo1 accomplished its unexpected influence. In glycolysis, glyoxylase 1’s job is to metabolize and reduce levels of a byproduct called methylglyoxal, or MG for short. So Distler tried an experiment so simple it almost obvious: if increasing Glo1 increases anxiety, would increasing MG levels alleviate it? After injecting mice with MG, the mice were less anxious in the behavioral experiments, suggesting that the metabolic byproduct does in fact play a role in anxiety — and a relatively fast role, at that.

“Methylglyoxal changed behavior within 10 minutes of administration, which means it’s a rapid onset. It’s not changing gene expression, and it’s not having long-term downstream effects,” Distler said. “That was our first breakthrough.”

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By Matt Wood

Adverse reactions to foods, including eggs, milk, peanuts, tree nuts, wheat, shellfish and soy, are on the rise, especially among children. The CDC reports (PDF) that between 1997 and 2007, food allergies increased 18 percent in children under the age of 18. While we generally categorize all adverse reactions as “allergies,” they actually cover a range of immune system responses and disorders of the digestive system, each with its own causes and varying levels of severity.

In a paper published in Current Gastroenterology Reports, Stefano Guandalini, MD, section chief of pediatric gastroenterology, hepatology and nutrition at the University of Chicago Medicine, and Catherine Newland, a pediatric gastroenterology fellow, reviewed the major forms of food allergies and intolerances to help navigate this confusion and provide a guide for treatment and prevention options.

While bad reactions to food are extremely common, only a few can be defined as allergic reactions. An allergic reaction is caused by an immune system response to a specific allergen present in food, such as the proteins in cow’s milk or soybeans. If a person with a food allergy is exposed to these proteins, their body flags them with Immunoglobulin E (IgE) antibodies, which normally help fight parasites. The body’s immune system then mistakenly thinks these proteins are harmful and triggers an allergic reaction, such as skin rash, gastrointestinal or respiratory distress and the more life-threatening anaphylactic shock. An example of another type of immune reaction, not mediated by IgE, is celiac disease. Celiac is an autoimmune condition in which the body responds to the wheat protein gluten by destroying its own villi that absorb nutrients in the small intestine.

Food intolerance, on the other hand, is a broader term encompassing all adverse food reactions. “A food sensitivity or intolerance is a more generic term, comprehensive of any adverse food reaction, that can be immune-mediated but also may not be immune-mediated,” Guandalini said. “For instance, some people react to the tyramine present in cheeses. This is due to release of histamine, and is not an immune process.” Lactose intolerance is another common problem caused by the inability of the body to digest lactose, a sugar present in milk. Unfortunately, this distinction makes little difference to someone suffering from any kind of food intolerance because the symptoms are often similar.

The reason for the increased prevalence of food allergies and intolerances is unclear, but Guandalini says a leading theory is the “hygiene hypothesis.” Lack of early childhood exposure to infectious diseases, microorganisms and parasites as a result of industrialization, clean drinking water and modern medicine may be suppressing natural development of the immune system and increasing our susceptibility to allergies. Cathryn Nagler, Ph.D., a food allergy professor at the University of Chicago, is also studying how modern lifestyles, including high-fat diets, antibiotics and the use of baby formula instead of breastfeeding are changing the bacteria that live inside our bodies to produce more sensitivity to certain foods.

Tactics to prevent food intolerances from developing in children, - such as mothers restricting their diets during pregnancy, then breastfeeding and waiting to introduce certain foods to baby’s diet - have mixed results. If allergies do develop, Guandalini says that desensitization, or controlled exposure to allergens, shows promise for helping people tolerate problem foods such as milk or peanuts, but it requires more research. Until then, the only option is avoidance, one that many people with a food intolerance figure out the hard way on their own.

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Guandalini, S., & Newland, C. (2011). Differentiating Food Allergies from Food Intolerances Current Gastroenterology Reports, 13 (5), 426-434 DOI: 10.1007/s11894-011-0215-7

By Rob Mitchum

The acorn worm is an eye-less, ear-less invertebrate that lives in the intertidal zone, scavenging food particles from the sand and water. One wouldn’t expect to find the developmental clues for the creation of the vertebrate brain in such a humble creature. But a new study led by a University of Chicago graduate student and published today in Nature finds that the signals that shape the brains of all vertebrates, including humans, can indeed be traced back to the ancestor we share with the acorn worm.

Perhaps due to a touch of vertebrate bias, human scientists have long looked for what biological factors separate the vertebrate brain from the simpler nervous system found elsewhere in the animal kingdom. When physically compared to the nervous system of invertebrate chordates, the brain of vertebrates stands out for its complex structure and specialized regions. But when researchers compare the genetics underlying nervous system development in these two groups, there are fewer differences than expected.

Notable exceptions are the “signaling centers,” areas of the vertebrate embryo that secrete factors to organize the elaborate construction of the brain and spinal cord. The lack of these centers or their associated genes in commonly used model invertebrate organisms suggested that they were the unique property of vertebrates.

“Based on the available data, the idea that these signaling centers could have been responsible for the morphological innovations in vertebrate brains was very compelling,” said Ariel Pani, graduate student in the University of Chicago Committee on Evolutionary Biology. “Scientists went looking for them in amphioxus and ascidians, but they were for most part either absent or divergent, which supported the hypothesis about their origin in vertebrates.”

But while modern-day amphioxus and ascidians are used as models for the ancient species that closely preceded the first vertebrates, it’s possible that they could have lost those signaling centers in the over 500 million years since they shared a common ancestor with their brainier vertebrate relatives. Pani, now completing his research at Stanford University in the laboratory of Christopher Lowe, decided to look at a slightly more distant relative of vertebrates, represented by Saccoglossus kowalevskii, a modern acorn worm.

Collected by the researchers at the Marine Biological Laboratory in Woods Hole, Massachusetts, acorn worms don’t resemble likely suspects for investigating the origin of the vertebrate brain. In fact, acorn worm embryos don’t have what could classically be called a brain at all, instead displaying a diffuse, circumferential organization…with some unique features.

“Their nervous system is still very controversial,” Pani said. “It has historically been described as diffuse, with neurons throughout the skin. But what people found most recently is that isn’t quite the case, as there is a dorsal nerve cord in adult animals with potential homology to the chordate nerve cord.”

Yet when Pani and collaborators in the laboratory of Elizabeth Grove, professor of neurobiology at the University of Chicago Biological Sciences, looked at gene expression in the acorn worm embryo, they found a surprise. Three signaling centers thought to be exclusive to vertebrates — ANR, ZLI, and IsO — were present and active in the developing acorn worm…just not performing their usual jobs. By blocking functions of several genes associated with the signaling centers one by one, the researchers discovered that they controlled the development of different regions in the acorn worm body instead of the formation of the nervous system specifically. Other than the ultimate anatomy, the signaling centers direct development in much the same way as they do in modern vertebrates — strong evidence for their evolutionary relatedness.

“That’s really the most conclusive support for homology between these signaling centers,” Pani said. “The gene expression is very similar, and it is also regulating regionalization of the body in a similar way.”

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By Matt Wood

It’s hard to avoid consumer advertising for prescription medications. Flip open a magazine and you’re likely to see a picture of a middle-aged couple, sitting in matching bathtubs, hawking erectile dysfunction pills. Turn on the TV and you’ll hear an actor rattling off a long list of scary-sounding side effects from a drug to help stop smoking. Direct-to-consumer pharmaceutical advertising is the fastest growing form of marketing, rising 330 percent from 1996-2005. About $4.3 billion was spent in the United States in 2009 on drug ads, and companies have expanded their marketing efforts to social media.

A recent study in the Journal of Medical Internet Research found that all of the top ten global pharmaceutical companies now use Facebook, Twitter, blogs, and other sites to market their products, and eight out of the top ten have their own mobile applications. Of the top ten highest grossing drugs of 2009, nine of them have dedicated websites, Facebook pages or Twitter accounts, and disturbingly, illegal online retailers were also selling nine of the ten top drugs via social media.

With this deluge of legal and illegal marketing pitches, how does someone know what to believe when they look for medical information online? The FDA has provided general guidance to the pharmaceutical industry (PDF) for responding to unsolicited requests for information, but consumers are on their own. “The problem with the medical information online is that it’s not well regulated. In many cases it’s not easy to see who is behind a particular website and what their agenda is,” said Ves Dimov, MD, assistant professor of pediatrics and medicine at the University of Chicago Medicine.

Dimov is an allergist and immunologist who has been a leading advocate of using social media in medicine. He is ranked as one of the top three social media influencers in medicine by Klout.com, a service that measures a user’s influence on various social networks, and his AllergyCases.org website is one of the most popular online allergy and immunology resources, with more than one million page views. He says that the solution to wading through the flood of suspect medical information online is for physicians to provide their own stream of trusted, verifiable information.

“In an ideal world, every single physician in the country should have his or her own presence online via a Twitter feed, blog or a Facebook page,” he said. “Studies show that we trust our friends’ opinions more than Google results, so if somebody you know posts a link to an article you’re much more likely to click on it. Patients’ own doctors can provide quick reference links to high quality information online, such as key recommendations, new studies, etc.”

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