by Rob Mitchum

The brain is a privileged organ, afforded protections denied to all the other organs of the body. Though the circulatory system functions much the same way above and below the neck, using blood to exchange nourishment for waste with cells, the exchange is conducted under much heavier security in the central nervous system. This TSA for the brain and spinal cord is known as the blood-brain barrier, and its role is protecting the fragile, irreplaceable cells of the nervous system from external disease and the body’s own immune weapons.

While we can all be thankful for the unceasing service of the blood-brain barrier (sometimes abbreviated as BBB), many scientists are interested in figuring out how it can be breached. Many neurological diseases, including multiple sclerosis and stroke, can be attributed in part to breakdowns of the BBB. Drugs designed to treat brain disease must also find a way through the BBB’s strong defenses to get to their desired targets.

That made the blood-brain barrier the perfect subject for this year’s Chicago Symposium on Translational Neuroscience, an annual gathering of neurologists and laboratory neuroscientists from the University of Chicago Medicine and other institutions. This year, the Neuro contingent was joined by UChicago’s young Institute for Molecular Engineering in presenting the conference, underscoring that the topic is very much an engineering problem: how do you build a blood-brain barrier, and how do you selectively knock it down?

The day’s first speaker, Richard Daneman of the University of California, San Francisco, explained what the field currently knows about the unique properties of the BBB. In most of the body, the capillaries of the circulatory system are “leaky,” he said, allowing many molecules to pass between the cells and the blood through the cracks between the endothelial cells that make up the blood vessel walls. But in the BBB, those cells form a tight seal, and molecules are transported into and out of the vessels by highly selective transporters instead of passive diffusion. Daneman illustrated these defenses with an experiment where blue dye is injected into an animal, which is later dissected. While organs such as the kidney or liver take on a distinct blue hue, the brain and spinal cord remain free from the dye, which cannot penetrate the barrier.

Daneman is interested in “barriergenesis,” how the BBB is constructed during development. Previously, researchers hypothesized that brain cells called astrocytes were responsible for building the BBB. But using mice and rat models, Daneman’s laboratory determined that this defense system is already in place during embryonic stages, before astrocytes first appear. Instead, Daneman’s experiments pointed to another cell group called pericytes as critical architects of the BBB. When the genes for forming pericytes were knocked out in a mouse line, the BBB did not form its tight seal…as indicated by the appearance of blue brains after a dye injection.

Now Daneman’s lab is digging into the molecular signals that construct the BBB during development and maintain its integrity throughout life. Some of those experiments involve taking the endothelial cells that form the BBB out of their native habitat to study them on the lab bench, the subject of a talk from Eric Shusta of the University of Wisconsin - Madison. Endothelial cells only make up about one-tenth of one percent of the cells in the brain, Shusta said, and don’t form the tight seals characteristic of the BBB in the lab dish unless they are co-cultured with other neural cell types.

Shusta’s laboratory has tackled these problems using the hot prospects of laboratory science: pluripotent stem cells. When researchers in his group decided to try to differentiate stem cells into BBB-like endothelial cells, Shusta said “I thought they were a little bit crazy, but the initial experiments worked.” What’s more, with neural stem cells, the researchers could also generate other nervous system cell types that might play an important role in barriergenesis. That experimental set-up can now be used to test for the cellular factors that build the BBB and as well as assess different drugs’ ability to pass through the barrier, without the constraints of having to endlessly harvest scarce endothelial cells.

“From one rat brain we can get about 6 to 12 filters, but from one vial of stem cells, we can easily get ten thousands of filters,” Shusta said. “We think that we can keep optimizing this, and hopefully make an impact in developmental and drug screening applications.”

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Photo courtesy Yerkes National Primate Research Center

By Rob Mitchum

From the teenage years through adulthood, people spend a lot of time worrying about their social status. Whether measured in wealth as economic class or by more abstract terms of leadership and popularity in the office or among friends, social standing can weigh heavily upon a person’s mind. But can an individual’s position in their social network also leave a mark on biology, changing the regulation of genes and the strength of immune defenses against disease? Exciting new research conducted in one of our close primate relatives suggests that social factors can indeed penetrate deep into DNA.

In both their natural habitat, rhesus macaque monkeys organize into a hierarchical social system based on the results of competition for food, the best grooming buddies, and (in the wild) sexual partners. At the Yerkes National Primate Research Center in Atlanta, females housed in groups of five also organize into a dominance ranking, based on order of introduction to the group.

“In the wild, females would not ordinarily leave the social group they were born into,” said Jenny Tung, a former postdoctoral researcher in the laboratory of Yoav Gilad at the University of Chicago Department of Human Genetics. “They inherit their social rank from their mothers. But in this unnatural situation, order of introduction determines rank — the newcomer is generally lower status.”

That well-defined social system gave Tung, now an assistant professor of evolutionary anthropology at Duke University, and a team of collaborators the rare opportunity to look at how social status affects gene expression — and how that relationship is affected by a change in social rank. Other scientists had previously looked at the influence of social factors on gene regulation in species such as honeybees and cichlids, but nobody had looked in animals closer to humans on a genome-wide scale.

In a paper published by PNAS, the researchers used gene chips and blood samples to compare high-ranking monkeys to their low-ranked peers on the expression of nearly 6,000 genes. A significant difference was found for 987 of those genes, with the largest representation (112 genes) coming from the immune system. The result fits with data in monkeys where low rank and chronic stress lead to compromised immune function, and, more loosely, with human studies such as the legendary Whitehall Study that linked low socioeconomic status and high social stress to elevated disease risk.

The occasional transfer of monkeys from one social group to another at Yerkes offered the researchers another experimental opportunity. When a high-ranking female is removed from a group, the remaining monkeys benefit from an increase in rank. So researchers could compare gene expression before and after the rank shifts, and test whether the genetic “signature” of social status changed enough to predict their new position.

“We were able to use gene expression to classify individuals based on their rank,” said Gilad, associate professor of human genetics at the University of Chicago Biological Sciences and senior author of the study published in PNAS. “Demonstrating these very plastic and temporal changes was novel and quite interesting.”

The researchers were also able to look at potential mechanisms by which social status could influence genetic regulation. Two previously observed mechanisms — the activity of the stress hormone glucocorticoid system and changes in the cell composition of the blood samples  — were both found to contribute to the gene expression differences between high and low ranking monkeys.

But a new, third mechanism was also described: the reversible shutdown of genes through DNA methylation. When a methyl group is added to a gene, it effectively turns that gene off. The researchers found a significant association between social rank and methylation on the 987 genes exhibiting expression changes, suggesting that this epigenetic modification contributes to the interaction of social status and genetic regulation.

“That’s a novel mechanism that people haven’t considered in primates,” Gilad said. “I know that some have been resistant to the possibility of methylation changes on this timescale, but this is a demonstration that this mechanism also matters.”

Beyond the biological nuts and bolts, the study raises a provocative question: is a lower social status actually bad for your health?

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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 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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Roughly 30 million Americans suffer from migraines, and as you might expect, there’s a large pharmaceutical market to prevent or stop these debilitating headaches. Drugs such as Imitrex and Verapamil employ different pharmacological modes of action, reducing migraines by adjusting neurotransmitter levels, blocking ion channels, or simulating the body’s natural painkillers. There’s also a less pharmaceutical migraine treatment strategy, recommended by many headache specialists, that follows the old adage: “Active Body, Active Mind.” One recent study even found that 40 minutes of exercise three times a week can be as effective at preventing migraines as popular anti-migraine medications.

Still, prescribing exercise or environmental enrichment (keeping the mind busy through activities such as reading, crossword puzzles, exercise, or socialization) can strike some doctors and patients as frustratingly vague. Understanding the biological mechanism that makes these activities protective against migraines could help convince doctors and patients of their utility, while also giving researchers the opportunity to translate the factors associated with environmental enrichment into highly effective treatments.  In the laboratory of Richard Kraig, William D. Mabie Professor in the Neurosciences at University of Chicago Medicine, that very effort is underway.

“We are interested in environmental enrichment as a way to stop cognitive decline from aging, injury after stroke, Parkinson’s disease, and cell death after seizures.  With our new work, we apply this search for how the brain protects itself against disease to include migraines,” Kraig said.  ”The ‘why’ of it has sometimes been left in the realm of holistic medicine, with little scientific support.  So establishing the hard science makes it more credible to the psychologists, physiologists, physiatrists, because here’s the chemistry.”

Working with graduate students Yelena Grinberg and Aya Pusic as well as senior technician Heidi Mitchell, Kraig discovered three different natural signals elevated by exercise and environmental enrichment: insulin-like growth factor-1 (IGF-1), interleukin-11 (IL-11), and interferon gamma (IFN-γ). When these “cytokines” are applied to brain slices, they reduce the probability of triggering a spreading depression — a transient wave of reduced brain activity associated with migraines. Understanding how those cytokines stop spreading depression — and the nasal route by which they might be delivered — may revolutionize how migraines and other neurological conditions are treated.

A spreading depression of brain is a chain reaction of dramatic events. After an initial burst of increased neuronal activity, a subsequent ripple of absent activity slowly spreads across involved brain at a rate of about 3 mm per minute — lasting a few minutes overall.  While the event sounds brief, the consequences can last from hours to days, causing harmful oxidative stress, elevated inflammatory factors, moving microglia, and significant pain and discomfort for the migraine sufferer.

Paradoxically, the way to stop this chain reaction may not be to simply reduce or block the byproducts of a spreading depression, but to expose the brain to moderate levels of inflammatory factors, which include the cytokines described above. To interrupt the cycle of repeated migraines, treatments could take place before the process begins or in small steps after the recurrent spreading depression that underlies chronic migraine. While these factors may have negative effects in the short-term, in the long-term they prime the neurons to make antioxidants that are protective against oxidative stress.

“Spreading depression increases oxidative stress in a big fashion — it depolarizes all the brain cells. It’s like an engine kicking out a lot of exhaust, and the exhaust makes the brain hyper-excitable,” Kraig said. “But you have to let the engine run. The engine is running with stimuli that include cytokines that are initially irritative, but then adapt to stop spreading depression.”

The trick, Kraig said, is to mimic the natural cycles of cytokine levels the brain would experience during healthy, active behavior, rather than drowning the system in abnormally high concentrations of the factors that can occur with disease. The cytokines would be delivered to the brain in an on/off pattern rather than chronically, theoretically recreating the rise and fall of natural cytokines during a person’s sleep/wake cycle. By giving just a little bit of a factor normally considered harmful, the treatment could strengthen the brain’s resistance to spreading depression and migraines via the principle of hormesis, or “what doesn’t kill me makes me stronger.”

“The treatment is unique in that it’s the opposite of putting a Band-Aid on something,” Grinberg said. “It’s triggering cells to produce their own antioxidants instead of just providing the antioxidants exogenously. In that way it’s really unique and the opposite of how a lot of people think about medical treatment.”

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As another year comes to a close we’d like to look back at the fascinating research breakthroughs and inspiring patient stories from 2011. ScienceLife ran 168 posts this year, and while we wish we could highlight all of them, here are a handful of our favorites from each month.

January

Patrick Wilson found out that the H1N1 virus could end up helping us fight all types of flu. Stephen Pruett-Jones studied how some male birds mimic the sounds of predators to pick up the ladies (with an audio clip). We interviewed David Gozal about his study on the link between childhood obesity and lack of sleep, and took a look at NCAA regulations mandating sickle cell testing for athletes.

February

Harold Pollack gave a lecture on why violent crime in urban, minority communities should be considered a public health epidemic. Siri Atma Greeley studied the actual medical benefit of widespread genetic testing. Stacy Lindau wanted to know why so few women get help for sexual problems after surviving cancer. We talked to Bana Jabri about the causes of celiac disease, and Sliman Bensmaïa showed us how the brain processes the basic elements of touch very much like it handles visual information.

March

Sola Olopade educated women in Nigeria about using clean-burning stoves to prevent indoor pollution. Stefano Allesina and Jonathan Levine looked at how rock-paper-scissors helps explain evolution. Joshua Miller went to Yellowstone Park to see what stories the ghostly bones of animals can tell, and Scott Eggener questioned the wisdom of indiscriminate prostate cancer screening.

Photo by Gerald Waddell

Andrea King studied the wide range of responses to drinking alcohol, and why it can be fun for some people and a bummer for others. Cheryl Reed took a ride in a helicopter with our UCAN nurses. Kamal Sharma looked at the genes that control animals’ gait, and Ningqi Hou studied how urban environments can dictate how much exercise people get.

May

Daniel McGehee looked at the long-term effects of nicotine on the brain. Habibul Ahsan went to Bangladesh to study the health impacts of accidental exposure to arsenic in drinking water. The brain’s overlooked supporting cells got their due at a conference on neuroscience, and we remembered a landmark discovery about a once popular drug taken during pregnancy that we now know can cause cancer.

June

As we headed into summer, Diana Lauderdale used Google to track MRSA. We learned about an extraordinary transplant where a man received a new heart, liver AND kidney. Daniel Geynisman gave us the rundown on whether or not cell phones are killing us (they’re not, as long as you don’t use them in the car), and some UChicago undergrads studied what happens to gorillas on the birth control pill.

July

We spoke to Donald Jensen and Andrew Aronsohn about the new outlook for patients with hepatitis C. Igor Schneider made a time machine to find the genetic switch for limb development. Farr Curlin led a study about the benefits of addressing spiritual needs alongside medical care, and Adam Cifu looked at the phenomenon of scientific study reversals.

August

Stefano Allesina dug into the long, shady history of nepotism in academia in Italy. John Schneider talked about his work addressing sexual health and stigma in India. Michael Becker discovered a new treatment for the Royal Disease, and we had the rare chance to name check a Spiderman villain in a post.

September

Martha McClintock and Suzanne Conzen studied the connection between social isolation, stress and breast cancer. Gallego Romero traveled to India to search for the origins of lactose intolerance. Stephanie Dulawa developed a mouse model for OCD, and Paul Vezina looked at a different kind of obsession, compulsive gambling.

October

Arshiya Baig started a pilot project to help people learn about life with diabetes through pictures. Manyuan Long found that some of the youngest genes are in the brain. Jens Ludwig and Stacy Lindau published a landmark study about the connection between neighborhood poverty and health, and Issam Awad studied a rare brain disease that soon could be treated with a drug instead of surgery.

November

Cathy Pfister and Tim Wootton figured out how to use seashells to track climate change over the years. Lianne Kurina found a link between loneliness and sleep quality. Shantanu Nundy, Monica Peek and Marshall Chin developed a program to send text message reminders to people with diabetes, and Pan Chen looked at the links between childhood abuse and aggressive behavior in adults.

December

Inbal Ben-Ami Bartal, Jean Decety and Peggy Mason discovered that rats can show empathy for their fellow rats in distress. Maciej Lesniak performed a scary but amazing brain surgery on a patient who was awake. Cathryn Nagler searched for the source of food allergies within our bodies, while Stafano Guandalini uncovered the challenges in educating doctors about one of those allergies, celiac disease.

Whew. Hope you were able to click through at least a few of those. We look forward to another great year of research in 2012. We’re taking a break next week, but we’ll be back on January 5. Happy holidays!

If you are an avid reader of food packaging materials or a parent of an elementary school student, you might get the feeling that food allergies are on the rise. Statistics back up this notion, with the CDC reporting an 18 percent increase [pdf] in child food allergies between 1997 or 2007. That puts current estimates of food allergy prevalence at 4 percent for children and 2 percent for adults, with allergies to peanuts (3.3 million Americans) and shellfish (6.9 million) leading the way.

The factors driving this surge remain a scientific mystery, and answers are even more scarce when it comes to treating or preventing dangerous allergic reactions. Currently, the only way to prevent anaphylaxis caused by a food allergy is avoidance, a strategy that can be very cumbersome for parents raising small children who cannot be exposed to basic food groups. Dave and Denise Bunning faced this challenge with their two children, both of whom were allergic to milk and eggs, leading to “several emergency room visits before the age of 5,” Dave Bunning said. Those experiences inspired the family’s philanthropy for research into the science of food allergies, which included this year’s founding of the Bunning Food Allergy Professorship at the University of Chicago Medical Center.

At the official naming ceremony for the new position, the inaugural Bunning Food Allergy Professor Cathryn Nagler presented her latest research to a large crowd including the Bunning family themselves. Nagler’s intriguing theory about food allergies looks within, at the bacterial universes that exist inside the human body. In parallel with other laboratories on campus looking at the impact of the human “microbiome” upon diseases such as inflammatory bowel disease and diabetes, Nagler is focused on the trillions of bacterial tenants that occupy each of our bodies.

“It’s becoming clear that we are outnumbered,” Nagler said. “There are 10 trillion human cells encoding 20,000 genes [in an individual], but 100 trillion bacterial cells encoding an estimated 2 to 20 million genes. So there are as many E. coli in each of our digestive tracts as there are people on Earth…and that’s not even one of the more popular species.”

All those bacteria, sometimes called the “commensal microbiota” to distinguish them from disease-causing pathogens, could play the environment role in the genes + environment recipe for food allergies. Many of the trappings of modern life, including high-fat diets, antibiotic treatments, and the use of baby formula instead of breastfeeding, can affect the census of our bacterial inhabitants. In food allergies, where the immune system mistakenly treats innocuous dietary proteins as harmful invaders, these microbiota changes might tip the balance towards over-sensitivity to components of peanuts or shrimp.

“An increase in disease prevalence in 10 to 15 years’ time can’t be explained by genetics, so there’s got to be other factors that are driving this increase in disease prevalence,” Nagler said. “All of these environmental variables lead to alterations of the commensal microbiota, which in genetically susceptible individuals could drive allergic responses to food and other antigens.”

To study this model, Nagler’s laboratory gave a long-term treatment of antibiotics to lab mice, finding that this prolonged exposure did indeed trigger an allergic response to peanuts. Using genetic identification methods, her group compared the gut microbiomes of mice treated with antibiotics versus mice who did not receive the drugs, finding several differences in the bacterial populations colonizing their digestive system. One bacterial family, called Clostridia, were reduced in the mice treated with antibiotics, while another was increased — suggesting that reducing or decreasing different species of bacteria might affect the chances of developing food allergy.

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The University of Chicago can fill a couple of classrooms with all of the Nobel Laureates affiliated with the school, from Milton Friedman to Saul Bellow to Barack Obama. After Monday, a third room might have to be opened up, as Pritzker School of Medicine graduate Bruce Beutler became the 86th member of the exclusive club. Beutler, who graduated from our medical school in 1981, was honored with this year’s Nobel Prize in Physiology or Medicine, along with Jules Hoffman and Ralph Steinman. The three scientists were credited with advancements in the field of immunology that have paved the way for new strategies fighting infections, cancer, and other diseases.

“I thought it was possible, but nobody can count on winning the Nobel Prize, so I’m just ecstatic,” Beutler, now at University of Texas Southwestern Medical Center, told the Chicago Tribune.

In the confusing calculus of the Nobel, Beutler and Hoffman split half of the total award for research on the innate immune system, known as the first line of the body’s defenses against infectious invaders. In the late 1990’s both scientists’ laboratories were looking for immune receptors that respond to signals on the surface of bacteria - Hoffman looking in fruit flies with genetic mutations, Beutler in mice. Within two years of each other, Hoffman discovered a fly mutant named “Toll” involved in the response to an infection, and Beutler found a similar gene in mice for a receptor (named, appropriately, the “Toll-like receptor”) that binds to lipopolysaccharide (LPS), a signal on the surface of bacterial cells.

These findings opened the floodgates to learning about new players in the innate immune system, including the discovery of a dozen more Toll-like receptors that recognize various pathogen signals - what some call “the eyes of the immune system.” Clinically, mutations in these genes can lead to either increased susceptibility to infection (if the innate immune system is too weak) or autoimmune and inflammatory disorders (if the innate immune system is too strong). Drugs that target this system might therefore be promising for the treatment of many different diseases.

“I think the most hopeful line or realm is in inflammatory and autoimmune disease,” Beutler told the Nobel website. “Inflammation is something that evolved to cope with infection, and when we speak of sterile inflammatory diseases like rheumatoid arthritis and autoimmune diseases like lupus, probably some of the same pathways are utilized. It may very well be that by blocking TLR signalling you’ll have very specific therapies for those kinds of diseases.”

Beutler said that he received the news in bed, waking up in the middle of the night and reading an e-mail on his cell phone.

“I was a little bit disbelieving, so I went downstairs to look at my laptop,” Beutler said. “I went to Google News and saw my name there, so I knew it was real.”

At the University of Chicago Medical Center campus, the news quickly spread among former colleagues and teachers of Beutler, as well as scientists that who work in his field.

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The 2009 H1N1 pandemic, better known as the season of swine flu, was not like other flu seasons of recent vintage. A typical seasonal strain of influenza is most deadly at the extremities of age, with the highest mortality rates in the very young and very old. One of the reasons why experts were concerned about the 2009 flu was that it went off-script, killing mostly people in their twenties and thirties. Influenza researchers speculated on why the normally vulnerable elderly appeared to have the advantage against this particular pandemic. But it wasn’t until a recent study by University of Chicago and Stanford scientists looking at the failure of flu vaccines in older adults that the source of this advantage revealed itself.

In a typical season, senior citizens are among the priority groups for receiving the flu vaccine, due to their increased risk of severe symptoms. Yet the success rate of the standard influenza vaccine is reduced in those above 65 years of age, falling from 90 percent efficacy to as low as 17 percent. Most have attributed this decline to a general principle called “immunosenescence,” the weakening of a person’s immune system as they grow older. Since vaccines work by stimulating the production of antibodies against an inactivated flu strain to protect against the real virus, is the deficiency in the aged a matter of antibody quantity, quality, or both?

A multi-institutional team led by co-first authors Meghan Sullivan of UChicago and Sanae Sasaki of Stanford developed a new assay to test this question for a recent article in The Journal of Clinical Investigation. Two groups of volunteers - one aged 18-30, one aged 70-100 - received the seasonal flu vaccine in the winter of 2007-08, and researchers took blood samples from them seven days later, when vaccine-induced antibody production is at its peak. Scientists could then measure the number of antibody-secreting cells, called plasmablasts, and antibodies circulating in the blood of the volunteers. They could also run experiments testing how well those immune defenses bind different strains of influenza, the first step in fighting off a virus.

Their first experiments replicated the clinical data - even in a test tube, younger volunteers (or at least their antibodies) are much more likely to respond to the influenza strains included in the vaccine than samples from older subjects. Subsequent experiments revealed that the immune systems of elderly subjects were at a numerical disadvantage, with significantly fewer plasmablasts observed in serum compared to the samples from their younger counterparts.

“It had been appreciated before that there are fewer immune cells in older people, but this is the first time showing that fewer antibody secreting cells are raised in response to vaccination,” said Sullivan, a graduate student in the laboratory of Patrick Wilson (and a contributor to ScienceLife).

But surprisingly, that was where the immune deficits in older patients started and ended. Though there were fewer plasmablasts in older subjects, each produced the same number of antibodies as those of the young. What’s more, when the antibodies from young and old were compared for their ability to bind the viral strains targeted by the vaccine, they were nearly identical. So the failure rate of vaccines in elderly can be explained by the lower quantity of antibody “factories,” rather than a defect in the quality of the antibodies themselves.

“We would think that antibody activity would be decreased in older people, but in fact the ability to bind is basically identical,” Sullivan said. “The antibody secreting cells are the weak point; elderly people are just not making enough.”

Amid the media storm surrounding the rapid spread of swine flu in 2009, the research team used the same samples to test another idea. One theory for why senior citizens were protected against that particular H1N1 strain was that they may have been exposed to a similar influenza that circulated before 1950. With their blood samples, the researchers could compare how the antibodies of their old and young subjects responded to the 2009 H1N1, which neither group had been vaccinated against two years prior. In this competition, the senior citizens were the surprise winners - antibodies from older subjects (especially those older than 78) were more responsive to the H1N1 virus than those from younger volunteers.

The result suggests something off an immune system trade-off in the elderly. Though they may have a harder time producing sufficient antibodies to fight off the flu, the antibodies they do produce are able to attack a more diverse range of influenza strains.

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“A pox of this gout! or a gout of this pox! for the one or the other plays the rogue with my great toe.” - Falstaff, Henry IV

Gout was once called “the king of diseases and the disease of kings.” Thanks to that proximity to power, gout has been well documented through history, from the Egyptians to the Greeks to 17th century England, when physician Thomas Sydenham described an outbreak as “The night is passed in torture.” But today, gout has been democratized, afflicting roughly 6 million people in the United States and connected with obesity, heart disease, and alcohol abuse. Fortunately, treatments for gout have kept pace with its numbers, and in this week’s Journal of the American Medical Association, another option has been added to the physician’s arsenal against the rheumatic disorder.

The new treatment, pegloticase, has its origins in an unlikely place for a “royal” disease: an enzyme from the common swine. Unlike humans, most animals can avoid gout thanks to an enzyme called uricase that converts uric acid (high levels of which cause gout) to the harmless and excretable allantoin. Duke University chemists spent decades modifying pig uricase for therapeutic use in humans, adding a protective coating that can keep the enzyme active for days instead of hours. Perfected at last, the treatment showed positive results in its first two major clinical trials, run by researchers at the Medical Center.

“This represents the first effective therapy for a group of patients who previously had no options at all,” said the study’s senior author, Michael Becker, professor of medicine at the University of Chicago. “This is for patients with severe gout, including major disabilities and high levels of pain. Many of these people had dramatic responses within months…as well as reduced levels of pain and disability. The rapidity of these outcomes is unheard of.”

Gout is caused by the gradual accumulation of uric acid, either from over-production or inadequate removal. When levels exceed the saturation point, uric acid forms tiny urate crystals, like thousands of little needles, that deposit in the lining of joints and other tissues. The crystals can cause inflammation, swelling and intense pain, including painful swollen joint nodules known as tophi.

Many patients are treated with medications that block the synthesis of uric acid or help the kidneys remove it. But not everyone with gout finds relief from these medications, or can tolerate their side effects. Three percent of gout patients - about 120,000 to 180,000 Americans - have chronic, disabling disease with no effective therapy.

Those types of patients made up the two parallel trials of pegloticase, conducted at over 50 rheumatology clinics across North America. Patients in the treatment groups were given an intravenous infusion of pegloticase once every two weeks or once every month, and monitored for six months to see if their uric acid levels fell and their symptoms resolved. The results showed an interesting split: although uric acid levels dropped in all patients given the drug, only 42 percent (in the every-two-weeks group) sustained those decreased levels over the entire six months.

Still, helping two out of five patients without any other treatment option is a significant clinical achievement. And in those patients where the drug worked, the magnitude of relief was great, resolving at least one tophi and improving quality of life and physical function. The drug, brought to market under the name Krystexxa, is expected to cost about $60,000 a year.

“People are dramatically helped by the drug,” said rheumatologist John Sundy, director of the Duke Clinical Research Unit and lead author of the study. The drug’s response among patients who have failed common therapies is typically an “all-or-nothing result,” he added, “providing marked relief for those who benefit.”

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In the recent kerfuffle over the national debt, one of the rhetorical flashpoints was the $800 billion “stimulus package” pushed by the Obama administration in 2009 to fight the economic slowdown. Though the benefits of the American Recovery and Reinvestment Act on unemployment and the economy are fiercely debated, the impact upon the scientific world is just beginning to be felt. Roughly $5 billion of the stimulus money went to the National Institutes of Health for funding biomedical research - and $42 million of that sub-total came to projects involving University of Chicago researchers. Two years later, the fruits of that investment are beginning to ripen, as stimulus-funded projects reach the point of publishing results.

The largest piece of the stimulus pie awarded to UChicago researchers was the $5.6 million designated to form the EVE consortium, an unprecedented national effort to search for the genetic and environmental causes of asthma. Over 34 million Americans are diagnosed with asthma during their lifetime, and the rates are increasing every year. But the origins of this respiratory disease are still mysterious, with the relative contributions of genetics and environmental factors such as air quality and smoking still being unraveled.

One recent tool in decoding the causes of asthma has been genome-wide association studies, or GWAS, where genetic information from a large pool of patients with the disease are compared to a control pool of asthma-free people. But to find a gene or gene variant associated with a complex disease like asthma, a huge number of subjects are needed for statistical reasons. The expenses of successfully recruiting, diagnosing, and genotyping the thousands of people needed to create a sufficiently powerful GWAS were beyond the means of any one research group, frustrating the search for asthma-related genes.

“It has become clear to geneticists studying nearly every common disease that GWAS are often under-powered,” said Carole Ober, Blum-Riese Professor of Human Genetics and obstetrics/gynecology at the University of Chicago. “Unless you pull together many people doing the same thing you’re just not going to have the power to find genes.”

In the world of asthma genetics, nine groups of investigators were encouraged by the National Heart, Blood, and Lung Institute to pool their respective GWAS results to create a shared pool of data large enough to sniff out genes associated with the disease. But that collaboration was easier said than done - until the $5.6 million ARRA grant enabled the hiring of personnel to make the EVE consortium a reality.

“It would never have been possible without the grant, this was a huge amount of work,” said Dan Nicolae, PhD, associate professor of medicine, statistics, and human genetics at University of Chicago, and co-chair of the consortium with Ober. “The key was the ARRA funding that allowed us to move it faster.”

Now, just short of two years since the grants were announced, the EVE consortium has announced their initial results in the journal Nature Genetics. With a new larger data set of over 5,000 asthma cases, the group was able to pinpoint with high accuracy five genetic regions associated with asthma, including one with a very selective profile. Unlike a similar consortium formed in Europe (called GABRIEL), the EVE dataset reflected the ethnic diversity of the American melting pot with subjects of European origin, African origin, and Hispanics. That diversity proved useful, as the EVE data revealed an asthma-associated variant in a gene called PYHIN1 that only appeared in African-Americans and African-Caribbeans - ethnic groups not present in the GABRIEL sample published last year.

“Asthma rates have been on the rise in recent years, with the greatest rise among African Americans,” said Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute, which co-funded the study. “Understanding these genetic links is an important first step towards our goal of relieving the increased burden of asthma in this population.”

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The mortality curves separate. (From Goodin et al. poster)

To conduct a clinical trial of a new drug, the researchers need to pick an ending: a place where the experiment will be stopped and the results between those taking the drug and those who haven’t can be compared. If the drug is a clear improvement, the trial will be stopped, and patients in the control group will be allowed to start taking the newly-proven treatment. Follow-up studies may then be difficult to conduct, particularly if the disease is too deadly or the patients are too hard to track.

So when almost every single member of a landmark study can be tracked down more than 20 years after its completion, that’s an impressive feat. Even more so when comparing the treatment and control groups two decades later reveals an unexpected, and very meaningful, long-term benefit. A new study, co-presented at two recent meetings by Anthony Reder, professor of neurology at the Medical Center, reveals that a multiple sclerosis drug first tested here 23 years ago continues to show benefits in patients on perhaps the most important outcome of all: mortality.

Interferon-β-1b was the first drug proven effective in slowing the progression of MS, based on a trial of 372 patients conducted at the University of Chicago and 10 other centers from 1988 to 1993. When the FDA approved the drug in 1993, its effects on quality of life were emphasized by Barry Arnason, professor of neurology and one of the study’s lead investigators, who told the New York Times that “People are going to stay on their feet longer, work longer and be happier.”

The researchers could not have anticipated that the drug might also help MS patients live longer as well. But when follow-up data was collected 16 years after the trial’s completion, a promising hint emerged. Researchers successfully re-established contact with 88 percent of the original subject pool for a paper in the journal Neurology, and confirmed the long-term safety of interferon treatment - their primary goal. But a secondary finding also attracted interest. Of the 328 patients contacted from the original trial, 35 had died, but only 6 of those were from the original high-dose interferon group, vs. 20 from the control group.

Because patients in the control group were also placed on interferon treatment after completion of the trial, the result suggested that starting interferon earlier had long-term benefits on mortality. But to confirm the effect, the researchers had to find even more patients from the original study, alive or deceased. For the 21-year follow-up, they expanded the coverage to an astonishing 98.4 percent of the original subject pool, lacking information on only 6 of the original patients.

Fortunately, the larger dataset confirmed the earlier promising hints on mortality. As presented at the American Academy of Neurology Meeting this month by Reder and neurologist Douglas Goodin of UCSF, patients who received interferon during the 1988-1993 trial were less likely to have died at the time of the follow-up. Of 81 patients who had passed away in the 21 years since the trial, nearly half were originally in the placebo group, meaning they had started interferon treatment roughly 4 years later than those enrolled in the two treatment groups. Remarkably, even those who had received interferon in the pivotal trial weren’t started on the drug until an average of 8 years after MS symptoms first appeared, much later than current clinical standards, Reder said.

“Even stacking the deck against us by relatively late treatment, and accounting for a follow-up period where all of the people were on the best possible medicine for them, we still see this huge difference,” Reder said. “We think this means there’s a very important survival effect of interferons.”

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Animal models are useful for testing and developing future treatments and procedures before they are tried in humans. Before bone marrow transplants were first tried clinically in the 1950’s for the treatment of radiation poisoning or leukemia, they had already been shown to work in rats, dogs, and primates. But even after the proven success of the method to replenish a patient’s hematopoietic stem cells - the precursors of all the different types of blood cells - animal models continued to be useful for improving the procedure and better understanding the system’s biology. Now, more than 50 years after those first experiments, a new animal model for transplanting marrow has been developed - under water.

Zebrafish, the tiny, striped fish often found in pet stores, lead a double life as scientific heroes. Because of their fast reproductive cycle, translucent embryos (seen above), and well-studied genome, zebrafish are an increasingly popular animal model for scientists to study embryonic development, genetics, and diseases such as cancer. The ability to easily mutate zebrafish genes and screen for interesting biological changes makes the species an ideal fit for studying the function of hematopoietic stem cells and how they can be better used in medical procedures. But there was only one problem for a team of researchers at the Harvard Stem Cell Institute: nobody had tried to do a marrow transplant in zebrafish before.

“We wanted to be able to have an assay where you could compare mutant marrow with wild type marrow and see whether the hematopoietic stem cells function differently,” said Jill de Jong, member of the Harvard research team and now assistant professor of pediatrics at the University of Chicago Medical Center. “The only way to do that was with a transplant assay. Since you’re talking about mutants in fish, it really would have to be a transplant assay in fish - and that didn’t exist.”

Translating a stem cell transplant procedure developed in mammals to fish required several modifications. For one, zebrafish do not carry their hematopoietic stem cells in bone marrow, but rather in their kidneys. In recipient fish, nobody had calibrated the amount of radiation needed to knock out the native marrow cells, or the amount of donor cells needed to successfully replenish the marrow and blood. And while it is easy to match mice for transplantation purposes - because they are inbred and immunologically identical - the fish require more precise matching of donor and recipient, just like humans. The low success rate in the first batch of zebrafish transplants reflected this difficulty.

“These fish were like random donors, they were not immunologically matched at all,” de Jong said. “In some ways, it’s kind of miraculous that it even worked at all.”

But one by one, the kinks were worked out and the procedure was standardized (and published earlier this year in the journal Blood). A number of the immune system MHC genes, which are carefully matched in human bone marrow transplants, were located on chromosome 19 of the zebrafish genome. Each fish could then be genotyped and paired with a closer match for the transplant, which raised the success rate of the procedure.

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Imagine if your comfortable existence was suddenly and traumatically disrupted by a disaster. Your home is destroyed, food becomes scarce, and social structures suddenly break down. Even the most civilized people would respond to this situation with desperation, doing whatever it takes to survive in the short-term without the usual considerations for the long term.

Now imagine you are a bacterium, living inside the human gut (this might take a bit more imagination). For as long as you can remember, everything has been cool there - a steady stream of nutrients pass by to feed on, the police force of the body’s immune system does not perceive you as a threat, and a happy society has been established with the thousands of other bacterial species in the area. But suddenly, the world as you know it is shaken. The human in which you have made your home contracts a serious illness, and undergoes surgery and intense antibiotic treatment. Millions of your fellow citizens are killed, the food supply dries up, the immune system declares martial law. Facing this desperate situation, bacteria tend to act just like humans would - they riot.

This pattern of ecological collapse leading to chaos may underlie one of the most difficult problems facing health care today: hospital infections. Since surgeon Joseph Lister discovered in the 1860’s that carbolic acid can be used to sterilize surgical instruments and wounds to reduce infection rates, hospitals have grown obsessed with cleanliness to protect patients from bacterial invasion. Yet even perfect diligence cannot prevent serious infections from occurring in a small population of patients, causing scientists such as John Alverdy, professor of surgery at the Medical Center, to ask: Could the threat of bacterial infection be coming from within?

“It’s a new way of thinking about infection, because we’re already doing already we can - washing our hands, sterilizing the site, giving our patients antibiotics - and yet some of the infections seem to be getting worse,” Alverdy said. “There has to be a strategy change, and I think we’re at the forefront of understanding that.”

Alverdy’s group has spent the last decade studying a member of the gut microbiome (the world of bacteria living inside our digestive system), called Pseudomonas aeruginosa. Most of the time, Pseudomonas is a passive colonizer of the human body, an “accidental pathogen” that we pick up through our diets or other environmental exposure that causes no harm. But when the body is severely stressed by a surgical procedure, illness, chemotherapy, or radiation, Pseudomonas occasionally panics and becomes an extremely dangerous inhabitant. Alerted to the body’s emergency by immune system factors and starved for food, it begins tunneling through the lining of the gut to invade the unfortunate patient’s blood. Once the bacteria goes on the attack, it’s very difficult to treat, giving it the highest mortality rate of any hospital infection.

“I have seen some people postulate that Pseudomonas isn’t a very virulent pathogen, and I say ‘what are you talking about?’,” Alverdy said. “If you provoke it the right way, it will kill everything in its wake. It’s very virulent.”

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Photo by Bruce Powell

Yesterday wasn’t just St. Patrick’s Day for fourth-year medical students around the country - it was also Match Day, the tense and celebratory day when aspiring doctors learn the residency program where they will spend their next 3-7 years. At the Pritzker School of Medicine, green-clad students and supporters absolutely packed the hospital’s Billings Auditorium for the big event Thursday morning, cheering their peers as they were called one by one at random to collect their match envelope. In a local tradition, it literally pays to go last, as students throw into an informal prize pot for whoever has to wait and squirm the longest to pick up their envelope (second-to-last gets a Hershey bar as consolation). In the video below, you can see some of that process - including the outcry when the last envelopes are miscounted - followed by the amazing tension-release of the countdown and unison envelope opening.

The numbers from the day are just as exciting as the video. At Pritzker (recently ranked #12 among medical schools by US News and World Report), 110 students were matched in 24 specialties at 46 institutions, including 23 students who will stay with us here at the Medical Center. The most popular specialties for Pritzker students were internal medicine (25% of the class), general surgery (11%), and pediatrics (11%). Nationally, trends continued to shift for the second consecutive year toward primary care specialties such as internal medicine, family medicine, and pediatrics, according to the National Residency Matching Program, a step in the right direction to meet some of the increased demand for primary care doctors expected in the wake of health care reform. MedPageToday’s Kristina Fiore breaks down the numbers.

Podcast 0.3: Transplants, Rock-Paper-Scissors Ecology, and More

We have settled on a name for our young research podcast: Bench to Bedside. However, we are still keeping the training wheels on as we work out the technical kinks and explore the best ways to deliver audio versions of our latest research and medical stories. Please enjoy the third installment of our podcast, featuring a recent coast-to-coast kidney transplant chain that involved the Medical Center, how Rock-Paper-Scissors can explain biodiversity, the fight against indoor air pollution in Nigeria, and the new numbers on the eating disorders epidemic in the United States. As always, we would love to hear feedback on what we’re doing right and wrong at robert.mitchum@uchospitals.edu or dianna.douglas@uchospitals.edu.

Bench to Bedside Episode #0.3 by robmitchum

Elsewhere…

Some people keep ant farms, some people keep multiple flasks of bacteria growing for 13 years (and counting) to study evolution. Ed Yong writes about experiments from Michigan State University that show “tortoise” bacteria can beat out “hare” bacteria over the long run. (And if you’re a science communicator of any sort, do listen to Ed and Carl Zimmer’s “Death to Obfuscation” session from January’s Science Online meeting)

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