By John Easton

Once considered the cause of cancer, a tiny organelle known as the “powerhouse of the cell” may soon spawn a new treatment.

In 1955, Otto Warburg, recipient of the 1931 Nobel Prize for Medicine or Physiology, attributed cancer to damage to the mitochondria, tiny structures within each cell that are involved in energy production, the manufacture of ATP. Because of irreversible damage to the mitochondria, he argued, tumor cells shifted from respiration to fermentation, a much less efficient method for producing ATP.

“What was formerly only qualitative has now become quantitative,” Warburg said during a Stuttgart lecture reprinted by Science. “What was formerly only probable has now become certain. The era in which the fermentation of cancer cells or its importance could be disputed is over, and no one today can doubt that we understand the origin of cancer cells if we know how their large fermentation originates.”

With those confident words, Warberg hoped to put an end to disputes about the many potential causes of cancer. “I should like to add, as a further argument,” he continued, “the fact that there is no alternative today… From this point of view, mutation and carcinogenic agents are not alternatives, but empty words.”

As new information became available, the words mutation and carcinogenic agents were gradually reinflated and the notion of mitochondrial damage as the root cause of all cancers lost favor. Interest in mitochondria shifted from oncologists to scientists interested in liver or muscle biology, especially cardiologists studying heart muscle.

But Stephen L. Archer, the Harold Hines Jr. Professor of Medicine at the University of Chicago Medicine, a cardiologist specializing in pulmonary hypertension, and Jalees Rehman, a German scientist who worked with Archer, got interested all over again in studying mitochondria after reading some of Warburg’s historical papers. Instead of causing cancer, they wondered, could mitochondria provide a target for cancer therapy?

Within each cell, mitochondria are perpetually splitting in two, a process called fission, and merging back into one, called fusion. Before a cell can divide, the mitochondria must increase their numbers through fission and separate into two piles, one for each cell.

This makes them a promising new target for cancer therapy. By manipulating two of the biochemical signals that regulate the numbers of mitochondria in cells, the researchers found they could shrink human lung cancers transplanted into mice, a discovery they reported in February in the journal FASEB.

By tipping the balance toward fusion and away from fission in rapidly dividing cancer cells, Archer and colleagues were able to dramatically reduce cell division and prevent the rapid cell proliferation that is a hallmark of cancer growth. Increasing production of the signal that promotes fusion caused tumors to shrink to one-third of their original size. Treatment with a molecule that inhibits fission reduced tumor size by more than half.

“By boosting the fusion signal or blocking the fission signal we were able to tip the balance the other way, reducing cancer cell growth and increasing cell death,” said Archer, senior author of the study. “We believe this provides a promising new approach to cancer treatment.”

“This could be a potential new Achilles’ heel for cancer cells,” said lead author, Rehman, now an associate professor of medicine and pharmacology at the University of Illinois at Chicago. “Many anticancer drugs target cell division. Our work shifts the focus to a distinct but necessary step: mitochondrial division. The cell division cycle comes to a halt if the mitochondria are prevented from dividing. This new therapy may be especially useful in cancers which become resistant to conventional chemotherapy that directly targets the cycle.”

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By Rob Mitchum

Among the most hyped cancer therapies for the future, microRNA looms large. While much smaller than the RNA produced by protein-coding genes, these tiny transcripts play an important regulatory role in cells by acting as a brake on the process of making proteins from genes. MicroRNAs bind to their relatives, the messenger-RNAs, which are used by the cell as a recipe for making new proteins. When this binding occurs, the protein builders (called ribosomes) can no longer attach to messenger-RNA, essentially halting production.

Because many kinds of cancers are caused by the excessive production of protein from various “oncogenes,” researchers have fixated upon the interrupting power of microRNAs as a potential targeted therapy. In theory, treating a patient with the right microRNA for their over-expressed oncogene could bring the out-of-control protein back to normal levels, preventing the unrestrained cellular growth that characterizes cancer. But a new discovery published this week in Nature Communications by researchers from the University of Chicago Medicine Section of Hematology/Oncology cautions that microRNAs are not straightforward weapons against cancer.

One promising anti-cancer target is a microRNA called miR-196b, which is associated with certain types of leukemia associated with translocations of the mixed lineage leukemia (MLL) gene. In a translocation, two chromosomes are accidentally broken and the pieces are put back together incorrectly, leaving two unnatural hybrid genes. In this Frankenstein manner, the MLL gene can be abnormally combined with 60 different partner genes, and this “fusion protein” boosts the transcription of a handful of genes, such as HOXA9 and MEIS1, that cause white blood cells to grow and proliferate uncontrollably.

In 2009, a team of researchers including assistant professor of medicine Jianjun Chen and University of Chicago legend Janet Rowley discovered that miR-196b expression is also boosted by MLL fusions, and that the microRNA is necessary for the immortality and proliferation of the leukemic cells. The finding suggested that reducing levels of miR-196b could be an effective therapeutic strategy in fighting leukemia, while raising the levels of the microRNA would accelerate the disease.

But when Chen’s laboratory tested the second part of that hypothesis by experimentally boosting the levels of miR-196b in mice, they found the exact opposite effect: higher levels of the supposedly cancer-promoting microRNA actually delayed the onset of leukemia.

“It was a surprise result for us, because people already reported that by knocking down expression you delay leukemogenesis, so we expected overexpression would promote leukemogenesis,” said first author Zejuan Li, research associate assistant professor at the University of Chicago Medicine. “We didn’t believe the result, we thought something had gone wrong during our experiment. So we repeated and repeated and repeated several times and we got the same result. Finally, we found this mechanism.”

The miR-196b mystery boiled down to looking at the full set of gene transcripts that the microRNA targets and represses. Surprisingly, the researchers discovered that miR-196b reduces the expression of HOXA9 and MEIS1, two oncogenes also upregulated in MLL-related forms of leukemia. But this anti-cancer action is opposed by another target of the microRNA — a tumor suppressor gene called Fas. Since like many microRNAs, miR-196b has many different targets in the genome (41 were detected by this paper alone), it’s a fallacy to consider the factor as either one-dimensionally pro-cancer or anti-cancer.

“I think this is a very common phenomenon, and this should cause caution for the basic research scientists,” Chen said. “When doing research [on one microRNA function], you could be ignoring half of the potential targets.”

So why in the world would a cell need a regulatory factor with seemingly contradictory effects?

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By Rob Mitchum

In 1972, a physicist named Robert May tried his hand at a different scientific discipline, publishing a simple formula that inflamed the field of ecology. Scientists studying the structure of natural ecosystems had long assumed that diversity was an inherently good thing — those ecosystems stocked with thousands of species were likely more resistant to extinctions, changes in climate, or other challenges. May, with a physicist’s eye for simplicity, crafted a model that predicted the stability of an ecosystem using just the number of species and how strongly they interact with each other. But when it was used, May’s formula provided a surprising and counter-intuitive result: species-rich ecosystems, such as rain forests and coral reefs, should be too unstable to exist.

That paper, published in Nature under the title “Will a Large Complex System be Stable?” (May’s answer: No), was both a major step for computational ecology and the ignition of what came to be called the diversity-stability debate. The disagreement between May’s model and what ecologists saw in reality provoked the question of how nature rescues what should be an unstable ecosystem, allowing it to survive. Ecologists began looking for what May called “devious strategies” — the workarounds that a natural system uses to increase its species capacity without sacrificing its stability. Soon, May’s elegant formula became swollen with additions meant to reconcile the mathematical predictions with field observations.

Stefano Allesina, assistant professor of Ecology & Evolution at the University of Chicago, decided to take a different approach. Rather than building even more complex additions on to May’s model, Allesina and graduate student Si Tang, sharpened their pencils and went back to the original source, tweaking the model by thinking about the general types of ways species interact in nature. Their new model, published 40 years after the original in the same journal, adjusted May’s formula to incorporate predator-prey or consumer-resource relationships, where one species profits at the expense of another. The small changed allowed the model to describe an ecosystem where stability is possible even with an infinite number of species.

“Predator-prey relationships are stabilizing. We can fit much larger ecosystems if there’s a backbone of predator-prey interactions, and see a lot of species happily co-existing ever after,”Allesina said. “We kind of solved this one puzzle of how can we see very many species in an ecosystem. But then we open different puzzles.”

May’s original model, designed to be as general as possible, assumed random interactions between species. But in nature, two species can interact with each other in one of three general ways: as predator and prey, as competitors, or as part of a mutalistic relationship. In the predator-prey or consumer-resource relationship, one species benefits from another species’ loss, be it a lion eating a gazelle or a caterpillar eating a leaf. Competition theoretically has a negative effect on the two species fighting over the same food source, while mutualism (rarely seen in nature) can benefit both participants. By building each of these three relationships separately into May’s model, Allesina and Tang discovered that these interactions each produce very different ecosystems.

In the predator-prey condition, the stability of the ecosystem is increased such that a large number of species can be supported. In the competition and mutualism systems, the ecosystem is highly unstable and vulnerable to perturbation.

“What we are showing is that of all the types of interactions you can have, only predator-prey can support an infinite number of species,” Allesina said. “If you look in nature, there are very obvious consumer-resource relationships everywhere, and maybe this system assembles so easily because these relationships provide a lot of stability.”

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By Rob Mitchum

Since its approval by the FDA in 2006, varenicline has become a valuable aide for people trying to get over the hump of quitting smoking. Marketed as Chantix, the drug has joined buproprion and nicotine replacement therapy as popular options for helping smokers fight cravings and withdrawal as they try to kick the habit. But like any drug, varenicline has its side effects: most commonly nausea, with some rare occurrences of things like constipation, abdominal pain, and depression. But one unexpected side effect of varenicline upon a complete different vice may in fact turn out to be a secondary use for the drug.

In addition to helping them avoid nicotine, patients taking Chantix sometimes report that the drug cuts down on their drinking, taking some of the joy out of cocktail hour. Some researchers have chased this lead down in animal and human research, finding that rats will consume less alcohol after treatment with varenicline and that heavy-drinking smokers on the medication report reduced craving for alcohol. But nobody had yet looked at exactly why varenicline puts people off of booze, or what a single dose of the drug could do compared to the prolonged exposure a smoker experiences during a Chantix prescription.

To answer these questions, a team led by Emma Childs, research associate (assistant professor) in the Department of Psychiatry at the University of Chicago Medicine, recruited 15 moderate-to-heavy social drinkers for a controlled laboratory experiment. Each subject spent six afternoons in the lab, receiving a dose of varenicline or placebo in each session, and then three hours later drinking either a non-alcoholic beverage or a drink containing one of two different concentrations of alcohol. Researchers monitored the subjects’ blood pressure, heart rate, and eye movements for an objective take on how the alcohol affected their system, and also asked questions about their enjoyment of the drink and its effects.

The results, published this week in the journal Alcoholism: Clinical and Experiment Research, determined that varenicline keeps people off the bottle by bringing out the worst effects of alcohol. Compared to placebo, varenicline increased feelings of nausea in the subjects even before receiving an alcoholic drink — a known side effect of the drug. But even when researchers controlled for the effects of this nausea, the subjects reported increase dysphoria (the opposite of euphoria) after drinking an alcoholic drink, and reported enjoying the drink less than on the afternoons where they were pre-treated with placebo. Eye movements associated with alcohol were also lessened by varenicline, implying that the drug interferes with objective effects of the substance as well as self-reported effects.

By reducing the allure of alcohol, varenicline might help people prone to binge drinking say no to subsequent drinks by ruining the good vibes of the night’s first cocktail.

“Our findings shed light on the mechanism underlying why people consume less alcohol when they have taken varenicline,” said Childs. “The pleasurable effects of alcohol, for example feeling ‘buzzed’ and talkative, are associated with greater consumption and binge drinking. Some people lose control of their alcohol consumption during a drinking episode, for example they may aim to only have one or two drinks but end up drinking say four or five. If varenicline counteracts these positive effects by producing unpleasant effects, then as a result people may consume less alcohol during a drinking episode.”

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A cell is full of language. There’s the four-letter code of DNA, the slightly different four-letter dialect of RNA, and the three-letter words that direct the construction of proteins, which are built out of an alphabet of 20 amino acids. In recent years, scientists have slowly revealed another vocabulary superimposed on top of this language, comprised of chemical groups attached to genes and proteins. When groups such as methyl or phosphate are stuck to various places on a protein or gene, they can dramatically change its function, switching it on or off or marking it for transport or destruction. On a disease level, these changes can contribute to cancer, aging, and other conditions, making them an enticing target for drug design.

One area where protein modification is making a big splash is the relatively new field of epigenetics, which looks at how changes to DNA and DNA-related proteins can affect gene expression. The methylation of DNA is known to turn genes off, and a number of modifications to histones - proteins that package and organize DNA - can also have functional consequences. Scientists suspected that they hadn’t found all of the modifications possible on histones, but discovering each new modification and proving its role was considered a painstaking process requiring years of experiments. Finding a new modification, such as Yingming Zhao’s 2010 discovery of lysine succinylation, is an achievement worthy of publication in a high-ranking journal.

So what happened when Zhao’s laboratory discovered sixty-seven new modifications to histones in one paper? The research not only was published in the esteemed journal Cell, but was featured by the journal as one of its top five 2011 highlights.

Zhao, a professor in the Ben May Department of Cancer Research at the University of Chicago Medicine, said he believes the extra accolades reflect the volume of his laboratory’s latest breakthrough, and the paper’s expected influence on how scientists will understand the language of protein modification and epigenetic mechanism.

“If we are going to understand epigenetics and its role in disease we need to identify the full vocabulary of the histone modifications, a major group of epigenetic marks,” Zhao said. ” We thought we had a comprehensive histone vocabulary because of extensive studies by the whole research community in the past 3-4 decades, but in our study, in a single paper, we increased it by 70 percent.”

The laboratory put the pedal to the floor on histone modification discovery by developing new technologies and improving the resolution of pre-existing methods. By using the staple lab method of mass spectometry, which measures the mass and charge of particles, and an algorithm of their own design called PTMap, the researchers could scan the entire histone at once and detect more protein modifications than ever before. Their scan yielded a total of 130 different modification sites — 63 that had previously been observed and reported, and 67 that were new to science.

So large was the yield of new modifications that the current paper wasn’t big enough to fully explore the dynamics and function of all of them. The research team chose to more thoroughly study the novel modification that appeared the most: lysine crotonylation, where a crotonyl group is added to the amino acid lysine. Experiments determined that histone lysine crotonylation is evolutionarily conserved (found in yeast, flies, and humans), is often found in promoter or enhancer regions upstream of genes, suggesting a role in transcriptional control. Furthermore, histone lysine crotonylation was found to be enriched on sex chromosomes, specifically marking testis-specific genes, which implies a role in spermatogenesis.

As for what the other never-before-seen modifications are doing in cells, that will have to wait for future papers, Zhao said.

“This is still a very preliminary study,” Zhao said. “Hopefully, we and the research community will figure out if these modifications have a role in cancer and other diseases. Given the fact that lysine methylation and acetylation pathways are already popular drug targets, I assume these new modifications and the enzymes that regulate these modifications and pathways are highly likely to be drug targets for diseases.”

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By Rob Mitchum

In 2004, the Food and Drug Administration placed their equivalent of a scarlet letter on the antidepressant fluoxetine. Acting on the compiled results of several clinical trials, the FDA affixed its foreboding “black box warning” on to the drug best known as Prozac, preaching caution about increased suicide risk in children and young adults who take the medication. The decision made headlines around the world, leading to similar warnings in other countries and widespread decreases in the amount of prescriptions issued for the drugs to both pediatric and adult patients.

The FDA’s decision, voted on by a 23-member scientific advisory panel, was not unanimous, passing 15-8. One of the panel’s dissenters was Robert Gibbons, a health statistician then at UIC who later joined the University of Chicago Medicine in 2010. Gibbons thought that the studies used by the FDA, based largely upon retrospective data and adverse event reports, left too much room for alternative explanations.

“I didn’t find the data compelling,” Gibbons said. “For example, kids randomized to drugs would have more side effects, more contact with their doctor, and would have more opportunity to talk about suicidal thoughts.”

Despite Gibbons’ misgivings, there wasn’t an alternative data set to replicate or dispute the conclusions of the FDA’s meta-analysis. But earlier this week, Gibbons and a group of collaborators published their own statistical analysis of the clinical trials assessing the relationship between antidepressants and suicide risk in Archives of General Psychiatry…and reached a very different conclusion.

The new analysis used longitudinal data collected in 40 pharmaceutical company clinical trials and one large NIH study of antidepressants in adults, senior citizens, and children. Instead of measuring suicide risk through reports of adverse events, these data sets contained the results of weekly planned assessments for each patient on a psychiatric scale that measures depressive and suicidal thoughts — allowing researchers to trace week-by-week the effects of drug vs. placebo on the symptoms.

Adult and geriatric clinical trials for two different antidepressant drugs, fluoxetine and venlafaxine, were analyzed, and both medications were found effective in reducing suicide risk and depression symptoms. Furthermore, the two effects were also found to be statistically associated, suggesting that the drugs reduced suicidal thoughts and behavior by alleviating depression. Therefore, Gibbons said, effective treatment of major depressive disorder and careful monitoring that the drug is actually working are both important for a patient’s safety.

“Basically, the results say that the mechanism by which the antidepressants affect suicide rates is by decreasing depression,” Gibbons said. “It follows that if a treatment is not working for an individual, the risk for suicidal behavior and perhaps worse remains high.”

The four pediatric trials included in the new analysis, which all tested fluoxetine, offered more mixed results. A significant reduction in depression symptoms was found across the four studies, suggesting that the drugs were working on their primary aim. But instead of supporting the justification for the black box warning, the new analysis found that the antidepressant did not increase suicidal thoughts and behaviors in children. Nor, however, did the antidepressant decrease suicidality in the population, suggesting that the riddle is not completely solved.

“I think that this paper supports the general idea that the effects of antidepressants in kids and adults are not really the same,” Gibbons said. “In kids, we don’t see a harmful effect, but we do see a disassociation between the beneficial effects on depression and the potential beneficial effect on suicide. Maybe children think about suicide in part because of depression, but also maybe due to other reasons not related to depression that are not affected by antidepressants.”

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Image © 1983, Wong-Baker FACES™ Foundation. Used with permission.

By Matt Wood

We hear a lot these days about online social networks, but the size and strength of a person’s real-life social network has major consequences for his or her health and quality of life. Studies have shown a statistical link between social interaction and mortality, and research has linked loneliness to a range of ailments and diseases, from high blood pressure and poor sleep to heart disease and breast cancer.

Older people are particularly sensitive to changes in their social networks. They often rely on others to help with everyday tasks such as shopping, cooking, cleaning or getting to medical appointments, and like everyone they benefit from the general sense of happiness and well-being that comes from having a robust network of family and friends.

Cognitive impairment from conditions such as dementia is known to limit a person’s social network, causing them to withdraw from the community and become more isolated. Another factor that contributes to social engagement, particularly among older people, is chronic pain. But how much of an impact a painful condition such as arthritis or a bad back can have on social engagement was the focus of a recent study by researchers at the University of Chicago Medicine, which found that chronic pain can affect social vulnerability just as much as cognitive impairment.

“In older adults, so much emphasis is on the physical impact of pain, particularly on functional disability, and the psychological impacts like depression, but not as much attention has been paid to how pain affects one’s socialization,” said Joseph Shega, MD, associate professor of medicine in the Section of Geriatrics and Palliative Medicine and lead author on the study. “More and more research has been done showing that social isolation is associated with worse health outcomes for older adults, so the opportunity came up to try to better understand if pain is associated with more social vulnerability or not.”

The Canadian Study of Health and Aging (CSHA) offered a unique opportunity to address this question by providing data on community-dwelling adults — people who live on their own, not in assisted living or nursing homes — over the age of 65. Shega, William Dale, MD, PhD, associate professor of medicine and chief of the Section of Geriatrics and Palliative Medicine, Kathleen Cagney, PhD, associate professor of sociology, and colleagues from the University of Pennsylvania, the University of Pittsburgh and Dalhousie University in Canada used a cross-sectional analysis of this data to understand the relationship of pain and cognitive impairment with social vulnerability. The study was published in the January issue of Pain Medicine.

The CSHA data included responses about pain levels, cognitive ability and a social vulnerability index, which comprises a variety of variables measuring important social factors. These variables included a person’s ability to engage in the wider community, their living situation, social support system, ability to maintain social ties and a sense of mastery over one’s life circumstances. Statistical analysis showed that moderate to severe pain increased the likelihood of being socially vulnerable just as strongly as moderate cognitive impairment.

Surprisingly, however, being in pain didn’t compound the effect of cognitive impairment on social vulnerability, or vice versa. “Our hypothesis was that they would,” Shega said. “We expected their social vulnerability to be greater than just the impact of the two separate conditions added together, but that ended up not being the case.”

Dale said the understanding that pain and cognitive impairment act similarly and independently to affect a person’s social vulnerability is important, because it puts more appropriate attention on pain management. “I think the big message is that pain is relatively neglected in the big scheme of things,” he said. “You’ll see tons of work on cognitive impairment and its negative impact on social engagement, but it’s fairly unusual to see some recognition of pain’s role being basically equivalent.”

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By Rob Mitchum

In cells, DNA doesn’t often hang out in the long, stretched-out strings you see in science textbooks. Most of the time, it is stored tight in a package called a nucleosome, wound like a ball of yarn around a protein called chromatin. In order for a gene to be “activated,” the stretch of DNA where it resides must first be unspooled from the nucleosome, so that cellular factors can attach to the strand and begin making protein from the DNA recipe. In a new study published this week in Nature, a team of University of Chicago researchers took advantage of this connection between unspooling and activation to solve a mystery that haunts many a recent genetics study.

Genome-wide association studies, commonly called GWAS, look for genetic variants associated with diseases or other genetic traits such as height or hair color. Since the completion of the Human Genome Project and the development of gene chip technology, scientists have performed hundreds of these studies. But many of them offer a befuddling result, with some of the most significant GWAS “hits” coming from variants that lie in the spaces between the protein-encoding genes, regions once dismissed as “junk DNA.” Nevertheless, some of these variants have been observed to affect the expression of nearby genes by some unknown process, leading them to be named expression quantitative trait loci, or eQTLs.

But how do these “non-coding” variants exert their dramatic effects upon gene expression — and ultimately, upon diseases and traits? The Department of Human Genetics laboratories of Jonathan Pritchard and Yoav Gilad found one potential method by selectively targeting the unspooled segments of DNA.

“Much of the regulation is occurring in these regions where the DNA is unfolded, so it’s accessible for proteins to come in,” said Pritchard, professor of human genetics at the University of Chicago Biological Sciences. “What we were interested in was figuring out the main mechanisms by which variation is affecting regulation. We postulated that changes in these open regions would be a major mechanism.”

In cell cultures of B cells (a kind of white blood cell) from 70 West African individuals, researchers used an enzyme called DNaseI to cut the DNA into short segments. Because DNaseI can only work on segments that are unspooled from chromatin, the chopping process left the team with markers of DNA regions that are open for business - in this case the team measured a total of 2.7 billion DNaseI cut sites. The researchers could then use the DNaseI cut sites to create a detailed map and test for genetic variants that predict whether a given stretch of DNA was more likely to be open or closed in an individual, with open segments likely reflecting genes actively under transcription.

“Basically what we’re doing is mapping these locations,” Pritchard said. “The power of DNaseI is that it’s giving us a slightly indirect way of measuring transcription factor occupancy, but it’s giving us information about essentially all factors at once.”

The nearly 10,000 variants found in that test were dubbed “DNaseI sensitivity QTLs,” or dsQTLs for short. The naming similarity to eQTLs was no accident, as the researchers found a significant overlap between the two classes of genetic markers. Up to half of eQTLs were estimated to also be dsQTLs, meaning that the gene variant exerted its power to increase or decrease expression of its gene by affecting the probability of the DNA segment being opened or closed. “dsQTLs are therefore a major mechanism by which genetic variation may affect gene expression levels,” the authors write.

“I think one of the things this paper does is to clarify one of the main mechanisms by which eQTLs arise,” Pritchard said. “Many people measure eQTLs, but generally it has been very difficult to figure out what are the causal variants that drive them and how they act. This is kind of filling in the black box for perhaps as many as half the eQTLs.”

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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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The most common cause of death from breast cancer is not the primary tumor, but metastatic disease, when the cancer travels and takes root in the brain. About 1 in 5 women with metastatic breast cancer will contract a brain lesion, and median survival for those patients is less than a year after diagnosis. Yet physicians currently have few tests to predict which breast tumors will eventually involve the brain and which will not. As it becomes more accepted that no two patients’ cancers are alike, physicians recognize that they need more “biomarkers” that can both reliably predict how the disease will progress and suggest the best method of treatment.

Just as successfully treating cancer often requires the cooperation of different disciplines, finding sufficiently predictive cancer biomarkers needs to be a collaborative effort. An ongoing University of Chicago Medicine search for a factor that can help physicians calculate the risk of brain metastasis in breast cancer patients has united researchers from neurosurgery, oncology, pathology, and Health Studies. The first fruit of that large collaboration, published late last year in the journal Cancer, discovered a promising biomarker with an innocuous name: KISS1.

The interest in brain metastases started in the laboratory of Maciej Lesniak, professor of surgery and neurology and director of neurological oncology. Lesniak, who often treats patients with these types of brain tumors, said that there is a gap in knowledge about what predisposes some women to this serious complication of breast cancer.

“If you have breast cancer, does this automatically mean that you will develop a brain metastasis? We don’t know,”  Lesniak said. “Are there any risk factors or biological phenomena behind this form of the disease? That was the question that we set out to answer.”

Fortunately, the means to test that question were available through the Specialized Program of Research Excellence (SPORE) in Breast Cancer at the University of Chicago Comprehensive Cancer Center, led by medical oncologist and Walter L. Palmer Distinguished Service Professor Olufunmilayo Olopade. The Breast Cancer SPORE maintains a bank of tissue and tumor samples that researchers could use to look for potential biomarkers. Working with Peter Pytel, assistant professor of pathology, the research team developed an assay to test levels of target proteins in tissue from metastatic and non-metastatic breast cancer patients.

For the first potential biomarker, the research team led by Ilya Ulasov chose KISS1, levels of which were previously associated with the progression of bladder, ovarian, and other cancer types. Using antibody staining techniques, the researchers measured KISS1 levels in breast tissue from patients with cancer, non-cancerous breast tissue, and brain lesions from metastatic cancer patients. The comparison found lower levels of KISS1 protein in the brain metastases relative to breast tumors, suggesting that a reduction of this protein is associated with increased spread of cancer to the brain. Another analysis correlated KISS1 levels in the patient’s tissue samples with their clinical outcome, finding that those with higher levels of KISS1 expression exhibited slower disease progression and reduced chance of developing brain metastases.

Interestingly, the relationship between brain metastasis and KISS1 expression was not correlated with previously established breast cancer subtypes that use the estrogen receptor, progesterone receptor, and HER2 gene as biomarkers.

“KISS1 is an interesting protein that seems to at least play a role which subset of patients go on to develop brain metastases from breast cancer,” Lesniak said. “The beauty of this paper is that it carries across different subtypes of tumors.”

However promising the data, the authors caution that their study is only the first step toward establishing KISS1 as a valid biomarker for predicting the course of metastatic breast cancer. Until the biological link between KISS1 expression and cancer progression can be determined, the relationship can’t be considered more than a correlation. But if a mechanism is discovered, Lesniak speculated that KISS1 may hold clues to a way to stop or slow brain metastases from occurring.

“The question is how can you modulate KISS1 expression for the benefit of patients,” Lesniak said. “One approach would be to restore KISS1 expression in patients with advanced metastatic breast cancer, and see whether it makes the tumor less aggressive or less prone to metastatic disease. It’s an interesting thought, but it’s probably too premature to know whether that would hold true.”

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In the aftermath of a mass extinction, nature tends to get creative. Those lucky species that survive often explode with Seussian abandon into a diverse array of shapes, sizes, and behaviors, capitalizing upon the ecological opportunities left available by their less fortunate peers. Usually, the oddities produced by these “adaptive radiations” are whittled down by natural selection to only a few surviving forms. But evolutionary biologists are interested in the course these radiations take — the dynamics that result when nature hits the “randomize” button.

Scientists have tried to understand the order underlying this chaos by studying modern animals that have established broad diversity, such as the immense cichlid family of fishes (which encompasses over 1,000 documented species) or Darwin’s finches of the Galapagos islands. But these studies can only work backwards from the species that exist today. To watch an adaptive radiation unfold, a better source is the fossil record, as the University of Chicago’s Lauren Sallan and the University of Oxford’s Matt Friedman discovered in a recent journal article for Proceedings of the Royal Society B.

Sallan and Friedman used fossil databases from two prehistoric mass extinction events: the Hangenberg event, of roughly 359 million years ago, and the end-Cretaceous extinction, which ended the age of dinosaurs. By measuring how surviving fish species changed body shape and size after these ecological disturbances, the researchers could test two common theories of adaptive radiation inspired by studying surviving species. One model proposed a free-for-all “burst” of divergence followed by a long period of relative stability. Another, sometimes known as the “general vertebrate model,” introduced the idea of staged divergences, with habitat-driven changes in body type preceding diversification of head types.

“There hadn’t been any tests of these things using fossils,” said Sallan, a graduate student in the Department of Organismal Biology and Anatomy. “You have all these analyses of diversification, yet not one of them goes back to the fossil record and says what’s happening at this time period, and the next time period, and the one after that.”

When Sallan and Friedman looked carefully at their data, they didn’t find evidence for either of the pre-existing theories. Instead, they saw a staged radiation that started not tail-first, but head-first, with surviving species initially trying out a wide range of head shapes attached to similar bodies. The driver of this diversity may have been a simple factor: food. Faced with far less competition, the surviving fish evolved new types of teeth, jaws, and heads to take advantage of the expanded menu suddenly available. Later, once head shapes stabilized, different body types from broad and flat to thin and eel-like appeared as new species adapted to their surroundings.

“It seems like resources, feeding and diet are the most important factors at the initial stage,” said Sallan, who works in the laboratory of University of Chicago Professor Michael Coates.

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In baseball, much is made of the half-second or less a batter is given to swing or not swing at each 100-mph fastball. But another important snap decision is made by the home plate umpire, who must pinpoint the position of the ball as it crosses the plate and immediately decide whether it counted as a ball or a strike. To complicate matters, the strike zone changes size depending on the hitter, pitchers throw balls at varying speeds and with knee-buckling spin, and a good number of pitches fall into a gray zone on the “corners” of the strike zone. Given the hundreds of ejections each year resulting from players arguing balls and strikes with the umpire, the competitive stakes for this task is incredibly high.

Fortunately, the human brain is quite accomplished at rapidly sorting visual information into categories. Even if you’ve never stood behind home plate to call a game, you have experienced this ability. Imagine you are crossing a street, and from the corner of your eye you see a quickly moving object heading your way. From even the most basic of visual features, your brain can quickly categorize a four-wheeled vehicle of any make and model as a “car”…or “thing that will cause me serious harm if I don’t jump out of the way.” Nobody is born with the innate ability to recognize an automobile, but the collected experience of life reinforces the rules of what is a car and what isn’t — as well as complicated sub-categories such as sportscars and SUVs — and keeps them in the brain for rapid retrieval.

The laboratory of David Freedman, assistant professor of neurobiology at the University of Chicago, is interested in where exactly these categories are stored in the brain. For over a decade, Freedman has conducted experiments looking for the brain area that is the earliest responder when an individual must quickly categorize a stimulus.

“Making effective decisions and evaluating every situation that you’re in moment by moment is critical for successful behavior,” Freedman said. “We’re really interested in what changes occur in the brain to allow you to recognize not just the features of a stimulus, but what it is and what it means.”

Typically, these studies are done using monkeys who are taught to play a simple video game while researchers record brain activity from different regions looking for the signals that underlie decision-making, called category signals. In a study published in Science in 2001, Freedman and colleagues at MIT found the first evidence for brain category signals in a region called the prefrontal cortex (PFC). The site made sense, as the PFC (an area that is especially large in humans) has long been associated with complex, cognitive functions such as memory, planning, and decision-making.

However, the trail didn’t end with that finding. Freedman moved on to study another part of the brain, called the parietal cortex, which is located on the sides of the brain and thought to be involved in processing sensory information. By happy accident, Freedman discovered that the parietal cortex also responded while the monkeys played the categorization task, and the signals looked as though they might be even stronger than those seen previously in the PFC. But to determine which of the two brain areas was the original source of category signals, a direct comparison was needed.

That comparison, published this week in Nature Neuroscience by Freedman and graduate student Sruthi Swaminathan, offers the best evidence to date that the parietal cortex is the primary residence for visual categories in the brain. As monkeys played their categorization game, deciding whether two groups of moving dots fell into the same category or different categories, a sub-region of parietal cortex known as the lateral intraparietal areas (LIP) reacted faster and more strongly.

“This is as close as we’ve come to the source of these abstract signals,” Freedman said. “The relative timing of signals in the two brain areas gives us an important clue about their roles in solving the categorization task. Since category information appeared earlier in parietal cortex than prefrontal cortex, it suggests that parietal cortex might be more involved in the visual categorization process, at least during this task,” Freedman said.

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In books and movies, time travel is typically fraught with negative consequences. Any attempt to change the past — say, stopping the JFK assassination, or taking your mom to the Enchantment Under the Sea dance — is bound to produce ripples of change that alter the future. But what if you could safely contain a trip back in time within the boundaries of a test tube? In a new paper published in Nature, a University of Chicago geneticist used a form of “molecular time travel” to observe a crucial event in the evolutionary history of life on Earth…and extinguish a favorite argument of intelligent design advocates.

The concept of “irreducible complexity” is a favorite talking point of the forces against evolution, both today and historically. As the argument goes, the complex structures found within modern organisms — from the eye to the microscopic protein machines that conduct business in cells — are far too complicated to be the result of the random genetic mutations and selective forces at the core of Darwin’s grand theory. The argument is so old that Darwin himself addressed it in On the Origin of Species, speculating on how an accumulation of small changes could lead from a simple photoreceptor to the wondrous eye shared by many organisms today.

The best way to demonstrate how the minute changes of evolution could produce great complexity is to capture that process in action. But to happen upon such a leap live would be a biological needle in an enormous haystack. A better strategy would be to pick a historic leap in complexity from the evolutionary past, and then go back and observe how it happened. Easy, right?

To accomplish this task, Joe Thornton, a new faculty member in the Departments of Human Genetics and Ecology & Evolution, developed the method of “molecular time travel.” Instead of a Delorean, Thornton’s method uses a computational analysis of the genes from modern-day species to resurrect the genes of ancestral species that lived hundreds of millions of years ago. For the new paper, Thornton and colleagues at the University of Oregon decided to “travel” back to look at a complex molecular machine found in various species of fungus.

“Our strategy was to use ‘molecular time travel’ to reconstruct and experimentally characterize all the proteins in this molecular machine just before and after it increased in complexity,” said Thornton, professor of human genetics and evolution & ecology at the University of Chicago, professor of biology at the University of Oregon, and an Early Career Scientist of the Howard Hughes Medical Institute. “By reconstructing the machine’s components as they existed in the deep past,” Thornton said, “we were able to establish exactly how each protein’s function changed over time and identify the specific genetic mutations that caused the machine to become more elaborate.”

Their target was a molecular machine called the V-ATPase proton pump, which helps maintain the proper acidity of compartments within cells. In modern Fungi, this pump contains a six-part ring made up of three separate proteins, but that wasn’t always the case. Some 800 million years ago, that same ring was made from only two proteins, meaning some kind of event occurred around then to increase the complexity of this machine.

Thornton’s group calculated the genetic sequence of the ring proteins from that ancient ancestor using the sequences of 139 modern Fungi family members, computationally tracing their common elements back up the Tree of Life to their ancient predecessor. The researchers could then reproduce the protein before the split (called Anc.3-11) and the two proteins that came after the split (Anc.3 and Anc.11), and see how they functioned in the proton pump’s ring.

Surprisingly, the “newer” proteins were less versatile than the ancestral Anc.3-11, which could substitute for either of its descendants when transplanted into modern Fungi. The result suggests that the pump’s increase in complexity resulted not from the evolution of a new, “better-designed” function, but from an initial loss of versatility.

“It’s counter-intuitive but simple: complexity increased because protein functions were lost, not gained,” Thornton said. “Just as in society, complexity increases when individuals and institutions forget how to be generalists and come to depend on specialists with increasingly narrow capacities.”

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All of the animal life on Earth, including human beings, can be traced back to a unicellular ancestor somewhat similar to the modern-day protozoa. In one sense, the hundreds of millions of years of evolution is the story of how organisms became more and more complex, growing from a single cell to trillions of highly specialized cells forming different organs and tissues in a single body. Yet while you could easily tell a protozoa from a human in a police lineup, cells from the two species are made up of many of the same proteins, performing similar jobs. What changed to produce these profound differences in complexity?

One potential area where this complexity may have bloomed is tyrosine phosphorylation, a key cellular signal for pathways that control cell growth, proliferation, and structure. Enzymes called tyrosine kinases add a phosphate group to a wide range of cellular targets, which can act like a light switch, turning their function on or off. The phosphorylated proteins are recognized by another group of proteins with a special “sensor” called the SH2 domain. Because tyrosine kinases will promiscuously phosphorylate many targets in the cell, the very picky SH2 domain proteins are responsible for sorting out the noise.

“Tyrosine kinases tend to be not that selective,” said Piers Nash, assistant professor in the Ben May Department of Cancer Research at the University of Chicago who studies this system. “They’ll phosphorylate a lot of things, and that creates all of these docking sites for SH2-domain-containing proteins. It’s really up to the SH2 domains to interpret those signals and convert them into downstream signaling pathways.”

The more complex the cell, the more unique types of SH2 domains that are needed to perform this important sorting function. In the unicellular cousins of animals, organisms can get by with just a single SH2 domain. But in humans, some 121 SH2 domains are known to exist, managing many different pathways in many different cells. In two recent papers, Nash’s laboratory studied how these SH2 domains manage their impressive selectivity and the evolutionary pathway that they took from simple protozoa to complicated human.

It’s essential that SH2 domains only bind to the right phosphorylated protein — repeatedly screwing up and activating the wrong pathway could lead to diabetes, cancer, or worse. But scientists have struggled to figure out how SH2 domains choose their appropriate target, with some even concluding that they aren’t so selective at all, merely in the right part of the cell at the right time to only bind the correct protein. However, that wasn’t what a research team led Bernard Liu from Nash’s laboratory found when they looked at how SH2 domains bind actual cell targets such as the insulin receptor.

“It turned out that the SH2 domains were exquisitely selective, much more selective than the general motifs for the SH2 domains that had previously been mapped,” Nash said. “So it was clear there was additional information encoded in the peptide that the SH2 domain makes use of.”

The researchers then deduced that the SH2 domains select their target through a kind of language, looking for the exact sequence of amino acids - or “word” - that marks the appropriate match. Because each amino acid (akin to the letters of the word) will either attract a particular SH2 domain or reject its peers, changing only one amino acid can completely change the meaning, like altering the word “light” to “fight.”

“For SH2 domains, that makes all the difference in the world. They can sense incredibly subtle differences,” Nash said. “It’s looking at the entire peptide and seeing both the permissive and the non-permissive residues, integrating that and making this collective decision about what to bind.”

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If you called someone a rat, they probably wouldn’t take it as a compliment. But in a clever new study published today in Science, a team of University of Chicago neurobiologists show that rodents could serve as role models for how humans should behave. Rats were given a difficult choice between heart and stomach: either open a container of chocolate chips and enjoy the feast, or free a companion and share the chocolate chip bounty. The results argue that humans aren’t the only species to feel empathy for the distress of another and act upon it, suggesting a deep evolutionary basis for helping your fellow creature.

When Inbal Ben-Ami Bartal was a master’s student in Israel researching immunosuppression after surgery, she noticed a strange phenomenon in her laboratory rats. When rats were brought to the room where she regularly conducted surgical procedures, they grew extremely agitated.

“It was very obvious that rats could sense what was going on with other rats,” Bartal said. “They freaked out and were affected by the emotional state of the other rats once they were removed from the cages.”

Other researchers had previously noticed this phenomenon in both humans and animals and gave it the name “emotional contagion,” describing when the distress or pain of one individual spreads to others. In 2006, Jeffrey Mogil of McGill University found evidence of this effect in mice, observing that when one mouse is given a mildly painful stimulus, a second mouse viewing the first mouse’s pain will exhibit increased sensitivity to pain. When that paper was published, it was considered by some to be the first evidence for empathy in a rodent. But Bartal, having started as a graduate student advised by Jean Decety, Irving B. Harris Professor of Psychology and Psychiatry at the University of Chicago, wanted to find more definite proof of rat compassion.

Collaborating with the laboratory of Peggy Mason, professor of neurobiology, Bartal designed a test to see whether emotional contagion could actually drive a rat to take action. Two rats who live together in the same cage were placed in a special arena, with one held in a transparent, tube-shaped restrainer and one allowed to roam free. The restrainer’s door could be opened by a nudge from the outside, though the free rat - at least initially - didn’t know that. But after several sessions where the free rat was visibly agitated by his trapped companion’s distress, he figured out how to pop open the restrainer. As you can see in this video from Science, once the free rat learned this trick, he would take action almost immediately upon being placed in the arena during subsequent sessions.

“We are not training these rats in any way,” Bartal said. “These rats are learning because they are motivated by something internal. We’re not showing them how to open the door, they don’t get any previous exposure on opening the door, and it’s hard to open the door. But they keep trying and trying, and it eventually works.”

Proving that the free rat’s actions were motivated by empathy required more experimental conditions. When the restrainer was left empty, or when researchers put a stuffed toy rat in the tube, the free rat showed no interest in opening the restrainer door. He did, however, when the arena was rigged so that opening the restrainer released the trapped rat into a separate compartment from the free rat, showing that the free rat was not motivated by the “reward” of social interaction. The experiments left behavior motivated by empathy as the simplest explanation for the rats’ behavior.

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