By Rob Mitchum

Arsenic is a deadly toxin, but it’s not one dose fits all. Two people exposed to the same level of the chemical can have entirely different responses, with Patient A developing the skin lesions, cancers, and respiratory conditions that are a hallmark of arsenic toxicity, while Patient B is entirely unaffected. Currently, no test exists to tell in advance who might be more vulnerable to the effects of arsenic, but scientists suspect that some clues may lie in a person’s genes. In the latest paper from Habibul Ahsan’s massive study of arsenic exposure in Bangladesh, researchers uncovered a promising genetic story that could help identify people at higher risk — and potentially help protect them from toxicity.

As discussed before on ScienceLife, Ahsan’s two studies in Bangladesh follow the victims of an almost unfathomable mass poisoning event. In the 1970’s, an international effort was put together to switch millions of Bangladeshis from disease-ridden water sources to well-water. Unfortunately, the groundwater tapped by those wells turned out to contain very high levels of arsenic…a dark fact that wasn’t discovered until some 20 years after their installation. Over those decades, some 77 million people in the country were drinking water containing arsenic concentrations as high as 27 times safe limits.

For more than a decade, Ahsan has studied the epidemiology of that long-term exposure in some 20,000 volunteers, as well as low-priced interventions to try to reduce toxicity. In his latest paper, published last week in PLoS Genetics, Ahsan’s team zoomed in on the DNA of those subjects, looking for genetic variants that predict higher arsenic toxicity in a pool of 3,000 Bangladeshi citizens from the larger studies. Using the methods of genome-wide association studies (GWAS) — one of the first such studies conducted in the developing world — the researchers found a genetic region that offers a promising and refreshingly logical story about what creates individual differences in vulnerability to arsenic.

“These results add clarity to the genetic architecture that is playing a role in arsenic toxicity and its underlying biology,” said Ahsan, Louis Block Professor of health studies, medicine and human genetics at the University of Chicago Medicine. “It’s a rare type of study for a major problem affecting millions of people around the world, and it opens up opportunities for genetic studies of other major public health problems in developing countries.”

Led by Ahsan and Brandon Pierce, assistant professor of epidemiology at the University of Chicago Medicine, the team looked for potential genetic influences on phenotypes such as arsenic metabolism and the risk of acquiring arsenic-induced skin lesions. After ingestion, the body metabolizes inorganic arsenic into first monomethylarsonic acid (MMA) and then dimethylarsinic acid (DMA). MMA is considered to be more toxic, while DMA is water-soluble and more easily excreted. Higher levels of DMA or lower levels of MMA measured from an individual’s urine are associated with lower toxicity.

A GWAS search for variants associated with high or low DMA/MMA ratios turned up several candidates in the region of a likely suspect gene: arsenite methyltransferase (As3MT), an enzyme known to be involved in arsenic metabolism. A second GWAS that compared subjects who suffered skin lesions after arsenic versus subjects who did not pointed to variants in the same region, offering more evidence for the gene’s involvement and a rare straightforward result for a genomic study.

“This makes perfect sense,” Ahsan said. “It gives us a very coherent story that we can now investigate in relation to other arsenic pathologies and in relation to a wide range of arsenic doses in this population. Many genomic signals that we see are not robust enough or do not pertain to a large population. But in this study, that is not the case. The finding is robust, and the impact is massive.”

read more

By Rob Mitchum

Cells, like people, are not perfect. If a cell’s primary responsibility is to produce proteins, then it makes a remarkable amount of mistakes in that job, with some studies estimating that an error appears in as many as 1 out of every 5 proteins. Defective proteins can be a serious problem — scientists are learning that many aging-related neurological illnesses, such as ALS, Alzheimer’s, and Parkinson’s disease, are caused in part by faulty proteins clumping together into neuron-killing aggregates. Cells have a quality inspection and trash disposal system in place to neutralize these toxic defects, but that’s an expensive way to deal with a problem with a simpler solution: why don’t cells just make better proteins?

That question has fascinated D. Allan Drummond, assistant professor of biochemistry and molecular biophysics at the University of Chicago Biological Sciences, since his graduate work in the laboratory of Frances Arnold at CalTech studying directed evolution. His work on the high error rate of protein production, otherwise known as a cell’s “translational infidelity,” led to Drummond’s inclusion in the 2012 class of Sloan Research Fellows, an award recognizing young scholars with exciting ideas across various scientific fields. Drummond’s previous research has revealed some promising clues about why protein errors, in some cases, may be a good thing for a cell, and he thinks the field is on the verge of real progress thanks to technical advances.

“There previously existed no method at all to assess and measure the true infidelity of translation,” Drummond said. “Now we have higher quality mass spectrometry, which allows you to do essentially do for proteins what DNA sequencing does for genomes. Mass spectrometry is now sensitive enough to detect mistranslated proteins on a large scale.”

One hypothesis that Drummond would like to tackle with that technology is the idea that cells are unexpectedly crafty in how they deal with their protein error rate. Experiments have shown that the errors are a necessary sacrifice cells will make to increase the speed of protein translation. Cells with more stringent quality control grow more slowly, which under the highly competitive conditions of natural selection, can be a fatal luxury. So if the cells must endure a fairly high error rate in order to keep up with the Joneses, the least they can do is pick and choose the best places to put those errors.

Some proteins, like the enzymes used in glycolysis, are kept at high levels in cells, with as many as a million copies floating around at any one time. Other proteins, such as the transcription factors, are nowhere near as plentiful, with only tens or hundreds of copies on hand. If a cell could somehow channel its error rate toward the second group of proteins and away from the first, it would be much better off, Drummond said.

“It’s going to be devastating in the case of the glycolytic enzymes, because the misfolded products alone will be more abundant than most proteins in the cell. It’s spamming the cell with all sorts of garbage,” Drummond said. “If you put errors in a low abundance protein, the amount of misfolding you’re going to get is probably negligible.”

Fortunately, cells do have a way to selectively disperse their protein errors. Proteins are built out of amino acids, directed by RNA codons that correspond to the original DNA recipe. But each amino acid is associated with multiple codons, and some codons are more error-prone than others. Analyses by Drummond’s laboratory found that the higher-fidelity codons that make fewer errors are used more often in building high expression proteins, while the less reliable codons appear more frequently in rarer proteins.

But that strategy begs the question: why would a cell ever use anything but the most reliable codons? Drummond has a provocative answer that challenges whether all mistakes are created equal.

“The most exciting idea is that these are not errors,” Drummond said. “They’re so frequent, they’re believed to be present at such high levels, that it is almost inconceivable that cells have not become addicted to the presence of some of them. In a sense, they could be using a single DNA sequence to make multi-functional proteins.”

read more

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.”

read more

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?

read more

By Matt Wood

Substance use among adolescents and young adults in the United States is a perennial problem. Despite decades of campaigns by health care providers, schools and the government warning about the dangers of alcohol, tobacco and marijuana, substantial numbers of young people still report using these substances on a regular basis.

Research has shown that substance use increases from early to late adolescence, peaks around the mid-20s and declines thereafter, but is that pattern of use the same for everyone? A recent study by researchers from the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago Medicine looked at a nationally representative sample of youths in the United States and found distinct gender and racial differences in the developmental trajectories of various types of substance use from early adolescence to young adulthood. This suggests opportunities for more targeted intervention and prevention programs.

Pan Chen, Ph.D and postdoctoral scholar, and Kristen Jacobson, Ph.D and associate professor in psychiatry and behavioral neuroscience, wanted to get a true picture of how substance use changes over time for young people in the United States, from early adolescence all the way through adulthood. Previous studies on substance use were generally not nationally representative, meaning they didn’t reflect the gender and racial makeup or substance use behaviors of youths in the entire country. Studies that did use nationally representative data focused on shorter periods of time, such as early to late adolescence only.

Using a large sample of more than 20,000 participants in the National Longitudinal Study of Adolescent Health, Chen and Jacobson were able to measure substance use in students from 12 years old all the way up to 34-year-old adults. “This is important because when you are focusing on a nationally representative sample, you will be better able to generalize your findings to the population of adolescents in the US,” Chen said.

The data also included four types of substance use: alcohol use, heavy or binge drinking, cigarette smoking and marijuana, making it the first study to compare developmental patterns of these different behaviors simultaneously. The study was published in the Journal of Adolescent Health.

In their analyses, Chen and Jacobson found that patterns for all four types of substance use held to the typical curve, increasing from early adolescence to the mid-20s and then tapering off. But they found some important differences as well. First, while females reported higher substance use in early adolescence, males’ substance use behaviors increased at a significantly faster rate and peaked at a much higher level from middle adolescence to young adulthood. Hispanic youths displayed higher rates of use than other groups at age 12, but Caucasians peaked at much higher levels in their 20s. All racial groups tapered off to roughly the same levels by age 34 except for African Americans, who reported higher levels of cigarette smoking and marijuana use into adulthood.

Understanding these differences offers insight into how and when to intervene with different groups of young people. “This type of project is important because it provides crucial implications for intervention and prevention projects,” Chen said. “It offers insights into critical time periods, as well as the target population.”

read more

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.”

read more

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.”

read more

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.”

read more

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.”

read more

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.”

read more

By Dianna Douglas

A pregnancy is considered at “term” after 37 weeks. But there are critical growth stages that come next–a baby’s lungs, brain, and liver develop in the last few weeks in the womb. Women in the United States are often induced before the baby has fully gestated, which leads to a host of negative consequences. Kenneth Nunes, MD, assistant professor of obstetrics and gynecology, led an effort to slow down the rate of elective “early-term” deliveries between 37 and 39 weeks at the University of Chicago. In these video interviews, he discusses his motivations, methodology, and results.

In the first, Nunes discusses the risk of delivering early versus the risk of prolonging a pregnancy.

Nunes discusses how a pregnancy is induced, when it is necessary, and the possible effects of inducing.

Nunes discusses how he and the Women’s Care Group reversed the number of elective “early-term” deliveries at the University of Chicago.

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.”

read more

By Rob Mitchum

Treating a brain tumor in a lab dish is easy. Scientists have developed a full arsenal of treatments to kill tumor cells, using natural toxins, chemotherapeutic drugs, and even gene therapy to send them to an early grave. But making those therapies work in the actual setting of the brain is a much different ballgame. The first major challenge is even delivering the therapy to the right place, as any drug must get past the brain’s defense systems and navigate the organ’s complex architecture. In addition, the therapy must be a picky killer, eradicating tumor cells while leaving the healthy brain cells intact.

Researchers are therefore searching for a smarter delivery system that can maximize the effectiveness of these brain tumor therapies, collaborating with experts in the world of chemistry, materials science, and engineering. Bakhtiar Yamini, an assistant professor of surgery at the University of Chicago Medicine, is collaborating on one such effort with a biotechnology company in Nebraska, targeting the most difficult malignant brain tumors Yamini sees in his neurosurgery practice. By designing a new nanoparticle “shell” capable of selectively targeting therapeutics to brain tumor cells — and capable of being watched as it travels through the brain — the research team hopes to make eradicating these cells in their native environment as simple as killing them in a dish.

“Even though new therapies are being developed that can kill cells in culture, getting them into the brain tumor is a big problem, so development of a vehicle is an important step,” Yamini said. “People have previously used both targeting and image guidance in the treatment of other cancers, but bringing these two strategies together in one vehicle is something that would be really useful.”

In Phase I of their NIH-funded project, Yamini and collaborators at LNKChemsolutions developed a nanoparticle made from materials such as polylactic acid and polycaprolactone. Despite the complicated chemical names, these materials are commonly used in biodegradable products — a feature that offers an advantage over other nanoparticles made from gold, titanium, and other metals. The nanoparticles are also customizable, able to carry a variety of therapeutics and different targeting signals, and incorporate a metal, iron oxide, that allows doctors to visualize the nanoparticles’ travels using MRI technology.

For Phase II of the project, funded late last year, the team is taking their technology to animal models. A nanoparticle designed to target a protein called the EGF receptor (often overexpressed by tumor cells) and deliver the chemotherapy drug temozolomide will be tested in mice and rats that have brain tumors. If those experiments are a success, the team will try the therapy on a larger animal model: dogs. Partnering with veterinary clinics in Chicago and Minnesota, the researchers will offer the treatment to pet owners willing to volunteer their sick dog for a cutting-edge therapy.

“That’s how we will develop the treatment, but at the same time it should be effective at helping the dogs,” Yamini said. “It’s essentially a clinical trial for dogs that have brain tumors, and because their tumors are very similar to human ones, the results in the dogs will have relevance to humans.”

Because of the blood-brain barrier, which prevents most molecules from passing from the body’s blood supply into the brain, just injecting the nanoparticles into a vein won’t work. Directly infusing particles into the brain during surgery to remove the tumor is possible, but the spread of particles by that method can be unpredictable and may miss the target. Instead, Yamini will use a method known as convection enhanced delivery to push the nanoparticles very slowly into the desired area of the brain, squeezing them through the space between brain cells. The iron oxide tags will allow surgeons to monitor the path of the nanoparticles by MRI as they are being infused through the brain.

“The image guidance is a big factor, because ‘blind’ infusion of the nanoparticles can be problematic,” Yamini said. “If you plan to treat the upper right corner and you see, on MRI, that the infusion actually went to the lower left, you can put your catheter back in and try again. This paradigm of ‘adaptive image guidance’ allows you to adjust subsequent treatments to target the areas that were missed on the original injection.”

read more

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.”

read more

By John Easton

Few people realize the important role that math plays in organ transplants. Complex formulas convert medical information about each patient, including diagnosis, age, and test results, into a single “allocation score” that determines who has priority when an organ becomes available. One factor not included in these calculators is proximity of the organ to a patient. More than a decade ago, the U.S. Department of Health and Human Services issued the “Final Rule,” intended to ensure that organs were allocated “based on medical criteria, not accidents of geography.” However, new data show that where a transplant candidate lives continues to influence access to donated lungs.

The current system for allocating donated lungs based on proximity and not on need appears to decrease the potential benefits of lung transplantation and increase the number of patients who die waiting, researchers said at an annual meeting of thoracic surgeons in Fort Lauderdale. Using data provided by the United Network for Organ Sharing (UNOS), Mark Russo and colleagues at the University of Chicago Medicine and Columbia University found that donor lungs were routinely allocated to less urgent, local candidates even when there were patients within the region but outside the local donor service who were in much greater need.

One unfortunate but not unusual example was a 27-year-old man with cystic fibrosis who was in an intensive care unit awaiting a lung transplant. He had a lung allocation score of 91 out of 100, one of the highest of such scores in the U.S. at the time. He was expected to die within a week without a transplant. An appropriately matched lung donor did became available less than 20 miles from the hospital where this man was waiting, but because the candidate was just outside of the donor’s local service area, two candidates from within the service area, each with an LAS in the 40s, took priority. One of these candidates received the organs. Five days later the 27-year-old patient died.

Such circumstances are not uncommon, said Russo, assistant professor of surgery at the University of Chicago Medicine.

“Ideally, a suitable donor organ would be available for every person who could benefit from transplantation,” he said. “Unfortunately, there remains a critical scarcity of donor organs. More efficient allocation of this scarce and precious resource could dramatically increase the overall benefit from lung transplantation.”

Among the 580 locally allocated double-lung transplants performed in 2009, 480 less needy candidates, or 83 percent of all double-lung transplants, received the organs even though a well-matched candidate in greater need existed in the region.

Twenty-four percent of such cases involved skipping over regional candidates with lung allocation scores — which range from 1 to 100, based on need and likely benefit — more than 10 points higher than the local recipient. More than 7 percent of the events involved a regional candidate with a lung allocation score (LAS) more than 25 points higher than the local recipient. Overall, 185 of the bypassed regional candidates ultimately died on the waitlist.

“We found that too often, and to many patients’ detriment, organs are allocated according to geography rather than urgency,” Russo said. When lungs go to less needy candidates within the local Donor Service Area and never become available to sicker candidates at the regional or national level, “this decreases the overall benefits of a transplant,” he said.

read more