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.”

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

January

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

February

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

March

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

Photo by Gerald Waddell

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

May

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

June

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

July

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

August

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

September

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

October

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

November

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

December

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

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

Loneliness has had a tough run of late, with a growing body of research blaming it for everything from high blood pressure to heart disease to depression and cognitive decline. The research group of John Cacioppo, director of the Center for Cognitive and Social Neuroscience at the University of Chicago, has been among the leaders in leveling these medical charges against loneliness. But one missing piece of the puzzle remains - what biological mechanism connects a person’s feelings of inadequate social contact with the negative health outcomes? A new collaboration with epidemiologists and geneticists at the Medical Center suggest that the missing link might be in the bedroom.

For decades, professor of human genetics Carole Ober has studied a unique society called the Hutterites [pdf]. A religious group that originated in the 16th century, the Hutterites have formed several communal farms in the United States where some 150 people live and work together. The stability and isolation of the Hutterites make them a perfect population for studying the interplay between genes, environment, and disease - the mission of Ober’s research. Those qualities also made them the perfect group of people for a team lead by Lianne Kurina, assistant professor of epidemiology in the University of Chicago Department of Health Studies, to test the link between loneliness and sleep quality.

The new study, which appears in the journal Sleep, is not the first to examine this connection. A 2002 study led by Cacioppo used the most accessible pool of subjects on a college campus - college students - and found that those who scored higher on a psychological loneliness test displayed reduced sleep “efficiency” with no change in sleep duration. In other words, the loneliest subjects slept just as long as their socially satisfied peers, but suffered more “microawakenings” and lower sleep quality.

Because college students reflect only a narrow band of society, it was important to replicate the result in an entirely different population. Enter the Hutterites, who were also tested using a loneliness scale and asked to wear wristband sleep monitors to track their activity during sleep. Because of their communal lifestyle, even the loneliest Hutterites were less lonely than the general population. But the same correlation was detected between loneliness and sleep quality - for each point increase on the loneliness scale used to test the subjects’ social feelings, the researchers observed an 8 percent increase in sleep fragmentation. Furthermore, the lonelier Hutterites did not themselves report poor sleep or daytime sleepiness, indicating that the effects are mostly subconscious.

“Loneliness has been associated with adverse effects on health,” Kurina said in a press release. “We wanted to explore one potential pathway for this, the theory that sleep - a key behavior to staying healthy - could be compromised by feelings of loneliness. What we found was that loneliness does not appear to change the total amount of sleep in individuals, but awakens them more times during the night.”

The evidence is still not strong enough to conclusively place sleep deficits as the intermediary between loneliness and poor health. As the paper admits, the opposite relationship could be true: sleep fragmentation could increase feelings of social disconnection. But a flood of recent evidence, much of it from the University of Chicago Sleep, Metabolism, and Health Center, suggests that the third of each day we spend sleeping can dramatically affect several different aspects of our health, including diabetes, obesity, dieting success, and testosterone levels. Certainly, the newly replicated connection between a lonely heart and restless nights offers an intriguing theory for future study.

But why would feelings of social inadequacy disrupt a person’s time in bed?

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When scientists picture the miniature machines that live inside cells, they often have to settle for indirect evidence and a bit of imagination. Proteins on the nanoscale - one million times smaller than a millimeter - can’t be seen with your typical microscope, so scientists turn to electrical measurements, genetic mutations, and chemical assays to deduce a rough sketch of their target’s structure. More recently, tools such as X-ray crystallography and electron microscopes have allowed scientists to see cellular proteins. But both techniques require steps that change the natural environment of the protein, and can only offer a single photograph rather than a “movie” of its dynamic changes in shape.

So when Joanna Gemel, a research associate assistant professor in the laboratory of Eric Beyer, decided to look at the structure of cellular proteins called connexins and the channels they form, she wanted a different option. Connexins are found within the membrane of a cell in groups of 6, called connexons or hemichannels. When two cells come into contact, their connexons “dock” with each other to form a pathway between the two cells called a gap junction channel. In organs such as the heart or smooth muscle, gap junctions play an important role by facilitating the rapid passage of ions and small molecules from cell to cell.

“Gap junctions are critical for the propagation of electrical impulses in the heart. Abnormalities or mutations in them can cause a lot of problems, such as arrhythmias and atrial fibrillation,” said Gemel, author of a recent paper in The Journal of Biological Chemistry. “We decided that we would like to do something different. Since we never see channels, we asked what would be the best way to see channels and learn more about them?”

The question led them to the Center for Nanomedicine, a laboratory run by Michael Allen, a research associate assistant professor in the Department of Medicine. Allen’s tool of choice is atomic force microscopy, a technology invented in the mid-1980’s that remains useful for the visualization of the very, very small. The method, known as AFM for short, uses a strategy similar to an old record player: an extremely tiny needle (2 nanometers at its tip) moves slowly across the surface of a sample, creating a topographic map of the molecular landscape.

“AFM is really good at measuring height, the resolution in the z-axis,” Allen said. “With AFM we can look at 3-dimensional architecture, and in the z-axis the resolution is a tenth of a nanometer.”

But before tapping the potential of AFM, Gemel had to first create a stretch of membrane containing only the connexin she wanted to study, a form called connexin40 that is expressed in certain regions of the heart. Through painstaking transfection, purification, and reconstitution, Gemel produced a layer as thin as a cell membrane, swarming with connexin proteins. After imaging with the microscope, the researchers produced images (like the one posted above) that resembled dense mountain ranges viewed from an airplane, bumps floating in a dark field. Remarkably, the individual subjects and even the channel opening - narrow enough to pass individual atoms - were visible, not unlike the cartoon representation of gap junctions seen in textbooks.

With the extremely fine resolution of the AFM needle, Allen and Gemel set about measuring the heights of individual objects in their sample. Even though they knew that connexin40 was the only protein present in the membrane, their images contained particles of two different heights: some “bumps” were roughly 2.5 nanometers tall, and others were approximately 4 nanometers in height. They subsequently showed that the two different-sized bumps corresponded to whether the asymmetric hemichannels were facing inward or outward in the membrane.

“While it was something that we did not expect, it was an accomplishment to be able to monitor channels from both sides,” Gemel said.

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Brain surgery remains one of the more complex procedures in the clinical arsenal, an intervention any doctor would like to avoid if possible. But many conditions - a growing brain tumor, a bleeding hemorrhage - require the surgeon to go in, opening the skull, dodging blood vessels, and preserving healthy tissue to correct the problem. If these maladies were somehow preventable or treatable with a medication, it could cut down on the complications and cost of neurosurgery. Even so, you might be surprised to find a surgeon doing the research that could someday reduce his own workload.

That’s the case with Issam Awad, professor of surgery at the University of Chicago Medical Center, and the latest paper in his project studying an abnormality of the brain’s blood vessels. Cerebral cavernous malformation (CCM), alternatively known as cavernous angioma, occurs when the small blood vessels of the brain grow abnormally large. These malformations can occasionally form a dangerous lesion, leading to headaches, bleeding in the brain, or stroke. But it wasn’t until the routine use of MRI technology until clinicians discovered just how commonly CCM can be found - 1 in 500 people - even though it is often non-symptomatic.

The presence of non-symptomatic CCM complicates the matter further for neurosurgeons, who must decide whether to perform surgery to correct the lesion or wait to see if it worsens. This dilemma is especially difficult in patients with a family history of CCM, which makes up about one-third of the cases. Waiting to see if the angioma is going to become problematic enough to require surgery can be a frustrating experience.

“There is currently no treatment in clinical use to either prevent the formation or the maturation of these lesions,” Awad said. “The way we deal with them now is we wait until a lesion gets bad or does something bad, and then we take it out.”

Awad and colleagues Douglas Marchuk from Duke University and Mark Ginsberg at the University of California, San Diego have used those familial CCM cases to find the cause of the condition, focusing on a gene called KRIT1 (or CCM1 for its clinical significance). By knocking down KRIT1, they could create a mouse model that formed CCM lesions, and study the cellular signals that accompany the condition. It turned out that reducing the activity of KRIT1 increased the activity of a signal called ROCK, which made CCM lesions leakier and more severe. CCM lesions removed surgically from human subjects by Awad also tested for high levels of ROCK, suggesting that the mechanism was the same across species.

So the obvious hypothesis to test was whether an inhibitor of ROCK could block the formation of CCM lesions. For a paper published yesterday in Stroke, researchers from the three laboratories performed the experiments in their mouse model of CCM, treating the mice for four months with a ROCK inhibitor drug called fasudil. When they compared the brains of these drug-treated animals to the brains of animals treated with a placebo, they found fewer lesions, smaller lesions, and a reduction in inflammation and hemorrhage after fasudil.

“This animal model and humans have lesions that are aggressive and symptomatic: They leak blood, they show inflammatory properties, and endothelial cells multiply or proliferate,” Awad said. “None of these features were present in the fasudil-treated mice. It was like the lesion was chilled down and shrunk.”

Though promising, this early experiment was performed in only a small number of mice. More extensive testing in animals - and if everything goes well, in human clinical trials - will be required before the drug can be deployed in the neurology practice. Fasudil is also not yet approved for use in the United States, though it is used in Japan for a different neurological condition and has been “clinically well tolerated” there, Awad said.

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Writing about science means looking up a lot of numbers. Trying to find a figure for the number of cells in the body or the protein-encoding genes in human DNA or patients diagnosed with ovarian cancer from 1980 through 1995 can eat up a lot of time and internet bandwidth. For some of these oft-cited numbers, there’s a mutually agreed upon estimate that science writers can drop into the articles, such as the 23,000 usually tossed around for the number of human genes. But it’s worth remembering that these figures are subject to change - after all, it was thought as recently as 10 years ago that there were 100,000 genes in human DNA.

A new counting kerfuffle broke out this week for yet another oft-cited scientific figure: the number of species on Earth. Last year, zoologist Robert May proposed in Science that the human race would be “embarrassed” should aliens show up tomorrow and ask how many different types of organisms live on our planet. Depending on the model used, one could argue for a number anywhere between 3 and 100 million eukaryotes, May wrote - and that doesn’t even count viruses and bacteria, which far outnumber the larger species.

But as the authors of the PLoS Biology article “How Many Species Are There on Earth and in the Ocean?” found out this week, picking a number within that range is hazardous territory. Using a mathematical model based on the roughly 1.2 million species we currently know about, the research team calculated a new estimate: approximately 8.7 million species from land and sea. Of those, only 14% of land species and 9% of sea species have so far been cataloged by humans, the authors concluded, and describing those remaining could take over 1,000 years and $364 billion. “Our results also suggest that this slow advance in the description of species will lead to species becoming extinct before we know they even existed,” they wrote.

Dramatic stuff, but what about the math? In Carl Zimmer’s article on the study for the New York Times, the first bubbles of discontent can be felt around the biology world, from fungi experts to entomologists who argue that the 8.7 million number is far too low. Scientists who study microbes were even less pleased with the mathematical model, which they said dramatically under-counted their favorite species. On his blog, Phylogenomics, microbiologist Jonathan Eisen pish-poshed the paper’s estimates of 10,000 prokaryote species: “I think without a doubt the number of bacterial and archaeal species on the planet is in the range of millions upon millions upon millions.  10,000 is clearly not even close.” Two other microbiologists wrote a letter to the Washington Post, pointing out that “a teaspoon of soil contains more than 10,000 species of bacteria.” For the time being, it looks like our alien visitors will have to be satisfied with the answer, “Lots.”

Elsewhere…

Speaking of the importance of bacteria and microbes, consider the discovery of antibiotic-resistance genes in 30,000-year-old bacteria from the Yukon Territory. Though these bacteria lived approximately 29,930 years before the discovery of penicillin, they possessed defenses against the naturally-occurring weapons scientists have seized upon to develop infection-fighting drugs. That long history means outsmarting drug-resistant bacteria may be even harder than scientists thought, and makes the case for even more selective use of antibiotics. “Bacteria share these genes like baseball cards with each other,” Stuart Levy at Tufts University told Nicholas Wade of the New York Times.

Has an important culprit in amyotrophic lateral sclerosis, aka Lou Gehrig’s disease, been discovered? The Medical Center’s Raymond Roos comments on a recent Northwestern University study.

On the blog, we’ve covered the link between sleep loss and testosterone, weight gain, and blood sugar. A new study from UCSD and Harvard now finds a connection between sleep quality and blood pressure. Our sleep research guru Eve Van Cauter commented on the research for TIME.

Just another reminder to check out the Medical Center’s new Facebook page, where this week you can find articles from the blog, information on the DNA Discovery Lab at the Field Museum, and President Sharon O’Keefe’s letter to the editor on hospital charity care. If you like it, please hit that “like” button!

To prepare for the grueling 2,200 miles of the Tour de France, cyclists train their muscles at both low and high altitudes. Riding at elevation does more than prepare them for the infamous mountain stages in the Alps, it has a biological effect, increasing the capacity of red blood cells to carry oxygen and improving how their muscles use energy. Though it may seem counter-intuitive, training in the low oxygen conditions found at high altitude is actually beneficial to an athlete’s muscular performance long-term. Could the same be said for another important muscle - the one located inside your skull?

That’s one implication of a new study from University of Chicago researchers on the relationship between the sleep disorder sleep apnea and strokes. Patients with sleep apnea suffer from repeated breathing “pauses” during the night, moments where their brain is briefly deprived of oxygen (known scientifically as “hypoxia”). One or two of these hypoxic episodes may not be dangerous by themselves, but cumulatively, they can be very harmful - sleep apnea has been associated with cognitive impairment, behavioral effects, and cardiovascular disease.

Indeed, sleep apnea increases the danger twice over for one especially serious vascular problem: stroke. Research indicates that patients with the disorder are more likely to suffer a stroke, and if a stroke occurs, it is more likely to cause severe brain damage than in people without sleep apnea. Both sides of this connection have been targeted by investigators from the Department of Pediatrics sleep research group at the University of Chicago Medical Center. In one recent study, led by David Gozal, chair and professor of pediatrics, and Richard Li, assistant professor of pediatrics, the researchers found a mechanism for why putting rats through “intermittent hypoxia” during sleep (an animal model of sleep apnea) can increase the risk of atherosclerosis, the hardening of the arteries involved in many cardiovascular conditions.

But another study, published last month in The Journal of Neuroscience, focused on stroke’s aftermath, testing whether the extra brain damage from a stroke in sleep apnea patients was due to the low-oxygen episodes or an associated risk factor such as obesity. A team led by Yang Wang, associate professor of pediatrics and director of basic research for the sleep medicine laboratory, again simulated sleep apnea in otherwise normal rats with intermittent hypoxia (IH), comparing them with rats that slept in normal oxygen conditions. When a controlled stroke was induced in each of these groups, the resulting damage was very different - the IH rats suffered more damage than controls, indicating a direct effect of hypoxic episodes upon recovery after stroke.

“It seems that something very bad is happening that affects the ability of the cells to survive or to recover after stroke,” Gozal said.

The researchers then focused on a possible mechanism for why intermittent hypoxia leads to more severe strokes, choosing energy metabolism as their primary suspect. When the brain is active - or trying to recover from damage - it needs a lot of fuel. As with the rest of the body, glucose is the first option for providing energy. But like muscles, a healthy brain can also use lactate as an alternative energy source in times of high demand. The gas pump for getting lactate into neurons is a protein called monocarboxylate transporter 2, or MCT2. Wang and colleagues looked at how intermittent hypoxia affected levels of MCT2 and how MCT2 levels affected the severity of stroke.

The pathway fell into place - exposing rats to IH decreased the expression of the MCT2 gene, while decreasing MCT2 activity through various methods increased brain damage after stroke. A transgenic mouse with elevated MCT2 was even created, and found to be protected against a stroke’s damaging effects. Thus, repeated hypoxia events during sleep could disrupt MCT2 and impair the brain’s ability to use lactate for energy - perhaps by “crying wolf” too many times. Gozal used the metaphor of a night watchman repeatedly running up the stairs for minor smoke alarms, only to be too tired to respond when the big fire starts.

“I think we have dissected in a very careful way, with a lot of work, the mechanisms that may explain why patients with sleep apnea are not only at increased risk of stroke, but also why when that stroke hits, they have a risk of not really recovering,” Gozal said.

The study also raised an intriguing idea about how to prevent this elevated sensitivity to stroke in sleep apnea patients.

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The odds of acquiring a disease are often portrayed as a tug of war between two foes: genes and environment. The battle is not always evenly matched. A disease such as cystic fibrosis is entirely genetic - if a child inherits the mutated CFTR gene from both parents, no environment will prevent the condition. On the other hand, environment can trump genetics for many other diseases, such as the relationship between exposure to the toxic substance arsenic and the cancer mesothelioma. But in most places, the tug of war is a more balanced contest, with the genetic factors controlling risk competing with a range of environmental factors from diet and exercise to education and climate.

Scientists have traditionally kept score on these competitions using a measure called heritability, the percentage of a phenotype (a disease or characteristic) that is determined by genetic factors. One way to measure heritability is with twin studies, which assemble data from thousands of pairs of identical or fraternal twins as a natural experiment of whether genes or environment win out. But a new study from University of Chicago psychiatry researchers shows that the blanket term of “environment” does not have to mean things outside the body - it can also refer to the biological state inside the body.

For the paper, published last month in Behavioral Genetics, a team led by post-doc Terrie Vasilopoulos set out to test the relationship between two health conditions: hypertension and cognitive decline. Previous research examining this link established hypertension as a risk factor for the loss of cognitive ability late in life, producing decreases in performance similar to those seen in Alzheimer’s disease and other forms of dementia. Meanwhile, heritability research revealed that genetics play a large part in a person’s risk of cognitive decline in their golden years. So does the “internal environment” of hypertension - and whether it is treated - move the tug-of-war of heritability for cognitive issues toward genes or environment?

To test this hypothesis, the team used data from the Vietnam Era Twin Study of Aging - over 1,200 male-male twin pairs who served in the military between 1965 and 1975. With an age range between 51 and 60, the researchers looked at an important time in a man’s cognitive lifetime before the first signs of dementia typically set in, Vasilopoulos said.

“We really think we are capturing a very important developmental period with the guys that we’re studying, especially for cognitive phenotypes,” said Vasilopoulos, a researcher in the laboratory of Kristen Jacobson, assistant professor of psychiatry. “The groundwork for these bad things that are happening to you later in life are being laid when you’re much younger. By finding these mechanisms early in life, we can start to figure out better game plans of trying to protect people and help people make smarter choices when younger so we don’t see these bad effects when they’re older.”

The men were divided into three groups: those with hypertension receiving treatment, those with untreated hypertension, and those without hypertension. On overall measures of cognitive ability, the three groups showed no differences in performance, suggesting that the researchers were indeed looking at an age before any noticeable decline begins. But when the heritability of different cognitive measures was examined, a relationship with hypertension and anti-hypertension medication emerged.

For two measures - episodic memory and visual-spatial ability - the heritability of how a person performed on the tests actually decreased in those with untreated hypertension, relative to the other two groups. That is, in men with high blood pressure not taking medication, the “internal environment” of the disease outweighed the influence of genetics on two early warning signs of cognitive problems.

“These are the two types of cognitive domains that are first affected by age-related cognitive decline,” Vasilopoulos said. “In Alzheimer’s disease or other types of neurodegeneration or just regular aging, those are the most affected or first affected. So we really think we are honing in on the mechanisms of why hypertension is bad for cognitive performance late in life.”

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Popular Mechanics typically offers step-by-step guides for changing your oil or building a bookcase. But in a recent feature they seriously upped the instructional ante with an “Extreme How-To” - How to Perform Open Heart Surgery. The expert chosen to guide their readers through this don’t-try-this-at-home process was Medical Center cardiac and thoracic surgeons Jai Raman and Shahab Akhter who helped develop a new technique in heart surgery called the “wrap procedure.” The surgeons do a great job of explaining how the surgery has changed over the years, particularly in the materials used for repairing the heart and sternum after surgery to speed recovery and decrease scarring. “You’ve got to get comfortable putting stitches into a beating heart,” is just some of the sage advice that Raman offers in the piece.

The end of the academic year always brings a bounty of teaching honors, voted on by medical students, residents, and faculty peers. For the 2010-2011 year, more than two dozen awards were handed out by the Pritzker School of Medicine, the Biological Sciences Division, and departments of the Medical Center. For an awards roundup from both sides of campus, visit this article at the University of Chicago News Site.

The pediatric cancer patients at Comer were treated to a celebrity visit last weekend, though their parents and staff may have recognized her more by voice than by sight. Delilah, the easy listening disc jockey known for her “Love Someone” radio dedications, visited families at Comer before making 3-year-old leukemia patient Atia Lutarewych her “Brave Child of the Week.” You can listen to her segment on the visit here [mp3].

Another inspiring story of pediatric cancer was told in the Chicago Tribune this week, focusing on 6-year-old neuroblastoma patient Theofanis Yianas. After Theo’s hair fell out from chemotherapy treatment, 30 friends and family members shaved their heads in solidarity with the young boy. Theo’s doctor, professor of pediatrics Susan Cohn, comments on the importance of support in a patient’s recovery.

What did St. Vitus’ Dance - the 14th century outbreak of weeks and months-long uncontrolled dancing across Europe - have to do with mirror neurons in the brain? UChicago psychologist John Cacioppo weighs in on this fascinating phenomenon for ABC News.

An interesting plan to create “mystery shoppers” for assessing the primary care shortage in the United States was revealed in the New York Times on Sunday, then disappeared by Tuesday after doctors bristled about “snooping.” The survey, which would have been conducted by the University of Chicago National Opinion Research Center, shows how far the administration will go to collect data on the current health care system…and how stiff the medical field’s resistance can be to being measured.

By Dianna Douglas

Darryl Williams got winded while running an annual 10K race in Oak Park in 1995. Puzzling, since he was in excellent shape. Over the next five years, he had irregular heartbeats and felt strange sensations in his chest. But none of the treatments his doctors tried made a difference.

Allen Anderson, associate professor of medicine and director of the Advanced Heart Failure Program, met Williams in 2000. The arrhythmia was becoming life-threatening. Anderson diagnosed Williams with sarcoidosis of the heart, an inflammatory disease, and began to treat him with medication.

Williams was determined to get better. He followed his doctor’s orders and took his medications, even when they had toxic side effects. “We were able to control it for 10 years,” Anderson said. “He did his part as well, by taking care of himself.”

But Williams’ sarcoidosis continued to grow. The disease, which affects about 18 people per 100,000 annually, spread to his liver. Soon his ailing heart and liver put serious strain on his kidneys. Anderson decided that his only hope was a new heart, liver and kidney. “He was in heart failure and liver failure. He was critically ill. He was going to die.”

The criteria to be considered for a three-organ transplant are stringent. “We have to be very careful about patient selection,” Anderson said. A heart, liver and kidney transplant is a massive surgery. “We have to pick patients who have a good chance of survival.”

Williams’ case was the subject of many multidisciplinary meetings, with hematologists, surgeons, nutritionists, psychiatrists, social workers, infectious disease specialists. “The fundamental question is: are you going to commit organs to this person?” said John Renz, professor of surgery and director of the Liver Transplant Program. “You have to look at all aspects of a patient. And you have to feel that you are committing that precious resource well.”

After multiple screenings, the team was convinced. At 55 years old, Darryl Williams didn’t have any other health problems that would complicate his recovery. He was always careful to follow his doctors’ instructions, and would likely keep taking his medications after a transplant surgery. And, as important as anything, he had a large family and community of friends to support him through the ordeal.

After three months of waiting in the hospital for the transplants, Williams was rolled into an operating room.

“It’s an extraordinary surgery,” said Valluvan Jeevanandam, professor and chief of cardiac and thoracic surgery. “People don’t do well after any open heart surgery without a good functioning liver,” he said. “The liver has to filter out toxins and promote coagulation. Similarly, a new liver won’t do well without a good heart.”

He compares multi-organ heart transplants to “walking a tight rope without a net under you.”

There are other pressures, too. After leaving the deceased donor, the heart is only good for about five hours. A liver can be transplanted for 18 hours, and a kidney can sometimes be good for up to 48 hours. So, the heart goes in first.

“From a technical point of view, all three surgeries have to be perfect,” Jeevanandam said. “The challenging thing is sewing in all three organs in an environment hostile to any transplant procedure.”

The heart transplant was over in about four hours, but the heart was struggling. “We had to maintain his heart until he could get his liver,” Jeevanandam said. The surgeons used inotropes to stimulate the heart and a balloon pump to keep oxygen flowing.

Then Renz and the liver transplant team took over. read more

Anyone with a video game console at home can simulate  a variety of occupations: airplane pilot, race car driver, baseball player, Old West zombie hunter. As technology improves, the experience that can be created for these tasks grows ever more accurate and immersive, causing some experts to wonder whether simulation can be used for actual education as well as vicarious thrills. In the aeronautics field, this is old news - pilots have been trained on flight simulators for decades, gaining experience on high-risk, low-frequency tasks such as landing a damaged plane on a river. But in medicine, the use of simulation has only started picking up speed in the last decade, employing a mix of high-tech and low-tech to prepare doctors and nurses for both the usual and unusual.

In their Department of Medicine Grand Rounds presentation last week, Ernest Wang and Morris Kharasch from our partners at NorthShore University HealthSystem described the current state of simulation in medicine on the eve of their state-of-the-art simulation center’s grand opening. But while the idea might sound modern, it’s actually been around for more than 40 years, as Wang illustrated using a clip from the 1972 film Future Shock, narrated by Orson Welles.

Welles’ portentous warnings were a bit premature, it turned out. Never mind the leap from medical simulation dummy to humanoid robot, a generation would pass from when the first dummies were engineered in the late 1960’s before the broader field would accept simulators as a valid training tool for doctors.

“It looked pretty much what our current high-fidelity simulators look like, but didn’t have traction,” said Wang, a clinical associate professor at NorthShore. “There’s a Chinese saying: ‘When the student is ready the teacher will appear,’ and clearly they were too far ahead of their time and the conditions weren’t right.”

However, since 2000 the use of simulation in medicine has gathered momentum. A wide range of technologies are currently used for teaching sessions, from complex simulation environments that fully recreate the experience of being in an operating room to computer programs and table-top gadgets that rehearse medical decision-making and the performance of specific tasks. Medical simulation has grown to the point where a new specialty - the simulationist - may need to be created, Wang said.

“This would be a practitioner of simulation, who takes a recipe of clinically important cases, lessons learned from other industries, computer-driven full body simulators, realistic task trainers, and a dash of theater, to create a memorable learning experience that can be transferred directly to patient care,” Wang said. “In the end, that’s what this is about: education and patient care.”

Winning acceptance for medical simulation involves proving its success and determining its most effective uses. At the NorthShore center, educators have focused on designing simulation courses around “high-liability, low-frequency” events, said Kharasch, clinical director of the Center for Simulation Technology & Academic Research. The students in these courses might be residents encountering these situations for the first time, or older doctors who need a refresher on tasks they haven’t performed in many years before serving as an attending on the wards or in the emergency room.

“We’ve learned that as the years go on after you come out of residency, you are less able to do things that you once did as residents,” Kharasch said. “We spend a lot of time training on simple tasks that can be life-saving.”

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A Magic 8-Ball for Cardiac Arrest

Cardiac arrest is one of the most common ways that people die, and hospitals need to be constantly vigilant about the threat of heart stoppage in their patients. So physicians have long sought to develop a way of predicting who is most at risk for cardiac arrest when checked into the hospital, such that extra care and surveillance can be taken. At the 2011 international meeting of the American Thoracic Society, held this past week in Denver, two Medical Center fellows presented research refining these early warning systems to make them a more effective hospital tool.

In the first study, pulmonary and critical care fellow Gordon E. Carr connected cardiac arrest with another frequent sight on the hospital ward: pneumonia. Carr’s study found that patients admitted with pneumonia are at elevated risk of cardiac arrest over the next three days after admission, and that almost 40 percent of these cardiac arrests occurred while the patient was outside of the intensive care unit. “We found a compelling signal that some patients with pneumonia may develop cardiac arrest outside of the ICU, without apparent shock or respiratory failure,” Carr said in a press release. “If this is true, then we need to improve how we assess risk in pneumonia.”

Adding extra caution about cardiac arrest to the care of patients with pneumonia is a specific way to improve surveillance. But to apply to more patients, a broader scale is needed, one that can be easily assembled from the vital signs that are already routinely measured in the wards. One such scale, called the Modified Early Warning Score or MEWS was tested by pulmonary and critical care fellow Matthew Churpek as a predictor of cardiac arrest, who found it to be better at predicting a cardiac arrest in the next 48 hours than any individual vital sign. But MEWS was designed for general risk of death, not specifically for cardiac arrest, and Churpek suggested a more specialized risk score could be calculated for use by hospitals. The benefits of such a measure, he said in a press release, would be immense.

“Rapid response teams are a complex and resource-intensive intervention, so providing evidence-based criteria for their activation is crucial,” Churpek said. “Our patients will do better if we can detect who is at high risk early enough to intervene and prevent a cardiac arrest.”

Doctors Against Ronald McDonald

Childhood obesity is a growing problem in the United States, and doctors point the finger of blame directly at increased consumption of junk food and fast food. Chains such as McDonalds have made noise about making their food healthier, especially for children, by posting calorie counts on menus and offering snacks such as apples and carrots instead of fries. But according to an open letter signed by over 500 health care professionals and placed in newspapers around the country this week, they have not done enough.

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Kristen Knutson, PhD, recently added to the growing body of research from the University of Chicago on the long-term consequences of skimping on sleep. She found that diabetics who sleep poorly have a harder time controlling their insulin and glucose levels than diabetics who sleep well. The research was published in the journal Diabetes Care. We conducted an extended interview with Kristen Knutson about her research, and below are some of the highlights.

Q: Why study diabetes and chronic sleep problems?

A: Many of our laboratory studies, led by Dr. Eve Van Cauter, have shown that restriction of sleep is associated with alterations in glucose metabolism. Usually, these lab studies are a week. But we wonder about the long-term effects of being a chronic short sleeper.

We think that chronic poor sleep could put people at risk of many health problems, including diabetes.

Q: How did you design your study?

A: We used data from an epidemiologic study called CARDIA (coronary artery risk development in young adults). It started in 1985, and has been going on for more than 20 years.

We gave the participants wrist activity monitors—it’s like a wristwatch that measures the subject’s sleep duration. The participants wore the activity monitors for three nights in a row. A year later, they wore the monitors three more nights. So we had a total of six days of data.

We also asked them about their sleep. Did they wake up frequently during the night, three or more times per week? Did they have trouble falling asleep?

To get the measurements of their fasting blood glucose and fasting blood insulin, we used the data from the CARDIA study, in which the participants gave fasting blood samples. Their fasting blood glucose and insulin give us an estimate of insulin resistance.

Q: Explain your most striking findings, especially with the diabetics who slept poorly.

A: We saw more significant associations between measures of sleep and glucose metabolism markers in the patients with diabetes. In particular, we saw that poor sleep quality was associated with higher fasting glucose and greater estimated insulin resistance. So poor sleep quality meant worse control of their blood glucose levels.

Also, we separated people with and without insomnia. Among the people with type 2 diabetes, those who also had insomnia had worse glucose levels and greater estimated insulin resistance. That suggests that it’s not just sleep duration that’s important, which laboratory studies have shown. But sleep quality is important as well.

The data show that people with diabetes who are poor sleepers will have a more difficult time controlling their glucose levels.

Q: Does this mean that sleeping poorly makes diabetes worse?

A: It could go the other way. It could be that people who are having trouble controlling their glucose will have more complications, more pain, more need to get up in the middle of the night to urinate, and therefore they’re not sleeping as well. What we need to do now is find people with diabetes who aren’t sleeping well, and see if improving their sleep also improves their glucose metabolism.

This study is observational, but suggests that there is a relationship between poor sleep and controlling glucose. We don’t know which factor leads to which outcome. read more

Today, nearly everyone is aware of the dangerous health effects of smoking cigarettes. Even fewer people would deny the harmful effects of drinking water contaminated with arsenic. But when these two toxic influences are mixed together, is the sum of their damage more than the individual effect of each? To put it another way: for a person in an area with low, “safe” amounts of arsenic in the groundwater smokes, is their risk of disease increased as though they were drinking unsafely contaminated water?

To study this question, University of Chicago epidemiologist Habibul Ahsan returned to his project studying the consequences of accidental arsenic exposure in the people of Bangladesh. Ahsan’s Health Effects of Arsenic Longitudinal Study (HEALS) has tracked thousands of Bangladeshi citizens who unknowingly consumed well water with high levels of arsenic after health organizations installed wells to reduce water-borne infectious disease. That study, which has expanded to 20,000 subjects, discovered a 70 percent higher risk of death from chronic disease in those drinking water with the highest levels of arsenic. Even people exposed to moderate levels of arsenic, amounts that can be found naturally in some regions of the United States, were at a 20 to 30 percent higher risk of dying from chronic disease.

Ahsan and his team from UChicago, Columbia University, New York University, and Bangladesh, looked at whether the combination of arsenic exposure and smoking made the odds even scarier on one particular mortality endpoint: cardiovascular disease. While arsenic is traditionally thought of as causing different types of cancer and skin lesions, chronic exposure can also produce various heart and circulatory problems such as hypertension and atherosclerosis. Previous studies of these cardiovascular effects have been small, retrospective, and focused on extremely high exposures in Taiwan and Chile. With the Bangladesh study, Ahsan and colleagues could look at a broader spectrum of exposure, and follow subjects carefully over time to isolate the effect of arsenic from other factors.

For the study, published last week in the British Medical Journal, the researchers tracked nearly 12,000 Bangladeshis, taking urine samples to measure arsenic exposure and registering the cause of death in those who died over the time they were tracked (an average of 6.6 years). Overall, 460 subjects died, with nearly half of those (198 people) dying from some form of cardiovascular disease. Associating those deaths with arsenic exposure confirmed the Taiwan and Chile studies on people exposed to high concentrations (as high as 80 times the safe limit of 10 parts per million) of the toxin. But a worrisome trend also emerged for more moderate exposures, with a 50 percent increase in cardiovascular mortality risk observed at levels as low as 2.5 times the safe limit.

“We were able to show that, even at lower doses than previously reported, there seems to be a deleterious effect of arsenic regarding cardiovascular disease mortality, particularly from ischemic and other heart diseases,” Ahsan said.

For those subjects who were smokers - even those who had quit - a deadly synergy emerged. For a current smoker exposed to the high levels of arsenic, the increased risk of dying from cardiovascular disease jumped from 50 percent to 328 percent. Former smokers saw a lower bump in risk, but if exposed to moderate levels of arsenic, they shared the same risk as those exposed to high levels that had never smoked. Ahsan said that the result emphasized the importance of targeting multiple risk factors in improving public health around the world.

“This tells us that there are some individuals who are dying from cardiovascular disease solely because of the presence of both factors, not because of the presence of one or the other,” Ahsan said. “It’s one more reason to pay attention to arsenic exposure, but yet another reason that will underscore the importance of smoking cessation.”

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Late last year, we relayed the announcement of an exciting new academic program here at the University of Chicago, the Institute of Molecular Engineering. At the time, the IME had a future home (sharing the new William Eckhardt Research Center with the Physical Sciences Division) and a vision, but did not yet have a leader. Yesterday, that crucial headpiece was officially put in place, as biomolecular engineering and nanotechnology expert Matthew Tirrell was named the first Pritzker Director of the IME.

Tirrell will come to UChicago from California, where he has spent time at the University of California campuses in Berkeley and Santa Barbara over the last 12 years. His research specialty is the surface properties of polymers, chains of molecules that can be manipulated for building better materials used for everything from energy to technology to medicine. Those versatile aspirations make Tirrell the perfect leader for the IME, where the mission is to bridge disciplines at UChicago and Argonne National Laboratory and bring the tools of biology, chemistry, engineering, and physics to bear on finding solutions to some of science’s most important challenges.

“This isn’t going to be directed narrowly toward one scientific discipline, but at creating an institute that attacks societal problems from a technological viewpoint,” he said in the official announcement. “Many important societal problems in energy or health care or the environment can be addressed by new molecular-level science. When you are trying to solve problems, you need people from different kinds of disciplines. That’s something the Institute for Molecular Engineering can create right from the beginning.”

In his nearly 300 scientific publications, Tirrell has often studied and discussed how the surface properties of polymers are important for the success of biomaterials. Materials “communicate” with their surroundings through their surfaces, and designing new synthetic devices for technological uses requires a firm grasp on this process. As a result, bioengineers have taken inspiration from how natural materials such as mollusk shells and animal tissue solve surface compatibility problems to understand these interactions on a molecular level.

One application of that accumulated knowledge about biomaterials is novel solutions to clinical problems. In a phone interview Monday with ScienceLife about the biomedical goals of the IME, Tirrell talked about how these new technologies will not be merely passive construction materials, but active biological compounds.

“There are going to be ways of using biology not only to make things but also to do things,” Tirrell said. “Therapeutic organisms can be engineered with the tools of modern biology: living devices, if you will, as well as man-made devices.”

One example from Tirrell’s own research career expands upon designing living machines as a sort of multi-functional Swiss Army knife for diagnosing and treating diseases such as cancer and cardiovascular disease. A 2009 paper, published in Proceedings of the National Academy of Sciences, used a self-assembling lipid sphere called a micelle (pictured at right) to target the fatty plaques that form in blood vessels during atherosclerosis. When those plaques rupture, dangerous clots can form and  block blood vessels. To treat those clots, physicians currently prescribe blood thinning drugs that can produce unwelcome side effects, because the drug is not specifically targeted to the clot and acts throughout the body.

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