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

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

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

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

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

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

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

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

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

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

read more

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

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

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

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

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

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

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

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

read more

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!

By Matt Wood

Each day people make decisions about how much effort they’re willing to put into various tasks. The decision about how much effort to invest in an activity is influenced by the reward for doing something and the probability of actually getting it. You might be willing to work hard at your job because the reward—a paycheck—is both valuable and fairly certain. But you might not be willing to try a complicated new recipe for dinner, even though it sounds delicious, because of the chance that it won’t turn out well.

Animal studies suggest that the neurotransmitter dopamine plays an important role in this type of decision-making, especially the decision to expend effort. In rats, dopamine levels influence tolerance for effort and probability costs. Rats with higher levels of dopamine are more willing to press levers and climb over barriers to reach better food, whereas those with lower levels will settle for food that’s less tasty but within easy reach.

Little is known about how dopamine affects effort-based decision-making processes in humans. But a new study published in The Journal of Neuroscience by Margaret Wardle, a post doctoral researcher in the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago, her mentor Harriet de Wit, Professor and Director of the Human Behavioral Pharmacology Laboratory, and colleagues at Vanderbilt University shows for the first time that people behave in much the same way. Their research, sponsored by the National Institute on Drug Abuse, not only sheds light on how dopamine influences decision-making in humans, but also points toward possible treatment for psychiatric disorders like depression.

read more

By Rob Mitchum

A surgical procedure is a daunting experience for any patient, though thanks to general anesthesia, it’s not typically a memorable one. That’s not the case for patients who go through an awake craniotomy — a unique procedure that allows surgeons to react based on feedback from the patient during removal of a brain tumor.

“I remember them waking me up using a flashlight and talking to me,” Anna Litchfield, a 49-year-old patient who was operated on by Maciej Lesniak, MD, Professor of Surgery and Neurology, said in August. “I remember Dr. Lesniak saying ‘Anna, are you OK?’ and I remember saying ‘Great, Dr. L!’ out of nowhere. I never thought I’d call him Dr. L! In retrospect, I feel like my brain was thrilled that he was there operating.”

Awake craniotomies are unique, complex procedures typically used to remove tumors nestled close to functional areas of the brain. Though the macabre nature of the surgery might induce shudders, the benefits for the patient are great. As the tumor is carefully removed by the surgeon, a neurologist can continuously monitor the patient’s language, motor and sensory function to make sure critical parts of the brain suffer minimal damage.

“When tumors are in what we call eloquent, functional areas, the margin of error is a millimeter,” Lesniak said. “You have to ask yourself whether you feel comfortable with a patient being asleep, potentially missing that millimeter while taking out the tumor and having them wake up devastated, or minimizing that risk.”

Lesniak and his team at the University of Chicago Medical Center perform more awake craniotomies than any other group in the Chicago area — more than 30 each year. Each surgery utilizes a truly interdisciplinary and experienced team of neurosurgeons, neurologists, anesthesiologists and operating room nurses who must collaborate to ensure the unusual surgery’s success. Often, craniotomy candidates are referred to Lesniak from hospitals around the area and country, as the surgery can be performed only by individuals with significant expertise and experience.

read more

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

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

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

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

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

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

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

read more

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.

read more

Finding the cause and the cure for a deadly disease is a little bit like investigating a murder. Clinicians collect clues from their patients, bring them back to the lab, and try to reconstruct the crime and identify the killer. For amyotrophic lateral sclerosis (aka ALS or Lou Gehrig’s Disease), this investigation has lasted over a hundred years - since neurologist Jean-Marie Charcot first described the disease in 1874. But it’s only in the last two decades that ALS researchers have started to find major breaks in the case, revealing genetic clues to the origin of this deadly neurodegenerative disease. At a special ALS gathering at the University of Chicago, Medical Center neurologist Raymond Roos told nearly 200 patients and caregivers that the case may finally be cracked soon.

“I think the field is on fire now,” said Roos, the Marjorie and Robert E. Straus Professor of Neurology. “I think it’s astounding and exciting what’s going on with respect to neurodegenerative diseases and absolutely ALS. We have all these things piling up now and we are continuing [to look]. Should we be optimistic about the future? Yes.”

Wednesday’s gathering, put together by the Greater Chicago Chapter of the ALS Assocation, was a unique two-part event featuring both a symposium for researchers of the disease and a luncheon/health expo for the patients and their families. In one room of historic Ida Noyes Hall, 14 Chicago scientists studying the origins of ALS and developing new treatments for what is currently an incurable disease shared their latest results. Meanwhile, patients and their families learned about medical devices and advocacy opportunities, and shared stories of how they cope with their disorder.

The day’s scientific component demonstrated both why the ALS investigation has taken so long, and why Roos thinks there is cause for optimism. The central mystery of ALS is why it selectively targets the motor neurons of the nervous system, the extremely long cells that deliver instructions from the brain to the muscles of the body. As the motor neurons die off, the patient experiences a progressive paralysis, losing the ability to maintain balance, walk, and eventually, breathe. Figuring out what causes this specific population of neurons to perish will point the way to treatments that slow or even reverse the progression of the disease.

For suspects, scientists have looked to genes. Roughly 10 percent of ALS cases are inherited through generations of families, indicating a genetic cause. While this population might be only a small minority of cases compared to the more common “sporadic” cases, they could be a foothold along the path to understanding both types of ALS.

“Those are very important even though they make up this small group, because they open a window,” Roos said. “If we can identify the gene that’s mutated, we can figure out what the function of that gene is. The hope and assumption and, I think, the reality, is that information will guide us into understanding the non-inherited, sporadic form.”

In 1993, scientists discovered the first ALS-associated gene/suspect, called SOD1. Though mutations of this gene explain only 20 percent of the familial 10 percent, they have been an important clue into exactly what goes wrong inside a motor neuron during the disease’s tragic march. The morning’s sessions zoomed in on these details, describing how a faulty SOD1 can kill off a cell through to the aggregation of cellular proteins, the interruption of the cell’s highway-like transport system (presented by UIC’s Gerardo Morfini and Scott Brady), and the creation of a “toxic channel” (as told by UCMC’s Michael Allen). The damage caused by SOD1 mutants might not even be limited to the motor neurons themselves, as Roos presented research demonstrating its toxic activity in the cells surrounding those neuronal types.

The path from what goes wrong to the creation of new potential therapies for ALS was explained by Richard Silverman, a chemist from Northwestern University. By screening for compounds that prevent the type of protein aggregations observed in the motor neurons of ALS patients, chemists hope to design new drugs that will slow the damage and hopefully, the physical symptoms they produce. Silverman detailed the incremental design of two new compounds in his laboratory that, in animal studies, produce an extension of life that is two to three times longer than seen with the only drug currently approved for use in ALS, riluzole.

read more

What made the human brain? According to Stanley Kubrick and Arthur C. Clarke, it was a giant obsidian monolith inspiring primates to use tools and weapons. Scientists have taken a more nuanced approach, looking for the biology behind the complex structures and enhanced function of the human brain. But merely comparing the genes expressed in adult human brains to those of other animals yielded few promising differences, leading scientists to focus on changes in the regulation of old genes rather than the arrival of new genes. After all, the construction of a structure as important as the brain cannot rely on unpredictable, novel genes with new functions, right?

However, those young genes are recently taking on a higher profile. In a 2010 paper, the University of Chicago laboratory of Manyuan Long demonstrated that new genes exclusive to a given species can be just as critical to an organism’s survival as the old, conserved genes it shares with other species. The implication at the time was that what makes us uniquely human could lie in those “young” genes that only appeared in our genome relatively recently.

“Animal models have proven to be very useful and important for dissecting human disease,” said Sidi Chen in 2010 about that study. “But if our intuition is correct, some important health information for humans will reside in the unique parts of the human genome.”

A new study from Long’s lab appearing yesterday in PLoS Biology identifies one important place where those new genes may play role: the human brain. By merging a database of gene age with gene transcription data from humans and mice, researchers looked for where young genes specific to each species were expressed.They found that a higher percentage of primate-specific young genes were expressed in the brain compared to mouse-specific young genes. Human-specific young genes also were more likely to be expressed in uniquely human brain structures, such as the neocortex and prefrontal cortex.

“Newer genes are found in newer parts of the human brain,” said Yong Zhang, PhD, postdoctoral researcher and first author on the study. “We know the brain is the most remarkable difference between humans and other mammals and primates. These new genes are a candidate for future studies, as they are more likely to underlie this difference.”

Another intriguing finding in the gene age data was inspired by Zhang’s visit to the obstetrician with his pregnant wife. While viewing an ultrasound of his unborn child, Zhang said he realized that much of human development takes place during fetal stages - suggesting those early months should be a critical time for gene expression. As predicted, young human-specific genes in the brain were more likely to be turned on during fetal or infant development.The early activity of these genes suggests scientists should be looking at earlier developmental stages for genetic activity that ultimately shapes the complexity of the human brain.

“What’s really surprising is that the evolutionary newest genes on the block act early,” said co-author Patrick Landback, a graduate student in Long’s laboratory. “The primate-specific genes act before birth, even when a human embryo doesn’t look very different from a mouse embryo. But the actual differences are laid out early.”

read more

Biology used to be the scientific discipline where data was at a premium, a rare resource painstakingly collected in the field or the laboratory. But today’s biologists are confronted with a flood of data, a fire-hose torrent of genetic and clinical information that only builds with the spread of fast sequencing and electronic medical records. But as these databases fill terabyte after terabyte of computer storage, the successful transformation of that data into practical information about human biology and disease has lagged behind. Genome-wide association studies (GWAS) have  explained only a small percentage of disease heritability, clinical records remain largely unstudied on a large scale, and the complications created by environmental influences and multi-gene disorders have frustrated scientists.

Into this impasse comes a new multi-institutional project based at the University of Chicago: the Silvio O. Conte Center, funded by a nearly $14 million combination of grants from the National Institute of Mental Health and the Chicago Biomedical Consortium. Led by Andrey Rzhetsky, professor of medicine and human genetics at the Medical Center, the collaboration of 15 scientists from 7 institutions will apply the power of advanced computation and data-mining to the growing tide of data collected about neuropsychiatric disorders. The trick will be to not just focus on one database, be it genetics or environmental factors or clinical outcomes, but all of them at once, creating a higher-resolution image of what goes awry in the brain to cause mental disease.

“A great deal of data already exists, yet nobody is already looking at it the way we plan to do and we have very smart people on this team,” said Rzhetsky, who is also a senior fellow of the Computation Institute at the University of Chicago and Institute for Genomics and Systems Biology. “When you have multiple communities that partially study the same subject you can get a kind of three-dimensional picture of a phenomenon.”

Rzhetsky has previously demonstrated the promise of data-mining - the discovery of patterns and information in large pools of data - using clinical records and scientific literature. In a 2007 study, his team examined 1.5 million patient records and found significant overlap between mental disorders such as schizophrenia, bipolar disorder, and autism, suggesting a similar overlap of the genetic factors that cause these conditions. Two years later, Rzhetsky and colleagues applied text-mining computation to the scientific literature database PubMed, creating a network of genes and biological interactions associated with cerebellar conditions such as ataxia and degeneration.

Beyond demonstrating the potential of data-mining, those studies also shed light on the hazy borders separating different psychiatric disorders. While the overlaps could complicate psychiatric diagnosis in the clinic, they might also make the disorders susceptible to the multi-faceted approach proposed by the Conte Center.

“Most studies are done one disorder at a time, and that’s like studying the trunk or the hoof or the tail of an elephant; you might miss the big picture,” said Benjamin Lahey, Irving B. Harris Professor of epidemiology at the University of Chicago and a co-investigator at the Conte Center. “This project will enable us to look at things in a way that has never been done before, at a scale that dwarfs anything that’s ever been done.”

read more

A visit to any casino will quickly demonstrate how vices clump together. At any hour of the day or night, many of the customers sitting intently in front of a slot machine will also be smoking cigarettes or drinking a cocktail. Sadly, addictions to these pursuits also tend to go hand in hand, with higher rates of compulsive gambling observed in people addicted to drugs such as cocaine and alcohol. Furthermore, when people perform gambling-like tasks while their brain is scanned by an MRI machine, the games activate areas of the brain also stimulated by drugs of abuse - perhaps accounting for the addiction-like behavior of gamblers.

“If you’ve ever been to a casino, and you watch people using slot machines, you’ll surely have noticed the sense of compulsion to put the next coin in, even though you get no money back most of the time,” said Paul Vezina, professor of psychiatry and behavioral neuroscience at the University of Chicago.

But does one bad habit truly lead to the other? In a recent paper for the journal Behavioural Brain Research, a team from Vezina’s laboratory offers evidence that the unpredictability crucial to gambling’s appeal can cross over to enhance the effects of abused drugs. By adapting self-administration, a common tool used to model drug-taking in animal research, to partially replicate the random pay-off of a slot machine, graduate student Bryan Singer was able to test whether gambling-like behavior influences a rat’s subsequent response to the drug amphetamine. The result suggests that gambling may have properties similar to a “gateway drug,” as an activity that can increase the abusive potential of drugs.

First of all, how do you simulate the casino experience for a rat? Self-administration - where the animal presses a lever to receive a food or drug reward - is fairly similar to a slot machine to begin with. In a self-administration protocol, the researcher sets the number of lever presses required before the reward is given. A “fixed ratio” of 5 means that the rat would have to hit the lever five times before receiving a food pellet or rewarding hit of cocaine. But with a “variable ratio” setup, unpredictability is introduced into the process. If the variable ratio is set to an average of 5, anywhere from 1 to 10 presses might be required to produce reward, a figure that changes every time like the random number generator of a slot machine. So while the rat does not have anything at stake other than the physical work it takes to hit the lever, it never knows when it will hit the “jackpot.”

“One of the main differences is that for a slot machine there’s a good chance you’re going to lose money, but here there’s little negative aspect,” Singer said. “It’s like a very loose slot machine.”

In this experiment, Singer and co-author John Scott-Railton used the non-caloric sweetener saccharine as a reward - a sweet treat that rats will work to acquire without ever getting full or intoxicated. For 55 days, half of the rats worked for saccharine under fixed ratio conditions and half worked under the variable ratio setup. Then, after a two week break, each rat was given a small dose of amphetamine, and researchers measured their activity as the dosed rats ran around their cage.

Even though the rats in each group received the same amount of saccharine and did the same amount of work during their lever-pressing careers, those exposed to the random rules of the variable ratio exhibited a stronger response to amphetamine. The result suggests that unpredictable rewards may prime the same brain areas hijacked by drugs of abuse, producing a stronger behavioral response - known in the field as sensitization - even upon first exposure to a stimulant drug.

“What this paper is showing is that unpredictable conditions may cause sensitization,” Vezina said. “There are activities that may play just as important a gateway role as drugs, and gambling may be one of them.”

read more

How do you know an animal model of a disease is really working? Researchers can create diseases such as cancer in a rat or mouse, but a tumor in a rodent may not behave the same way as a tumor in a human being. The challenge is even more difficult when scientists try to model psychiatric conditions, which in humans rely upon interviews and nuanced diagnosis. It’s hard to get a rat to stay on a therapist’s couch, much less ask whether they are feeling depressed or anxious.

So psychiatrists interested in using an animal model to probe the underlying biology of a mental condition are forced to be careful, clever and realistic. For a new model of obsessive-compulsive disorder (OCD) published last week by a team of scientists from the University of Chicago, the validity of the model was based on both the symptoms they observed in their animals and how those symptoms were treated.

More than 2 million people in the United States have been diagnosed with OCD, a condition marked by severe anxiety, repetitive behaviors, and intrusive thoughts. Yet only one drug has been found to help alleviate these symptoms - fluoxetine, a serotonin reuptake inhibitor originally developed for the treatment of depression - and the drug is only effective in roughly half of all OCD patients. Finding and testing better treatments for OCD will require animal models of the disease.

“Treatment for these people is greatly needed, and there really are very few highly valid animal models of the disorder,” said Nancy Shanahan, a postdoctoral researcher and lead author of the study in the journal Biological Psychiatry. “Having one that seems to mimic the disorder so well, especially in terms of the time course of treatments that work in humans, is potentially very useful for researching novel therapeutics.”

That’s easier said than done. The compulsive hand-washing, switch-flicking, or counting habits of human OCD sufferers would seem to be impossible symptoms to replicate in a rat, but some characteristics such as perseveration (repetitive movements or actions) and movement in an open field (a marker of a rodent’s comfort or anxiety in a strange environment) have been used by scientists as proxies for the debilitating effects of OCD. Some groups have created these behaviors by deleting genes, but for the new OCD model the UChicago team started with the unusual side effect of a migraine medication.

When the drug sumatriptan is given to people with OCD, it amplifies their symptoms, producing more intrusive thoughts and rituals. Shanahan gave her mice a similar drug that, like sumatriptan, activates a sub-class of receptors for the neurotransmitter serotonin called 1b receptors. In response, the mice showed behaviors that could be interpreted as OCD-like. Instead of exploring the entirety of their cage, they stayed close to the walls (as seen in the paths above) - a marker of high anxiety. Another test called prepulse inhibition that tests the animals’ startle response (thought to measure the brain’s ability to filter out intrusive thoughts), also revealed OCD-like behavior after the serotonin 1b drug was given.

Yet it’s still subjective to say that a mouse that paces around the walls of its cage is suffering from the same underlying biological issues as a human whose anxiety keeps them from leaving the house. More evidence was needed to prove the model’s “predictive validity” - how closely it resembles the human disease.

“A model should be evaluated on its ability to predict, not based on how much it looks like OCD,” explained Stephanie Dulawa, assistant professor in the Department of Psychiatry and Behavioral Neuroscience and senior author of the study. “The best way to do that is to evaluate manipulations with known effects in OCD.”

read more

By John Easton

Let’s start with a statistic: almost 2,000 citations a year. One paper by Paul Meier, the Ralph and Mary Otis Isham Distinguished Service Professor emeritus of statistics, pharmacological and physiological sciences, medicine, and the college, has been cited more often, by a wide margin, than any other paper in the field. At last count it was the fifth most cited research paper of all time, in any field. With about 34,000 citations to date, Kaplan, E. L., and Meier, P. (1958), “Nonparametric Estimation from Incomplete Observations,” has been cited by another scientific publication about once, on average, for every day of Meier’s long life—he was born in 1924—and still counting.

Sadly, however, that ratio can only increase. Citation counting will continue, but the numbering of days stopped on Sunday, August 7th, when Professor Meier, a world-class statistician who made “extraordinary contributions to statistics and to society,” according to Columbia University - and everyone else - passed away peacefully at his Manhattan home.

The Kaplan-Meier estimator is used ubiquitously in medical studies to estimate and depict the fraction of patients living for a certain amount of time after treatment. This is not as simple as it sounds. Survival curves are complicated by the uncooperative way in which research subjects often behave. Some leave a study part of the way through. Others elect not to die before the study ends. These are known as “censored observations.” The Kaplan-Meier estimate is a simple way to compute the survival curve despite such troublesome behavior.

There was almost a Kaplan estimator and a Meier estimator. Each had submitted a separate manuscript to the Journal of the American Statistical Association, but the editor recommended that their papers be combined into one. It took them four years. “At one place he solved a problem that I couldn’t solve,” Meier later recalled in an interview [pdf]. “Other places I solved problems he couldn’t.” Finally published in 1958, it was only cited 25 times over the next ten years. Then, boosted by statisticians’ increased computing power, it caught on. It has since been applied to data from clinical trials of therapies for every disease from cancer to cardiology to concussion.

Friends and colleagues point out that this was only one of Meier’s fundamental contributions. He published many more studies, was a persistent and outspoken advocate for randomization in clinical studies, helped design some of the 20th Century’s most important clinical trials and trained many of the leaders in the field.

“Paul was a friend and colleague as well as one of the most influential statisticians of an important era,” recalled Stephen Stigler, the current chair of statistics at the University of Chicago. “He left an indelible mark on us, and through his research on the world’s clinic analytical practice. He will be missed and cannot be replaced.”

“I have been so fortunate and privileged to know this truly great, wonderful, helpful, kind man who was always so generous with his skills and wise advice,” said toxoplasmosis expert Rima McLeod, professor of ophthalmology and visual sciences at the University. “He is one of the founding fathers and giants of statistics in the past century. He was at the same time simply a modest, helpful, supportive and warm colleague who only let you know how special he was by the quality and content of what he said and wrote.”

read more