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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By Rob Mitchum

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Last week, we brought you exclusive video from the rehearsal space of Turnover Time, the band of Medical Center employees formed to raise money for David Song’s relief efforts with Medical Aid for Children in Latin America. The band’s big debut took place at the Lend an Ear fundraiser Saturday night at the University of Chicago International House, and by all accounts, it was a roaring success. The event raised nearly $25,000 for the annual trips led by Song to the Dominican Republic to reconstruct ears and repair cleft palates, with an additional $17,000 donated via the MACLA website (where you can still make a donation). In exchange for their philanthropy, the standing-room-only crowd at the fundraiser was treated to two sets of music from Turnover Time, excerpts of which appear below. Enjoy the tunes!

Turnover Time is Shahab Akhter (drums), John Alverdy (keys), James Anderson (vocals), Kevin Johnson (vocals), Jeff Matthews (guitar), Joan Matthews (bass), Jono Matthews (guitar), Sarah Pae (vocals), Nikki Phillips (vocals).

Two weeks ago, we talked to Richard Cook by satellite phone when he was still in the field hospital in Fond Parisien with the first six-member team from the University of Chicago Medical Center’s Haiti relief effort. Cook, professor of Anesthesia & Critical Care, is remarkably eloquent about his experience in Haiti, whether in that sobering interview (”It is astonishing how many injuries we are seeing,” he reported then) or in front of the Medical Center’s monthly leadership forum, where his 20-minute presentation Wednesday was deeply moving. John Easton interviewed him earlier this week, and though Cook has been fighting a cough since returning from his two weeks of volunteering, he still was full of insight and emotions about the experience. I’ve edited the conversation down to two videos, which you can watch below. The first video contains photographs from the Fond Parisien camp taken by Justin Ide of Harvard University and Christian Theodosis from the Medical Center. In the second video, you’ll see two short video clips filmed by Theodosis of the pharmacy constructed from scratch in the field hospital by the Medical Center’s Dima Awad. 

Meanwhile, the second team is nearing the end of their two-week stint in Fond Parisien and Port-au-Prince. Pictures and updates from that team are being continuously posted at the Haiti Relief blog.

photos by Christian Theodosis

One week after two medical teams from the University of Chicago traveled to the earthquake-ravaged nation of Haiti, the situation remains critical. In a conference call Monday from the field hospital camp in Fond Parisien, where a six-person Medical Center team, including physicians, nurses and a pharmacist, are stationed, Haiti team co-leader Christian Theodosis gave a sobering reminder that the nation’s recovery is only beginning: “Being injured and homeless and without legs in Haiti is a very bad outcome.”

Though the focus has shifted in some parts of the country from acute surgery to post-operative care and the medical issues that accompany hundreds of thousands of newly homeless people, the need for expert help and supplies remains great. The Fond Parisien camp (pictured above and on Theodosis’ online gallery) is somewhere between a tent hospital and a refugee camp. Built on the grounds of a Haitian orphanage, the rows of tents sheltered 500 people when the University of Chicago team arrived, and now house 230 patients and their families. More patients are arriving every day by helicopter or bus; hospitals in Port au Prince and the USS Comfort - a US Navy ship that has served as a floating hospital since the quake - are sending recovering patients to the camp to clear space in their facilities for more operations. With only one facility equipped for surgical operations on site, medical personnel at the camp have largely tended to the post-operative and displaced, building shelters, vaccinating patients and their families, and providing rehabilitation services.

John Easton and I spoke to Richard Cook, associate professor of anesthesia and critical care at the University of Chicago Medical Center, by phone this morning from the Fond Parisien camp. Though Cook hasn’t been using his primary specialty - “You know, I haven’t given an anesthetic since I arrived,” he said - he has been incredibly busy acting as physician, electrician, construction worker, and anything else the camp needs. He says he’s been shaken by the severity of the injuries, but is comforted by the resilience of the Haitian people.

“I’ve seen more pediatric amputations in my nine days here than I have in the rest of my career combined. The devastation is almost incalculable,” Cook said. “But the Haitian people are stoic, gracious, polite, optimistic, and deeply faithful. They are responding as well as any community possibly could to such a disaster.”

The full interview is after the jump.

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The University of Chicago Medical Center team currently working in Jimani, Haiti. (L to R: Rex Haydon, Elvire LaPlanche, Richard Cook, Nicole Muse, Christian Theodosis)

More than two weeks after the earthquake that devastated the Caribbean nation of Haiti, the situation remains a humanitarian crisis as hundreds of thousands of injured and homeless seek treatment and shelter. There are more and more signs of hope: Hundreds of millions of dollars have been donated from around the world, some semblance of daily life is resuming on Haitian streets, and roughly 150 temporary hospitals and clinics - including a US Navy ship docked off the coast of Port-au-Prince - have set up to treat the wounded. Yet beyond the immediate triage, long-term health care worries about illness, infection and serious injuries persist, including the need for an estimated 200,000 amputations due to wounds suffered in the quake.

To bolster this continued effort to provide high-quality medical care in the coming weeks and months, two teams left the University of Chicago Medical Center for Haiti earlier this week. Made up of emergency medicine specialists, orthopedic surgeons, anesthesiologists and nurses, the teams are suited to assist both the immediate and long-term challenges of the medical crisis. One team, made up of physicians from the UCMC-affiliated North Shore University Health System as well as Northwestern University and Johns Hopkins University, flew into Port-au-Prince. Another team, with three physicians and two nurses (both Haitian natives), will set up in Fond Parisien, a town near the border between Haiti and the Dominican Republic that has become a hub of medical care to earthquake survivors. The team also brought more than 1,000 pounds of medical supplies with them, and additional teams of UCMC personnel will rotate into the camp every two weeks - more than 100 physicians and nurses have already volunteered for the effort.

The first dispatch from the arriving team underscored the urgency of the need for medical care and supplies. “Just finished getting crushed,” wrote team co-leader and emergency medicine physician Christian Theodosis the day after their arrival. “67 patients on 3 buses, after dark. Conditions quite intense, quite rough. Running short on tents, short on hands, several generators now, security intact. Many, quite vulnerable people. Hungry and tired.”

Updates from the latter team will be posted at Haiti Relief, a blog set up by the Medical Center’s Global Health Initiative. That space also hopes to start conversations among experts across the University of Chicago campus about how best to treat and rebuild Haiti, its health care, infrastructure and beyond. From there, you can read articles from UChicago anthropologist Greg Beckett on the underlying issues Haiti faced before the earthquake. If you would like to donate to efforts in Haiti, the University’s Chicago Studies project have set up a blog with links and information about local and global campaigns.

After the jump, some pictures from Dr. Theodosis of the Fond Parisien hospital camp.

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(photo courtesy hivresearch.org)

Rare Encouraging News in HIV and Parkinson’s Disease

HIV/AIDS and Parkinson’s Disease are two areas of medical research where good news is hard to come by, as researchers encounter countless setbacks in trying to translate promising laboratory findings into clinical practice. Both diseases have seen progress in the past decade in ex post facto treatments - preventing the maturity of HIV into AIDS with antiretroviral treatment or reducing the motor symptoms associated with Parkinson’s. But drugs that seemed to offer a cure for either disease, or in the case of Parkinson’s a mere brake to the progression of symptoms, have consistently disappointed in human trials.

That changed - slightly - this week, as two highly-publicized studies were published offering faint glimmers of hope on both disease fronts. Grabbing the most headlines was the first-ever demonstration of a successful HIV vaccine in a study conducted in Thailand but funded by the U.S. Army and the National Institutes of Health. The caveats are flying hot and heavy - the researchers saw only a 31% decrease in the number of HIV cases after treatment with a vaccine and a booster drug, one of the HIV strains protected against is specific to southeast Asia, and mystery lingers over why this particular combination of drugs was protective where so many others have failed. The two drugs used in the Thai trial - one a “primer” and one a “booster” - had themselves failed in previous large clinical trials. But the first small success in protecting against the deadly virus nevertheless encouraged many HIV/AIDS researchers; Dan Barouch, an immunologist at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, told Nature “It’s the largest step forward that’s ever occurred in the HIV-vaccine field, but there’s a tremendous amount of more work that will need to be done.”

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The death of Michael Jackson has made its expected transition from a celebration of his life and music to an uncomfortable public autopsy of how he died. More than a month after his death, the official coroner’s autopsy has yet to be officially released, but various media outlets have sniffed out one particular drug that is expected to appear in the pop star’s toxicology report: the general anesthetic propofol.

The widely-used but little-discussed drug has provoked a number of “what is Propofol?” news segments, including a piece by ABC’s Primetime: Crime that brought a camera crew to the University of Chicago Medical Center earlier this week. That segment, reported by former MTV newsman Chris Connelly aired Wednesday night, and you can watch it here.

For 30 seconds (from -2:17 to -1:47) of the video, you’ll hear briefly about research by Avery Tung, associate professor of anesthesia and critical care for the Medical Center (you will also see a rat being anesthetized with a completely different drug, halothane). In the early part of the decade, Tung conducted an NIH-funded research project examining relationships between sleep and anesthesia, and published several papers and scientific abstracts looking at how propofol mimicked the effects of actual sleep. After Tung sat down with ABC, I spent a little more time with him discussing the anesthetic and his research.

Q: First of all, what is propofol, and how often is it used?

Tung: Propofol is given intravenously to induce anesthesia in surgical patients and to provide sedation for patients in the Intensive Care Unit. It’s the most common induction agent of anesthesia in current use. It pretty much has replaced pentothal because it has fewer side effects and it makes people feel better when they wake up.

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