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 the weather finally starts to get seriously cold, we thought this would be a good time to revisit our conversation with Dr. Ginard Henry on Cold Hands Syndrome. While it seems like your frozen fingertips could be fixed by simply wearing a good pair of gloves, Cold Hands Syndrome is a real medical condition caused by a range of different diseases that restrict blood flow to extremities. It can strike at any time, not just the dark days of winter.

For more, check out our four-part video Q&A with Dr. Henry:

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The University of Chicago can fill a couple of classrooms with all of the Nobel Laureates affiliated with the school, from Milton Friedman to Saul Bellow to Barack Obama. After Monday, a third room might have to be opened up, as Pritzker School of Medicine graduate Bruce Beutler became the 86th member of the exclusive club. Beutler, who graduated from our medical school in 1981, was honored with this year’s Nobel Prize in Physiology or Medicine, along with Jules Hoffman and Ralph Steinman. The three scientists were credited with advancements in the field of immunology that have paved the way for new strategies fighting infections, cancer, and other diseases.

“I thought it was possible, but nobody can count on winning the Nobel Prize, so I’m just ecstatic,” Beutler, now at University of Texas Southwestern Medical Center, told the Chicago Tribune.

In the confusing calculus of the Nobel, Beutler and Hoffman split half of the total award for research on the innate immune system, known as the first line of the body’s defenses against infectious invaders. In the late 1990’s both scientists’ laboratories were looking for immune receptors that respond to signals on the surface of bacteria - Hoffman looking in fruit flies with genetic mutations, Beutler in mice. Within two years of each other, Hoffman discovered a fly mutant named “Toll” involved in the response to an infection, and Beutler found a similar gene in mice for a receptor (named, appropriately, the “Toll-like receptor”) that binds to lipopolysaccharide (LPS), a signal on the surface of bacterial cells.

These findings opened the floodgates to learning about new players in the innate immune system, including the discovery of a dozen more Toll-like receptors that recognize various pathogen signals - what some call “the eyes of the immune system.” Clinically, mutations in these genes can lead to either increased susceptibility to infection (if the innate immune system is too weak) or autoimmune and inflammatory disorders (if the innate immune system is too strong). Drugs that target this system might therefore be promising for the treatment of many different diseases.

“I think the most hopeful line or realm is in inflammatory and autoimmune disease,” Beutler told the Nobel website. “Inflammation is something that evolved to cope with infection, and when we speak of sterile inflammatory diseases like rheumatoid arthritis and autoimmune diseases like lupus, probably some of the same pathways are utilized. It may very well be that by blocking TLR signalling you’ll have very specific therapies for those kinds of diseases.”

Beutler said that he received the news in bed, waking up in the middle of the night and reading an e-mail on his cell phone.

“I was a little bit disbelieving, so I went downstairs to look at my laptop,” Beutler said. “I went to Google News and saw my name there, so I knew it was real.”

At the University of Chicago Medical Center campus, the news quickly spread among former colleagues and teachers of Beutler, as well as scientists that who work in his field.

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ScienceLife ran 219 posts in 2010, and choosing the best of them is as hard as picking a favorite gene.  So here’s a month-by-month scan of a busy year at the University of Chicago Medical Center, full of exciting discoveries in the laboratory and the clinic. The impact of some of this research is already being felt by patients receiving improved, evidence-based medical care. For other studies, the clinical benefit may be years in the future, and may take unpredictable forms. As a closing message for 2010, we’ll re-quote the recently departed Eugene Goldwasser, whose laboratory research isolating and purifying the hormone erythropoietin has helped millions of people worldwide.

“It is a particularly impressive example of how basic research can pay a dividend that could not be anticipated at the start,” Goldwasser wrote about his life’s work, “and it is a pity that the lesson still has not been learned by those who control public funding of science.”

January: Tong Chuan-He looked at how cancer may result from cells who don’t want to grow up. Scientists studied how sleep affects the language learning skills of starlings (with painstakingly acquired video of the experiment!). Richard Jones combined two laboratory staples - Western blots and DNA micro-arrays - to develop a new method for studying protein networks. While physicians such as Tammy Utset treat patients with lupus, UChicago scientists are looking for the genetic origins of the autoimmune disorder.

February: Many Medical Center employees returned from volunteering with relief efforts in Haiti, and we filmed video interviews with Rex Haydon, Tiffany Cupp, Richard Cook, and Dima Awad on their experiences. Most of the human genome is “junk” between protein-encoding regions, but Marcelo Nobrega developed a way to find important regulatory elements in that genetic sea. Like birds, human learning can be affected by sleep, and Leila Kheirandish-Gozal reported on the impact of obstructive sleep apnea upon learning in children. Can a single protein in the brain create behaviors associated with drug addiction in rats?

March: Everyone knows air travel is stressful, but did you know that eastbound flights cause stronger cortisol changes than westbound trips? The laboratory of Milan Mrksich found a way to direct stem cells to form fat or bone by shaping them into stars or flowers, a brilliant example of bioengineering. Computational neuroscientists discovered how touch is like vision in the brain, knowledge that could be used to someday re-engineer Luke Skywalker’s robot hand. Dartmouth president and Partners in Health co-founder Jim Yong Kim visited to talk about a new, needed area of research: health care delivery.

April: Researchers at the Field Museum and the University of Chicago teamed up for the Emerging Pathogens Project, an effort to find new viruses in animals before they jump to humans. Cardiologist Martin Burke tested out a new type of internal defibrillator device that can go under the skin, instead of into the heart (the clinical trial, reported in May, was a success). In a lecture to the MacLean Center of Clinical Medical Ethics, transplant surgeon J. Michael Millis described his efforts to bring American organ transplant practices to China.

May: A trial testing the erectile dysfunction drug Viagra for a rare, untreatable lung disease failed, but pulmonologist Imre Noth found a silver lining. Lauren Sallan and Michael Coates uncovered evidence of a previously unappreciated mass extinction event 360 million years ago that changed the path of life on Earth. Researchers from the University of Chicago and around the world presented science at the frontier of biotechnology at the annual BIO conference.

June: In a study that is literally the size of an entire country, epidemiologist Habibul Ahsan measured the toll of a tragic, accidental exposure of millions to arsenic in Bangladesh. Putting a gene from fireflies into the pancreas of mice isn’t mad science, it’s an imaging tool that will help study cures for diabetes. Epigenetics, the modifications that turn genes on and off, took off in 2010, and cardiologists Stephen Archer and Jalees Rehman linked one epigenetic factor to pulmonary artery hypertension.

July: Scientists don’t often get to see the fruits of their research in the flesh, but the Celebrating the Miracles gathering of diabetic children weaned off injected insulin thanks to genetic research was a moving exception (video of the event can also be viewed). Another hot topic in science and medicine this year was the use of computational analysis to sift through rapidly accumulating data, topics explored by Gary An and Andrey Rzhetsky. Or you can build a computer model of a brain network to study the dynamics of epilepsy, like neurologist Wim van Drongelen.

August: Air pollution is a problem indoors as well as outdoors in developing countries where dung and firewood are used to cook food - a problem being tackled in a project led by Sola Olopade. A study of the hormonal changes induced by a stressful test revealed a surprising protective effect of marriage and long relationships. Microbiologist Olaf Schneewind’s laboratory developed two new strategies against MRSA, the most-wanted cause of hospital-acquired infections.

September: To study multiple sclerosis, neurologist Brian Popko’ s laboratory developed a new mouse model that can replicate the disease, then spontaneously recover. Meanwhile, a new drug to treat MS, originally isolated from fungus found in wasps, was approved by the FDA and is being studied for broader uses at the Medical Center. The micro-organisms that live in humans were analyzed as part of a “microbiome” study looking at the protective effects of breast-feeding against a intestinal disease.

October: Common wisdom on quitting smoking says to stay away from cigarette-associated cues, but research from psychiatrist Harriet de Wit’s laboratory revealed that abstinence could make craving even worse. A study of how getting a good night’s rest affects dieting results suggested that “sleeping off the pounds” isn’t merely a fantasy. Graduate student Daniel Matute solved a 100-year-old riddle about how quickly new species become reproductively incompatible with each other.

November: In perhaps our favorite study of the year, geneticist George Perry found a way to acquire the genomic information of endangered species from…poop. The evolutionary biologist Leigh Van Valen passed away, but his Lewis Caroll-inspired Red Queen Hypothesis lives on. Sometimes statistics don’t tell the whole truth, as in the curious case of the aspirin paradox - why the cardio-protective drug may actually predict worse outcomes after heart attack.

December: Evolution textbooks may need a rewrite after geneticist Manyuan Long’s laboratory discovered that new genes can be just as essential as old genes. A study by neurobiologist Nicholas Hatsopoulos proved that the only thing better than a thought-controlled device is a thought-controlled device equipped with a robot arm. Ripped from the headlines: microbiologist Jack Miller weighed in on the hype over arsenic-based bacteria, and ethicist/physician/friar Daniel Sulmasy discussed the Presidential Bioethics Commission’s report on synthetic biology.

All told, it was a great year of science and medicine. Let’s do it again in 2011! Regular posting will resume Jan. 3rd. Happy Holidays.

As the weather warms in the Chicago area, it might seem like a strange time to be talking about cold hands. But for some people, uncomfortably cold hands is not just an artifact of the long Midwestern winter, but a medical syndrome that may require treatment. Defined by its primary symptom rather than a single cause, Cold Hands Syndrome is marked by, well, cold hands, as well as pain, numbness and occasionally discoloration or even tissue damage. The source of these symptoms is a loss of circulation to the hands and fingers, but the cause of that decreased blood flow can range from Raynaud’s Disease to blood clots to arteriosclerosis to lupus to scleroderma. As Ginard Henry, assistant professor of surgery at the University of Chicago Medical Center, describes it, Cold Hands Syndrome is “a range of different diseases” that cause similar symptoms in one’s extremities.

“Your hands are almost like a lawn at the end of a street, and you are giving the lawn water to grow,” Henry said. “If anything disrupts that flow of water then the lawn doesn’t grow and you have a problem.”

Henry and colleagues Lawrence Zachary, associate professor of surgery, and Nadera Sweiss, assistant professor of medicine, have launched the Cold Hands Clinic at the Medical Center, uniting expert physicians from a number of disciplines to focus on this unusual problem. I sat down with Henry to ask him about Cold Hands Syndrome: what it is, how it’s diagnosed, and how it is treated. Befitting the diverse causes of the disorder, there are a number of different treatments, including measures as simple as moisturizing and the use of drugs such as Viagra and Botox for, shall we say, purposes other than their primary use.

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General internal medicine might seem like an awfully vague term. But assuming the health care reform bill signed by President Obama in March will be fully implemented, the general internists will finally have their day. Many of the bill’s provisions are focused on a reshuffling of the American medical landscape, which is currently dominated by sub-specialists focused on one organ system. In recent years, fewer medical students have chosen to pursue lower-paid and less glamorous careers in internal medicine, leaving a worrisome shortage in primary care doctors and hospitalists just as 32 million uninsured Americans are about to go on the books. The spotlight is about to focus on internal medicine.

“About time,” would probably be the response from most of the doctors assembled in Minneapolis last week for the 2010 Society for General Internal Medicine national meeting. Over three days, thousands of internists met in discussion groups and research panels to chart the course for a new age of American medicine. Though some fears were expressed about how an already overwhelmed system would be able to deal with the new influx of patients, the conference was more focused on seizing the opportunity to rehabilitate U.S. primary care and bring medical services to those who are traditionally underserved. The urgency of the moment was expressed right in the caps-lock and exclamation point of the meeting’s theme: “Value(s)-based generalism: THE TIME IS NOW!”

Of course, many of these efforts to expand the net of primary care didn’t start when Obama used 22 pens to sign the health care bill on March 23rd. Many of the presentations by University of Chicago faculty at the conference discussed pilot programs already being tested to improve the care of those who have traditionally fallen through the health care cracks, efforts to reduce disparity that may be instructive as the reform measures fall into place.

A workshop moderated by Marshall Chin, professor of medicine, presented four examples of programs funded by Finding Answers, Chin’s Robert Wood Johnson Foundation-supported group for studying racial and ethnic health disparities. Chin said the mission was to “evaluate interventions that reduce racial and ethnic disparities,” and the short presentations showed the breadth of that mission. Projects using cultural awareness training, electronic medical record software, and pay-for-performance programs were all discussed as potential solutions, with researchers from Harvard, Brigham and Women’s Hospital and Baylor outlining projects currently underway. One fascinating approach, described by Barbara Turner from Penn, employed African-American patients who had successfully controlled their high blood pressure as “peer coaches” to help fellow patients struggling to adhere to treatment - an elegant way of using community bonds to spread healthy messages.

Another successful example of community health intervention was presented in tandem by Deborah Burnet, section chief of internal medicine at the Medical Center, and Lorri McClinton-Powell, a teacher from Woodlawn Elementary School on the southeast side of Chicago. Last year, Burnet and colleagues conducted a pilot study of the POWER-UP program, an anti-obesity effort based around after-school activities for children and parents, with 40 children and their parents at Woodlawn. Fourteen weekly sessions - focused on themes such as “Muscle Mania” and “Stop & Shop” - taught the children about healthy eating, exercise, and behavior at restaurants and grocery stores. Though small, the study’s results held promise, with declines in overall body mass index among all but the heaviest kids at baseline. The group is currently working with Chicago Public Schools on the possibility of expanding the program for a larger study, Burnet said.

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The protein structure of human interferon-alpha

As discussed yesterday, lupus is not an equal-opportunity disease. Ninety percent of lupus cases occur in women, the disease is three times more likely to affect African-American women than Caucasian women, and lupus is more common and severe in other minority populations as well. Given that the general cause of lupus remains unknown, the reason for these discrepancies is also mysterious. But a grant from the Lupus Research Institute recently awarded to Timothy Niewold, assistant professor of rheumatology at the University of Chicago Medical Center, hopes to turn the focus of science to this issue, looking for genetic factors that may explain why minority women are more seriously afflicted by lupus.

One of the few things that is clear about lupus is that it must have a strong genetic component. The disease is strongly inherited - if someone has a close relative with lupus, their own chances of having the disease are increased twenty-fold. Genetic linkage studies have found a number of promising genes and clusters of genes that are associated with an increased risk of contracting lupus. But while such results are promising, they also contain a couple of problems. 1) The genes don’t account for everything, suggesting an environmental role in triggering the disease. 2) The multiple linkages indicate that lupus cannot be traced back to just one gene, backing theories that the complexity of the disease is due to multiple genetic factors. 3) The linkage studies were conducted in patient populations that were predominantly Caucasian, obfuscating any genetic differences that could account for the increased incidence of lupus in minorities.

“We are excited that we are mapping a bunch of different genes, but it is kind of like we’re sketching some of the first maps of the continent,” Niewold said. “We’re getting something here, something there, and not everything is connected. It’s kind of a vague diagram.”

If all those caveats and complexities are giving you a headache, you’re not alone. But Niewold’s approach is to focus on particular portions of the map that look like they may be relevant to at least a large portion of lupus patients, while expanding genetic studies to start filling in some of the blank parts on the map.

One part of that effort is to focus on a likely suspect in lupus - cytokines. Small signaling molecules that play a role in the immune system, cytokines are normally responsible for helping marshal immune defenses to fight off infections. But one particular cytokine, called interferon-alpha, or IFN-α, may go awry in lupus patients, with elevated levels of the cytokine producing the disease’s characteristic overactive immune response. The theory is backed by both genetic linkage data (where several genes associated with the IFN-α pathway pop up) and acute measurements revealing high levels of IFN-α in lupus patients.

“One of the most common and consistent pathways dysregulated in lupus is type I interferon,” Niewold said. “It doesn’t give us a complete answer, but the data suggests that it’s an important pathway in lupus.”

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Autoimmune disorders are a strange type of disease, a case where the body’s biology isn’t breaking down but rather is functioning too well. In disorders such as Type I diabetes, arthritis and multiple sclerosis, the body’s natural defenses stage something of an internal coup, mistakenly attacking the body’s own tissues instead of viral or bacterial invaders. In a lot of these diseases, the immune system chooses just one system to mistakenly attack - the pancreas in diabetes, or the joints in arthritis. But one autoimmune disorder is less specific, striking out against multiple targets that can differ from patient to patient - lupus.

Known clinically by its longer name, systemic lupus erythematosus (SLE), lupus afflicts roughly 1% of the American population, according to CDC statistics. But that number could also be three times higher, the CDC cautions, an imprecise figure partially down to the difficulty of diagnosing the disease. As Tammy Utset, associate professor in the Section of Rheumatology at the University of Chicago Medical Center describes in the videos below, lupus can present with any number of different symptoms, from fever, rash and fatigue to hair loss, joint pain and kidney disorders.

“It’s a little tricky because the symptoms are so varied from person to person,” Utset said. “That’s why it can take a long time for lupus to come to diagnosis after the symptoms start, because the symptoms early on can be relatively non-specific.”

The diverse range of symptoms is only one of lupus’ mysteries. The disease also has a very skewed incidence between genders, with 9 out of 10 cases in women. Across ethnic lines, lupus strikes minority populations more often - the CDC states that the disease is three times more likely to strike African-American women than Caucasian women, and symptoms tend to be more severe in these populations. At the University of Chicago, the Gwen Knapp Center for Lupus and Immunology Research has been grappling with research questions regarding this discrepancy and potential genetic factors in the development of lupus. Tomorrow, I’ll discuss some of the genetic research coming from that group, but today, here are four videos of Dr. Utset talking about the unique clinical character of this unusual, but hardly rare, autoimmune disease.

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