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

Have you ever cheated on a test by glancing over at someone else’s work? Or relied on a fellow student to carry the load on a group project while you coast along with minimal effort? While few will admit to these forms of cheating, they have long been fixtures of the classroom. However, a lazy individual benefiting from the hard work of a colleague is not a trick exclusive to humans. In a recent study of bacterial infections in plants, the laboratory of evolutionary biologist Joy Bergelson demonstrated that these unsavory practices can also be found in pathogens - and that may be a good thing for us.

In the bacterial world, the goal is survival. What we perceive as an infection is merely colonization for the bacterial population, who are establishing a new home where they can happily feed off the host’s nutrients and reproduce. Bacteria build and release virulence factors to achieve this settlement and evade immune system defenses. But because these factors spread out, benefiting an individual bacterium’s neighbors as well as itself, a sneaky bacterium can get by without producing its own virulence factors. In laboratory dish experiments, scientists observed that bacteria engineered without the ability to release factors can still thrive so long as they are paired with normal, pathogenic partners.

Though scientists described this “cooperator-cheater model” in the artificial environment of the dish, nobody had yet observed it in a natural setting. For a study published in September by the journal Ecology Letters, a team led by postdoctoral fellow Luke Barrett discovered the model in action within the cells of the popular genetic model plant Arabidopsis thaliana.

“We’re showing that cheating actually happens in nature, and that the cheaters persist,” Bergelson said. “You can make cheaters that do well in the lab, and you can show that these systems may be stable in theory, but to show that it is actually happening in nature is novel.”

Recently, researchers discovered that Arabidopsis carried two strains of the bacteria Pseudomonas syringae, a common plant pathogen. While one strain had all the normal pathogenic activity, another was a kind of bacterial pacifist, with a broken system for secreting virulence factors. Surprisingly, these two strains appear with almost equal frequency in Arabidopsis, suggesting that the non-pathogenic strains are far more successful in nature than previously thought.

To test the nature of this relationship, researchers took the two natural strains and experimentally infected plants with only one or the other. When grown alone, the “cheater” strain was not nearly as successful without its more aggressive partner around to unwittingly “donate” virulence factors. Additional modeling suggested that the more aggressive the virulent strain, the more likely it was that cheaters would be found nearby eager to exploit the hard work of their pathogenic peers. The cheater strains are also harder for the host immune system to spot, since the machinery that produces and releases virulence factors is a frequent target of those defenses.

“When you go into the field, it’s kind of a curiosity: why would non-pathogenic cheaters be almost as common as pathogens inside the host?” Bergelson said. “It turns out that the cheaters can do really well as long as they’re with the pathogenic variety, and they don’t pay the price of having to actually make a secretion system or effectors. They also don’t run any risk of being recognized because it is the presence of secreted effectors that causes the recognition events in the first place. So, these non-pathogens have some good things going for them.”

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

The late December quiet has given way to a post-holiday flurry of exciting research news, most of which I can’t tell you about until next week. But in the meantime, here’s our first weekly roundup for 2011 of the most interesting science and medical news around the web.

Tears for Fears

Scientists have discovered a multitude of ways by which animals communicate through chemical signals, such as those in the urine that dogs use to mark their territory and the path left by ants to guide their compatriots to food sources. But whether such pheromone signals exist in humans has been much more controversial. Martha McClintock, professor of psychology at the University of Chicago, has published many papers showing evidence for communicative signals in human sweat that can influence menstrual cycling, mood, and brain function in other people. But the behavioral effects of human chemical signals have so far been small, producing nowhere near the sensational effects that marketers of “pheromone” perfumes claim on less than reputable websites.

But another mediator of chemical communication in humans may have been traced this week, in a paper published by Science on the ability of women’s tears to affect sexual interest in males. The Israeli study used a hilarious method of collecting their experimental substance, sitting women down in front of sad movies and catching their tears in test tubes (”We obtained negative-emotion tears from 2 donor women who watched sad movies in isolation,” the authors right in scientist-ese). The fluid was then placed under the nose of male subjects, who viewed pictures of women’s faces and rated their attractiveness. As described by Ed Yong at Not Exactly Rocket Science, the males’ sexual interest decreased when exposed to the tears, as compared to being exposed to a control of saline. Differences in brain activity and testosterone levels were also detected while men sniffed the tears of sadness.

Consulted by the New York Times, McClintock said the study “really broadens the possibilities of where signals are coming from,” but expressed skepticism that the tears’ effect would be restricted to sexual behavior. “I have no doubt that it affected sexuality as they report, but I would be very surprised if it doesn’t turn out to affect other emotions in other contexts. Maybe it’s affecting some deeper, more fundamental psychological process that drives the effect that they’re reporting,” she told the newspaper. Other critics have asked whether the chemical signal lies in the tears themselves, or are collected by the tear from the skin as they roll down a subject’s cheeks. The nature of the chemical still remains to be found, but the evidence suggests another entry in the previously hidden chemical vocabulary of humans.

Fraudulent Science, Human Cost

Last year, the infamous 1998 Lancet paper purporting to show a link between the measles, mumps, rubella vaccine and childhood autism was finally retracted after years of criticism for biased selection of subjects and unethical behavior. But the research, led by Andrew Wakefield, went beyond scientific mistakes to fraudulent falsification of data, a new report from the British Medical Journal released this week discovered. Investigative reporter Brian Deer found that Wakefield, who was being receiving payments from a lawyer seeking to file a lawsuit against vaccine manufacturers before he started the study, changed the timeline of autistic symptoms appearing in patients to make it look more like vaccines were the cause. The article is a rigorous and thorough deconstruction of a scientific fraud that has had concrete consequences for children around the world - in the  12 years since the article was published, measles cases have spiked in England and America as vaccination rates have dropped, and other vaccination-sensitive diseases such as whooping cough have also made a resurgence.

read more

Many neurological disorders struggle with the same problem as their cousins, the psychiatric disorders: a fuzziness of diagnosis. Even well-known diseases such as Parkinson’s and Alzheimer’s are tricky for physicians to diagnose, since their hallmark symptoms (dementia, or movement issues) show up late and can reflect any number of conditions with different treatment strategies. Meanwhile, the subjective elements of diagnosis for a disease like autism can produce even more confusion, particularly in parents wanting the best care for their child.

The hope is that, someday, diagnosing Alzheimer’s or autism will be as simple as running a quick test that says Yes or No. Two studies this week produced excitement that physicians are nearer to such a goal, but also revealed how difficult it will be to obtain such a definitive answer. The coverage of the papers also revealed the importance of carefully reading the results of testing the test, knowing the difference between the testing terminology of “sensitivity” and “specificity.”

The most glaring example of this confusion was over a paper announcing a new biomarker test for Alzheimer’s Disease in the journal Archives of Neurology. Here, a group of scientists used an interesting technique to find the best way to predict Alzheimer’s disease from a spinal tap test, working from a data set of hundreds of patients with Alzheimer’s, mild cognitive impairment, or no dementia. With an unbiased analysis, the researchers determined thresholds for two markers involved in the pathology of Alzheimer’s (beta-amyloid and tau protein) that successfully predicted a diagnosis of Alzheimer’s from the spinal tap alone. This “sensitivity,” the ability to make the correct diagnosis in someone who has the disease and avoid false negatives, was reported at impressive levels of 94 to 100 percent.

However, news reports mistakenly said that the new biomarkers were a “100 percent accurate” test for Alzheimer’s. As many blogs have already pointed out, that’s just not, well, accurate, and in fact obscures the most interesting part of the study. As reported by the authors, the biomarkers misidentified about one-third of “control” subjects, that is patients who showed no signs of dementia or impairment, as being positive for Alzheimer’s. That’s a pretty low “specificity,” since it means the test generates significant false positives. But are they really false? The authors also report preliminary results that “there was a tendency for more progression to MCI in cognitively normal subjects with the AD feature,” meaning that people who were normal at baseline, but showed biomarkers for Alzheimer’s, may be on the cusp of developing symptoms of the disease. The “wrong” answers might just be the most useful answers, drawing attention to people on the verge of developing Alzheimer’s, a population that may be helped more by early treatment.

Another neurological condition where an early, clear diagnosis would be very helpful is autism. The current psychiatric means of diagnosing autism may be the main driver of its steadily increasing rates, a fact which has caused some to wonder whether those guidelines are specific enough, and whether autism is even one single disease at all. Rather than basing the diagnosis on interviews and psychiatric assessments, some are working towards genetic or imaging techniques that can give more definitive answers on autism.

read more

For the next month, the world’s attention (and mine) will be focused on South Africa for the 2010 World Cup. Though it’s just starting to break through the public consciousness in the States, the World Cup is such a massive cultural force in the rest of the world that its tremors are felt even in scientific circles. A recent psychology study on how to take the best penalty kick got a lot of media play this week, and at least two different economists developed models to predict the winner via a country’s GDP and other factors (both picked Brazil).

I jumped into PubMed to see what other World Cup-related research could be found, and it turned out the water there was very deep. Since the last World Cup in 1996, dozens of scientific and medical articles have been published, ranging from editorials advising fans about potential diseases they need to be immunized against in South Africa to surveys of injuries suffered by referees during the tournament. But one topic appeared to drive much of the World Cup-related scientific debate, and it explains just how seriously the competition is taken around the world: does watching important World Cup games cause heart attacks?

The controversy started with a 2008 New England Journal of Medicine article called “Cardiovascular Events During World Cup Soccer.” A team of German researchers looked at emergency medicine records from June 9 to July 9, 2006, when the last World Cup was taking place in Germany, and compared the period to two control months free from international tournaments. According to the authors, “six of the seven games in which the German team participated were associated with an increase in the number of cardiac emergencies,” averaging out to a 2.5-fold increase in heart attacks. People with a history of coronary artery disease had an even higher health risk of watching their countrymen on the pitch: a four times increase in events. Blog founding father Jeremy Manier wrote about the study for the Chicago Tribune, and related it to local stress about the Cubs and Bears.

But wait - a counter-attack was sprung this year by an Italian team of researchers, who focused upon their own population during not only the 2006 World Cup, but the 2002 event as well as the 2004 European Championships. Studying more than 25,000 hospital admissions, the authors failed to find any uptick in heart-related events, even when Italy’s national team defeated France in a tense penalty shootout to win the ‘06 Cup (there was, however, at least one Italian with a chest injury that day). The Italian authors claim that their negative results are more in line with previous literature, including an English study that found only a small (but significant) increase in heart attacks and strokes during club soccer matches.

read more

There are few areas of medicine filled with more controversy than psychiatry. Compared to heart disease or a viral infection, mental illness is far more difficult to diagnose, with symptoms that are often vague, subjective, or difficult to accurately measure. To try and bring order and reliability to the assessment and treatment of mental illness, the American Psychiatric Association has published The Diagnostic and Statistical Manual of Mental Disorders since 1952. The DSM, as it’s known for short, is a guidebook for psychiatrists, psychologists, mental health researchers and insurance companies, a framework by which to define the amorphous world of mental health for treatment, research and coverage.

Of course, our knowledge and perception of mental health and illness has changed somewhat over the past 60 years. The DSM has changed as well, undergoing several revisions - the current version is the awkwardly named DSM-IV-TR, a sort of intermediate revision that was published in 2000. Virtually since that time, psychiatrists have been working on the fifth total revision of the DSM, an exhaustive process that yielded the “draft” version of the DSM-V published online earlier this month.

Now, the real fun begins. For the next two months, public comments will be accepted on the draft DSM-V, allowing all parties who craft and use the manual to fight it out over several controversial changes before they are officially codified. Because of the competing interests involved in the creation of the DSM, this process can lead to  psychiatric pyrotechnics.

“It’s a little bit like watching a circus,” said Scott Hunter, director of pediatric neuropsychology at the University of Chicago Medical Center. “Ultimately, it’s as much political and cultural as it is scientific. That’s why I’m both encouraged in some ways, and amused in others.”

Hunter has a particular interest in the revisions. As controversial as adult mental illness may be, pediatric mental illness turns the discussion’s temperature up even higher - as Exhibit A, just look at the debate that perpetually rages around autism. Sure enough, the strongest disagreements and the bulk of the media attention surrounding the DSM-V draft have to do with the mental health of children, and autism is sitting shotgun.

read more

A brain from a person with mad cow disease, caused by prions (compared to a normal brain).

A Place for Prions

We previously discussed the bizarre infectious proteins called prions in the context of kuru, the disease of muscle tremors and uncontrollable laughter spread by cannibalistic rituals in Papua New Guinea. In diseases such as kuru or mad cow disease, abnormal prion proteins wreak havoc by binding to native prions and other cellular elements, creating clumps that kill off cells in the nervous system. But one important thing I didn’t mention in the kuru article - nobody’s really sure what the native, normal prions actually do!

That mystery may have been somewhat dispelled by an article published by Nature Neuroscience last weekend from a team of scientists in Sweden and Germany. Those researchers knocked out or interrupted the gene for prions in a number of different mouse strains, a strategy that had previously yielded a pretty normal mouse without much to say about the prion’s purpose. But for the current experiment, the researchers were patient, allowing the mice to live to the grand old age of 60 weeks (mice typically live for about two years) before looking for deficiencies related to their lack of prions.

What they found in their elderly mice links back to another ScienceLife post - peripheral neuropathy, a motor disorder marked by the demyelination of peripheral neurons. The nerve cells running from the spinal cord to muscles of the prion-free mouse’s body were normal, save for a thinned-out sheath of myelin along the axon. As discussed previously for multiple sclerosis (where central nervous systems neurons are demyelinated), this loss of myelin leaves cells less insulated and like a frayed power cable, unable to transmit signals at optimum speeds. Hence, the motor difficulties associated with peripheral neuropathy, which in humans manifests itself as twitching, paralysis, and loss of dexterity.

That could be a promising finding for not just one field but two. Recall that motor difficulties are usually one of the first symptoms of prion diseases - “kuru” is the word for “shiver” in the Fore language of Papua New Guinea’s Eastern Highlands. Prion gene knockout mice may have their issues, but have the small consolation of being resistant to prion diseases. And the study of peripheral neuropathies (plural, because the term covers several different diseases) could benefit from the new identity of the prion as a mediator of myelin maintenance.

read more

The latest in our video series where experts from the University of Chicago Medical Center answer frequently asked questions about popular medical topics. To suggest a topic or a question, please contact the editors.

Last week, we heard from Sharon Hirsch on how autism is diagnosed and what established, evidence-based treatments for the disorder are currently available. But the cause of autism and related autism spectrum disorders remains a scientific mystery, where a multitude of clues have yet to add up to a comprehensive theory. Because autism is a highly heritable condition - twins often share the disorder, and siblings of autistic children are much more likely to be autistic themselves - the most promising avenues of autism research appear to be in the realm of genetics.

Sure enough, several different genes have been found to be associated with autism. Many of these genes have to do with the development of the brain, such as neurexin and neuroligin, two molecules discovered by Stanford’s Thomas Sudhof to be important in the construction of synapses that allow brain cells to communicate. But even these genetic clues don’t offer easy answers, as scientists increasingly learn that autism is a complex disorder, likely caused by multiple defects rather than a single, smoking-gun gene.

William B. Dobyns, a professor of human genetics, neurology and pediatrics at the University of Chicago Medical Center, studies the genetics of autism and other developmental disorders. A few months ago, we wrote about his work with Kathleen Millen, associate professor of human genetics and neurobiology, in uncovering genes responsible for Dandy-Walker syndrome, a brain disorder that shares some symptoms with autism. Dobyns’ laboratory has also been directly involved in the search for autism genes, publishing earlier this year on a gene mutation found in an autistic patients that affects synaptic vesicles, another component of communication between neurons.

In the following videos, Dobyns talks about why the search for autism-related genes is both promising and frustrating, the treatments that those searches may someday yield, and the dangers associated with treating autistic children with unproven treatments. Most importantly, Dobyns talks about the hope that parents of autistic children should have due to the effectiveness of current established treatments (such as cognitive-behavioral therapy) and the promise of more effective treatments in the coming years.

Here at ScienceLife, we often focus on fresh laboratory findings that could be years away from being applied to patients in a clinic. Popular newspapers and magazines, meanwhile, sometimes get caught up in controversies surrounding health and medicine without focusing in on core questions that many patients have about common diseases and conditions. And with a tangle of information - reputable and otherwise - about common health topics available on the internet, it is often hard for people to navigate quickly to the reliable medical answers they seek.

So we’re launching a recurring feature here on the blog where a University of Chicago Medical Center physician will address - in a series of short Q&A-style videos - frequently asked questions about a popular medical topic. These videos are meant to be patient-focused and to offer clear, accurate information about common diseases and the accepted medical treatments currently available. If you have a medical topic you would like to see featured in future videos, or if you have questions you would like to have answered by a University of Chicago physician, please don’t hesitate to contact the editors.

There’s really no better subject to kick off this series than autism, the psychiatric disorder of communication and social behavior most commonly seen in children. Autism is in the news on an almost daily basis, and this week was no exception - Chicago Tribune reporters Trine Tsouderos and Patricia Callahan continued their excellent series Sunday and Monday on the proliferation of dangerous experimental treatments for autism that have little to no scientific basis. Last month, the journal Pediatrics published the results of a national survey that found that slightly more than 1 out of every 100 children have been diagnosed with an autism spectrum disorder, a higher figure than previously estimated - though experts have debated whether this reflects a rise in autism rates or an increase in diagnosis of the disease.

Sharon Hirsch, Section Chief for child & adolescent psychiatry at the University of Chicago Medical Center, treats many children with autism spectrum disorders each year through the Medical Center’s neurodevelopmental clinic. We interviewed her in her office last week about the latest autism numbers, how the disease is diagnosed by psychiatrists, how it is currently treated, and the types of challenges children with the disorder face at school and at home.

read more

As described on Monday and hinted at all week, this weekend marks the start of Neuroscience 2009, the annual mega-conference of more than 30,000 neuroscientists. After years of staging the meeting in areas with distractingly nice climates such as New Orleans, Orlando and San Diego, this year should be all business with the rainy chill of Chicago keeping people indoors. But there’s still a lot of fun to be had, with big-time speakers, immersive poster sessions, the never-ending hunt for the best vendor knick-knack giveaway and the night-time socials. Because of Neuroscience’s massive size, there are a million different ways to navigate a path through the science, but here’s a quick extremely long guide to what I’m looking forward to experiencing. Remember to tune in to ScienceLife all weekend (and through Wednesday) for coverage.

Saturday: Magicians Were the First Neuroscientists

Each year one of the most interesting lectures falls under the sober heading of “Dialogues Between Neuroscience and Society,” which basically means “we invited someone from outside of neuroscience to talk about neuroscience.” At previous meetings I’ve attended, that meant hearing public figures such as the Dalai Lama and Frank Gehry offering their own perspective on the brain, the mind and thinking - necessary reminders that the microscopic neurons those 30,000 scientists are concentrated on actually add up to some pretty amazing things in practice. 

This year’s Dialogues speakers are neuroscientists of a different sort: magicians Apollo Robbins and Eric Mead. Even though I saw a local version of this talk earlier this year with Robbins and neuroscientist Susana Martinez-Conde (which I wrote about it for the Tribune), I’m excited to see it again, because it really is a neat demonstration of how magicians have used the brain’s limitations to produce convincing illusions. Robbins, whose act is centered on his considerable abilities as a pickpocket, is a master of using diversion to direct a person’s attention one direction while he slips off their watch from another angle. As Robbins and Martinez-Conde explained back in January, this deceptively simple trick actually says a lot about how the brain shifts attention from stimulus to stimulus, and how a normal brain is “tricked” may help us learn about the neurobiological process that underlie an attentional disorder like ADHD. You can watch a video of a similar symposium organized by Martinez-Conde back in 2007 called “The Magic of Consciousness” - which includes Teller of Penn & Teller in a rare speaking role.

Also Saturday: We’re only two weeks away from the University of Chicago’s big Darwin conference, but I still will probably take in at least part of the symposium on Evolution of Brain and Behavior. Harvard’s Elizabeth Spelke caps off the day with a lecture on how the brain processes math - thankfully, it’s scheduled early in the conference, before my own brain will surely grow too tired to handle such a heavy topic.

read more

The development of the human brain is a massive biological construction project that scientists are still only beginning to understand. From the first few cells of the human embryo, billions of neurons and glia cells must be formed and positioned in exactly the right place with all of the proper connections. Hundreds of genes, chemical signals and growth factors have been found to be foremen and tradesmen on this neurological construction site, and if any one of those workers doesn’t show up for work or does their job incorrectly, the consequences can range from severe mental retardation to prenatal death.

That incredible feat of engineering is the backdrop for a new paper published online Sunday in Nature Genetics by a team of scientists and clinicians led by Kathleen Millen, assistant professor human genetics at the University of Chicago, and William Dobyns, a professor of human genetics, neurology and pediatrics at the University of Chicago Medical Center. For the last 8 years, Millen and Dobyns have been looking at a case where the brain’s construction goes awry: a common birth defect of the brain called Dandy-Walker malformation (DWM). In 2004, they found the first two genes that contribute to some children born with DWM, which can lead to motor delays, mental retardation, hydrocephalus and autism. In their new paper, a third gene is implicated in the development of DWM – and it was not one that the authors expected to find.

The researchers found that people with a missing or defective version of a gene called FOXC1 exhibited the characteristic deformity of Dandy-Walker: an improperly formed cerebellum, the region at the back of the brain that controls coordination, balance and other motor processes. But FOXC1 is not a likely culprit for a brain disorder, as it’s never actually expressed in the brain. Instead, it shows up in embryonic tissue called mesenchyme, which later develops into the skull and membranes that wrap around the brain.

read more

The Chicago Tribune’s new medical reporter Trine Tsouderos (my successor at the paper) has a must-read article in today’s Trib about misguided efforts to use the “chemical castration” drug Lupron as a treatment for young kids with autism. It’s part one in a two-part series, with contributions from an all-star cast including veteran national reporter Tim Jones and investigative reporters Patricia Callahan and Steve Mills.

I can’t say enough good things about the piece. It draws on an impressive array of endocrinologists and pediatricians who attest that the children being treated are not suitable for the testosterone-lowering drug. Bonus: They quote the brother of the actor who plays “Borat,” noted Cambridge University autism researcher Simon Baron-Cohen.

The father-and-son physician team who developed the suspect protocol claim that many experts back their approach, including Baron-Cohen - but Baron-Cohen delivers a stinging rebuke of their reliance on Lupron: “The idea of using it with vulnerable children with autism, who do not have a life-threatening disease and pose no danger to anyone, without a careful trial to determine the unwanted side effects or indeed any benefits, fills me with horror,” Baron-Cohen said. So much for that endorsement.

One of the best things about the piece that it gives both sides room to make their case without falling into a “he said/she said” routine, which would not reflect the consensus against using this therapy. Autism is a terrifying condition, but that doesn’t justify trying powerful treatments without evidence that they will work safely. These physicians claim to have seen some effect in patients, but that’s not surprising - any potent drug with psychiatric effects could influence a child’s behavior in the short term. The article indicates that the daily dose the doctors use for autism patients is 10 times the normal amount typically given for children with early puberty. With that kind of dosage I’d be surprised if there weren’t some psychiatric effect. But that doesn’t mean it’s the right effect, or that the drug is safe for children. Only a trial can determine that.

So kudos to Trine, and to the Tribune for giving these careful reporters the time and space to explain a difficult issue and a treatment that could put kids at risk. It’s a heartening sign during a gut-wrenching time for newspapers. I can’t wait for part two.