By John Easton

Few people realize the important role that math plays in organ transplants. Complex formulas convert medical information about each patient, including diagnosis, age, and test results, into a single “allocation score” that determines who has priority when an organ becomes available. One factor not included in these calculators is proximity of the organ to a patient. More than a decade ago, the U.S. Department of Health and Human Services issued the “Final Rule,” intended to ensure that organs were allocated “based on medical criteria, not accidents of geography.” However, new data show that where a transplant candidate lives continues to influence access to donated lungs.

The current system for allocating donated lungs based on proximity and not on need appears to decrease the potential benefits of lung transplantation and increase the number of patients who die waiting, researchers said at an annual meeting of thoracic surgeons in Fort Lauderdale. Using data provided by the United Network for Organ Sharing (UNOS), Mark Russo and colleagues at the University of Chicago Medicine and Columbia University found that donor lungs were routinely allocated to less urgent, local candidates even when there were patients within the region but outside the local donor service who were in much greater need.

One unfortunate but not unusual example was a 27-year-old man with cystic fibrosis who was in an intensive care unit awaiting a lung transplant. He had a lung allocation score of 91 out of 100, one of the highest of such scores in the U.S. at the time. He was expected to die within a week without a transplant. An appropriately matched lung donor did became available less than 20 miles from the hospital where this man was waiting, but because the candidate was just outside of the donor’s local service area, two candidates from within the service area, each with an LAS in the 40s, took priority. One of these candidates received the organs. Five days later the 27-year-old patient died.

Such circumstances are not uncommon, said Russo, assistant professor of surgery at the University of Chicago Medicine.

“Ideally, a suitable donor organ would be available for every person who could benefit from transplantation,” he said. “Unfortunately, there remains a critical scarcity of donor organs. More efficient allocation of this scarce and precious resource could dramatically increase the overall benefit from lung transplantation.”

Among the 580 locally allocated double-lung transplants performed in 2009, 480 less needy candidates, or 83 percent of all double-lung transplants, received the organs even though a well-matched candidate in greater need existed in the region.

Twenty-four percent of such cases involved skipping over regional candidates with lung allocation scores — which range from 1 to 100, based on need and likely benefit — more than 10 points higher than the local recipient. More than 7 percent of the events involved a regional candidate with a lung allocation score (LAS) more than 25 points higher than the local recipient. Overall, 185 of the bypassed regional candidates ultimately died on the waitlist.

“We found that too often, and to many patients’ detriment, organs are allocated according to geography rather than urgency,” Russo said. When lungs go to less needy candidates within the local Donor Service Area and never become available to sicker candidates at the regional or national level, “this decreases the overall benefits of a transplant,” he said.

Russo and colleagues previously demonstrated that 82 percent of lung transplants went to patients with an LAS of less than 50. For patients in this low-priority group, five-year life expectancy even without transplant is good — better than 50 percent. For these patients, early transplantation brings limited survival benefit, he said.

“At the same time,” Russo said, “candidates most in need and who could receive the greatest benefit are dying at high rates without the benefit of transplantation.” Most patients with high LAS are still alive after five years if they get transplanted quickly, but very few of those who do not get an organ survive more than a few months.

This study considered only double-lung candidates. It did not factor in the possibility of national matching or allow for blood groups to be crossed. As a result, “it likely underestimates the frequency of these events and lives lost,” Russo said. “Despite recent improvements in lung allocation, significant inefficiencies remain, resulting in diminished net benefit from transplantation and lost lives.”

The paper, “Local Allocation of Donor Lungs Results in Transplanting Lower Priority Lung Transplant Candidates,” by M. J. Russo, D. Meltzer, R. Gibbons, W. T. Vigneswaran of the University of Chicago and A. Iribarne and J. R. Sonett of Columbia University, was presented at the annual meeting of the Society of Thoracic Surgeons on Tuesday, Jan. 31, 2012.

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.”

Another logistical question remains: how do you get those cytokines to the brain? The body protects its most important organ with the blood-brain barrier, a biological wall that prevents most drugs given orally or intravenously from entering the brain. To solve this problem, Kraig’s laboratory has proposed borrowing a drug delivery system best known for allergy sufferers: nasal spray. For migraine, nasal delivery could be focused directly to the brain.  In theory, a spritz up the nose of IGF-1, IL-11, IFN-γ, or some combination of the three once a day might provide the necessary protection to ward off migraines.

“It’s a selective brain delivery and it’s really efficient. It’s impressive how well it works,” Grinberg said.

The laboratory has filed patents for their new treatment idea, but much more science remains to be done. While the brain slice experiments have confirmed a protective effect of cytokines against spreading depression, the same effect must be proved in whole animals before the concept can be considered for testing in humans. The laboratory is also testing whether a combination of the cytokines will be more effective than any individual factor, as well as other pressing questions of how best to use this potential new weapon against migraines.

“I think it has an extremely valuable conceptual advantage for patients, because it is derived from naturally occurring signaling by which the immune and nervous systems interact to improve brain health,” Kraig said. “Our hope is not only to develop novel therapeutics for migraine but to empower patients with the knowledge of how enrichment can lessen the severity of their migraines.”

[Photo of nasal spray by robin_24, from Wikimedia Commons.]

By Meghan Sullivan

On her visit to the University of Chicago earlier this month, Megan Urry gave two very different talks, both backed with empirical evidence and arriving at clear, well-supported conclusions. However, while her afternoon talk to the astronomy department focused on her research of Active Galactic Nuclei, Urry’s earlier talk was on a subject more universal to academia: why are there so few women in science?

Expressing a sentiment that is common among young female scientists, Urry, Israel Munson Professor of Physics & Astronomy and Chair of Physics at Yale University, started out by admitting that as a student it was hard to imagine that the blatant discrimination of the 1950s and 60s could possibly affect her career in the 1980s. Harder still was the dawning realization that many of the obstacles were based more on gender than merit, though the symptoms of bias were more subtle than they had been in the past.

“It turns out that we scientists are a species that are of great interest to [sociologists],” Urry said, describing her research into the sociological literature on gender in the STEM sciences (science, technology, engineering, and math). “Sociologists understand very well why there are so few women in science.”

The fact that there are fewer women in science is beyond doubt. Data has repeatedly shown that women’s academic careers progress more slowly and they are less likely to be hired into academic positions, where they are then less likely to get tenured. Such trends become obvious when the numbers of PhDs awarded to women and the number of female faculty members hired are compared; women are lost between each level (described previously by Nancy Hopkins as the “Leaky Pipeline”).

“Our scientific fields are not fully utilizing the talent that is out there,” Urry pointed out. “We are basically dipping deeper into the talent pool of men instead of finding the outstanding women that are out there…if we hire a smaller fraction of women as professors than there are women with PhDs we have basically thrown away talent.”

To address why women were underrepresented in these fields, Urry debunked several myths surrounding women in science, key among them being family status.

“Family is the number one hypothesis that people come up with when I talk with them about these issues,” Urry admitted with some frustration. “But the truth is this cannot be the explanation.”

Considering that 70 percent of American women with children under the age of two work, it seems unlikely that having children would uniquely affect women in science. A well-known study by Mason & Goulden titled “Do Babies Matter?” is often interpreted as concluding that if women have children, they will fall behind. In fact, women who have children are more likely to become part-time employees. This, Urry said, certainly affects women’s progress in academia. However, among women who stay full time, those without children are not more successful than women with children, indicating family status cannot define how women succeed.

“Having a family is hard, but it’s so much easier to do it as a grad student, a post doc, a tenured professor than it is - for instance - to do it as an employee at Walmart,” Urry said. “Grad students at Yale make more than your average Walmart employee. You have control of your hours, work, and you can get help pretty easily.”

Since family status is an unsupported explanation for the gender imbalance, the issue of scientific aptitude often arises. A study published by the National Academy Press entitled “Beyond Bias and Barriers” reported findings on women’s ability, persistence in science, evaluation by peers, and reviewed strategies that effectively kept women in science. By almost all measures there was no difference in ability, the one exception being rotation of 3D objects in space, which seems to be more attributable to childhood play than inborn aptitude.

“There are no measured differences between the abilities of men and women that could possibly explain the large gender gap seen in science professions,” Urry stated.

If under-representation of women in these fields is not due to family status, differences in innate ability, or conscious decisions by universities and recruiters to admit fewer women, a more subtle and, arguably, more difficult source emerged: unconscious gender bias. Various studies have repeatedly and consistently shown that work associated with a woman’s name is not rated as well as work of equal quality associated with a man’s name. Interestingly, this trend persists whether the reviewers are men or women (for a test of your objectivity, go here, a website run by Mahzarin Banaji, who studies bias across several social stratifications).

These subconscious categories bleed into real world issues in a variety of ways, including letters of recommendation, in which women are more likely to receive pedestrian descriptors such as “reliable” or “persistent” whereas men are described as “brilliant” or “creative.” Furthermore, coaching styles used by mentors are not equally effective for both men and women - men respond better to direct criticism while women improve with reinforcement of their achievements. The idea persists that if women need mentoring, or a different form of mentoring, they’re simply not good enough.

“What mentors need to understand is your graduate students are not a homogenous set of clones of you,” Urry said, stressing the need for mentors to react to the needs of their students.

So what can we do to change the status quo? While certain fields are slowly approaching equilibrium, others, such as mathematics and physics, still lag behind. Among advice she gave to young female researchers, Urry encouraged women to work at something they love, something they’ll be able to publish high-impact papers about, and to develop connections with other women in science. Such networks, Urry pointed out, are fantastic seeds of change and help provided much needed mentorship among young women. Confidence, she assured the audience, must be cultivated among young women, who should not apologize for their aspirations or become discouraged.

“Own your ambitions,” she said, “It really scares me the way young women dial back their aspirations because they’re anticipating that they’ll have to make compromises - believe me, the young men aren’t doing that.”

For citations to the studies referenced above and copies of Dr Urry’s recent talks on Active Galactic Nuclei and women in science, visit her homepage.

Just as successfully treating cancer often requires the cooperation of different disciplines, finding sufficiently predictive cancer biomarkers needs to be a collaborative effort. An ongoing University of Chicago Medicine search for a factor that can help physicians calculate the risk of brain metastasis in breast cancer patients has united researchers from neurosurgery, oncology, pathology, and Health Studies. The first fruit of that large collaboration, published late last year in the journal Cancer, discovered a promising biomarker with an innocuous name: KISS1.

The interest in brain metastases started in the laboratory of Maciej Lesniak, professor of surgery and neurology and director of neurological oncology. Lesniak, who often treats patients with these types of brain tumors, said that there is a gap in knowledge about what predisposes some women to this serious complication of breast cancer.

“If you have breast cancer, does this automatically mean that you will develop a brain metastasis? We don’t know,”  Lesniak said. “Are there any risk factors or biological phenomena behind this form of the disease? That was the question that we set out to answer.”

Fortunately, the means to test that question were available through the Specialized Program of Research Excellence (SPORE) in Breast Cancer at the University of Chicago Comprehensive Cancer Center, led by medical oncologist and Walter L. Palmer Distinguished Service Professor Olufunmilayo Olopade. The Breast Cancer SPORE maintains a bank of tissue and tumor samples that researchers could use to look for potential biomarkers. Working with Peter Pytel, assistant professor of pathology, the research team developed an assay to test levels of target proteins in tissue from metastatic and non-metastatic breast cancer patients.

For the first potential biomarker, the research team led by Ilya Ulasov chose KISS1, levels of which were previously associated with the progression of bladder, ovarian, and other cancer types. Using antibody staining techniques, the researchers measured KISS1 levels in breast tissue from patients with cancer, non-cancerous breast tissue, and brain lesions from metastatic cancer patients. The comparison found lower levels of KISS1 protein in the brain metastases relative to breast tumors, suggesting that a reduction of this protein is associated with increased spread of cancer to the brain. Another analysis correlated KISS1 levels in the patient’s tissue samples with their clinical outcome, finding that those with higher levels of KISS1 expression exhibited slower disease progression and reduced chance of developing brain metastases.

Interestingly, the relationship between brain metastasis and KISS1 expression was not correlated with previously established breast cancer subtypes that use the estrogen receptor, progesterone receptor, and HER2 gene as biomarkers.

“KISS1 is an interesting protein that seems to at least play a role which subset of patients go on to develop brain metastases from breast cancer,” Lesniak said. “The beauty of this paper is that it carries across different subtypes of tumors.”

However promising the data, the authors caution that their study is only the first step toward establishing KISS1 as a valid biomarker for predicting the course of metastatic breast cancer. Until the biological link between KISS1 expression and cancer progression can be determined, the relationship can’t be considered more than a correlation. But if a mechanism is discovered, Lesniak speculated that KISS1 may hold clues to a way to stop or slow brain metastases from occurring.

“The question is how can you modulate KISS1 expression for the benefit of patients,” Lesniak said. “One approach would be to restore KISS1 expression in patients with advanced metastatic breast cancer, and see whether it makes the tumor less aggressive or less prone to metastatic disease. It’s an interesting thought, but it’s probably too premature to know whether that would hold true.”

Regardless, the search for breast cancer biomarkers won’t settle for just one factor, be it KISS1, HER2, or other cellular proteins. The hope is that more and more reliable predictive biomarkers will be discovered, until a patient’s cancer can be tested and diagnosed in detail, pointing the way to effective and personalized treatment.

“I think this shows what kind of studies we have to do to get better at predicting this process,” Pytel said. “At the moment, it’s only one marker, which is not where we want it to be. But it offers hope for a future where we could come up with panel of markers that would be helpful in predicting details about the progression of cancer in a patient.”

Scientists have tried to understand the order underlying this chaos by studying modern animals that have established broad diversity, such as the immense cichlid family of fishes (which encompasses over 1,000 documented species) or Darwin’s finches of the Galapagos islands. But these studies can only work backwards from the species that exist today. To watch an adaptive radiation unfold, a better source is the fossil record, as the University of Chicago’s Lauren Sallan and the University of Oxford’s Matt Friedman discovered in a recent journal article for Proceedings of the Royal Society B.

Sallan and Friedman used fossil databases from two prehistoric mass extinction events: the Hangenberg event, of roughly 359 million years ago, and the end-Cretaceous extinction, which ended the age of dinosaurs. By measuring how surviving fish species changed body shape and size after these ecological disturbances, the researchers could test two common theories of adaptive radiation inspired by studying surviving species. One model proposed a free-for-all “burst” of divergence followed by a long period of relative stability. Another, sometimes known as the “general vertebrate model,” introduced the idea of staged divergences, with habitat-driven changes in body type preceding diversification of head types.

“There hadn’t been any tests of these things using fossils,” said Sallan, a graduate student in the Department of Organismal Biology and Anatomy. “You have all these analyses of diversification, yet not one of them goes back to the fossil record and says what’s happening at this time period, and the next time period, and the one after that.”

When Sallan and Friedman looked carefully at their data, they didn’t find evidence for either of the pre-existing theories. Instead, they saw a staged radiation that started not tail-first, but head-first, with surviving species initially trying out a wide range of head shapes attached to similar bodies. The driver of this diversity may have been a simple factor: food. Faced with far less competition, the surviving fish evolved new types of teeth, jaws, and heads to take advantage of the expanded menu suddenly available. Later, once head shapes stabilized, different body types from broad and flat to thin and eel-like appeared as new species adapted to their surroundings.

“It seems like resources, feeding and diet are the most important factors at the initial stage,” said Sallan, who works in the laboratory of University of Chicago Professor Michael Coates.

“Strange heads show up first — crushing jaws, animals with big teeth, with long jaws — but they’re all pretty much attached to the same body. Ecological limits are taken away, and there’s more opportunity out there, more available resources, and they’re taking advantage of that. Later, they’re taking advantage of specializing to new habitats. So it’s not something within the animals themselves; it’s more opportunity that matters.”

While the new study refutes previous theories and offers two distinct examples of head-first diversification separated by hundreds of millions of years, the universality of the model remains to be conclusively proven, the authors said.

“Evolution is really complex, and it’s not really clear that there should be only one model,” Sallan said. “It might be that this model might apply to fishes in certain time periods, or might apply to vertebrates, but a lot more investigation is needed to see whether that is actually true.”

[Read more about the study at Scientific American and Discovery News.]

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Sallan LC, & Friedman M (2011). Heads or tails: staged diversification in vertebrate evolutionary radiations. Proceedings. Biological sciences / The Royal Society PMID: 22189401

Joseph Kirsner, MD, continues to report to work after 76 years as a gastroenterologist at the University of Chicago Medical Center. At 102, he must be doing something right. Sure, he keeps his mind and body active by keeping up with research and coming into the office. But how much of longevity is attributable to a healthy lifestyle and good genes, and how much is due to luck?

Two researchers at the Center on Aging at the University of Chicago have found that luck plays a significant role in living to 100. In a new study published in The Journal of Aging Research, they found that people born in September, October or November had higher odds to crack the century mark than those born in the spring.

Leonid Gavrilov, PhD, and his colleague and wife, Natalia Gavrilova, PhD, look for clues to longevity at the Center on Aging, which is part of NORC at the University of Chicago. They study potential predictors and determinants of human longevity, such as family background and environment. “It’s a way to get insights into mechanisms of aging and longevity, and hopefully to find new approaches to extend healthy human life,” Leonid Gavrilov said.

In past studies they found that chances for exceptional longevity are higher for U.S. citizens who were born to young mothers, had a slender or medium body build at age 30 and were farmers or spent their childhood on a farm. Studying pooled data about longevity for large populations can be tricky though.

“People from families with different ethnic, educational and income background may have somewhat different chances for long life,” Natalia Gavrilova said. “Also, different families may have slightly different seasonal patterns of births, because of religious and cultural traditions, holidays and vacation preferences.”

To control for unobserved differences between families in their latest study, they used a “within-family” approach by studying differences in life span between siblings within the same families, with the same parents and family background. They also studied spouses in the same families who lived together and shared their living conditions at adult age.

The study, supported by the National Institute on Aging, is based on data collected from Rootsweb, a publicly available repository of online genealogies. Using computer scripts to sift through the data, they found more than 2,800 families with enough information on birth and death dates of siblings to analyze. “The within-family approach significantly adds credibility to the claim that human longevity is indeed affected by the month of birth,” Leonid Gavrilov said.

How exactly it affects longevity isn’t clear yet, but Gavrilov said he has several hypotheses that he’d like to test. One possible explanation is maternal diet during pregnancy. Nutritional deficiencies during early development can have long-lasting effects later in life and play a major role in DNA damage, aging, and premature deaths from cancer and heart disease. Seasonal vitamin deficiencies in a mother’s diet during pregnancy, or the child’s diet during infancy, can affect longevity.

Another possible explanation is exposure to seasonal infections during pregnancy. Seasonal peaks for infections during spring and summer are common, and exposure to diseases such as German measles, chickenpox and poliovirus during gestation can result in birth defects.

Birth month can also influence longevity through climate, such as seasonal temperature and sun exposure. Experiencing higher summer temperatures during the first year of life can cause severe diarrhea and dehydration in infancy, with long-lasting effects. Higher temperatures at the time of conception can also affect sperm quality.

All of these factors mean that people born during the fall avoid the accumulation of birth defects, diseases and general wear and tear on the body that can limit life expectancy. Gavrilov said this highlights the importance of prenatal care and early life experiences. “The roots for overall health and adult survival are likely to be in human development during pregnancy and childhood,” he said. “This is the time when reserve capacity, numbers of functional cells and units, of different tissues and organs is determined, thus affecting physiological reliability and durability in later life.”

But while looking back at family histories helped find this link between birth month and longevity, the study found that the effect of the season of birth is declining for more recent generations. Modern diets are less seasonal than in the past, lessening the effects of seasonal nutritional deficiencies during pregnancy, and modern immunization regimens limit the impact of infectious diseases.

A group of researchers from Boston University recently studied the genomes of two 114-year-olds and found, surprisingly, that they were basically the same as other people’s. The secret to longevity may not lie exclusively in extraordinary genes, birth month or even luck. A whole host of genetic and environmental factors have to fall into place for someone to live past 60, let alone 100. “People with exceptional, healthy longevity represent the results of a successful, natural experiment on healthy life extension and delayed aging,” Gavrilov said. “We have to find out the secrets of longevity by studying deeply all the details of this natural experiment.”

To learn more, visit the authors’ scientific website and discussion blog.

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Gavrilov LA, & Gavrilova NS (2011). Season of birth and exceptional longevity: comparative study of american centenarians, their siblings, and spouses. Journal of aging research, 2011 PMID: 22187646

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

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

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

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

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

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

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

In another experiment, the researchers threw their subjects a category curveball. The monkeys were shown an ambiguous set of moving dots on the border between the two learned categories, then asked to compare them with a second set of non-ambiguous dots — a test with no correct answer, akin to an umpire’s borderline pitch. The subjects were required to make a decision about which category the ambiguous stimuli belonged to, and once again LIP neurons corresponded to that decision more closely than PFC.

“During the decision process, parietal cortex activity is not just correlated — it even predicts ahead of time what the monkey will tell you,” Swaminathan said. “You can record neuronal activity in parietal cortex and, in many cases, predict with great reliability what the monkey will report.”

Due to technical hurdles, running the same experiments in actual baseball umpires would be very difficult. But the underlying principle is likely the same in his gamer monkeys and MLB’s Men in Blue, he said: “It’s an interesting learned behavior that’s highly critical for an individual to perform with great reliability, and it’s a spatial categorization with a sharp boundary, so we think it’s the same process.” Studying how those categories are learned and stored in the brain is one of the laboratory’s next goals, with the long-term aim of understanding more about how the brain organizes the busy world into useful groups…and perhaps even how to improve that process.

“The number of decisions we make per minute is remarkable,” Freedman said. “Understanding that process from a basic physiological perspective is bound to lead to ways to improve the process and to help people make better decisions. This is particularly important for patients suffering from neurological illnesses, brain injuries or mental illness that affect decision making.”

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Swaminathan, S., & Freedman, D. (2012). Preferential encoding of visual categories in parietal cortex compared with prefrontal cortex Nature Neuroscience DOI: 10.1038/nn.3016

Parents of young children know the drill for childproofing a home: covers on electrical outlets, gates at the top and bottom of stairs, cabinets and drawers locked, fragile knickknacks placed safely out of reach of little hands. But how many parents worry about toddlers using a microwave oven?

As you probably know from reheating leftovers or whipping up a batch of ramen noodles, microwaves can heat food to extremely high temperatures very quickly. It’s hard enough for adults to avoid singeing fingers while pulling a hot bowl of soup out of the microwave; imagine the danger posed to kids. A new study by researchers at the University of Chicago Medical Center found that children as young as 17 months old can turn on a microwave, open the door and remove items, putting them at significant risk for scald injuries.

Scalds are the leading cause of burn-related injury to children living in the United States. In 2009 an estimated 1,230 children younger than 5 years old were treated in emergency rooms for burns related to microwave ovens. Marla Robinson, assistant director of Inpatient Therapy Services at the Medical Center and lead author on the study, said that over the past four years the emergency department has treated an increasing number of young children for burns related to taking items out of a microwave. “These young children were getting very significant burns causing disfiguring scars and putting them at risk for contractures and deformity,” she said. “They can push the button and take something out, and it spills down their face, neck, chest and arms.”

Robinson and colleagues from the University of Chicago Burn Center, Children’s Memorial Hospital, Central DuPage Hospital and the University of Illinois at Chicago wanted to draw attention to the risk for these injuries and build a case for the need to redesign microwaves with more safety features for children. So they took a group of 40 kids ranging from 15 months to 5 years old and put them in a test kitchen with microwaves on a counter that they could reach. They asked the children to turn on a microwave, open the door on two different styles of ovens, with either a push button or handle, and remove a cup with a small amount of water (not one that was heated, of course).

What they found is enough to make any parent lock up the microwave in the highest cabinet, if not get rid of it altogether. By age 2 more than 80 percent of the children could turn on the microwave, open both types of doors and remove the cup. By age 4, all of them could, and even one 17-month-old could perform all the tasks. Robinson says the results weren’t surprising, because kids are naturally attracted to microwaves. “It makes noise. It beeps. It’s fun,” she said. “You push buttons, so it looks like a toy.”

She says the key to preventing scald injuries is educating parents about the risks. “A lot of times these injuries happen in the child’s home while under the supervision of their primary caregiver. The parents just weren’t in the room and the kids were imitating their behavior,” she said.

Children from lower-income homes where the microwave is the only cooking source or who may be under the care of older siblings for long periods of time are especially at risk. But as any parent knows, keeping an eye on little ones every second is nearly impossible. Kids are also remarkably ingenious at getting into the wrong places, so even putting the microwave out of reach isn’t a perfect solution.

Kyran Quinlan, MD, a former University of Chicago pediatrician now with Northwestern University who also worked on this study, has begun working with the Consumer Product Safety Commission to urge regulatory changes in the way microwaves are designed to prevent children from operating them. Locking mechanisms on doors and key codes that require two-handed operation could make microwaves safer. Until those safety features become standard, the only solution is awareness.

Robinson hopes this study can lead to guidelines like the CPSC issued for temperature settings on hot water heaters to prevent scalds. “We do get tap water scalds but not as much, with the overall decrease in those injuries nationwide, because those regulations have been put in place,” she said. “What we are seeing more now are these food-related injuries, and it’s amazing that it’s affecting these kids.”

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Robinson MR, O’Connor A, Wallace L, Connell K, Tucker K, Strickland J, Taylor J, Quinlan KP, & Gottlieb LJ (2011). Behaviors of young children around microwave ovens. The Journal of trauma, 71 (5 Suppl 2) PMID: 22072042

Imagine your doctor says he plans to increase your oral medication to control your diabetes. You do not like taking pills. Should you:
A. Not rock the boat with your doctor and agree to take the increased dosage?
B. Agree, but keep taking the same number of pills?
C. Try to discuss another option with your doctor?

Monica Peek, MD, assistant professor of internal medicine at the University of Chicago, believes the best answer for long-term health and happiness is C. But she knows that low-income African Americans with diabetes will often, for a variety of reasons, agree with the doctor and then ignore the advice. Peek has spent hours leading classes with patients from this vulnerable group. They role-play talking to their doctor, critique each other as they practice, and give a debriefing on whether they could ever truly feel comfortable taking an active approach with a physician.

The classes are part of a new program to chip away at the disparities in diabetes among low-income African Americans. The gap is huge. The prevalence of diabetes on the South Side is 19.3 percent, compared with an average prevalence in Chicago of about 7 percent. African American neighborhoods in Chicago have five times the rate of diabetes-related leg amputations as primarily white neighborhoods do.

Three years ago, about 40 people at the University of Chicago Medical Center with expertise in nutrition, cultural tailoring, communication, quality improvement, and even community organizing launched an effort to close this gap. They were prepared to tackle multiple factors that exacerbate diabetes outcomes on the South Side. Among them are unhealthy eating habits, limited safe places to exercise, food insecurity and less access to health care.

Their first move was to get out of the hospital.

The group created teams at six community health clinics to focus on improving diabetes care. They led patients on field trips to local grocery stores to practice making smart food choices. The physicians were constantly on the radio, at health fairs, in churches and high school gymnasiums, educating South Siders about diabetes. Still, the Medical Center team ran into challenges from all sides.

“The economic factors of people choosing between food and medications don’t account for all of the disparities,” Peek said. “There is racial and cultural baggage that creeps into clinical encounters between doctors and poor African American patients.” As an example of this long history of bias, Peek cites a famous 1999 study from Georgetown University in which cardiologists were found to offer better care to men over women who complained of heart problems, and to white patients over black patients.

“People who have had bad interactions with the health care system may delay treatment until their condition is dire,” Peek said. Some say they are afraid of being experimented on, that they don’t trust doctors to do right by them, or that they dislike the perceived power imbalance of being in a doctor’s office.

Peek said she was surprised to learn how some low-income African Americans view the doctor-patient relationship. A woman told her that she gets agitated when she goes to a doctor’s office and hears, “What brings you here today?” — she thinks the doctor is saying, “Why are you sitting in front of me when I’m so busy?”

“It was eye-opening to me,” Peek said. “This is how we teach our medical students to serve their patients, but it can actually alienate low-income African Americans.”

Believing that she could change this mistrust through education, Peek started a weekly class with diabetes patients.

The class used questions like the one about a doctor increasing medication dosages to discuss how patients could be more involved during meetings with their physician. “We culturally tailored the curriculum for our audience and made it more hands-on and more entertaining. We also made it more appropriate for lower literacy levels,” Peek said. Instead of written handouts, there were games and videos.

The class was so popular and the exit interviews so encouraging that Peek has repeated the entire 10-week course three additional times. Class participants have not only visited a food pantry that stocked healthy foods and joined public fitness centers, but their glucose monitoring, foot care, and glucose control improved significantly.

Marshall Chin, MD, professor of medicine and an internist at the University of Chicago, focused his efforts on improving not the patients, but their medical care. “If a physician sees a patient for 15 minutes, three times a year, and tells her to exercise and lower her sugar intake without helping her figure out how, it’s a set-up for failure,” he said.

Quality improvement teams worked at the six community health clinics on the South Side, trying to improve their diabetes care and their use of programs and support systems within each patient’s community. “The patient spends most of his life at home, in his community, in his workplace. Without additional support systems outside the clinic, we’re sunk,” he said.

Chin believes that medical providers may understand the challenges that poor black patients face in caring for themselves, but the health care system is not currently set up to address these problems. Part of the solution is to connect diabetes patients to the resources in her community. For example, a physician can write a “fitness prescription” for a patient, to give her six months of free access to a Chicago Park District gym.

The community health center staff is also developing “food prescriptions” that give patients access to free or discounted healthy food, and trying to connect their patients to a popular community center with cooking demonstrations and a food pantry.

“People sometimes feel overwhelmed with the challenges of diabetes on the South Side, but there are tremendous strengths in this community,” Chin said.

The early data from the program are promising. Since the program started three years ago, 4,000 people who were using the Emergency Department for primary care have been connected to a medical home.

The results of the first three years of this all-out assault against diabetes, called “Early Lessons From an Initiative on Chicago’s South Side to Reduce Disparities in Diabetes Care and Outcomes,”  are published in the January issue of Health Affairs.

The program has funding for seven years from the Merck Company Foundation and the National Institutes of Health, and will continue to grow as the data show improvements in diabetes outcomes.

“Diabetes is a huge problem that hurts a lot of people and takes up a lot of resources. But until now, the solutions we have seen haven’t been powerful enough,” Chin said. “Finally, we have a model showing that we can make a difference.”

The concept of “irreducible complexity” is a favorite talking point of the forces against evolution, both today and historically. As the argument goes, the complex structures found within modern organisms — from the eye to the microscopic protein machines that conduct business in cells — are far too complicated to be the result of the random genetic mutations and selective forces at the core of Darwin’s grand theory. The argument is so old that Darwin himself addressed it in On the Origin of Species, speculating on how an accumulation of small changes could lead from a simple photoreceptor to the wondrous eye shared by many organisms today.

The best way to demonstrate how the minute changes of evolution could produce great complexity is to capture that process in action. But to happen upon such a leap live would be a biological needle in an enormous haystack. A better strategy would be to pick a historic leap in complexity from the evolutionary past, and then go back and observe how it happened. Easy, right?

To accomplish this task, Joe Thornton, a new faculty member in the Departments of Human Genetics and Ecology & Evolution, developed the method of “molecular time travel.” Instead of a Delorean, Thornton’s method uses a computational analysis of the genes from modern-day species to resurrect the genes of ancestral species that lived hundreds of millions of years ago. For the new paper, Thornton and colleagues at the University of Oregon decided to “travel” back to look at a complex molecular machine found in various species of fungus.

“Our strategy was to use ‘molecular time travel’ to reconstruct and experimentally characterize all the proteins in this molecular machine just before and after it increased in complexity,” said Thornton, professor of human genetics and evolution & ecology at the University of Chicago, professor of biology at the University of Oregon, and an Early Career Scientist of the Howard Hughes Medical Institute. “By reconstructing the machine’s components as they existed in the deep past,” Thornton said, “we were able to establish exactly how each protein’s function changed over time and identify the specific genetic mutations that caused the machine to become more elaborate.”

Their target was a molecular machine called the V-ATPase proton pump, which helps maintain the proper acidity of compartments within cells. In modern Fungi, this pump contains a six-part ring made up of three separate proteins, but that wasn’t always the case. Some 800 million years ago, that same ring was made from only two proteins, meaning some kind of event occurred around then to increase the complexity of this machine.

Thornton’s group calculated the genetic sequence of the ring proteins from that ancient ancestor using the sequences of 139 modern Fungi family members, computationally tracing their common elements back up the Tree of Life to their ancient predecessor. The researchers could then reproduce the protein before the split (called Anc.3-11) and the two proteins that came after the split (Anc.3 and Anc.11), and see how they functioned in the proton pump’s ring.

Surprisingly, the “newer” proteins were less versatile than the ancestral Anc.3-11, which could substitute for either of its descendants when transplanted into modern Fungi. The result suggests that the pump’s increase in complexity resulted not from the evolution of a new, “better-designed” function, but from an initial loss of versatility.

“It’s counter-intuitive but simple: complexity increased because protein functions were lost, not gained,” Thornton said. “Just as in society, complexity increases when individuals and institutions forget how to be generalists and come to depend on specialists with increasingly narrow capacities.”

The scientists also looked under the hood at exactly what genetic changes were responsible for the ancient shift from two ring proteins to three, finding that no tricky moves were required. A duplication of the Anc.3-11 gene and two single nucleotide mutations — both common genetic events — were all it took to split one gene into two and produce the more complex modern ring.

“The mechanisms for this increase in complexity are incredibly simple, common occurrences,” Thornton said. “Gene duplications happen frequently in cells, and it’s easy for errors in copying to DNA to knock out a protein’s ability to interact with certain partners. It’s not as if evolution needed to happen upon some special combination of 100 mutations that created some complicated new function.”

That’s a direct hit upon the claim of intelligent design that extraordinary events were necessary to create the extraordinary molecular machines that make life possible. Thornton, no stranger to arguments with ID proponents, says that his simple experiment provides proof that small changes can lead to big biological effects, and expects that similar minute shifts with great consequences could be found driving the evolution of other seemingly irreducible elements.

“These really aren’t like precision-engineered machines at all,” he added. “They’re groups of molecules that happen to stick to each other, cobbled together during evolution by tinkering, degradation, and good luck, and preserved because they helped our ancestors to survive.”

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Finnigan, G., Hanson-Smith, V., Stevens, T., & Thornton, J. (2012). Evolution of increased complexity in a molecular machine Nature DOI: 10.1038/nature10724