by Rob Mitchum

Too often, art and science are treated as intellectual adversaries. Educational systems typically route students toward one pole or the other, with the artistic and scientific spheres rarely intersecting by the time one reaches the undergraduate and graduate levels. But for the last two years, the University of Chicago has paved a path between these two fields with the Arts|Science Initiative, which offers grants to collaborations that reach across the traditional boundary lines.

This year’s presentation, which took place in the “performance penthouse” of the brand-new Logan Center for the Arts on the south end of campus, featured six such partnerships formed between scientists and doctors-in-training on one side and artists, sculptors, and filmmakers on the other. The projects covered a wide span of ideas and technologies, from 3-D sculptures based on math theorems to hacked Wii controllers that allow dancers to make music as they move. In each case, the participants raved about how the collaboration allowed them to flex a different part of their mind, approaching familiar topics with a fresh set of eyes and think about new, creative ways to merge the artistic and the scientific.

Trauma Under the Microscope: Collected Perspectives on PTSD

Post-traumatic stress disorder has frequently been in the headlines lately, as tragedies such as the killing of 17 Afghan civilians by a US soldier draws attention to the high incidence of the condition in veterans of war. But the definitions of “trauma” and “PTSD” vary widely from person to person, clouding the issue of what causes the disorder and how it is diagnosed and treated. Many journalists and laypeople misuse the term, or fail to understand that PTSD is caused by a constellation of factors, not a single incident of trauma, said Nicole Baltrushes, a Pritzker School of Medicine student.

So Baltrushes collaborated with Sravana Reddy of the Computer Science program and Carmen Merport of the English Department to create an interactive website on PTSD. Starting with a print flyer, the team asked friends, family, faculty members from several disciplines and health professionals to annotate the flyer based on their understanding of the disorder and its terminology. They then took those notes, plus various multimedia links to poetry, videos, pictures, Facebook posts and other sources, and built an interactive webpage that can be added to and customized by users.

“The hope is that as more people visit the site, and as more people hear about the site, that there can be a web-based conversation that we start about what is trauma and PTSD, to broaden our understanding,” Baltrushes said. “Because as of yet, we have not the greatest understanding of what these things are, or how to even approach healing of these things on any level.”

Opening

As laboratory imaging technologies improve, science becomes more and more of a visual discipline. In the film “Opening,” Jared Clemens of the Committee on Neurobiology and Marco G. Ferrari of the Department of Visual Art make the connection between scientific videos and the world of film explicit through innovative use of split screens, montage, and audio editing. While original footage featuring neuron-esque trees on the University of Chicago campus runs in the middle of the screen, laboratory videos of actual neurons run on the left side while scenes captured from films such as Elephant Man, The Shining, and Rear Window play on the right. Meanwhile, the audio track alternates between scientific descriptions of the structure and function of the brain and movie dialogue that touches on the nature of the mind.

“This piece originated in a personal interest in the disconnect that exists between much of the public and the sciences,” Clemens said. “I wanted to explore this in a non-traditional way…the structure of the piece is an abstraction of the chaos and dynamics that exist in neural circuits, as well as the chaos that exists between the public and the sciences.”

read more

By Rob Mitchum

Alan Turing is best known as the father of the modern computer, a skillful World War II codebreaker, and a pioneer in the study of artificial intelligence. But in the last years before Turing’s death at age 41, he  aimed his genius at a different target: the then-stalled field of developmental biology. By the middle of the 20th century, many scientists had tried and failed to explain how a complex organism could form itself from a simple embryo originally made up of identical cells. One 19th century biologist, Hans Driesch, grew so frustrated with the problem that he gave up and wrote a text on vitalism, the doctrine that life cannot be explained by science alone.

In a 1952 paper called “The Chemical Basis of Morphogenesis,” Turing rushed headlong into this challenge, building a mathematical model of how patterned cells can be formed from non-patterned beginnings. It was Turing’s only published work on the topic; he died two years later. But in those 35 pages, he predicted elements of developmental biology that wouldn’t be discovered for 30 more years, coined a term that is central to the field today, and accidentally sparked a new sub-field of mathematical study for a bonus. In a recent Nature retrospective commemorating Turing’s 100th birthday, University of Chicago scientist John Reinitz wrote, “What Turing should receive credit for is opening the door to a new view of developmental biology…He was well ahead of his time.”

Reinitz’s own research is deeply indebted to Turing’s landmark paper. A professor with appointments in Statistics, Ecology & Evolution, and Molecular Genetics & Cell Biology, Reinitz’s laboratory studies how gene expression controls the development of the fruit fly Drosophila melanogaster. As part of those efforts, the laboratory has built several computational models of gene transcription and fly development, one of which is a specific example of a class of equations in Turing’s paper, Reinitz said in an interview about his essay.

Beyond that direct lineage, Reinitz admires the paper (”The article is just a pile of interesting ideas.”) and teaches it in his courses. But it wasn’t fully appreciated in the field of developmental biology until decades after its publication, when the role of DNA and the molecules that Turing preemptively named “morphogens” became more widely known in biology.

“When I was in grad school, this paper was circulating, and it was considered to be a sort of interesting but crazy paper,” Reinitz said. “It didn’t have anything about genes, and when I first saw it, it was really before any of these morphogens had actually been found. So it didn’t seem to have any direct bearing on actual experimental science.”

The core of the paper is a computational model — one of the first ever published, Reinitz said — that mathematically proved one could create complex patterns from a symmetrically organized cell. Early in development, the “pluripotent” cells of the embryo are each capable of developing into a wide range of cell types, from blood to skin to muscle to hair. Indeed, if an embryo is split in two early enough, it can form two entire organisms…as is the case with identical twins.

Classic linear mathematics can’t explain how one generic cell can produce so many unique descendants. So Turing’s model employed a “mathematical trick,” using the interplay of two diffusing factors (Turing’s “morphogens”) to produce the temporary instability necessary for a pattern to form. That these morphogens had never been observed in scientific experiments at the time he published was beside the point; Turing simply wanted to show that pattern-making could be done with a minimum of elements.

“I think that one of the things that’s seriously misunderstood about the paper is that a lot of people read it and think it’s making specific predictions about biological systems,” Reinitz said. “The main thing he was concerned about was just demonstrating that you could form patterns from non-patterns. He wanted to show with chemistry that you can have patterns form spontaneously.”

read more

Under normal circumstances, people want to keep infections away from their computers. But for Gary An, reconstructing nasty infections inside a computer is a research project, not an act of cyber-terrorism. In collaboration with laboratories at the University of Chicago Medicine studying infectious diseases, An is creating computer models that simulate the delicate, complex balance between bacteria and their home in the human gut. By replicating the results of previous experiments within computational space, An hopes to enable in silico experiments that can push scientific discovery beyond the confines of the lab bench.

In two recent papers, An, associate professor of surgery at the University of Chicago Medicine, describes computer models that simulate a common post-surgical infection and a rare but very serious gastrointestinal condition that strikes premature infants. In both cases, the model uses research findings to recreate at least a portion of the microbe-host relationship in the gut, in order to look for clues as to why bacteria that normally live peacefully inside the intestines suddenly decide to attack.

Pseudomonas aeruginosa, a common cause of infection in patients recovering from surgery, is one such tenant turned aggressor. Most people are colonized by P. aeruginosa without ever realizing it, as it finds a quiet home in the lining of the gut alongside thousands of other bacterial species. That’s until the human host grows ill or undergoes major surgery and the comfort of the gut is disrupted, sometimes causing P. aeruginosa to riot. But this breakdown of what John Alverdy, professor of surgery, calls “molecular diplomacy” doesn’t always occur, creating a need for models that can describe how this system works — and fails.

“Part of the point of studying this particular bacterium and its role in infection is that there is a dynamic interplay between the bacterium itself and its environment…which happens to be a human,” An said. “The idea is to use the modeling as an iterative tool to help basic science labs do what they do a bit more efficiently. Using this model, we can gain insight into what they need to work on in the future.”

Surgical fellow John Seal led the effort to create a computer simulation of P. aeruginosa in the gut using agent-based modeling, where the simple actions of individual bacteria or cells sum up to a dynamic, complex system. In this case the “agents” are the bacterial and epithelial cells, which are set in Seal’s model against a backdrop of the gut’s mucosal layer and intestinal lumen. How those agents interact, and what various changes in the environment do to their behavior, were modeled after the results of experiments conducted over many years in Alverdy’s laboratory. As the model grew, the designers frequently tested it back against those experiments, to make sure the results of running the model accurately replicated what has been observed in the lab.

“It’s actually a very rigorous sort of thing, since we’re making it all up,” An said. “There are no laws of physics or chemistry in the model. It will do whatever you make it do. It’s potentially dangerous to get off track easily, therefore you constantly need to have reality checks back to the behavior of the system.”

Now that the system is in place, the science can move into the in silico world. Researchers can challenge the system in ways that would be difficult to do in a lab dish or an animal model, and can receive feedback on how the bacteria will respond. In the 2011 paper, published in Theoretical Biology and Medical Modeling, the team simulated conditions of host stress by adding inflammatory factors or endogenous opioids to the model to observe how they affect the virulence of P. aeruginosa — the likelihood that it will break its truce with the surrounding gut and attack. These simulations can generate new hypotheses to test in the laboratory, and also clue researchers into how best to run those experiments, such as suggesting the best timepoints to sample in a real-world experiment.

In another model, the same principles are applied to a disease called necrotizing enterocolitis, or NEC. Seen most often in babies born prematurely, the disease causes severe inflammation of the intestines that must be treated with severe surgery to avoid mortality. But despite clues gathered from animal experiments about the importance of early diet, feeding tubes, and the makeup of the gut’s bacterial ecosystem, no full model exists to predict which babies are at risk for this disease. An NEC computer model, built by An with fellow Moses Kim and professor of surgery and pediatrics Donald Liu and published in Surgical Infections, could help identify factors that put a premature infant at risk.

“It can’t be every kid that’s born early, can’t be every kid that you feed by tube, can’t be every kid that swallows some bugs. It has to have some particular component associated with that,” An said. “If, for instance, you could find a gene or an expression level in a premature infant that would suggest that their metabolic stress management capability is decreased, then you could identify a sub-population of kids that were at risk beyond the 3 in 1,000 incidence that it currently is at.”

read more

By Rob Mitchum

In 1972, a physicist named Robert May tried his hand at a different scientific discipline, publishing a simple formula that inflamed the field of ecology. Scientists studying the structure of natural ecosystems had long assumed that diversity was an inherently good thing — those ecosystems stocked with thousands of species were likely more resistant to extinctions, changes in climate, or other challenges. May, with a physicist’s eye for simplicity, crafted a model that predicted the stability of an ecosystem using just the number of species and how strongly they interact with each other. But when it was used, May’s formula provided a surprising and counter-intuitive result: species-rich ecosystems, such as rain forests and coral reefs, should be too unstable to exist.

That paper, published in Nature under the title “Will a Large Complex System be Stable?” (May’s answer: No), was both a major step for computational ecology and the ignition of what came to be called the diversity-stability debate. The disagreement between May’s model and what ecologists saw in reality provoked the question of how nature rescues what should be an unstable ecosystem, allowing it to survive. Ecologists began looking for what May called “devious strategies” — the workarounds that a natural system uses to increase its species capacity without sacrificing its stability. Soon, May’s elegant formula became swollen with additions meant to reconcile the mathematical predictions with field observations.

Stefano Allesina, assistant professor of Ecology & Evolution at the University of Chicago, decided to take a different approach. Rather than building even more complex additions on to May’s model, Allesina and graduate student Si Tang, sharpened their pencils and went back to the original source, tweaking the model by thinking about the general types of ways species interact in nature. Their new model, published 40 years after the original in the same journal, adjusted May’s formula to incorporate predator-prey or consumer-resource relationships, where one species profits at the expense of another. The small changed allowed the model to describe an ecosystem where stability is possible even with an infinite number of species.

“Predator-prey relationships are stabilizing. We can fit much larger ecosystems if there’s a backbone of predator-prey interactions, and see a lot of species happily co-existing ever after,”Allesina said. “We kind of solved this one puzzle of how can we see very many species in an ecosystem. But then we open different puzzles.”

May’s original model, designed to be as general as possible, assumed random interactions between species. But in nature, two species can interact with each other in one of three general ways: as predator and prey, as competitors, or as part of a mutalistic relationship. In the predator-prey or consumer-resource relationship, one species benefits from another species’ loss, be it a lion eating a gazelle or a caterpillar eating a leaf. Competition theoretically has a negative effect on the two species fighting over the same food source, while mutualism (rarely seen in nature) can benefit both participants. By building each of these three relationships separately into May’s model, Allesina and Tang discovered that these interactions each produce very different ecosystems.

In the predator-prey condition, the stability of the ecosystem is increased such that a large number of species can be supported. In the competition and mutualism systems, the ecosystem is highly unstable and vulnerable to perturbation.

“What we are showing is that of all the types of interactions you can have, only predator-prey can support an infinite number of species,” Allesina said. “If you look in nature, there are very obvious consumer-resource relationships everywhere, and maybe this system assembles so easily because these relationships provide a lot of stability.”

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

Like a basement in a flood plain, a cell needs a good pump. Cells must maintain a particular mix of ions inside their membrane walls, with low concentrations of sodium and high concentrations of potassium. The only problem is that cells are leaky, and sodium constantly rushes into the cell while potassium rushes out. To fight against this tide, the cell uses a very important and peculiar membrane protein called the sodium-potassium pump.

Since its discovery in the 1970’s, cell biologists have been baffled by the strange features of this powerful pump. Rather than an even one-to-one swap of potassium for sodium, in each cycle the pump transports three sodium ions out for every two potassium ions it takes in. Later, scientists discovered that both sodium and potassium could bind to the same locations on the pump, a fickle temperament that is unusual among membrane proteins typically very picky about the type of ion they bind. That presented an intriguing molecular engineering problem — how could the pump modify itself to bind sodium when it’s accessible to one side of the membrane and potassium when it’s accessible to the other?

Some biologists have suggested that this riddle could only be answered by analyzing the highly precise geometry of the binding sites. Thus, many predicted that the model could not be solved until the most minute details of the structure of the sodium-potassium pump was fully captured in both its sodium-bound and potassium-bound states. So far, only the latter pictures (taken by X-ray crystallography) exist. But Benoit Roux, professor of biochemistry and molecular biophysics, decided that half the information was good enough to form a new theory of how the pump pulls double duty.

“Biologists have swept this under the rug, saying we need to know the structure of both the sodium and potassium bound forms with a sub-angstrom accuracy to address this issue,” Roux said. “Our point of view is that proteins are flexible macromolecules and that the mechanism of ion selectivity ought to be fairly robust, even when there are small sub-angstrom thermal fluctuations.”

Roux’s group, which included Haibo Yu of UChicago and Ian Ratheal and Pablo Artigas from Texas Tech, applied a computational method called molecular dynamics to the two existing crystal structures of the pump - isolated, strangely, from the rectal gland of a shark. For a paper published in Nature Structural & Molecular Biology last week, the team ran computer simulations that tested the possibilities of how four important amino acids in the binding sites mediate the pump’s change in selectivity under normal conditions. Instead of a complicated transformation from sodium-binding to potassium-binding mode, Roux’s model identified a small change that could account for the pump’s changed loyalties.

Protonation is a chemical reaction that adds a single hydrogen atom to a molecule. The four binding site amino acids of interest happen to carry negatively-charged acidic side chains that may or may not bind an extra proton. Roux’s group found that when the four acidic residues lose that extra proton (called deprotonation), they strongly prefer sodium to potassium. In their protonated state, the preference reverses to potassium over sodium.

“At this point it’s speculation because we do not know the structure of the sodium-bound state. But perhaps protonation and deprotonation play a more active role on modulating selectivity of these sites during the functional cycle of the pump,” Roux said. “It’s a provocative idea, nobody has ever proposed something like that to the best of our knowledge. Some people might be a bit shocked.”

read more

There’s something quaint and charming about a family business, where multiple generations work shoulder to shoulder to keep an enterprise afloat. But when the business in question is academia and the salaries are paid by tax dollars, suddenly keeping it in the family carries the stink of nepotism. In the public universities of Italy, it’s no secret that nepotismo is the rule, not the exception. Despite repeated legislative efforts to reform university hiring, scandals such as the one at University of Bari’s economics department - where a father, two sons, and five grandchildren all work together - remain a perennial problem in Italy.

Stefano Allesina, an assistant professor of evolution & ecology at the University of Chicago, witnessed the damaging effects of these unfair hiring practices as a student in Italy. While pursuing his PhD, Allesina’s advisor told him not to waste his most productive years trying to get a job in Italy - advice he followed in emigrating abroad to the United States. Many of his Italian peers followed similar paths, while those who stayed behind languished in limbo waiting for scarce tenure track positions to open. Frustrated with the broken Italian system, Allesina decided to apply his talents for creating computational models in ecology to measuring the full scope of nepotism in the university system of his home country.

“In Italy, there is an enormous brain drain,” Allesina said. “Italy is losing so many graduate students to other countries, it’s unbelievable. It’s because the hiring is extremely slow, complicated, and not really based on quality…and I think these kind of hiring practices contribute a lot to this brain drain and the fact that Italian universities are not ranked very high internationally.”

In a study published yesterday in PLoS ONE, Allesina used a public directory containing the last names and fields of study for over 61,000 professors to look for systemic signs of nepotistic hiring. With a simple computer model, Allesina detected unusual clustering of last names within disciplines such as law and medicine, far from the random distribution expected with unbiased hiring.

“It’s not a few bad apples, it’s really bad,” Allesina said. “I found that in many disciplines there are much fewer names than you would expect to find at random, indicating a very, very high probability of nepotistic hires.”

The original model worked like a random lottery, repeated one million times. Over the entire dataset, more than 27,000 different last names were represented. For each discipline, Allesina tested whether certain names appeared more than expected at random. So for medicine, where there are 10,783 faculty members with 7,471 different last names, Allesina programmed his computer to test how likely it was to randomly draw only 7,471 names (or fewer) from the total name pool in 10,783 tries.

“It’s very basic, anybody with a laptop can do this analysis,” Allesina said. “I wanted to keep it as coarse-grained and simple as possible. Because then it’s more powerful - if this works, anything else will work. Even this very simplistic analysis can find that some disciplines are above and beyond what one could expect.”

Under this model, the worst offenders were law, medicine, and industrial engineering, all of which showed only a 1-in-1,000 chance of having so few last names by random. On the other end, psychology, demography, and linguistics  each contained a last name distribution close to random, suggesting that hiring was more fair in these fields. Another analysis, which mapped the likelihood of two faculty members in the same field sharing a name by geographic region, found that indicators of nepotism were stronger in the south - a result that would surprise few Italians, Allesina said.

“For an Italian, this is not that surprising,” Allesina said. “It is a narrative of two separate countries, where in the public sector we have more problems in the south.”

A much trickier task than measuring the breadth of nepotism in Italy is finding an effective solution for ending the unfair hiring practices.

read more

In the recent kerfuffle over the national debt, one of the rhetorical flashpoints was the $800 billion “stimulus package” pushed by the Obama administration in 2009 to fight the economic slowdown. Though the benefits of the American Recovery and Reinvestment Act on unemployment and the economy are fiercely debated, the impact upon the scientific world is just beginning to be felt. Roughly $5 billion of the stimulus money went to the National Institutes of Health for funding biomedical research - and $42 million of that sub-total came to projects involving University of Chicago researchers. Two years later, the fruits of that investment are beginning to ripen, as stimulus-funded projects reach the point of publishing results.

The largest piece of the stimulus pie awarded to UChicago researchers was the $5.6 million designated to form the EVE consortium, an unprecedented national effort to search for the genetic and environmental causes of asthma. Over 34 million Americans are diagnosed with asthma during their lifetime, and the rates are increasing every year. But the origins of this respiratory disease are still mysterious, with the relative contributions of genetics and environmental factors such as air quality and smoking still being unraveled.

One recent tool in decoding the causes of asthma has been genome-wide association studies, or GWAS, where genetic information from a large pool of patients with the disease are compared to a control pool of asthma-free people. But to find a gene or gene variant associated with a complex disease like asthma, a huge number of subjects are needed for statistical reasons. The expenses of successfully recruiting, diagnosing, and genotyping the thousands of people needed to create a sufficiently powerful GWAS were beyond the means of any one research group, frustrating the search for asthma-related genes.

“It has become clear to geneticists studying nearly every common disease that GWAS are often under-powered,” said Carole Ober, Blum-Riese Professor of Human Genetics and obstetrics/gynecology at the University of Chicago. “Unless you pull together many people doing the same thing you’re just not going to have the power to find genes.”

In the world of asthma genetics, nine groups of investigators were encouraged by the National Heart, Blood, and Lung Institute to pool their respective GWAS results to create a shared pool of data large enough to sniff out genes associated with the disease. But that collaboration was easier said than done - until the $5.6 million ARRA grant enabled the hiring of personnel to make the EVE consortium a reality.

“It would never have been possible without the grant, this was a huge amount of work,” said Dan Nicolae, PhD, associate professor of medicine, statistics, and human genetics at University of Chicago, and co-chair of the consortium with Ober. “The key was the ARRA funding that allowed us to move it faster.”

Now, just short of two years since the grants were announced, the EVE consortium has announced their initial results in the journal Nature Genetics. With a new larger data set of over 5,000 asthma cases, the group was able to pinpoint with high accuracy five genetic regions associated with asthma, including one with a very selective profile. Unlike a similar consortium formed in Europe (called GABRIEL), the EVE dataset reflected the ethnic diversity of the American melting pot with subjects of European origin, African origin, and Hispanics. That diversity proved useful, as the EVE data revealed an asthma-associated variant in a gene called PYHIN1 that only appeared in African-Americans and African-Caribbeans - ethnic groups not present in the GABRIEL sample published last year.

“Asthma rates have been on the rise in recent years, with the greatest rise among African Americans,” said Susan B. Shurin, acting director of the National Heart, Lung, and Blood Institute, which co-funded the study. “Understanding these genetic links is an important first step towards our goal of relieving the increased burden of asthma in this population.”

read more

One of the sectors closely monitoring the debt debate in Washington is the medical world, where hospitals, physicians, and patients anxiously await the final agreement on cuts to Medicare and Medicaid. Of particular concern to academic medical centers [pdf] are proposed cuts to graduate medical education, funding used to pay the salary of residents and fellows who are both training as physicians and specialists and working on the front lines of patient care. In a time when a patient’s wait time to see a specialist grows longer and longer, squeezing the bottleneck of physicians-in-training even tighter could have long-term consequences.

This week, the Medical Center’s executive vice president for medical affairs and dean Kenneth Polonsky took to the newspapers to argue against these damaging cuts. In an op-ed letter published by the Chicago Tribune, he expressed concern that the proposed cuts would “would reduce access to doctors, multiply waiting times and do lasting harm to patients in Illinois and nationwide.”

No one questions the need to rein in spending on health care or the obligation of hospitals to do their part. But we need to maintain a high level of patient care, and to make certain that our country has enough physicians in the future. Policymakers in Washington must maintain their support for graduate medical education and find more equitable ways to distribute the budget-cut burden.

Elsewhere…

Speaking of Washington and health care policy, without the Patient Protection and Affordable Care Act, 63-year-old Glenn Bovard of Valparaiso would not have been able to receive life-saving gift this past Father’s Day: a new heart. The Post-Tribune profiled Bovard’s story and surgery, performed by the Medical Center’s Valluvan Jeevanadam and Jai Raman. “The surgery was a cakewalk compared to the heart attack,” Bovard told the paper.

As many as one-third of patients with epilepsy cannot control their seizures with medication. Local newsmagazine Chicago Tonight profiles efforts by Wim van Drongelen, technical and research director of our pediatric epilepsy center, to develop new ways of helping these patients by modeling how seizures begin and spread in the human brain.

At the end of a long, difficult week, many people like to unwind on a Friday evening with a drink? But does alcohol relieve stress, or prolong it? A new study by Emma Childs of the University of Chicago Behavioral Pharmacology Laboratory and written up by the Gannett News Service suggests a double-edged sword - stress reduces the positive effects of alcohol, while a drink may extend the tense feelings produced by a stressful event.

A cautionary tale about when newspapers twist the words of scientists for sensationalist ends - did paleozoologist Darren Naish really say that the Loch Ness Monster was “more fact than fiction?”

Evolution isn’t only a process that happened in the distant past. Carl Zimmer’s wonderful cover story in the Science Times this week follows New York evolutionary biologists as they hunt for signs of urban evolution in progress for mice, fish, ants, and other city-dwelling critters.

Cancer used to be a black box, a disease that physicians could only monitor through surgical biopsies and indirect measures. But for the last thirty years, the use of computed tomography imaging, better known as CT scans, has allowed oncologists and cancer researchers to keep close watch on the growth or shrinkage of a tumor for many different types of cancer. A patient with a lung tumor, for example, can be scanned every few months in order to see whether their therapy is working - and if it’s not, doctors may choose to switch treatments. Clinical trials of new therapies for cancer also make use of CT scans, using the increase or decreased size of the tumor as a primary data point.

But for all the benefits of scans over surgeries to monitor tumor size, flaws remain for CT scans. A new study published this week in the Journal of Clinical Oncology shines a harsh light on one of the primary problems - the technology’s variability. Patients usually are given CT scans months apart, and trained radiologists measure the tumors to see whether they are growing or receding. But how much of those changes can be attributed to random error from the imperfect resolution of the scan or the breathing of the patient?

To test this baseline error, researchers from Memorial Sloan-Kettering Cancer Center got a little tricky. Instead of taking two scans from a patient months apart, they took two scans in quick succession, within 15 minutes. The scans were then handed off to experienced radiologists, who were told to measure the change in tumor size without knowing how much time had elapsed between the images. The results were sobering - despite the tumor being biologically identical between the two near-simultaneous scans, the radiologists found changes in size of 1mm or more in more than half of the samples and a 10 percent error range in either direction overall. Although the criteria for tumor progression is an increase in size of 20 percent or more, that 10 percent error could considerably distort the data when clinical and research decisions are made using normally-spaced scans.

The result doesn’t render CT scans obsolete, but offers new caution about the method’s shortcomings.

“It’s the sense of, ‘Really? Is this first happening now?’” Michael Maitland, assistant professor of medicine at the Medical Center, commented to Reuters Health about the study findings. “This is telling us scientifically how much noise is naturally there without any treatment or the cancer getting worse. It’s an important thing to do whenever you are going to use any kind of marker for a disease.”

In an accompanying editorial in the Journal of Clinical Oncology, Maitland went further, writing with his co-authors that it was time for oncologists to rely less upon CT scans alone and move toward integrating those images with other measures to create more precise monitoring technologies. As cancer edges toward more personalized treatment strategies, developing better diagnostic tools will become even more important, they argued.

“It is time to cast away familiar conventions and turn to better methods of evaluating malignant disease therapeutics,” they wrote. “It is time to replace these systems with more innovative, quantitative approaches that have the potential to define relationships between solid tumors, disease progression, and therapeutic outcomes in patients.”

Elsewhere…

It might have come out a few days late for the 4th of July, but Travis Carter’s study of the effects of seeing the American flag on political beliefs is still timely. If the Booth Business School researcher is right, we’ll all be slightly more Republican for at least the next 8 months. Ed Yong at Not Exactly Rocket Science did a great writeup that was featured on the Colbert Report this week (and also wrote up our own Neil Shubin’s study on the origin of limb genetic programs this week as well).

read more

The latest cult favorite in the sphere of human genetics is the microbiome, the genes of the bacterial species that live inside and upon the human body. Because bacterial cells outnumber human cells in an adult by approximately ten to one, and tens of thousands of different species make up the human ecosystem, studying this world will be even more of a challenge than the Human Genome Project, which only had to concern itself with a single species: us. But as the microbiome is increasingly discovered to play a role in obesity, diabetes, infant diseases, and hospital-acquired infections, the number of researchers pondering a bacterial angle for their own disease of interest is exploding.

So the microbiome was the ideal topic for the first lecture of the Institute for Translational Medicine seminar series on Advanced Tools, a monthly meeting designed for University of Chicago researchers to share methodological know-how. Leading the discussion was a veteran of the young microbiome scene - Eugene Chang, professor of medicine and an expert on gastroenterology. For several years, Chang has applied the tools of microbiology to the bacterial populations of the human gut, looking for mechanisms involved in digestive diseases. As the techniques for studying the microbiome have evolved, Chang said he has seen the pros and cons of the field’s growth.

“This is an area that is really hot,” Chang said. “It isn’t coincidental that this interest has coincided with emerging technologies, because the emerging technologies over the last decade have allowed us to look at the microbiome in many different ways….but this is a field where you can be easily consumed by the technology.”

Those techniques have changed alongside the trends of the broader field of microbiology, Chang said. Scientists interested in bacteria were once limited to studying what they could both find and grow in a lab dish, which left the vast majority of species unexplored. But new genetic techniques have brought those hidden worlds into the light, allowing scientists to take a more complete census of the bacteria present in a given sample from the Earth’s environment, or the special environments within the human body. With this added power has come a whole new menu of choices for scientists, from low-cost methods (i.e. T-RFLP) that can take a surface-level snapshot of the most common members of a microbial community to deeper sequencing that can identify rare microbes that may turn out to be relevant to disease (i.e. pyrosequencing).

“We have a number of techniques that have advantages and limitations,” Chang said. “What you use is dependent on what your question is and how deep you need to go.”

In Chang’s laboratory, the questions relate to the origins of inflammatory bowel diseases such as ulcerative colitis. A recent study looked at the microbial diversity within the colon, comparing the bacterial populations present in the mucosa of the proximal colon (near the small intestine) to the distal colon (near the anus). A T-RFLP analysis, which looks at fragments of ribosomal DNA in the mucosal samples, found that the microbes present in the two regions were distinct, with higher “richness” (the number of species present) observed in the proximal versus distal colon.

But to determine the role of the microbes in disease, just taking a census isn’t enough. The newest wave of microbiome research is focused on function, using techniques that find out what those billions of bacteria are actually doing inside our bodies or out in the world. With metagenomics, scientists can analyze all the genes from a given sample of soil, skin, or mucus, then group those genes by their functional role (metabolism, transport, etc.) using a technique developed by Argonne called MG-RAST. Many groups, including Chang’s team, are also interested in measuring host-microbe relationships - how the bacterial population affects the biology of their home organism.

“Sure we can say who’s there, but how do we actually know what’s important?,” Chang said.

read more

Around the pediatric cancer wards at Comer Children’s Hospital, he was known by the rhyming nickname of “Doc Nach” and for delighting patients with his Mickey Mouse watch. On a ward where a smiling face goes a long way, Dr. James Nachman was always happy to provide a cheerful presence. Behind the scenes, he was also a dogged researcher, developing new protocols for children who didn’t respond to the standard treatment for acute lymphoblastic leukemia (ALL) and working to save the limbs of children diagnosed with sarcoma, a cancer of the bones.

Sadly, Nachman passed away last week at the age of 62, while on a rafting trip in the Grand Canyon. This week, Medical Center colleagues remembered “Doc Nach” for his skill with patients and scientific expertise.

“Jim was an outstanding clinician, teacher, and clinical researcher,” said John Cunningham, professor of pediatrics and chief of pediatric oncology. “He made seminal observations in leukemia and lymphoma that have impacted the lives of many children and adults with these diseases. He was an outstanding doctor, beloved by his patients, their families, and his colleagues. He was an irreplaceable member of our cancer team. We will miss him deeply.”

Patients’ families also were quick to pay tribute to Nachman. At the ChicagoNow blog “Ay Mama,” Laura Lutarewych wrote a moving post about her encounters with Nachman during the treatment of her 2-year-old daughter, Atia.

He’d walk into a room with a smile asking, “How’s my favorite girl?” It didn’t matter who the patient was - they were all his favorite, so it was fitting and each child wore their title proudly.

Without exception, he’d hold out his wrist and ask, “Who’s on my watch?” Atia especially loved that part, because she knew the script; she didn’t even have to look at the watch. With a huge smile, she’d point at it and exclaim, “Mickey Mouse!”

Earlier this year, we shot a video with Nachman for a series of informational segments on pediatric cancer topics that you can view below. Even in answering technical questions about how ALL is diagnosed and treated, you can see the good cheer and optimism in Nachman’s demeanor that was so comforting to his patients. For all of the people he touched during his life, that positive attitude will be missed.

“He was an optimistic, sunny person,” his brother Robert Nachman said in the Chicago Tribune obituary, “and his eyes lit up whenever he was talking about children.”

Elsewhere…

Linkage was off last week, so we didn’t have a chance to post this excellent front-page Chicago Tribune article about the neuroprosthetics research program here at the University of Chicago. Reporter Cynthia Dizikes also penned an online supplement that explains the link between assistant professor Sliman Bensmaia’s favorite Star Wars scene and his research on the neural mechanisms of touch.

read more

An enzyme from three different species is compared, with structural "flaws" shown in green. (From Fernández & Lynch, Nature, 2011)

One common misconception about evolution is that it produces “better” organisms with time - a seductive opinion to humans who would like to think of themselves as the pinnacle of natural selection. In a way, it’s an easy error to make, for who would look at a single-celled bacterium next to a human and think that the four billion years of evolution between the two species hadn’t produced some improvements? But when Ariel Fernández and Michael Lynch compared the proteins that bacteria and humans share, they found that the unicellular organisms held a surprising advantage. Though the overall shape of the proteins were the same, the human proteins were leakier, more vulnerable to the destabilizing effects of water than those of the bacteria.

But according to the paper published yesterday by Fernández and Lynch in Nature, those protein flaws may have been the key spark that led to the evolution of complex organisms.

“We hate to hear that our structures are actually lousier,” said Fernández, a visiting scholar at the University of Chicago and senior researcher at the Mathematics Institute of Argentina (IAM) in Buenos Aires . “But that has a good side to it. Because they are lousier, they are more likely to participate in complexes, and we have a much better chance of achieving more sophisticated function through teamwork. Instead of being a loner, the protein is a team player.”

The engineering advantage of bacteria over humans boils down to one simple fact: they will always far outnumber us. Billions of bacterial organisms can fit into a single Petri dish, and in a single human body there are over 100 times more bacterial cells than there are humans on Earth . When a genetic mutation with a negative effect pops into existence in these huge populations, natural selection quickly disposes of it, preserving the integrity of the protein that gene encodes. But when a mildly negative mutation appears in a relatively small population, such as that of humans or elephants or pine trees, selection is less efficient and the mutation may spread - a phenomenon called genetic drift.

The direct effect of these mild mutations would be to introduce minor flaws into the structure of proteins. If the change in protein function was too severe, it would cease to function and likely kill the organism. But if the change was just a small nick in the armor of the protein, making it chemically more vulnerable to water, the mutation might stick around long enough to be passed on to offspring. That theory informed Fernández and Lynch’s hypothesis: proteins from species with small population sizes would contain more of these flaws than those from species with large populations.

Their idea was proven true: compare the same protein between, say, humans, flatworms, and bacteria, and you’ll find a descending frequency of protein flaws. Even within a single species, the difference can be measured. Some bacteria have both endosymbiotic populations that live inside other organisms and larger, free-living populations, and the proteins from the endosymbiotes were found to contain more structural errors than their free-living peers.

But the exciting part is what happens after those errors accumulate. read more

by Meghan Sullivan

It would be easy to mistake the images in Harry Noller’s presentation last Thursday for shards of gemstones or modern art. “This part of the talk was influenced by our visit to the Art Institute,” he quipped, advancing through a gallery of slides that showed off a variety of crystals, ranging in color and shape. This was not, however, a geology talk. Noller, professor of molecular cell & developmental biology at the University of California, Santa Cruz, was this year’s invited speaker for the 6th annual Haselkorn Lecture, a seminar series named for UChicago molecular biologist Robert Haselkorn that invites leading researchers to the University for several days to interact with young scientists. His visit drew to a close with a lecture on the molecule he’s spent most of his life studying, the ribosome.

Every living thing possesses ribosomes. It makes sense, then, that ribosomes are fundamentally necessary for life, and may predate proteins and even DNA in the history of life on Earth. Since the identification of DNA, an overarching rule of life has emerged called the Central Dogma, which states that an organism’s DNA is transcribed into RNA, which is then translated into proteins. It’s as if you’re copying instructions from a cookbook. The cookbook - in this case, DNA - holds all the recipes, and you can copy out only the individual recipe you need - the RNA. The copied recipe can then be used as a reference to make the final product, proteins. But as with cooking, you can’t simply turn words on a page into chocolate chip cookies. Like a baker might hold a recipe with one hand and mix the ingredients together with the other, the ribosome is the stepping stone between RNA and proteins.

“Going from DNA to RNA is something like going from Spanish to Portuguese - they’re similar types of molecules,” Noller pointed out, “But going from RNA to protein is like going from Portuguese to Chinese - they’re two totally unrelated languages. In this case, the ribosome is the Rosetta stone.”

The ribosome, which can be found in the fossil record going back 3.5 billion years, is a molecular machine that reads RNA and assembles the protein it encodes. Unlike many of our enzymes, it is composed mostly of RNA, not proteins. Its unusual composition and the fact that it lies at the heart of a process fundamental to life has made it a frequent subject of research.

Noller’s laboratory focuses on the structure and function of the ribosome. This is where the gallery of crystals comes in. Ribosomes, while relatively large cellular structures, are small enough that microscopy can’t provide the kind of detail necessary to understand the nuances of their structure. To get around this, scientists use a method called X-ray crystallography. In essence, Noller’s lab tries a variety of conditions to coax ribosomes into forming microscopic crystals, made up of repeating units, which forces the ribosomes to form symmetrical, 3D structures. At low power on the microscope, researchers can see angular crystals. However, when placed in the path of a X-ray, the crystal breaks up the X-ray beam into a complex scatter, which is caught and recorded. Using a mathematical operation called a Fourier transformation, the scatter of dots, each of which represents a single atom in the molecule, is resolved into a 3D model.

The problem with crystallography is that it only gives us a snapshot of its target. By forcing the ribosomes into crystals, they lose all ability to move. It’s well established that ribosomes, which must deal with growing proteins and move along the RNA, are dynamic molecules, moving and changing conformation as they work. Thus, still images don’t tell the whole story, a limitation Noller described with the parable of the cavemen and the Ferrari.

“The caveman and his cave-buddies are having beers and telling stories and they come out of the cave and see this.” Noller showed an image of a vintage Ferrari.

read more

The University of Chicago is the birthplace of nuclear energy. So like proud but concerned parents, UChicago has kept a close eye on the benefits and challenges of nuclear power over the years since the first self-sustained nuclear reaction under Stagg Field. Thus, the battle to manage the consequences of the damaged reactors at the Fukushima I Nuclear Power Plant in Japan has drawn the University’s interest, and the short-term and long-term effects of that ongoing situation were the subject of a unique panel held on campus yesterday, “Lessons from Fukushima.”

Though nuclear power was created by scientists, discussing its use requires input from political and economic spheres as well. So the panel, assembled by the University of Chicago Alumni Association, brought together nuclear technologists (Hussein Khalil, director of the nuclear energy division at Argonne National Laboratory, and Mark Peters, deputy director of Argonne), nuclear policy watchdogs (Kennette Benedict, executive director of the UChicago-based Bulletin of Atomic Scientists), and energy economics experts (Robert Topel, director of the University of Chicago Energy Initiative). With such different perspectives, it didn’t take long for the panelists to find points of debate, reflecting the tug-of-war over nuclear power that has gone on for several decades.

Nobody disputed the magnitude of the Fukushima incident, with workers at the plant still struggling to limit core meltdown in at least three of the reactors as well as re-cooling spent fuel rods at the site. As well, the panelists agreed that the incident was very relevant to nuclear power in the United States, where roughly one-fifth of electricity is provided by nuclear plants, many of which use the same model as the Fukushima reactors. But opinions differed on what those consequences would be.

Khalil pointed out that this was the first natural disaster to cause “grave damage” to a nuclear power plant in nearly 60 years of their use, and that a similar occurrence was very unlikely in the United States. But Benedict argued that “very unlikely” wasn’t good enough for “the most dangerous technology on Earth,” and that not every safety precaution possible had been taken at Fukushima. Topel agreed with the latter point - “why build generators on the ocean side in a country that coined the term ‘tsunami’?” he asked - and noted that the renewed attention to the long-term dangers of nuclear power would only make it more difficult to build new reactors.

In fact, no new nuclear reactor has come online in the United States in 32 years, Khalil said. So while Argonne continues to research new designs for nuclear plants and new strategies for containing nuclear waste, the economic (and possibly now public opinion) barriers are too large. The most likely rescue for nuclear power may come from an unlikely source: climate change.

“If other technologies turn out to be a bust, and if we really are serious about reducing our carbon footprint and carbon pricing becomes important, then there is a technology we have that can produce a lot of energy at relatively low cost compared to the alternatives,” Topel said. “Then, nuclear energy will prosper.”

By the end of the 90-minute discussion, the panelists came back to common ground on a hopeful note. If a thin silver lining could be found on a disaster that hasn’t yet been completely averted, it’s that the events at Fukushima have re-opened the international dialogue on nuclear power - its immense benefits and equally immense costs.

“One of the positive externalities of the Fukushima accident is that many more people are interested in nuclear energy, and I think that’s terrific,” Benedict said. “It’s unfortunate that it takes an accident to do it.”

Elsewhere…

The conversation about cancer is changing, from a single disease classified by the organ where it appears to multiple diseases grouped by genetic and biological similarities. As ScienceLife has written before, the Chicago Cancer Genome Project is our local contribution to this strategic shift against “the emperor of all maladies.” This week the Los Angeles Times examined that research effort and others like it, speaking with project leader Kevin White and many of the Medical Center’s cancer experts collaborating on this new vision of how to classify and battle cancer.

read more