Welcome to Dr. Polonsky

Today’s big news on campus is the announcement of Kenneth S. Polonsky, our new dean and executive vice president of medical affairs. The position puts Polonsky, an endocrinologist and diabetes researcher, at the helm of our Biological Sciences Division, the Pritzker School of Medicine, and the University of Chicago Medical Center. Polonsky was most recently chair of medicine at Washington University in St. Louis, but before that he was a faculty member at the University of Chicago from 1981 to 1999.

As such, Friday morning’s announcement event felt more like a homecoming than an introduction, with many faculty members cheerfully reuniting with Polonsky and his wife Lydia, a former math teacher at the University of Chicago Laboratory Schools. In his first remarks to the University community, Polonsky admitted to feeling a little “intimidated and nervous,” but excited about the future of the Medical Center and BSD.

“It really does feel right,” Polonsky said. “I do really think that we have an opportunity to continue a spectacular tradition. I have retained the utmost respect for the University of Chicago broadly, but particularly for the medical school and the biological sciences division. When I walk around this campus, I see all these buildings, including the new hospital, that weren’t here in 1999. I thought we were pretty great then, so I think that we have an enormous potential to be even better, and I hope to facilitate that.”

Polonsky will begin his new duties on October 1st, when our current interim dean and CEO, Everett Vokes, will step back to his prior role as chair of medicine. University of Chicago President Robert J. Zimmer also had kind words for Vokes, saying that he “took on this role at a challenging moment for this enterprise, and I think everybody recognizes the absolutely extraordinary job that he’s done.”

You can watch video of today’s ceremony here.

Feed the World with Science

In the year 2050, the world population is estimated to pass 9 billion people, nearly a 50 percent increase over today’s number. Among many concerns with that growing population is whether all those new people will be able to be fed; after all, an estimated 1 billion people today do not get enough food for minimum energy requirements. The journal Nature devotes a big chunk of this week’s issue to the question of food’s future, and perhaps surprisingly, there’s no panic amid the fancy graphics and editorials. The percentage of hungry people has dropped over the last few decades (with a slight rebound due to the current economic crisis), food production is growing at a faster pace than the population, and productivity can be lifted even further through the spread of existing technology.

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In 2008, a twenty-year-old environmental treaty had a dramatic impact upon the care of asthma in the United States. Due to the 1987 ban on chlorofluorocarbons (CFCs), the ozone-depleting propellents once found in hair spray and other aerosol-can products, the inhalers used by millions of asthmatics underwent a mandatory switch to a CFC-free version. Unfortunately, patient education about the switch was scarce, leaving many unaware that they would be receiving the new inhalers. Even more concerning, many physicians were equally uninformed about the switch and how to counsel their patients on use of the new devices, called HFA inhalers.

That impending storm of confusion, as highlighted by a May 2008 New York Times article, inspired a group of University of Chicago Medical Center residents and faculty to launch the Chicago Breathe Project. Modeled upon the Medical Center’s community-based Neighborhood Health Exchange, an effort to raise health literacy on diet, nutrition and heart health in underserved communities, the project focused on asthma education - for patients and medical residents alike. Their two-pronged educational effort was described this month in the Journal of the National Medical Association.

“Reports were saying that patients and physicians are completely unprepared for this transition,” said Valerie Press, instructor in the section of hospital medicine and one of the Chicago Breathe Project founders. “We found that a large majority of the residents really didn’t know much about these HFAs, and also didn’t know a ton about how to teach patients about inhalers in general.”

Community health clinics and respiratory health organizations also reported a need for patient education on the new inhalers, Press said. Minority populations in Chicago suffer at least twice the national hospitalization rate and mortality rate for asthma. More recently, a litany of complaints and questions related to the new inhalers - that the spray was too cold, tasted different, wasn’t working, was working too strongly, or was too expensive - had come in from patients, the organizations reported.

So the Chicago Breathe Project set about educating both groups, and like the Neighborhood Health Exchanges, a team of residents led the educational efforts. With a grant from the American College of Physicians Foundation, the team was able to go to four other Chicago medical centers and teach a workshop to their residency programs, with the added allure of free lunch. Residents learned about the inhaler switch, how to best instruct a patient on inhaler use, and discussed case studies of patients having trouble with the devices. Those surveyed 6 months after the workshops said that they were more likely to assess a patient’s inhaler technique and were more comfortable discussing proper use with their patients.

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It’s traditional at the University of Chicago to invite a faculty member to deliver the convocation speech, rather than invite an outside speaker as many schools do. This year’s chosen faculty for Spring Convocation (the first campus-wide ceremony since 1929) was a well-known name from the rolls of the Biological Sciences Division: Paul Sereno, our world-famous fossil hunter. Despite being the year after the Year of Darwin, Sereno still did an excellent job of weaving the father of evolution and the theory itself into his advice for the graduating Class of 2010.

In evolutionary biology, random events with unpredictable consequences are collectively known as “historical contingency.” That randomness can be just as significant to an individual’s personal “evolution”: just as Darwin diverted from the seminary to his famous trip aboard the HMS Beagle, Sereno switched from art school to a career in paleontology. As such, Sereno advised the graduates to keep a firm hold on their liberal arts education, never knowing when it will be useful for the unforeseeable twists and turns in one’s life and career.

“I recount these life stories to extol the virtues of pathways marked by unpredictable, life-changing events small and large,” Sereno said. “Contingency is to be embraced, not feared.”

Below, watch the full video of Sereno’s convocation speech. As a side attraction, admire the amazing transformation of the University of Chicago main quad into a temporary outdoor auditorium able to hold 20,000 attendees.

CREDIT: ADAPTED BY P. HUEY/SCIENCE

The public perception of science in action typically involves a person in a white coat pouring brightly-colored fluids in and out of test tubes. Sure, a little bit of that does go on in a laboratory. But before the glassware is broken out, a lot of less glamorous stuff has to happen. Every experiment is built on a foundation of reading - devouring the scientific literature that came before you and keeping up with the pile of new journals from your field that arrive on a weekly basis.

Once upon a time - say the 17th century - it was possible for a scientist to keep up with the flow of science because there were only a couple dozen of people contributing to it. Today, University of Chicago sociologist James Evans and professor of medicine Andrey Rzhetsky estimate, a cancer biologist is confronted with millions of relevant journal articles within their field, with thousands more added every month. Obviously, there’s no way for a mere mortal to keep up with that kind of reading list, much less keep an eye on other fields to inspire creative ideas.

In last week’s issue of Science, Evans and Rzhetsky suggest a potential substitute to handle this impossible task: the computer. Appearing the same day as Gary An’s pitch for using computer models to test hypotheses, Evans and Rzhetsky’s piece is an argument for using computers to generate those hypotheses by boiling down the unreadable avalanche of scientific literature into promising questions.

“During Newton’s time, a scientist could read everything that was published, at least in English,” Rzhetsky, a senior fellow of the University’s Computation Institute, told Wired’s Brandon Keim in an interview. “That’s just not an option anymore. We can’t deal with all this information.”

But the answer is not to just simply plug data into a computer with zero context and hope for promising treatments to pop out the other end, Rzhetsky told Keim, deploying an excellent film reference as a metaphor.

“In the movie Memento, a man has only a short-term memory. Every 15 minutes has to reconstruct causal relationships. He observes people talking to him, and doesn’t know who’s a friend and who’s a foe. That’s my metaphor for abandoning hypothesis and context,” Rzhetsky said.

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Many people consider human evolution to be a done deal, something that happened in our distant, wild past. But as Nicholas Wade wrote last week in the New York Times, there is increasing scientific evidence that natural selection has continued to act upon humans, producing observable evolutionary changes as recently as 3,000 years ago. Studies have found that everything from high altitude tolerance in Tibet to dry earwax may have evolved in relatively recent human history, producing subtle but significant population differences in the frequency of certain rare gene variants.

One of the genetic approaches cited by Wade in his article is the work of Anna Di Rienzo, professor of human genetics at the University of Chicago. In a paper published earlier this year in the Proceedings of the National Academy of Sciences, a group from Di Rienzo’s laboratory led by graduate student Angela Hancock went looking for recently evolved human genes in an unusual way. Their results uncovered new ways humans evolved in the recent past, with consequences still felt in our modern age of obesity.

Many genetic studies take an intentionally “naive” approach to such a genetic hunt, comparing gene variants between regional populations with no preconceptions so as not to bias the data. But sometimes a little bias doesn’t hurt; in fact, it may help find differences that fall through the cracks of a broad, unbiased sweep. Hancock and colleagues hit upon the idea of filtering their comparisons by predictable selective pressures expected to drive evolution, such as ecology and diet.

“A lot of the studies done before have been done in a way that was sort of agnostic to the selective pressure,” Di Rienzo said. “We are using aspects of human environments to learn about natural selection and the way humans adapted specifically at genetic level. We use genetic as well as ecological data, and we think that this combination allows us to tap into a set of genetic adaptations that are not accessible by other studies.”

To do this, the team took a particular variable expected to drive evolution, such as polar ecoregion. Because modern humans first arose in the tropical temperatures of Africa, those populations who migrated to a colder environment would be expected to need dramatic genetic changes to survive. So the researchers (using data from the Human Genome Diversity Project, the International HapMap Project, and their own original sequencing) compared the genomes of polar populations against non-polar populations, to see if it revealed specific gene variant differences.

Indeed it did. Several genes were found to appear at different frequencies in the polar populations, and most were found to have the kind of function one would expect to be selected for in a cold environment. Genes that helped people regulate body temperature, for instance, were more likely to have changed in a polar population. Energy metabolism also appeared to have been selected for, with the genes for enzymes that degrade sugars showing differences. The results lined up nicely with a 2008 paper by Hancock and colleagues that used a different analysis method to detect a relationship between climate and genes associated with metabolic disorders.

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There are many today who argue that the future of medicine is in data mining. Massive computational efforts are underway to collect mountains of data from multiple sources - genomic sequencing, clinical trial results, laboratory experiments - and put them to work in the unbiased, abstract mind of the high-throughput supercomputer. The biological world is too complicated in many places for us to make significant therapeutic advances, the argument goes, so only a computer can sniff out the intricate patterns that can be exploited to fight disease.

But eventually, this new approach to science will come up against an old obstacle: the best ideas, whether born in a computer or on a laboratory chalkboard, don’t always work. Coming up with a hypothesis - intervention x will affect disease y - is only the first part of the scientific method. Testing that hypothesis is where the real advances are made, and where many new drugs and therapies have crashed upon the shores of reality. In a new article this week in Science Translational Medicine, a University of Chicago surgeon argues that computers also have a role to play in that second part of the equation.

Gary An, a brand new member of the surgical faculty at the University of Chicago Medical Center, observed the “translational dilemma” firsthand early in his career. Working in the critical care unit at Cook County Hospital, An saw patient after patient succumb to sepsis, an overwhelming, stubborn infection of the body that leads to organ failure and often death. An enormous body of research has described the biological steps that underlie sepsis, but almost every intervention proposed by that research has failed in clinical trials.

“None of those things tried at that time worked; in fact, some of them were even detrimental,” An said. “The critical care literature were filled with editorials - ‘What are we doing wrong? What’s the problem?’”

Those failures led An to the study of complexity, systems where the overall behavior is not explained simply by the underlying rules. An reasoned that the only way to properly study such a system is to generate computer models capable of testing hypotheses, not just creating them. With computer modeling software that was relatively easy to learn - “designed to teach elementary school students about bird and traffic,” he said - An created an in silico model of sepsis.

The model drew upon published research to create a biological network of immune system factors that simulated a real patient experiencing sepsis. Then he re-ran the strategies tested in the clinical trials - and found results (published in 2004) that could have saved drug companies and researchers a lot of time and money.

“As it turns out, none of them worked, and some of them actually hurt simulated patients, which is what the trials showed,” An said. “The result of the simulated trial itself is not novel, we knew that was how it would happen. But if you had these means of testing the plausibility of the interventions that you had in mind [before the trial], it would have caused you to think about whether this is actually a good idea before you spend millions on clinical trials.”

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The concept of viral cancer has only recently begun to take root in public awareness, predominantly through the disease of cervical cancer. Nearly all cases of cervical cancer are now known to be caused by the human papilloma virus, HPV, which is transmitted through sexual contact. The 2006 approval of Gardasil, a vaccine against HPV, has offered a preventive measure against infection and cervical cancer.

But it’s becoming increasingly clear that the cervix is not the only place that HPV-positive cancer can appear. Since the 1980’s, physicians have found the virus in certain cases of head and neck cancer, primarily in younger patients with oropharyngeal tumors. Since then, the incidence of HPV-positive head and neck cancer has increased by 3 percent each year, said Ezra Cohen, an assistant professor of medicine and an expert on the disease.

“Many people are beginning to call this an epidemic, and I think that’s a fair description,” Cohen said. “Three percent may not sound like a lot, but if you multiply that over 30 or 40 years then you have a dramatic increase in the number of cases we are seeing, to the point where now…the majority of patients with oropharyngeal cancer we see in the United States and Western Europe are HPV-positive.”

As a result, the rates of head and neck cancer in the United States have remained steady despite drop-offs in smoking behavior, another major risk factor. Like cervical cancer, the spread of HPV-positive head and neck cancer appears to occur via sexual transmission - in this case oral sex - and the disease may be prevented by early use of the vaccine in both females and males.

In these videos, Cohen explains how the link between HPV and head and neck cancer was originally discovered and how researchers currently think the virus causes cancer to form. Cohen also discusses the use of HPV vaccines in preventing head and neck cancer and the use of HPV as a biomarker for determining the most effective and appropriate treatment for a patient.

In nature, species evolve thanks to those lucky organisms who cheat death. An environmental pressure may come in and kill of a high percentage of critters, but those critters who survive the bloodbath live on to spread their genes. When this bottle-necking occurs in disease-causing bacteria, we call it drug resistance: an antibiotic may knock off 99 percent of a species, but the 1 percent immune to the treatment will live on to reproduce and create an entire population immune to the drug.

As the drugs developed to fight cancers become more and more sophisticated, a similar principle is in play for tumor cells. New “targeted” chemotherapy drugs, such as sorafenib or imatinib, which attack tumor cells by one specific mechanism, have typically shown initial success followed by recurrence and resistance. The reason, suggests Wei Du, associate professor in the Ben May Department for Cancer Research at the University of Chicago, is evolutionary.

“If you really think about it, it’s sort of like evolution on the scale of your body,” Du said. “Cancers are heterogeneous and often display genomic instability. When the selective pressure of a drug is applied, a small number of cancer cells will likely be able to survive and grow. This will eventually lead to the development of resistance, just like antibiotics for the bacteria.”

In bacterial infections, doctors get around the resistance threat by ganging up on the bacteria, hitting a patient with multiple antibiotics that each employ unique killing strategies. That “Magnificent Seven” approach would be ideal for treating cancers, but physicians are limited by the limited number of mechanistically unique chemotherapy drugs available.

In a recent paper published in Cancer Cell, Du’s laboratory set out to remedy that problem by laying the groundwork for a new cancer-killing strategy. When a cell becomes cancerous, its genetic factory goes haywire, with some gene products being over-produced and others under-produced. Many drugs are developed to try to rein in the former, known as oncogenes, but few attempt to target the inactivated “tumor-suppressor” genes normally tasked with policing excessive cell growth.

One of those lost policeman is a gene called retinoblastoma protein, or Rb. The Rb gene is mutated in roughly 10 percent of tumors and functionally inactivated in many more, making the protein a factor in a majority of cancers. Rb-inactivated cells lose the brakes for proliferation, producing the uncontrolled cell growth characteristic of tumors. Du’s group launched a hunt for a “synthetic lethal” gene, a second, coincident mutation that would cause Rb-negative cells to self-destruct while sparing the innocent, non-cancerous cells standing by.

“The idea will be that the mutation by itself does not cause cell death, but in conjunction with loss of tumor suppressors you actually have a synergistic effect for cell death induction,” Du said. “That type of drug would be really nice in that it will have very low toxicity, but have specificity for the cancer cells.”

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ED and STDs: Unfortunate Acronym Bedfellows

With the constant drumbeat of advertisements for erectile dysfunction drugs, most of us can probably recite the list of precautions and side effects by heart by now. Though some of them inspire juvenile giggling (the one about “lasting more than 4 hours,” in particular), one warning is a head-scratcher: “does not protect against sexually transmitted diseases, including HIV.” Saying so always struck me as sort of a “duh” statement, but there had to be a reason for it to be there as part of the FDA-mandated laundry list of disclaimers for pharmaceutical advertising.

Indeed, there have been some studies that suggest men using ED drugs are at higher risk for STDs, which makes sense if you consider they will presumably be having more sex. But a new study in Annals of Internal Medicine of the STD rate in older men both before and after they receive a prescription for ED medication indicates that it’s not so much the drug, but the patient. The authors, which include Amee Kamdar of the University of Chicago Booth Graduate School of Business, analyzed the insurance claims of nearly 1.5 million men older than 40, comparing the rates of diseases such as HIV, chlamydia and syphilis in those who did or did not receive a prescription for an erectile dysfunction drug.

Those who sought treatment for ED did indeed have roughly twice the STD rate of the control population. But when those numbers were broken down into the year before ED prescription and the year after, the STD rate and risk was unchanged for those who received the drugs. That finding suggests that treatment of ED is not responsible for riskier sexual behavior, but people who engage in risky sexual behavior are more likely to seek treatment for ED. “The observed associated between ED drug use and STDs may have more to do with types of patients using ED drugs rather than a direct effect of ED drug availability on STD rates,” the authors conclude.

Clinically, the paper adds further argument for improved discussion of sexual issues with older patients, a topic covered previously on the blog regarding the research of our own Stacy Tessler Lindau. Studies have found that only 9 percent of adults between the age of 40 and 80 discussed sexual health with their physician during a routine visit, and opinion pieces (one called “Time for ‘the talk’ - again”) have argued that doctors should monitor the sexual practices of aged patients as much as younger ones. As the new study shows, when patients “talk to their doctor about ED,” the doctor should talk back about STDs.

What a Fumbled Handoff Looks Like

Last week, as expected, the Accreditation Council for Graduate Medical Education recommended further restrictions on the number of hours that medical residents can work. Under the new guidelines, first-year residents will not be allowed to work for longer than 16 consecutive hours (as opposed to the occasional 30-hour shift today) and more direct supervision by older residents and attending physicians will be required. The new guidelines are not yet settled - there’s a 45-day public comment period currently underway - but there is already plenty of research into the pros and cons of further restricting a resident’s time in the hospital (we’ll have more coverage of the guidelines debate soon).

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On the grim top 10 list of the most common cancers in the United States, familiar faces sit at the top of the charts. Prostate cancer for men, breast cancer for women, lung and colon cancer for both sexes - all are diseases that have inspired massive awareness and fundraising efforts to inform patients and bolster scientific research. But the #5 cancer on the list (the #4 most commonly diagnosed cancer in men) has not gotten nearly as much attention as the Big Four. Bladder cancer was diagnosed in an estimated 71,000 people last year, according to the Bladder Cancer Advocacy Network, but does not have the high profile of its kin.

Bladder cancer survivors and physicians hope to change that with the first Bladder Cancer Awareness Day, to be held this Saturday, July 17 with events around the country. It seemed like a good opportunity to sit down with our resident expert on bladder cancer, Dr. Gary Steinberg, for a comprehensive overview of the disease. Steinberg, the Bruce and Beth White Family Professor at the University of Chicago Medical Center, is a surgeon that specializes in the treatment of bladder cancer - both the removal of tumors and the bladder reconstruction that sometimes follows.

The risk factors for bladder cancer are not unique - smokers are twice as likely to develop the disease, while several industrial chemicals have been linked with tumors of the bladder, Steinberg says. As with many cancers, it’s a misnomer to think of bladder cancer as just one disease. Steinberg talks about the different types or “grades” of bladder cancer, and the range of treatment options available to patients with those diagnoses. He also describes ongoing research efforts to improve those treatments, from work with the Cancer Genome Atlas to find novel therapeutic targets for chemotherapy drugs to trials using stem cells to construct new urethras and bladders.

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Diseases are rarely turned off like a light switch. As satisfying as it is to explain a biological mechanism at the genetic or cellular level, extrapolating those discoveries to a human level requires the mind to make difficult leaps of scale. What’s more, even when a basic science finding is effectively translated into clinical treatment, that success is almost always partial and variable.

So with all that realism holding expectations in check, it’s even more powerful when a treatment makes a dramatic, practically overnight difference in a patient. Such stories are few and far between - and yet at the downtown Gleacher Center last week, there were dozens on display as part of the first Celebrating the Miracles family forum put on by the University of Chicago Kovler Diabetes Center.

“It’s really a rare, rare opportunity as a scientist,” said Siri Atma Greeley, instructor of pediatrics at the University of Chicago, “because not only do you get to make some discoveries that might elucidate a molecular pathway for our intellectual curiosity, but you get to see the actual real life impact and benefit to the people right in front of you who are telling these wonderful stories. It’s beautiful from a professional and personal level.”

The miracles of the conference’s name were the young monogenic diabetes patients gifted a unique alternative to a lifetime of insulin treatment. Due to a mutation in a potassium channel that controls the natural secretion of insulin, the patients were diagnosed with diabetes as early as days after their birth. Their parents were told that their son or daughter would likely have to be on insulin - delivered by injection or pump - for the rest of their lives.

But in 2004, British scientist Andrew Hattersley discovered a mutation that caused some of these early-onset diabetes cases. In 2006, he determined that such diabetes cases could be treated with sulfonylurea drugs - cheap oral medication originally designed for people with type 2 diabetes. Later that year, 6-year-old Lilly Jaffe was treated by Louis Philipson of the University of Chicago and became one of the first Americans to be switched from insulin to the pills, a story that was publicized in the Chicago Tribune and other media outlets.

As Lilly’s story spread around the country and world, more and more eligible cases were brought to the attention of Medical Center physicians. Last week, many of those patients and their families traveled to Chicago from as far away as Alaska and Venezuela to share their stories and learn about the latest monogenic diabetes research.

There was Ethan Sabala from Cleveland, who suffered from diabetes along with his father, grandmother, uncles and cousins. When his son Owen was born, Ethan and his wife, Maria, tested him with Ethan’s blood-sugar kit as soon as he showed the telltale signs of hyperglycemia, finding his glucose to be nearly four times the normal level. Owen was diagnosed with monogenic diabetes - and his father was found to have the same mutation. Together, father and son “transitioned” last year to the drug glyburide, and both have been insulin-free with stable blood sugar since.

“Originally I just did it because I wanted to see if there were any side effects or adverse reactions, to see what he’d be feeling,” Ethan said. “It was just a good side effect that my numbers improved too.”

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The Human Genome Project has had a rough year, from a PR perspective. To mark the 10th anniversary of the completion of a “working draft” for the human genome, many media outlets have chosen the “what have you done for me lately?” angle in assessing the project’s impact upon everyday medicine. Outlets such as the New York Times, The Economist, and The Guardian all ran articles about the as-yet-unfulfilled promises of the Human Genome Project in finding new cures for a wide range of diseases, a reality far from the “complete transformation in therapeutic medicine” promised in 2000 by Francis Collins.

One prominent area of frustration has been with genome-wide association studies (GWAS), which compare a population with a particular disease such as atherosclerosis or lung cancer with a healthy population to identify genes associated with disease risk. Many of the “hits” from these studies offered confusing results; as Nicholas Wade wrote in the Times: “most of the sites linked with diseases are not in genes - the stretches of DNA that tell the cell to make proteins - and have no known biological function, leading some geneticists to suspect that the associations are spurious.”

But Marcelo Nobrega, assistant professor of human genetics at the University of Chicago Medical Center, disagrees with that conclusion. And in a paper published today in the journal Genome Research, Nobrega’s laboratory demonstrates how these “non-genetic” GWAS hits can have dramatic biological effects significant for disease risk.

“The alternative, which we’ve known for a while now, is that the genome is not only comprised of genes,” Nobrega said. “Only one percent of the genome becomes proteins, but there are these regulatory elements everywhere that have important biological roles but are not protein-encoding sequences. Mutations in these proteins presumably will lead to disease or increase the risk of disease, there’s no reason to believe otherwise.”

The paper, authored by Nobrega with Nora Wasserman and Ivy Aneas, demonstrated this principle by tracking down a GWAS hit associated with cancer of the prostate and other organs. Studies identified a segment on the 8th chromosome that was associated with an increased risk of cancer, but it pointed to a region that contained no protein-encoding genes - a stretch known as a “gene desert.” In previous work, Nobrega’s team had tracked down small regulatory elements within these deserts that help choreograph the expression of genes for the development of organs. The new search had the opposite mission: to find not the regulatory elements that build an organ, but the elements that could someday send cell growth awry in those organs.

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Last month, we discussed the garage doors of the body’s ion channels, the millions of microscopic machines that control the heart’s beat and the nervous system’s communication. Benoît Roux and his colleagues employed 25 million computational hours to model the potassium channel voltage sensor, a kind of garage door control box that determines when the channel opens its gate. But the metaphor breaks down a bit when the channel is open, as the potassium channel does more than just wait to close again. Instead, there’s an in-between phase that keeps excessive potassium from stampeding through the open gate while the door prepares to close, a state called inactivation.

Determining the mechanism for inactivation has befuddled scientists for the same reason as the voltage sensor: how do you reverse-engineer a biological machine that works at the  nanoscale level, moving less than one-billionth of a meter at a time? One solution is to take pictures of the channel in motion, but doing so in the channel’s native habitat of the cell is beyond current technical means. Scientists have therefore resorted to a method called X-ray crystallography, a trick of chemistry and physics where the atomic structure of a protein can be determined.

X-ray crystallography has been used on potassium channels before - one such experiment even won the Nobel Prize for Chemistry in 2003. But each crystallographic portrait only catches the channel frozen at one particular moment of time, leaving scientists to make (educated) guesses about the movements that take place between each laboriously-obtained picture. The more pictures available, the less guesswork required.

More pictures and better theory are the result of two papers appearing in Nature today from the laboratory of Eduardo Perozo, professor of biochemistry and molecular biology at the University of Chicago Medical Center. Perozo’s group added to the potassium channel crystallography gallery by using a slightly mutated channel to keep the gate locked open and expose the elusive inactivation state to portraiture. From experiments conducted at Argonne National Laboratory, they hoped to get a new snapshot portraying a form of inactivation known as the C-type. But to their surprise and delight, they got 15 slightly different structures for the channel, which were determined to represent sequential stages between the open and inactivated state.

“By sheer luck, we happened to trap the channel in the process of opening, just like a movie,” Perozo said.

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An EEG recording of a seizure.

The electrical symphony of the human brain, with billions of neurons firing at different rates, up to hundreds of times per second, likely looks like chaos to any outside observer. But there are patterns in the ongoing brain activity seen, for instance, on an EEG: slow oscillations, rhythmic coordination, and purposeful ripples of communication. The importance of this intricate harmony is best displayed when it is disrupted by an epileptic seizure, which turns the fascinating complexity of the EEG into an angry scrawl.

You don’t have to be a neurologist to see the difference between a brain’s normal behavior and a seizure, but the causes of those seizures are much less obvious. Current antiepileptic drugs have shown success in treating some forms of epilepsy, but in many cases therapeutic success or failure is poorly understood and positive results are almost accidental - doctors are not entirely sure how medications suppress seizures, but are happy when they do. But for roughly a third of patients with epilepsy, those with intractable epilepsy, there remain no such happy accidents. Understanding what sparks a seizure would provide a rational basis for scientists to develop new drugs to treat the untreatable, as well as to reduce the side-effects of the existing treatments.

“Nothing has moved in the last 20 to 25 years,” said Wim van Drongelen, professor of neurology at the University of Chicago Medical Center. “There have been a lot of new anti-convulsant medications, but that one-third of patients who do not respond to medication has remained the same. My conclusion from that is that apparently all the new medications that have been developed address more or less the same type of epilepsy. In this context, epilepsy is comparable to cancer - there’s not just one type of cancer, and there’s not just one type of epilepsy, there are multiple types.”

To understand the different ways a seizure can form, scientists need a model. Experimentalists have recorded EEGs or used higher-resolution methods such as electrophysiology to measure cellular activity in a slice of animal or human brain tissue (obtained during surgery). But to truly model the brain’s rhythms - both normal and abnormal - requires nothing less than the most powerful computers currently available, a task that van Drongelen’s lab has undertaken.

“It’s a lot easier to do an experiment with a computer model than in a real slice,” van Drongelen said. “In a real slice, you have drugs to affect a certain channel, but these drugs are dirty, they also affect other things. In a model you can really very purely see what the effects are of certain manipulations and components. An additional huge advantage is that this approach gives you simultaneous access to what the population on the whole is doing, and what the individual agents are doing.”

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There aren’t too many tabloid stories that have implications for science and medical ethics. But in January 2009, the sensational saga of Nadya Suleman, the mother of octuplets crudely dubbed Octomom, simultaneously lit up the TMZs and National Enquirers of the world and posed tough questions to the field of assisted reproduction. Methods such as in vitro fertilization and artificial insemination have been a miracle for many families who would not otherwise have been able to conceive their own children. But B.O. (Before Octomom) little attention had been paid, at least publicly, to the question of when assisted reproduction should and should not be offered to a patient.

Suleman, who was a single mother of six even before in vitro fertilization led to the rare occurrence of octuplets, was an extreme example, to be sure. Many physicians spoke out against the use of assisted reproduction in Suleman’s case, and the Beverly Hills doctor that provided the treatment was charged with gross negligence by the Medical Board of California. But what about cases that are less clear-cut? How many pre-existing children are too many for a doctor to approve of further assisted reproduction? Does it matter whether the mother seeking artificial insemination is married or single? What about if the couple looking to conceive is homosexual?

Obstetrician-gynecologists are the physicians closest to the nexus of these questions, and Pritzker School of Medicine student Ryan Lawrence and Farr Curlin, associate professor of medicine, decided to take the temperature of the field on these issues. In a paper published this month in Obstetrics & Gynecology, Lawrence and his colleagues report on the results of a survey filled out by more than 1,000 ob-gyns. The doctors were asked whether they morally or ethically object to commonly-used reproductive technologies and given seven scenarios to test whether they would discourage or refuse to offer those methods to particular women:

• the patient is not married to their sexual partner
• the patient will raise the child or children as a single parent
• the patient’s partner is female
• the patient is HIV positive
• the patient is 56 years old and postmenopausal
• the patient already has five biological children
• the patient has a 25 percent risk of dying from a heart condition during pregnancy

As you might expect, the survey results showed widespread acceptance of assisted reproduction technologies, with less than 5 percent of ob-gyns objecting to IVF or artificial insemination. Slightly more objections were found when the procedures were conducted with donor sperm or eggs, rather than sperm or eggs taken from the intended parents. Physicians who self-identified as strongly religious were more likely to balk at the use of donor cells, which the authors speculated may have to do with Roman Catholic beliefs against separating sexual intercourse from procreation and Jewish or Muslim concerns over lineage and legitimacy.

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