How does an organ know when to stop growing? It may sound like a riddle, but it’s a serious biological question with the potential for grave consequences. During development, an organism grows from a single cell up to trillions of cells. If that growth process overshoots its goal and doesn’t stop generating new cells, the result can be the unrestrained proliferation of cancer. Scientists have thus looked for the regulators of that growth, a search that led them to a cast of unusual characters: hippos, Yorkies, and warts.

That colorful menagerie is the result of research in fruit flies, where naming conventions steer away from the cold acronyms used by the rest of biology. Researchers of the fruit fly Drosophila melanogaster run screens where individual genes are deleted or suppressed, then name the gene according to the unusual appearance or activity this modified fly displays. So when a genetic deletion created a fly with organs of unusually large size, researchers named that missing gene Hippo. Conversely, the name Yorkie was assigned to a gene that, when deleted, produced a fly that grew abnormally small organs.

In the early 2000s, researchers determined that Hippo and Yorkie - and a handful of other genes found to control organ size - were all part of the same system, dubbed the Hippo-Salvador-Warts (HSW) signaling pathway. These elements were not exclusive to flies, but found in a host of other organisms, suggesting that the system goes far back in evolutionary time as a critical controller of cell function. Early returns also indicate that the HSW pathway is a likely contributor to human cancers, said Rick Fehon, professor and chair of molecular genetics and cell biology at the University of Chicago.

“The basic components are in yeast, worms, flies, and humans, so it’s a really fundamentally conserved pathway,” Fehon said. “It’s a pretty fresh field in general, and I think the mammalian cancer implications are far from having been fully explored.”

While the Hippo to Salvador to Warts to Yorkie pathway has been firmly established, scientists are still looking for how elements upstream turn the pathway on and off. In a new paper published this week in the journal Developmental Cell, Julian Boggiano and Pamela Vanderzalm of Fehon’s laboratory discovered one of these HSW pathway “switches,” and lengthened the cellular chain of how organ size is regulated.

Boggiano and Vanderzalm were looking for proteins that interact with another cell growth regulator called Merlin, a gene responsible for the disease neurofibromatosis in humans. One by one, they depleted a family of proteins called the Sterile 20 kinases, looking for an element that regulates Merlin activity. In the process, they found that suppressing one gene, called Tao-1 (this name originates from studies in mammals, not flies), created a fly that looked similar to Hippo, displaying an abnormal growth of organs called imaginal discs that form the wings and eyes of adult flies (seen above).

“We were looking for one thing, and serendipitously found something else,” said Vanderzalm, a postdoctoral fellow. “Imaginal discs undergo about 1,000 fold growth in four days. During that time they go from about 50 cells to 50,000 cells. You can tell right away that the overall shape is disrupted and wherever we’ve driven Tao-1 RNAi, those cells have a growth advantage, and they’ve overgrown relative to the remaining wild type cells in that tissue. They’re dividing more frequently.”

“That was when we realized it was probably a new component of this pathway,” said Boggiano, a graduate student in the Committee on Development, Regeneration, and Stem Cell Biology.

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

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

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

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

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

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

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

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

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Loneliness can be deadly. In humans, there is a statistical relationship between social interaction and mortality - the more isolated you are, the lower your chances of living a long life. Rats kept in social isolation their entire life die at a younger age than littermates who lived in groups closer to their natural social structure. But how exactly does isolation kill a rat? Under normal conditions, an infectious disease such as pneumonia is typically the cause of earlier mortality in a lonely rat. But when rats are kept in the sterile conditions of a laboratory animal facility, the cause of death is something quite surprising: breast cancer.

Those experiments - conducted by the group of Martha McClintock, professor of psychology at the University of Chicago - sparked a fruitful collaboration between McClintock and Suzanne Conzen, professor of medicine and a cancer expert. Last week, McClintock and Conzen gave a tag-team talk at the Chicago Breast Cancer SPORE seminar to present an overview of their research into the connection between social isolation, stress, and breast cancer, a line of study that could flip the current thinking about the disease. Traditionally, the psychological and social effects of breast cancer are considered to be the consequence of its diagnosis and treatment, but the research of these two laboratories suggests that these factors could be a cause as well, just as much as genetics or other biological sources.

“What I brought to the classic traditional approach is trying to flip it on its head,” McClintock said, “where you recognize that there are truly social forces which then change the psychological states of individuals in those interactions, and in turn their hormone function, cell receptors for those hormones, and then ultimately changes in gene expression.”

The link between the two labs was made over a hormone known for its role in stress responses, cortisol. McClintock observed that solitary rats behaved more anxiously than their group-housed peers, and found that they exhibit a larger and prolonged cortisol increase after a stressful event. Conzen’s laboratory was already studying the role of a receptor for cortisol, the glucocorticoid receptor (GR), in breast cancer, because women with the harder-to-treat “triple negative” form of the disease often show increased GR levels. Researchers in Conzen’s laboratory discovered that activating GRs can stimulate proliferation of breast cells and block the effects of chemotherapy drugs.

Could this be the missing biological step between isolation stress and breast cancer? At the lecture, Conzen tagged back to McClintock to talk about experiments on the tumors from her socially isolated rats. Unlike more common animal models of breast cancer where the tumor is instigated by a toxin or a genetic mutation, the naturally-occurring tumors in isolated rats show a similar diversity to that seen in human tumors. Some rats grow benign tumors, some malignant, and different tumors have the different hormone receptor profiles that are used for classification and treatment choices in patients - including, in some cases, glucocorticoid receptors.

“This to me was very exciting because in the rat model we have a good model of the diversity of breast pathology that happens [in humans] and it is increased by isolation,” McClintock said. “I was happy to see it in the more natural, spontaneously-occurring cancer model rather than something that was induced.”

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By John Easton

Let’s start with a statistic: almost 2,000 citations a year. One paper by Paul Meier, the Ralph and Mary Otis Isham Distinguished Service Professor emeritus of statistics, pharmacological and physiological sciences, medicine, and the college, has been cited more often, by a wide margin, than any other paper in the field. At last count it was the fifth most cited research paper of all time, in any field. With about 34,000 citations to date, Kaplan, E. L., and Meier, P. (1958), “Nonparametric Estimation from Incomplete Observations,” has been cited by another scientific publication about once, on average, for every day of Meier’s long life—he was born in 1924—and still counting.

Sadly, however, that ratio can only increase. Citation counting will continue, but the numbering of days stopped on Sunday, August 7th, when Professor Meier, a world-class statistician who made “extraordinary contributions to statistics and to society,” according to Columbia University - and everyone else - passed away peacefully at his Manhattan home.

The Kaplan-Meier estimator is used ubiquitously in medical studies to estimate and depict the fraction of patients living for a certain amount of time after treatment. This is not as simple as it sounds. Survival curves are complicated by the uncooperative way in which research subjects often behave. Some leave a study part of the way through. Others elect not to die before the study ends. These are known as “censored observations.” The Kaplan-Meier estimate is a simple way to compute the survival curve despite such troublesome behavior.

There was almost a Kaplan estimator and a Meier estimator. Each had submitted a separate manuscript to the Journal of the American Statistical Association, but the editor recommended that their papers be combined into one. It took them four years. “At one place he solved a problem that I couldn’t solve,” Meier later recalled in an interview [pdf]. “Other places I solved problems he couldn’t.” Finally published in 1958, it was only cited 25 times over the next ten years. Then, boosted by statisticians’ increased computing power, it caught on. It has since been applied to data from clinical trials of therapies for every disease from cancer to cardiology to concussion.

Friends and colleagues point out that this was only one of Meier’s fundamental contributions. He published many more studies, was a persistent and outspoken advocate for randomization in clinical studies, helped design some of the 20th Century’s most important clinical trials and trained many of the leaders in the field.

“Paul was a friend and colleague as well as one of the most influential statisticians of an important era,” recalled Stephen Stigler, the current chair of statistics at the University of Chicago. “He left an indelible mark on us, and through his research on the world’s clinic analytical practice. He will be missed and cannot be replaced.”

“I have been so fortunate and privileged to know this truly great, wonderful, helpful, kind man who was always so generous with his skills and wise advice,” said toxoplasmosis expert Rima McLeod, professor of ophthalmology and visual sciences at the University. “He is one of the founding fathers and giants of statistics in the past century. He was at the same time simply a modest, helpful, supportive and warm colleague who only let you know how special he was by the quality and content of what he said and wrote.”

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By John Easton

As of July 2010, nearly 600 genome-wide association studies of 150 distinct diseases and traits had been published. They revealed hundred of specific genomic locations, each with a relatively small effect. There were more than 40 genetic variants, for example, associated just with type 1 diabetes and 30 more related to Crohn’s disease.

Despite hundreds of studies, hundreds of thousands of volunteers and billions of genotyped markers, few of the genetic signposts identified “have clear functional implications,” wrote Teri Manolio of the National Human Genome Research Institute in a review article for the New England Journal of Medicine. Narrowing an implicated locus to a single variant that directly causes susceptibility to disease by disrupting the expression or function of a protein, he added, “has proved elusive to date.”

Enter children’s cancer specialist Kenan Onel, MD, PhD, with a vastly smaller sample size, about 300 - a fraction of the usual GWAS brigade - and a much narrower, tightly focused question. Are there genetic variations, he asked, in patients who were treated with radiation therapy for Hodgkin lymphoma as children and then acquire second cancers decades after treatment?

Hodgkin lymphoma is one of the most treatable cancers, with more than 90 percent of patients surviving after a combination of radiation and chemotherapy. But nearly 20 percent of patients treated as children develop a second cancer within 30 years. The younger the patients are when treated and the higher the radiation dose, the greater the risk. This late side effect is the second leading cause of death for long-term Hodgkin’s survivors.

In Onel’s GWAS search, published last week in Nature Medicine, he found two variants relevant to these secondary cancers. Only three percent of patients with both of the protective versions developed second cancers within 30 years. But those with both of the high-risk variations-a combination found in 50 percent of those of European descent-had ten times the risk: more than 30 percent of them developed second cancers.

“This means we can identify children who are most susceptible to radiation-induced cancers before treatment begins and modify their care to prevent this serious long-term complication,” said Onel. “Our options for Hodgkin’s are broad enough that we can find ways to control the initial disease without relying on radiation therapy.”

Onel and colleagues “used very wise scientific intuition and they got some place very interesting,” Stephen Channock, head of translational genomics at the National Cancer Institute told Spoonful of Medicine. “It’s a very exciting scientific finding. They did a GWAS in a very small study…but the effect they saw was very strong.”

Onel and colleagues analyzed the genomes of 178 Hodgkin’s patients who had been treated between the ages of 8 and 20 with chemotherapy and radiation therapy. Within 30 years after treatment, 96 of them had developed second cancers and 82 had not.

When they scanned each patient’s genome, focusing on 665,313 tiny genetic variations known as SNPs, they found three variations that appeared far more often in patients with second cancers. When they repeated the study using a different set of patients - 62 cases with second cancers and 71 without - two of the three markers were significant.

Those two markers were both from a small region known as 21q on chromosome 6. Both are positioned near a gene known as PRDM1. The genetic variations closely associated with increased cancer risk, and with each other, appeared to decrease activation of the PRMD1 gene. They had no detectable effect on any other genes. Cells with the protective version of both markers expressed PRDM1 after being exposed to radiation. Cells with the variants linked to subsequent cancers did not produce any PRDM1.

Previous studies have found that PRDM1 is involved in a variety of fundamental cellular processes, including proliferation, differentiation and apoptosis - which can all go awry in cancer. The gene’s activity is lost in many cancer types.

“Taken together,” the authors note, “our findings support a novel role for PRDM1 as a radiation-responsive tumor suppressor.” PRMD1 may be important for understanding the causes of second cancers in survivors of pediatric Hodgkin’s lymphoma as well as in other cancer patients treated with radiation therapy.”

This study should also “bring some optimism” back to genome-wide association studies, Onel added.

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A large portion of medical research is dedicated to designing and testing new and better drugs for treating disease. But what if we could improve treatments with the drugs we already have - and potentially cut costs at the same time? That’s the proposal made in an editorial this week in the Journal of the American Medical Association written by the Medical Center’s M. Eileen Dolan and Vanderbilt University’s Russell Wilke. Their article, “Genetics and Variable Drug Response,” is an optimistic snapshot of the current state of pharmacogenetics, the use of genetic information to improve the use of pharmaceuticals.

Though individualized or personalized medicine has been a goal of physicians and researchers for several years, the science (as it tends to do) is moving slowly. But as Dolan and Wilke write, promising pharmacogenetics examples are beginning to accumulate, from genes for enzymes found to influence the metabolism of chemotherapy and anti-clotting drugs to genetic variants that predict severe side effects from various agents. Some of these discoveries have already made it to the clinic, such as the genetic test (developed at the University of Chicago by Mark Ratain) for a variant that affects the response to the cancer drug irinotecan. Physicians can use the test to lower the dose in patients found to carry the variant associated with severe side effects at the normal dose.

Dolan and Wilke dream even bigger about pharmacogenetics. Currently, the standard drug dose is set by the average response of a large population, hoping to capture a level where people get the most benefit at the least risk. But as more information about the genetics of drug response are revealed, those doses can be better shaped to each patient according to their own personal risk-benefit. This could bring some drugs deemed “too dangerous” back to common use, if some patients have a genetic profile that enables them to endure the treatment safely.

“For drugs with a narrow therapeutic index, pharmacogenetic studies may hold the potential to resurrect treatments previously withdrawn from the market, particularly for agents designed to fill underserved clinical niches,” they write.

If smarter dosing can truly bring effectiveness up and toxicity down, it would be a benefit to both patients and the health care system in general. One suggestion by the authors is to start building gene-based drug dosing into electronic medical records, creating alerts for doctors about “drug-gene interactions” similar to current alarms for potentially dangerous drug-drug interactions. The future of medication may be more complicated than “take two of these,” but smart implementation may save dollars and lives.

Cohen Video

The American Society of Clinical Oncology recently filmed a short video with Medical Center associate professor of medicine Ezra Cohen, where he talks about how he decided to treat cancer patients while working as a small-town family physician. It’s a nice piece about how doctors are inspired to do their work and the connection between laboratory research and clinical care. If you want to see more videos with Dr. Cohen, he discussed head-and-neck cancer with ScienceLife almost exactly one year ago.

Elsewhere…

Right after his very cool study on the genetic origins of limb development was published, evolutionary biologist Neil Shubin departed for his annual expedition to the Canadian Arctic in search of fossils from the earliest limbed creatures. If you want to follow along with the hunt, Shubin’s teammate (and Tiktaalik co-discoverer) Ted Daeschler is blogging from the dig for the Philadelphia Inquirer! Read about how their remote site on Devon Island is “almost like Mars,” and how the expedition is already finding interesting fossils two days into the trip.

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In a typical clinical trial, the results are reported in purely medical or biological terms. Did the patients in the treatment group live longer than those in the control group? Did the drug shrink the tumor or reduce symptoms? Were clinical measures such as blood pressure or cell counts affected? These are the details that the Food & Drug Association and the physician community look for when they decide to approve or prescribe new therapies. But looking at a new treatment’s effects in a medical vacuum might miss critical details about its actual usefulness out in the real world, where patients have different priorities and health care dollars are finite.

To create a more well-rounded and practical clinical trial, medical researchers need to reach outside of their discipline for expertise. Or, they can bring those experts into the hospital fold, as was recently done with the establishment of the University of Chicago Program in the Economics of Cancer. Led by Ya-Chen Tina Shih, an economist who specializes in the economic aspects of cancer care, the program has a unique premise: to study the economics of a disease that produces estimated yearly costs of $270 billion and rising in the United States. In a field where new treatments, devices, and procedures appear with startling frequency, Shih’s group aims to weigh the costs and benefits of these new technologies so that patients receive the best, most logical care rather than just the hot, new, often-pricey thing on the market.

“I see it as a place to bring researchers together to look at economic issues in cancer,” Shih said. “The issues to be addressed can be large policy issues or a cost-effectiveness analysis comparing two different treatments. What we would like to do is provide an environment where if there are oncologists who want to study those questions, they don’t have to try to learn everything themselves. They can team up with economists or people in operation research or health services research, and can work on issues together. Similarly, people with no medical training who are interested in exploring those questions can find their clinical collaborators here.”

Calculating the cost of cancer is harder than it might seem. A diligent researcher could, with much effort, simply total up all the money spent on drugs, procedures, doctor’s appointments, and devices, and calculate a price tag for cancer or cancer treatment. But one must also take into account the indirect cost of missing work, either temporarily due to illness, side effects, or surgery, or permanently due to death. Other factors are even harder to convert into dollars, such as quality of life under different treatments, while still others are politically fraught, such as cost-effective analysis to determine whether a new treatment is a significant enough improvement over the current standard of care to justify coverage by insurance companies.

Economists can estimate these figures retrospectively, after a given treatment has been out on the market for a few years or more, but at that point the horse is long out of the barn. If a new treatment is given to patients for three years, then found to be less cost-effective than the standard of care it replaced, it could unnecessarily cost society millions or billions of dollars. Shih hopes that the Program in the Economics of Cancer will help cancer researchers design clinical trials with such economic questions in mind, so that information about costs can be gathered before the widespread diffusion of a new technology that provides a very small benefit at substantial cost.

“You don’t at the conclusion of a trial say ‘let’s add a cost-effectiveness analysis to that.’ By then, it’s way too late,” Shih said. “The idea is to get more people interested in collecting this data at early timepoints, so by the time they really want to answer a question, they have the data to answer it.”

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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).

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By John Easton

At 1:30 pm, on Monday, December 12, at its Annual Meeting and Exposition in San Diego, The American Society of Hematology will recognize Janet Rowley of the University of Chicago Medical Center, and Brian Druker of Oregon Health & Science University, with the 2011 Ernest Beutler Lecture and Prize for their significant advances in the diagnosis and treatment of chronic myeloid leukemia (CML), a cancer of the blood characterized by an overproduction of white blood cells.

This is a great honor - and a storage problem.

Rowley has received many prizes over the course of her career: the Lasker Award, the Gruber Genetics Prize and the American Association for Cancer Research Award for Lifetime Achievement. President Jimmy Carter appointed her to the National Cancer Advisory Board. President Bill Clinton awarded her the National Medal of Science. George W. Bush selected her for his President’s Council on Bioethics. She stood with President Barack Obama when he signed the stem cell research bill and she returned to the Obama White to accept the Presidential Medal of Freedom. Then she moved to a new office with a better view, but less shelf space.

Rowley has long been known for brilliant insights, intellectual rigor, and relentless tenacity, but never for extreme neatness. “Her filing system involved piles,” said MaryBeth Neilly, a senior research technician who works with her. When preparing for the move, “we found awards all over the place,” she said. “We knew we needed a place to put them, and that her office was not that place.”

Thus was born the shrine. “Once we moved, but before we unpacked, we ordered a display case,” said Neilly. She and Rowley sorted through the honors and picked the cream of the crop; those that were the most significant, or that looked really cool. Lots of them, some of the trophies, most of the plaques and the vast majority of honorary doctorates, were transported - lovingly, but in bulk - to the University archives.

The display case soon filled to capacity. “There’s a lot of crystal in there, a lot of shiny metal,” Neilly said, such as the National Cancer Institute’s Rosalind E. Franklin Award for Women in Cancer Research, a big carved glass bowl, or the National Medal of Science, a golden medallion.

A few favorites - for reasons aesthetic or sentimental - wound up in Rowley’s office, including the Lasker, the Presidential Medal of Freedom, a large, twisting crystal chromosome from the Jeffrey M. Trent Lectureship in Cancer Research, and a bronze sculpture from the Leukemia and Lymphoma Society. A few more are at Rowley’s house. Two made of a particularly valuable soft, shiny heavy metal, stay at a local bank. The exact positioning of the Beutler Prize has not yet been determined.

Elsewhere…

Vijay S. Dayal, a longtime fixture of the Medical Center’s otolaryngology department, passed away last week at the age of 74. A head-and-neck surgeon and expert on hearing and balance, Dayal was also known as a skilled inventor, obtaining patents for an artificial voice box and a customized “rotating chair” used to test dizziness and balance. “Testing in the chair is not uncomfortable for the patient,” Dayal said in 1991. “It’s like a mild ride on a merry-go-round and it provides us with information we cannot get any other way.” You can read another obituary for Dr. Dayal at the Chicago Tribune.

What’s it like to be a medical student? Pritzker first-year Akash Parekh narrates a day in his life for US News & World Report. Spoiler alert: there’s not much free time, or sleep.

If parents refuse vaccinations for their child, should pediatricians be allowed to refuse to take them as a patient? That interesting ethical question was the subject of an article by the Chicago Tribune’s Deborah Shelton.

The new Scientific American blog network officially launched this week, and provides a new home to many of my favorite science bloggers. For a taste, check out Lucas Brouwers’ post on the evolution of E. coli, and this interview with John Boswell of Symphony of Science (best known for the Carl Sagan autotune track “A Glorious Dawn”).

Popular Mechanics typically offers step-by-step guides for changing your oil or building a bookcase. But in a recent feature they seriously upped the instructional ante with an “Extreme How-To” - How to Perform Open Heart Surgery. The expert chosen to guide their readers through this don’t-try-this-at-home process was Medical Center cardiac and thoracic surgeons Jai Raman and Shahab Akhter who helped develop a new technique in heart surgery called the “wrap procedure.” The surgeons do a great job of explaining how the surgery has changed over the years, particularly in the materials used for repairing the heart and sternum after surgery to speed recovery and decrease scarring. “You’ve got to get comfortable putting stitches into a beating heart,” is just some of the sage advice that Raman offers in the piece.

The end of the academic year always brings a bounty of teaching honors, voted on by medical students, residents, and faculty peers. For the 2010-2011 year, more than two dozen awards were handed out by the Pritzker School of Medicine, the Biological Sciences Division, and departments of the Medical Center. For an awards roundup from both sides of campus, visit this article at the University of Chicago News Site.

The pediatric cancer patients at Comer were treated to a celebrity visit last weekend, though their parents and staff may have recognized her more by voice than by sight. Delilah, the easy listening disc jockey known for her “Love Someone” radio dedications, visited families at Comer before making 3-year-old leukemia patient Atia Lutarewych her “Brave Child of the Week.” You can listen to her segment on the visit here [mp3].

Another inspiring story of pediatric cancer was told in the Chicago Tribune this week, focusing on 6-year-old neuroblastoma patient Theofanis Yianas. After Theo’s hair fell out from chemotherapy treatment, 30 friends and family members shaved their heads in solidarity with the young boy. Theo’s doctor, professor of pediatrics Susan Cohn, comments on the importance of support in a patient’s recovery.

What did St. Vitus’ Dance - the 14th century outbreak of weeks and months-long uncontrolled dancing across Europe - have to do with mirror neurons in the brain? UChicago psychologist John Cacioppo weighs in on this fascinating phenomenon for ABC News.

An interesting plan to create “mystery shoppers” for assessing the primary care shortage in the United States was revealed in the New York Times on Sunday, then disappeared by Tuesday after doctors bristled about “snooping.” The survey, which would have been conducted by the University of Chicago National Opinion Research Center, shows how far the administration will go to collect data on the current health care system…and how stiff the medical field’s resistance can be to being measured.

When the media fixates on a medical topic, doctors know that a flurry of patient questions will inevitably follow. So it helps to be prepared with responses to hot-button questions, such as those surrounding the recent resurgence of the potential link between cell phones and brain cancer. Inspired by the World Health Organization moving the radiofrequency magnetic fields produced by cell phones to the classification of “possibly” causing cancer in late May, some newspapers handled the topic with subtle headlines like IS YOUR CELL PHONE KILLING YOU?. Though the fevered media response of some outlets was countered by thoughtful explainers from other sources, many physicians will surely still face questions from patients on the topic. But how does a busy doctor brush up on the extensive literature testing the link between cell phones and cancer?

A: You attend a literature review talk, such as the one given by hematology/oncology fellow Daniel Geynisman at Monday’s installment of the department’s weekly seminar. In half an hour, Geynisman sped through the most important studies examining cell phones and brain cancer, drawing out the important results, criticisms, and implications of the experiments. The primary message was simple - there’s no need to panic, or to go back to using exclusively landlines and pagers. But a true danger does exist with cell phones, Geynisman said, one that’s worth sending a warning to patients - and doctors themselves.

The lingering mystery around cell phones and cancer is caused by an epidemiological quirk, Geynisman explained. Proving the link between a rare exposure and a rare cancer - such as asbestos and mesothelioma - is relatively straightforward. Finding a link between a common exposure and a common cancer is more difficult, but can be done, as it was with smoking and lung cancer. But conclusively proving the connection between a common exposure, such as cell phones, with a rare cancer, such as glioma or acoustic neuroma, is much more difficult. Only about 10,000 new cases of glioma are diagnosed each year in the United States, while more than 300 million cell phones are currently in use in the country. To prove that the use of phones significantly increases brain cancer rates, enormous numbers of subjects would have to be collected and followed.

Those challenges have forced most researchers into a flawed study design, Geynisman said. Retrospective case control studies are commonly used in epidemiology, but are subject to an important confounding factor called recall bias. If you ask 3,000 people with brain tumors and 3,000 controls about their history of cell phone use, those with  cancer are more likely to remember and report unusually high amounts of use. In one study, subjects were found to over-estimate their cell phone use by almost three times, adding a hefty dose of salt to any case control results.

Despite this issue, early case control studies found a relative risk of 1, indicating no increased or decreased risk for brain tumors in users of cell phones. But the question did not go away, fueled by the research of a Swedish group who dialed the data down to find increased risk among very specific groups: people who used cell phones for more than 10 years, or people who started using the phones before the age of 20. The INTERPHONE study, which surveyed over 6,000 people with brain tumors and 7,000 controls from 13 countries, might have settled the dispute but for one result. Published last year, most of the risks calculated for various groups and tumors showed a negative association with cell phone use, suggesting (improbably) that talking on the phone protected against brain cancer. But one association still stuck out - heavy cell phone users showed a 40 percent increase in the risk of glioma. Statistical anomaly, or cause for concern?

The result was apparently enough for the WHO to place cell phone radiation in the same group as other potentially carcinogenic compounds ranging from lead and coffee, and for more studies to be conducted, Geynisman said. After all, ubiquitous cell phone use is a relatively recent development, so more time may need to pass before the health effects can be accurately assessed. A prospective study, called COSMOS, will tackle some of these questions, as it follows a quarter-million subjects for at least 25 years and measures cell phone use as it happens, instead of through memory. But while scientists, physicians, reporters, and the general public wait for those results, they can caution the world about the real dangers of cell phones, which have nothing to do with cancer.

“What’s not shaky is that cell phone users are four times more likely to be distracted drivers and texting poses a risk of 23 times more collisions. 81 percent of Americans use their cell phones while driving, and almost a third of crashes involve cell phones,” Geynisman said. “So you can keep using your cell phone probably, but don’t do it while driving.”

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.

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By Meghan Sullivan

That there even was a luncheon at Crerar library last week to welcome Nancy Hopkins was a sign of progress. Speaking of a committee formed at MIT in 1995 to explore gender discrimination among tenured faculty, she commented that their meetings were generally held off campus since “having that many women in one room at MIT was so unusual that we were afraid to be seen meeting on campus…it was sure to arouse suspicion.”

Fifteen years later, the packed luncheon in the middle of Crerar was hard to miss. A few dozen women - and a few men - had gathered to discuss her work uncovering and fighting gender discrimination at MIT. More than a relaxed opportunity to ask Hopkins questions before her afternoon lecture, the lunch was a chance for graduate students and post-docs to discuss their experiences and ask for advice. While the prevalence of gender discrimination in the sciences and elsewhere tends to incite strong emotion, Hopkins carried herself with sensibility and humor that was contagious.

Hopkins, a professor of biology at MIT and accomplished cancer biologist, is the first to admit that she never intended to be a feminist. It wasn’t until pervasive and arguably unconscious barriers at MIT began to impede her research in 1995 that she took action against the status quo. Science, she pointed out, has always been touted as a meritocracy, yet she saw her female colleagues repeatedly passed over for tenure, funding, even lab space. In the early stages of her work on gender discrimination, Hopkins perused the MIT staff listings looking for other women in science. She was shocked to learn that out of 274 faculty positions, only 22 were filled by women. “I said check the back of the catalog,” she laughed, “Perhaps they list them separately.”

But why was science losing women? By the nineties the percentages of male and female graduate students in the sciences were about equal, yet that equality failed to emerge in tenured faculty positions. To explain this, Hopkins described a well-established phenomenon known as “the Leaky Pipeline.” In essence, while the proportions of male and female students entering science are comparable, women are more likely to leave (or leak out of) the scientific career path due to issues which primarily affect women.

Like many, Hopkins believed the Civil Rights Act and affirmative action policies were the answer to getting more women in science. But over the next thirty years, less obvious issues proved serious barriers, including sexual harassment, connecting with an empowering mentor, and managing a successful family-work balance. The last was especially frustrating, as high level science can often require more than 70 hours of work a week, leaving little time for family and children. As Hopkins put it, many were required to be “nuns of science,” working in an environment where talking about family and children was far from the norm.

However, it wasn’t until one of the more insidious barriers to women in science began to interfere with Hopkins work that she got involved. Called unconscious gender bias, this subconscious undervaluation of work done by women has been studied for years by psychologists. For example, when people are shown work done by a man or a woman and asked to rate it, the panel will value the man’s work over the woman’s, even if the objective quality of both is identical. Such undervaluation of women’s work not only directly impedes their progress up the academic hierarchy, but also self-selects female researchers out of science, caving to feelings of inadequacy and disappointment. As Hopkins said, she felt that “no matter what I discovered, I wouldn’t be accepted in this field.”

Rather than give up a career she’d already sacrificed so much for, Hopkins and 16 other tenured female faculty members drafted a letter to MIT’s Dean of Science at the time, Robert Birgeneau, concerning the unfair gender biases prevalent in the MIT system. Birgeneau responded immediately and impressively to the committee’s report, instituting an aggressive hiring campaign designed to recruit top female researchers from around the world. The resulting increase in the percentage of women faculty was fondly called “the Birgeneau bump.” In addition to the hiring of more women, MIT set to work on increasing day care options and set up committees that would oversee equality in working conditions and institutional policy. These institutional changes would go on to become a standard in the academic world and be adopted by institutions throughout the country.

Yet problems remain.

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In the 2000s, a new kind of genetic experiment was born: the genome-wide association study, or GWAS. If geneticists could recruit enough people with a particular disease and compare them to an equal number of disease-free controls, they believed GWAS would point the way to common gene variants associated with disease risk and novel biological pathways. One of the strengths of GWAS was that it was hypothesis-free, an unbiased comparison that could reveal surprising risk-associated genes that had not occurred to scientists in the past. More than 1,000 GWAS studies have been conducted to date, on diseases ranging from diabetes to Parkinson’s disease to Crohn’s disease to various types of cancer.

While these studies have identified thousands of gene variants (called single nucleotide polymorphisms, or SNPs) associated with disease risk, they can still only explain a small fraction of the heritability of disease. Some scientists have thus moved on from GWAS to the next wave of genetic studies, including whole-genome sequencing to look for rare variants and gene-environment interaction studies. But some geneticists think the field may be moving too quickly onto the next big thing, and that there remains value in the volumes of GWAS data collected over the last decade. A second generation of GWAS is taking place, where the data from the first round is approached in new ways to find previously hidden gems of information.

In two recent studies, assistant professor of health studies Brandon Pierce applied this Reuse/Recycle/Reduce philosophy to GWAS data on pancreatic cancer risk, a disease where genetic and biological explanations are particularly lacking. For both experiments, Pierce bended the “hypothesis-free” rule of GWAS in order to narrow the field of gene variant candidates and allow for a more selective scan of pre-existing data. By reducing the number of candidates from the ~550,000 of a full GWAS, the statistical threshold for confirming a SNP association with risk can be set lower. If the original GWAS experiments were the equivalent of looking for a needle in a haystack, the new techniques are a much less daunting task, he said.

“You conduct fewer tests, so the haystack is smaller,” Pierce said. “In all of the tests you are conducting, you know the SNPs are biologically meaningful, whereas in a typical GWAS, a large percentage of the SNPs may have very little to do with human biology.”

In the first study, published in March in Cancer Causes & Control, Pierce adapted a connection discovered by epidemiology studies to his genetic scan. Patients with type 2 diabetes were measured to have elevated risk for pancreatic cancer - a logical relationship given that diabetes is primarily a disease of the pancreas. Pierce took 37  SNPs associated with type 2 diabetes and tested them in the GWAS data collected by a previous study of pancreatic cancer. None of the SNPs tested showed a strong association with pancreatic cancer, though two new gene variants produced suggestive evidence of an association. The results suggested that the biological link between type 2 diabetes and pancreatic cancer may not be as strong as the epidemiology data indicated.

“We didn’t find any major associations that popped out at us from the diabetes study, so the conclusion was that these established genes for type 2 diabetes don’t seem to have a big effect on pancreatic cancer risk,” Pierce said.

But a second study, published in Cancer Research, would lead Pierce almost full circle. This time around, he ran the pancreatic cancer GWAS data through what he dubbed a “pleiotropy scan,” testing only SNPs previously demonstrated to have a biological effect in humans. For many of the more than half-million SNPs typically tested in a GWAS, scientists have yet to discover a linkage to any disease or biological effect, suggesting that these markers may sit without effect in the long gaps between protein-encoding genes in human DNA. Like the first study, limiting his GWAS tests to only these SNPs (1,087 in this case) allowed Pierce to pick up more subtle associations than in a full-blown GWAS.

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Teaching with Treadmills

Inside the Biological Sciences Learning Center on the Medical Center campus is a laboratory that looks more like a gymnasium. Six state-of-the-art treadmills and six futuristic exercise bikes sit around the room, each connected to a computer alongside modified oxygen masks and suction cup sensors. Instead of dissecting frogs or mixing chemicals, students show up to lab sections in shorts and running shoes, prepared to sweat for science. In Mark Osadjan’s “Metabolism and Exercise” course, part of a two-quarter Exercise and Nutrition sequence, there’s no sitting on the sidelines.

Since joining the University of Chicago as a senior lecturer in 2003, Osadjan has designed courses that teach undergraduates about biology by connecting with what most college students care about: keeping fit, and sex. As part of the UChicago core curriculum, every undergraduate must fulfill a biology requirement, even if their interests lie in political science, music theory, or philosophy. With his “Metabolism and Exercise” and “The Biology of Gender” courses, Osadjan has met these science-shy students halfway, filtering instruction on evolution, physiology, and genetics through their own personal hobbies and interests. The efforts have been such a success that Osadjan’s courses fill up soon after registration is opened.

Today, Osadjan was announced as one of this year’s recipients of the Quantrell Award for Excellence in Undergraduate Teaching, an esteemed UChicago honor that goes back to 1938. Last week I met with Mark to talk about his award and his career path, from a graduate student studying Antarctic fish to an instructor of graduate-level science to his current position, teaching predominantly undergraduate non-biology majors.

“It’s always a trick to figure out how to teach with enough enthusiasm, such that it spills over to the students,” Osadjan said. “It’s our challenge not only to teach these students a certain number of facts, but to show them why those facts are important, relevant, and worth thinking about throughout life.”

You can read more about Osadjan and the other Quantrell winners in the award package at The University of Chicago news site.

Elsewhere…

Most college students spend their summers traveling the country or working an internship, but 20-year-old Rachel Garneau had other plans: donating a kidney. On Tuesday morning, Garneau came to the Medical Center and made the rare gift of an altruistic kidney donation, triggering a kidney swap chain that helped patients in need of the organ in New York and Madison. Neil Steinberg at the Chicago Sun-Times followed the story before and during the surgery, and got some great play-by-play commentary from Yolanda Becker, professor of surgery and director of the kidney and pancreas program.  For instance: “‘The pancreas is the bitch of the abdomen,” she confided.’”

Are clinical trials handicapped by their own success? A new analysis from Anup Malani and Tomas Philipson of the University of Chicago Law School finds that trial enrollment for a given disease plummets when a treatment is found to be effective, using AIDS clinical trials after the approval of anti-retroviral therapy to illustrate the point. Richard Schilsky, professor and section chief of hematology/oncology at the Medical Center, agreed with the findings at Nature News: “There are so many options that patients are not flocking to get into clinical trials like they used to.”

Read how turtles move to warm areas to bask - even in their own eggs as embryos. Adorable photos and interesting commentary (are they determining their own sex?) at Not Exactly Rocket Science.

That news about the World Health Organization adding cell phones to their list of possible carcinogens? Here’s an article from Cancer Research UK to reassure your fears. Another reassuring fact: it was placed by the WHO into the same risk category [pdf] as coffee, dry cleaning, and pickled vegetables.

Can jazz musicians tell the difference between another musician improvising or following composed music? A new study finds the answer, and a ScienceNOW article gives you the chance to test yourself.

Did you know UChicago evolutionary biologist Neil Shubin does a regular science news roundup on local newsmagazine show Chicago Tonight called Scientific Chicago? Well he does, and the latest edition discussed a story familiar to readers of the blog: the mass extinction 360 million years ago that ended “The Age of Fishes.” Watch the video here.