By John Easton

Even in the court of ethics and medical professionalism, there’s nothing wrong with the occasional honor or award. On day two of the conference, the Maclean Center awarded its first Prize in Clinical Ethics and Health Outcomes - at $50,000, the largest such prize in the ethics field - to John Wennberg, the Peggy Y. Thomson Professor for Evaluative Clinical Sciences at Dartmouth Medical School and founding editor of The Dartmouth Atlas of Health Care.

In 2007, the journal Health Affairs named Wennberg as “the most influential health policy researcher of the past 25 years.” Fitzhugh Mullan, former director of the Bureau of Health Professions in the U.S. Department of Health and Human Services, described Wennberg as “both the Christopher Columbus and the Johnny Appleseed of clinical variation,” meaning he not only discovered the field but also brought it to the attention of the medical and health policy communities.

“While John Wennberg is regarded as a health services researcher,” said Mark Siegler, MD, director of the MacLean Center, “his fundamental work on patient preferences and shared decision making highlight his contributions to the field of clinical medical ethics.”

The Dartmouth Atlas examines the patterns of medical resource intensity and utilization in the United States, with special emphasis on end-of-life care, inequities in the Medicare reimbursement system and the under-use of preventive care.

From the start, it has brought surprises, according to Kenneth Polonsky, dean of the Division of the Biological Sciences and the Pritzker School of Medicine at the University of Chicago, who introduced Wennberg. The report comprehensively documented the “striking differences” in the amount of health care provided in different regions, adding the provocative observation that the amount or cost of care delivered did not correlate with good outcomes.

Joking that “when you get paid so much to give a lecture, you get a little nervous,” Wennberg spoke about the early days of the Atlas and how their studies of practice variation in the mid-1970s “challenged the notion that science was driving utilization.” Instead, decisions about surgical treatment for benign prostate hyperplasia revealed what the researchers called “surgical signatures,” patterns of practice based on the beliefs of individual surgeons.

When Wennberg’s team developed short, balanced videos to show to patients, explaining the risks and benefits of surgical treatment and showing taped interviews with two physicians who had made different decisions, patients were much less likely to choose surgery. “This was the first evidence,” he said, “that engagement of patients could lead to the right utilization rate.”

However, only about 25 percent of medical care turns out to be so “preference-sensitive,” forming what Wennberg calls “little islands of rationality.” Studies of end-of-life care found a far more limited role for shared decision making between patients and their caregivers. Instead, demand for resources appears to be driven by supply. Empty hospital beds and unused capacity strongly correlate with increased medical care late in life. For example, more than twice as many patients were admitted to an intensive care unit in the last six months of life at UCLA compared to Dartmouth.

Wennberg described the four goals of the Atlas’s end-of-life team for the next five years: to better inform patient choices, improve the science behind these decisions, promote organized care and constrain undisciplined capacity spending. At this point, he said, “we don’t need more research, we need more action.”

Another session at the conference focused on a very different book, not an atlas but a historical novel, based on true events and real people. Open Wound: The Tragic Obsession of Dr. William Beaumont, by former ethics fellow Jason Karlawish, a professor of medicine and medical ethics at the University of Pennsylvania, examines the professional and ethical issues raised by William Beaumont, a 19th-century surgeon who cared for - and experimented on - a patient with a shotgun-blast-induced hole in his stomach. Beaumont saved the patient’s life, but then used this wound, which never quite healed, as a window to decipher the mysteries of digestion.

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The ability to drink animal milk into adulthood is something that most of us take for granted.  But lactose tolerance is a genetic marvel, an exclusive human trait facilitated by a genetic mutation that only appeared in the last 10,000 years. In fact, the persistent production of the enzyme lactase (which digests lactose) has been so useful to humans, it has evolved several times in different populations around the world. The mutation that allows for lactose tolerance in people of European origin is different from the mutation observed in African or Saudi Arabian populations - an example of what is called “convergent evolution.”

One corner of the world where lactose tolerance has not been well studied is India. Cattle have a long history in India, both as an agricultural animal and a figure of worship. In fact, India has grown to become the world’s largest producer of milk, using both cattle and water buffalo as dairy animals. Cheese, yogurt, and cream-based curries are a staple of the Indian diet, and many Indian citizens consider themselves lactose tolerant. But other than a few small studies, nobody had looked at whether Indians have their own unique mutation - or whether they were even as tolerant of dairy as commonly thought.

“India is fantastic because it’s really, really diverse culturally and geographically,” said Irene Gallego Romero, a post-doctoral researcher in the University of Chicago Department of Human Genetics. “They have a history of milk consumption, but nobody had looked at whether they were actually lactose tolerant or not.”

Gallego Romero’s research, conducted while a graduate student at the University of Cambridge and recently published in Molecular Biology and Evolution, allowed her to do more fieldwork than a genetics project typically allows. To collect samples, Romero went on two separate trips to India in 2008, spending two months each time traveling the country and asking for saliva samples from remote populations to assemble a truly countrywide data set. Along the way, there were some unforeseen technical obstacles to collecting samples from inhabitants of rural Indian villages: “It’s really hard to get 2 milliliters of saliva from toothless men,” Gallego Romero said.

The final tally included almost 2,300 individuals from 105 different tribes and castes, five different language families, 22 of 28 states, and even one group from Nepal. Romero and a team of researchers from the United Kingdom, Estonia, India, and the United States then zeroed in on the chromosomal region where most of the previously-detected lactose tolerance mutations are located. To the authors’ surprise, what they found there was not a new India-specific mutation, but a familiar genetic pattern - a single switch from C to T, characteristic of the common European mutation.

“We thought they would have a different mutation, because they’ve had cattle for a long time and they’ve been drinking milk,” Gallego Romero said. “But it was all European, except for a couple mutations that we haven’t proven yet do anything. We were very shocked by that, it was interesting.”

The finding suggests that the most common lactose tolerance mutation made a two-way migration out of the Middle East less than 10,000 years ago. While the mutation spread across Europe, another explorer must have brought the mutation eastward to India - likely traveling along the coast of the Persian Gulf where other pockets of the same mutation have been found, Gallego Romero said. Once the ability to take nourishment from milk in adulthood met the pastoralist cattle-herding cultures of northwest India, it made for the perfect evolutionary mix.

“All you need is a few people,” Gallego Romero said. “It’s not disadvantageous if you’re not drinking milk, it’s just sitting there, so it’s going to drift like anything else that’s neutral and then it’s going to hit some advantageous population and spread,” Gallego Romero said. “So then you have to ask the important question: Who decided to start drinking milk from a cow the first time?”

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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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It has been a couple months since the end of the spring quarter, and the with it the end of many of the Medical Center’s weekly lecture series. But a recent batch of videos posted to the website of the MacLean Center for Medical Ethics brought a whiff of the school year to the dog days of summer. The videos feature a selection of the lectures from the third and final segment of the 2010-2011 theme, “Health Disparities: Local, National, Global,” [pdf] and run the gamut of expert perspectives from libertarian law and the insurance industry to black history and medical education. If you are going through lecture withdrawal or want to get excited for next year’s MacLean Center series (“Medical Professionalism and the Future of American Medicine” [pdf]) beginning in late September, enjoy these videos.

The Case for Health Disparities - Richard Epstein, University of Chicago

Richard Epstein’s annual contribution to the seminar series is always a combustible reaction, where the classically conservative law professor’s market economics conflict with the more liberal lean of the regular audience. This year’s topic was especially flammable - after a couple dozen lectures on the struggle to reduce the health care gap in the United States and around the world, here was Epstein arguing for preserving those very same inequities. Beyond the deliberately provocative title, Epstein’s characteristically off-the-cuff speech recommended that health care reformers should choose a different target - instead of minimizing the health care differences between top and bottom, push policies that support growth and innovation for all patients, rich or poor, while encouraging charity instead of coercive giving.

Future Directions for Health Equity - Anne Beal, Aetna Foundation

The Aetna Corporation is in the business of providing health insurance to Americans. The Aetna Foundation is the charitable arm of that company, dispensing grants and funds to research ways of improving the health care system and reducing costs. Researcher and author Anne Beal is the current president of the Aetna Foundation, and focused her talk on reducing costs and inequalities via improving the quality of health care in America. “Giving people the right care at the right time and preventing disease is an amazing way for us to really rein back a lot of these health care costs,” Beal said. [Original Article]

“Without Health and Long Life All Else Fails”: African-Americans and the History of the Elimination of Racial Disparities in Health and Health Care - Vanessa Northington Gamble, George Washington University

Obviously, racial disparities in health care are not a new phenomenon. Efforts to improve the health of African-Americans also didn’t begin with the civil rights movement, though the strategies employed by the disparity-fighters of the segregation era were very different from today.

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In evolutionary biology today, it’s the ugly guys who get famous. But that hasn’t always been the case. When paleontologists were assembling a library of prehistoric life in the 19th century, they wanted to find the fossils they could easily categorize. The freaks, the weirdos, and the oddities were less well received, square pegs that wouldn’t fit in the round holes on a tree of life. However, today, it’s those hard to categorize fossils that tell the richest stories to biologists seeking to map evolutionary history, with all of its strange tributaries.

When Ramsay Heatley Traquair first described a 332-million-year-old fossil of a holocephalan (a relative of sharks and rays), he gave it a name that marked it as an outcast: Chondrenchelys problematica. Both parts of the name revealed his frustration with finding the right category for the ancient fish - Chondrenchelys means “cartilage eel” (a kind of oxymoron), and problematica is obvious. But the same features that made it so hard to classify in 1935 - plus a frightful new feature never observed before - made the long extinct species especially interesting to John Finarelli and Michael Coates of the University of Chicago.

Despite their obscurity today, holocephalans are an important group to scientists looking at the origins of jawed vertebrates - a group that would eventually include us. The holocephalans, including still-existing oddballs such as ratfish, the rabbit fish, and the elephant shark, split off from the rest of the fish world 400 million years ago, and have evolved in their own direction ever since. Studying the biology of modern holocephalans can tell us about some of our earliest ancestors, and studying holocephalan fossils gives the field even more direct insight into the early days of vertebrates.

“It represents an awful lot of vertebrate evolutionary history, that’s why it’s important,” said Finarelli, a research associate professor in the Department of Organismal Biology and Anatomy (OBA). “You’re getting down to a fundamental split at a very early point in the vertebrate family tree with what’s around today.”

“You look at these specimens to see what kind of insight you can get into the very general properties or conditions of how to make a jawed vertebrate, because you’re getting this independent pipeline,” said Coates, professor of OBA and senior author of the study.

Yet Chondrenchelys problematica lingered in obscurity until two new specimens were unearthed in the Mumbie Quarry in Scotland, described for the first time last week in the Proceedings of the Royal Society B. More complete than previously described fossils of the species, Finarelli and Coates noticed something unusual and unexpected about the long, skinny fish’s dental structure that sets it apart from other creatures, alive or extinct.

“It’s got teeth where you shouldn’t have teeth. Imagine a full set of teeth in your lips - that’s what this thing has,” Finarelli said. “They’re just fundamentally different from everything else we’ve ever seen in the jaw.”

To confirm that they didn’t just stumble upon mutant representatives of the species, the researchers went back and looked at the older Chondrenchelys fossils. Their re-examination confirmed that the unusual teeth was present in those less well preserved specimens as well, meaning the extra set of choppers was a standard feature for the species - and for no other species seen before or since.

The researchers haven’t yet commissioned an artist to reconstruct the face - “It would be pug ugly,” Coates said - but its homeliness is useful to scientists. Chondrenchelys existed at a time when holocephalans were exploding in diversity and the species newly-discovered weirdness only adds to the possible forms the group can take.

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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.

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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Many people who suffer from regular migraines experience a kind of prelude to their attack, known as a migraine aura. Less than an hour before the headache begins, the person experiences a sensory or motor disturbance, such as flickering shapes and a blind spot, or disturbances of a motor or language nature. In 1941, a psychologist named Karl Lashley took the very scientific step of measuring how fast his own migraine aura moved across his visual field, indirectly calculating the speed of the unknown brain process causing his symptoms. In an organ where normal communication is as fast as flicking on a light switch, the aura moved at a relative crawl - only 3 millimeters/minute.

Seventy years later, University of Chicago scientists have discovered a highly unusual consequence of that slow brain phenomenon. Brains are dynamic structures, with neurons constantly changing the strength of their connections and extending and retracting their branches. But cells in the brain don’t normally pick up and travel. So when Yelena Grinberg, a graduate student in the laboratory of neurologist Richard Kraig, simulated the electrical changes thought to underlie migraine aura in a slice of brain, the response of a type of cell called microglia was quite amazing.

“We have found cells doing something different than they’ve ever been known to do,” said Kraig, a professor of neurology and expert on migraines. “They’re moving the same way an organism would…that’s never been seen before in cells from a tissue.”

Microglia are the resident immune cells of the central nervous system, attacking infection and repairing damage in the brain. To get to the brain in the first place, microglia must travel from the bone marrow (where they are born as monocytes) across the blood-brain barrier into the brain, so their wanderlust is well known. But once they set up shop in a neighborhood of neurons, their subsequent movement was largely thought to be restricted to the motion of their branches.

In an article for the journal PLoS ONE, Grinberg roused microglia from their new homes by triggering an effect called “spreading depression” in her cultured rat brain slices. In the 1950’s, the slow speed of Lashley’s aura was matched to this electrical phenomenon, which travels at an equally methodical crawl through the brain tissue, inhibiting neurons as it passes. From its origin point, the spreading depression spirals out through susceptible gray matter areas of the brain, “like a ripple on a pond,” Grinberg said. When it crosses the cells of the occipital lobe responsible for visual perception, it corresponds to the flickering dots and blind spots of a migraine aura.

After triggering the synaptic depression, Grinberg tracked the movement of microglia for 6 hours, and observed another interesting pattern. To the naked eye, the microglia might look as though they are moving at random with no discernible purpose. But a mathematical analysis suggested by co-author John Milton revealed that the microglia wanderings actually conformed to a well-known natural pattern known as a Lévy flight. Described as an optimal search pattern, Lévy flights are marked by a flurry of small movements interrupted by large steps - behavior often observed in animals scavenging or hunting in the wild (or as Grinberg said, someone looking for their lost keys).

“Scientists have observed the same pattern in the swimming or flight of sharks and seagulls,” Grinberg said. “The idea is that within these stops along the journey they are searching the nearby environment, and once they do or don’t find something there they move to a different spot.”

[Video: Microglia move in response to a spreading depression. The video is sped up to show the distance traveled in the hours following the stimulus. From Grinberg et al., PLoS ONE, 2011]

Why would microglia take Lévy flight after a spreading depression?

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By John Easton

Even by academic standards, the language was restrained. “It is likely,” the authors note, near the end of the discussion section, “that more patients with this tumor will appear as girls who were exposed in utero come to maturity.”

That quaint, passive construction, in the April 22, 1971, issue of the New England Journal of Medicine, triggered an active response. The three-page paper, “Adenocarinoma of the Vagina,” focused on eight young women, ages 15 to 22, with an extraordinarily rare tumor.

“While the disease had been described in older women, none of us had heard of it in young people,” recalled study author Arthur Herbst, MD, the Joseph Bolivar DeLee distinguished service professor emeritus and former chairman of obstetrics and gynecology at the University of Chicago.

Thanks to luck, diligence and some clever detective work, Herbst and colleagues figured out why. Early in their pregnancies, the mothers of seven of the eight women had taken a drug - a synthetic hormone called diethylstilbestrol, DES for short - to prevent miscarriage. The problem was that in the previous 25 years, an estimated 4.8 million women in the United States - and as many as 10 million worldwide - had taken DES during pregnancy. These eight cases were the first warning of a rare, delayed, but devastating side effect.

“While the medical community was being cautious,” recalled Susan Helmrich, a DES daughter who is now 55, “mothers who took DES were hysterical. They were basket cases. The daughters,” she added, “also went a little crazy.”

DES, created in 1938, was the first synthetic estrogen. It was a cheap, potent, unpatented pill - for humans or livestock. The FDA approved it in 1941 for a wide range of “estrogen-deficient states.” In 1947 they added miscarriage prevention. One advertisement claimed that DES could prevent abortion, miscarriage and premature labor and was “recommended for routine prophylaxis in ALL pregnancies.” In 1953, William Dieckmann, MD, chairman of obstetrics at the University of Chicago at the time, showed that DES had “no beneficial effect whatsoever on the prevention of miscarriage.” Nevertheless, the drug remained in use for that purpose. But then, beginning in 1966, the first few odd cases began turning up - young women with an old-lady tumor.

“Dr. Robert Scully, gynecologic pathologist at the Mass General and I got together seven cases of clear-cell adenocarcinoma and described their clinical and pathological characteristics,” said Herbst. They began interviewing the mothers. One mentioned that she took a drug during pregnancy, something called DES, and wondered if that had anything to do with it.”

“I was also following a mother whose daughter unfortunately died of this disease because it had never been diagnosed properly,” Herbst said, “and she mentioned the same thing.”

So he, his section chief Howard Ulfelder, MD, and epidemiologist David Poskanzer, MD, decided to design a study. By that time they had an eighth case; they then selected 32 controls: four for each case, daughters born at about the same time to women at the same hospitals. They found that seven of the eight mothers of daughters with cancer took DES during the first trimester for either bleeding or prior miscarriage, and only one of the 32 controls did. The odds of that happening by chance were less than one in 100,000.

As soon as the paper was published “it was all over the news,” Herbst said. read more

In Akira Kurosawa’s 1950 film Rashomon, the story of a crime is told three times from the perspective of three different witnesses/participants. Due to the biases of each storyteller, the details of the three accounts fail to align, ultimately leaving the film’s narrator - and the viewer - unsure about what truly happened in the central incident. Historians have their own version of the Rashomon effect, filtering past events and organizing historical narratives according to their own beliefs, whether the influence is subtle or overt.

In an attempt to offset any such potential bias in his Regis J. Fallon Lecture at the University of Chicago, health law expert Timothy Jost of Washington and Lee University School of Law chose to present three parallel narratives in his discussion of the history and future of American health insurance. Despite a relatively brief run as a major player in our country’s health care system (”there are many people alive today in Chicago who were born before modern health insurance arrived,” Jost said), health insurance has quickly risen to a place of great importance, as demonstrated by the industry’s role in last year’s passing of the Affordable Care Act. The goal of that legislation to make sure that all American citizens have health coverage will likely be a key turning point in the story of American health insurance. But to understand which direction health insurance will travel after the ACA is fully implemented, you need to understand how it got there in the first place, for which Jost offered three tales.

1. A Failure of Socialized Medicine

In this tale, the public’s push for universal government health care was repeatedly rebuffed by special interests and conservative politicians throughout the 20th century. Though incremental victories were achieved, from the push by labor unions for employer-provided health benefits to the passage of Medicare and Medicaid during the Johnson Administration, the century ended with a whimper for socialized medicine advocates thanks to the doomed health care reform of the Clintons. Opposition from organized medicine, small-government Republicans, and an increasingly powerful private insurance industry thwarted the push to join other developed countries who had switched over to government-run health care after World War II - “for two decades, we saw no progress,” Jost said.

2. A Failure of Market-Driven Medicine

But according to the second narrative, this lack of progress was good news. From this perspective, Americans are “overinsured…because of misguided government policies that have encouraged private insurance for routine as well as catastrophic medical costs,” Jost said. By placing the cost burden on employers and government programs, the American health insurance system has severed consumers from the true price of their own health care - the main culprit, many economists believe, for the exponential rise in medical spending over the last century. Under this narrative, the steering wheel of health care should be handed back to the market with a strategy of tax credits, vouchers, and the roll-back of Medicare - key components of the current Republican budget plan.

3. A Messy Compromise That Kind of Works

Mixing the two narratives together creates a third storyline, one that Jost seemed to prefer despite describing it as “muddling through to moderate success.” In this history of health insurance, the industry grew haphazardly over the 20th century, incorporating elements of both government- and market-driven approaches according to the fickle political winds of different eras. From the birth of modern health insurance as “health services plans” (guaranteeing coverage of hospital costs) in Dallas in 1929, through the expansion of coverage to all types of care including routine visits, pharmaceuticals, and even dental, the unlikely bedfellows of consumer demand and labor union pressure combined to nurture the explosive growth of the industry. And for a while, this worked, Jost said - 82.4 percent of the population held private heath insurance in 1980, the peak of such coverage.

“The United States seemed to have solved, through private initiative supplemented by public programs…the problem of health security that other nations had addressed through social insurance or public provision,” Jost said.

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Reducing health disparities in the United States has been a top priority for our health care system in these early years of the 21st century. But efforts to narrow the health gap between black and white patients go much farther back, to the start of the previous century when the first African-Americans were graduating from medical schools and Ph.D. programs around the United States. Those early black professionals looked at the state of African-American health at the turn of the 20th century and were appalled, said Vanessa Northington Gamble, professor of medical humanities and history at George Washington University, at her MacLean Center for Clinical Medical Ethics seminar in late April. No less a figure than Booker T. Washington spoke out about the direct link between African-American health and civil rights in the early 1900’s, saying:

“Without health … it will be impossible for us to have permanent success in business, in property getting, [and] in acquiring education …. Without health and long life all else fails.”

The solutions those black intellectuals chose to improve the health of their race, in a time of national segregation, were very different from the options under consideration today. But Gamble said that discussion of those efforts is missing from the conversation about health disparities interventions in today’s society.

“We don’t talk about the history of these disparities - what are some of the programs that came in the past to address these disparities,” Gamble said. “I do think that many people think it’s only been in the past 20 to 25 years… but I want to talk about what the black community did to take care of itself.”

At the time, black patients faced segregated hospitals and racist theories, such as those put forth by statistician Frederick L. Hoffman in his book, “Race Traits and Tendencies of the American Negro.” Hoffman, an actuary for Prudential insurance, argued that the company should not cover African-Americans because they were destined to die out due to unchangeable biological factors of their race. To refute those claims, W.E.B. Du Bois published his 1906 study, “The Health and Physique of the Negro American,” which pinpointed socioeconomic factors, rather than biology, as the cause of poor health in the black community.

“Du Bois agreed that the health status of African-Americans was worse than that of white Americans,” Gamble said. “Where there was disagreement was on what were the causes of what we would now call health disparities or inequities…for example, he said the high infant mortality rate in Philadelphia was not a ‘Negro affair,’ but an index of social conditions.”

In the wake of that research, black professionals united to try to beat back higher rates of infant mortality, pneumonia, and tuberculosis - the latter of which Du Bois called “the greatest enemy of black people.” One of the best strategies, in the face of segregated hospitals and discrimination from white physicians, was to establish black hospitals to improve access to health care. One example on the South Side of Chicago was Provident Hospital, founded in 1891 by Emma Reynolds and Daniel Hale Williams, who would go on to perform the first successful open-heart surgery there. Similarly, black doctors formed the National Medical Association in 1895, because of their difficulties in joining the American Medical Association. Playing along with segregation wasn’t unanimously popular in the black population of the time; in fact, Gamble said one minister prayed Provident would burn to the ground because it catered to racism.

“You have to look at [black hospitals] in the context of segregation,” Gamble said. “Many black physicians said we wish we didn’t have to start black hospitals, but if we wait for integration, the health of the race would suffer.”

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The mortality curves separate. (From Goodin et al. poster)

To conduct a clinical trial of a new drug, the researchers need to pick an ending: a place where the experiment will be stopped and the results between those taking the drug and those who haven’t can be compared. If the drug is a clear improvement, the trial will be stopped, and patients in the control group will be allowed to start taking the newly-proven treatment. Follow-up studies may then be difficult to conduct, particularly if the disease is too deadly or the patients are too hard to track.

So when almost every single member of a landmark study can be tracked down more than 20 years after its completion, that’s an impressive feat. Even more so when comparing the treatment and control groups two decades later reveals an unexpected, and very meaningful, long-term benefit. A new study, co-presented at two recent meetings by Anthony Reder, professor of neurology at the Medical Center, reveals that a multiple sclerosis drug first tested here 23 years ago continues to show benefits in patients on perhaps the most important outcome of all: mortality.

Interferon-β-1b was the first drug proven effective in slowing the progression of MS, based on a trial of 372 patients conducted at the University of Chicago and 10 other centers from 1988 to 1993. When the FDA approved the drug in 1993, its effects on quality of life were emphasized by Barry Arnason, professor of neurology and one of the study’s lead investigators, who told the New York Times that “People are going to stay on their feet longer, work longer and be happier.”

The researchers could not have anticipated that the drug might also help MS patients live longer as well. But when follow-up data was collected 16 years after the trial’s completion, a promising hint emerged. Researchers successfully re-established contact with 88 percent of the original subject pool for a paper in the journal Neurology, and confirmed the long-term safety of interferon treatment - their primary goal. But a secondary finding also attracted interest. Of the 328 patients contacted from the original trial, 35 had died, but only 6 of those were from the original high-dose interferon group, vs. 20 from the control group.

Because patients in the control group were also placed on interferon treatment after completion of the trial, the result suggested that starting interferon earlier had long-term benefits on mortality. But to confirm the effect, the researchers had to find even more patients from the original study, alive or deceased. For the 21-year follow-up, they expanded the coverage to an astonishing 98.4 percent of the original subject pool, lacking information on only 6 of the original patients.

Fortunately, the larger dataset confirmed the earlier promising hints on mortality. As presented at the American Academy of Neurology Meeting this month by Reder and neurologist Douglas Goodin of UCSF, patients who received interferon during the 1988-1993 trial were less likely to have died at the time of the follow-up. Of 81 patients who had passed away in the 21 years since the trial, nearly half were originally in the placebo group, meaning they had started interferon treatment roughly 4 years later than those enrolled in the two treatment groups. Remarkably, even those who had received interferon in the pivotal trial weren’t started on the drug until an average of 8 years after MS symptoms first appeared, much later than current clinical standards, Reder said.

“Even stacking the deck against us by relatively late treatment, and accounting for a follow-up period where all of the people were on the best possible medicine for them, we still see this huge difference,” Reder said. “We think this means there’s a very important survival effect of interferons.”

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

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

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

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

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

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

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

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

Elsewhere…

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

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Reading The Emperor of All Maladies, Siddhartha Mukherjee’s “biography of cancer” from last year, one is struck by both the long and short history of cancer. Descriptions of breast cancer can be found as long ago as an Egyptian papyrus dated to 2500 BC and ancient Greek histories, and tumors have been found in thousand-year-old mummified remains from Peru. But the idea of cancer as a treatable disease is barely a hundred years old, and as recently as the 1940’s, clinicians could do little more than help patients die from the disease as comfortably as possible. Despite these deep historical roots, Mukherjee chooses to start his book in 1947, with Sidney Farber’s first experiments on chemotherapy for children with leukemia.

From there, the pace of the “war on cancer” (though not known by that phrase until 1971’s National Cancer Act) accelerates rapidly, as chemotherapy, radiation and surgical protocols were improved through scientific inquiry. Progress in understanding and treating cancer no doubt seemed incremental as it was happening, and even today some still question its overall success. But Mukherjee’s skillful portrayal presents an astonishing difference in the experience of cancer patients only 50 years apart - from being hidden in out-of-the way wards because of the hopelessness of their condition, to the ultra-modern cancer centers of today offering targeted treatments that offer the promise of a cure, if not yet a certainty.

But stumbling blocks still exist in the scientific progress against cancer. One place where reinforcements are desperately needed is at the level of clinical cancer trials, where the true benefits of laboratory discoveries are put to the test in a human population. While there is no shortage of ideas for new cancer therapies, clinical trials have struggled due to insufficient accrual of patients. Though 25,000 to 30,000 patients are enrolled in cancer trials each year, they only represent 3 to 5 percent of all U.S. adult cancer patients,  Richard Schilsky, professor of medicine and chief of hematology/oncology, wrote in a commentary for Science Translational Medicine last week.

“Despite various attempts to remedy the accrual problem, such as awareness campaigns, establishment of clinical trial registries, and the development of search engines to match patients to trials, annual enrollment on cooperative group clinical trials has remained essentially unchanged throughout the past decade,” he writes. As a result, “up to 40% of cooperative group phase III trials have failed to complete accrual and closed without achieving study endpoints, wasting the contribution of those patients willing to enroll in the trial.”

There are plenty of barriers against getting cancer patients into appropriate trials, Schilsky says. Many are institutional - physicians outside of the academic world may not have dedicated research staffs than can help coordinate patients, deal with regulations and insurance issues, and fill out the extensive paperwork. To circumvent these issues, some doctors would rather write off-label prescriptions for drugs being tested in a clinical trial, getting the potential benefits of the drug without the logistical commitments. On the other side, patients may not be aware of the trials available to them, or may misunderstand the purpose of a clinical trial.

The new era of molecular medicine could raise some of these obstacles even higher or knock them down, Schilsky writes. In 2001, the drug Gleevec ushered in the age of smarter drugs that directly interfere with the cause of the disease, rather than general features of tumor growth. Testing these types of drugs requires new types of trials, with more biospecimens (blood, tumor tissue, DNA) collected from patients and tighter rules about who is eligible for the experiments. Classifying broad cancers into more specific subtypes may eventually improve treatment effectiveness, but in the short term could make testing those treatments even more difficult.

“The challenge is that many patients may need to be screened if the biomarker used for patient selection is of low prevalence in the tumor type under study,” Schilsky writes.

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