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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“If sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process ever made.” - Allan Rechtschaffen.

We spend approximately one-third of our lives asleep, and yet there is still much to learn about why. Modern sleep research only began less than a century ago, when Nathaniel Kleitman founded the world’s first sleep laboratory at the University of Chicago in 1925. Since then, many of the mysteries of sleep have been uncovered by UChicago researchers, including the discovery of REM sleep by Kleitman and Eugene Aserinsky in 1953, and the characterization of the first sleep disorder, narcolepsy, by Rechtschaffen and Gerry Vogel in the early 1960’s.

But in the last two decades, the study of sleep has shifted from how it works and doesn’t work to the serious consequences when sleep is lacking. Locally, the hub of this new wave of sleep research is Eve Van Cauter, who has linked insufficient or irregular sleep to a long list of chronic diseases including diabetes, obesity, and heart disease. Earlier this week, Van Cauter was doubly honored in receiving the Frederick H. Rawson Professorship and headlining the christening of the new University of Chicago Sleep, Metabolism, and Health Center (SMAHC, pronounced “Smack”). Sleep scientists from UChicago, Northwestern University, and Harvard University gathered to discuss the latest evidence on just how important sufficient sleep is for good health. The consensus message was frightening: From infancy to the golden years, the failure to get a good night’s sleep can cause a wide variety of problems - and may be a major contributor to today’s most worrisome health trends.

The importance of sleep starts with birth, said David Gozal in his talk, and maybe even before due to epigenetic imprinting during the mother’s pregnancy. Gozal reviewed his paper from last month on the elevated risk of obesity in children with shorter and less consistent sleep patterns, but also presented even newer findings, including altered expression of metabolic genes in children who snore and mouse studies that found frequently-disrupted sleep can cause animals to ingest more food and retain more fat tissue. Meanwhile, more and more studies are finding that young children are not getting nearly as much sleep as recommended.

“Sleep curtailment is not only a problem of our adult society, but clearly has pervasively infiltrated to infants and young toddlers,” Gozal said.

The effect of poor sleep upon children may go beyond metabolic issues such as obesity and diabetes, proposed neurobiologist Daniel Margoliash. In both humans and birds, Margoliash’s laboratory has found evidence that sleep helps the brain consolidate information learned during the day into memory. As young birds sleep after a day of practicing their distinctive song, the brain recreates its activity patterns from those earlier performances, presumably part of the process of making that newly learned skill permanent. For schoolchildren, the lesson is clear: lose out on sleep, and you could be losing what you were taught during the preceding day.

Later in life, the problems associated with insufficient sleep only appear to grow worse. In older adults, chronic insomnia has been linked to cognitive decline, perturbations in hormones associated with hunger, and insulin sensitivity, said Northwestern’s Phyllis Zee. Women with polycystic ovary syndrome, a condition marked by infertility, hormonal dysregulation, obesity, and diabetes, are more than 8 times more likely to suffer from obstructive sleep apnea, said David Ehrmann. And the medical effects of poor sleep can literally appear overnight - Vineet Arora’s study of poor sleep in noisy hospital wards found an average blood pressure increase of 6.2 mmHg for every hour of sleep lost. read more

Eodromaeus, or "Dawn Runner" (Copyright Todd Marshall)

While ScienceLife was away at the Science Online 2011 meeting two weeks ago, our friends in the University of Chicago News Office tried to sneak a dinosaur story past us. Eodromaeus, the “dawn runner,” is the latest edition to the dinosaur discovery menagerie of Paul Sereno, professor of organismal biology and anatomy, discovered in the fossil dig site of Argentina known as the “Valley of the Moon.” While only four feet tall and roughly 10-15 pounds, Eodromaeus was (as Chicago Tribune great Bill Mullen puts it) a “nasty looking little critter,” a carnivorous predecessor to the T. Rex in a time (230 million years ago) when dinosaurs were not yet the dominant lifeform on the scene. [You can watch a cool time-lapse movie of the reconstruction of Eodromaeus here, as well as an interview with Sereno about the discovery and its significance for the rise of dinosaurs.]

As the excellent fossil blogger Brian Switek describes at the Smithsonian’s Dinosaur Tracking site, the discovery of Eodromaeus rearranges scientific theories about the early days of dinosaurs. A previous discovery of Sereno’s team in the same area, Eoraptor or “dawn plunderer,” was once thought to be an ancestor of the larger meat-eating dinosaurs that came later. But comparing the teeth of Eoraptor and its neighbor Eodromaeus suggests that the former was actually an omnivore ancestor of the more benevolent sauropods, with Eodromaeus near at the top of the T. Rex family tree.

“We’re looking at the dawn of the dinosaur era where the fork in the road is still very narrow in the divergence of plant eaters from meat eaters,” Sereno told the Tribune. “That is why Eoraptor and Eodromaeus look so much alike.”

But as in Hollywood, your 15 minutes of fame are very short in the world of dinosaurs. In the mere two weeks since Eodromaeus was unveiled, another thunder lizard has stolen the spotlight: the hilarious-looking Linhenykus, the “one-fingered” dinosaur. Seriously, imagine trying not to laugh as one of these ran towards you (bear in mind that they were also small enough to “s[t]and comfortably in the palm of your hand.”). As Switek points out at Dinosaur Tracking, a current theory goes that Linhenykus, and other dinosaurs with one pronounced digit, may have used their comedically short arms to dig for ants and termites.

Nabokov’s Hobby

The research of lepidopterist Vladimir Nabokov never quite got the credit it deserved while he was alive and working as curator of butterflies at Harvard’s Museum of Comparative Zoology. Perhaps it was his outlandish ideas, about butterflies migrating from Asia through Siberia and Alaska and down to South America. Or perhaps it was because he was better known as the experimental novelist responsible for Lolita, Pale Fire, and other books. Catching and studying butterflies was a lifelong hobby for the Russian-born Nabokov, but despite publishing at least one manuscript (pdf, found via Carl Zimmer’s twitter) on the evolution of a group of species known as Polyommatus blues, he was largely ignored by the scientific community as an amateur.

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It is widely acknowledged that racial or ethnic discrimination can negatively affect a person’s health. But how can a scientist measure this impact? The treatment that a person encounters due to the color of their skin, their language, or their country of origin is likely a chronic stimulus, encountered over their entire life rather than during a discrete period of time. How that person perceives or reacts to discrimination may also vary widely from individual to individual - some may shrug it off or internalize the damage, some may grow angry and lash out. Wrapping one’s statistical arms around such a huge variable is nearly impossible.

One way around this problem is to locate a finite period of elevated discrimination against a particular group, and measure the impact of that event upon health. Diane Lauderdale, professor of epidemiology in the Department of Health Studies, found just such an event in the terror attacks of September 11, 2001, and the brief but intense harassment of Arab-Americans that followed. In her talk for the MacLean Center of Clinical Medical Ethics seminar series in January, Lauderdale detailed how she studied a link between post-9/11 discrimination and birth outcomes for a paper in the journal Demography (pdf).

While it might be hard to pin down the discrimination experienced by people of Arabic origin over the course of their lives in the United States, their life in the months after the attacks was undoubtedly more stressful. According to the American-Arab Anti-Discrimination Committee, more than 700 violent incidents were directed toward persons who were perceived to be Arab in the nine weeks after 9/11. But a massive media and government pushback likely limited the duration of this out-of-control hatred, with the director of the ADC commenting in December 2001 that “My impression is that we are rapidly returning to what one would unfortunately call a normal amount of hate crimes.”

Lauderdale chose to focus on pregnant women, who are particularly sensitive to stress. High levels of corticotropin-releasing hormone - a peptide increased by stress - can induce early labor, producing babies that are premature and/or underweight. Lauderdale hypothesized that pregnant Arab-American mothers might have given birth to more low birth weight babies in the six months following 9/11 than they had during the same months in the previous year.

One problem: while Lauderdale had access to the birth certificates of more than 1.5 million children born in California from 2000-2002, the certificates categorized race only by black, white, American Indian, Asian, and Other - no Arabic. Fortunately, previous work by Lauderdale and colleagues had developed an algorithm for predicting a person’s Arab origin using their first and last names. While the algorithm was admittedly imperfect, it was able to create enough of an enriched sample to conduct the comparison, Lauderdale said.

Her analysis found that the births of most groups (white mothers, black mothers, foreign born mothers) were unaffected by the events of 9/11, with virtually no difference in the risk of having a low birth weight baby between the two years. But for the 15,000 Californian women with Arabic names analyzed, there was a small but significant spike in low birth weight babies from October 2001 to March 2002. Children born to those mothers were 34 percent more likely to be underweight than babies born to Arabic mothers from October 2000 to March 2001.

To break the Arabic group down even further, Lauderdale looked at whether each child was given a traditionally Arabic name, potentially a sign of stronger ethnic identity. While the number of Arab names given to newborns did not change before and after 9/11, babies with “traditional” names were more than twice as likely to be born underweight in 01-02 compared to the same months in 00-01. Babies with more “American” names, on the other hand, were almost unperturbed, with only a 16% higher chance of being underweight at birth.

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The late December quiet has given way to a post-holiday flurry of exciting research news, most of which I can’t tell you about until next week. But in the meantime, here’s our first weekly roundup for 2011 of the most interesting science and medical news around the web.

Tears for Fears

Scientists have discovered a multitude of ways by which animals communicate through chemical signals, such as those in the urine that dogs use to mark their territory and the path left by ants to guide their compatriots to food sources. But whether such pheromone signals exist in humans has been much more controversial. Martha McClintock, professor of psychology at the University of Chicago, has published many papers showing evidence for communicative signals in human sweat that can influence menstrual cycling, mood, and brain function in other people. But the behavioral effects of human chemical signals have so far been small, producing nowhere near the sensational effects that marketers of “pheromone” perfumes claim on less than reputable websites.

But another mediator of chemical communication in humans may have been traced this week, in a paper published by Science on the ability of women’s tears to affect sexual interest in males. The Israeli study used a hilarious method of collecting their experimental substance, sitting women down in front of sad movies and catching their tears in test tubes (”We obtained negative-emotion tears from 2 donor women who watched sad movies in isolation,” the authors right in scientist-ese). The fluid was then placed under the nose of male subjects, who viewed pictures of women’s faces and rated their attractiveness. As described by Ed Yong at Not Exactly Rocket Science, the males’ sexual interest decreased when exposed to the tears, as compared to being exposed to a control of saline. Differences in brain activity and testosterone levels were also detected while men sniffed the tears of sadness.

Consulted by the New York Times, McClintock said the study “really broadens the possibilities of where signals are coming from,” but expressed skepticism that the tears’ effect would be restricted to sexual behavior. “I have no doubt that it affected sexuality as they report, but I would be very surprised if it doesn’t turn out to affect other emotions in other contexts. Maybe it’s affecting some deeper, more fundamental psychological process that drives the effect that they’re reporting,” she told the newspaper. Other critics have asked whether the chemical signal lies in the tears themselves, or are collected by the tear from the skin as they roll down a subject’s cheeks. The nature of the chemical still remains to be found, but the evidence suggests another entry in the previously hidden chemical vocabulary of humans.

Fraudulent Science, Human Cost

Last year, the infamous 1998 Lancet paper purporting to show a link between the measles, mumps, rubella vaccine and childhood autism was finally retracted after years of criticism for biased selection of subjects and unethical behavior. But the research, led by Andrew Wakefield, went beyond scientific mistakes to fraudulent falsification of data, a new report from the British Medical Journal released this week discovered. Investigative reporter Brian Deer found that Wakefield, who was being receiving payments from a lawyer seeking to file a lawsuit against vaccine manufacturers before he started the study, changed the timeline of autistic symptoms appearing in patients to make it look more like vaccines were the cause. The article is a rigorous and thorough deconstruction of a scientific fraud that has had concrete consequences for children around the world - in the  12 years since the article was published, measles cases have spiked in England and America as vaccination rates have dropped, and other vaccination-sensitive diseases such as whooping cough have also made a resurgence.

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Racial health disparities in the United States have been repeatedly measured, demonstrated, and presented to the point where their existence is no longer in question. But still up for discussion is how to fix them, whether through sweeping legislation like this year’s federal health care reform, local efforts to improve health care access or social determinants of poor health, and/or by customizing care to better serve minority populations. But what about that time-honored American way of dealing with injustice and unfairness - why not tell disparities “I’ll see you in court!”?

The idea is not so far-fetched, said Anup Malani, a professor of law and medicine at the University of Chicago, in his lecture to the MacLean Center for Clinical Medical Ethics in early December. After all, the Civil Rights Act of 1964 was created to address segregation and inequality in schools, employment, and other important aspects of life, so why not medicine? History shows that Title VI of the Civil Rights Act, which forbids racial discrimination by any body that receives federal funds, was one of the most effective strategies ever in reducing racial health gaps. After its passage, hospitals and other medical providers (nearly all of whom receive federal funding in the form of Medicare/Medicaid), could no longer legally segregate patients into different wards or treat them with different personnel. The result was a rapid improvement of health care for black populations, and a brisk narrowing of the disparity in measures such as infant mortality, Malani said.

“It was a huge, huge success,” Malani said. “We spend a lot of time in law school thinking about the great civil rights successes in education, and we’re studying the wrong thing. In four months, you got 1,000 hospitals to integrate. This is unbelievable…One would like to achieve that sort of result again.”

But the rapid integration of American hospitals in the 1960’s only reduced the gap, it didn’t eliminate it. Some hospitals also exploited a loophole in Title VI and simply moved to more affluent, predominantly white communities, a strategy that turned out to be difficult to litigate in Title VI court cases. Because hospitals could plead at least one legitimate reason for the move - usually the argument that they would no longer be financially viable in the inner city - the charges of civil rights violation were denied. Other limitations of civil rights cases, including federal limits on damages, high cost, slow pace, and inadequate penalties, also make Title VI the wrong weapon to use in fighting today’s racial disparities, Malani argued.

Those loopholes may have even created a major driver of health gaps, Malani’s research has found, in that a disproportionate number of minority (and poor) patients receive their treatment from the country’s worst-performing hospitals. This dynamic creates what Malani called a “between” disparity, where minorities receive care from lower-quality providers than white patients, rather than receiving poorer care from similar-quality providers. Statistics have supported that observation, showing that hospitals and ambulatory care centers that treat more minorities have lower scores on measures such as mortality.

Therefore, though it hurt Malani to admit it (”it’s awkward for me as a lawyer to say I’m not the solution,” he joked), the most effective strategy may not be litigation but policy efforts to help the low-performing hospitals. Improve the statistics of these health care providers, and you hopefully reduce the racial gap by reducing “between” disparities.

“Let’s send funds to these hospitals,” Malani said. “If you just target the worst hospitals in America, you’re going to disproportionately help minorities.”

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When Eugene Goldwasser launched the project that would become his life’s work, he thought it would only take a matter of months. Since the early 20th century, biologists had predicted that a hormone they named erythropoietin must exist to promote the production of red blood cells when the body was running low. But in 1955, nobody had found it. Working at the University of Chicago after World War II, Goldwasser was challenged by his mentor, Leon Jacobson, to find erythropoietin, or Epo as it would come to be known.

“Very few biochemists were foolhardy enough to commit themselves to working on this seemingly intractable protein,” wrote Goldwasser, who passed away last week at the age of 88. “My thought was that any reasonably good biochemist ought to be able, in a relatively short time, to purify a hormone with a measurable biological effect.”

It took 22 years. But the purification of Epo, and the hormone’s eventual commercialization as the drug Epogen, ended up being one of the most significant discoveries of its time. A godsend for people struggling with anemia, either directly or as a consequence of kidney failure, cancer, or AIDS, Epo has helped millions of patients avoid blood transfusions that were once a regular part of their disease. A less savory use of Epo, as a performance-boosting drug, led to widespread controversy in the Tour de France in the late 1990’s. The billions of dollars made off of Epogen, and the legal and political battles over that windfall, also made it an important landmark (for better and worse) in the early days of the biotechnology industry.

Goldwasser himself was the recipient of almost none of that fortune, having failed to pursue a patent on the hormone when his purification experiments finally reached fruition in 1977. For him, the pursuit of Epo was pure basic science, and the potential for clinical application, never mind the money to be made off that translation, was a low priority. In a 1996 essay for the journal Perspectives in Biology and Medicine (not online, sadly), Goldwasser wrote about how he was so unconcerned with patenting his discovery, he forgot that he had even tried until discovering an unanswered disclosure form in his files decades later.

“After submitting the form I promptly forgot about it, since nothing was ever done about filing for a patent,” Goldwasser wrote. When the hormones was eventually patented and sold by the company Amgen, Epo brought them well over a billion dollars a year in revenue.

Even in the midst of this boom, Goldwasser was more interested in the scientific history of Epo than its profitability and legal wrangling. The 1996 essay is a gripping narrative of a scientific hunt, riddled with pitfalls and obstacles that Goldwasser and his collaborators were forced to navigate in order to grab hold of the elusive Epo. The biggest obstacle was the hormone itself, which is so effective in promoting red blood cell production that it is only secreted for brief periods and in very small amounts to produce millions of cells. As Merrill Goozner, author of “The $800 Million Pill,” wrote: “the amount of Epo needed to produce that lifetime supply could be dried and formed into a tablet no larger than an aspirin.” Finding such an ephemeral factor and then gathering a quantity large enough to study and replicate it was a gargantuan task, despite Goldwasser’s early confidence.

When Goldwasser began his search, scientists weren’t even sure which organ secreted Epo. So they started with a crude experiment: removing different organs from rats and injecting them with a salt known to induce red blood cell production. When the kidneys were removed, the salt had no effect, leading the researchers to believe they had found their organ (another clue was the anemia often seen in people with chronic kidney disease).

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When it comes to genes, evolutionary biologists have traditionally favored seniority. Genes thought to be most essential to life must be ancient and conserved, the assumption goes, handed down from species to species as the basic instructions of life. That sharing is evident in early developmental stages, which 19th-century biologist Ernst Haeckel observed to be very similar between different organisms in his famed recapitulation theory. The genes that drive those early stages of development are also shared by creatures as different as flies, mice, and humans, lending support to the idea that the most important genes for life go a long way back on the evolutionary tree.

By comparison, new genes haven’t gotten nearly as much credit. Arising more recently in evolution’s history, rookies that only count their age in tens of millions of years were thought to be less important - providing new functions and features that were nice, but not essential. If old genes were the bread and butter of life…

“Maybe the new genes serve a function like vinegar or soy sauce,” said Manyuan Long, professor of ecology & evolution at the University of Chicago. “They make your life better, change behavior, help a male find females more efficiently, but that’s all.”

But that ageist perspective is shaken in this week’s Science, courtesy of an exciting new study from Long’s laboratory. Using the fly species Drosophila melanogaster, Long, graduate student Sidi Chen, and postdoctoral researcher Yong Zhang tested whether silencing a new gene would be as fatal as silencing an old one. With RNA-interference (RNAi), a method which interrupts the translation of genes into proteins, they silenced 195 new genes between the age of 3 and 35 million years, one at a time.

The tests found that these young, supposed “condiment” genes could be just as deadly when they were silenced. Thirty percent of the genes were fatal when knocked out, suggesting that new genes can quickly become an essential part of an organism’s survival. What’s more, new genes were nearly as likely to be essential as old genes - when RNAi experiments were repeated on a sample of older genes, a similar 35 percent of them were fatal.

“A new gene is as essential as any other gene; the importance of a gene is independent of its age,” Long said. “New genes are no longer just vinegar, they are now equally likely to be butter and bread. We were shocked.”

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“In this sense, we may indeed say that medicine has saved the life of ethics, in that it has given back to ethics a seriousness and relevance which it seemed to have lost for good.”

-Stephen Toulmin, 1982

“The emergence of medical ethics in the latter half of the 20th century helped revive medicine, saved it…from its narrow focus on science and technology to restore to it its former human dimensions of care, compassion and case focus.”

-Mark Siegler, 2010

Did medicine save the life of ethics? Toulmin , a professor in the University of Chicago Department of Philosophy and Divinity School until 1986, argued that it did in his 1982 essay. But at the 22nd Annual Dorothy J. MacLean Fellows Conference - dedicated to the memory of Toulmin - his former colleague Mark Siegler, the director of the MacLean Center for Clinical Medical Ethics, said the opposite might also be true. His argument found support in the sessions of the conference’s second day, which examined medicine’s present and future from the angle of ethics, and occasionally recommended applying the brake to the runaway train of science.

The first session of the day focused on the genetic testing of newborns, the kind of medical concept that sounds great on paper, but loses some of its luster with close, careful scrutiny. In theory, the ability to quickly screen a baby for disease immediately after birth should be a medical wonder, allowing physicians to quickly react and treat the child for medical conditions. But the history of such screening is far from ideal, as Norman Fost of the University of Wisconsin presented.

Consider the case of phenylketonuria (PKU), a nutritional deficiency that can cause mental retardation in around 1 of every 10,000 births. Spurred by John F. Kennedy’s call to action against the causes of mental retardation, scientists developed a cheap, simple test for PKU in newborns that was made mandatory. However, the test was “one of the worst tests ever devised,” Fost said, with a 95 percent false positive rate. To make matters worse, the special diet used to treat PKU turned out to be as harmful to children as the original disorder. As an isolated case, that story is frightening enough, but the pattern of unreliable tests and ill-considered treatments has repeated itself several times over, Fost said.

“Santayana said, ‘Those who do not study history are not doomed to repeat it,’” Fost said. “In newborn screening, it doesn’t really matter if you study history, it just keeps getting repeated anyway.”

Rather than slowing down to correct these flaws, the field of newborn screening is poised to expand using the latest genetic technology. Lainie Ross, professor of pediatrics at the University of Chicago Medical Center, talked about the near future where all 3 billion base pairs of a newborn baby can be sequenced from a single blood spot. That data can then be matched against the library of all known genetic disorders and markers of disease risk, giving parents an avalanche of information about their child’s current and future health.

But can anything be done with that information? Will an inability to treat genetic disorders produce unnecessary anxiety in parents? How do you determine who should have access to that child’s information? What if the child, when they reach adulthood, wants that information withdrawn? How should that information be used by insurers, employers, or law enforcement, if at all? In light of all these questions, genetic testing appears more and more inadvisable, even if the science to do so is nearly there.

“Clearly many issues need to be addressed before newborn genetic profiling should become routine,” Ross said.

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Eric Green fields a question from James Watson. (photo by Galen Sjostrom)

In its 13-year history, the National Human Genome Research Institute has had three directors. The first was James D. Watson, who had the small résumé advantage of being the co-discoverer of DNA. Watson was replaced by Francis Collins, who merely led the Human Genome Project effort to determine the first complete sequence of human DNA. When Collins went on to become director of the National Institutes of Health in 2008, he was succeeded by Eric Green, another leading scientist in the Human Genome Project.

Friday, the first and third names in that list were both at the University of Chicago for this year’s Jean Mitchell Watson lecture, an annual event named for Watson’s late mother. In his brief introduction, the 82-year-old Watson reminisced about growing up on the South Side of Chicago, birdwatching with his father, and how his undergraduate education at the University set him apart when he went on to graduate school. “My Chicago education really showed, because Chicago taught me how to think, whereas the other students had been taught to remember,” Watson said.

But the main event was Green, who has taken the baton from Watson and Collins in the race to maximize the benefits of genetic research. This year’s tenth anniversary of the Human Genome Project’s first milestone - the completion of the genome’s first draft - received mixed publicity, including a high-profile critique by the New York Times on the project’s lack of immediate medical impact. In his talk, Green laid out a rebuttal to those criticisms, arguing that the Human Genome Project was the beginning, not the end of the genomic revolution in medicine.

“Effective advances in health care sometimes take decades. We shouldn’t think it’s going to be any simpler just by bringing genomics to the table,” Green said.

The structure of Green’s talk was therefore about the bottlenecks that yet needed to be broken in order to realize the potential of genetic-based personalized medicine. In a sense, Green said, the Human Genome Project was just the first bottleneck-breaker, giving scientists a publicly-accessible reference genome to use for their own research. But in true scientific fashion, completing the initial challenge only created several more:

1. How Does This Thing Work?

As Green demonstrated with a slide full of tiny As, Cs, Ts, and Gs, just knowing the content of the human genome is far from enough. Only 1.5 percent of the 3 billion base pairs are in genes that code for proteins, the primary purpose of DNA. Another 3.5 percent is under evolutionary pressure - which means it’s biologically important - but scientists don’t know why. Understanding how DNA regulates itself, a field called epigenetics, will be an important step toward resolving this mystery and gaining more control over genetic function. The University of Chicago and Argonne National Laboratory are heavily involved in one such effort, called the ENCODE project.

2. Variation Matters

Of course, we don’t all share the same 3 billion base pairs, and our unique combination of genetic variation has a lot to do with who we are, for better or worse. Understanding those variations and their role in human disease and development will be crucial in turning science-fiction genetic promises into reality. Two major efforts already underway, the International HapMap Project and the 1000 Genomes Project, have begun cataloging the millions of variants present in populations around the world for future use in predicting and treating disease.

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Is evolution like a soccer game, with long periods of stability interrupted by brief flashes of exciting activity? Or is it like a treadmill, perennially churning? In the early 1970’s, evolutionary biologist Leigh Van Valen sat down to answer that question, manually graphing “survivorship curves” for all organism groups which were sufficiently well represented in the fossil record at the time. His conclusion - so controversial at the time he started his own journal to publish it - was dubbed the Red Queen Hypothesis, one of the most famous literary metaphors in evolutionary science.

In Lewis Carroll’s Through the Looking Glass, Alice experiences the strange physics of the Red Queen’s country, where no progress is made no matter how fast you run. “Now here, you see, it takes all the running you can do, to keep in the same place,” the Red Queen tells Alice. Van Valen, who passed away October 16, used that episode and quote in his legendary 1973 paper to encapsulate his findings on the mercurial, unceasing nature of evolution.

Looking at the fossil record for several different biological genera (groups of similar species), the University of Chicago biologist saw the same pattern again and again: a steady decline in survival over time as species from each genera fizzle out and go extinct. To explain this uniform decline, Van Valen proposed the law of constant extinction, the tenet that species have an equal probability of going extinct at any time, never becoming more vulnerable or more resistant to being snuffed out.

But how could this be, if evolution is the story of species becoming gradually more adapted to their environment and, presumably, less likely to go extinct? Van Valen’s Red Queen Hypothesis filled that gap, proposing that no species could obtain perfect “fitness” because that goal was a moving target. While a species adapts to best fit its environment, the environment isn’t standing still. Gradual climate change, competition between species for the same food source, simultaneous evolution by the predators and prey of a species - all these elements and more are constantly shifting, making evolution a constant process rather than an occasional flurry.

“The Red Queen hypothesis was that the biological environment was constantly in flux in a way that was detrimental to the organisms living in it,” said David Jablonski, professor of geophysical sciences at the University of Chicago and a close colleague of Van Valen. “It’s like the Red Queen’s race in that everyone is madly scrambling, getting better all the time, but no one is gaining ground. A species can’t get far enough ahead of the pack such that it would be extinction-proof.”

Vivid examples of this constant turnover are found in nature through the “arms race” of hosts and parasites or predator and prey. Biologist Sean B. Carroll wrote about one such competition last week in the New York Times, discussing the ongoing tug of war between king cobras and mongooses evolving stronger venom and better venom resistance. Studies of the Red Queen relationship between snails and parasitic worms offered an elegant argument for why organisms reproduce sexually rather than asexually; the genetic reshuffling produced through sexual reproduction helps snails avoid parasitic infection.

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Racial disparities might seem to be an abstract, hard-to-visualize concept. But at least in Chicago, it can be simply portrayed with a neighborhood map. The picture at left is for violent crime in 2005, but if one inserted statistics for infant mortality, diabetes, obesity, or other health issues, roughly the same pattern would repeat.

This clustering of negative attributes in Chicago neighborhoods has been observed and studied since at least 1945’s Black Metropolis, a landmark sociological study of the South Side. Subsequent studies, such as the 1965 Moynihan Report and more recent observational research, have found the same concentrations, even if their exact locations have drifted south and west in the city. The sad persistence of that pattern raises two questions, one immense, one naive: what can be done to break the tragic cycle of these neighborhoods, and why don’t the people in those neighborhoods just move out?

In “The Social Reproduction of Health Disparities,” his talk in the MacLean Center for Clinical Medical Ethics seminar series, Harvard sociologists Robert Sampson addressed those two questions with a unique data set: the Chicago Neighborhoods Project. A longitudinal study that is following 6,500 children across the Chicago area, the project is producing reams of information about the structures of neighborhoods and how they affect the people within. It’s the kind of data that takes decades to sort through, but Sampson gave attendees a taste of how neighborhoods choose people, rather than the other way around.

The project, more formally called the Project on Human Development in Chicago Neighborhoods, tracked the children and their environments from 1995 to 2002. That involved not only surveying the children and their families at three different time points, but also measuring characteristics of their home neighborhoods. Researchers videotaped Chicago streets to measure aspects of social disorder such as graffiti and broken windows, and conducted unusual field experiments such as dropping fake letters in the street to see how many were returned to a mailbox by a neighborhood’s residents.

“The idea was we’re going to study individuals and follow them through time, but we’re also going to independently assess their context,” Sampson said.

When researchers looked at their neighborhood data, they didn’t find immobility; in fact, nearly half of their subjects moved over the 7 years of data collection. But deconstructed statistically, those movements were far from random, falling into regular networks along the lines of income, education, and racial factors. The nature of mobility is socially driven, Sampson said, putting restrictions on the ability of an individual to control their “escape” from neighborhoods with failing structures.

“Yes, you’re sorting, but neighborhoods are also sorting you. The idea that we are the controlling factor is a bit misleading,” Sampson said.

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When the novel H1N1 flu virus began to appear in North America and Europe in Spring 2009, it contained some worryingly familiar signs to flu experts. The new strain appeared suddenly in a season when flu typically declines, spread at a rapid pace, and seemed to disproportionately affect the young more than the old. The last influenza to display those features was the notorious 1918 flu, which killed as many as 100 million people around the world before burning out a year later.

“It was the most devastating infectious diseases episode in world history,” said Michael David, Instructor of Medicine at the University of Chicago Medical Center. “In numbers, it was probably 10 to 100 times more severe in terms of the absolute number of people killed than were killed in The Black Death.”

Of course, last year’s H1N1 pandemic was nowhere near as deadly, causing only an estimated 12,500 deaths in the United States despite approximately 60 million infections. The low mortality among elderly populations from H1N1 may have actually made the 2009-10 flu season less deadly than usual, as the Centers for Disease Control and Prevention estimate a yearly average of roughly 36,000 influenza deaths. But comparing 1918 to 2009 still reveals interesting similarities, David said in his October 14 talk at the Department of Pediatric Grand Rounds.

In the spring, when the virus first showed up on public health radar as a novel strain with all the right ingredients for a pandemic (jumped from animal to human, easily transmissable), the worst case scenario of 1918 couldn’t be ruled out. Like the 2009 strain, the 1918 influenza also made a relatively modest appearance in the spring, David said - graphs of the pandemic’s death rate revealed a small spike in the summer. Come October, that mild hill was overwhelmed by the shocking spike of influenza deaths that raged across the United States and Europe. In 8 weeks, 25 million people were infected with the virus, and some 600,000 died - in the U.S. alone.

“That’s more than the number of soldiers that were killed on both sides in the U.S. Civil War,” David said. “It’s something that’s really hard for us to grasp with our imaginations.”

[If you have a JAMA subscription, you can read this 1918 first-hand account of the pandemic at Cook County Hospital in Chicago - "During the past five weeks, more than 2,000 patients were admitted to the hospital. The disease is highly contagious and the mortality among our patients has totaled 31 percent. The epidemic has seriously crippled the medical and most especially the nursing staff of our hospital."]

In addition to its ferocious spread and mortality rate, the 1918 influenza was also unusual for the victims it chose: 20 percent of the deaths were in children under the age of 5, and 15 percent were between 20 and 25 years old. The line formed by these two mortality peaks combined with deaths in the elderly formed the pandemic’s characteristic “W curve” (pictured above), in contrast to the usual “U curve” seen when only the very young and old die from influenza.

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When long-hidden information about U.S. syphilis experiments on Guatemalan prisoners in the 1940’s surfaced last week, the shocking case contained echoes of the infamous Tuskegee study. Conducted from 1932 to 1972, the Tuskegee syphilis experiment followed African-American sharecroppers with the disease, and gained notoriety for withholding antibiotic treatment from the men in order to study the disease’s “natural progression.” The damage left by this unethical research persists to this day as an example frequently cited by minority communities distrustful of medical research.

“Most folks in the black community who know very little about research know about the Tuskegee study,” said Rick Kittles, in his Sept. 29 MacLean Center seminar “Race, Biomedical Research, and the Politics of Trust.” “It’s as if it was imprinted in our genes. There’s no Sunday morning breakfast discussion about it, but we know about it. We know something bad happened. We know that we were exploited. It has some serious implications still today.”

Indeed, the shadow of Tuskegee looms large over modern efforts to reduce the growing health disparities in the United States between Caucasian and minority populations, said Kittles, an associate professor at the University of Illinois School of Medicine. Many factors contribute to health gaps on parameters such as obesity, diabetes, and cancer: genes, socioeconomic status, environment, behavioral and cultural practices, and discrimination. But attempts to study any of these factors in the hope of reducing disparities must face the troubled history of research on the undeserved. As researchers find new ways to improve health, from advanced genetic medicine to improving access to fresh food with weekend farmers markets, community involvement is essential for such measures to close the disparity gap instead of further widening the distance between haves and have-nots.

“As this new technology and information is emerging - new treatments and intervention that could hopefully eliminate disparities - if [the community] is not involved, they’re not going to accept it. You have to bring them into the mix,” Kittles said.

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Among evolution’s best tricks is the act of turning one species into two. Speciation, the foundation of a new species from an accumulation of small changes in an old one, has given birth to the incredible diversity of life on our planet. But in order for a new species to be founded, a sort of genetic restraining order must be put in place. Within a species, individual organisms can evolve extraordinary differences without spawning a new species - think dog breeds, for example. It’s only when two organisms grow so different that they lose the ability to come together and successfully reproduce, that a new speciation event can be declared - think the lion, the tiger, and the sad, sterile liger.

The nuts and bolts of speciation have given headaches to evolutionary biologists all the way back to the very first one. In his books, Charles Darwin laid out the outlines of how a new species could form from an old one, but left the dirty work of figuring out the actual mechanism to the field he created. Some of the most famed evolutionary biologists of the early 20th century took up the challenge and left the field with the DM model of hybrid dysfunction, named for Theodosius Dobzhansky and HJ Muller. For nearly 100 years, that theory stood as an explanation of how natural selection eventually produces sterile offspring, while being too technically difficult to explicitly test. But this year, in the laboratory of University of Chicago professor Jerry Coyne (and simultaneously and independently in an Indiana laboratory), the theory was finally confirmed.

With his first graduate student Allen Orr, Coyne had figured out the experiments and the mathematics that one could use to test the DM theory. The only problem was finding a set of species in which to do those experiments. Three species were necessary, and those three species had to still be closely related enough that breeding was possible, but not successful. A fast reproductive cycle would also be helpful, so the experiment wouldn’t require decades to execute, and the genetic information of those species would have to be fairly well characterized.

It wasn’t until two years ago that all those tools became available, and in a paper published in Science earlier this month, Coyne’s current graduate student Daniel Matute brings 100 years of theory and research into the end zone. Matute ran his experiments with the noble fruit fly from the Drosophila genus, and his project was made possible by the recent discovery of a new species in that genus, called Drosophila santomea. When Coyne and Matute realized that the new species finally completed the triad of closely-related species they would need to test the DM Theory, it launched Matute into a long series of breeding experiments.

Drosophia melanogaster (from Wikimedia Commons)

The central question was how quickly genes responsible for hybrid inviability accumulated. The DM Theory proposes that those genes don’t merely add up at a steady pace as two species split off from a common ancestor, they “snowball” at an exponential pace with time. To test that notion, Matute needed to count the genes responsible for inviability in two different pairs of species, with different divergence times. That meant a lot of time putting two Drosophila species together, allowing them to mate, and then counting their offspring under a microscope - essentially following the instructions Coyne and Orr had laid out 20 years prior.

Fortunately, all that work yielded exciting numbers. For Drosophila santomea and Drosphila melanogaster, estimated to have diverged 12.8 million years ago, 65 genes were found to cause inviability. For the more recently split Drosphila melanogaster and Drosophila simulans (who diverged only 5.4 million years ago), the number was far lower: only 10 genes caused inviability. Some simple math and curve-fitting later, and Matute had determined that the inviability genes were accumulating at an quadratic, faster than linear rate, confirming the central tenet of the DM Theory at long last.

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