By Matt Wood

More than 1.25 million children in the United States, or one in every 58, suffered some kind of neglect or physical, emotional or sexual abuse in 2005-2006. Such maltreatment interferes with normal development and can lead to a host of psychological disorders and behavioral problems as they become adults, particularly aggression.

A new study by researchers from the Department of Psychiatry and Behavioral Neuroscience at the University of Chicago takes that understanding a step further by examining the pattern of interaction between childhood maltreatment and “social information processing,” or the set of cognitive and emotional processes that control how people interpret social cues and determine the appropriate response. To help think about how social information processing works in everyday life, imagine if another driver cuts you off in traffic. Do you assume he did it on purpose, or just wasn’t paying attention? Do you get angry and honk your horn, or tap the brakes and let him pass?

Current research on the links between childhood maltreatment and aggression focuses mostly on how abuse or neglect affects the development of social information processing skills. Experiencing abuse or neglect during childhood is associated with increased deficits in the social information processing skills needed to handle potentially hostile situations like this, which in turn leads to higher levels of aggression in adolescence or adulthood. This is the “cycle of violence” that can lead children who were maltreated to become violent as adults.

The new study examines whether abuse or neglect actually amplifies the risk effects of biased social information processing on adult aggression. Pan Chen, a post-doctoral researcher and first author on the study, said, “Basically we expected to find evidence that biased social information processing is more likely to lead to aggressive behavior among people who were exposed to childhood maltreatment in comparison to those who were not.”

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Texting has grown from technological fad to a primary route of communication popular around the world. With cell phones in the pockets of people of all incomes and ages, the quick, no-frills conversations enabled by texting have made almost everyone more proficient with their thumbs. Due to such impressive ubiquity, people in health care are starting to ask whether text-messaging can be harnessed as a cheap and user-friendly tool for communicating with patients outside of the clinic - particularly hard-to-reach patients in urban and low income areas.

“People are ignoring that unlike every other technology, mobile phones reverse the digital divide,” said Shantanu Nundy, clinical instructor of medicine at the University of Chicago Medical Center. “More low income patients are using phones for text messaging and internet than other groups. So shouldn’t we then be developing technology for this type of population?”

Nundy and Jonathan Dick, a Pritzker graduate now in residency at Columbia University Medical Center, arrived independently at this same idea after separate trips overseas, where they saw clinics in Uganda and India using text messages as part of their operation. With texts, physicians could follow up with patients with chronic diseases, making sure they were taking medications and doing the types of self-examinations necessary to manage diabetes or HIV - tasks that are just as challenging at home as they are abroad. In some areas of Chicago the diabetes rate is as high as 25 percent, and African-American populations have much higher rates of diabetes complications such as blindness and amputation.

“It seemed to me that we had a lot of the same problems on the South Side of Chicago, so why not try it there?,” Dick said.

To test this premise, Nundy and Dick joined efforts with Medical Center faculty Monica Peek and Marshall Chin, who recently received grants from the Alliance to Reduce Disparities in Diabetes and the National Institutes of Health to look for new ways to improve outcomes in South Side neighborhoods. For a pilot study published last month in the Journal of Diabetes, Science, and Technology, the team recruited 18 African-American diabetes patients to try out a new automated text-messaging communication system that they programmed.

The study participants were not your typical teenage texters, instead reflecting an age range (38-72) more commonly afflicted with diabetes.

“If this is going to work, we needed to look at middle aged people and people in their 60s and 70s. I’m less interested in having this as a hip thing for teenagers with diabetes,” said Peek, assistant professor of medicine. “It needs to be able to work in people I see in clinic. A 55-year-old black woman with diabetes, if it works for her, I’m interested.”

Each participant was asked at the beginning of the study what kinds of text message they would like to receive, with candidates including reminders to take diabetes medications, check blood sugar, or conduct self-examinations to detect potential complications. Participants could also customize when they received the message, and how often they came in over the one-month pilot.

Some were purely notifications (i.e. “Please take your medications now.”) while others required a text response (”How many times did you check your feet this week?”). In one early sign that the messages were reaching their targets, participants often texted back whether a response was required or not, sending an “OK” or a “Thank you” message to what they knew was an automated system. The study reports, “Many participants found that they began anticipating the text messages and readying themselves to answer the questions in an affirmative way, such as preparing the insulin syringe ahead of the expected message.” That enthusiasm was reflected in surveys of the patients after the study period ended, where all but one participant said they were very satisfied with the text reminders.

“In the context of a population that typically has very few interactions with the health care system and may have experiences that are negative or bad or fearful, it was very fulfilling for them to have positive reinforcing messages where they really felt cared for by the system in a way they hadn’t in the past,” Peek said.

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By Matt Wood

Celiac disease is an inherited autoimmune disorder that affects the digestive process of the small intestine. When a person who has celiac disease consumes gluten, a protein found in wheat, rye and barley, the individual’s immune system responds by attacking the small intestine and inhibiting the absorption of important nutrients into the body. At least 1% of Americans, or nearly 3 million people, have celiac, but 97% of them are undiagnosed.

The University of Chicago Celiac Disease Center is an international center of excellence providing comprehensive patient and professional education, expert diagnosis and treatment for both children and adults, groundbreaking bench and clinical research, and active leadership in advocacy efforts. Their goal is finding a cure for celiac disease by 2026. We spoke to Dr. Stefano Guandalini, medical director of the Celiac Disease Center, about this unique, comprehensive research and treatment approach. We also discussed the link between celiac and diabetes, and asked pediatric dietitian Lara Field from Comer Children’s Hospital how people with both diseases manage their diets. Lara also discussed how children with celiac disease can learn to go gluten-free.

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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Every patient wants their doctor to be a professional. But the broader concept of “medical professionalism” is not a cut-and-dry matter, as it opens the door to debates over how physicians interact with politics and society, the regulation of doctors’ ethical and legal behavior, and the role of the physician in the new world of health care. Those are large enough questions to warrant a year of discussion in the MacLean Center for Clinical Medical Ethics Seminar Series, and a centerpiece slot at the 23rd annual Dorothy J. MacLean Fellows Conference, held last week.

“In recent decades, there has been a renewed focus in medical education on professionalism being seen as a way to improve patient care, strengthen the doctor-patient relationship, reduce conflict of interest, improve physician self-regulation and ultimately to strengthen the alliance between medicine, patients, and society,” said Mark Siegler, Director of the MacLean Center, in his opening remarks.

If professionalism is too abstract, the themes on the first day of the conference could be simplified as what a doctor should and should not do in today’s tumultuous health care waters. Driving that instability is the ever-growing chunk of the world economy eaten up by the health care industry, said the conference’s first speaker, Arthur Rubenstein of the University of Pennsylvania (and formerly of UCMC). The United States spent $2.3 trillion on health care in 2009, he said, roughly equivalent to the GDP of France. With economies slowing around the world, those costs are unsustainable, and physicians must come together as a profession to work with patients and policymakers to find solutions that benefit all parties.

“We need to do something about that as a medical profession. If we don’t, the future is going to be quite problematic,” Rubenstein said. “If in the financial crisis which we are now surely in, at both the state and national level, the medical profession puts their own interests before those of patients - particularly the poor and elderly patients - our now privileged position in society will be given up, and our contract with society will be changed for the worse, and we may not recover in the foreseeable future.”

Participation was also one take-home message of Christine Cassel’s talk, which emphasized how the classical definition of the medical professional would have to evolve in the new health care landscape envisioned by last year’s Affordable Care Act. Cassel, the president and CEO of the American Board of Internal Medicine (and another former UChicagoan), said that the three primary goals of health care reforms are affordability, access, and quality. Creating a system that addresses all three will require balancing the intrinsic motivations of physicians to help patients with the extrinsic motivations of financial and regulatory oversight. A new kind of medical professionalism that accepts a health care system based around technology and teamwork will help the field achieve that balance with a minimum of pain, Cassel said.

“To my mind it’s a new kind of professionalism that leaves behind these old ideas of what the nostalgic profession was, and becomes committed to collaboration, evidence, measurement, and transparency so that it’s not at odds with accountability, but in fact becomes accountability,” Cassel said. “This is a challenge for many of us, and it’s going to take change.”

A case study of how that change can happen was presented by Troy Brennan, Chief Medical Officer for the pharmacy chain CVS. Brennan recapped efforts over the last decade to eliminate gifts from pharmaceutical companies to physicians at academic medical centers. While this practice was once thought to be innocuous by many physicians, others argued that it created a conflict of interest. In an example of extrinsic regulation to alter physician behavior, the American Board of Internal Medicine proposed that academic medical centers regulate these interactions between Big Pharma and physicians - an initiative supported by medical students. As a result, physician-industry relationships dropped, though a CVS study is still collecting data on whether that has affected prescription behavior, driving more doctors toward prescribing generics instead of brand name drugs.

Preserving physicians’ integrity and reputation is important for the role of the medical professional proposed by Paul Starr of Princeton University. In a time of ideological polarization and lack of trust in public institutions, it’s important for professionals to bring trustworthy knowledge to the public debate, Starr said, citing the recent Republican debate where candidate Michele Bachmann claimed a link between the HPV vaccine and mental disability.

“When prominent political figures make uninformed statements on national television about the effects of a vaccine, or distort the findings of researchers on a cancer screening test, then politicians may have a real, substantial impact on public understanding,” Starr said. “It is just at those moments when the scientific community should hold its ground and insist on abiding by the evidence.”

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

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

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

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

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

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

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

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

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Loneliness has had a tough run of late, with a growing body of research blaming it for everything from high blood pressure to heart disease to depression and cognitive decline. The research group of John Cacioppo, director of the Center for Cognitive and Social Neuroscience at the University of Chicago, has been among the leaders in leveling these medical charges against loneliness. But one missing piece of the puzzle remains - what biological mechanism connects a person’s feelings of inadequate social contact with the negative health outcomes? A new collaboration with epidemiologists and geneticists at the Medical Center suggest that the missing link might be in the bedroom.

For decades, professor of human genetics Carole Ober has studied a unique society called the Hutterites [pdf]. A religious group that originated in the 16th century, the Hutterites have formed several communal farms in the United States where some 150 people live and work together. The stability and isolation of the Hutterites make them a perfect population for studying the interplay between genes, environment, and disease - the mission of Ober’s research. Those qualities also made them the perfect group of people for a team lead by Lianne Kurina, assistant professor of epidemiology in the University of Chicago Department of Health Studies, to test the link between loneliness and sleep quality.

The new study, which appears in the journal Sleep, is not the first to examine this connection. A 2002 study led by Cacioppo used the most accessible pool of subjects on a college campus - college students - and found that those who scored higher on a psychological loneliness test displayed reduced sleep “efficiency” with no change in sleep duration. In other words, the loneliest subjects slept just as long as their socially satisfied peers, but suffered more “microawakenings” and lower sleep quality.

Because college students reflect only a narrow band of society, it was important to replicate the result in an entirely different population. Enter the Hutterites, who were also tested using a loneliness scale and asked to wear wristband sleep monitors to track their activity during sleep. Because of their communal lifestyle, even the loneliest Hutterites were less lonely than the general population. But the same correlation was detected between loneliness and sleep quality - for each point increase on the loneliness scale used to test the subjects’ social feelings, the researchers observed an 8 percent increase in sleep fragmentation. Furthermore, the lonelier Hutterites did not themselves report poor sleep or daytime sleepiness, indicating that the effects are mostly subconscious.

“Loneliness has been associated with adverse effects on health,” Kurina said in a press release. “We wanted to explore one potential pathway for this, the theory that sleep - a key behavior to staying healthy - could be compromised by feelings of loneliness. What we found was that loneliness does not appear to change the total amount of sleep in individuals, but awakens them more times during the night.”

The evidence is still not strong enough to conclusively place sleep deficits as the intermediary between loneliness and poor health. As the paper admits, the opposite relationship could be true: sleep fragmentation could increase feelings of social disconnection. But a flood of recent evidence, much of it from the University of Chicago Sleep, Metabolism, and Health Center, suggests that the third of each day we spend sleeping can dramatically affect several different aspects of our health, including diabetes, obesity, dieting success, and testosterone levels. Certainly, the newly replicated connection between a lonely heart and restless nights offers an intriguing theory for future study.

But why would feelings of social inadequacy disrupt a person’s time in bed?

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When scientists picture the miniature machines that live inside cells, they often have to settle for indirect evidence and a bit of imagination. Proteins on the nanoscale - one million times smaller than a millimeter - can’t be seen with your typical microscope, so scientists turn to electrical measurements, genetic mutations, and chemical assays to deduce a rough sketch of their target’s structure. More recently, tools such as X-ray crystallography and electron microscopes have allowed scientists to see cellular proteins. But both techniques require steps that change the natural environment of the protein, and can only offer a single photograph rather than a “movie” of its dynamic changes in shape.

So when Joanna Gemel, a research associate assistant professor in the laboratory of Eric Beyer, decided to look at the structure of cellular proteins called connexins and the channels they form, she wanted a different option. Connexins are found within the membrane of a cell in groups of 6, called connexons or hemichannels. When two cells come into contact, their connexons “dock” with each other to form a pathway between the two cells called a gap junction channel. In organs such as the heart or smooth muscle, gap junctions play an important role by facilitating the rapid passage of ions and small molecules from cell to cell.

“Gap junctions are critical for the propagation of electrical impulses in the heart. Abnormalities or mutations in them can cause a lot of problems, such as arrhythmias and atrial fibrillation,” said Gemel, author of a recent paper in The Journal of Biological Chemistry. “We decided that we would like to do something different. Since we never see channels, we asked what would be the best way to see channels and learn more about them?”

The question led them to the Center for Nanomedicine, a laboratory run by Michael Allen, a research associate assistant professor in the Department of Medicine. Allen’s tool of choice is atomic force microscopy, a technology invented in the mid-1980’s that remains useful for the visualization of the very, very small. The method, known as AFM for short, uses a strategy similar to an old record player: an extremely tiny needle (2 nanometers at its tip) moves slowly across the surface of a sample, creating a topographic map of the molecular landscape.

“AFM is really good at measuring height, the resolution in the z-axis,” Allen said. “With AFM we can look at 3-dimensional architecture, and in the z-axis the resolution is a tenth of a nanometer.”

But before tapping the potential of AFM, Gemel had to first create a stretch of membrane containing only the connexin she wanted to study, a form called connexin40 that is expressed in certain regions of the heart. Through painstaking transfection, purification, and reconstitution, Gemel produced a layer as thin as a cell membrane, swarming with connexin proteins. After imaging with the microscope, the researchers produced images (like the one posted above) that resembled dense mountain ranges viewed from an airplane, bumps floating in a dark field. Remarkably, the individual subjects and even the channel opening - narrow enough to pass individual atoms - were visible, not unlike the cartoon representation of gap junctions seen in textbooks.

With the extremely fine resolution of the AFM needle, Allen and Gemel set about measuring the heights of individual objects in their sample. Even though they knew that connexin40 was the only protein present in the membrane, their images contained particles of two different heights: some “bumps” were roughly 2.5 nanometers tall, and others were approximately 4 nanometers in height. They subsequently showed that the two different-sized bumps corresponded to whether the asymmetric hemichannels were facing inward or outward in the membrane.

“While it was something that we did not expect, it was an accomplishment to be able to monitor channels from both sides,” Gemel said.

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By Matt Wood

Sometimes scientific discoveries happen by accident. Henri Becquerel discovered radioactivity when a uranium rock he left wrapped up in a drawer with some X-ray equipment imprinted itself on a photographic plate. Alexander Fleming discovered penicillin when he noticed that mold growing in a staphylococcus culture was killing all the bacteria around it. In 2007, Catherine Pfister and her colleague Timothy Wootton made their own accidental discovery. They were studying how species interact in the coastal waters around Tatoosh Island off the northwestern tip of Washington state when they found something alarming about the chemistry of the seawater—a discovery that points to the adverse effects of increasing amounts of fossil fuel carbon in the atmosphere.

As a routine part of their work, Pfister and Wootton were measuring pH levels in the waters around Tatoosh Island. Such readings are usually the boring part of field research, providing context for the rest of the experiments. “If you were studying tree growth you’d always have to be measuring the weather,” said Pfister, an associate professor of ecology and evolution at the University of Chicago, “And this is the weather for us, what the ocean is like.”

Instead of the slight declines predicted by models, however, Pfister and Wootton, a professor of ecology and evolution, found that pH levels in the water were dropping at an order of magnitude faster than expected.

The pH levels in seawater are part of the basic chemistry of the ocean. Plants and animals develop and interact in a certain pH and evolve as it changes naturally over time. What concerned Pfister and Wootton was how the rapid drop in pH they recorded would affect the ecosystem. “We all know that there’s a strong pH dependence of biological reactions, and we don’t know how those reactions will change if pH changes rapidly,” Pfister said.

Rapid decline in seawater pH is a symptom of what’s called “ocean acidification,” or decreasing alkalinity as ocean water absorbs increasing amounts of carbon dioxide from the atmosphere generated by burning fossil fuels. Scientists estimate that the ocean absorbs at least a third of that carbon dioxide.

In 2008, they published their findings about the declining pH levels in PNAS. What they didn’t know at the time was whether those readings were part of a sustained trend or just an unexpected natural variation. “We have a lot of concern about that,” Pfister said. “We haven’t been measuring [pH levels] for that long in the ocean. There’s a very short instrumental record in the ocean, and the instrumental record only goes back to the 1990s.” Most of the pH data on record was also from tropical waters and the open ocean, in areas with less species diversity than the rich coastal waters around Tatoosh Island.

To find out if their measurements represented a new trend, they turned to a tried and true method of measuring historical ocean environments: sea shells, specifically the shells of the California mussel (cross section pictured above). Mussel shells are made of calcium carbonate and grow annual layers or bands just like trees. Scientists often use hard structures like this to infer things about the environment in which an organism lived, so the chemical composition and growth patterns of these mussel shells can be used to study the chemical composition of the ocean.

The results of this study are published in a new paper in PLoS ONE. Pfister, Wootton, graduate student Sophie McCoy and colleagues from the University of Chicago Department of Geophysical Sciences analyzed carbon and oxygen isotopes in shells that had been growing near their instruments for the past decade, as well as shells collected by researchers 30 to 40 years ago and ones provided by the local Makah tribe from over 1,000 years ago. Carbon isotope levels drop in conjunction with pH. When they compared the shells from the three different time periods, they found that the ones from the last decade showed a precipitous drop in carbon isotope values similar to the pH decline recorded by their instruments in the earlier research. The findings both confirmed the earlier measurements and demonstrated that shells might be used to measure historical pH levels in water when no instrumental record exists.

Unfortunately, Pfister says that they’re left with another mystery. read more