A visit to any casino will quickly demonstrate how vices clump together. At any hour of the day or night, many of the customers sitting intently in front of a slot machine will also be smoking cigarettes or drinking a cocktail. Sadly, addictions to these pursuits also tend to go hand in hand, with higher rates of compulsive gambling observed in people addicted to drugs such as cocaine and alcohol. Furthermore, when people perform gambling-like tasks while their brain is scanned by an MRI machine, the games activate areas of the brain also stimulated by drugs of abuse - perhaps accounting for the addiction-like behavior of gamblers.

“If you’ve ever been to a casino, and you watch people using slot machines, you’ll surely have noticed the sense of compulsion to put the next coin in, even though you get no money back most of the time,” said Paul Vezina, professor of psychiatry and behavioral neuroscience at the University of Chicago.

But does one bad habit truly lead to the other? In a recent paper for the journal Behavioural Brain Research, a team from Vezina’s laboratory offers evidence that the unpredictability crucial to gambling’s appeal can cross over to enhance the effects of abused drugs. By adapting self-administration, a common tool used to model drug-taking in animal research, to partially replicate the random pay-off of a slot machine, graduate student Bryan Singer was able to test whether gambling-like behavior influences a rat’s subsequent response to the drug amphetamine. The result suggests that gambling may have properties similar to a “gateway drug,” as an activity that can increase the abusive potential of drugs.

First of all, how do you simulate the casino experience for a rat? Self-administration - where the animal presses a lever to receive a food or drug reward - is fairly similar to a slot machine to begin with. In a self-administration protocol, the researcher sets the number of lever presses required before the reward is given. A “fixed ratio” of 5 means that the rat would have to hit the lever five times before receiving a food pellet or rewarding hit of cocaine. But with a “variable ratio” setup, unpredictability is introduced into the process. If the variable ratio is set to an average of 5, anywhere from 1 to 10 presses might be required to produce reward, a figure that changes every time like the random number generator of a slot machine. So while the rat does not have anything at stake other than the physical work it takes to hit the lever, it never knows when it will hit the “jackpot.”

“One of the main differences is that for a slot machine there’s a good chance you’re going to lose money, but here there’s little negative aspect,” Singer said. “It’s like a very loose slot machine.”

In this experiment, Singer and co-author John Scott-Railton used the non-caloric sweetener saccharine as a reward - a sweet treat that rats will work to acquire without ever getting full or intoxicated. For 55 days, half of the rats worked for saccharine under fixed ratio conditions and half worked under the variable ratio setup. Then, after a two week break, each rat was given a small dose of amphetamine, and researchers measured their activity as the dosed rats ran around their cage.

Even though the rats in each group received the same amount of saccharine and did the same amount of work during their lever-pressing careers, those exposed to the random rules of the variable ratio exhibited a stronger response to amphetamine. The result suggests that unpredictable rewards may prime the same brain areas hijacked by drugs of abuse, producing a stronger behavioral response - known in the field as sensitization - even upon first exposure to a stimulant drug.

“What this paper is showing is that unpredictable conditions may cause sensitization,” Vezina said. “There are activities that may play just as important a gateway role as drugs, and gambling may be one of them.”

read more

Like a basement in a flood plain, a cell needs a good pump. Cells must maintain a particular mix of ions inside their membrane walls, with low concentrations of sodium and high concentrations of potassium. The only problem is that cells are leaky, and sodium constantly rushes into the cell while potassium rushes out. To fight against this tide, the cell uses a very important and peculiar membrane protein called the sodium-potassium pump.

Since its discovery in the 1970’s, cell biologists have been baffled by the strange features of this powerful pump. Rather than an even one-to-one swap of potassium for sodium, in each cycle the pump transports three sodium ions out for every two potassium ions it takes in. Later, scientists discovered that both sodium and potassium could bind to the same locations on the pump, a fickle temperament that is unusual among membrane proteins typically very picky about the type of ion they bind. That presented an intriguing molecular engineering problem — how could the pump modify itself to bind sodium when it’s accessible to one side of the membrane and potassium when it’s accessible to the other?

Some biologists have suggested that this riddle could only be answered by analyzing the highly precise geometry of the binding sites. Thus, many predicted that the model could not be solved until the most minute details of the structure of the sodium-potassium pump was fully captured in both its sodium-bound and potassium-bound states. So far, only the latter pictures (taken by X-ray crystallography) exist. But Benoit Roux, professor of biochemistry and molecular biophysics, decided that half the information was good enough to form a new theory of how the pump pulls double duty.

“Biologists have swept this under the rug, saying we need to know the structure of both the sodium and potassium bound forms with a sub-angstrom accuracy to address this issue,” Roux said. “Our point of view is that proteins are flexible macromolecules and that the mechanism of ion selectivity ought to be fairly robust, even when there are small sub-angstrom thermal fluctuations.”

Roux’s group, which included Haibo Yu of UChicago and Ian Ratheal and Pablo Artigas from Texas Tech, applied a computational method called molecular dynamics to the two existing crystal structures of the pump - isolated, strangely, from the rectal gland of a shark. For a paper published in Nature Structural & Molecular Biology last week, the team ran computer simulations that tested the possibilities of how four important amino acids in the binding sites mediate the pump’s change in selectivity under normal conditions. Instead of a complicated transformation from sodium-binding to potassium-binding mode, Roux’s model identified a small change that could account for the pump’s changed loyalties.

Protonation is a chemical reaction that adds a single hydrogen atom to a molecule. The four binding site amino acids of interest happen to carry negatively-charged acidic side chains that may or may not bind an extra proton. Roux’s group found that when the four acidic residues lose that extra proton (called deprotonation), they strongly prefer sodium to potassium. In their protonated state, the preference reverses to potassium over sodium.

“At this point it’s speculation because we do not know the structure of the sodium-bound state. But perhaps protonation and deprotonation play a more active role on modulating selectivity of these sites during the functional cycle of the pump,” Roux said. “It’s a provocative idea, nobody has ever proposed something like that to the best of our knowledge. Some people might be a bit shocked.”

read more

Medical students spend the first half of their education learning anatomy and physiology, and the second half applying that knowledge in the hospital. But where in that process do they learn the very important skill of listening and talking to their patients? In the panel discussion that followed yesterday’s announcement of The Bucksbaum Institute for Clinical Excellence, it was clear that even physicians who graduated from medical school decades ago remember exactly when and from whom they learned those important lessons. In some cases, that mentor was sitting just a few feet away, such as when Mark Siegler spoke of his time as a medical student learning from the now 102-year-old Joseph Kirsner.

“The way you learn medicine is by seeing, not by talking. You have to show what good care is about. I learned from studying people like Joe,” Siegler said. “Joe told us that everything was important, [including] science and clinical inquiry, but patients came first, patients were the absolute first priority.”

The Bucksbaum Institute, made possible by a $42 million pledge from The Matthew and Carolyn Bucksbaum Family Foundation, has borrowed that sentiment as its defining principle. Teaching bedside manner may not be as straightforward as teaching biology, but creating a system of mentorship can help experienced physicians pass lessons down to young and aspiring doctors. Perhaps with serendipity, the panel represented that kind of mentorship family tree, with Dr. Siegler seated next to his former trainee Holly Humprey, dean for medical education, and Dr. Humphrey adjacent to current Pritzker 4th-year medical student Rebecca Levine.

[Watch video of yesterday's announcement and panel discussion.]

Each panelist and speaker at the event talked about the doctor-patient relationship as a phenomenon under threat in the modern health care system. Though better tests, treatments, and procedures have saved and extended countless lives, an increased reliance upon technology can interfere with the “old-fashioned” methods of taking a good patient history and answering patients’ questions.

“We were always taught that 90 percent of the diagnosis in medicine was based on what the patient tells you,” said Kenneth Polonsky, dean of the Division of the Biological Sciences and the Pritzker School of Medicine. “There are tendencies on the part of physicians to rely more on technologies than on what the patients tell them, their interactions with patients, and what they learn at the bedside.”

It makes sense then to start with doctors-in-training, and the foundation of the Bucksbaum Institute is the financial support of three to five new medical students a year as Bucksbaum Student Scholars [read more on the Insitute's organization in the FAQ]. Because of the Pritzker School of Medicine’s reputation as a “teacher of teachers,” (30 percent of Pritzker graduates go on to faculty positions at academic medical centers, Humphrey said), the hope is that the emphasis on doctor-patient communication seeded at the University of Chicago will spread around the country.

“This gift allows our medical school to make a very public statement to our students at the time they are applying to medical school and then during their experience in medical school, that the doctor-patient relationship is fundamentally important in the education of a physician,” Humphrey said. “Then, upon graduation, our students populate schools across the country and carry on that Bucksbaum tradition wherever they go.”

read more

In the physician’s office, the communication between doctor and patient can be just as important as any medical exam or test. To set a patient on a healthy path, a doctor must explain diseases and treatments in a manner that is accessible and relevant to each individual. The conversation must also be a two-way street, with the doctor listening to the patient instead of merely lecturing. In the increasingly technical and hurried world of medicine, more and more of that critical interaction is lost to 10-minute appointments and physician switching.

To counter that trend, an exciting new institute was announced at the Medical Center this morning. The Bucksbaum Institute for Clinical Excellence at the University of Chicago will be made possible by a $42 million pledge from The Matthew and Carolyn Bucksbaum Family Foundation. The institute, inspired by the relationship between the Bucksbaums and their long-time physician Mark Siegler, will focus on how to improve doctor-patient interaction and train the next generation of doctors how to be advisers, counselors, and navigators for their patients.

“These generous donors have pinpointed a fundamental aspect of medical practice that deserves greater attention,” said Kenneth S. Polonsky, MD, dean of the Division of the Biological Sciences and the Pritzker School of Medicine at the University of Chicago. “They are giving us the resources to concentrate on training physicians who not only possess extraordinary technical knowledge but can work effectively with patients to reach the best clinical decisions.”

An announcement ceremony this morning will be followed by a panel discussion of the patient-doctor relationship and patient outcomes, with Siegler, dean of medical education Holly Humphrey, and Pritzker medical student Rebecca Levine participating. That event will be webcast live, and coverage will follow here on the blog this afternoon. In the meantime, you can read more about the institute at the New York Times, hear a story about it at WBEZ, and watch the official announcement video below.

How do you know an animal model of a disease is really working? Researchers can create diseases such as cancer in a rat or mouse, but a tumor in a rodent may not behave the same way as a tumor in a human being. The challenge is even more difficult when scientists try to model psychiatric conditions, which in humans rely upon interviews and nuanced diagnosis. It’s hard to get a rat to stay on a therapist’s couch, much less ask whether they are feeling depressed or anxious.

So psychiatrists interested in using an animal model to probe the underlying biology of a mental condition are forced to be careful, clever and realistic. For a new model of obsessive-compulsive disorder (OCD) published last week by a team of scientists from the University of Chicago, the validity of the model was based on both the symptoms they observed in their animals and how those symptoms were treated.

More than 2 million people in the United States have been diagnosed with OCD, a condition marked by severe anxiety, repetitive behaviors, and intrusive thoughts. Yet only one drug has been found to help alleviate these symptoms - fluoxetine, a serotonin reuptake inhibitor originally developed for the treatment of depression - and the drug is only effective in roughly half of all OCD patients. Finding and testing better treatments for OCD will require animal models of the disease.

“Treatment for these people is greatly needed, and there really are very few highly valid animal models of the disorder,” said Nancy Shanahan, a postdoctoral researcher and lead author of the study in the journal Biological Psychiatry. “Having one that seems to mimic the disorder so well, especially in terms of the time course of treatments that work in humans, is potentially very useful for researching novel therapeutics.”

That’s easier said than done. The compulsive hand-washing, switch-flicking, or counting habits of human OCD sufferers would seem to be impossible symptoms to replicate in a rat, but some characteristics such as perseveration (repetitive movements or actions) and movement in an open field (a marker of a rodent’s comfort or anxiety in a strange environment) have been used by scientists as proxies for the debilitating effects of OCD. Some groups have created these behaviors by deleting genes, but for the new OCD model the UChicago team started with the unusual side effect of a migraine medication.

When the drug sumatriptan is given to people with OCD, it amplifies their symptoms, producing more intrusive thoughts and rituals. Shanahan gave her mice a similar drug that, like sumatriptan, activates a sub-class of receptors for the neurotransmitter serotonin called 1b receptors. In response, the mice showed behaviors that could be interpreted as OCD-like. Instead of exploring the entirety of their cage, they stayed close to the walls (as seen in the paths above) - a marker of high anxiety. Another test called prepulse inhibition that tests the animals’ startle response (thought to measure the brain’s ability to filter out intrusive thoughts), also revealed OCD-like behavior after the serotonin 1b drug was given.

Yet it’s still subjective to say that a mouse that paces around the walls of its cage is suffering from the same underlying biological issues as a human whose anxiety keeps them from leaving the house. More evidence was needed to prove the model’s “predictive validity” - how closely it resembles the human disease.

“A model should be evaluated on its ability to predict, not based on how much it looks like OCD,” explained Stephanie Dulawa, assistant professor in the Department of Psychiatry and Behavioral Neuroscience and senior author of the study. “The best way to do that is to evaluate manipulations with known effects in OCD.”

read more

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?”

read more

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

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

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

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

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

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

read more

Actin is the Lego of the cell. The small proteins can be assembled into many different forms for a wide variety of uses: serving as a scaffold to keep the cell’s shape, a railroad for shipping packages, or a powerful motor to propel the cell or tear it in half. But actin itself is a blank slate, an interchangeable material that needs guidance to do anything more than stick together in chains called filaments. To truly understand the Lego of the cell, you have to understand the factors that prompt it to form into its many useful conformations.

“The actin itself is boring. It’s just a building block,” said David Kovar, assistant professor of cell & molecular biology and molecular biophysics at the University of Chicago. “These filaments have to be assembled at the right time and place, they have to be organized with the right architecture, and the dynamics have to be correct - some structures are assembled and stable for minutes to hours, whereas others are assembled and disassembled on the order of seconds.”

Kovar’s lab studies actin-binding proteins, the cellular tools that shape formless actin into functional filaments. This area of research has exploded as scientists discovered multiple actin-binding proteins, each with their own unique properties. One element, the actin-related protein 2/3 complex (Arp2/3 for short), creates branches in the normally linear filaments. Another, called formin, attaches to the end of the filament and steps on the gas, causing it to grow at an accelerated rate.

Scientists have learned a lot about actin engineering by using a method called TIRF microscopy, which allows them to watch as actin filaments form, grow, and take shape. [A short video of Arp2/3-induced branching is available below.]

“This enables us to actually watch these things in real time, and it has revolutionized the field,” Kovar said.

In a new paper, published last week in the journal Nature Structural & Molecular Biology, Kovar’s laboratory and collaborators at the University of Pennsylvania eavesdropped on the activity of a newly-discovered class of actin-binding proteins, named for a shared feature called the WH2 domain. By studying one such WH2 domain protein, isolated from a water-dwelling bacteria that causes gastrointestinal problems in humans, the lab found themselves watching a new, chaotic kind of actin-forming behavior - akin to how a toddler might choose to play with Legos.

read more

Writing about science means looking up a lot of numbers. Trying to find a figure for the number of cells in the body or the protein-encoding genes in human DNA or patients diagnosed with ovarian cancer from 1980 through 1995 can eat up a lot of time and internet bandwidth. For some of these oft-cited numbers, there’s a mutually agreed upon estimate that science writers can drop into the articles, such as the 23,000 usually tossed around for the number of human genes. But it’s worth remembering that these figures are subject to change - after all, it was thought as recently as 10 years ago that there were 100,000 genes in human DNA.

A new counting kerfuffle broke out this week for yet another oft-cited scientific figure: the number of species on Earth. Last year, zoologist Robert May proposed in Science that the human race would be “embarrassed” should aliens show up tomorrow and ask how many different types of organisms live on our planet. Depending on the model used, one could argue for a number anywhere between 3 and 100 million eukaryotes, May wrote - and that doesn’t even count viruses and bacteria, which far outnumber the larger species.

But as the authors of the PLoS Biology article “How Many Species Are There on Earth and in the Ocean?” found out this week, picking a number within that range is hazardous territory. Using a mathematical model based on the roughly 1.2 million species we currently know about, the research team calculated a new estimate: approximately 8.7 million species from land and sea. Of those, only 14% of land species and 9% of sea species have so far been cataloged by humans, the authors concluded, and describing those remaining could take over 1,000 years and $364 billion. “Our results also suggest that this slow advance in the description of species will lead to species becoming extinct before we know they even existed,” they wrote.

Dramatic stuff, but what about the math? In Carl Zimmer’s article on the study for the New York Times, the first bubbles of discontent can be felt around the biology world, from fungi experts to entomologists who argue that the 8.7 million number is far too low. Scientists who study microbes were even less pleased with the mathematical model, which they said dramatically under-counted their favorite species. On his blog, Phylogenomics, microbiologist Jonathan Eisen pish-poshed the paper’s estimates of 10,000 prokaryote species: “I think without a doubt the number of bacterial and archaeal species on the planet is in the range of millions upon millions upon millions.  10,000 is clearly not even close.” Two other microbiologists wrote a letter to the Washington Post, pointing out that “a teaspoon of soil contains more than 10,000 species of bacteria.” For the time being, it looks like our alien visitors will have to be satisfied with the answer, “Lots.”

Elsewhere…

Speaking of the importance of bacteria and microbes, consider the discovery of antibiotic-resistance genes in 30,000-year-old bacteria from the Yukon Territory. Though these bacteria lived approximately 29,930 years before the discovery of penicillin, they possessed defenses against the naturally-occurring weapons scientists have seized upon to develop infection-fighting drugs. That long history means outsmarting drug-resistant bacteria may be even harder than scientists thought, and makes the case for even more selective use of antibiotics. “Bacteria share these genes like baseball cards with each other,” Stuart Levy at Tufts University told Nicholas Wade of the New York Times.

Has an important culprit in amyotrophic lateral sclerosis, aka Lou Gehrig’s disease, been discovered? The Medical Center’s Raymond Roos comments on a recent Northwestern University study.

On the blog, we’ve covered the link between sleep loss and testosterone, weight gain, and blood sugar. A new study from UCSD and Harvard now finds a connection between sleep quality and blood pressure. Our sleep research guru Eve Van Cauter commented on the research for TIME.

Just another reminder to check out the Medical Center’s new Facebook page, where this week you can find articles from the blog, information on the DNA Discovery Lab at the Field Museum, and President Sharon O’Keefe’s letter to the editor on hospital charity care. If you like it, please hit that “like” button!