By Rob Mitchum

Treating a brain tumor in a lab dish is easy. Scientists have developed a full arsenal of treatments to kill tumor cells, using natural toxins, chemotherapeutic drugs, and even gene therapy to send them to an early grave. But making those therapies work in the actual setting of the brain is a much different ballgame. The first major challenge is even delivering the therapy to the right place, as any drug must get past the brain’s defense systems and navigate the organ’s complex architecture. In addition, the therapy must be a picky killer, eradicating tumor cells while leaving the healthy brain cells intact.

Researchers are therefore searching for a smarter delivery system that can maximize the effectiveness of these brain tumor therapies, collaborating with experts in the world of chemistry, materials science, and engineering. Bakhtiar Yamini, an assistant professor of surgery at the University of Chicago Medicine, is collaborating on one such effort with a biotechnology company in Nebraska, targeting the most difficult malignant brain tumors Yamini sees in his neurosurgery practice. By designing a new nanoparticle “shell” capable of selectively targeting therapeutics to brain tumor cells — and capable of being watched as it travels through the brain — the research team hopes to make eradicating these cells in their native environment as simple as killing them in a dish.

“Even though new therapies are being developed that can kill cells in culture, getting them into the brain tumor is a big problem, so development of a vehicle is an important step,” Yamini said. “People have previously used both targeting and image guidance in the treatment of other cancers, but bringing these two strategies together in one vehicle is something that would be really useful.”

In Phase I of their NIH-funded project, Yamini and collaborators at LNKChemsolutions developed a nanoparticle made from materials such as polylactic acid and polycaprolactone. Despite the complicated chemical names, these materials are commonly used in biodegradable products — a feature that offers an advantage over other nanoparticles made from gold, titanium, and other metals. The nanoparticles are also customizable, able to carry a variety of therapeutics and different targeting signals, and incorporate a metal, iron oxide, that allows doctors to visualize the nanoparticles’ travels using MRI technology.

For Phase II of the project, funded late last year, the team is taking their technology to animal models. A nanoparticle designed to target a protein called the EGF receptor (often overexpressed by tumor cells) and deliver the chemotherapy drug temozolomide will be tested in mice and rats that have brain tumors. If those experiments are a success, the team will try the therapy on a larger animal model: dogs. Partnering with veterinary clinics in Chicago and Minnesota, the researchers will offer the treatment to pet owners willing to volunteer their sick dog for a cutting-edge therapy.

“That’s how we will develop the treatment, but at the same time it should be effective at helping the dogs,” Yamini said. “It’s essentially a clinical trial for dogs that have brain tumors, and because their tumors are very similar to human ones, the results in the dogs will have relevance to humans.”

Because of the blood-brain barrier, which prevents most molecules from passing from the body’s blood supply into the brain, just injecting the nanoparticles into a vein won’t work. Directly infusing particles into the brain during surgery to remove the tumor is possible, but the spread of particles by that method can be unpredictable and may miss the target. Instead, Yamini will use a method known as convection enhanced delivery to push the nanoparticles very slowly into the desired area of the brain, squeezing them through the space between brain cells. The iron oxide tags will allow surgeons to monitor the path of the nanoparticles by MRI as they are being infused through the brain.

“The image guidance is a big factor, because ‘blind’ infusion of the nanoparticles can be problematic,” Yamini said. “If you plan to treat the upper right corner and you see, on MRI, that the infusion actually went to the lower left, you can put your catheter back in and try again. This paradigm of ‘adaptive image guidance’ allows you to adjust subsequent treatments to target the areas that were missed on the original injection.”

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By Rob Mitchum

In cells, DNA doesn’t often hang out in the long, stretched-out strings you see in science textbooks. Most of the time, it is stored tight in a package called a nucleosome, wound like a ball of yarn around a protein called chromatin. In order for a gene to be “activated,” the stretch of DNA where it resides must first be unspooled from the nucleosome, so that cellular factors can attach to the strand and begin making protein from the DNA recipe. In a new study published this week in Nature, a team of University of Chicago researchers took advantage of this connection between unspooling and activation to solve a mystery that haunts many a recent genetics study.

Genome-wide association studies, commonly called GWAS, look for genetic variants associated with diseases or other genetic traits such as height or hair color. Since the completion of the Human Genome Project and the development of gene chip technology, scientists have performed hundreds of these studies. But many of them offer a befuddling result, with some of the most significant GWAS “hits” coming from variants that lie in the spaces between the protein-encoding genes, regions once dismissed as “junk DNA.” Nevertheless, some of these variants have been observed to affect the expression of nearby genes by some unknown process, leading them to be named expression quantitative trait loci, or eQTLs.

But how do these “non-coding” variants exert their dramatic effects upon gene expression — and ultimately, upon diseases and traits? The Department of Human Genetics laboratories of Jonathan Pritchard and Yoav Gilad found one potential method by selectively targeting the unspooled segments of DNA.

“Much of the regulation is occurring in these regions where the DNA is unfolded, so it’s accessible for proteins to come in,” said Pritchard, professor of human genetics at the University of Chicago Biological Sciences. “What we were interested in was figuring out the main mechanisms by which variation is affecting regulation. We postulated that changes in these open regions would be a major mechanism.”

In cell cultures of B cells (a kind of white blood cell) from 70 West African individuals, researchers used an enzyme called DNaseI to cut the DNA into short segments. Because DNaseI can only work on segments that are unspooled from chromatin, the chopping process left the team with markers of DNA regions that are open for business - in this case the team measured a total of 2.7 billion DNaseI cut sites. The researchers could then use the DNaseI cut sites to create a detailed map and test for genetic variants that predict whether a given stretch of DNA was more likely to be open or closed in an individual, with open segments likely reflecting genes actively under transcription.

“Basically what we’re doing is mapping these locations,” Pritchard said. “The power of DNaseI is that it’s giving us a slightly indirect way of measuring transcription factor occupancy, but it’s giving us information about essentially all factors at once.”

The nearly 10,000 variants found in that test were dubbed “DNaseI sensitivity QTLs,” or dsQTLs for short. The naming similarity to eQTLs was no accident, as the researchers found a significant overlap between the two classes of genetic markers. Up to half of eQTLs were estimated to also be dsQTLs, meaning that the gene variant exerted its power to increase or decrease expression of its gene by affecting the probability of the DNA segment being opened or closed. “dsQTLs are therefore a major mechanism by which genetic variation may affect gene expression levels,” the authors write.

“I think one of the things this paper does is to clarify one of the main mechanisms by which eQTLs arise,” Pritchard said. “Many people measure eQTLs, but generally it has been very difficult to figure out what are the causal variants that drive them and how they act. This is kind of filling in the black box for perhaps as many as half the eQTLs.”

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In books and movies, time travel is typically fraught with negative consequences. Any attempt to change the past — say, stopping the JFK assassination, or taking your mom to the Enchantment Under the Sea dance — is bound to produce ripples of change that alter the future. But what if you could safely contain a trip back in time within the boundaries of a test tube? In a new paper published in Nature, a University of Chicago geneticist used a form of “molecular time travel” to observe a crucial event in the evolutionary history of life on Earth…and extinguish a favorite argument of intelligent design advocates.

The concept of “irreducible complexity” is a favorite talking point of the forces against evolution, both today and historically. As the argument goes, the complex structures found within modern organisms — from the eye to the microscopic protein machines that conduct business in cells — are far too complicated to be the result of the random genetic mutations and selective forces at the core of Darwin’s grand theory. The argument is so old that Darwin himself addressed it in On the Origin of Species, speculating on how an accumulation of small changes could lead from a simple photoreceptor to the wondrous eye shared by many organisms today.

The best way to demonstrate how the minute changes of evolution could produce great complexity is to capture that process in action. But to happen upon such a leap live would be a biological needle in an enormous haystack. A better strategy would be to pick a historic leap in complexity from the evolutionary past, and then go back and observe how it happened. Easy, right?

To accomplish this task, Joe Thornton, a new faculty member in the Departments of Human Genetics and Ecology & Evolution, developed the method of “molecular time travel.” Instead of a Delorean, Thornton’s method uses a computational analysis of the genes from modern-day species to resurrect the genes of ancestral species that lived hundreds of millions of years ago. For the new paper, Thornton and colleagues at the University of Oregon decided to “travel” back to look at a complex molecular machine found in various species of fungus.

“Our strategy was to use ‘molecular time travel’ to reconstruct and experimentally characterize all the proteins in this molecular machine just before and after it increased in complexity,” said Thornton, professor of human genetics and evolution & ecology at the University of Chicago, professor of biology at the University of Oregon, and an Early Career Scientist of the Howard Hughes Medical Institute. “By reconstructing the machine’s components as they existed in the deep past,” Thornton said, “we were able to establish exactly how each protein’s function changed over time and identify the specific genetic mutations that caused the machine to become more elaborate.”

Their target was a molecular machine called the V-ATPase proton pump, which helps maintain the proper acidity of compartments within cells. In modern Fungi, this pump contains a six-part ring made up of three separate proteins, but that wasn’t always the case. Some 800 million years ago, that same ring was made from only two proteins, meaning some kind of event occurred around then to increase the complexity of this machine.

Thornton’s group calculated the genetic sequence of the ring proteins from that ancient ancestor using the sequences of 139 modern Fungi family members, computationally tracing their common elements back up the Tree of Life to their ancient predecessor. The researchers could then reproduce the protein before the split (called Anc.3-11) and the two proteins that came after the split (Anc.3 and Anc.11), and see how they functioned in the proton pump’s ring.

Surprisingly, the “newer” proteins were less versatile than the ancestral Anc.3-11, which could substitute for either of its descendants when transplanted into modern Fungi. The result suggests that the pump’s increase in complexity resulted not from the evolution of a new, “better-designed” function, but from an initial loss of versatility.

“It’s counter-intuitive but simple: complexity increased because protein functions were lost, not gained,” Thornton said. “Just as in society, complexity increases when individuals and institutions forget how to be generalists and come to depend on specialists with increasingly narrow capacities.”

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As another year comes to a close we’d like to look back at the fascinating research breakthroughs and inspiring patient stories from 2011. ScienceLife ran 168 posts this year, and while we wish we could highlight all of them, here are a handful of our favorites from each month.

January

Patrick Wilson found out that the H1N1 virus could end up helping us fight all types of flu. Stephen Pruett-Jones studied how some male birds mimic the sounds of predators to pick up the ladies (with an audio clip). We interviewed David Gozal about his study on the link between childhood obesity and lack of sleep, and took a look at NCAA regulations mandating sickle cell testing for athletes.

February

Harold Pollack gave a lecture on why violent crime in urban, minority communities should be considered a public health epidemic. Siri Atma Greeley studied the actual medical benefit of widespread genetic testing. Stacy Lindau wanted to know why so few women get help for sexual problems after surviving cancer. We talked to Bana Jabri about the causes of celiac disease, and Sliman Bensmaïa showed us how the brain processes the basic elements of touch very much like it handles visual information.

March

Sola Olopade educated women in Nigeria about using clean-burning stoves to prevent indoor pollution. Stefano Allesina and Jonathan Levine looked at how rock-paper-scissors helps explain evolution. Joshua Miller went to Yellowstone Park to see what stories the ghostly bones of animals can tell, and Scott Eggener questioned the wisdom of indiscriminate prostate cancer screening.

Photo by Gerald Waddell

Andrea King studied the wide range of responses to drinking alcohol, and why it can be fun for some people and a bummer for others. Cheryl Reed took a ride in a helicopter with our UCAN nurses. Kamal Sharma looked at the genes that control animals’ gait, and Ningqi Hou studied how urban environments can dictate how much exercise people get.

May

Daniel McGehee looked at the long-term effects of nicotine on the brain. Habibul Ahsan went to Bangladesh to study the health impacts of accidental exposure to arsenic in drinking water. The brain’s overlooked supporting cells got their due at a conference on neuroscience, and we remembered a landmark discovery about a once popular drug taken during pregnancy that we now know can cause cancer.

June

As we headed into summer, Diana Lauderdale used Google to track MRSA. We learned about an extraordinary transplant where a man received a new heart, liver AND kidney. Daniel Geynisman gave us the rundown on whether or not cell phones are killing us (they’re not, as long as you don’t use them in the car), and some UChicago undergrads studied what happens to gorillas on the birth control pill.

July

We spoke to Donald Jensen and Andrew Aronsohn about the new outlook for patients with hepatitis C. Igor Schneider made a time machine to find the genetic switch for limb development. Farr Curlin led a study about the benefits of addressing spiritual needs alongside medical care, and Adam Cifu looked at the phenomenon of scientific study reversals.

August

Stefano Allesina dug into the long, shady history of nepotism in academia in Italy. John Schneider talked about his work addressing sexual health and stigma in India. Michael Becker discovered a new treatment for the Royal Disease, and we had the rare chance to name check a Spiderman villain in a post.

September

Martha McClintock and Suzanne Conzen studied the connection between social isolation, stress and breast cancer. Gallego Romero traveled to India to search for the origins of lactose intolerance. Stephanie Dulawa developed a mouse model for OCD, and Paul Vezina looked at a different kind of obsession, compulsive gambling.

October

Arshiya Baig started a pilot project to help people learn about life with diabetes through pictures. Manyuan Long found that some of the youngest genes are in the brain. Jens Ludwig and Stacy Lindau published a landmark study about the connection between neighborhood poverty and health, and Issam Awad studied a rare brain disease that soon could be treated with a drug instead of surgery.

November

Cathy Pfister and Tim Wootton figured out how to use seashells to track climate change over the years. Lianne Kurina found a link between loneliness and sleep quality. Shantanu Nundy, Monica Peek and Marshall Chin developed a program to send text message reminders to people with diabetes, and Pan Chen looked at the links between childhood abuse and aggressive behavior in adults.

December

Inbal Ben-Ami Bartal, Jean Decety and Peggy Mason discovered that rats can show empathy for their fellow rats in distress. Maciej Lesniak performed a scary but amazing brain surgery on a patient who was awake. Cathryn Nagler searched for the source of food allergies within our bodies, while Stafano Guandalini uncovered the challenges in educating doctors about one of those allergies, celiac disease.

Whew. Hope you were able to click through at least a few of those. We look forward to another great year of research in 2012. We’re taking a break next week, but we’ll be back on January 5. Happy holidays!

All of the animal life on Earth, including human beings, can be traced back to a unicellular ancestor somewhat similar to the modern-day protozoa. In one sense, the hundreds of millions of years of evolution is the story of how organisms became more and more complex, growing from a single cell to trillions of highly specialized cells forming different organs and tissues in a single body. Yet while you could easily tell a protozoa from a human in a police lineup, cells from the two species are made up of many of the same proteins, performing similar jobs. What changed to produce these profound differences in complexity?

One potential area where this complexity may have bloomed is tyrosine phosphorylation, a key cellular signal for pathways that control cell growth, proliferation, and structure. Enzymes called tyrosine kinases add a phosphate group to a wide range of cellular targets, which can act like a light switch, turning their function on or off. The phosphorylated proteins are recognized by another group of proteins with a special “sensor” called the SH2 domain. Because tyrosine kinases will promiscuously phosphorylate many targets in the cell, the very picky SH2 domain proteins are responsible for sorting out the noise.

“Tyrosine kinases tend to be not that selective,” said Piers Nash, assistant professor in the Ben May Department of Cancer Research at the University of Chicago who studies this system. “They’ll phosphorylate a lot of things, and that creates all of these docking sites for SH2-domain-containing proteins. It’s really up to the SH2 domains to interpret those signals and convert them into downstream signaling pathways.”

The more complex the cell, the more unique types of SH2 domains that are needed to perform this important sorting function. In the unicellular cousins of animals, organisms can get by with just a single SH2 domain. But in humans, some 121 SH2 domains are known to exist, managing many different pathways in many different cells. In two recent papers, Nash’s laboratory studied how these SH2 domains manage their impressive selectivity and the evolutionary pathway that they took from simple protozoa to complicated human.

It’s essential that SH2 domains only bind to the right phosphorylated protein — repeatedly screwing up and activating the wrong pathway could lead to diabetes, cancer, or worse. But scientists have struggled to figure out how SH2 domains choose their appropriate target, with some even concluding that they aren’t so selective at all, merely in the right part of the cell at the right time to only bind the correct protein. However, that wasn’t what a research team led Bernard Liu from Nash’s laboratory found when they looked at how SH2 domains bind actual cell targets such as the insulin receptor.

“It turned out that the SH2 domains were exquisitely selective, much more selective than the general motifs for the SH2 domains that had previously been mapped,” Nash said. “So it was clear there was additional information encoded in the peptide that the SH2 domain makes use of.”

The researchers then deduced that the SH2 domains select their target through a kind of language, looking for the exact sequence of amino acids - or “word” - that marks the appropriate match. Because each amino acid (akin to the letters of the word) will either attract a particular SH2 domain or reject its peers, changing only one amino acid can completely change the meaning, like altering the word “light” to “fight.”

“For SH2 domains, that makes all the difference in the world. They can sense incredibly subtle differences,” Nash said. “It’s looking at the entire peptide and seeing both the permissive and the non-permissive residues, integrating that and making this collective decision about what to bind.”

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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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Brain surgery remains one of the more complex procedures in the clinical arsenal, an intervention any doctor would like to avoid if possible. But many conditions - a growing brain tumor, a bleeding hemorrhage - require the surgeon to go in, opening the skull, dodging blood vessels, and preserving healthy tissue to correct the problem. If these maladies were somehow preventable or treatable with a medication, it could cut down on the complications and cost of neurosurgery. Even so, you might be surprised to find a surgeon doing the research that could someday reduce his own workload.

That’s the case with Issam Awad, professor of surgery at the University of Chicago Medical Center, and the latest paper in his project studying an abnormality of the brain’s blood vessels. Cerebral cavernous malformation (CCM), alternatively known as cavernous angioma, occurs when the small blood vessels of the brain grow abnormally large. These malformations can occasionally form a dangerous lesion, leading to headaches, bleeding in the brain, or stroke. But it wasn’t until the routine use of MRI technology until clinicians discovered just how commonly CCM can be found - 1 in 500 people - even though it is often non-symptomatic.

The presence of non-symptomatic CCM complicates the matter further for neurosurgeons, who must decide whether to perform surgery to correct the lesion or wait to see if it worsens. This dilemma is especially difficult in patients with a family history of CCM, which makes up about one-third of the cases. Waiting to see if the angioma is going to become problematic enough to require surgery can be a frustrating experience.

“There is currently no treatment in clinical use to either prevent the formation or the maturation of these lesions,” Awad said. “The way we deal with them now is we wait until a lesion gets bad or does something bad, and then we take it out.”

Awad and colleagues Douglas Marchuk from Duke University and Mark Ginsberg at the University of California, San Diego have used those familial CCM cases to find the cause of the condition, focusing on a gene called KRIT1 (or CCM1 for its clinical significance). By knocking down KRIT1, they could create a mouse model that formed CCM lesions, and study the cellular signals that accompany the condition. It turned out that reducing the activity of KRIT1 increased the activity of a signal called ROCK, which made CCM lesions leakier and more severe. CCM lesions removed surgically from human subjects by Awad also tested for high levels of ROCK, suggesting that the mechanism was the same across species.

So the obvious hypothesis to test was whether an inhibitor of ROCK could block the formation of CCM lesions. For a paper published yesterday in Stroke, researchers from the three laboratories performed the experiments in their mouse model of CCM, treating the mice for four months with a ROCK inhibitor drug called fasudil. When they compared the brains of these drug-treated animals to the brains of animals treated with a placebo, they found fewer lesions, smaller lesions, and a reduction in inflammation and hemorrhage after fasudil.

“This animal model and humans have lesions that are aggressive and symptomatic: They leak blood, they show inflammatory properties, and endothelial cells multiply or proliferate,” Awad said. “None of these features were present in the fasudil-treated mice. It was like the lesion was chilled down and shrunk.”

Though promising, this early experiment was performed in only a small number of mice. More extensive testing in animals - and if everything goes well, in human clinical trials - will be required before the drug can be deployed in the neurology practice. Fasudil is also not yet approved for use in the United States, though it is used in Japan for a different neurological condition and has been “clinically well tolerated” there, Awad said.

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Finding the cause and the cure for a deadly disease is a little bit like investigating a murder. Clinicians collect clues from their patients, bring them back to the lab, and try to reconstruct the crime and identify the killer. For amyotrophic lateral sclerosis (aka ALS or Lou Gehrig’s Disease), this investigation has lasted over a hundred years - since neurologist Jean-Marie Charcot first described the disease in 1874. But it’s only in the last two decades that ALS researchers have started to find major breaks in the case, revealing genetic clues to the origin of this deadly neurodegenerative disease. At a special ALS gathering at the University of Chicago, Medical Center neurologist Raymond Roos told nearly 200 patients and caregivers that the case may finally be cracked soon.

“I think the field is on fire now,” said Roos, the Marjorie and Robert E. Straus Professor of Neurology. “I think it’s astounding and exciting what’s going on with respect to neurodegenerative diseases and absolutely ALS. We have all these things piling up now and we are continuing [to look]. Should we be optimistic about the future? Yes.”

Wednesday’s gathering, put together by the Greater Chicago Chapter of the ALS Assocation, was a unique two-part event featuring both a symposium for researchers of the disease and a luncheon/health expo for the patients and their families. In one room of historic Ida Noyes Hall, 14 Chicago scientists studying the origins of ALS and developing new treatments for what is currently an incurable disease shared their latest results. Meanwhile, patients and their families learned about medical devices and advocacy opportunities, and shared stories of how they cope with their disorder.

The day’s scientific component demonstrated both why the ALS investigation has taken so long, and why Roos thinks there is cause for optimism. The central mystery of ALS is why it selectively targets the motor neurons of the nervous system, the extremely long cells that deliver instructions from the brain to the muscles of the body. As the motor neurons die off, the patient experiences a progressive paralysis, losing the ability to maintain balance, walk, and eventually, breathe. Figuring out what causes this specific population of neurons to perish will point the way to treatments that slow or even reverse the progression of the disease.

For suspects, scientists have looked to genes. Roughly 10 percent of ALS cases are inherited through generations of families, indicating a genetic cause. While this population might be only a small minority of cases compared to the more common “sporadic” cases, they could be a foothold along the path to understanding both types of ALS.

“Those are very important even though they make up this small group, because they open a window,” Roos said. “If we can identify the gene that’s mutated, we can figure out what the function of that gene is. The hope and assumption and, I think, the reality, is that information will guide us into understanding the non-inherited, sporadic form.”

In 1993, scientists discovered the first ALS-associated gene/suspect, called SOD1. Though mutations of this gene explain only 20 percent of the familial 10 percent, they have been an important clue into exactly what goes wrong inside a motor neuron during the disease’s tragic march. The morning’s sessions zoomed in on these details, describing how a faulty SOD1 can kill off a cell through to the aggregation of cellular proteins, the interruption of the cell’s highway-like transport system (presented by UIC’s Gerardo Morfini and Scott Brady), and the creation of a “toxic channel” (as told by UCMC’s Michael Allen). The damage caused by SOD1 mutants might not even be limited to the motor neurons themselves, as Roos presented research demonstrating its toxic activity in the cells surrounding those neuronal types.

The path from what goes wrong to the creation of new potential therapies for ALS was explained by Richard Silverman, a chemist from Northwestern University. By screening for compounds that prevent the type of protein aggregations observed in the motor neurons of ALS patients, chemists hope to design new drugs that will slow the damage and hopefully, the physical symptoms they produce. Silverman detailed the incremental design of two new compounds in his laboratory that, in animal studies, produce an extension of life that is two to three times longer than seen with the only drug currently approved for use in ALS, riluzole.

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What made the human brain? According to Stanley Kubrick and Arthur C. Clarke, it was a giant obsidian monolith inspiring primates to use tools and weapons. Scientists have taken a more nuanced approach, looking for the biology behind the complex structures and enhanced function of the human brain. But merely comparing the genes expressed in adult human brains to those of other animals yielded few promising differences, leading scientists to focus on changes in the regulation of old genes rather than the arrival of new genes. After all, the construction of a structure as important as the brain cannot rely on unpredictable, novel genes with new functions, right?

However, those young genes are recently taking on a higher profile. In a 2010 paper, the University of Chicago laboratory of Manyuan Long demonstrated that new genes exclusive to a given species can be just as critical to an organism’s survival as the old, conserved genes it shares with other species. The implication at the time was that what makes us uniquely human could lie in those “young” genes that only appeared in our genome relatively recently.

“Animal models have proven to be very useful and important for dissecting human disease,” said Sidi Chen in 2010 about that study. “But if our intuition is correct, some important health information for humans will reside in the unique parts of the human genome.”

A new study from Long’s lab appearing yesterday in PLoS Biology identifies one important place where those new genes may play role: the human brain. By merging a database of gene age with gene transcription data from humans and mice, researchers looked for where young genes specific to each species were expressed.They found that a higher percentage of primate-specific young genes were expressed in the brain compared to mouse-specific young genes. Human-specific young genes also were more likely to be expressed in uniquely human brain structures, such as the neocortex and prefrontal cortex.

“Newer genes are found in newer parts of the human brain,” said Yong Zhang, PhD, postdoctoral researcher and first author on the study. “We know the brain is the most remarkable difference between humans and other mammals and primates. These new genes are a candidate for future studies, as they are more likely to underlie this difference.”

Another intriguing finding in the gene age data was inspired by Zhang’s visit to the obstetrician with his pregnant wife. While viewing an ultrasound of his unborn child, Zhang said he realized that much of human development takes place during fetal stages - suggesting those early months should be a critical time for gene expression. As predicted, young human-specific genes in the brain were more likely to be turned on during fetal or infant development.The early activity of these genes suggests scientists should be looking at earlier developmental stages for genetic activity that ultimately shapes the complexity of the human brain.

“What’s really surprising is that the evolutionary newest genes on the block act early,” said co-author Patrick Landback, a graduate student in Long’s laboratory. “The primate-specific genes act before birth, even when a human embryo doesn’t look very different from a mouse embryo. But the actual differences are laid out early.”

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By Meghan Sullivan

What is it about viruses that so easily captures our attention? With the teeth mostly taken out of bacterial infections by the advent of penicillin and parasites a rare and mostly exotic concern, viruses remain one nemesis that we often struggle to treat. Unlike complex bacteria and parasites, viruses are little more than genetic material wrapped up in a vessel designed to take its blue prints to the next host. Once in a host, viruses inject their genetic material into cells and take over the cellular machinery to carry out their lifecycles. Imagine terrorists sneaking into a Ford factory and using the assembly lines to crank out WMDs. Infected cells eventually die, but not before triggering immune responses (coughing, sneezing, etc) that aide their spread to the next host.

Taken starkly, viruses execute an elegant life cycle. If the aim of life is to pass on one’s genetic material, viruses have succeeded by reducing themselves to only genetic material, relying on other organisms for the messy business of replicating and spreading. The only way to make the process more streamlined would be to cut out the effort of budding, replicating, and finding its next host.

Which, it seems, viruses have also done.

Called human endogenous retroviruses (HERVs), some viruses have slipped their genetic material into our genome, inserting themselves between host genes or in the long stretches of inaptly named “junk” DNA. Over the course of evolution, these genetic stowaways were passed down to the host’s offspring right alongside genes for blue eyes and attached earlobes. Millions of years later, we find remnants of the viruses encountered by our ancestors written in our DNA like graffiti in a bathroom stall. HERVs comprise as much as 8% of the human genome and some may have integrated into our genomes as long ago as 60-70 million years ago.

Considering the vast changes our genome has undergone in the past 70 million years (by comparison, the human-chimpanzee split occurred only 6 million years ago) it makes sense that the HERVs fossilized in our genome have also been changing. HERVs, like the rest of our genome, acquire DNA mutations at a low but consistent rate. Scientists are able to estimate when a HERV integrated - and by extension, when it was last infectious - by comparing mutations in long terminal repeat (LTR) sequences, stretches of DNA that flank the viral genes like book ends. At the time of integration, these regions are identical, but the longer the HERV has been in the genome, the more mutations the LTRs acquire. By comparing the differences in LTRs flanking HERVs, scientists can estimate how long a HERV has been in the genome.

Previously, the youngest HERVs were estimated to be 800,000 years old. For a recent paper in the journal PLoS ONE that explored how recently HERVs were actually circulating as viruses, Aashish Jha, a University of Chicago graduate student in the Department of Human Genetics and former member of Douglas Nixon’s lab at UCSF, looked for recent integrations into the human genome. Using a genome browser at UCSC, Jha and colleagues tracked all the human-specific, full-length HERVs at a particular place in the human genome. Interestingly, one HERV called k106 didn’t fit the normal timeline.

“It looked interesting because it did not have any mutations in its LTRs,” Jha said.

This was an unusual find, as the age of most HERVs insures at least a few mutations that would aid in dating it. Using genetic information from 51 ethnically diverse individuals, Jha and colleagues were able to estimate that the k106 HERV integrated between 92 and 100 thousand years ago, making it one of the youngest HERVs ever identified.

“This time period is exactly the time modern humans were emerging,” Jha pointed out, “So someone was infected and, given that it was a small population size, it rapidly became fixed in the genome. Then humans moved out of Africa…so even though the virus is new we find it fixed in every human population.”

Having identified this recently integrated, human-specific HERV, it’s possible to gain insight on the ways HERVs have affected the course of our development. LTRs flanking HERVs contain signals that control when and where genes are turned on and off. Placing these viral signals in front of host genes could impact how and when they are expressed and, in some cases, lend an advantage to the individuals possessing it.

“There are multiple ways they [affect evolution],” Jha said.

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The evidence for recent, accelerating global climate change is very strong, as it is for the role we humans have played in influencing our Earth’s weather. But for the most part, there have been few direct tests of how climate change could affect the organisms that inhabit our planet. Much of the evidence on this point is either anecdotal, correlational, or based upon predictive models, such as reports that 1 billion people will be forced to relocate due to climate changes or predictions of increased extinction risk due to changes in temperature, ocean chemistry, sea level, and other factors. None of these studies get at a crucial question that will determine the true impact of these environmental shifts: in a footrace between climate change and evolution, what will win?

Two studies published today in Science suggest an answer for one particular species, the small flowering plant Arabidopsis thaliana. Just as the fruit fly Drosophila melanogaster has become an important tool for scientists studying animal genetics, Arabidopsis is the model organism of choice for studying plant genes. Researchers around the world - including the laboratory of Joy Bergelson, professor and chair of evolution & ecology at the University of Chicago - have characterized the genome of Arabidopsis and looked at the variation within the species.

“Arabidopsis is pretty much ubiquitous; it’s been collected in most parts of the world. You find it throughout Eurasia, Russia, up through Scandinavia and down through the Iberian peninsula,” Bergelson said. “So, as a community, we now we have thousands and thousands of lines from all over, many of which are housed in this lab.”

Those resources allowed Bergelson’s laboratory and another group from Brown University to study the relationship between climate change and evolution in this plant species via two separate experiments. In the first, a team led by University of Chicago postdoctoral researcher Angela Hancock applied the popular methodology of genome-wide association studies (GWAS) to the plant, with a twist. Instead of looking for gene variants associated with a particular characteristic of the plant itself, the team looked for variants associated with different climate variables, such as temperature, precipitation, and humidity. (If it sounds familiar, ScienceLife wrote about a similar study Hancock performed with human genetics in 2010.)

Their analysis produced a list of climate-associated genes that reflect familiar biological processes, controlling aspects of photosynthesis, growth, energy metabolism, and other activities important to plant health. To test whether these genes were truly related to a plant’s fitness in a given climate, the researchers tested their ability to predict how well a plant would grow when grown in one particular climate, that of Lille France, based on the number of favorable variants that they carried. Happily, the gene variants were truly predictive, suggesting that the variants produced by their GWAS indeed played a role in a plant’s ability to grow and reproduce in a given climate.

“You can actually predict pretty decently changes in the relative fitness of plants just based on the results from our worldwide scan,” Bergelson said. “It didn’t have to work - it was a longshot really - but we were happy to see that it did work.”

But for the future of climate change, the more critical question was how these variants initially appeared in the Arabidopsis genome. For many of the climate-associated variants, the University of Chicago team found evidence of “selective sweeps,” an evolutionary process where a new, favorable mutation appears and spreads rapidly through a species. In the case of Arabidopsis, this finding suggests that the plant adapted to shifts in climate thanks to the random appearance and subsequent spread of these helpful mutations, rather than drawing from pre-existing genetic variation. But in times of rapid climate change, there may not be sufficient time to wait for those genetic changes to occur.

“The key there is that the variant is novel, and so the extent to which a plant or an organism depends on sweeps to adapt to climate means that there is an intrinsic delay,” Bergelson said. “As the climate continues to change, they may not have the standing variation that they would need to adapt. That’s going to slow things down.”

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Biology used to be the scientific discipline where data was at a premium, a rare resource painstakingly collected in the field or the laboratory. But today’s biologists are confronted with a flood of data, a fire-hose torrent of genetic and clinical information that only builds with the spread of fast sequencing and electronic medical records. But as these databases fill terabyte after terabyte of computer storage, the successful transformation of that data into practical information about human biology and disease has lagged behind. Genome-wide association studies (GWAS) have  explained only a small percentage of disease heritability, clinical records remain largely unstudied on a large scale, and the complications created by environmental influences and multi-gene disorders have frustrated scientists.

Into this impasse comes a new multi-institutional project based at the University of Chicago: the Silvio O. Conte Center, funded by a nearly $14 million combination of grants from the National Institute of Mental Health and the Chicago Biomedical Consortium. Led by Andrey Rzhetsky, professor of medicine and human genetics at the Medical Center, the collaboration of 15 scientists from 7 institutions will apply the power of advanced computation and data-mining to the growing tide of data collected about neuropsychiatric disorders. The trick will be to not just focus on one database, be it genetics or environmental factors or clinical outcomes, but all of them at once, creating a higher-resolution image of what goes awry in the brain to cause mental disease.

“A great deal of data already exists, yet nobody is already looking at it the way we plan to do and we have very smart people on this team,” said Rzhetsky, who is also a senior fellow of the Computation Institute at the University of Chicago and Institute for Genomics and Systems Biology. “When you have multiple communities that partially study the same subject you can get a kind of three-dimensional picture of a phenomenon.”

Rzhetsky has previously demonstrated the promise of data-mining - the discovery of patterns and information in large pools of data - using clinical records and scientific literature. In a 2007 study, his team examined 1.5 million patient records and found significant overlap between mental disorders such as schizophrenia, bipolar disorder, and autism, suggesting a similar overlap of the genetic factors that cause these conditions. Two years later, Rzhetsky and colleagues applied text-mining computation to the scientific literature database PubMed, creating a network of genes and biological interactions associated with cerebellar conditions such as ataxia and degeneration.

Beyond demonstrating the potential of data-mining, those studies also shed light on the hazy borders separating different psychiatric disorders. While the overlaps could complicate psychiatric diagnosis in the clinic, they might also make the disorders susceptible to the multi-faceted approach proposed by the Conte Center.

“Most studies are done one disorder at a time, and that’s like studying the trunk or the hoof or the tail of an elephant; you might miss the big picture,” said Benjamin Lahey, Irving B. Harris Professor of epidemiology at the University of Chicago and a co-investigator at the Conte Center. “This project will enable us to look at things in a way that has never been done before, at a scale that dwarfs anything that’s ever been done.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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