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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Roughly 30 million Americans suffer from migraines, and as you might expect, there’s a large pharmaceutical market to prevent or stop these debilitating headaches. Drugs such as Imitrex and Verapamil employ different pharmacological modes of action, reducing migraines by adjusting neurotransmitter levels, blocking ion channels, or simulating the body’s natural painkillers. There’s also a less pharmaceutical migraine treatment strategy, recommended by many headache specialists, that follows the old adage: “Active Body, Active Mind.” One recent study even found that 40 minutes of exercise three times a week can be as effective at preventing migraines as popular anti-migraine medications.

Still, prescribing exercise or environmental enrichment (keeping the mind busy through activities such as reading, crossword puzzles, exercise, or socialization) can strike some doctors and patients as frustratingly vague. Understanding the biological mechanism that makes these activities protective against migraines could help convince doctors and patients of their utility, while also giving researchers the opportunity to translate the factors associated with environmental enrichment into highly effective treatments.  In the laboratory of Richard Kraig, William D. Mabie Professor in the Neurosciences at University of Chicago Medicine, that very effort is underway.

“We are interested in environmental enrichment as a way to stop cognitive decline from aging, injury after stroke, Parkinson’s disease, and cell death after seizures.  With our new work, we apply this search for how the brain protects itself against disease to include migraines,” Kraig said.  ”The ‘why’ of it has sometimes been left in the realm of holistic medicine, with little scientific support.  So establishing the hard science makes it more credible to the psychologists, physiologists, physiatrists, because here’s the chemistry.”

Working with graduate students Yelena Grinberg and Aya Pusic as well as senior technician Heidi Mitchell, Kraig discovered three different natural signals elevated by exercise and environmental enrichment: insulin-like growth factor-1 (IGF-1), interleukin-11 (IL-11), and interferon gamma (IFN-γ). When these “cytokines” are applied to brain slices, they reduce the probability of triggering a spreading depression — a transient wave of reduced brain activity associated with migraines. Understanding how those cytokines stop spreading depression — and the nasal route by which they might be delivered — may revolutionize how migraines and other neurological conditions are treated.

A spreading depression of brain is a chain reaction of dramatic events. After an initial burst of increased neuronal activity, a subsequent ripple of absent activity slowly spreads across involved brain at a rate of about 3 mm per minute — lasting a few minutes overall.  While the event sounds brief, the consequences can last from hours to days, causing harmful oxidative stress, elevated inflammatory factors, moving microglia, and significant pain and discomfort for the migraine sufferer.

Paradoxically, the way to stop this chain reaction may not be to simply reduce or block the byproducts of a spreading depression, but to expose the brain to moderate levels of inflammatory factors, which include the cytokines described above. To interrupt the cycle of repeated migraines, treatments could take place before the process begins or in small steps after the recurrent spreading depression that underlies chronic migraine. While these factors may have negative effects in the short-term, in the long-term they prime the neurons to make antioxidants that are protective against oxidative stress.

“Spreading depression increases oxidative stress in a big fashion — it depolarizes all the brain cells. It’s like an engine kicking out a lot of exhaust, and the exhaust makes the brain hyper-excitable,” Kraig said. “But you have to let the engine run. The engine is running with stimuli that include cytokines that are initially irritative, but then adapt to stop spreading depression.”

The trick, Kraig said, is to mimic the natural cycles of cytokine levels the brain would experience during healthy, active behavior, rather than drowning the system in abnormally high concentrations of the factors that can occur with disease. The cytokines would be delivered to the brain in an on/off pattern rather than chronically, theoretically recreating the rise and fall of natural cytokines during a person’s sleep/wake cycle. By giving just a little bit of a factor normally considered harmful, the treatment could strengthen the brain’s resistance to spreading depression and migraines via the principle of hormesis, or “what doesn’t kill me makes me stronger.”

“The treatment is unique in that it’s the opposite of putting a Band-Aid on something,” Grinberg said. “It’s triggering cells to produce their own antioxidants instead of just providing the antioxidants exogenously. In that way it’s really unique and the opposite of how a lot of people think about medical treatment.”

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Cells are often described as factories, and their product is protein. Thousands of different proteins are built by cellular structures called ribosomes, which translate DNA instructions into chains of amino acids. But in a cell, as in industry, manufacturing is only the first part of the story: products must also be shipped to their final destination. Within the cell, that’s often the membrane, the site where many proteins are deposited to perform their functions. Studying these delivery systems - the postal service of the cell - is an important pursuit of cell biologists.

In the last few years, scientists have discovered that there are actually two separate routes to deliver eukaryotic proteins from the ribosome to the endoplasmic reticulum membrane. For most of these proteins, a system discovered in the 1970s known as the co-translational system does the job. But for a certain type of membrane protein, called ‘tail-anchored’ proteins, a specialized delivery pathway exists - call it the UPS to the rest of the cell’s postal service.

The laboratories of Robert Keenan at the University of Chicago and Ramanujan Hegde of the Medical Research Council in Cambridge have been among the leaders in studying this new pathway, and a paper published today in Nature is the latest and most comprehensive description of its workings.

Tail-anchored proteins make up only 5 percent of the total inventory of membrane proteins, but even that small slice represents hundreds of biologically important products, Keenan said. If you genetically delete one of the components in the trafficking of these proteins to the membrane in mice, it has catastrophic consequences, killing the animal before it is even born.

“These things play all sort of important roles in a variety of different cellular functions,” Keenan said. “If you screw this pathway up, bad things will happen. At that level they are just fundamentally important.”

Previous studies from the Keenan/Hegde collaboration and other laboratories had identified the key components of a tail-anchored protein transport pathway. In yeast, these include a soluble protein called Get3 and two membrane-bound ‘receptor’ proteins, called Get1 and Get2. But until the current paper, nobody had tested whether these three pieces alone were sufficient to ship a protein from ribosome to membrane. To try this, the team (led by postdoctoral researchers Malaiyalam Mariappan and Agnieszka Mateja) created an artificial system that only contained the three Get proteins and a tail-anchored protein for cargo. To their delight, this streamlined system worked, targeting and inserting the proteins in their proper position.

“We have a minimal system, completely purified, that’s only three components plus the substrate,” Keenan said. “Now we can basically do whatever we want. We can make mutants or chemical modifications, and then we can reconstitute the system and ask, does it work? And if it doesn’t work, we can ask where in this process does it actually fail, and why.”

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A large portion of medical research is dedicated to designing and testing new and better drugs for treating disease. But what if we could improve treatments with the drugs we already have - and potentially cut costs at the same time? That’s the proposal made in an editorial this week in the Journal of the American Medical Association written by the Medical Center’s M. Eileen Dolan and Vanderbilt University’s Russell Wilke. Their article, “Genetics and Variable Drug Response,” is an optimistic snapshot of the current state of pharmacogenetics, the use of genetic information to improve the use of pharmaceuticals.

Though individualized or personalized medicine has been a goal of physicians and researchers for several years, the science (as it tends to do) is moving slowly. But as Dolan and Wilke write, promising pharmacogenetics examples are beginning to accumulate, from genes for enzymes found to influence the metabolism of chemotherapy and anti-clotting drugs to genetic variants that predict severe side effects from various agents. Some of these discoveries have already made it to the clinic, such as the genetic test (developed at the University of Chicago by Mark Ratain) for a variant that affects the response to the cancer drug irinotecan. Physicians can use the test to lower the dose in patients found to carry the variant associated with severe side effects at the normal dose.

Dolan and Wilke dream even bigger about pharmacogenetics. Currently, the standard drug dose is set by the average response of a large population, hoping to capture a level where people get the most benefit at the least risk. But as more information about the genetics of drug response are revealed, those doses can be better shaped to each patient according to their own personal risk-benefit. This could bring some drugs deemed “too dangerous” back to common use, if some patients have a genetic profile that enables them to endure the treatment safely.

“For drugs with a narrow therapeutic index, pharmacogenetic studies may hold the potential to resurrect treatments previously withdrawn from the market, particularly for agents designed to fill underserved clinical niches,” they write.

If smarter dosing can truly bring effectiveness up and toxicity down, it would be a benefit to both patients and the health care system in general. One suggestion by the authors is to start building gene-based drug dosing into electronic medical records, creating alerts for doctors about “drug-gene interactions” similar to current alarms for potentially dangerous drug-drug interactions. The future of medication may be more complicated than “take two of these,” but smart implementation may save dollars and lives.

Cohen Video

The American Society of Clinical Oncology recently filmed a short video with Medical Center associate professor of medicine Ezra Cohen, where he talks about how he decided to treat cancer patients while working as a small-town family physician. It’s a nice piece about how doctors are inspired to do their work and the connection between laboratory research and clinical care. If you want to see more videos with Dr. Cohen, he discussed head-and-neck cancer with ScienceLife almost exactly one year ago.

Elsewhere…

Right after his very cool study on the genetic origins of limb development was published, evolutionary biologist Neil Shubin departed for his annual expedition to the Canadian Arctic in search of fossils from the earliest limbed creatures. If you want to follow along with the hunt, Shubin’s teammate (and Tiktaalik co-discoverer) Ted Daeschler is blogging from the dig for the Philadelphia Inquirer! Read about how their remote site on Devon Island is “almost like Mars,” and how the expedition is already finding interesting fossils two days into the trip.

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Anyone with a video game console at home can simulate  a variety of occupations: airplane pilot, race car driver, baseball player, Old West zombie hunter. As technology improves, the experience that can be created for these tasks grows ever more accurate and immersive, causing some experts to wonder whether simulation can be used for actual education as well as vicarious thrills. In the aeronautics field, this is old news - pilots have been trained on flight simulators for decades, gaining experience on high-risk, low-frequency tasks such as landing a damaged plane on a river. But in medicine, the use of simulation has only started picking up speed in the last decade, employing a mix of high-tech and low-tech to prepare doctors and nurses for both the usual and unusual.

In their Department of Medicine Grand Rounds presentation last week, Ernest Wang and Morris Kharasch from our partners at NorthShore University HealthSystem described the current state of simulation in medicine on the eve of their state-of-the-art simulation center’s grand opening. But while the idea might sound modern, it’s actually been around for more than 40 years, as Wang illustrated using a clip from the 1972 film Future Shock, narrated by Orson Welles.

Welles’ portentous warnings were a bit premature, it turned out. Never mind the leap from medical simulation dummy to humanoid robot, a generation would pass from when the first dummies were engineered in the late 1960’s before the broader field would accept simulators as a valid training tool for doctors.

“It looked pretty much what our current high-fidelity simulators look like, but didn’t have traction,” said Wang, a clinical associate professor at NorthShore. “There’s a Chinese saying: ‘When the student is ready the teacher will appear,’ and clearly they were too far ahead of their time and the conditions weren’t right.”

However, since 2000 the use of simulation in medicine has gathered momentum. A wide range of technologies are currently used for teaching sessions, from complex simulation environments that fully recreate the experience of being in an operating room to computer programs and table-top gadgets that rehearse medical decision-making and the performance of specific tasks. Medical simulation has grown to the point where a new specialty - the simulationist - may need to be created, Wang said.

“This would be a practitioner of simulation, who takes a recipe of clinically important cases, lessons learned from other industries, computer-driven full body simulators, realistic task trainers, and a dash of theater, to create a memorable learning experience that can be transferred directly to patient care,” Wang said. “In the end, that’s what this is about: education and patient care.”

Winning acceptance for medical simulation involves proving its success and determining its most effective uses. At the NorthShore center, educators have focused on designing simulation courses around “high-liability, low-frequency” events, said Kharasch, clinical director of the Center for Simulation Technology & Academic Research. The students in these courses might be residents encountering these situations for the first time, or older doctors who need a refresher on tasks they haven’t performed in many years before serving as an attending on the wards or in the emergency room.

“We’ve learned that as the years go on after you come out of residency, you are less able to do things that you once did as residents,” Kharasch said. “We spend a lot of time training on simple tasks that can be life-saving.”

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An enzyme from three different species is compared, with structural "flaws" shown in green. (From Fernández & Lynch, Nature, 2011)

One common misconception about evolution is that it produces “better” organisms with time - a seductive opinion to humans who would like to think of themselves as the pinnacle of natural selection. In a way, it’s an easy error to make, for who would look at a single-celled bacterium next to a human and think that the four billion years of evolution between the two species hadn’t produced some improvements? But when Ariel Fernández and Michael Lynch compared the proteins that bacteria and humans share, they found that the unicellular organisms held a surprising advantage. Though the overall shape of the proteins were the same, the human proteins were leakier, more vulnerable to the destabilizing effects of water than those of the bacteria.

But according to the paper published yesterday by Fernández and Lynch in Nature, those protein flaws may have been the key spark that led to the evolution of complex organisms.

“We hate to hear that our structures are actually lousier,” said Fernández, a visiting scholar at the University of Chicago and senior researcher at the Mathematics Institute of Argentina (IAM) in Buenos Aires . “But that has a good side to it. Because they are lousier, they are more likely to participate in complexes, and we have a much better chance of achieving more sophisticated function through teamwork. Instead of being a loner, the protein is a team player.”

The engineering advantage of bacteria over humans boils down to one simple fact: they will always far outnumber us. Billions of bacterial organisms can fit into a single Petri dish, and in a single human body there are over 100 times more bacterial cells than there are humans on Earth . When a genetic mutation with a negative effect pops into existence in these huge populations, natural selection quickly disposes of it, preserving the integrity of the protein that gene encodes. But when a mildly negative mutation appears in a relatively small population, such as that of humans or elephants or pine trees, selection is less efficient and the mutation may spread - a phenomenon called genetic drift.

The direct effect of these mild mutations would be to introduce minor flaws into the structure of proteins. If the change in protein function was too severe, it would cease to function and likely kill the organism. But if the change was just a small nick in the armor of the protein, making it chemically more vulnerable to water, the mutation might stick around long enough to be passed on to offspring. That theory informed Fernández and Lynch’s hypothesis: proteins from species with small population sizes would contain more of these flaws than those from species with large populations.

Their idea was proven true: compare the same protein between, say, humans, flatworms, and bacteria, and you’ll find a descending frequency of protein flaws. Even within a single species, the difference can be measured. Some bacteria have both endosymbiotic populations that live inside other organisms and larger, free-living populations, and the proteins from the endosymbiotes were found to contain more structural errors than their free-living peers.

But the exciting part is what happens after those errors accumulate. read more

Late last year, we relayed the announcement of an exciting new academic program here at the University of Chicago, the Institute of Molecular Engineering. At the time, the IME had a future home (sharing the new William Eckhardt Research Center with the Physical Sciences Division) and a vision, but did not yet have a leader. Yesterday, that crucial headpiece was officially put in place, as biomolecular engineering and nanotechnology expert Matthew Tirrell was named the first Pritzker Director of the IME.

Tirrell will come to UChicago from California, where he has spent time at the University of California campuses in Berkeley and Santa Barbara over the last 12 years. His research specialty is the surface properties of polymers, chains of molecules that can be manipulated for building better materials used for everything from energy to technology to medicine. Those versatile aspirations make Tirrell the perfect leader for the IME, where the mission is to bridge disciplines at UChicago and Argonne National Laboratory and bring the tools of biology, chemistry, engineering, and physics to bear on finding solutions to some of science’s most important challenges.

“This isn’t going to be directed narrowly toward one scientific discipline, but at creating an institute that attacks societal problems from a technological viewpoint,” he said in the official announcement. “Many important societal problems in energy or health care or the environment can be addressed by new molecular-level science. When you are trying to solve problems, you need people from different kinds of disciplines. That’s something the Institute for Molecular Engineering can create right from the beginning.”

In his nearly 300 scientific publications, Tirrell has often studied and discussed how the surface properties of polymers are important for the success of biomaterials. Materials “communicate” with their surroundings through their surfaces, and designing new synthetic devices for technological uses requires a firm grasp on this process. As a result, bioengineers have taken inspiration from how natural materials such as mollusk shells and animal tissue solve surface compatibility problems to understand these interactions on a molecular level.

One application of that accumulated knowledge about biomaterials is novel solutions to clinical problems. In a phone interview Monday with ScienceLife about the biomedical goals of the IME, Tirrell talked about how these new technologies will not be merely passive construction materials, but active biological compounds.

“There are going to be ways of using biology not only to make things but also to do things,” Tirrell said. “Therapeutic organisms can be engineered with the tools of modern biology: living devices, if you will, as well as man-made devices.”

One example from Tirrell’s own research career expands upon designing living machines as a sort of multi-functional Swiss Army knife for diagnosing and treating diseases such as cancer and cardiovascular disease. A 2009 paper, published in Proceedings of the National Academy of Sciences, used a self-assembling lipid sphere called a micelle (pictured at right) to target the fatty plaques that form in blood vessels during atherosclerosis. When those plaques rupture, dangerous clots can form and  block blood vessels. To treat those clots, physicians currently prescribe blood thinning drugs that can produce unwelcome side effects, because the drug is not specifically targeted to the clot and acts throughout the body.

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photo by Cheryl Reed

A quick round-up of science around the web to end a busy, snowy week:

The “facepalm” has become a popular piece of the internet lexicon, alongside peers such as “epic fail” and “OMG.” But, as Ed Yong writes at Not Exactly Rocket Science, humans aren’t the only ones who make the universal expression of disgust and embarrassment. A group of Mandrill monkeys in an English zoo have started to make the expression. However, he writes, they may be signaling something different than facepalming humans: “Why are they doing it? It’s unlikely that they’ve found something stupid on the Internet.”

Jerry Coyne posts another example of purportedly human behavior observed in animals with the green heron - a bird that not only has a crazy expandable neck, but also has been filmed “fishing” by using a piece of bread as bait (yes, there is video). A webpage he links to at Tufts University contains a few other examples of bird tool use.

Earlier this week, in discussing his study on sleep and child obesity, David Gozal theorized that the modern family structure of two working parents has disturbed sleep routines for adults and children alike. Another study, released this week, appears to support that hypothesis, as a team including Ariel Kalil of the Harris School for Public Policy found an association between working mothers and their children’s body-mass index. Lead author Taryn Morrissey of American University stressed to Time magazine that the study is not meant to bash working moms, but rather to remind busy families about the importance of maintaining sleep schedules.”If all moms were to leave the workforce tomorrow, it wouldn’t solve childhood obesity,” she says.

With the Super Bowl coming up this weekend, allow us to point you back to a post written last year at the start of the World Cup about heart attacks in sports fans while watching important games. Some new research has come out in time for this year’s Big Game, including a study of LA fans during the 1980 and 1984 Super Bowls profiled by Ferris Jabr at New Scientist.

When you’re a hospital, you can’t call a snow day. If you’re curious as to how the Medical Center handled this week’s third-snowiest Chicago blizzard ever, here’s your answer: a lot of cots, and free lunch.

University of Chicago chemistry post-doc Niels Holton-Andersen views evolution as a “beautiful, amazingly huge experiment” that has produced elegant solutions to biological problems. His latest discovery is a self-healing, powerful adhesive produced by mussels, published last week in the Proceedings of the National Academy of Sciences. Mussels secrete the substance to stick to rocks in rivers and lakes, and researchers found that tweaking the pH of the adhesive can turn it into a self-healing gel, “kind of like Silly Putty,” Holton-Anderson said. The potential of the discovery was covered by “Green movement” blog Tainted Green.

ScienceLife ran 219 posts in 2010, and choosing the best of them is as hard as picking a favorite gene.  So here’s a month-by-month scan of a busy year at the University of Chicago Medical Center, full of exciting discoveries in the laboratory and the clinic. The impact of some of this research is already being felt by patients receiving improved, evidence-based medical care. For other studies, the clinical benefit may be years in the future, and may take unpredictable forms. As a closing message for 2010, we’ll re-quote the recently departed Eugene Goldwasser, whose laboratory research isolating and purifying the hormone erythropoietin has helped millions of people worldwide.

“It is a particularly impressive example of how basic research can pay a dividend that could not be anticipated at the start,” Goldwasser wrote about his life’s work, “and it is a pity that the lesson still has not been learned by those who control public funding of science.”

January: Tong Chuan-He looked at how cancer may result from cells who don’t want to grow up. Scientists studied how sleep affects the language learning skills of starlings (with painstakingly acquired video of the experiment!). Richard Jones combined two laboratory staples - Western blots and DNA micro-arrays - to develop a new method for studying protein networks. While physicians such as Tammy Utset treat patients with lupus, UChicago scientists are looking for the genetic origins of the autoimmune disorder.

February: Many Medical Center employees returned from volunteering with relief efforts in Haiti, and we filmed video interviews with Rex Haydon, Tiffany Cupp, Richard Cook, and Dima Awad on their experiences. Most of the human genome is “junk” between protein-encoding regions, but Marcelo Nobrega developed a way to find important regulatory elements in that genetic sea. Like birds, human learning can be affected by sleep, and Leila Kheirandish-Gozal reported on the impact of obstructive sleep apnea upon learning in children. Can a single protein in the brain create behaviors associated with drug addiction in rats?

March: Everyone knows air travel is stressful, but did you know that eastbound flights cause stronger cortisol changes than westbound trips? The laboratory of Milan Mrksich found a way to direct stem cells to form fat or bone by shaping them into stars or flowers, a brilliant example of bioengineering. Computational neuroscientists discovered how touch is like vision in the brain, knowledge that could be used to someday re-engineer Luke Skywalker’s robot hand. Dartmouth president and Partners in Health co-founder Jim Yong Kim visited to talk about a new, needed area of research: health care delivery.

April: Researchers at the Field Museum and the University of Chicago teamed up for the Emerging Pathogens Project, an effort to find new viruses in animals before they jump to humans. Cardiologist Martin Burke tested out a new type of internal defibrillator device that can go under the skin, instead of into the heart (the clinical trial, reported in May, was a success). In a lecture to the MacLean Center of Clinical Medical Ethics, transplant surgeon J. Michael Millis described his efforts to bring American organ transplant practices to China.

May: A trial testing the erectile dysfunction drug Viagra for a rare, untreatable lung disease failed, but pulmonologist Imre Noth found a silver lining. Lauren Sallan and Michael Coates uncovered evidence of a previously unappreciated mass extinction event 360 million years ago that changed the path of life on Earth. Researchers from the University of Chicago and around the world presented science at the frontier of biotechnology at the annual BIO conference.

June: In a study that is literally the size of an entire country, epidemiologist Habibul Ahsan measured the toll of a tragic, accidental exposure of millions to arsenic in Bangladesh. Putting a gene from fireflies into the pancreas of mice isn’t mad science, it’s an imaging tool that will help study cures for diabetes. Epigenetics, the modifications that turn genes on and off, took off in 2010, and cardiologists Stephen Archer and Jalees Rehman linked one epigenetic factor to pulmonary artery hypertension.

July: Scientists don’t often get to see the fruits of their research in the flesh, but the Celebrating the Miracles gathering of diabetic children weaned off injected insulin thanks to genetic research was a moving exception (video of the event can also be viewed). Another hot topic in science and medicine this year was the use of computational analysis to sift through rapidly accumulating data, topics explored by Gary An and Andrey Rzhetsky. Or you can build a computer model of a brain network to study the dynamics of epilepsy, like neurologist Wim van Drongelen.

August: Air pollution is a problem indoors as well as outdoors in developing countries where dung and firewood are used to cook food - a problem being tackled in a project led by Sola Olopade. A study of the hormonal changes induced by a stressful test revealed a surprising protective effect of marriage and long relationships. Microbiologist Olaf Schneewind’s laboratory developed two new strategies against MRSA, the most-wanted cause of hospital-acquired infections.

September: To study multiple sclerosis, neurologist Brian Popko’ s laboratory developed a new mouse model that can replicate the disease, then spontaneously recover. Meanwhile, a new drug to treat MS, originally isolated from fungus found in wasps, was approved by the FDA and is being studied for broader uses at the Medical Center. The micro-organisms that live in humans were analyzed as part of a “microbiome” study looking at the protective effects of breast-feeding against a intestinal disease.

October: Common wisdom on quitting smoking says to stay away from cigarette-associated cues, but research from psychiatrist Harriet de Wit’s laboratory revealed that abstinence could make craving even worse. A study of how getting a good night’s rest affects dieting results suggested that “sleeping off the pounds” isn’t merely a fantasy. Graduate student Daniel Matute solved a 100-year-old riddle about how quickly new species become reproductively incompatible with each other.

November: In perhaps our favorite study of the year, geneticist George Perry found a way to acquire the genomic information of endangered species from…poop. The evolutionary biologist Leigh Van Valen passed away, but his Lewis Caroll-inspired Red Queen Hypothesis lives on. Sometimes statistics don’t tell the whole truth, as in the curious case of the aspirin paradox - why the cardio-protective drug may actually predict worse outcomes after heart attack.

December: Evolution textbooks may need a rewrite after geneticist Manyuan Long’s laboratory discovered that new genes can be just as essential as old genes. A study by neurobiologist Nicholas Hatsopoulos proved that the only thing better than a thought-controlled device is a thought-controlled device equipped with a robot arm. Ripped from the headlines: microbiologist Jack Miller weighed in on the hype over arsenic-based bacteria, and ethicist/physician/friar Daniel Sulmasy discussed the Presidential Bioethics Commission’s report on synthetic biology.

All told, it was a great year of science and medicine. Let’s do it again in 2011! Regular posting will resume Jan. 3rd. Happy Holidays.

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

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

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

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

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

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

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

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The bacteria that started it all.

When scientist/entrepreneur J. Craig Venter announced that his company had created “synthetic life” in March, a predictable tsunami of media hype followed. Though the discovery was more accurately an important step in synthetic biology, rather than the creation of life from scratch in a laboratory, the story provoked rampant speculation about what this new field might be capable of. Interest in the promise and dangers of synthetic biology went up to the very top - the White House, where President Obama ordered his Presidential Commission for the Study of Bioethical Issues to look at this new science as their first item of business.

Today, seven months later, the commission’s report [pdf] is being released, with recommendations on what the federal government should do - and not do - about the growing field of synthetic biology. Our own Daniel Sulmasy, professor of medicine and ethics at the University of Chicago Medical Center and the Divinity School, is one of 13 members of the commission, and was kind enough to walk ScienceLife through the highlights of the report. The over-arching theme is one of “prudent vigilance,” Sulmasy said.

“We rejected the position that progress is so good, let’s just forget about any kind of regulation,” Sulmasy said. “But we also rejected the very cautious ‘precautionary principle,’ that says until something is proven safe we shouldn’t do it. I think that would cripple scientists and the potential of progress here that may be of significant benefit.”

Someday, synthetic organisms may provide renewable fuel sources, efficient vaccines, new ways of fighting pollution, and improved agriculture. While those applications are a long way off, Sulmasy said now was the right time for the commission to start a conversation about the ethics of such scientific breakthroughs, even if it is decades before they come to fruition. There’s a danger in being too early, he said: ethicists discussed the possibility of cloning organisms as early as the 1970’s, yet those discussions were largely unacknowledged, leaving policymakers unprepared for the ramifications of Dolly the Sheep in 1997. But open the ethical conversation too late, and it’s “like trying to put the cat back in the bag,” Sulmasy said.

“I hope that we can take a look early enough that we can have the ethical debate before the science is being done in widespread fashion and it’s impossible to regulate,” Sulmasy said.

Still, not knowing where synthetic biology may lead left the commission in a tough spot. Of the 18 recommendations listed in their report, the majority suggest using public funding organizations such as the National Institutes of Health, the Department of Energy, and NASA to share lifeguard duties over the field, without proscribing any specific restrictions. The agencies should fund promising research projects in synthetic biology, the report says, and make sure that adequate testing is done before the products of thatresearch are released beyond the laboratory.

Keeping scientists at academic institutions and private research companies in line should be possible under this structure, but the report identifies a newer, less predictable group of experimenters: DIY scientists. Shrinking costs of genome sequencing and scientific tools have led to a community of hobbyists doing synthetic biology research at home, Sulmasy said.

“There already is a lot of regulation and oversight on the academic and industrial side, so we didn’t think there was a need to create an independent commission or mechanism for assuring the safety of this work there,” Sulmasy said. “Where we did discover a gap is in a small number of people who are doing this kind of work at home and are very intrigued by it. For those who fall outside of the usual communities, we want to bring them into the fold without causing resistance.”

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(image from comics.org)

In Iron Man, Tony Stark engineers himself a robotic suit of armor that serves two purposes, fighting against the terrorists who took him captive while keeping pieces of shrapnel from puncturing his heart. Based on a new study from a University of Chicago neuroscience laboratory, wearable robots like Iron Man’s suit may also serve a dual purpose for a different type of user: quadriplegic patients.

Scientists, in an effort worthy of comic books, have successfully developed brain-machine interfaces that allow people to move computer cursors and prosthetic arms with their thoughts alone. When paralysis occurs due to a spinal cord injury or neurological disease, signals from the brain fail to reach the muscles of the body. But the brain electrical activity normally responsible for movement remains intact, and brain-machine interfaces (BMIs) seek to translate that information into the operation of an external device. One such BMI, called BrainGate, was successfully tested in quadriplegic patients 4 years ago.

However, while those patients were able to hit various computer targets and even type e-mails with their thoughts, their control of the cursor was somewhat shaky. When a person moves a computer cursor the old-fashioned way - with their hand on a mouse - information moves in two directions. Signals from the brain travel to the hand directing the movement, and sensory feedback goes back to the brain reporting on the movement’s success, both from the eyes tracking the cursor and from the location and movement of the hand in space. This latter sense, called proprioception or kinesthetic feedback, was not present in BrainGate trials; the patients’ had only visual feedback to help adjust their movement.

“In the early days when we were doing this, we didn’t even consider sensory feedback as an important component of the system,” said Nicholas Hatsopoulos, professor and chair of computational neuroscience at the University of Chicago. “We really thought it was just one-way: signals were coming from the brain, and then out to control the limb. It’s only more recently that the community has really realized that there is this loop with feedback coming back.”

To test whether adding proprioception back in would improve the performance of a BMI, Aaron Suminski and Dennis Tkach added an additional component to the BMI set-up: an exoskeletal robot arm worn like a sleeve by the subject. Monkeys trained to move a computer cursor without moving their limbs wore the robot arm, which was programmed to move in tandem with the cursor’s movement. So while the monkeys operated the cursor with only their thoughts, the arm responded to the motion and provided kinesthetic feedback to the brain.

With this additional sensory information, use of the BMI improved. As reported in the The Journal of Neuroscience, the monkeys moved their cursors to the targets faster and on a straighter line than in trials without the robot arm providing feedback. The effect could also be seen directly in the brain, where activity in the motor cortex contained more information with the robot arm than without, demonstrated by an improved signal-to-noise ratio.

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Artist's rendering of the new Eckhardt Center (Courtesy of HOK/JCDA/AJSNY)

Today, the University of Chicago announced plans to construct the William Eckhardt Research Center, an innovative new building along Ellis Avenue that will be home to many researchers in the physical sciences.

But just as newsworthy as the new building is one of its prominent tenants: the Institute for Molecular Engineering, the largest new department launched at the University since the Harris School of Public Policy in 1988. The Institute, called the IME for short, will serve as a bridge between the Physical Sciences Division and the Biological Sciences Division for shared goals in research and education.

But what exactly is molecular engineering? The specific mission of the IME will be set next year when a director is named, but the general direction of this exciting new discipline was summarized last year by a faculty committee appointed to evaluate the IME’s creation. ScienceLife talked to a few of those committee members to learn about what molecular engineering is, what kinds of problems it might solve, and what kind of students it will create.

Biology and medicine is increasingly focused on how small scale interactions are important for both normal function and disease. Simultaneously, engineers grounded in physics and chemistry are looking toward biological systems for ideas and solutions. Increasingly, physical and biological sciences are speaking the same language, said Raphael Lee, Paul and Ailene Russell Professor of Surgery, Medicine, and Organismal Biology & Anatomy.

“On the molecular scale, behavior is described by laws of physics and chemistry,” Lee said “The rules of biology and physics are identical at the molecule scale. That’s where the fields boundaries blur and overlap.”

At this common ground, molecular engineering provides a skill set for the next generation of scientists to address the world’s biggest problems. The knowledge gathered through basic science in biology, chemistry, and physics laboratories can be combined and applied to major issues, such as providing clean water to undeveloped countries, or developing more efficient energy sources.

“This is making the science much more applied: we know how it works, so let’s try to make it better. How do we apply that knowledge to these problems that we see,” said Erin Adams, Assistant Professor of Biochemistry and Molecular Biophysics.

Molecular engineering innovation may also lead to the development of new technologies for medical care. Scaffolds for stem cell treatment might be designed through engineering, chemistry, and biology collaboration. Animals that have evolved natural self-healing abilities could inform the design of materials that repair themselves, which could in turn be used for the design of industrial products and medical devices.

“I think it’s entirely possible that new kinds of tools could be generated in molecular engineering that would have therapeutic implications,” said Julian Solway, Professor of Medicine and Pediatrics. “The problems that we’re addressing are the same problems, and the solutions that we want to find are well-suited to be approached by both camps.”

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Genomic sequencing has made incredible strides in recent years, with both the cost and the time required to sequence an individual’s entire DNA sequence dropping meteorically. Yet one rate-limiting step for securing an organism’s genome remains: in order to sequence a species’ genetic information, you need a sample to start with. In humans or laboratory animals, a sample of blood or tissue is easily obtained. But what if a scientist wants to do a genomic study on an endangered species population, in the wild, without having to “trap 0r dart” a number of the animals to take blood samples?

George Perry, a genetics researcher at the University of Chicago, pondered this dilemma in planning his own research on endangered lemurs in Madagascar. In discussions with colleagues, he considered whether a “non-invasive” sampling technique might be possible for the collection of genomic data useful for conservationists and evolutionary biologists. The process led him to an unorthodox idea.

“We started thinking, ‘Is there a way to use fecal samples but to still do genomics work?’,” said Perry, a postdoctoral researcher in the laboratory of Yoav Gilad. “Then everyone would have the flexibility to collect population genomics data from any species at any time, as long as you can collect poop.”

Believe it or not, the collection of genetic data from feces has a long scientific history. Alongside the unwanted parts of an organism’s diet, solid waste contains a small number of cells stripped from the lining of the organism’s digestive system. Scientists have extracted small segments of DNA from those cells for study, mostly from the intracellular structures called mitochondria, which have their own genes. But more extensive genetic mapping of nuclear DNA from fecal samples has been thwarted by another of its ingredients: bacteria. The dominance of bacteria over host DNA inside the digestive system carries over to its product, where an organism produces less than 2% of the DNA deposited in its droppings.

To apply the awesome power of next-generation sequencing technology to a fecal sample, the DNA you want has to be separated from all that DNA you don’t want. Perry decided to modify an existing technique known as DNA capture (which has also been used to sequence Neanderthal DNA), to accomplish this task. With DNA capture, custom-made RNA sequences are used as bait to fish specific stretches of DNA out of a mixture; metallic beads are attached to the RNA sequences, and a magnet separates out the target DNA from the unwanted material. Perry boosted the specificity of this model, incorporating extra washes and two separate rounds of DNA capture, to turn his lower-quality fecal sample into starting material sufficient for sequencing. In part, that means starting with a lot more DNA that typically used for DNA capture, which means starting with roughly 2 grams of poop from each animal. Fortunately, it’s an abundant resource.

“It’s not that you can only study rhinoceros because they have huge poop,” Perry said.

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Photo by John Amend/Cornell

I’ve always been fascinated with the rock solid bags of coffee bought at the store, which have all the density of a brick until opened, when they crumble into scoopable grounds. Turns out that’s a physical concept at work, known as “jamming transition,” when separate, particulate materials are pushed so close together they act like a solid structure. It turns out jamming transitions are useful for more than just compact packaging, but can also help solve a persistent, basic problem in robotics: how can you make a robot “hand” as good as the human hand at picking up objects?

An answer was published this week in the Proceedings of the National Academy of Sciences by researchers from the University of Chicago, Cornell University, and private company iRobot. The scientists created a finger-free “universal robot gripper” by filling a balloon-like elastic bag with particulate material - such as, yes, coffee grounds - pressing the bag down on to the object, then removing the air from the bag, triggering the jamming transition and creating a perfectly shaped, tight hold. There’s video below, demonstrating some of the objects and functions the device can be used for. But when will they be installed in prize claw machines?

[Coverage from Engadget, Gizmodo, and Wired]

Resurrection of the Beagle

The HMS Beagle was the Royal Navy ship that transported a very special passenger, a naturalist named Charles Darwin, around the world in 1831. What’s left of the ship may currently lie at the bottom of a marsh, but the name has lived on as a favorite for ambitious science projects. First, the Beagle name was attached to the Mars space probe Beagle 2, and now it has been affixed to the University of Chicago Computation Institute’s newest toy: a 150-teraflop supercomputer, one of the 50 fastest supercomputers in the world. Housed at Argonne National Laboratory, this Beagle will sail the seas of data produced by researchers in physics, biology, and medicine.

As discussed previously on ScienceLife, the next wave of science will be less about collecting data and more about actually doing constructive things with it. The Beagle’s maiden voyages will be to help projects such as the Membrane Protein Structural Dynamics Consortium, the UChicago-led effort to study the shape and function of cellular machines. Other immediate uses may be for genomics projects, where scientists have struggled to keep up with analysis of the data created by cheaper and cheaper gene sequencing technology. In the Beagle’s announcement, Conrad Gilliam, UChicago’s dean of research for the biological sciences division, looks forward to a time when electronic medical records provide valuable data for the development of more effective treatments.

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