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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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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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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The latest cult favorite in the sphere of human genetics is the microbiome, the genes of the bacterial species that live inside and upon the human body. Because bacterial cells outnumber human cells in an adult by approximately ten to one, and tens of thousands of different species make up the human ecosystem, studying this world will be even more of a challenge than the Human Genome Project, which only had to concern itself with a single species: us. But as the microbiome is increasingly discovered to play a role in obesity, diabetes, infant diseases, and hospital-acquired infections, the number of researchers pondering a bacterial angle for their own disease of interest is exploding.

So the microbiome was the ideal topic for the first lecture of the Institute for Translational Medicine seminar series on Advanced Tools, a monthly meeting designed for University of Chicago researchers to share methodological know-how. Leading the discussion was a veteran of the young microbiome scene - Eugene Chang, professor of medicine and an expert on gastroenterology. For several years, Chang has applied the tools of microbiology to the bacterial populations of the human gut, looking for mechanisms involved in digestive diseases. As the techniques for studying the microbiome have evolved, Chang said he has seen the pros and cons of the field’s growth.

“This is an area that is really hot,” Chang said. “It isn’t coincidental that this interest has coincided with emerging technologies, because the emerging technologies over the last decade have allowed us to look at the microbiome in many different ways….but this is a field where you can be easily consumed by the technology.”

Those techniques have changed alongside the trends of the broader field of microbiology, Chang said. Scientists interested in bacteria were once limited to studying what they could both find and grow in a lab dish, which left the vast majority of species unexplored. But new genetic techniques have brought those hidden worlds into the light, allowing scientists to take a more complete census of the bacteria present in a given sample from the Earth’s environment, or the special environments within the human body. With this added power has come a whole new menu of choices for scientists, from low-cost methods (i.e. T-RFLP) that can take a surface-level snapshot of the most common members of a microbial community to deeper sequencing that can identify rare microbes that may turn out to be relevant to disease (i.e. pyrosequencing).

“We have a number of techniques that have advantages and limitations,” Chang said. “What you use is dependent on what your question is and how deep you need to go.”

In Chang’s laboratory, the questions relate to the origins of inflammatory bowel diseases such as ulcerative colitis. A recent study looked at the microbial diversity within the colon, comparing the bacterial populations present in the mucosa of the proximal colon (near the small intestine) to the distal colon (near the anus). A T-RFLP analysis, which looks at fragments of ribosomal DNA in the mucosal samples, found that the microbes present in the two regions were distinct, with higher “richness” (the number of species present) observed in the proximal versus distal colon.

But to determine the role of the microbes in disease, just taking a census isn’t enough. The newest wave of microbiome research is focused on function, using techniques that find out what those billions of bacteria are actually doing inside our bodies or out in the world. With metagenomics, scientists can analyze all the genes from a given sample of soil, skin, or mucus, then group those genes by their functional role (metabolism, transport, etc.) using a technique developed by Argonne called MG-RAST. Many groups, including Chang’s team, are also interested in measuring host-microbe relationships - how the bacterial population affects the biology of their home organism.

“Sure we can say who’s there, but how do we actually know what’s important?,” Chang said.

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The University of Chicago is the birthplace of nuclear energy. So like proud but concerned parents, UChicago has kept a close eye on the benefits and challenges of nuclear power over the years since the first self-sustained nuclear reaction under Stagg Field. Thus, the battle to manage the consequences of the damaged reactors at the Fukushima I Nuclear Power Plant in Japan has drawn the University’s interest, and the short-term and long-term effects of that ongoing situation were the subject of a unique panel held on campus yesterday, “Lessons from Fukushima.”

Though nuclear power was created by scientists, discussing its use requires input from political and economic spheres as well. So the panel, assembled by the University of Chicago Alumni Association, brought together nuclear technologists (Hussein Khalil, director of the nuclear energy division at Argonne National Laboratory, and Mark Peters, deputy director of Argonne), nuclear policy watchdogs (Kennette Benedict, executive director of the UChicago-based Bulletin of Atomic Scientists), and energy economics experts (Robert Topel, director of the University of Chicago Energy Initiative). With such different perspectives, it didn’t take long for the panelists to find points of debate, reflecting the tug-of-war over nuclear power that has gone on for several decades.

Nobody disputed the magnitude of the Fukushima incident, with workers at the plant still struggling to limit core meltdown in at least three of the reactors as well as re-cooling spent fuel rods at the site. As well, the panelists agreed that the incident was very relevant to nuclear power in the United States, where roughly one-fifth of electricity is provided by nuclear plants, many of which use the same model as the Fukushima reactors. But opinions differed on what those consequences would be.

Khalil pointed out that this was the first natural disaster to cause “grave damage” to a nuclear power plant in nearly 60 years of their use, and that a similar occurrence was very unlikely in the United States. But Benedict argued that “very unlikely” wasn’t good enough for “the most dangerous technology on Earth,” and that not every safety precaution possible had been taken at Fukushima. Topel agreed with the latter point - “why build generators on the ocean side in a country that coined the term ‘tsunami’?” he asked - and noted that the renewed attention to the long-term dangers of nuclear power would only make it more difficult to build new reactors.

In fact, no new nuclear reactor has come online in the United States in 32 years, Khalil said. So while Argonne continues to research new designs for nuclear plants and new strategies for containing nuclear waste, the economic (and possibly now public opinion) barriers are too large. The most likely rescue for nuclear power may come from an unlikely source: climate change.

“If other technologies turn out to be a bust, and if we really are serious about reducing our carbon footprint and carbon pricing becomes important, then there is a technology we have that can produce a lot of energy at relatively low cost compared to the alternatives,” Topel said. “Then, nuclear energy will prosper.”

By the end of the 90-minute discussion, the panelists came back to common ground on a hopeful note. If a thin silver lining could be found on a disaster that hasn’t yet been completely averted, it’s that the events at Fukushima have re-opened the international dialogue on nuclear power - its immense benefits and equally immense costs.

“One of the positive externalities of the Fukushima accident is that many more people are interested in nuclear energy, and I think that’s terrific,” Benedict said. “It’s unfortunate that it takes an accident to do it.”

Elsewhere…

The conversation about cancer is changing, from a single disease classified by the organ where it appears to multiple diseases grouped by genetic and biological similarities. As ScienceLife has written before, the Chicago Cancer Genome Project is our local contribution to this strategic shift against “the emperor of all maladies.” This week the Los Angeles Times examined that research effort and others like it, speaking with project leader Kevin White and many of the Medical Center’s cancer experts collaborating on this new vision of how to classify and battle cancer.

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Since the time of Linnaeus, scientists have loved classifying the world around them. But while centuries of biologists have worked to collect and categorize the plants and animals of Earth, all that work likely only covers about a minute fraction of our planet’s life. As much as 99 percent of the biodiversity on Earth is smaller than 2 microns - bacteria, viruses, and tiny eukaryotes - and most of these remain to be discovered by humans. There are more microbial cells on earth (1 nonillion, or 1×10^30) than there are stars in the sky, and all of this new life exists in soil, in seawater, and inside animals, plants, and even us.

“You are mostly microbes,” Jack Gilbert told the Institute for Genomics and Systems Biology in a lecture last month. “The world is mostly microbes, and yet we have less of an understanding of how microbes run the universe than we do of the universe itself.”

Gilbert, an assistant professor of evolution and ecology at the University of Chicago, is part of an international project to remedy that shortage of knowledge about the microbial world. The Earth Microbiome Project, a group bringing together scientists from several different institutions, is dedicated to filling in these gaps in the tree of life and, more importantly, figuring out how they may be secretly pulling the strings of Earth’s ecosystems. In his talk, Gilbert rapidly narrated the group’s aims and his own research projects until he ran out of breath, leading an hour-long tour around globe in search of nature’s smallest and most abundant participants.

Classically, microbiology has taken place in cell culture dishes and incubators, as scientists grew bacteria in the laboratory in order to study its identity and function. But the field has benefited greatly in recent years from genetic advances opening up new paths of discovery. As the price of accurately sequencing DNA and its products has exponentially dropped - driven largely by the demand for human genomics - ecologists interested in microbes have borrowed the technology for their own uses. Now, instead of growing bacterial populations in the laboratory, microbiologists can take a genetic sample of whatever environment they wish and use the genes in that sample to reconstruct its microbial denizens. This process is called “metagenomics,” and it is expanding our knowledge of the bacterial world in leaps and bounds, Gilbert said.

“We can take a sample, sequence it, look at the microbial taxa in there, and identify things we couldn’t culture,” Gilbert said. “There are four trillion base pairs of genetic information in a millileter of seawater, in one teaspoon. In a gram of soil, there are about 4 quadrillion base pairs.”

With so much information out there waiting to be discovered, one of the most important questions is where to start. The Earth Microbiome Project is overseeing dozens of projects, each with their own hypotheses and environmental targets. Gilbert outlined just a few: analyzing samples from near the site of the Gulf of Mexico oil spill; comparing soil samples - some as old as 135 years old - from China, France, Australia, and South America; characterizing the microbial communities from the vaginal canals of fertile and infertile pandas in the San Diego Zoo (seriously). Importantly, the procedures used to analyze such widely different samples are being standardized by the project to ensure that comparisons between different research groups and samples are possible.

“The goal of this project is to systematically approach the problem of characterizing microbial life on Earth,” Gilbert said. “We’re reaching a zenith point in our ability to do things individually, and if we want to start generating synthesis of our understandings, we need to start working as a team, as a group, like the physicists do. We want to do the same thing: Come together as a group and say ‘we have a really good idea, a life-changing idea that will change the way we live on this planet, we just need to do it in a systematic and well organized fashion.’”

As a discrete example, Gilbert offered one of his own research projects, conducted before he relocated to Argonne National Laboratory last summer. As senior scientist at Plymouth Marine Laboratory in England, Gilbert and his team studied a section of the English Channel that has been sampled by scientists every week since 1864 - interrupted only by the two World Wars. Since 2000, the team has taken samples suitable for metagenomic analysis, and has methodically characterized what microbes live in this patch of water and how that population changes.

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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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Sen. Dick Durbin tours Argonne National Laboratory with Rick Stevens, Professor of Computer Science (photo courtesy of Argonne)

In Washington, the fight over budget cuts is well underway, as a Republican majority in the House and a Democratic majority in the Senate tussle over the best way to reduce a multi-trillion dollar federal deficit. The first bill of the new House, H.R.1, set federal appropriations for the rest of fiscal year 2011 (ending in September) and snipped $61 billion from the budget, predominantly from discretionary domestic spending. One target of those cuts would be the National Institutes of Health budget, which would lose roughly $1.6 billion of its $32 billion budget for funding scientific research in the United States.

As you might expect, this news was not welcomed by Chicago-area researchers, who turned up in lab coats to support a news conference by Sen. Dick Durbin last Sunday at Northwestern University’s downtown campus. Durbin vowed to fight against the cuts as H.R.1 is discussed in the Senate, saying that interrupting the funding would slow progress toward new treatments for diseases such as AIDS, diabetes, and cancer. (video here)

“When you put these research projects on hold, you can’t ask the laboratory mice to take a nap,” Durbin said. “You can’t ask the cultures to stop growing - we’ll get back to you at the end of the fiscal year. And you can’t expect the professional researchers, the men and women who have dedicated their lives to medical research, to have certainty that next year they’ll have a job.”

Researchers from each of the major Chicago academic hospitals appeared at the conference and talked about how the proposed budget cuts could harm their own projects. Michelle Le Beau, director of the University of Chicago Comprehensive Cancer Center, discussed the biomedical research underway at UChicago thanks to the nearly $300 million in NIH funding received this year and last. Le Beau focused in on her own research examining therapy-related acute myeloid leukemia - a “very cruel and ironic” cancer caused by the chemotherapy and radiation treatment of a prior tumor. Any job losses that follow from NIH cuts could break up the expert team she has formed to study causes and treatment of the disease, she said.

“A lapse in funding will result in dismantling our highly specialized research team, and this leads to a loss of capability, because it takes years to assemble these teams again,” Le Beau said. “These are individuals who have trained for years to apply their extraordinarily unique skills. They have families to support and bills to pay.”

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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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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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The human body is not just an organism, it’s an ecosystem. To the billions of microscopic bacteria, viruses and fungi living in the various nooks and crannies of our intestines, mouth, nose, and other areas, we are the world, the environment that drives their evolution. Though scientists and physicians have long known that humans are housing projects for a wide array of species, research on the clinical impact that microscopic population exerts upon its host is just starting to establish momentum. Many researchers are now exploring links between what’s become known as the “microbiome” and everything from infectious disease to diabetes and obesity to psychiatric disorders.

An official seal of approval was stamped on to these efforts by the National Institutes of Health in 2008, with the announcement of the $157 million “Human Microbiome Project.” Tuesday, the project was given another $42 million bolus of funding, $1.1 million of which went to a team of University of Chicago and Argonne National Laboratory scientists. But research into the microbiome is already yielding interesting results on the world inside your gut, and how it is affected by diet from the very start of life.

The debate over giving babies breast milk or formula has swung like a pendulum since the mid-20th-century, with medical societies now endorsing breastfeeding infants whenever possible. Studies have shown that breastfeeding has advantages in protecting infants from infection and disease and provides essential, easily-digestible nutrients. But what is the biological basis for breast milk’s superiority? Scientists have speculated that it has to do with the effect of diet on the microbes of the gut. In a paper published last month at PLoS ONE, Michael Morowitz, assistant professor of surgery and pediatrics at Comer Children’s Hospital, sought to test that hypothesis with the latest genetic technology.

Morowitz was drawn from surgery to microbiology after witnessing the damage caused by a frightening infant disease: neonatal necrotizing enterocolitis (NEC). Seen often in premature babies, NEC causes intestinal inflammation that can require surgical removal and may lead to lifelong complications or death. As the surgeon on such procedures, Morowitz said he became interested in ongoing research on how to reduce the number of NEC cases.

“You say to yourself, ‘How can you prevent it?’ The literature tells you there aren’t many ways other than supporting breast milk usage,” Morowitz said. Others had proposed a link between breast milk, gut bacteria, and protection against NEC, but until recently the technology did not exist to take a full census of the microbial world, he said.

For the PLoS ONE paper, Morowitz and his team decided to study the effects of breast-milk versus formula on the microbe population in the intestines of piglets. By recording a “transcriptome” - a snapshot of gene expression - from the intestinal fluid of the piglets, Morowitz’s team could detect which bacterial species were present and active in the two groups.

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Last month, we discussed the garage doors of the body’s ion channels, the millions of microscopic machines that control the heart’s beat and the nervous system’s communication. Benoît Roux and his colleagues employed 25 million computational hours to model the potassium channel voltage sensor, a kind of garage door control box that determines when the channel opens its gate. But the metaphor breaks down a bit when the channel is open, as the potassium channel does more than just wait to close again. Instead, there’s an in-between phase that keeps excessive potassium from stampeding through the open gate while the door prepares to close, a state called inactivation.

Determining the mechanism for inactivation has befuddled scientists for the same reason as the voltage sensor: how do you reverse-engineer a biological machine that works at the  nanoscale level, moving less than one-billionth of a meter at a time? One solution is to take pictures of the channel in motion, but doing so in the channel’s native habitat of the cell is beyond current technical means. Scientists have therefore resorted to a method called X-ray crystallography, a trick of chemistry and physics where the atomic structure of a protein can be determined.

X-ray crystallography has been used on potassium channels before - one such experiment even won the Nobel Prize for Chemistry in 2003. But each crystallographic portrait only catches the channel frozen at one particular moment of time, leaving scientists to make (educated) guesses about the movements that take place between each laboriously-obtained picture. The more pictures available, the less guesswork required.

More pictures and better theory are the result of two papers appearing in Nature today from the laboratory of Eduardo Perozo, professor of biochemistry and molecular biology at the University of Chicago Medical Center. Perozo’s group added to the potassium channel crystallography gallery by using a slightly mutated channel to keep the gate locked open and expose the elusive inactivation state to portraiture. From experiments conducted at Argonne National Laboratory, they hoped to get a new snapshot portraying a form of inactivation known as the C-type. But to their surprise and delight, they got 15 slightly different structures for the channel, which were determined to represent sequential stages between the open and inactivated state.

“By sheer luck, we happened to trap the channel in the process of opening, just like a movie,” Perozo said.

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An EEG recording of a seizure.

The electrical symphony of the human brain, with billions of neurons firing at different rates, up to hundreds of times per second, likely looks like chaos to any outside observer. But there are patterns in the ongoing brain activity seen, for instance, on an EEG: slow oscillations, rhythmic coordination, and purposeful ripples of communication. The importance of this intricate harmony is best displayed when it is disrupted by an epileptic seizure, which turns the fascinating complexity of the EEG into an angry scrawl.

You don’t have to be a neurologist to see the difference between a brain’s normal behavior and a seizure, but the causes of those seizures are much less obvious. Current antiepileptic drugs have shown success in treating some forms of epilepsy, but in many cases therapeutic success or failure is poorly understood and positive results are almost accidental - doctors are not entirely sure how medications suppress seizures, but are happy when they do. But for roughly a third of patients with epilepsy, those with intractable epilepsy, there remain no such happy accidents. Understanding what sparks a seizure would provide a rational basis for scientists to develop new drugs to treat the untreatable, as well as to reduce the side-effects of the existing treatments.

“Nothing has moved in the last 20 to 25 years,” said Wim van Drongelen, professor of neurology at the University of Chicago Medical Center. “There have been a lot of new anti-convulsant medications, but that one-third of patients who do not respond to medication has remained the same. My conclusion from that is that apparently all the new medications that have been developed address more or less the same type of epilepsy. In this context, epilepsy is comparable to cancer - there’s not just one type of cancer, and there’s not just one type of epilepsy, there are multiple types.”

To understand the different ways a seizure can form, scientists need a model. Experimentalists have recorded EEGs or used higher-resolution methods such as electrophysiology to measure cellular activity in a slice of animal or human brain tissue (obtained during surgery). But to truly model the brain’s rhythms - both normal and abnormal - requires nothing less than the most powerful computers currently available, a task that van Drongelen’s lab has undertaken.

“It’s a lot easier to do an experiment with a computer model than in a real slice,” van Drongelen said. “In a real slice, you have drugs to affect a certain channel, but these drugs are dirty, they also affect other things. In a model you can really very purely see what the effects are of certain manipulations and components. An additional huge advantage is that this approach gives you simultaneous access to what the population on the whole is doing, and what the individual agents are doing.”

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This is the third day of our coverage of the 2010 BIO International Convention, a massive biotechnology conference being held this week at McCormick Place in Chicago. Come back all day for reports from panels, lectures, and the exhibit floor on how scientists, government leaders, and industry hope to use the combined forces of science and technology to tackle some of the world biggest problems. For the first two days of our coverage, click here and here.

6:00 PM - Biotechnological Patriotism and the Petabye Age

Walking through the elaborate castles erected by countries from Europe, Asia, and South America on the exhibit floor (pictured below), an American might develop some anxiety about their country’s status as undisputed champion of biotechnology. That’s partially an illusion - if all of the kiosks for individual American states and U.S.-based biotech companies were pooled into one giant USA! USA! booth, it would take up the majority of the exhibition. But paranoia that the rest of the world is hot on America’s trail was palpable through the conference, with rumblings of new biotech epicenters in China and India rippling through McCormick Place.

A panel organized by Scientific American this afternoon sought to set some of those fears at bay, and the message was delivered through a persuasive moderator: CNN’s Fareed Zakaria. With his keynote address, Zakaria talked about the economic landscape as the world recovers from a global financial crisis, but said that the real economic story of the last 50 years was not bubbles and recessions, but the broader participation in the world economy. No longer is all the exciting innovation and economic development happening in a few North Atlantic nations, Zakaria said; now even small countries have robust, independent economies and an impact on the global system.

The downside of that phenomenon, for Americans at least, is that we are no longer the one place where the world’s biggest achievements are located. The biggest mall in the world, Zakaria pointed out, is no longer Minneapolis’ Mall of America - it’s the South China Mall in Beijing. The richest man in the world lives in Mexico City. The world’s largest refinery is in India. But the United States can still lay claim to the most highly-respected universities in the world, and the “extraordinary quantity of high quality research” that goes along with that system.

Joined by a panel of biotechnology industry leaders, the reassurance continued. China and India - while several orders of magnitude larger in population than the United States - are too concerned with building infrastructure to pose a near-term threat to American biotech expertise. The American investment system, which rewards creativity and understands that many big ideas fail, remains a model for the world. And as long as United States universities are perceived as the world’s best, they will attract the best students from around the globe to our shores - even if, increasingly, those students return to their home countries to apply their education.

With all those warm feelings, it was a little disheartening to find what I thought would be one of the day’s most engaging research sessions - on applications of computational science to drug discovery - to be also the day’s most sparsely attended. Fascinating, exciting research was presented by scientists from the University of Illinois and Argonne National Laboratory on how the rapid growth of computing power capabilities has made new types of experiments possible.

Emad Tajkhorshid showed animations representing the dynamic wobble of protein interactions, drugs and targets undulating like ocean waves - suggesting that scientists will no longer be constrained by the necessary simplifications of benchtop science. Rick Stevens, from Argonne, talked about grabbing a small soil sample and sequencing every organism within, grabbing potentially thousands of complete genomes - many of them never before seen - at once. As one questioner said, we’ve brought everyone into the genomic age, but the next step will be the petabyte age, an age of previously unfathomable computation enabling the creation of new science. Unfortunately, this afternoon there were few there to witness the new age’s early steps.

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