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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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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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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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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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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This past week has been Nobel Prize week, and while none of the winners so far have had a University of Chicago connection (unlike last year’s trio), it’s still good fun for science spectators. Trying to divine a common theme from all of a year’s winners is probably futile - the selection process at the Royal Swedish Academy of Sciences is still pretty mysterious, and doesn’t seem to follow any consistent logic in the laureates it spits out. This year, the Thomson Reuters predictions - considered by many to be the best - have produced an ohfer so far, despite throwing out anywhere from 4-7 names for each of the prizes. The 2010 list is typically scattershot, with a mix of established science and science with yet unrealized potential; the only theme I can pick up is “non-American.”

Medicine: Occasionally, the Nobel committee is accused of waiting too long to award a prize. This year’s award in physiology or medicine, awarded to British scientist Robert G. Edwards for his work on in vitro fertilization, may fit that charge. The first baby produced by IVF procedures developed by Edwards and colleague Patrick Steptoe was born more than 30 years ago, on July 25, 1978. Since then, over 4 million “test tube babies” have been born to parents who would not otherwise have been able to have children. It’s kind of amazing, then, that the leaders of IVF had not previously been awarded the Nobel Prize - and sadly, Steptoe did not live to receive the honors, having died in 1988 (Nobel rules forbid posthumous awards). According to media reports, Edwards himself is in poor health and was unable to grant interviews about winning the award. Of course, the Vatican had its own criticisms of the winners.

Physics: Rather than rewarding a scientific discovery several decades after the fact, this award was given to science that, according to many experts, hasn’t yet ripened. Russian scientists Andre Geim and Konstantin Novoselov were recognized for the development of graphene, an extremely thin and extremely strong material thought to be useful in everything from solar panels to satellites. The emphasis is on “thought to be,” because the material was only discovered in 2004, and has yet to be incorporated into a commercially available product. Interestingly, the main gripe here was that it may have been more appropriate for the chemistry Nobel rather than the physics prize. Geim also notably becomes the first scientist to win both the Nobel Prize and its illegitimate brother, the Ig Nobel Prize, which he won for his research on levitating frogs.

Chemistry: If this were a fairytale, this prize would seem to be not too stale, not too fresh, but just right. Richard Heck, Ei-ichi Negishi, and Akira Suzuki each have an organic chemistry reaction that bears their name, and are considered to have laid important early groundwork for the burgeoning field of molecular engineering. The trio invented and refined the art of “palladium-catalyzed cross-coupling,” which finds a way to stick formerly contact-shy carbon atoms together. While the process is not exactly a household name, its impact is felt in medicine cabinets around the world. “Cross-coupling methods are now used in all facets of organic synthesis, but nowhere more so than in the pharmaceutical industry, where they are used on a daily basis by nearly every practicing medicinal chemist,” organic chemist Eric Jacobsen told ScienceNOW.

Elsewhere…

In the same issue of Archives of General Psychiatry where Daniel Le Grange’s study of family-based anorexia treatment was published, another Medical Center study probed the link between ADHD and teenage suicide. A study of 125 children diagnosed with attention deficit hyperactivity disorder between 4 and 6 years of age were three times as likely to attempt suicide between ages 9 and 18, compared to a control group of non-ADHD children. “The importance of this study is simply that it confirms that ADHD in children is not something to take lightly,” lead author Benjamin Lahey, professor of epidemiology, told WebMD.

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(flickr photo by kjten22)

Brain tumors are some of the hardest cancers to treat - unresponsive to treatment, difficult to access surgically, and quick to grow. Surgery, radiation, and chemotherapy drugs may all be enlisted to fight off a malignant glioma, but still the prognosis is often measured in months, according to Maciej Lesniak, associate professor of surgery and director of the Brain Tumor Center at the University of Chicago Medical Center. That creates a demand for inventive thinking about creative strategies to target tumor cells and extend the life of patients with brain cancer, Lesniak said.

“There have been advances in new therapies, but they haven’t been significant enough to make a tremendous difference in terms of extending the life of patients,” Lesniak said. “That puts you in a situation where due to the desperation, you start to look at novel, exciting and potentially interesting ways of developing new therapies for an incurable disease.”

Creative strategies such as really, really tiny magnetic golden pancakes.

Scientists from the Center for Nanoscale Materials and the Material Sciences Division at Argonne National Laboratory have been studying the “magnetic vortex state” of microdiscs - small iron-nickel discs so small that even “microscopic” over-characterizes their size - for several years. Applying even a weak magnetic field to these discs causes them to rotate, a property that Argonne’s Dong-Hyun Kim, Elena Rozhkova and Valentyn Novosad thought would be a possible weapon against cancer cells. If one could attach these discs to tumor cells, then expose them to a magnetic field to set them rotating, would their vibrations tear the cells apart?

The microdiscs (courtesy of Argonne)

That rather odd hypothesis was demonstrated to work in a recent paper published in the journal Nature Materials (News & Views article here), at least in the controlled environment of the test tube. Researchers coated the microdiscs in gold (to prevent rejection by the cells) and attached an antibody to target the discs to cancer cells but not normal cells. After giving the discs time to bind to cells, a very weak, alternating magnetic field - about the same strength as a magnetic screwdriver, Novosad said - was applied to the cells at a low frequency for 10 minutes.

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A three-dimensional image of a "BK" cellular ion channel (Yale University/Futurity)

I apologize for the lack of a Linkage post last Friday - instead of blogging, your editors were learning about Chicago’s downtown architecture as we floated along the green if not Green Chicago River on one of summer’s final days. But like the reversed flow of that waterway, the science never stops, and last week saw the official launch of a new source for science news: Futurity.

Disclosure alert: the University of Chicago is one of the contributors to Futurity’s content, and our esteemed paleontologist Paul Sereno’s new “punk-size” T-Rex spent much of last week as the site’s featured story. But as both producers and consumers of science writing, we’re genuinely excited about the site, which will aggregate articles from an initial pool of 39 universities in an attempt to the gap left by shrinking science and medicine staffs at newspapers and television stations. With reduced space and time for science stories in the mainstream media, the news offices of these universities have taken it upon themselves to bring their science to the public directly, sometimes by employing refugees from those very same shrinking science staffs.

Yes, that largely means publishing press releases, though it must be said that many press releases are now themselves written and laid out like a news article, with an eye-catching lead, quotes from researchers and outside sources, historical perspective and photo or graphic art. Sites like ScienceDaily and Eurekalert are well-known depositories for these releases, but can be sensory overload for the casual reader with hundreds of new releases posted to the site each day. Futurity looks like it will filter out some of the noise and present the most exciting research in an aesthetically pleasing manner, with the hope that general audience readers, not just other science journalists and news office personnel, will find it entertaining and informative.

The site had a soft launch in the spring and went full-on live last Tuesday, so there’s already been a bit of attention paid to it by sites such as Inside Higher Ed, the San Jose Mercury News, and the Columbia Journalism Review. Skeptics note, appropriately, that there is a certain preaching-to-the-niche quality, where only people actively seeking out science news will be exposed to science news. But through deals with wider-audience news aggregators like Google and Yahoo!, the hope is that a casual reader will be distracted by interesting science news on their way to sports scores or celebrity gossip, just like they used to do in a newspaper.

Here are a few of the Futurity stories that caught our eye in the website’s opening week:

• Scientists cure color blindness in monkeys with a human gene (University of Washington)
• Using Legos to model nanobiology (Johns Hopkins)
• Thin, overeating friends can inspire unhealthy eating behavior (Duke; with a slick YouTube video that makes us very envious)
• Using trees to generate electricity (University of Washington)
• An “open-source” camera with a brilliant name: Frankencamera (Stanford)

(Note: This article was corrected on 12/9/09 - previously, it said that the nanoparticles were activated by UV light, but the TiO2 particles are actually modified to be activated using normal, visible light. Also, the light exposure time was only 5 minutes, not 6 hours as previously reported in the text.)

As reported everywhere today, Sen. Ted Kennedy died Tuesday night after a year-plus fight with malignant glioma, a type of brain cancer. The condition, in which tumor cells arise from glia cells of the brain, is known to be especially deadly and hard to treat - only about 16 percent of patients diagnosed with the condition survive five years. Treatment involves radiation, surgery and chemotherapy, but long-term survival is a challenge.

“In some cancers, the brain or pancreatic cells are multiplying at such a rapid rate,” said Dr. Maciej Lesniak, director of neurosurgical oncology at the University of Chicago Brain Tumor Center.  ”When you have a cancer that grows that rapidly, the prognosis can usually be measured in months or years at most. It’s always a battle between how quickly the cancer is growing and the available therapies.”

Those grim numbers have inspired many researchers to look at improved ways of treating brain tumors, employing some of the latest technologies available in biomedicine. One promising tool, currently being tested by Lesniak and scientists at Argonne National Laboratory, is the use of nanomaterials to target and kill tumor cells with minimal damage to nearby healthy tissue. A laboratory demonstration of this method was published last month in the journal Nano Letters.

“This paper overcomes a potential challenge in nanomedicine,” Lesniak said. “While nanotechnology is very interesting in terms of applications, targeting nanoparticles to specific parts of the body is a problem. They are so small, they can go anywhere.” read more