by Rob Mitchum

The brain is a privileged organ, afforded protections denied to all the other organs of the body. Though the circulatory system functions much the same way above and below the neck, using blood to exchange nourishment for waste with cells, the exchange is conducted under much heavier security in the central nervous system. This TSA for the brain and spinal cord is known as the blood-brain barrier, and its role is protecting the fragile, irreplaceable cells of the nervous system from external disease and the body’s own immune weapons.

While we can all be thankful for the unceasing service of the blood-brain barrier (sometimes abbreviated as BBB), many scientists are interested in figuring out how it can be breached. Many neurological diseases, including multiple sclerosis and stroke, can be attributed in part to breakdowns of the BBB. Drugs designed to treat brain disease must also find a way through the BBB’s strong defenses to get to their desired targets.

That made the blood-brain barrier the perfect subject for this year’s Chicago Symposium on Translational Neuroscience, an annual gathering of neurologists and laboratory neuroscientists from the University of Chicago Medicine and other institutions. This year, the Neuro contingent was joined by UChicago’s young Institute for Molecular Engineering in presenting the conference, underscoring that the topic is very much an engineering problem: how do you build a blood-brain barrier, and how do you selectively knock it down?

The day’s first speaker, Richard Daneman of the University of California, San Francisco, explained what the field currently knows about the unique properties of the BBB. In most of the body, the capillaries of the circulatory system are “leaky,” he said, allowing many molecules to pass between the cells and the blood through the cracks between the endothelial cells that make up the blood vessel walls. But in the BBB, those cells form a tight seal, and molecules are transported into and out of the vessels by highly selective transporters instead of passive diffusion. Daneman illustrated these defenses with an experiment where blue dye is injected into an animal, which is later dissected. While organs such as the kidney or liver take on a distinct blue hue, the brain and spinal cord remain free from the dye, which cannot penetrate the barrier.

Daneman is interested in “barriergenesis,” how the BBB is constructed during development. Previously, researchers hypothesized that brain cells called astrocytes were responsible for building the BBB. But using mice and rat models, Daneman’s laboratory determined that this defense system is already in place during embryonic stages, before astrocytes first appear. Instead, Daneman’s experiments pointed to another cell group called pericytes as critical architects of the BBB. When the genes for forming pericytes were knocked out in a mouse line, the BBB did not form its tight seal…as indicated by the appearance of blue brains after a dye injection.

Now Daneman’s lab is digging into the molecular signals that construct the BBB during development and maintain its integrity throughout life. Some of those experiments involve taking the endothelial cells that form the BBB out of their native habitat to study them on the lab bench, the subject of a talk from Eric Shusta of the University of Wisconsin - Madison. Endothelial cells only make up about one-tenth of one percent of the cells in the brain, Shusta said, and don’t form the tight seals characteristic of the BBB in the lab dish unless they are co-cultured with other neural cell types.

Shusta’s laboratory has tackled these problems using the hot prospects of laboratory science: pluripotent stem cells. When researchers in his group decided to try to differentiate stem cells into BBB-like endothelial cells, Shusta said “I thought they were a little bit crazy, but the initial experiments worked.” What’s more, with neural stem cells, the researchers could also generate other nervous system cell types that might play an important role in barriergenesis. That experimental set-up can now be used to test for the cellular factors that build the BBB and as well as assess different drugs’ ability to pass through the barrier, without the constraints of having to endlessly harvest scarce endothelial cells.

“From one rat brain we can get about 6 to 12 filters, but from one vial of stem cells, we can easily get ten thousands of filters,” Shusta said. “We think that we can keep optimizing this, and hopefully make an impact in developmental and drug screening applications.”

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The rise of optogenetics — where flashes of light can manipulate brain activity and behavior — have excited scientists looking for more precise ways of manipulating cells and their components in the laboratory and the clinic. Two papers published this month by University of Chicago laboratories explore new methods with great scientific potential of controlling cells through light.  We’ll cover them in two installments.

Many researchers hope that the light-activated cell technologies currently being used in laboratories will eventually cross the threshold into the clinic. The ability of optogenetics to relieve anxiety in lab rats could someday inform a similar human treatment, where psychiatric symptoms are reduced through a light-delivery implant that stimulates the right brain regions and neurotransmitters on command. But most methods that tweak cell activity with light require some form of genetic manipulation to work, and researchers have so far encountered steep barriers to effectively and safely performing gene therapy in humans.

One potential workaround would be to use a method of light activation that requires no genetic tinkering: infrared light. These long-wavelength light spectra are already used for a variety of purposes, from night vision devices to weather observation to detecting fraudulent paintings. In biology, scientists found that infrared light is capable of exciting cells that discharge electricity, such as neurons or heart cells, prompting optimism about medical uses for this less complicated form of photo-activity.

“If you’re thinking about clinical applications, already the requirement of a light fiber to deliver the light stimulus is a hurdle,” said Mikhail Shapiro, a Miller Research Fellow at the University of California, Berkeley. “If you add on top of that the need for gene therapy or using caged neurotransmitters or other light-sensitive chromophore molecules, you’re adding an additional layer of complications. I think part of the appeal of the infrared approach is all you need is the light.”

However, there was one caveat underlying the promise of infrared cell excitation: nobody was exactly sure how it worked. That was the question that Shapiro set out to tackle during a postdoctoral scholarship in the laboratory of Francisco Bezanilla, Lillian Eichelberger Cannon Professor of Biochemistry and Molecular Biophysics at the University of Chicago Biological Sciences. Over several months of experiments, recently published in an article in Nature Communications, Shapiro and his colleagues searched for the mechanism by which infrared light excites cells…eventually settling on a surprising conclusion.

“I think the interesting thing here is it’s a case where the use of the technology leaps ahead of the understanding of how it works,” Shapiro said. “But if you’re implanting things into your body and stimulating and you don’t know how it works, how comfortable can you really be with that? Are you making little holes in these cells that are exciting them?”

Zapping a cell with infrared light produces an inward current, a sign that the cell is depolarizing. In a neuron, those types of inward currents are created by the opening of ion channels, allowing positive ions such as sodium to come flooding into the cell and pushing it toward the firing of an action potential. So Shapiro, Bezanilla, and collaborators Kazuaki Homma, Sebastian Villareal, and Claus-Peter Richter started their experiments by testing infrared light on Xenopus oocytes — frog egg cells that serve as a common laboratory cell model — injected with DNA for different types of ion channels. Frustratingly, the experiments did not initially provide a simple answer.

“We tested the infrared light, and found out that regardless of what you injected, it was exactly the same response,” Bezanilla said. “Then we said, maybe we don’t need to inject anything. Sure enough, if you don’t inject anything you get exactly the same response again.”

The failure to find an ion channel sent the researchers back to basics. Infrared’s long wavelengths are capable of locally exciting molecules, producing very rapid increases in temperature. So Shapiro measured the effect of the infrared laser on water held at the same distance as their cells, and found that his beams did indeed have a heating effect. What’s more, the inward current caused by infrared light correlated with the rate of this temperature change. The results indicated that the cellular component sensitive to infrared light wasn’t a complex protein, but plain old water.

“It was very challenging, because the type of responses we were getting were very unusual,” Bezanilla said. “But when we started looking at the temperature changes, that really gave us some clue what was happening here. You don’t need to put in a special molecule, because the molecule that you use to produce the effect is the water. You don’t have to genetically engineer anything, you just apply the infrared in the right place and you get the effect.”

Further experiments determined how these temperature changes could produce cell excitation.

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The rise of optogenetics — where flashes of light can manipulate brain activity and rat behavior — have excited scientists looking for more precise ways of manipulating cells and their components in the laboratory and the clinic. Two papers published this month by University of Chicago laboratories explore new methods with great scientific potential of controlling cells through light  We’ll cover them in two installments.

Many important cellular functions are principally the result of factors being in the right place at the right time. The complex pathways that handle important jobs such as cell growth or migration can have hundreds of components that must arrive at the same location within the busy cellular environment. As such, biologists would like the ability to move proteins to different parts of the cell at will, giving them control over the staging of these pathways and their functions. With a new system that draws upon the work of several University of Chicago laboratories, researchers have figured out how to achieve this power with light.

Like many good ideas in science, the collaboration that created TULIPs began with a question posed at a bar. At the annual Molecular Biosciences retreat in Galena, Illinois, Devin Strickland and Tobin Sosnick challenged their colleague Michael Glotzer with a provocative question.

“They asked, ‘If you could control any protein you wanted, what would you control?’,” recalled Glotzer, Professor of Molecular Genetics & Cell Biology at the University of Chicago.

Strickland, then a graduate student in the laboratory of Sosnick, Professor and Chair of Biochemistry & Molecular Biophysics, were looking for applications of  their strategy of using light to control the activity of a specific protein. Glotzer realized that the system could bring two proteins together in a cell, whenever and wherever researchers wanted. The result was an exciting new technique, called TULIPs, published this month in Nature Methods.

The acronym TULIPs stands for TUnable, Light-controlled Interacting Protein tags. Instead of  the light-activated ion channels or gene transcription used by other optogenetic methods, the TULIPs use a LOV domain, a light-sensitive component from a protein plants use to detect and grow toward sunlight. By attaching different proteins to this domain and another known as an ePDZ “clamp,” the researchers built a customizable way of precisely manipulating cellular signals in both space and time.

“Basically nothing previously had been designed to control cell signaling that wasn’t engineered on a case-by-case basis,” said Strickland, now a postdoctoral researcher in Glotzer’s laboratory. “We started off wanting to be the first people to create an adaptable system.”

In the Nature Methods paper, the authors describe testing the system by attaching it to fluorescent proteins and applying it to Glotzer’s chosen target, a GTPase pathway that controls growth and genes related to mating in yeast. The experiments demonstrated both that the TULIPs worked, and that it could be easily adapted to manipulate a wide range of cellular signals.

“The idea was let’s solve this generic problem once, and then we’ll be able to reuse that solution in many different contexts,” Glotzer said. “Looking at lots of different biological phenomena, it’s pretty clear that a lot of functions correlate with changes in sub-cellular localization of specific proteins. So there’s almost no limit; you’re only limited by your imagination.”

[Light flashes on the right demonstrate the successful localization of fluorescent proteins attached to the TULIPs system. Video by Elizabeth Wagner]

The TULIP system is made up of two components that draw upon work done previously by the University of Chicago laboratories of Shohei Koide, who developed the ePDZ clamp, and Keith Moffat, who characterized the LOV domain and first suggested its use in the TULIP system.

“It’s really a nice story of how basic research can lead to things that aren’t really anticipated,” Strickland said.

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

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

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

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

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

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

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

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

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

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Many of the most interesting processes in nature are so fast, they can make “a blink of an eye” look like a millennium. Cellular proteins undergo elaborate transformations in as little as a picosecond - one millionth of one millionth of a second. That astonishing time scale presents an enormous challenge to scientists who would like to study the structure and behavior of those proteins. To catch the extremely fleeting moments of transition between different structural states of one such protein, a University of Chicago laboratory used a strategy straight out of science fiction: freezing time.

Xiaojing Yang, a senior research professional in the laboratory of Keith Moffat, wanted to look at a particular protein called a bacteriophytochrome, a red light photoreceptor from bacteria related to phytochromes in plants. Photoreceptors are found everywhere in nature, from plants to eyes, and are activated by light to change their shape and transform a light signal into a biological signal.  Yang was interested in the contortions a photoreceptor makes when changing from the “dark” state to the “light” state, and chose a particular phytochrome from the bacterial species Pseudomonas aeruginosa.

Yang started with a method called X-ray crystallography, where proteins are maneuvered into crystal formation and then imaged at the atomic level using an X-ray beam. With traditional X-ray crystallography, Yang could determine the structure of the P. aeruginosa phytochrome in the dark state, before activation with the light signal - data she reported in a 2008 PNAS paper. But in order to see the transition between dark and light in finer detail, the researchers needed to develop a new trick.

“We applied an innovative application of crystallography called temperature-scanning cryocrystallography, where we use temperature to mimic time,” Yang said of the work, published this week in Nature. “So this is a new way of doing dynamic crystallography.”

Cryocrystallography, or “cryotrapping,” involves performing the method at a very low temperature to freeze the target molecule in a particular conformation. The temperature-scan aspect that Yang and colleagues added was to hold the crystal at an escalating series of temperatures (from -279° F to -135° F), each one moving the super-fast structural changes the slightest bit forward. The researchers could then do an X-ray scan at each temperature level to capture those normally-fleeting in-between stages.

“We shine the light at different temperatures, higher and higher,” Yang said. “The reaction progresses further as the temperature rises, and then you have a different mixture of reaction intermediates.”

“It’s a cunning way of slowing things down from picoseconds to minutes or even tens of minutes,” said Moffat, Louis Block Professor of Biochemistry & Molecular Biology at UChicago.

The experiments, using ten temperature levels in all, revealed three predominant intermediate states, called L1, L2, and L3. Transitions between states resemble a “molecular earthquake,” Moffat said, with the changes initially appearing at one corner of the light-sensitive chromophore of the phytochrome before spreading outwards until the entire structure is in flux. And as dramatic as the motion is, it’s only the initial steps of the phytochrome’s dance. Moffat uses the analogy of filming a sprint to describe the action they captured - the flash of light that starts the reaction is the starting gun - and says that they are so far only able to observe the first 15 meters of a 100 meter dash.

“We’re not in a position to observe the rest of the race,” Moffat said. “Yes, we would like to see the entire race going all the way to the finish, but we believe that the overall reaction from beginning to end involves quite a large molecular convulsion, which is probably not compatible with the crystals.”

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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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Medical school isn’t cheap. Today, medical students graduate with an average debt over $155,000, and the need to pay off those mortgage-sized loans drives many a young doctor away from more modestly compensated but sorely needed fields such as primary care and family medicine. To alleviate this financial pressure, many organizations have started scholarships to help with the med school tuition bill, rewarding scholastic achievements and commitments to work in underserved populations. The American Medical Association’s Physicians of Tomorrow program is one such effort, and this week’s announcement of the 2011 recipients [pdf] carried a heavy Pritzker School of Medicine presence.

Two of the 18 (11 percent, but who’s counting) fourth-year medical students receiving the $10,000 scholarship were from the University of Chicago’s medical school. Laura Blinkhorn (left) and Maggie Moore (right) are the two very impressive Pritzker students among the recipients, each with very impressive biographies already built in their young careers. Blinkhorn has done work with South Side neighborhoods as part of the Pritzker Summer Service Partnership, works with the Washington Park Free Children’s Clinic, and is planning to spend 3 months of the next year doing a clinical rotation in the African country of Gabon. Moore volunteered at the Maria Shelter Clinic for Women and Children and the South Side “Girls on the Run” program, and somehow finds time to write poetry about her medical experiences. Because of poems such as “Cadaver Memorial” and a collection called “A Third Year’s Life in Lyrics,” Moore was given the Johnson F. Hammond, MD Scholarships supporting medical journalism by the AMA. Congrats!

New Furniture for Molecular Engineering

When you are building a new house, you’re gonna need some furniture. The same thing goes for building a new research institute - before you can fill it with people, you need somewhere for them to sit. The University of Chicago’s Institute for Molecular Engineering, which was born in December and acquired a leader in March, has this week announced four named professorships made possible by anonymous donations. The funded positions give the institute the power to recruit prominent researchers to help realize the institute’s unique vision blending biology, chemistry, and physics.

“The big job in front of us is to bring together people with expertise in broadly applicable areas of enabling technology, such as synthesis of new materials, biological engineering, new ways of doing computing and quantum information science,” said Matthew Tirrell, the founding Pritzker Director of the Institute for Molecular Engineering and senior scientist at Argonne.

Elsewhere…

The San Diego Union-Tribune Keith Darcé wrote an excellent overview of the Earth Microbiome Project, the global study of the world’s bacterial populations that has previously been featured on the blog. Our own Jack Gilbert is featured (he mentions their current project swabbing bacteria from the animals of the San Diego Zoo), and an interesting hunt for bacteria able to survive in high-salt conditions is also explained.

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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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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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The immune system relies heavily on memory and recognition, with its success dependent on marshaling defenses against only the right infectious invaders. Scientists are finding that this memory requires a lot of moving parts, including molecules that grab pieces of bacteria and viruses, specialized cells that can determine whether those pieces are dangerous or not, and cells that attack and kill those microbes if they are ruled to be a threat. The key at each step of this complex system is specificity; if each component only binds or attacks certain types of molecules, it makes the process of remembering the correct response that much easier. As with a condo building, having the right locksmith can make all the difference.

Bacteria are largely made up of proteins and lipids, and when they first get inside a cell, the initial defense system strips them down to these parts. For proteins broken up into smaller pieces called peptides, the MHC molecules are the designated grabbers, binding the molecules and bringing them to the cell surface for recognition. But for lipids, a different group of molecules, the CD1 family, performs this task. Because lipids make up the bacterial cell wall - the critical outer barrier of the microbe - they are good, reliable candidates for jogging the immune system’s memory and initiating a response.

“It’s a really excellent way of recognizing a bacterial lipid, because they look a lot different than what they look like in us,” said Erin Adams, assistant professor of biochemistry & molecular biophysics at the University of Chicago. “If you are a bacteria, you can mutate your protein to evade the immune response and not be recognized any more, but it’s really difficult to change the structure of a lipid. If you screw it up too much, then the bacteria doesn’t survive.”

Understanding more about how these CD1 molecules function could be helpful in building better vaccines or treatments against bacteria and viruses. But the traditional scientific approach of taking a snapshot of these molecules (through the method of X-ray crystallography) was frustratingly difficult. So a multi-disciplinary team led by Louise Scharf in Adams’ laboratory set about using some molecular engineering to solve that problem, and their work was published last month in the journal Immunity.

The mission was to catch one of the CD1 family, CD1c, in the act of binding with a bacterial lipid; in this case, a component of the bacteria that causes tuberculosis called mannosyl-ß1-phosphomycoketide (MPM, for much-needed short). The protein was normally too unstable for crystallography, so Scharf and colleagues meticulously changed pieces of CD1c to create a more stable structure, without betraying the molecule’s original function.

“We did a lot of tests to make sure that the protein that we made, our Frankenstein protein, was only Frankenstein in the bits that didn’t count, the structural parts of the protein,” Adams said. “We had to keep validating along the way, step by step, to make sure we weren’t creating a monster.”

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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.

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 Lloyd DeGrane)

Here in Chicago, we’re entering the second of our two seasons: transitioning from “Construction” into “Winter.” The rampant highway repair that happens during warm weather months is largely due to the stresses of the cold weather months, which leave our roads cracked and potholed. But perhaps we’ll be saved from all that misery if a team of Dutch researchers are successful in their efforts to create biologically self-healing concrete. The process embeds calcite-precipitating bacteria into concrete paste, so that when cracks occur, the microorganisms can secrete a mineral that will fill those fractures. It’s a cool example of biology-inspired engineering, and was mentioned as part of the New York Times’ interesting “What’s Next in Science?” feature this week.

Two exciting studies from the other side of the University of Chicago campus came out in this week. In the first, Chuan He in the Department of Chemistry helped characterize the activity of “the most exciting protein family now in biology,” a DNA repair protein called AlkB. In charge of demethylating DNA, AlkB has the power to re-activate silenced genes, a valuable epigenetic function that could someday be harnessed to treat diabetes, obesity, and cancer. The study also utilizes a delightful science word to describe one of the protein’s intermediate states: “zwitterionic,” when an object has a neutral charge, but acts positive or negative when interacting with other objects.

In another study, University of Chicago psychologist Susan Levine found that a child’s early exposure to mathematics can influence later success in the subject. Researchers videotaped interactions between parents and their children when they were between the ages of 14 and 30 months, counting how many “number words” were used by the parents. When the children were given a simple math test at the end of the experiment, those that heard more about math from their parents tended to perform better.

Today and tomorrow, the MacLean Center for Clinical Medical Ethics will hold its 22nd annual conference, a two-day festival of ethical lectures and discussion. Today’s session will expand upon the local, national, and global health disparities theme of the center’s weekly seminar series, while the second day takes a broader approach with topics such as pediatric ethics, palliative care, transplant medicine, and a session dedicated to the memory of faculty member Stephen Toulmin. The schedule is available here (pdf), and we’ll have coverage of the conference next week.

ScienceLife is very excited to have gotten in during the very brief window that registration for Science Online 2011 was open this week. The “unconference,” held in North Carolina in January brings together a dream team of science bloggers for open discussions and workshops on the growing field of internet science journalism. Expect to hear more about it.