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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Very busy today, so please forgive the light posting.

In December, we wrote about a unique collaboration between Argonne National Laboratory and the University of Chicago Medical Center to fight brain tumors with microscopically tiny gold nano-discs. ABC-7-Chicago recently ran a story on that research which you can watch below:

 

And if you have time for two science videos today, enjoy this neurobiological explanation of why the good guys always win gunfights in old Westerns. (from the University of Birmingham)

Do Polish Tracks Trump Tiktaalik?

A bit of a firestorm with local significance was stirred up this week when a paper published in Nature purported to reset the clock on when marine animals took their first step out of water. Grzegorz Niedzwiedzki and colleagues from Warsaw and Sweden presented a fossil “trackway” made up of what the team identified as several hand and footprints from a tetrapod four-limbed vertebrates thought to be a key step in evolution from marine animals to land dwellers. The tracks, found in south-eastern Poland in a layer dated as 395 million years old (video), reveal some fascinating details in the authors’ analysis, including distinct hand and foot prints, toes and ankles - all critical aspects of the transition from fin to limb. It’s also the earliest known evidence for a tetrapod, predating fossil findings of “fish-with-limbs” such as Tiktaalik by nearly 20 million years.

While some are convinced of these conclusions, others are skeptical. Tiktaalik, discovered in 2004 in far northern Canada by a team led by University of Chicago paleontologist Neil Shubin, remains the earliest known tetrapod fossil, a remarkably complete specimen that clearly shows limb-like bone structure. Footprints, on the other hand, are acceptable as paleontological evidence, but much more open to question. Indeed, no tetrapod fossils - or any fossils, for that matter - were found near the trackway, which the authors attribute to the soil being a poor environment for preserving skeletons. Nevertheless, in a news article accompanying the Nature paper, other paleontologists express caution in accepting the veracity of the trackway fossil, and Phillippe Janvier of the Muséum National d’Histoire Naturelle in Paris suggested “a risk” that natural processes could have produced track-like markings.

Shubin, currently on sabbatical writing the follow-up to this award-winning Your Inner Fish, wasn’t immediately available for comment. But when he’s back, ask him what he thinks of the new discovery and how it changes our view of early tetrapod evolution.

The Cell Phone Treatment

In an almost too-weird-to-be-true piece of science news this week, a story started kicking around that the type of electromagnetic fields (EMFs) generated by cell phones was found to be effective at protecting against or even reversing the effects related to Alzheimer’s disease in mice. Studies of cell phone radiation - usually focused on proving that the phones’ electromagnetic waves cause harm - are notoriously unreliable. Time and again, studies have shown these waves do not cause brain tumors or other diseases…but in looking for damage from cell phone use, were scientists overlooking benefits?

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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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(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