Tuesday, July 29, 2014

How do mom's microbes affect pregnancy outcomes? UAB research aims to find out

As a baby slides out of the birth canal, on the way to its first breath, its body becomes coated in its mother’s microbes. This first interaction with outside organisms could be key to shaping the development of the baby’s immune system.

Our microbes, collectively called the microbiome, most often live in harmony with our bodies. They support the immune system, help to digest food and keep the metabolism on track, and fight off disease-causing bacteria. But researchers suspect that mom’s microbiome could play a role in when her children are born, and what happens to them as they grow.

“Most people know about the microbes that colonize the gut,” says Rodney Edwards, M.D., an associate professor in UAB’s Department of Obstetrics and Gynecology. “But there are bugs in and on us in many other sites—our skin, our mouths, our noses, our genitalia.”

During pregnancy, it turns out, the new needs and demands of a woman’s body change the numbers and types of these microbes. Alterations in how the body divvies up nutrients, stores fat, and produces hormones shift the properties of the microbes’ environments. But exactly how the microbiome changes over this nine-month period varies between pregnancies. And these variations, researchers are discovering, could impact not only the well being of a pregnant women herself, but the likelihood of pregnancy complications and the long-term health of a baby.

Rodney Edwards has launched a
research program to probe how the
microbiome of an expectant mother shapes
maternal and fetal health. 
Edwards has launched a research program in the UAB School of Medicine to probe how the microbiome of an expectant mother—especially the flora that inhabit the genital tract—shape maternal and fetal health. He wants to know if the microbiome’s composition could make a woman go into labor early, or influence a baby’s chance of developing asthma or allergies, among other questions.

“If we could find a few organisms that—when present in the microbiome—were associated with a particular pregnancy or childhood outcome,” Edwards says, “we could use it as a targeted test for high-risk pregnancies and test putative interventions in that group.”

Investing in the Microbiome

Over the past decade, scientists around the world—armed with the new ability to take a genetic snapshot of the microbiome in any person at any given time—have been probing how changes to the microbe populations in a person’s gut can make them sick, weaken their immune system, or even change their risk of cancer or heart disease.

A few years ago, when the National Institute of Health’s Human Microbiome Project was announcing its early results, Casey Morrow, Ph.D., a professor in the UAB Department of Cell, Developmental and Integrative Biology, became excited about the possibilities of microbiome research and the potential to improve human health.

Morrow’s microbiology laboratory teamed up with UAB’s Heflin Center for Genomic Science—with its next-generation DNA sequencing capabilities—and bioinformaticians in the UAB Center for Clinical Translational Science to establish the necessary components at UAB to do microbiome analysis. With early seed support from the UAB Cancer Center and later from the UAB Center for AIDS Research and School of Medicine, they were able to launch a shared facility supporting microbiome research.

Today, barely two years later, the UAB Microbiome Resource is flourishing, says Morrow. “Any UAB researcher who wants to analyze a microbiome can submit a sample to the facility and from the microbiome analysis pipeline established at UAB can determine what microbes are present,” he says.

Casey Morrow says the UAB Microbiome
Resource gives researchers a strong
foundation to link basic science
and clinical science.
“Armed with that analysis, researchers can start figuring out the differences between different samples and what those differences might say about disease states,” says Morrow. “This is really giving us a strong foundation to link basic science and clinical science when it comes to the microbiome.”

UAB researchers are already studying how the gut microbiome could influence colon, breast, stomach, pancreatic, and brain cancer; how chronic infections in the digestive system can be cured by restoring microbial populations; and how chemotherapy and diet change the microbiome. (Learn more about research on cancer and the microbiome in the latest issue of the UAB Comprehensive Cancer Center magazine.)

Beginning with Bacterial Infections

Edwards’ interest in the microbiome began not with basic science, but with a clinical question: Why does bacterial vaginosis (BV) during pregnancy increase the risk of preterm births and low birth weight babies? BV is not an infection but rather a condition in which the normal flora of the vagina, dominated by Lactobacilli, is replaced by a mix of bacteria dominated by anaerobes and Gram-negative aerobic bacteria. BV increases the risk of going into labor before 39 weeks of gestation. But when clinicians aggressively screen for and treat BV in populations of pregnant women, they don’t see changes in preterm birth rates.

Researchers began to understand that BV is what is known as a heterogeneous problem, says Edwards. In other words, “BV in one woman isn’t the same as BV in another.”

The UAB Microbiome Resource offers researchers
many ways to analyze samples, including "heatmaps"
depicting levels of various microbes.
But classic methods of diagnosing BV didn’t give detailed information about what microbes take over the vagina during an infection—it’s typically diagnosed by measuring the acidity of the vagina (a high pH suggests BV) and looking at a smear from the vagina under a microscope to confirm the presence of bacteria. Edwards, though, wants to get a better sense of the exact species of bacteria normally present in the vagina, how that balance could change in different ways in women with BV, and which variants of BV are most dangerous to pregnant women.

In a pilot study, UAB researchers collected samples from 19 pregnant women diagnosed with BV. In collaboration with the UAB Microbiome Resource, they were able to detect the identity of the microbes present in each sample.

“What we’ve already found is that the organisms we used to think were predominant in BV may not actually be predominant,” Edwards says. “At least not in all cases.”

Now, with the knowledge that microbiome analysis can give more detailed information on a case of BV than classic, microscopy-based approaches, Edwards is moving toward understanding the link with preterm births. To that end, he’s working to establish, within the existing Center for Women’s Reproductive Health, a new UAB Prematurity Prevention and Research Related to the Microbiome (PREPARE-M) Clinic.

His first project within the new clinic: prospectively following women throughout pregnancy to track changes to their microbiomes. The women he plans to initially follow are those who have previously had a preterm birth, putting them at high risk of repeating that outcome. He’s received a grant from the General Endowment Fund of the UA Health Sciences Foundation to get the study off the ground.

If he can find specific subsets of BV that increase a woman’s chance of preterm birth, Edwards believes clinicians will be well on their way to determine how to best treat these women to decrease those odds.

Microbes Linger Long-Term

Simply preventing preterm births—at least those associated with infections—is a leap toward improving infant health, as babies born preterm are prone to health problems. But Edwards thinks that a mother’s microbiome does far more than affect her chances of an early delivery.

"There could be something we should be doing immediately after childbirth to make sure a baby's microbiome is shaped properly," Edwards says. "And this could have long-term childhood effects."
In the PREPARE-M Clinic, Edwards has launched a long-term study on how the transfer of microbes from mother to baby—which some researchers have found happens even in the womb—could alter a child’s health for years down the road. Initially, he’s going to follow mothers and children only through their first post-partum doctor’s visit, six weeks after birth. But eventually, he’d like to follow children through their fifth birthday.

“There could be something we should be doing immediately after childbirth to make sure a baby’s microbiome is shaped properly,” Edwards says. “And this could have long-term childhood effects.”
Of course, there are also plentiful basic questions about the genital microbiome: how it’s shaped by the microbes of the gut or skin, how it interacts with the immune system, and how it changes over a person’s lifetime. “Scientists have been studying the gut microbiome for 15 years now,” Edwards says, “But the applications to the vagina and obstetrics are even newer. So we have more basic questions left to answer.”

One day, microbiome analysis could become commonplace—not only during pregnancy, but at doctor’s visits throughout a person’s life, Morrow says. “Just as your doctor takes a blood sample today, taking samples of your microbiome to make sure your microbes are all in balance will become routine. We anticipate that 'microbiome management' will be an important component of a personalized medicine plan to monitor and improve human health.”

—Written by Sarah C.P. Williams

Wednesday, July 16, 2014

Tools of the Trade: Scanning Electron Microscope

The high-tech look of UAB's Scanning Electron Microscope facility makes it a popular spot on campus tours, but the machine's ability to image everything from exotic metals to living tissues makes it an invaluable research tool, says facility director William Stonewall Monroe (above).

When you need to see something so tiny that light skips right over it—and you don't want it vacuum-sealed and messed with in the way that a transmission electron microscope requires—you're in the market for a scanning electron microscope (SEM).

An SEM is the go-to machine for materials engineers, who are very interested in close-up pictures of faulty pipes or the inner workings of exotic, lab-created composites. That's why UAB's SEM is located on the ground floor of the School of Engineering. But the device is also gaining a following with researchers all over campus, says William Stonewall Monroe, director of the UAB Scanning Electron Microscope facility.

"If you want to look inside something, you use a transmission electron microscope," Monroe says. "That's what most people think of as an electron microscope. But the samples have to be elaborately prepared and able to survive the vacuum conditions."

Story continues after the quiz

The SEM only shows the surface of an object, but its prep requirements are much more forgiving. And what it lacks in clarity—it can magnify objects up to 30,000 times, as opposed to the millions of times that a transmission electron microscope can achieve—it makes up in versatility. (There are several TEMs in the UAB High Resolution Imaging Facility.)

In its environmental mode, "we can put things that are still wet into this microscope," says Monroe. Researchers from the Department of Pathology are using the SEM to examine bone slices. A group in the Department of Physics is poring over its nanodiamonds in the device. And biologists are using it to look at how various processes affect cell growth. "They've been surprised by how much they can see," Monroe says.

Monroe spends his days at the Star Trek-style controls of the SEM, adjusting a range of dials and settings to bring out glorious details in a shattered pipe or sliver of sea urchin. Researchers often sit next to him while he works, observing the results on the lab's giant overhead flat-screen monitors. [The lab is so sleek it is a popular spot on campus tours.] The images he acquires help advance research; they also help it attract attention. "A picture really helps your case if you are publishing," Monroe observes.

Because the SEM lab is open to any investigator on campus, "I get to see research from all over," Monroe says. "It's a fascinating job."

More Information

The Scanning Electron Microscope facility is open to academic and commercial users, both from UAB and outside the institution. Learn more about rates and booking time. 

Wednesday, June 25, 2014

A Parkinson's therapy makes its way through the "valley of death"

Andrew West is pursuing a compound to inhibit LRRK2, an enzyme that appears to be a central enabler
of the brain cell death seen in Parkinson's disease.

In its long journey from the petri dish to the first human patient, every new drug has to cross a wasteland called the "valley of death." Therapeutic programs enter, but most don’t come out the other side.

"The government is good at funding basic research to identify drug targets, and Big Pharma is good at taking drugs and putting them through clinical trials," says Andrew West, Ph.D., John A. and Ruth R. Jurenko Endowed Professor in Neurology at UAB. "But all of the in-between work, the pre-clinical and drug development components, is called the 'valley of death' for research, because nobody funds it, nobody pays attention to it. That's a big part of the lack of new drugs."

In fact, less than 10 percent of drugs that make it into preclinical testing will end up getting FDA approval, according to the agency's figures. But West is part of a new approach to the drug-discovery process designed to upend those odds: a partnership between UAB and Birmingham-based Southern Research Institute known as the Alabama Drug Discovery Alliance (ADDA).

The partnership is built around the strengths of each institution. UAB labs identify molecular targets that play a key role in disease. In West's case, that's the enzyme LRRK2 (pronounced "lark two"), which appears to be a central enabler of the brain cell death seen in Parkinson's disease.

Southern Research has decades of experience in drug discovery and testing. It employs a host of researchers who are adept at the chemical tweaking needed to make a drug work in humans. Southern Research scientists are also experts at proving a drug's safety and efficacy to the FDA and to large pharmaceutical companies. Big Pharma is often willing to step in and fund new drug projects—but only after they have demonstrated initial success.

Thanks to several years of work, "we're most of the way through the valley of death now," West says. "We have dozens of compounds that are fantastic drugs. We just have a little bit left to go—sometimes the last mile of the marathon can be the most painful."

On the Move

This month, West's lab published a new study in the Proceedings of the National Academy of Sciences that suggests LRRK2 inhibitors could play a wide role in slowing the progression of Parkinson's disease, or even preventing it altogether.

"This is a critical first step showing that inhibition of LRRK2 may be beneficial to protect against the cell loss and degeneration that occurs in Parkinson's disease," says West. It's another sign that the team's approach is taking it in the right direction across the valley of death—and a welcome oasis to recharge their efforts.

Robotic systems at Southern Research Institute allow UAB investigators such as Andrew West
to screen hundreds of thousands of potential compounds to find the best candidates for new therapeutics.

Screen Team

The LRRK2 project's first step was high-throughput screening—using the advanced robotic testing machines at Southern Research to analyze hundreds of thousands of potential compounds and find candidates capable of slowing down LRRK2.

They emerged with hundreds of potential compounds. Further analysis has whittled that down to the best candidates. What makes a "drug great in a tissue culture dish may not be a great thing for a preclinical candidate," West says. "We want to know how well it crosses the blood-brain barrier, if it interacts with any other protein besides LRRK2, how fast it metabolizes, if it collects anywhere abnormally in the body, and if it causes toxicity."

Medicinal chemists at Southern Research specialize in taking promising chemicals and tweaking them to make them even better. "We make very small changes," says West. "We'll put a nitrogen here, a carbon there, and look at the effects in a hypothesis-driven way."

The collective knowledge of the Southern Research scientists is an extremely valuable resource, West emphasizes. "Most of the time you only see these people at big pharmaceutical companies. The relationship between UAB and Southern Research in the ADDA is unique. I haven't seen it built anywhere else in the country, where we get a high-throughput group, drug development group, and biologists sitting at the same table every two weeks discussing the issues."

Getting Close

In the next few months, West's lab will evaluate each remaining compound in its animal models of Parkinson's disease. The best ones will then move into toxicology studies, "and hopefully next year we'll begin first-in-man studies," West says.

The team has already come very close. "We had a great candidate last year that passed all of the key measures," West says. "It went to the brain perfectly, had good potency, seemed to only interact with LRRK2, no side effects, no toxicity." But when the drug got to living models, "we discovered that the metabolism was way off the charts," says West. "It only survived 15-20 minutes in the body before it was destroyed by the liver. We were close—if we could just have slowed what the liver did by a little bit, we'd be in humans now. But it turns out that was not the right molecular scaffold."

The good news, says West, is that "we have two or three other series that are getting to that same point now." Even more important, he says, "we have a clear pipeline to go to a phase 1 clinical trial," the first evaluation of a potential new drug in humans.

Strong Local Support

It's important to note that these advances have been accelerated significantly "through local philanthropic support," says West. "There are many people in this area who are disappointed to see that the government doesn't fund a lot of research into Parkinson's disease cures. I think patients are frustrated. You get a diagnosis of Parkinson's disease and there is nothing you can do to stop it. The best advance we have, L-dopa, was developed 50 years ago. There’s really been no breakthrough like that since."

But West is convinced that is about to change. "As soon as I found during post-doctoral work in 2006 that all mutations we know about that cause Parkinson's disease increase LRRK2 activity, the next step in my career was finding somewhere I could do something about that," he says. "And the only place I found in the country was Birmingham, so I moved here immediately."

Now, eight years later, the end may be in sight. "We have to take these drugs to the next level and make them suitable for use in humans," West says. "It's a formidable trek, but I think we have some really good compounds, and more important, the right people that will get us there."

Friday, June 13, 2014

The Mix Quiz: Are You Smarter Than a Medical Resident?

Just like you, doctors love their smartphones. And they like playing games. But a new game pioneered at the UAB School of Medicine has lots more ROI than Farmville.

It's called Kaizen, a word borrowed from the Japanese auto industry that means something like "continuous improvement." This Web-based quiz game challenges medical residents at the School of Medicine's campuses in Birmingham and Huntsville with two questions every day. They're brief scenarios meant to highlight key practice skills and new evidence-based findings from a range of specialties.

Learn all about Kaizen in this feature from UAB Magazine. And test your medical knowledge with our five-question quiz below.

Friday, June 6, 2014

Hit man: A suspect emerges in the chaos of aggressive brain cancer

New research from UAB oncologist Markus Bredel identifies the splicing enzyme PTBP1 as a key factor
in the spread of glioblastoma multiforme.  

Glioblastoma multiforme is one of the deadliest human cancers. "The tumor can double in size within a few weeks," says Markus Bredel, M.D., Ph.D., a professor in the UAB Department of Radiation Oncology and senior scientist in the neuro-oncology program at the UAB Comprehensive Cancer Center. "Usually, by the time we see a patient, they often have apple-size lesions."

That explosive growth "comes with a substantial amount of genetic chaos," Bredel says. "If you look at the whole genome in a brain tumor, out of the 30,000 genes, you very often have changes in up to 50 percent; they're up or down, lost, amplified, mutated."

A Change for the Worse

Markus Bredel
But in that chaos, patterns emerge with surprising regularity, Bredel says. "When Gene A is up, Gene B is very often down." In two papers published in JAMA in 2009, Bredel's research team argued that "there needs to be a reason why glioblastomas co-select for certain genetic events. The tumor cells must benefit."

In those papers, Bredel's lab identified dozens of gene-gene links that were candidates for additional scrutiny. They focused on one particular pair: The oncogene EGFR, or epidermal growth factor receptor, which is crucial for normal cell growth and wound healing, and the tumor-suppressor ANXA7 or annexin A7. EGFR is of interest in many cancers, because it is often hijacked to fuel the aggressive growth of tumor cells.

"We found that ANXA7 is probably a regulator of EGFR," Bredel says. "So it's to the benefit of the tumor cell to knock down this regulator." But it wasn't clear at the time how this was happening. "ANXA7 resides on a different chromosome from EGFR, so it's a completely independent event, but somehow the tumor cells were disabling it," says Bredel.

Now, in a paper published May 27 in the Journal of Clinical Investigation, Bredel's lab has revealed how ANXA7 normally keeps EGFR in check—and how cancer cells manage to sabotage this system. Those discoveries have also identified a promising new target for treating glioblastoma, a cancer with few therapeutic options.

Taking Out the Trash

Normal cells have ways of dealing with proteins that get too big for their britches. Cellular structures called endosomes degrade the proteins, acting as the "trash cans" of the cell, Bredel explains. "What we found is that ANXA7 promotes the sorting of EGFR into those trash cans."

Here's one way to think about the relationship, Bredel says: "EGFR is kind of the bad guy in the cells. When it's present, it promotes the tumor process. ANXA7 is the police, which under usual conditions constrains the bad guy. But in the absence of the police force, the bad guy can do whatever he wants."

But what is taking out the police force in glioblastoma? Bredel's team started with an observation: A "long form" of the ANXA7 gene exists in normal brain cells, but an altered version appears in glioblastomas.

Genes contain the code that tells the cell's factories how to make their specialized product—usually a protein. The parts of the gene that actually contain instructions are known as exons. Each of the exons in a gene codes for the amino-acid "building blocks" that make up each protein. (In between are non-coding sections: the introns.) In glioblastoma, Bredel found, exon 6 was missing from the ANXA7 gene. "Without exon 6, ANXA7 can't sort EGFR to the cell's trash cans," says Bredel. The "bad guy" has free rein.

Follow the Slices

Clearly, something is snipping exon 6 out of the picture. But that isn't necessarily abnormal. "In the past 15 years, we've realized that gene splicing plays a role in many biological processes, both normal ones and disease processes," Bredel says. Splicing is a way to increase efficiency; it allows the same gene to produce different proteins, depending on which of the underlying amino-acid parts are used.

To turn a gene into a specific isoform of a protein, the cell's copying mechanisms cut out the exons and stitch them together to form an uninterrupted message. The cutting is the job of splicing factors, and Bredel's attention focused on one: PTBP1.

Exon 6 is what is known as a "cassette exon," or "alternative exon," a section of the code that appears in that gene in some body tissues but not others. "A cassette exon might be present in the brain but not in the muscle tissue, for instance," Bredel says. In his team's latest paper, "we figured out that the PTBP1 gene is the splice factor that cuts cassette exon 6 out of ANXA7," he continues. They also established that PTBP1 proteins are overproduced in glioblastoma compared to normal brain tissue.

So PTBP1 turns bad in cancer, guts a key exon from ANXA7, and allows EGFR to replicate like crazy. Well... not quite, says Bredel. It's even more interesting than that. "We initially thought that this splicing was something specific to tumor cells, that it might even be an initiating event that allows the tumors to emerge," he says. But when the researchers looked at a set of normal brain cells called precursor cells or stem cells, they found this same ANXA7 splicing going on. "It wasn't present in mature neurons, but in the immature cells, the stem cells, there it was," says Bredel.

Deadly Inheritance

When you think about it, that makes sense. Neural and glial stem cells power initial brain development and, as is becoming increasingly clear, allow us to learn new things over the course of our lives. They also respond to injury and disease, such as strokes and Parkinson's disease. Having a way to turn off a growth suppressor like ANXA7 is "a useful trait in the stem cell, because the stem cells wants to be able to divide and grow," Bredel says.

The UAB scientists now believe that the ANXA7 splicing in glioblastoma "is something the tumor cells inherited from the stem cells, a potential tumor-initiating ancestor of glioblastoma," Bredel says. "When that stem cell, through accumulation of mutations, develops into a tumor cell, that splicing trait is still there. And then it's exploited further by the accumulation of mutations that enhance EGFR signaling." At this point, Bredel says, "I'm not sure if we can claim this process is involved in the initiation of glioblastoma, but it certainly is involved in the progression of glioblastoma."

PTPB1's role in healthy brain stem cells means eliminating it completely isn't an option. But targeting PTBP1 with the aim of lowering production to normal levels offers exciting treatment possibilities. Bredel's lab is now identifying promising compounds that could act on PTBP1. Restoring tumor suppressors such as ANXA7 directly in cancer hasn't been successful so far, Bredel says. "Having something that is operating in excess that we can target, like PTBP1, is much easier," he notes.

"We haven't been able to make any major, clinically meaningful progress in glioblastoma in the past 20 years," Bredel adds. "We are still a long way off from being able to take this to a clinical trial in patients, but this is an exciting discovery."

Wednesday, May 14, 2014

Speed metal: This nano-discovery is a really big deal

UAB researchers and colleagues have created an ultrafast, ultratiny on-off switch out of vanadium dioxide, a material that could be the future of high-tech. But before we get there, we'll probably need to answer this question: What in the world is vanadium dioxide, anyway?

What's the fastest thing you can imagine? How about the smallest?

Well never mind, because there really is no way to wrap your head around what's going on in David Hilton's laser lab in the UAB Department of Physics.

That is to say, you're about to find out what's going on, and it's amazing stuff. Hilton and one of his graduate students, Nate Brady, are hot on the trail of what might be the magic material of the 21st century: vanadium dioxide. This strange, manmade material could be the successor to silicon, paving the way to ultrafast, ultrasmall switches that will make the current information superhighway look like a slow drive down a country road.

But all this is happening so quickly that it staggers the brain.

Nate Brady (left) and David Hilton (right) worked with researchers from Vanderbilt University and Los Alamos National Laboratory to create an ultrafast switch from vanadium dioxide, a manmade material with unusual properties.


Super Cycle

Vanadium dioxide, also known as VO2, has a curious characteristic: below 153 degrees Fahrenheit, it's an insulator; when it hits 153 degrees or higher, VO2 turns into a metal. "It changes from being transparent to being opaque," says Brady. "It's really cool, especially because it happens so near room temperature that it could be useful in a lot of devices."

Like, say, ultrafast optical switches, which use photons to transmit a signal instead of electrons. Major computer makers such as Intel and IBM see optical switches as the way out of the current stagnation in computer speeds. (To make a computer processor run faster, you have to add more power. And at a certain point, basically where we are now, going faster means adding so much power that you fry your chip—or the user's legs.)

"You haven't been able to buy a processor faster than 4 gigahertz, mostly because it's going to melt in your lap," Hilton says. We may have reached the limits of silicon. And that's where VO2 comes in.

Speed Run

In the March 12, 2014, issue of Nano Letters, Brady and Hilton, along with collaborators at Vanderbilt University and Los Alamos National Laboratory, presented work showing they had reached terahertz speeds, or trillions of cycles per second, in a VO2-based switch. Just as important, they did it using as little as one-tenth of the energy required for previous VO2 switches.

Hilton is quick to point out that this breakthrough is still a long way from your local Best Buy. "We've shown that we can flip one switch on that fast," Hilton says. "To build a processor, we'd need to show we can do a couple billion of them." Long before that point, experimental physicists like Hilton and Brady will have given way to scientists at Intel and other major manufacturers. But right now, Hilton and company are still trying to answer their burning question: What causes vanadium dioxide to change from insulator to metal, anyway?

"Lots of really smart people have tried to figure that out,” says Hilton. “This is either one of the great questions in condensed matter physics—or Don Quixote's windmill.”

A Brief History of Time

We humans have a pretty firm grasp of how long a second is. (The word "Mississippi" is often involved.) But a second is built from milliseconds, or thousandths of a second. Remember when U.S. swimmer Michael Phelps beat Serbia's Milorad Cavic at the Beijing Olympics by a fraction of a fingertip? Phelps' margin of victory was 0.01 seconds, or 10 milliseconds, a distinction so fine it took super-slo-mo video to convince the Serbian delegation it had even happened.

The next step down from the millisecond is the microsecond, or one millionth of a second. At this point, the human brain is completely out of its depth. A microsecond is to a second as a second is to 11.5 days.

Next we come to the nanosecond, which is one billionth of a second—the time it takes a 1 gigahertz computer processor to execute one cycle, or the time it takes light to travel 30 centimeters. And underneath the nanosecond is the picosecond, one trillionth of a second. In this range, you're talking about "ultrafast" research. This is David Hilton's neighborhood.

Picoseconds are a crucial part of vanadium dioxide research. So are femtojoules, the unit of measurement for how much energy it takes to make VO2 toggle between its transparent and metallic states. It's clear that VO2 would make a good switch—it lets light through when it's transparent, and blocks light when it's metallic. The problem has been that it takes a relatively large amount of energy to drive that change.

"With this work, we have lowered the threshold energy needed to undergo the phase transition"—anywhere from one-fifth to one-tenth the energy needed in the past, Brady says. The team’s VO2 switch generates ten trillionths of a calorie, or 100 femtojoules, per bit. That low energy cost “is going to make the fabrication of these kinds of devices easier," Brady says.

Pass the Picoseconds

Richard Haglund and his team at Vanderbilt are experts in manipulating VO2. For the experiments described in the Nano Letters paper, they created a version with gold nanoparticles studded along the outside like Christmas lights. The idea "is that the nanoparticles act as antennas, focusing the light onto the VO2," Hilton says. But if you can't measure the exact point at which the phase transition happens, you can't tell exactly how much energy it takes to trigger that transition. That's where Brady and Hilton came in.

In 3.3 picoseconds, light travels 1 millimeter. A picosecond is to one second as one second is to 31,700 years. In other words, it passes pretty quickly. "There's not a detector in the world fast enough to measure this," Hilton explains. "That's our specialty here is to be able to do these very fast measurements," often using what are called "pump-probe experiments." This is the realm of the ultrafast, "where 'ultrafast' is a specific word that talks about picosecond or sub-picosecond dynamics," Hilton says.

In a pump-probe experiment, the pump is an ultrafast laser beam, and the probe is a second beam that arrives at the target slightly later. In this case, the pump excites the VO2 sample, and then the probe arrives to take note of what happened. Each run offers a data point; by adding up hundreds of data points, you can begin to get a picture of what is going on.

"This is very much like stop-motion photography," Hilton says. "And the ironic thing about ultrafast research is it takes a very long time to put it together."

Green Screens

Ultrafast switches aren't the only potential use for VO2. Another application, says Hilton, is in "green energy." "You could spray-coat the windows in an office building" with a vanadium dioxide solution, Hilton says. On a really hot summer day, the heat would activate the phase transition and "the windows would darken automatically," which could pay off in lower energy bills. And unlike an existing solution, silver halide, you could simply coat current windows rather than replacing all the glass in an entire building.

At VO2's current transition point, 153 degrees Fahrenheit, this is still theoretical. "That's pretty hot, even for Alabama in the summer," Hilton jokes. "But if we could get it down to 105 degrees, that's very reasonable."

Weird Science

Ever since the early 1960s, when VO2 was first created, it has clearly had plenty of potential. But there is plenty of mystery as well. "It has some aspects of the physics of something like silicon, which is a very well-understood material, and some aspects of a superconductor, which are not nearly as well understood," Hilton says.

There are many vanadium oxides, but only this one exhibits the insulator-to-metal phase transition. And of all the other materials that undergo that phase transition, VO2 is one of the few that does so at near room temperature. (Most phase transitions happen at the kind of supercold temperatures that make them of little use for mainstream electronics.)

Gold nanoparticles are one way to crank down the energy required to drive VO2's phase transition. But Hilton and Brady have lots of other ideas. "We're actually starting to be able to figure out how to play with dials on this phase transition, making it do what we want," Hilton says.

"The big question for me is our ability to manipulate matter and actually control these transitions, versus simply digging a material out of the ground and just using what nature gives us."


Even if the VO2 switch is years away from powering your laptop, one phase of this research is already in production: Nate Brady himself. He hopes to defend his dissertation this summer and then carry on his research in a position at a national lab like Los Alamos, where Hilton also got his start.

"The Department of Energy, the National Science Foundation, Department of Defense, and Department of Education are all investing heavily in nanotechnology," Hilton says. Brady is funded by a Department of Education grant, "because we know we need more nanotechnology researchers," Hilton adds. Several other UAB graduate students are funded by similar grants.

"These agencies know we're going to live and die based on the next generation of scientists that we are training right now to have the next generation of ideas and to push this type of technology forward," Hilton says. "Attracting bright people like Nate into this field is good for UAB—and for our future as a country."

Friday, May 2, 2014

Video selfies offer a new way to teach chemistry

Can making movies make you a better chemist? UAB chemistry professor Joe March (left) and graduate student Mitzy Erdmann (right) have proven that it does. Their research-tested approach is now implemented across UAB's introductory General Chemistry curriculum.

Hollywood has nothing on the UAB Department of Chemistry. While Tinseltown studios generate some 600 movies per year, students in the university's General Chemistry course produce nearly that many each semester.

"Avatar" this is not. Each video clocks in at five minutes or less and follows a strict formula:

OPEN in a UAB chemistry lab. THREE or FOUR students take turns demonstrating a fundamental lab technique. Each speaks directly to the camera while they explain how to use a balance, how to pipette, or how to do an accurate titration.

There is no scene 2.

The teaching assistants who grade dozens of these videos each year may relish the occasional creative approaches, such as the group who adopted a "Star Wars" theme (see below), or the ones who broke for commercials. But entertainment isn't the idea. Call it sci (non)fi.

(see an example below)

Formula Flicks

These videos may never go viral, but they could inspire a new generation of students to pursue virology—or other crucial science careers. The videos have proven themselves to be a remarkably effective—and cheap—teaching tool. And considering that Gen Chem is a foundational course for a host of careers, from medicine to engineering, anything that can improve student learning—and make students more comfortable with crucial lab techniques—is a big deal.

The Coen Brothers of this movie empire are associate professor Joe March, Ph.D., and graduate student Mitzy Erdmann. They have spent the past four years proving that making movies makes for better chemists. "The impact of seeing yourself do something is greater than seeing someone else do it," March says. In a randomized, controlled trial, he and Erdmann showed that movie-making students "were twice as likely to perform a technique accurately after having shot a video" compared to a control group that received traditional, verbal instruction alone, March says.

"We are seeing that students are better prepared to go into research labs," March says. That's good news for a major research university like UAB. But it's also good news for the United States, which is desperate to boost enrollment in the STEM (science, technology, engineering, and math) fields in order to maintain its global competitiveness in an increasingly science-centered world.

Ninety-five percent of Gen Chem students are STEM or pre-health majors, Erdmann says. But few have prior lab experience. As the researchers explain in a paper now under review at the Journal of Chemical Education, "the most technically astute member of the group often becomes responsible for the majority of the data collection" in the average chemistry course, while his or her partners become little more than spectators.

Movie Studio in a Pocket

March has been pondering this problem for some time. In fact, he is something of a pioneer in chemistry tech. At the University of Wisconsin, March was part of a project called ChemPages, which included expert video demonstrations of basic chemistry lab techniques. ChemPages has been adopted at many universities. "The idea was to show students the technique before they arrived in the lab so they had an idea of what to do," he says. "But I realized it would be a lot more powerful if you could watch yourself in the video."

March pursued the idea when he came to UAB. In 2010, he and Erdmann answered their first basic research question: Was it reasonable to expect hundreds of freshmen to provide their own cameras? (Buying enough cameras for the 1,500-plus students who take Gen Chem at UAB each year was clearly out of the question.)

A survey of UAB students showed that the timing was right. "Ten years ago they would have had to buy all the equipment to do something like this," March says. "Today, every study group has at least one person with a phone capable of shooting video."

Experimental Filmmaking

With the access question answered, March and Erdmann piloted an experiment in the Summer 2011 semester. Students got a detailed rubric—in effect a shooting script that told them exactly what they needed to do for the cameras. And teaching assistants provided quick feedback, giving groups a chance to reshoot to improve their grades.

Some similar projects have been tried in upper-level courses around the country, but never "on a large scale in a freshman chemistry course," Erdmann says. The required techniques are carefully chosen, she adds: "We've picked ones they're going to use again and again."

In March and Erdmann's research study, an independent proctor evaluated the entire cohort of students as they performed the techniques in the lab. "They didn't know which students had made the videos and which had not," March says. The students who had made videos—and watched themselves in action—were clearly superior.

Encouraged by the project's success, March and Erdmann rolled it out to ever larger groups in subsequent terms. "Once we decided it was working, we expanded it to all students," March says.

Creative Chemistry

Junior chemistry major Aaron Alford was part of one of those early experimental cohorts; today he's a teaching assistant in the Gen Chem lab. "Reading through the rubric and then watching yourself do the techniques" is very effective, Alford says. "Now every time I use a balance it's like second nature—it's cemented in."

The teaching assistants walk through the lab during filming days, coaching students through the techniques and correcting any errors in form. Students are told about the video requirement at the beginning of the semester. "So far, I've only ever had one group that didn't have a smartphone or video camera of some kind between them," Erdmann says. "And we dealt with that quickly by just swapping members between groups."

Presentation only accounts for two out of the 25 maximum points for the videos, but many groups go above and beyond to add some artistry to their films. "A good three-quarters of my students do pretty substantial editing," Erdmann says.

During his time in the class, "we decided to get the footage and then dub over it with a scripted voiceover," Alford says. Then he got a roommate who was majoring in film to edit the project with professional-level Final Cut software. He did the job himself for his second and third videos, using Apple's consumer-grade iMovie application.

But students don't need to have their own video editing software. The Digital Media Commons lab in the College of Arts and Sciences is open to all students. The lab is equipped with a host of workstations and the latest video editing tools. "When we opened the lab, some of the first people who came in were chemistry students," says Rosie O'Beirne, director of Digital Media and Learning at UAB. "We're seeing a lot of foot traffic from science students."

Social Success

Enrollment in Gen Chem is soaring. "UAB is heavily recruiting science majors" to help fuel the nation's drive for STEM students, March points out. "Our enrollment has doubled in the past few years," and currently stands at more than 1,500—95 percent of whom are STEM or pre-health majors.
That makes for a lot of videos for TAs like Alford and Erdmann to watch. "When they get creative it's always fun," Alford says. "One group took a Star Wars template and put important text in that, then cut to the regular video of them doing the technique. Some use music. One group paused for commercials."
Student engagement is a key ingredient in good teaching. And it gives visual and auditory learners a chance to shine, Erdmann says. Now, "we're trying to see if we can expand it—such as having students do actual lab reports on video," she says.

The lessons could be easily adapted beyond the lab, March adds. "It's an interesting alternate assessment technique for the sciences, but I think it has implications in the humanities as well," he says. "Whenever students can see themselves in a video, it has the opportunity for more impact. And they're more likely to share the lesson with family and friends through social media. We've shown that modern technology has a good educational foundation. This opens up lots of different possibilities."