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 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.

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.

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.

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:

SCENE 1, DAY

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.

There and back again: Space protein research at ISS, in Smithsonian

The SpaceX Dragon 3 capsule, carrying crucial protein crystal experiments from UAB, docked to the International Space Station on April 25. Image courtesy SpaceX.

On April 18, UAB's protein crystal experiments leapt into orbit aboard the SpaceX Dragon rocket. Check out some very cool photos and follow the mission live at www.spacex.com/webcast/. The experiments will take place aboard the International Space Station; want to find out when it passes overhead? Just visit the live tracker here.

While that work is going on in orbit, you can learn more about the history-making aspects of UAB's protein crystal expertise on the ground — in an exhibit now on display in Washington, D.C.

UAB-developed hardware from space shuttle missions in 1992 and 1995 is part of the "Moving Beyond Earth" gallery at the Smithsonian's Air and Space Museum. The equipment was first flown aboard the space shuttle Columbia from June 25-July 9, 1992, in the first flight of the U.S. Microgravity Laboratory-1. UAB's Larry DeLucas, who is principal investigator of the research now taking place at ISS, was a payload specialist on the 1992 flight.

Learn more about the exhibit here, and find out more details on research in UAB's Center for Biophysical Sciences and Engineering here.

Cable guys: Inside UAB's high-tech, custom-built approach to eye science

This machine, designed and built by UAB vision researcher Crawford Downs, is producing ultra-clear images of a key structure implicated in glaucoma, the world's second leading cause of blindness. See the machine in action in a video below.

The miracle of sight relies on a masterpiece of wiring. More than a million individual nerve cells scattered around the eye convert visual information into electricity. Then these individual cells are bundled together at the back of the eye into the optic nerve, which carries the signal to the brain.

Problems with this central cable are at the root of glaucoma, the world's second leading cause of blindness, after cataracts. The underlying causes of this optic nerve deterioration are still poorly understood. But a pioneering group of researchers and clinicians at UAB are exploring a new paradigm that could revolutionize our understanding of glaucoma and other eye conditions, including myopia and keratoconus.

The approach, known as ocular biomechanics, applies engineering principles to the eye. By creating detailed models of key eye structures, then stress-testing them in computer simulations, the scientists aim to identify the features of individual eyes that lead to glaucoma.

The work is led by J. Crawford Downs, Ph.D., vice chair of basic science research in the UAB Department of Ophthalmology and director of the new UAB Ocular Biomechanics and Biotransport Program, and Christopher Girkin, M.D., chair of the UAB Department of Ophthalmology. It has attracted the attention of the National Eye Institute, which awarded Downs and Girkin a $1.125-million grant in early 2013.

Zooming In on Glaucoma
Downs' efforts are focused on the lamina cribrosa, which acts as a mechanical seal at the optic nerve head where the optic nerve passes out of the back of the eye on its way to the brain. "The optic nerves go through pores in that structure," Downs explains. "It's also the place where the nerves get damaged in glaucoma. We want to understand the mechanics of the lamina cribrosa and what it looks like in three dimensions. That’s a key to understanding glaucoma biomechanics."

The problem is that this tiny structure—"it's about the size of a pencil lead," Downs explains—doesn't respond well to conventional microscopic imaging techniques. "Every time you put a section of the tissue on a slide for imaging, it's always warped or folded or stretched, so you can’t stack up successive images into a 3D structure" Downs says. So he built his own machine to do the job.

(See video below.)





This “fluorescent three-dimensional histologic reconstruction device” slices away tissue 1.5 micrometers at a time (about 1/100th the diameter of a human hair), snapping high-resolution pictures of the remaining tissues as it goes. With a volumetric resolution about 5 million times better than the best MRI, "I can see cell bodies with this technique," Downs says.

He reveals an engineer's pride in the clever details of his creation. For instance, the device automatically e-mails him a picture every 100 frames and texts him if it runs into problems. That way he can monitor the process remotely and allow the machine to run 24 hours a day. "There are only two in the world—the one here at UAB for eyes and one we built for colleagues at Imperial College London to study osteoarthritis in mouse knees," Downs says.

An individual image from Downs' machine

Image to Insights
Downs's first 3D rendering of the lamina, built from around 1,500 individual images, is just the beginning. Because everyone's lamina cribrosa is different, he is building a library of digitized models of laminas from the eyes of patients with and without glaucoma, as well as laminas from patients of different ages and ethnicities. "We can put the models in a computer, apply pressure to them, and simulate what happens mechanically," Downs says.

3D rendering of the lamina cribrosa

Downs was one of the first biomedical engineers to take up the study of the eye; now he is making UAB the hub of the rapidly growing field of ocular biomechanics. He has already recruited a team of fellow bioengineers to tackle complex problems in glaucoma and other eye diseases. Raphael Grytz, Ph.D., is studying the growth and remodeling of the sclera and lamina cribrosa; Massimo Fazio, Ph.D., is developing new, ultra-precise tools to measure scleral deformations with pressure and track deformations in images; and Vincent Libertiaux, Ph.D., is simulating how the optic nerve head reacts to different intraocular pressures. "We're one of the biggest groups in the world," Downs says.

Left to right: Massimo Fazio, Crawford Downs, Vincent Libertiaux, and Raphael Grytz

Defining Disparities
The gulf between surgeons and basic scientists isn't so wide in a specialty such as ophthalmology, where clinicians are used to doing their diagnosis at the tissue level. "I like to say that ophthalmologists are in vivo histopathologists," Girkin says.

Girkin's research is focused on health disparities in glaucoma, particularly in identifying why African Americans are at increased risk. Research by Downs and Girkin has helped uncover "some fundamental structural differences between the eyes of individuals with sub-Saharan African ancestry and those of individuals with European ancestry that may account for this elevated risk of glaucoma," Girkin says. "If we can define these differences we can target not just African Americans but anyone who is going to get glaucoma."

This basic research complements UAB's glaucoma service, which is among the nation’s busiest, Girkin notes. In addition to evaluating new treatment options, including laser therapy and minimally invasive surgeries, “our clinical research is looking at detection methods to allow us to find glaucoma earlier than ever, along with discovering novel pathways to treat this blinding disease," Girkin says.
In a pilot program led by Girkin, UAB's Department of Ophthalmology has installed sophisticated imaging devices in the offices of two central Alabama independent optometrists who are located adjacent to Walmart Vision Centers, with a centralized image-reading center housed at UAB.

(Learn more about the program in the video below.)




Toward Early Detection
The optical coherence tomography machines provide high-resolution images of the back of the eye. An optometrist can detect the earlier stages of glaucoma in those images, even before symptoms appear. Images of a patient’s eyes are electronically transmitted from the imaging machines at the optometrist’s office to the UAB center for confirmation of the diagnosis. UAB’s trained glaucoma specialists can then confer with the optometrist on complex cases to determine an appropriate treatment regimen. Patients who undergo the glaucoma testing also receive a dilated comprehensive eye exam and educational materials about glaucoma.

“This is an excellent example of the value of translating technology that has been evaluated and fine-tuned in the research setting and employing it in the field for the betterment of patients,” Girkin says. “This provides better access to care and better delivery of care within these hard-to-reach populations.”

The ultimate goal is to develop a noninvasive, image-based test "that a clinician can do in five minutes," Downs says. A human trial is at least a decade away, he predicts, but success would bring dramatic benefits: "You could cut the costs of treating glaucoma in half," saving billions of dollars per year.


Learn More
UAB Department of Ophthalmology

Ocular biomechanics at UAB

Research areas, UAB Department of Ophthalmology