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

UAB research rides into space on a Dragon

In 1992, UAB's Larry DeLucas, O.D., Ph.D., went into space aboard the Space Shuttle Columbia to conduct protein crystal growth experiments in orbit. Imaging protein crystals has great potential for drug discovery efforts; a good picture of a protein's structure can provide invaluable information to scientists looking for new ways to alter that protein in order to treat disease. The problem is, Earth's gravity interferes with protein formation. The gravity-free environment of space is much more conducive to crystal formation.

Today, DeLucas is director of the UAB Center for Biophysical Sciences and Engineering and principal investigator on a $6 million project to demonstrate the scientific and commercial potential of protein crystallization. (Learn more in this story from UAB News.)

Nearly 100 difficult-to-image proteins will soar into orbit on the SpaceX Dragon spacecraft.

In the meantime, check out the Dragon in this SpaceX video:

Murder, golf carts, and unintended consequences

In his bestselling book Freakonomics, University of Chicago economist Steven Levitt, Ph.D., showed how sophisticated math—and a knack for asking the right questions—can uncover "the hidden side of everything," from the bare-knuckle finances of a crack-dealing gang to the very real dangers of suburban pools.

You could say that Griffin Edwards, Ph.D., an assistant professor in the Department of Marketing, Industrial Distribution, and Economics in the UAB Collat School of Business, is taking freakonomics to court.

Edwards entered college "trying to figure out if I should be a lawyer or an economist." He ended up combining the two. Edwards specializes in empirical legal studies, a young discipline that applies the high-powered statistical methods of economics to lawmaking. By crunching everything from murder rates to crop yields, he is revealing the unintended consequences of mental health legislation, Prohibition, and more.

To Warn or Not to Warn
For decades, mental health professionals have chafed against "duty to warn" laws, which require them to notify authorities if their clients threaten others or themselves.

These laws can be traced back to a landmark California Supreme Court decision, Tarasoff vs. Regents of the University of California. Tarasoff was a young woman murdered in October 1969 by an unbalanced graduate student who had previously confessed his intentions to his psychologist.
In the years since, 43 states have passed so-called "duty to warn" laws. Some require mental health professionals to warn the authorities or the threatened party. Others say professionals can warn at their discretion.

Griffin Edwards

Giving a warning "may seem like a reasonable response, but from a psychologist's point of view, it is not," Edwards says. "They argue that the whole reason the doctor-patient relationship works is that everything said is confidential." According to mental health professionals, such laws make it less likely that potential victims will be protected, because patients will be less likely to divulge violent plans—and that means fewer opportunities for professionals to intervene through counseling.

"This debate has been going on for years," Edwards says, and determining an answer is not obvious. How can you tally up the number of people who were prevented from murder, or suicide, by a psychologist's warning? That is the goal of the law, after all, to stop these events from happening.

Unintended Consequences
Edwards came up with a solution: If the mental health professionals were right, there should be an increase in suicides and murders in states after these laws are passed. But you need to be careful to tease out this signal from a sea of other possible contributing factors. For example, suicide rates are higher in the Pacific Northwest due to the gloomy weather and plentiful supply of isolated bridges, Edwards points out.

Murder rates fluctuate as a factor of policing strategies, drug violence, and a host of other reasons.
So Edwards compared statistics from states after they passed duty to warn laws to the data from the same states prior to passing the laws. Then he compared that difference to the numbers from one of the states that have never passed duty to warn laws. Using econometric techniques, "I'm able to control for a lot," Edwards says. "This allows me to infer something similar to a randomized controlled trial, but with laws and states instead of individuals."

What happened? "I found that the psychologists are right," Edwards says. In a paper published in 2013 in The International Review of Law and Economics, "I found that these laws actually increase suicides among teens, but have no effect on adult suicides," he notes.

In a separate paper forthcoming at the Journal of Law and Economics, Edwards found that "homicides increase by anywhere from 5 to 7 percent" after mandatory duty to warn laws are passed. "Permissive" laws, which say mental health professionals can warn potential victims or the police, had no statistically significant effect.

"We tell our students that the great thing about economics is it's the study of everything," Edwards says. His own research interests range from mental health legislation to the effects of golf cart use on a player's score. "I try to do research that's not totally boring to my wife."

Edwards is now examining involuntary commitment laws. "Every state has a different length of time you can commit someone involuntarily if you suspect they are a danger to themselves or others," he explains. In some states the period is three days; in some it is three years. He wants "to see if locking someone up is actually stopping the crime from happening or just delaying it."

Grain and Greens
Edwards's interests range far beyond mental health. "We tell our students that the great thing about economics is it's the study of everything," he says. He has used official government data on hops and barley crops to estimate how much people were drinking during Prohibition (not as much as you may think), and pored over medical records to determine the effects of Prohibition on infant health (banning alcohol was good for babies).

Edwards is "really excited" about a new paper on golf carts and player performance—a question that caused an uproar in the early 2000s. Casey Martin, a talented golfer born with a degenerative knee condition that makes him unable to get around the course without a cart, sued the Professional Golf Association (PGA), which wouldn't let him use a cart in its mandatory Qualifying School. His case made it to the Supreme Court. The justices agreed with Martin's lawyers that the Americans with Disabilities Act applies at Pebble Beach and Augusta National just as much as it does in any other public place.

Many commentators were outraged. "Lots of people were saying, 'He's ruined sports; pretty soon we're going to see quarterbacks on crutches and referees with seeing-eye dogs,'" Edwards says.
The PGA and its defenders argued that walking was a crucial part of the game. But, Edwards wondered, how much of an advantage did Martin really get from his cart?

Searching for evidence, Edwards hit on a quirk of NCAA scheduling for college golf tournaments. Because these events need to be fit into a single weekend, all players use carts on one tournament day, and walk the other day. Analyzing hundreds of tournaments, Edwards found that players scored worse rather than better when they drove carts. (Possibly because the trudge to the next tee helps a player burn off steam from a bad shot on the previous hole, and gives that player a chance to visualize the approach needed on the upcoming hole, Edwards speculates.)

"It actually makes you better to walk," Edwards says. "So not only does it not give him an unfair advantage, it actually puts him at a disadvantage. The point of that paper is, maybe we could be a little more accommodating to people with disabilities."

There is evidence that judges are beginning to cite empirical legal studies research in their opinions, Edwards says—a trend that should continue as the discipline matures. But Edwards also has another motivating factor: "I try to do research that's not totally boring to my wife," he says. "Something she can at least pretend to be interested in."


Related:

The UAB Collat School of Business now offers completely online degrees in economics, finance, management, and marketing. Learn more here.

A self-portrait in cells: Grad student gets cheeky with art show entries

"Les Demo-cells d'Avignon"

Pablo Picasso's angular, proto-Cubist "Les Demoiselles d'Avignon," painted at the dawn of the 20th century, is one of the foundational works of modern art and a jewel in the collection of the Museum of Modern Art in New York City.

UAB doctoral student Shane Kelly's "Les Demo-cells d'Avignon" (above), currently on display in The Edge of Chaos as part of the annual UAB School of Medicine Art Show, represents new movements in 21st century art and science. "Les Demo-cells" is one of three micrograph images that Kelly has entered in the show. [His two other entries were also inspired by great art: "Cell-Flowers," from Vincent Van Gogh's blockbuster painting "Sunflowers," and "Arigato," whose robot-like appearance reminded Kelly of the classic Styx rock anthem "(Domo Arigato) Mr. Roboto."]

All three images are fluorescent confocal micrographs of cheek cells. "Some are my own and some from friends," Kelly explains. Separate fluorescent probes highlight DNA, the plasma membrane, and actin in the images. The art is definitely an "extracurricular project," says Kelly, who is a graduate research assistant in the lab of microbiologist David Bedwell, Ph.D. He thought it would be fun "to create a type of personal cellular art" by imaging his own cells, inspired by "DNA art" companies such as DNA11.com, which turn DNA samples into poster-size prints.

"Cell-flowers"

Kelly's studio is the "mini lab" he built at home. He scoured eBay to buy the centrifuges and other equipment he needed to collect and stain the cells. "Then I rent a microscope from UAB's High Resolution Imaging Facility to acquire the images," he says.

Kelly learned how to use fluorescent confocal microscopy under the tutelage of Shawn Williams at the High Resolution Imaging Facility as part of his day job in the Bedwell lab. Bedwell, a leading cystic fibrosis researcher, is focused on "inducing translation read-through of premature termination codons in order to treat patients with genetic disease," Kelly says.

Roughly 10 percent of patients with cystic fibrosis have a mutation in the CFTR gene that results in a premature "stop" codon, preventing the gene from working properly. Bedwell's lab has identified drugs that suppress these "stop" mutations in experimental models.

"Arigato"

"The idea being if a patient has a mutation in a gene that is a stop codon, the patient could take a drug that would allow the translating ribosome to 'read-through' the stop codon and produce the full-length protein," Kelly says. Ultimately, the approach could be applied to treat a wide range of genetic diseases.

Kelly's own work focuses on autophagy, a natural process by which cells rid themselves of "unwanted, unneeded, or damaging proteins," he says. "I'm studying how autophagy is controlled at the messenger RNA level," particularly when a cell is starved of nitrogen. Autophagy mRNA is known to be upregulated during nitrogen starvation, which increases the production of autophagy proteins. "We are studying how this occurs and will be submitting a manuscript of our findings soon," Kelly says.

Technological leaps make multiple, kidney-swapping surgeries more common

Chronic kidney disease affects 26 million American adults, with millions of those affected unaware because there are no symptoms until the disease is severe. When a person’s kidneys fail, they can go on dialysis or try to get a kidney transplant, which provides a better quality of life. The latter options requires that a friend or family member be willing to donate one. Otherwise, they face many years on a waiting list. 

But what if you have a donor who is not a match, which means the donated organ will be rejected by your immune system?  

The answer in Birmingham is UAB’s paired exchange and incompatible transplant programs. Ann Marie Reynolds, Gwendolyn Goldsmith and Frank Peters each needed a kidney and had a donor lined up that turned out to be incompatible. The swapping enabling them to be entered into a database that made all participants more likely to get a kidney, and this powerful story by UAB’s Tyler Greer describes their recent three-way transplant surgery.   

Their multiple, living-donor transplant has made it possible for each patient to live free of the constraints of dialysis for what doctors hope will be at least a decade and maybe two. Each of those who donated the kidney did so even though they knew their organ would be going to someone other than their family member or loved one. By the end of 2013, UAB is expected to complete perhaps 30 kidney swap transplants as part of the program.

A team of UAB surgeons, physicians and researchers in UAB’s Kidney/Pancreas Transplant Center has assembled and developed the technologies needed to make the multiple surgeries successful. We thought to talk to one of the UAB surgeons who oversaw the three-way transplant that day, Dr. Jayme Locke, and to ask her about this emerging field and what it means for patients. 

Show notes for the podcast:

1:52  The kidneys filter the blood, divert waste into urine and return useful proteins to the bloodstream. but can be damaged by diabetes, high blood pressure and cancer. 

3:00 As diseases progress, the kidneys become less and less able to function until they fail, at which points patients either go on dialysis, a mechanical system that filters the blood, get a kidney transplant or die. 

3:51 The field has shifted over the years from implanting kidneys from a stranger who recently died to organs donated by living people known to the recipient. In the United States there are about 100,000 people waiting for a kidney, but only 10,000 and 15,000 transplants done a year. The need far outweighs the supply, and those who have a family member willing to donate a kidney instead of going on a waiting list (ten-year wait in Alabama for some) has a tremendous advantage.  

5:12 It is important to note that about 35 percent of people who come forward and volunteer to donate a kidney to loved one are found to be incompatible with their would-be recipient. They have a blood type that means the recipient's immune system will immediately attack the donated organ and prevent it from functioning. Another 11 percent of willing donors will be found to be tissue incompatible. So almost half of would be donors cannot donate to their intended recipient. 

6:10  Paired exchange and incompatible transplant programs were born to address this problem, and to make it possible for many to get kidneys that would not otherwise happen.

6:37:  Paired exchange programs started in single hospitals, and now national databases have begun.  At UAB, the list of would be donors and patients is so large that the database locally is effective at making swaps possible in Alabama.

7:37: Ann Marie Reynolds, one of three patients in the transplant swap described above, has had three kidney transplants over the last 25 years. Some patients need more than one transplant because of rejection (sometimes years later) or because a systemic disease comes back in the new organ. Getting a second transplant is more difficult than the first because patients become sensitized. 

8:44 We all have labels on our cells that say self (made of a protein called human leukocyte antigen or HLA). Our immune system looks for this tag and spares self-labelled cells from immune attack, whereas those with other tags like bacteria are targeted. Thus, the goal is to find a transplanted organ made up of cells with an HLA that matches pretty closely with the patient's own tags. In the last ten years, researchers have developed the technology that enables patients to overcome some degree of mismatch if their blood and tissue types are close enough.  

10:30 Dr. Locke discussed the work of UAB's Dr. Roz Mannon, whose specialty is keeping the immune system from attacking a transplanted organ over the long term. While the field has gotten very good at preventing transplant rejection in the first year, gradual damage can cause the organ to fail five years later.

11:10 One approach to preventing long-term rejection, says Dr. Locke, is to find people better blood and tissue matches in donated organs in the first place. By carefully testing the expanded pool of potential donors and recipients in a swapping system, the chances increase that each patient will not only get a kidney, but a better matched kidney.  

11:45 The transplant researcher community also continues to work urgently to improve immunosuppressive medications such that they stop immune attack on a transplanted organ without making patients overly vulnerable to infections. UAB is a national leader in this regard, participating in several, ongoing clinical trials. 

12:57 A unique team at UAB makes multiple swap transplant operations possible. In some cases, six operations are underway at the same time, which requires skilled support by teams of nurses, anesthesiologists, pharmacists, etc., both in preparation and follow up to surgery. This tremendous and coordinated effort by UAB Nursing is led by people like Katie Stegner who runs the operating rooms and Debbie Sparks, the nurse manager on the kidney floor. 

15:35 The living donors that make the swapping system possible are willing to sacrifice part of themselves for their loved ones, a choice that has Dr. Locke's respect. Beyond that are those that chose to donate an organ into the system in honor of a family member or friend, hoping the swap system can give an organ back to that loved one. 

17:28  Dr. Locke would like to see a truly national swapping system develop, one that was not for profit. The huge size of such a database would make a great difference for many more patients in need of transplant. 

 

Image post 10: stunning vertebra makes contest list

This image shows a lumbar vertebra from a mouse with its back to the upper-left and its belly to the lower-right. There are muscle fibers in the upper-left corner, cartilage in blue merging into bone in green at the ends of the vertebra, red blood cells in the middle and intestinal contents in orange in the bottom-right corner. The image, which won 13th place in the Nikon Small World Contest, was captured by Dr. Michael Paul Nelson in the Division of Neuropathology, part of the Department of Pathology within the UAB School of Medicine. Dr. Nelson says he created this image, not for a specific research goal, but instead to help him understand aspects of mammalian anatomy. The tissue sample in the image was prepared with a series of dyes and was revealed when Dr. Nelson switched his microscope to fluorescent mode.

When he took the image, Dr. Nelson was attending the Immunohistochemistry and Microscopy Short Course offered by the Histochemical Society at the Marine Biological Laboratory at Woods Hole, MA. Also credited for the Nikon content entry was Samantha Smith, the representative from Carl Zeiss Microscopy who helped Dr. Nelson with technical aspects of using a Zeiss microscope.