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2005-2006 University Research Professors

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Sylvia Daunert: Fabricating “Smart Pills” with Genetically Engineered Proteins

Sylvia Daunert is visualizing a “smart pill” for diabetes. But it’s not the kind you swallow. Instead it’s a matchstick-sized device implanted in the abdomen that automatically releases medication to combat each dangerous surge in blood glucose.

Why is a chemistry professor focused on diabetes? “I’m interested in all kinds of medical uses for my protein-based biosensors,” says Daunert, a native of Barcelona, Spain, who is the UK Gill Eminent Professor of Analytical and Biological Chemistry. “I love to see that basic science has real applications.”

Photo of Sylvia DaunertHer smart-pill technology unites 11 years of research on biosensors (made from genetically engineered proteins) with drug delivery and nanotechnology. Daunert's research has been supported by NIH, National Institute of Environmental Health Sciences, NSF, DOE, NASA, and the Army.

“I’ve been developing new photoproteins—bacteria that are genetically engineered to glow and emit different colors when they detect key substances.” This bioluminescence is created by altering the same proteins that make jellyfish glow.

The first application for Daunert’s proteins was detection of environmental pollutants like arsenic, and she developed different types of field tools, including paper strips and CDs. These CDs are discs with a number of tiny wells (depressions) that can hold water samples. “We put the CD in an instrument—which can be miniaturized to look like a music CD player—that analyzes all of these samples at the same time to detect target pollutants. We also use this CD technology in clinical diagnosis to detect biomolecules in the human body,” she explains, adding that these CDs are fabricated by her collaborator Marc Madou at the University of California-Irvine, who is also fashioning her smart pills.

“The smart pill technology is ‘smart’ because it delivers only the amount of drug that is needed at each particular time. The proteins will detect the concentration of the target biomolecule and respond accordingly, by opening up vials to release more or less of the drug. Marc’s group fabricates these tiny vials with lids.”

Most of the vials are filled with drugs, but others house Daunert’s proteins and, she says, because the protein vials open for only a short time, the proteins have a long lifespan inside the smart pill.

But nano-vials aren’t her only means of drug delivery. In April 2005, Madou, Daunert and her husband Leonidas Bachas (also a professor in the UK chemistry department) published a paper in the journal Nature Materials that describes a method of using hydrogels to deliver drugs inside a smart pill.

“Hydrogels look like a spongy material that swells and shrinks. Have you ever seen those toys: ‘Grow a Dinosaur?’ Those are hydrogels. You put them in water and they expand.” Daunert and her team can control this swelling and shrinking in order to sense concentrations and release drugs.

Daunert has formed two Lexington-based companies since 2000: ChipRx and SenseOmics. “ChipRx is developing the smart pills to treat many different kinds of diseases. Although we’re advancing the technology by leaps and bounds, it’s one thing to do it in the lab, and another to test it in animals, and then go through FDA approval. We’re talking 10 years,” Daunert says, but adds with a smile, “SenseOmics is now. It markets the proteins that we’re developing in the lab for all kinds of applications: smart pills, environmental sensors, medical imaging, and disease management.”

This last application holds special meaning for Daunert. “My daughter has Crohn’s disease. That’s how I met Dr. H.R. Shashidhar in the UK pediatric gastroenterology department. He knew about my research and suggested I help him develop some new methods to help patients manage their disease.” Daunert has already made some progress tailoring her bioluminescent proteins for this purpose, with funding from the NSF.

She explains that in Crohn’s disease, an inflammatory bowel disease that affects the small intestine, flare-ups are caused by a higher concentration of pathogenic bacteria than of normal bacteria. And what she’s looking at are the signaling molecules bacteria use to communicate with each other. “What we’re trying to do is analyze the saliva of Crohn’s patients to detect the concentration of these signaling molecules in order to predict if the patient is heading toward a flare-up. We could then treat a patient aggressively before the flare-up starts.”

Daunert plans to use her University Research Professorship funds to organize a series of workshops for students and faculty from diverse fields to learn about medical applications for nanodevices, and for pursuing collaborations with researchers at UK’s Institute for Molecular Medicine.

—Alicia P. Gregory

Linda Dwoskin: Creating New Treatments for Nicotine and Methamphetamine Abuse

Linda Dwoskin is looking for a few good molecules. In two related projects—one focused on nicotine and the other on methamphetamine—she is trying to find small molecules that block receptors and transporter proteins responsible for the “reward” associated with nicotine and methamphetamine use. These molecules might serve as novel therapeutic agents to help those “hooked” on the drugs, Dwoskin says, and enable them to stop using. In both of these projects, she is teaming up with UK colleagues—Peter Crooks (pharmacy) and Michael Bardo (psychology).

Photo of Linda Dwoskin“The first project is focused on discovering small molecules that block nicotine receptors, proteins located in neuronal membranes in the brain. We chemically modify these molecules. Then, we see how the new molecules interact with specific nicotine receptors and determine their ability to block the rewarding effects of nicotine,” says Dwoskin, a professor of pharmaceutical sciences.

The most promising compounds are tested in animals, in this case rats. “Our best candidate small molecules are administered to rats that are conditioned to press a lever to get IV nicotine,” Dwoskin explains. “We determine which of our compounds is most effective in stopping the rewarding effects of nicotine and, perhaps, the craving for nicotine.”

Dwoskin likens nicotine to a skeleton key. “Nicotine fits into all of these different types of nicotine receptors,” she explains. “By making different chinks in the key, we should be able to focus in on one particular lock, providing an exact fit to the specific lock responsible for nicotine’s rewarding effect and in this way obtain a compound with a nicotine-blocking action.”

She believes this work may lead to drugs that help people stop smoking, and the National Institutes of Health obviously agrees: Two years ago the NIH awarded her a grant of more than $6 million to continue the work. This was the largest single grant ever received by the College of Pharmacy.

In a second project, which Dwoskin says is much further along, she is continuing work that could lead to new treatments for methamphetamine abuse. For the past 10 years, Dwoskin, Crooks and Bardo have been focusing on a compound called lobeline, an alkaloid from American Indian tobacco. Backed with NIH funding, their methamphetamine work uses a process similar to that of the nicotine study. “Lobeline is a much more complicated molecule than nicotine, so there’s more you can do to alter its structure,” Dwoskin says.

“After determining that lobeline blocked the neurochemical effects of methamphetamine, we found that when rats that press levers to obtain IV methamphetamine are given lobeline, they don’t want the drug anymore. Even when the rats were offered larger doses of methamphetamine, they still would not work to obtain the drug. This was very encouraging evidence from animal studies,” Dwoskin says.

This was such good news, in fact, that the researchers patented lobeline as a methamphetamine-blocking agent, and Crooks and Dwoskin began working with investors in 2002 to form a company to further develop and market it. The result was Yaupon Therapeutics Inc., a specialty pharmaceutical company that develops small molecule pharmaceuticals licensed from academic laboratories.

“Lobeline, with support from the National Institute on Drug Abuse, has now passed Phase I clinical trials with flying colors,” Dwoskin says. “In human subjects given the drug, it was shown to be safe; there were no adverse effects.”

Dwoskin says she is pleased to be named as a University Research Professor for 2005-2006 and she is using this award to support a postdoc from Belarus, Russia, to work on these projects. “She comes very highly recommended and will make a great addition to our lab.”

—Jeff Worley

Stephen Scheff: Working toward Better Head Trauma Treatment

You can count on Stephen Scheff, a professor of anatomy and neurobiology at the University of Kentucky, to be exuberant and at least a little unpredictable, so his response to a question about brain injury after head trauma was almost unsurprising.

“You want to talk about some things we know about head trauma? Well, why don’t we start with what happens on the football field?”

Photo of Stephen ScheffThen Scheff, who’s been teaching brain anatomy in the UK College of Medicine for nearly 24 years, explains. “It’s well known among football players that creatine monohydrate, a dietary supplement, helps their muscles respond better and recoup faster after, say, running 40 yards at top speed then being tackled and piled on by a few 300-pound men. With creatine, the guy’s ready to go again in a couple minutes.”

Although it’s unlikely, Scheff adds, that professional athletes use creatine specifically to lessen the severity of head trauma, that is one of its possible effects. “It’s commercially available and has been found to be very neuroprotective in experimental head trauma studies.”

But what doesn’t exist yet, and this is the focus of Scheff’s current research, is a substance that is neuroprotective after brain injury.

Using brain tissue from rats and mice with induced neurotrauma, Scheff is working to understand why certain cells in the brain respond the way they do to injury. “There’s a big push now to look at the genetic make-up of those cells,” says Scheff, who has also worked diligently on various facets of Alzheimer’s disease over the years. “We’re trying to discover what kind of proteins and genes those cells express, and what happens in those cells under different conditions following an injury.”

Working at UK’s Sanders-Brown Center on Aging, Scheff and his research team—two graduate students and three technicians—take brain tissue from rats with induced injuries and examine select neurons with a technique called laser capture microdissection. These selected cells can then be subjected to a number of scientific analyses.

In this process a plastic cap is put on the tissue and a laser is pulsed at the target cells. The cap, with a piece of plastic inside, “soaks up” the cells, is removed, and the RNA and DNA can then be extracted and analyzed.

“What we can do is identify the genes that are ‘upregulated,’ which means, in this case, an increase in activity in response to injury. We hope that some of these are genes that play a role in protecting the cell. The next step is to try to find ways to regulate precisely those particular genes after trauma.”

Currently, Scheff says, there is no therapeutic intervention following head trauma that’s very successful. “But we’re working right now on a substance that looks very promising—cyclosporin.” With Pat Sullivan, an assistant professor of anatomy and neurobiology at UK, Scheff has published several articles in the past half dozen years on the use of cyclosporin as a neuroprotective agent following injury.

“Ah! Now! Think about it! We’ve got a compound we know works when given prior to the injury, and have something we know works—at least in animal models—after the injury. The question is, Are the same type of genes upregulated or downregulated when affected by these two substances? And what can we do to enhance this?”

In his work on brain injury, Scheff’s lab will “benefit nicely,” he says, from the funding that goes along with his University Research Professorship. He plans to use the money to travel to Washington, D.C., for advanced training in laser capture microdissection and to purchase newer and better equipment for his lab.

“Our findings in the months ahead just might give us a real breakthrough in how we deal with head trauma.”

—Jeff Worley

Isaac Shlosman: Building Galaxies in His Basement

The birth, life and death of a hundred billion stars plays out in silence. But this galactic drama isn’t in the heavens. Instead, it’s down two flights of stairs from Isaac Shlosman’s office.

In the cool, dim basement of the UK Chemistry-Physics building, Shlosman’s own personal galaxies pulse on a cluster of computers. Created by software written by Shlosman and his team, this 3-D, animated model may one day help scientists grasp the formation and evolution of galaxies.

Photo of Isaac ShlosmanShlosman, a professor in the physics and astronomy department, was born in Russia and grew up in Israel. He begins with a lesson in the relative size of the celestial bodies he studies. From largest to smallest are universe, galaxy and solar system. “Galaxies are the building blocks of this universe, and inside each galaxy there is the part we can see—ordinary luminous matter like stars—and the part we can’t see, so-called dark matter.”

Scientists measure dark matter by the gravity it produces. “After the Big Bang, the universe was perfectly uniform and homogenous—like an even spread of butter on toast,” he says with a chuckle. But gravity stepped in. “Because the universe is relatively young, less than 14 billion years old, gravity was only partially successful in clumping the matter. Ordinary luminous matter falls into traps prepared by dark matter, so it clumps together with the dark matter.”

This clumping forms two types of galaxies: disks (circles with spiral arms) and ellipsoids (3-D ovals). “How does the universe decide which kind to form? That’s the question we’re trying to answer with our computer models.”

Shlosman’s models start with young galaxies. “We let gravity operate virtually to clump the matter and see what kind of products we get. We form stars, and our stars age and explode and disperse energy and matter.” These simulations are rooted in reality: the latest observations from world-class telescopes across the globe “and above it,” Shlosman adds, are used to test the models.

His 14 years at UK have been peppered with stints at Lawrence Livermore National Laboratory, Cal Tech, the University of Colorado at Boulder, the Canary Islands (the location of the largest European telescope) and Hawaii (Canada-France-Hawaii telescope). Time spent with observers, combined with analysis of images from the Hubble Space Telescope, allow him to “see how the individual galaxies behave, and we use that as an advantage to form them and test them virtually.”

But a huge part of this, Shlosman notes with excitement, involves the most bizarre objects in the universe: black holes. “Our universe is infested with black holes. In the last few years we’ve learned that they sit at the center of most galaxies—including our Milky Way. Black holes are the size of a solar system, a small fraction of a light year across, but they have a billion times more material squeezed into them than a solar system.”

A lot of junk is flying around in space, and black holes are galactic trash cans, but, Shlosman adds, this trash doesn’t just fall into a black hole. “It’s like a bathtub full of water. You want to empty the tub, so you pull the stopper. The water doesn’t rush straight down. It goes in spiraling.” Because of this, the space junk which closes in on a black hole forms a rapidly spinning disk. As it gets closer and closer it is squeezed by the black hole’s gravity and it heats up to hundreds of millions of degrees.

Heat makes light. “This material emits every possible color of visual light, and infrared, X-ray and gamma rays. This is the most luminous stuff in the universe.” The assembly of this superheated space junk is called accretion, and its motion around a black hole is what scientists call an accretion disk.

In 1989 Shlosman says he was contemplating this question: What is the source of gas in accretion disks around black holes? The prevailing theory was that the gas had a local origin—“Say, deposited by stars in the vicinity of the black hole. I took a different view—that the gas is supplied to the black holes from large distances, basically from the whole body of the host galaxy and beyond. My point was that there is a causal connection between the evolution of the galaxy and the evolution of the black holes in their very centers.” Shlosman and two colleagues published this theory in Nature magazine in 1989 and then a commissioned review article on the same subject in 1990.

“Ten years later new data started to come in, and it seems there is a tight correlation between the masses of black holes and the velocities of stars 3,000 light years away from them.”

Much more can be learned about black holes, Shlosman says. He is recruiting a new postdoc, funded by the University Research Professorship, to tackle this subject as part of his team.

—Alicia P. Gregory

The UK Board of Trustees first awarded University Research Professorships in 1977. The goal of these $35,000, one-year professorships is to enhance scholarly research and awareness of UK's research mission by recognizing outstanding faculty.

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