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Thursday, Sept. 29, 2005 12:20 am

The SIU explorers

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Research at the Southern Illinois University School of Medicine brings in $25 million a year in funding but, scientists say, their efforts are more about hope than about dollars and cents.

Working in laboratories in Springfield and Carbondale, they seek breakthroughs to ensure lifelong sharp hearing, a dependable night’s sleep, a life without cancer, and the prevention of such age-associated disorders as Alzheimer’s disease, heart disease, and diabetes.

That’s a lot of hope — and a lot to hope for.

SIU School of Medicine has more than 100 researchers; seven of them recently told Illinois Times how external funding supports the pursuit of science and fuels research in the laboratories. They shared hopes and dreams for their work and visions of a better life for all of us.

Every single day, as part of their mission, SIU School of Medicine researchers and colleagues in associated hospitals are among 123 schools of allopathic medicine seeking medical breakthroughs and innovative approaches to prevention, diagnosis, treatment, and cure.

Of the $25 million annual investment in research at the SIU School of Medicine, 45 percent comes from competitive awards by federal sources such as the National Institutes of Health, the Department of Defense, and the National Science Foundation — federal tax dollars returning to the community.

Another 20 percent represents competitive grants awarded by such national foundations as the American Diabetes Association, the Tinnitus Research Consortium, the Ellison Medical Foundation, and the American Cancer Society. These dollars come from fundraising campaigns, walk-a-thons, and private donations. The money, channeled through local, state, and federal organizations, supports research at the medical school.

Only about 15 of every 100 grant applications submitted to the NIH result in money for the research studies their authors propose — so the fact that money ends up in Springfield and Carbondale attests to the skill and merit of the scientist, as well as to the quality of the research.

Scientists must first develop and write grant proposals that describe their ideas and methods of investigation. Committees of other scientists review and judge the quality of each idea. This committee of peers decides whether the scientist has the expertise and requisite resources to complete the research as it’s been proposed. Only the best scientists and projects actually receive money. The process is time-consuming, grueling, and highly competitive.

Clinical trials — the ultimate translation of basic-science research into prevention, treatment, and cure — account for another 30 percent of SIU School of Medicine research funding. For patients, these trials, funded mainly by pharmaceutical companies and the NIH, represent local access to cutting-edge treatments and disease prevention.

Six of the researchers interviewed by IT have earned national and international recognition for their work in their specific areas of biomedical research. The seventh is starting what promises to be an exciting and successful career worth following.

MARY PAUZA, Ph.D.
Assistant professor, Department of Medical Microbiology, Immunology, and Cell Biology Research question: What causes type 1 diabetes, and how can it be treated and prevented? Funding: $628,500 (Juvenile Diabetes Foundation, ADA, NIH)

The media have given us an appetite for headlines trumpeting the discovery by some superstar scientist of a novel insight about a complex disease such as diabetes, but breakthrough discoveries and real scientific understanding rely on the self-disciplined day-to-day work of thousands of individual scientists in laboratories around the world.

Pauza focuses her research on type 1, or insulin-dependent, diabetes. She spends much of her time studying the T-cell, a kind of lymphocyte (one of several types of white blood cells found pulsing through our bloodstream along with red blood cells and platelets). Red cells carry oxygen throughout our bodies, platelets prevent bleeding, and white cells command our immune systems, fighting foreign invaders such as infection and triggering autoimmune diseases, among them type 1 diabetes.

Pauza can describe T-cells in detail, right down to explaining what each molecule on the surface of the cell does.

In her laboratory, Pauza modifies the function of T-cells, manipulating the molecules they contain by turning them on and off. She makes the cells do tricks, first expressing one function and then another, in a quest to understand why T-cells go awry and help trigger autoimmune diabetes. She has discovered that when she makes a T-cell perform one particular kind of trick — turning on molecules that inhibit their aggressive tendencies — she delays and perhaps even stops the development of autoimmune diabetes. This is one promising road to prevention of the disease. Every day in their Springfield laboratory, Pauza and her team seek to learn how this molecular strategy works to prevent diabetes.

What drives Pauza? She says she’s “motivated mainly by a strong desire to uncover new information and to teach others” and adds, “Work that uncovers new knowledge that goes against current dogma or existing paradigms is the most exciting and rewarding.”

ANDRZEJ BARTKE, Ph.D.
Professor of physiology, director of geriatrics research Research question: How do genetics and caloric restriction contribute to longer and healthier life? Funding: $9.7 million (NIH, Ellison Medical Foundation)

Andrzej Bartke has dedicated his research career to learning just how life goes on . . . and on . . . and on.

Early in his career, Bartke wondered how hormones triggered reproductive competence — or simply put, fertility and the drive and desire for sex. Specifically, he discovered that the production of prolactin, which is turned on by light — in nature, by the length of the day — leads to heightened levels of male sex hormones, interest in mating, and therefore reproduction in male hamsters. Bartke describes the finding as exhilarating, “a feeling of figuring out how things work, of improving understanding.” He and his team built on information that was already out there and, he says, were able to “connect the dots.”

This was the first time we could manipulate the male reproductive activity with the hormone prolactin [and] turn the whole thing on with just one hormone,” he says.

Ten years or so ago, Bartke made another observation that has brought him international recognition. “Genetically dwarf mice live about 50 percent longer than their normal-sized siblings, which was opposite of what you would expect,” he explains. He found that the dwarf mice had lower concentrations of three substances — growth hormone, insulin-like growth factor-1, and insulin — than did normal mice. Why?

Bartke noted that normal-sized mice fed a nutritious diet containing fewer calories than their usual diet appeared to live longer, healthier lives, just like their dwarf counterparts. In 2003, he was named the recipient of the inaugural Methuselah Mouse Prize for having, at the time, the longest-lived mouse in the world.

But Bartke’s work is not about just prolonging life; it’s about understanding and preventing such age-related conditions as heart disease, type 2 diabetes, and Alzheimer’s disease. Bartke is adamant that caloric restriction is not malnutrition. In fact, he says, the experimental diets are carefully prepared to ensure adequate nutrition, although the total amount of food — and therefore the calories — is restricted. The animal’s system consequently becomes insulin-sensitive, and obesity and various age-related diseases are avoided. Can these findings be applied to human beings? Bartke says, “If insulin resistance is as bad for people as it is for mice — and we know that insulin-sensitive mice live longer — it is not too far an extrapolation to assume that improving insulin sensitivity would make people younger, live longer, and be more healthy.”

CAROL BAUER, M.D.
Associate professor, Department of Surgery, Division of Otolaryngology–Head and Neck Surgery
Research question: What causes tinnitus, and how can it be treated and prevented? Funding: $1.9 million (NIH, Tinnitus Research Consortium)

If you have tinnitus — ringing in your ears — you are in famous company. Barbra Streisand ascribes her volatile temper to the ringing she has been hearing since she was 7, and William Shatner and Leonard Nimoy each suffer as a result of prop explosions on the set of the original Star Trek TV series.

Carol Bauer’s research is focused on why tinnitus occurs and how it ultimately leads to deafness. Bauer explains that within the cochlea, that spiral portion of the inner ear, are about 10,000 hair cells, “little microphones.” These cells are constantly searching for sound; when they are damaged in some way, the brain misses the sound and literally turns up the frequency, or the “gain,” so high that the affected individual begins to experience tinnitus.

Bauer and her team have demonstrated that when hair cells in the cochlea are subjected to overstimulating and damaging sound — noisy farm equipment, rock concerts, explosions — the hair cells lie down “like a field of wheat after a tornado,” she says. Sometimes that damage is temporary, and the hair cells regain their stance and function. But repeated assaults over time or when the damage is severe, the condition may intensify and become permanent.

This research has led Bauer and her team to examine the nerve fibers leading from the hair cells in the cochlea to the brain. She has found that a drug called gabapentin relieves tinnitus in some but not all patients. Why? That is one of the many questions Bauer and her team are asking.

KOUNOSUKE WATABE, Ph.D.
Professor, Department of Medical Microbiology, Immunology and Cell Biology and Cancer Institute Research question: What is the genetic basis of preventing cancer cells from metastasizing? Funding: $2.5 million (NIH, National Science Foundation)

Kounosuke Watabe plays go, an ancient Asian board game that requires discipline and concentration. Two players — one controlling black stones, one controlling white — battle to increase the territory they hold and try to capture the opponent’s stones.

Watabe conveys the same intensity and clarity of purpose when he talks about his effort to defeat cancer.
Watabe and his colleagues have identified genes — specifically, KAI1 and DRG1 — known as metastatic suppressor genes, that, when present and “turned on,” play a significant role in containing cancer cells and keeping them from metastasizing. Metastasis — the spread of cancer from one part of the body to others — is, Watabe says, the main event leading to death in 95 percent of the patients with cancer. Watabe and his research team want to figure out how the genes and the proteins they produce work. They know that when greater amounts KAI1 protein are present in the body, cancer cells do not wander from their primary site. This knowledge allows a surgeon to identify and remove a primary tumor with confidence that the cancer will not recur. But when the KAI1-regulated protein is present in low amounts, the risk of metastasis and danger of death are amplified.

Because the KAI1 protein is a factor in all cancers, it serves as a marker of the risk of metastasis, as well as a target for therapy and prevention efforts. Watabe and his collaborators have identified a protein that KAI1 recognizes and binds to. This protein is expressed on the inner layer of blood vessels. When a cancer cell enters the bloodstream and sticks to this molecule, the cell dies. Now Watabe, backed by his team, is “teasing out the players, one by one,” just as he would construct a strategy on the go board.

The goal, then, is to surround and eliminate the enemy, the cancer cell, by designing a drug that mimics the protective protein. Watabe holds out the optimistic guess that this work will take another three years before a drug similar to the protective protein is ready for human trials. He has been working on the project since 1996.

SOPHIA RAN, Ph.D.
Assistant professor, Department of Medical Microbiology, Immunology, and Cell Biology and Cancer Institute Research question: How does a cancer metastasize? Funding: $320,000 (Department of Defense, American Cancer Society, Penny Severns Breast and Cervical Cancer Research Fund)

In her hours outside the laboratory, Sophia Ran reads detective stories, admiring flawless logic and loving the surprise of whodunit. On the job, Ran works to solve a murder mystery of her own, trying to understand how a tumor grows the blood and lymph vessels that allow cancer cells to spread throughout the body and form secondary tumors. “Those guys are the killers,” Ran declares, as emphatically as if she were Hercule Poirot, solving a crime in an Agatha Christie novel.

On only few occasions do blood and lymphatic vessels form naturally — within the embryo, within the healing wound, during the menstrual cycle. The adult organism does not need new blood or lymph vessels, Ran says, so when new vessels begin to grow in an adult — for instance, when a cancer invades the body and moves to take over the system for its own nourishment and survival at the expense of the healthy body — it is always “a sign of disorder.”

Ran and her colleagues seek to unravel the mystery by which lymph vessels, in particular, begin to grow in cancerous tumors. They understand that a complex molecular mechanism induces the pathological growth. But how? Recent evidence suggests that tumor cells recruit neighboring lymphatic vessels and stimulate their growth in the malignant tissue. The lymphatic vessels contain fluid that is naturally designed to protect normal cells during transport throughout the body. Tumor cells take advantage of the comfortable transportation offered by the ingrown or nearby lymphatic vessels: The flow of the lymphatic fluid takes them first to the local lymph nodes and, from there, to other organs. The best way to deal with this problem is to keep lymphatic vessels from growing inside a tumor in the first place. To do that, Ran and her team must figure out which molecules attract the vessels to the tumor mass and force them to grow new branches. Better understanding of the process will enable the development of drugs to prevent it. “

If we can inhibit that, we will lock the tumor cells into their primary site; we will not let them escape,” Ran says.Once this happens, doctors will have a better chance of identifying, isolating, and removing primary tumors, in effect curing cancer.


JEREMY TURNER, Ph.D.
Assistant professor, Departments of Pharmacology and Surgery, Division of Otolaryngology–Head and Neck Surgery
Research question: How does the brain change with age-related hearing loss, and how does hearing loss change the brain? Funding: $150,000 (NIH)

Although new to the game of grant funding, Jeremy Turner has already received recognition and money for his research focused on age-related hearing loss. Turner studies the relationship between hearing loss and changes in the brain: “I look at age-related hearing loss not so much as an ear problem but as a brain problem.”

Without chemical changes and neurological signals in the brain, sound would not exist for any of us. As we age and lose hearing naturally, the hearing part of the brain gets less information from the ear and itself ages; as a result, we experience less and less of the sound around us. When, as a result of hearing loss and aging, the hearing part of our brain doesn’t get its normal input, it begins to atrophy, just like any muscle that goes unused for too long.

For some of us, this deterioration results in the need for a hearing aid, but Turner says that fewer than 20 percent of people who need hearing aids actually use them. By the time an older individual actually gets a hearing aid, the brain has atrophied to the point that it has trouble discerning meaningful sound, such as a spouse’s voice, from background noise. The hearing aid picks up every sound, makes it louder, and transmits it to the ear. However, at this point the brain has lost its ability to monitor and winnow important sounds from meaningless noise. As a result, a person who is wearing a hearing aid for the first time after an extended period of diminished hearing hears every sound, and the brain, rusty from disuse, translates the cavalcade of sounds into noise and nonsense. Turner says that it can take several months to retrain the brain of an individual new to hearing aids so that the person actually benefits from them. Most people give up in frustration long before that happens.

Turner’s findings also suggest that if we were to begin using hearing aids earlier in the aging process, just as our hearing is beginning to deteriorate, the brain might stay “fit” and some age-related hearing loss might be avoided. Turner notes that although people wear glasses without social stigma, the same is not true of hearing aids. Many people refuse for cosmetic reasons to appear in public wearing hearing aids, believing that they will be perceived as old or somehow defective.

A person who loses his or her hearing to age may lose something more: quality of life. The brain of a person who cannot hear actually changes, and in some cases the resulting silence is linked to social withdrawal, isolation, and depression.

LINDA TOTH, Ph.D., D.V.M.
Associate Dean of Research and Faculty Affairs Professor and director, Division of Laboratory Animal Medicine
Research question: What are the long-term causes of fatigue and altered sleep pattern in infection?
Funding: $5 million (NIH)

Linda Toth likes to dance the night away — the cha-cha, the waltz, the tango — but she’s just as passionate about learning what keeps us awake, or lulls us to sleep, after the party is over. Chronic fatigue and sleeplessness can impair health and enjoyment of living.

Toth studies the chemical changes during sleep deprivation, changes that can be life-threatening. Prolonged sleeplessness triggers a negative energy balance, impairs the immune system and results in a gradual deterioration of health leading to infection and even death.

Toth cites two motivations for her work. “One is the tremendous excitement,” she says, “that comes with discovering something new about the world of biology and medicine.” The second “is the hope that I can contribute to finding relief for the millions of people who suffer from problems with sleeplessness or from unwanted sleepiness.”

In the near future, Toth believes, scientists will “unravel much of the basic circuitry in the brain that leads us into sleeping and waking and will identify genes that influence sleep patterns or contribute to sleep disorders.” She and her colleagues have isolated the gene that controls wakefulness and sleeplessness. Now they want to know how this gene works in the brain and how to control it.

Learning how this gene functions will lay the groundwork for the development of therapies to permit a good night’s sleep.  

Jane Adrian is a Scottsdale, Ariz.-based freelance writer in science, health, and education. She is the former clinical laboratory director at Lincoln Developmental Center and director of the Clinical Laboratory Science Program at St. John’s Hospital in Springfield.

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