Research

Ranked 13th in the nation among public research institutions, The University of Arizona is committed to building on its strength in the life sciences. The BIO5 Institute is at the heart of the UA's efforts to strengthen life sciences research capabilities and plays a vital role in regional and state bioscience economic and workforce development plans. Examples of BIO5's research includes:

Arizona Cancer Center researcher announces results of clinical trial: up to 95 percent reduction in colon cancer risk

Dr. Eugene GernerResearchers announced today that the combination of a low dosage of the targeted agent difluoromethylornithine (DFMO) and sulindac, a non-steroidal anti-inflammatory drug (NSAID), has been shown to reduce the risk of recurrent colorectal polyps, a precursor to colon cancer, by up to 95 percent with minimal toxicity.

'Combination chemoprevention with DFMO and sulindac can substantially reduce colon polyp recurrence, especially those polyps associated with the greatest risk of colorectal cancer,' says Eugene W. Gerner, Ph.D, director of the Arizona Cancer Center's Gastrointestinal (GI) Cancer Program and the National Cancer Institute-funded Specialized Program of Research Excellence (SPORE) in GI Cancers at the University of Arizona College of Medicine. Dr. Gerner is also a member of the BIO5 Institute at The University of Arizona.

Dr. Gerner and Frank Meyskens, MD, director of the Chao Family Cancer Center at the University of California at Irvine, announced their research results earlier today at the annual meeting of the American Association for Cancer Research (AACR) in San Diego. The research results also were published online this week in the inaugural issue of the AACR's new journal, Cancer Prevention Research.

'The spectacular clinical results reported by Meyskens and colleagues in the lead article of this very first issue of this new AACR journal on cancer prevention represent a landmark advance in efforts to stop the current worldwide epidemic of cancer deaths,' says Michael B. Sporn, professor of pharmacology and toxicology at Dartmouth Medical School, Hanover, New Hampshire.

In earlier studies, the research team had established a safe and well-tolerated dose of DFMO, a specific inhibitor polyamine synthesis, that was 1/50th of what would typically be used to treat advanced cancers. By combining this reduced dose of DFMO with sulindac, researchers believed they could achieve a significant clinical effect with reduced toxicity.

'There is a great hope that we will be able to prevent colon cancer effectively using this method. We had not been able to do this before due to the high toxicity of available therapies. DFMO is a targeted agent that represents a new treatment paradigm,' says Dr. Meyskens.

For the current study, researchers enrolled 375 patients who had a history of at least one colorectal polyp within the previous five years. Patients were randomly assigned to either a combination of 500 mg of daily DFMO and 150 mg of sulindac, or placebo. Patients were followed for three years to measure adenoma recurrence.

Overall, the combination treatment reduced the risk of a recurrent adenoma from 41.1 percent in the placebo group to 12.3 percent with treatment, a 70 percent reduction.

When researchers measured advanced adenomas only, the rate was 8.5 percent in the placebo group compared with 0.7 percent in the treatment group, a 92 percent reduction. For adenomas larger than one centimeter, the rate was 7 percent in the placebo group compared with 0.7 percent in the treatment group, a 90 percent reduction. Among patients who had previously had more than one adenoma, the rate of subsequent adenomas was 13.2 percent in the placebo group compared with 0.7 percent in the treatment group, a 95 percent reduction.

The rate of reduction was so pronounced that the trial's independent data and safety monitoring board stopped the trial early.

An analysis of side effects and toxicity found no significant difference between the treatment and placebo groups. There was no significant difference in side effects requiring an overnight hospitalization, gastrointestinal side effects, cardiovascular side effects, or hearing loss between the two groups.

'Recent studies have provided proof of principle that chemoprevention of colorectal cancer through the use of natural or synthetic agents to prevent or suppress the progression of precursor lesions (colorectal adenomas) is possible, but positive effects have been modest and have been associated with unacceptable toxicities,' says Robert S. Bresalier, MD, professor of medicine and distinguished professor in GI oncology for The University of Texas MD Anderson Cancer Center.

'Dr. Meyskens and his colleagues have employed sound biological principles and a methodical approach to demonstrate that a very substantial reduction in new adenoma formation in at-risk individuals is possible without substantial risk using DFMO and sulindac,' Dr. Bresalier continues. 'I look forward to seeing the results of additional long-term trials with these agents.'

'Our research was funded by several grants, including the GI SPORE sponsored by the National Cancer Institute. We are very gratified that our study has produced such promising results,' says Dr. Gerner. The Arizona Cancer Center is one of only five institutions nationwide to receive a GI SPORE; the others include Harvard, Johns Hopkins, the University of North Carolina, and Vanderbilt University. Originally funded in 2002, the GI SPORE is the largest new grant awarded to the University of Arizona College of Medicine in the past 10 years. It was renewed in 2007 for another five years and funded at $12 million.

The Arizona Cancer Center is the state's premier National Cancer Institute-designated comprehensive cancer center. With research sites in Tucson, Phoenix, Mesa, Scottsdale and Sun City, the Center has 300 world-class physician and scientist members, working to prevent and cure cancer. For more information, go to www.arizonacancercenter.org

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Shocking Plants Produces Useful Chemicals

University of Arizona (UA) researchers are zapping garden-variety plants with electricity--and in doing so may be paving the way for new ways of producing everything from medicines and herbs to perfumes and pesticides.

The UA plant scientists have discovered that delivering non-lethal doses of electricity to many plants makes them produce secondary metabolites, a class of chemicals with a wide range of commercial uses. That in itself isn't unusual.

"The chemicals produced are the same ones routinely made by plants as a defense response," says BIO5 member and study coauthor Hans VanEtten, UA professor of plant pathology and microbiology.

Plants naturally produce secondary metabolites in response to environmental stresses such as fungi, viruses, and chemical exposure; engineers routinely use synthetic additives and genetic engineering to increase production of these metabolites. But using electric shocks has two distinct advantages: it allows repeated application of the stimulus--the shocks--that produce the chemicals, and it does so without harming the plants.

UA Researchers Engineer Self-Destructing Virus

Dr. Bentley FaneUA researchers have sown the seeds of a virus' destruction in its own genetic code--or rather, in the genetic code of the organisms it seeks to infect. Their work could improve both our understanding of how viruses work and our ability to make plants and animals more virus-resistant.

Working with a virus that infects bacteria, BIO5 member Bentley Fane, a professor in the Department of Veterinary Sciences and Microbiology in the College of Agriculture and Life Sciences, and James Cherwa, a graduate student in Fane's lab, pinpointed a region of a protein that's crucial to building the virus' structure; designed a modified version of that protein; and then engineered the bacteria's cells to produce the modified protein. When the virus infected cells of the bacteria, it "recognized" the modified protein and, following the instructions encoded in its own DNA, the virus tried to incorporate the altered protein into copies of itself. Instead the protein gummed up the works of the replication process, causing the virus to "die" without producing any "offspring."

"We were shocked by just how potent the inhibitory protein was," Fane says. The research casts light on the biology of how viruses work and how the proteins they create interact with one another. It was recently highlighted in the Spotlight section of the Journal of Virology.

We all have an interest in better understanding both how viruses work and how to stop them from working, Fane explains. Viruses are little more than strands of DNA or RNA surrounded by a protein coat; they can't reproduce on their own. Instead they invade the cells of more complex host organisms--everything from bacteria to plants and animals--and hijack the machinery inside those host cells in order to replicate. Along the way, viruses can cause any number of diseases, including blights in plants and colds, flu, and HIV in humans. Fane hopes to begin using what he's learned to engineer virus-resistant plants. While similar work has been done with plant viruses before, none of those viruses had the icosahedral shape and structure Fane and Cherwa's research focuses on.

The virus they're working with also reproduces quickly--a generation lasts all of about 20 minutes, which means their research provides an up-close view of evolution in action. Over the course of 200 generations, Fane and Cherwa have watched the virus evolve a mutant strain that can not only replicate in spite of the inhibitory protein, but that may also, according to some very preliminary research, be somewhat dependent on the protein. In other words, the original strain's inhibitory protein poison just may be the resistant strain's medicine.

That resistant strain would have a hard time surviving outside the lab, because its resistance is pretty much the only thing it has going for it, it is otherwise less healthy than the original virus. "When something mutates, it does so at a cost to its usefulness," Fane explains. "It's always illuminating to see how a virus adapts to something like this, though, because it always manages to. That's the power of evolution and selection."

On another note…

Dr. Fane is one of two artists featured in the AAAS Art of Science and Technology program art exhibits that opened June 16, 2008 in Washington D.C. In "Crystal Structures: Viruses in Glass," biologists Dr. Fane and Holly Wichman have created anatomically accurate virus sculptures using beads, wire and glass.

For more information:
http://www.aaas.org/news/releases/2008/0613art_exhibit.shtml

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UA Researcher Shares in Discovery of Microbe Filaments' Power

An immunoflourescent image of a neisseria

microcolony and its radiating pili

Researchers from The University of Arizona and Columbia University have discovered that tiny filaments on bacteria can bundle together and pull with forces far stronger than experts had previously thought possible.

The team of researchers, including Magdalene 'Maggie' So, a member of the BIO5 Institute and the department of immunobiology in the UA College of Medicine, studied Type IV pili - or filaments - on the surface of Neisseria gonorrhoeae, the bacterium that causes the infectious disease gonorrhea. The research results help them understand the role that Type IV pili play in initiating a variety of infectious diseases - including tuberculosis - and how retracting pili allow bacteria to crawl and to exchange genes with each other.

When a bundle of Type IV pili retracts, it pulls with a force in the nanoNewton range, which is 10 times the force of a single retracting filament. The study demonstrates the power and cooperative nature of the nanomotors that cause Type IV pili to retract.

'The motor that causes these filaments to pull is one of the strongest nanomotors known in biology,' So said.

In previous studies, the same group of investigators measured single filament retraction forces in the 50 to 100 picoNewton range. This force allows the bacterium to move an object 10,000 times its own body weight. Retraction forces from a bundle are roughly 10 times higher, allowing the bacterium to move objects 100,000 times its body weight.

Pilus retraction forces are an important factor in how N. gonorrhoeae starts an infection. So, who has studied these microbes for more than 20 years, says N. gonorrhoeae communicates with a human cell by pulling on it. These pulling forces perturb the normal circuitry of the cell. As a result, the infected cell is fooled into lowering its defenses against the infecting microbe.

So said that the team of investigators came up with a new method to measure the tremendous forces applied by retracting pili. They allow bacteria to sit on a dense brushwork of tiny elastic pillars. The pili attach to these pillars. When pili retract, they bend the pillars. By measuring how the pillars bend, the investigators calculate the retraction forces.

An article about the research, titled 'Cooperative Retraction of Bundled Type IV Pili Enables Nanonewton Force Generation,' was published in the latest issue of PLoS Biology, a leading open-access online journal published by the Public Library of Science.

Authors of the PLoS Biology article are Nicolas Biais and Mike Sheetz, Columbia University; Benoit Ladoux, Universit' Paris 7; So and Dustin Higashi, both from the UA.

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UA Researchers Tackling Unsolved Questions about Protein Structures

A University of Arizona research team is exploring the evolutionary origins of protein structures. Their findings help us better understand how proteins evolved to carry out the instructions encoded in the genes of every living thing.

Protein molecules are made up of chains of amino acids. These chains bend and fold into a dizzying array of three-dimensional shapes and structures, depending on the order of the amino acids in a given chain. Those varied structures are part of what allow the proteins, which are assembled based on instructions coded in DNA, to regulate everything from an organism's growth and metabolism to the ways messages are transmitted from cell to cell. Protein structures are at the heart of how organisms function.

However, the evolution of those structures is still poorly understood, because there are few observed examples of proteins that have clearly evolved from one shape to another. "The origin of the diversity of protein structures is a major unsolved problem," explains BIO5 member Matthew H.J. Cordes, an associate professor of Biochemistry and Molecular Biophysics at the UA.

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