OREGON STATE UNIVERSITY

college of science

“Flipping the switch” reveals new compounds with antibiotic potential

CORVALLIS, Ore. – Researchers at Oregon State University have discovered that one gene in a common fungus acts as a master regulator, and deleting it has opened access to a wealth of new compounds that have never before been studied – with the potential to identify new antibiotics.

The finding was announced today in the journal PLOS Genetics, in research supported by the National Institutes of Health and the American Cancer Society.

Scientists succeeded in flipping a genetic switch that had silenced more than 2,000 genes in this fungus, the cereal pathogen Fusarium graminearum. Until now this had kept it from producing novel compounds that may have useful properties, particularly for use in medicine but also perhaps in agriculture, industry, or biofuel production.

“About a third of the genome of many fungi has always been silent in the laboratory,” said Michael Freitag, an associate professor of biochemistry and biophysics in the OSU College of Science. “Many fungi have antibacterial properties. It was no accident that penicillin was discovered from a fungus, and the genes for these compounds are usually in the silent regions of genomes.

“What we haven’t been able to do is turn on more of the genome of these fungi, see the full range of compounds that could be produced by expression of their genes,” he said. “Our finding should open the door to the study of dozens of new compounds, and we’ll probably see some biochemistry we’ve never seen before.”

In the past, the search for new antibiotics was usually done by changing the environment in which a fungus or other life form grew, and see if those changes generated the formation of a compound with antibiotic properties.

“The problem is, with the approaches of the past we’ve already found most of the low-hanging fruit, and that’s why we’ve had to search in places like deep sea vents or corals to find anything new,” Freitag said. “With traditional approaches there’s not that much left to be discovered. But now that we can change the genome-wide expression of fungi, we may see a whole new range of compounds we didn’t even know existed.”

The gene that was deleted in this case regulates the methylation of histones, the proteins around which DNA is wound, Freitag said. Creating a mutant without this gene allowed new expression, or overexpression of about 25 percent of the genome of this fungus, and the formation of many “secondary metabolites,” the researchers found.

The gene that was deleted, kmt6, encodes a master regulator that affects the expression of hundreds of genetic pathways, researchers say. It’s been conserved through millions of years, in life forms as diverse as plants, fungi, fruit flies and humans.

The discovery of new antibiotics is of increasing importance, researchers say, as bacteria, parasites and fungi are becoming increasingly resistant to older drugs.

“Our studies will open the door to future precise ‘epigenetic engineering’ of gene clusters that generate bioactive compounds, e.g. putative mycotoxins, antibiotics and industrial feedstocks,” the researchers wrote in the conclusion of their report.

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Michael Freitag, 541-737-4845

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Pigment produced

Pigments produced



Fungal infection in corn

Fungus on corn

Breakthrough in study of aluminum should yield new technological advances

CORVALLIS, Ore. – Researchers at Oregon State University and the University of Oregon today announced a scientific advance that has eluded researchers for more than 100 years – a platform to study and fully understand the aqueous chemistry of aluminum, one of the world’s most important metals.

The findings, reported in Proceedings of the National Academy of Sciences, should open the door to significant advances in electronics and many other fields, ranging from manufacturing to construction, agriculture and drinking water treatment.

Aluminum, in solution with water, affects the biosphere, hydrosphere, geosphere and anthrosphere, the scientists said in their report. It may be second only to iron in its importance to human civilization. But for a century or more, and despite the multitude of products based on it, there has been no effective way to explore the enormous variety and complexity of compounds that aluminum forms in water.

Now there is.

“This integrated platform to study aqueous aluminum is a major scientific advance,” said Douglas Keszler, a distinguished professor of chemistry in the OSU College of Science, and director of the Center for Sustainable Materials Chemistry.

“Research that can be done with the new platform should have important technological implications,” Keszler said. “Now we can understand aqueous aluminum clusters, see what’s there, how the atomic structure is arranged.”

Chong Fang, an assistant professor of chemistry in the OSU College of Science, called the platform “a powerful new toolset.” It’s a way to synthesize aqueous aluminum clusters in a controlled way; analyze them with new laser techniques; and use computational chemistry to interpret the results. It’s simple and easy to use, and may be expanded to do research on other metal atoms.

“A diverse team of scientists came together to solve an important problem and open new research opportunities,” said Paul Cheong, also an OSU assistant professor of chemistry.

The fundamental importance of aluminum to life and modern civilization helps explain the significance of the advance, researchers say. It’s the most abundant metal in the Earth’s crust, but almost never is found in its natural state. The deposition and migration of aluminum as a mineral ore is controlled by its aqueous chemistry. It’s found in all drinking water and used worldwide for water treatment. Aqueous aluminum plays significant roles in soil chemistry and plant growth.

Aluminum is ubiquitous in cooking, eating utensils, food packaging, construction, and the automotive and aircraft industries. It’s almost 100 percent recyclable, but in commercial use is a fairly modern metal. Before electrolytic processes were developed in the late 1800s to produce it inexpensively, it was once as costly as silver.

Now, aluminum is increasingly important in electronics, particularly as a “green” component that’s cheap, widely available and environmentally benign.

Besides developing the new platform, this study also discovered one behavior for aluminum in water that had not been previously observed. This is a “flat cluster” of one form of aluminum oxide that’s relevant to large scale productions of thin films and nanoparticles, and may find applications in transistors, solar energy cells, corrosion protection, catalytic converters and other uses.

Ultimately, researchers say they expect new technologies, “green” products, lowered equipment costs, and aluminum applications that work better, cost less and have high performance.

The research was made possible, in part, by collaboration between chemists at OSU and the University of Oregon, through the Center for Sustainable Materials Chemistry. This is a collaboration of six research universities, which is sponsored and funded by the National Science Foundation.

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Douglas Keszler, 541-737-6736

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Aluminum in manufacturing

Aluminum manufacturing

Increasing toxicity of algal blooms tied to nutrient enrichment and climate change

CORVALLIS, Ore. – Nutrient enrichment and climate change are posing yet another concern of growing importance – an apparent increase in the toxicity of some algal blooms in freshwater lakes and estuaries around the world, which threatens aquatic organisms, ecosystem health and human drinking water safety.

As this nutrient enrichment, or “eutrophication” increases, so will the proportion of toxin-producing strains of cyanobacteria in harmful algal blooms, scientists said.

Researchers from Oregon State University and the University of North Carolina at Chapel Hill will outline recent findings in an analysis Friday in the journal Science.

Cyanobacteria are some of the oldest microorganisms on Earth, dating back about 3.5 billion years to a time when the planet was void of oxygen and barren of most life. These bacteria are believed to have produced the oxygen that paved the way for terrestrial life to evolve. They are highly adaptive and persistent, researchers say, and today are once again adapting to new conditions in a way that threatens some of the life they originally made possible.

A particular concern is Microcystis sp., a near-ubiquitous cyanobacterium that thrives in warm, nutrient-rich and stagnant waters around the world. Like many cyanobacteria, it can regulate its position in the water column, and often forms green, paint-like scums near the surface.

In a high-light, oxidizing environment, microcystin-producing cyanobacteria have a survival advantage over other forms of cyanobacteria that are not toxic. Over time, they can displace the nontoxic strains, resulting in blooms that are increasingly toxic.

“Cyanobacteria are basically the cockroaches of the aquatic world,” said Timothy Otten, a postdoctoral scholar in the OSU College of Science and College of Agricultural Sciences, whose work has been supported by the National Science Foundation. “They're the uninvited guest that just won't leave.”

“When one considers their evolutionary history and the fact that they've persisted even through ice ages and asteroid strikes, it's not surprising they're extremely difficult to remove once they’ve taken hold in a lake,” he said. “For the most part, the best we can do is to try to minimize the conditions that favor their proliferation.”

Researchers lack an extensive historical record of bloom events and their associated toxicities to put current observations into a long-term context.  However, Otten said, “If you go looking for toxin-producing cyanobacteria, chances are you won't have to look very long until you find some.”

There are more than 123,000 lakes greater than 10 acres in size spread across the United States, and based on the last EPA National Lakes Assessment, at least one-third may contain toxin-producing cyanobacteria. Dams; rising temperatures and carbon dioxide concentrations; droughts; and increased runoff of nutrients from urban and agricultural lands are all compounding the problem.

Many large, eutrophic lakes such as Lake Erie are plagued each year by algal blooms so massive that they are visible from outer space. Dogs have died from drinking contaminated water.

Researchers studying cyanobacterial toxins say it’s improbable that their true function was to be toxic, since they actually predate any predators. New research suggests that the potent liver toxin and possible carcinogen, microcystin, has a protective role in cyanobacteria and helps them respond to oxidative stress. This is probably one of the reasons the genes involved in its biosynthesis are so widespread across cyanobacteria and have been retained over millions of years.

Because of their buoyancy and the location of toxins primarily within the cell, exposure risks are greatest near the water's surface, which raises concerns for swimming, boating and other recreational uses.

Also, since cyanobacteria blooms become entrenched and usually occur every summer in impacted systems, chronic exposure to drinking water containing these compounds is an important concern that needs more attention, Otten said.

“Water quality managers have a toolbox of options to mitigate cyanobacteria toxicity issues, assuming they are aware of the problem and compelled to act,” Otten said. “But there are no formal regulations in place on how to respond to bloom events.

“We need to increase public awareness of these issues,” he said. “With a warming climate, rising carbon dioxide levels, dams on many rivers and overloading of nutrients into our waterways, the magnitude and duration of toxic cyanobacterial blooms is only going to get worse.”

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Tim Otten, 541-737-1796

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Green wake

Green wake


Toxic bacteria

Toxic bacteria


Lake sample

Toxic algal bloom

Beyond antibiotics: “PPMOs” offer new approach to bacterial infection

CORVALLIS, Ore. – Researchers at Oregon State University and other institutions today announced the successful use of a new type of antibacterial agent called a PPMO, which appears to function as well or better than an antibiotic, but may be more precise and also solve problems with antibiotic resistance.

In animal studies, one form of PPMO showed significant control of two strains of Acinetobacter, a group of bacteria of global concern that has caused significant mortality among military personnel serving in Middle East combat.

The new PPMOs offer a fundamentally different attack on bacterial infection, researchers say.

They specifically target the underlying genes of a bacterium, whereas conventional antibiotics just disrupt its cellular function and often have broader, unwanted impacts. As they are further developed, PPMOs should offer a completely different and more precise approach to managing bacterial infection, or conceptually almost any disease that has an underlying genetic component.

The findings were published today in the Journal of Infectious Diseases, by researchers from OSU, the University of Texas Southwestern Medical Center, and Sarepta, Inc., a Corvallis, Ore., firm.

“The mechanism that PPMOs use to kill bacteria is revolutionary,” said Bruce Geller, a professor of microbiology in the OSU College of Science and lead author on the study. “They can be synthesized to target almost any gene, and in that way avoid the development of antibiotic resistance and the negative impacts sometimes associated with broad-spectrum antibiotics.

“Molecular medicine,” Geller said, “is the way of the future.”

PPMO stands for a peptide-conjugated phosphorodiamidate morpholino oligomer – a synthetic analog of DNA or RNA that has the ability to silence the expression of specific genes. Compared to conventional antibiotics, which are often found in nature, PPMOs are completely synthesized in the laboratory with a specific genetic target in mind.

In animal laboratory tests against A. baumannii, one of the most dangerous Acinetobacter strains, PPMOs were far more powerful than some conventional antibiotics like ampicillin, and comparable to the strongest antibiotics available today. They were also effective in cases where the bacteria were resistant to antibiotics.

PPMOs have not yet been tested in humans. However, their basic chemical structure, the PMO, has been extensively tested in humans and found safe. Although the addition of the peptide to the PPMO poses an uncertain risk of toxicity, the potency of PPMOs reduces the risk while greatly improving delivery of the PMOs into bacterial cells, Geller said.

Geller said research is being done with Acinetobacter in part because this pathogen has become a huge global problem, and is often spread in hospitals. It can cause respiratory infection, sepsis, and is a special concern to anyone whose immune system is compromised. Wounds in military battle conditions have led to numerous cases in veterans, and A. baumannii is now resistant to many antibiotics. “Urgent new approaches to therapeutics are needed,” the scientists said in their report.

Continued research and eventually human clinical trials will be required before the new compounds are available for health care, the researchers said. This and continued studies have been supported by the National Institutes of Health, the other collaborators and the N.L. Tartar fund.

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Editor’s Note: A scanning electron microscope image of A. baumannii is available online (please provide image credit as indicated at web site): http://bit.ly/GztejR

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Bruce Geller, 541-737-1845

Red grapes, blueberries may enhance immune function

CORVALLIS, Ore. – In an analysis of 446 compounds for their the ability to boost the innate immune system in humans, researchers in the Linus Pauling Institute at Oregon State University discovered just two that stood out from the crowd – the resveratrol found in red grapes and a compound called pterostilbene from blueberries.

Both of these compounds, which are called stilbenoids, worked in synergy with vitamin D and had a significant impact in raising the expression of the human cathelicidin antimicrobial peptide, or CAMP gene, that is involved in immune function.

The findings were made in laboratory cell cultures and do not prove that similar results would occur as a result of dietary intake, the scientists said, but do add more interest to the potential of some foods to improve the immune response.

The research was published today in Molecular Nutrition and Food Research, in studies supported by the National Institutes of Health.

“Out of a study of hundreds of compounds, just these two popped right out,” said Adrian Gombart, an LPI principal investigator and associate professor in the OSU College of Science. “Their synergy with vitamin D to increase CAMP gene expression was significant and intriguing. It’s a pretty interesting interaction.”

Resveratrol has been the subject of dozens of studies for a range of possible benefits, from improving cardiovascular health to fighting cancer and reducing inflammation. This research is the first to show a clear synergy with vitamin D that increased CAMP expression by several times, scientists said.

The CAMP gene itself is also the subject of much study, as it has been shown to play a key role in the “innate” immune system, or the body’s first line of defense and ability to combat bacterial infection. The innate immune response is especially important as many antibiotics increasingly lose their effectiveness.

A strong link has been established between adequate vitamin D levels and the function of the CAMP gene, and the new research suggests that certain other compounds may play a role as well.

Stilbenoids are compounds produced by plants to fight infections, and in human biology appear to affect some of the signaling pathways that allow vitamin D to do its job, researchers said. It appears that combining these compounds with vitamin D has considerably more biological impact than any of them would separately.

Continued research could lead to a better understanding of how diet and nutrition affect immune function, and possibly lead to the development of therapeutically useful natural compounds that could boost the innate immune response, the researchers said in their report.

Despite the interest in compounds such as resveratrol and pterostilbene, their bioavailability remains a question, the researchers said. Some applications that may evolve could be with topical use to improve barrier defense in wounds or infections, they said.

The regulation of the CAMP gene by vitamin D was discovered by Gombart, and researchers are still learning more about how it and other compounds affect immune function. The unique biological pathways involved are found in only two groups of animals – humans and non-human primates. Their importance in the immune response could be one reason those pathways have survived through millions of years of separate evolution of these species.

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Adrian Gombart, 541-737-8018

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Blueberries

Blueberries


Grapes

Red grapes

Viruses associated with coral epidemic of “white plague”

CORVALLIS, Ore. – They call it the “white plague,” and like its black counterpart from the Middle Ages, it conjures up visions of catastrophic death, with a cause that was at first uncertain even as it led to widespread destruction – on marine corals in the Caribbean Sea.

Now one of the possible causes of this growing disease epidemic has been identified – a group of viruses that are known as small, circular, single-strand DNA (or SCSD) viruses. Researchers in the College of Science at Oregon State University say these SCSD viruses are associated with a dramatic increase in the white plague that has erupted in recent decades.

Prior to this, it had been believed that the white plague was caused primarily by bacterial pathogens. Researchers are anxious to learn more about this disease and possible ways to prevent it, because its impact on coral reef health has exploded.

“Twenty years ago you had to look pretty hard to find any occurrences of this disease, and now it’s everywhere,” said Nitzan Soffer, a doctoral student in the Department of Microbiology at OSU and lead author on a new study just published in the International Society for Microbial Ecology. “It moves fast and can wipe out a small coral colony in a few days.

“In recent years the white plague has killed 70-80 percent of some coral reefs,” Soffer said. “There are 20 or more unknown pathogens that affect corals and in the past we’ve too-often overlooked the role of viruses, which sometimes can spread very fast.”

This is one of the first studies to show viral association with a severe disease epidemic, scientists said. It was supported by the National Science Foundation.

Marine wildlife diseases are increasing in prevalence, the researchers pointed out. Reports of non-bleaching coral disease have increased more than 50 times since 1965, and are contributing to declines in coral abundance and cover.

White plague is one of the worst. It causes rapid tissue loss, affects many species of coral, and can cause partial or total colony mortality. Some, but not all types are associated with bacteria. Now it appears that viruses also play a role. Corals with white plague disease have higher viral diversity than their healthy counterparts, the study concluded.

Increasing temperatures that stress corals and make them more vulnerable may be part of the equation, because the disease often appears to be at its worst by the end of summer. Overfishing that allows more algae to grow on corals may help spread pathogens, researchers said, as can pollution caused by sewage outflows in some marine habitats.

Viral infection, by itself, does not necessarily cause major problems, the researchers noted. Many healthy corals are infected with herpes-like viruses that are persistent but not fatal, as in many other vertebrate hosts, including humans.

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Coral disease

Coral with white plague


Marine research

Taking samples

Schellman to head physics department

CORVALLIS, Ore.  – Heidi Schellman has been appointed to head the Department of Physics in the College of Science at Oregon State University, beginning in January, 2015.

Schellman, a fellow of the American Physical Society who does international research on high energy physics, has chaired the physics and astronomy program in the Weinberg College of Arts and Sciences at Northwestern University since 2010.

“Dr. Schellman will work with the Department of Physics to enhance our research excellence and to advance our teaching and learning initiatives,” said Sastry G. Pantula, dean of the OSU College of Science. “With her research experience, academic leadership, innovative approach to course development, and support for underrepresented student populations, I know she will be an excellent addition to our college and to Oregon State.”

At Northwestern, Schellman has increased funding support for graduate students, created smaller class sizes and drop-in tutoring for undergraduate students, developed courses to help underrepresented groups succeed in academia, and pursued other initiatives.

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Debbie Farris, 541-737-862

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Heidi Schellman

Heidi Schellman

Chemistry professors named ACS Fellows

CORVALLIS, Ore.  -  Two professors at Oregon State University have been named as fellows of the American Chemical Society.

Kevin P. Gable,  a professor of chemistry, was honored for the study of chemical processes important to industrial manufacturers of antifreeze, plastics precursors and the pharmaceutical industry. An expert in reaction processes involved in metal-catalyzed oxidations, Gable received his doctorate from Cornell University and has been on the OSU chemistry faculty since 1988. He has also been active in both academic and administrative leadership at OSU and with the ACS.

Robert J. McGorrin, the Jacobs-Root Professor and head of the Department of Food Science and Technology at OSU, was honored for his contributions to food chemistry and more than 35 years of leadership in ACS.  McGorrin, who is a national expert on flavor chemistry and trace volatile analysis, received his doctorate from the University of Illinois and has been on the OSU faculty since 2000. He worked in private industry for 23 years, and while at OSU has helped to greatly expand food science educational and research programs, along with student enrollment.

With more than 161,000 members, the ACS is the world’s largest scientific society and one of the world’s leading sources of authoritative scientific information. The 2014 ACS fellows will be inducted at the national meeting of the organization in San Francisco in August.

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Debbie Farris, 541-737-862

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Robert McGorrin
Robert McGorrin


Kevin Gable

Kevin Gable

Keszler named associate dean in OSU College of Science

CORVALLIS, Ore. - The College of Science at Oregon State University has named Douglas Keszler as associate dean for research and graduate studies.

Keszler, a distinguished professor in the OSU Department of Chemistry and director of the Center for Sustainable Materials Chemistry, earned his doctorate from Northwestern University and in 1984 joined OSU.

He is an expert on the synthesis and study of inorganic molecules and materials that will enable next-generation electronic and energy devices, including high-efficiency solar cells. His pioneering science contributions are being commercialized by three start-up companies – Inpria, Amorphyx, and Beet.

“I am confident that Doug will have a tremendous impact on the college’s research excellence, collaborations across departments and colleges, mentorship of faculty, industry partnerships and start-ups,” said Sastry G. Pantula, dean of the college, “while increasing the quality, quantity, and diversity of our graduate programs.”

The associate dean supports graduate and faculty research, cultivates collaborative research and large-scale interdisciplinary projects, and helps to identify potential industry partners and start-ups.

 “I look forward to enhancing a supportive and creative research environment, advancing high-quality graduate programs that support broad professional development of students, and enriching the scientific research community at OSU,” Keszler said.

Home to the life, statistical, physical and mathematical sciences, the College of Science has graduated more than 25,000 students since 1932 and is recognized for excellence in research and scholarship.

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Debbie Farris, 541-737-4862

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Doug Keszler

Doug Keszler

Noted researcher to speak at OSU commencement in June

CORVALLIS, Ore. – Ann A. Kiessling, director of the independent Bedford Stem Cell Research Foundation and a leader in both stem cell research and reproductive biology, will give the commencement address at Oregon State University’s graduation ceremony this spring.

Kiessling also will receive an honorary doctorate from the university at its 145th commencement, which begins at 10:30 a.m. on Saturday, June 14, in Reser Stadium.

“Ann Kiessling is a nationally recognized researcher and pioneer whose work in cutting-edge fields of stem cell research and the HIV virus should make for an enlightening talk for our graduates,” said Oregon State University President Edward J. Ray. “She has had a remarkable career that launched at Oregon State, where she earned her Ph.D.”

Kiessling, who has a doctorate in biochemistry and biophysics from Oregon State, joined the faculty of Harvard University in 1985, specializing in obstetrics, gynecology and reproductive biology, and working in the Department of Surgery. In the early 1990s, she pioneered reproductive options for couples living with the HIV disease and hepatitis C – techniques that led to the successful births of 121 children free of those diseases.

The Bedford Research Foundation was founded in 1996 as a Massachusetts public charity to support research. By the year 2000, the foundation’s research laboratory expanded to include human stem cell research. To date, the foundation has collaborated with more than 60 clinics globally to find treatment for infectious diseases and spinal cord injuries. Foundation officials say their belief is that international scientific collaboration is fundamentally important to rapid biomedical advances.

Kiessling’s book, “Human Embryonic Stem Cells: An Introduction to the Science and Therapeutic Potential,” published in 2003 and re-released in 2006, is the first textbook on the topic.

Before joining the Harvard University faculty, Kiessling had a faculty appointment at Oregon Health & Science University, where she worked from 1977-85.

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Sabah Randhawa, 541-737-2111; Sabah.randhawa@oregonstate.edu