Highlights and News

Mentors in the News: ‘Bad Guy’ Cells Unexpectedly Prove Vital

June 29, 2016 by

They Cause Allergies and Asthma, But They Also May Save Your Life

  • Surprising discovery points to way to prevent life-threatening consequences of C. difficile infections
  • diff kills one in seven infected in North America
  • But probiotics that ensure the presence of certain cells in the gut may stave off infection
  • Finding ‘as unexpected as it is important,’ with ‘immediate implications for therapy’

‘Bad Guy’ Cells Unexpectedly Prove Vital for Stopping Deadly C. Difficile

Researchers at the University of Virginia School of Medicine have identified immune cells vital for protecting us from potentially fatal C. difficile infection. Surprisingly, those cells are often vilified for their role in causing asthma and allergies. But when it comes to C. difficile, they could be the difference in life and death.

With the discovery, the researchers have answered some of the greatest questions about C. diff, shed light on why antibiotics lead to severe C. diff and identified a potential way for doctors to prevent the life-threatening infection – and possibly other infections as well.

The Role of Antibiotics

Bill Petri, MD, PhD, chief of the Division of Infectious Diseases and International Health at the UVA Health System, hailed the discovery by UVA’s Erica L. Buonomo, PhD, and colleagues as “the most remarkable breakthrough I have participated in as a scientist.”

“Antibiotics are really important, and very often you have to give antibiotics, but you do it knowing that you’re predisposing your patient to another infection [C. difficile] that is potentially lethal. About one out of seven people with this infection dies in North America. So it’s a terrible dilemma for physicians,” Petri said. “This is not a common complication of antibiotics, but when it happens, it’s a very serious one. This work enables a potential long-term solution to that, which is probiotics to restore the natural state of the gut.”

There were almost half a million C. diff infections in the United States in 2011, and approximately 29,000 patients died within 30 days of infection, according to a study released last year by the U.S. Centers for Disease Control and Prevention. The agency has classified the bacterium as an “urgent threat,” noting the rise of a new epidemic strain in recent years that has made the infection even deadlier.

Kris Chadee, PhD, a professor at the University of Calgary who was not involved in UVA’s C. diff work, called the discovery “as unexpected as it is important,” noting that the finding “has immediate implications for therapy: Probiotics designed to restore the healthy gut microbiome should be an effective way to prevent this life-threatening infection.”

Understanding C. Difficile

  1. difficile is primarily a hospital-acquired infection, and it predominantly affects the elderly, particularly elderly people on antibiotics. UVA’s discovery offers answers about why that is. The researchers showed that the gut bacteria stimulates the production of a protein called IL-25, which then recruits protective cells called eosinophils. As such, IL-25, the product of “good” bacteria, protects the lining of the gut from pathogens. Antibiotics, however, disrupt our body’s natural bacterial populations, leaving the gut lining vulnerable to C. diff and other infections.

Intriguingly, the researchers found an important and unexpected role for eosinophils, a type of white blood cells. These cells are often vilified for their role in causing both allergies and asthma, but in the battle against C. diff, they can be life-saving. IL-25, the UVA researchers show, protects us from C. diff by manufacturing eosinophils to guard the integrity of the gut lining. The epidemic strain of C. diff is so deadly specifically because it kills eosinophils, allowing it to breach the gut, the researchers determined.

“We found that if you deplete eosinophils, either genetically or by an antibody neutralization, you lost the integrity of the epithelial barrier in the gut,” Buonomo said. “Maintaining that barrier is very important for having a healthy response to C. difficile. It also prevents bacteria from spreading to other sites in the body, so if you have a breakdown in the barrier, you can have a septic response or bacteria in your blood or in other systemic organs.”

The findings suggest that researchers should be able to develop new probiotics that patients could take to ward off C. difficile. “We could end up that every person taking an antibiotic is taking a new probiotic that is specifically designed to maintain IL-25 and eosinophils,” Petri said.

Petri noted that Buonomo joined his lab while a graduate student at UVA, and he credited the discovery to the new perspective she brought. “Erica was a card-carrying immunologist before she came into my lab,” Petri recalled. “She came with an immunology mindset, and the lab wasn’t immunology focused at all. It’s changed. We’ve all seen the benefit of having that perspective, of looking at how the immune system is responding to the bacterial infection.”

Findings Published Online

The discovery has been described in a paper published online by the scientific journal Cell Reports. It was authored by Buonomo, Carrie A. Cowardin, Madeline G. Wilson, Mahmoud M. Saleh, Patcharin Pramoonjago and Petri.

Spring 2016 Edition of Vitals

The University of Virginia has released the Spring 2016 Edition of their e-magazine Vitals. You will see a few familiar faces! Congratulations!

Congratulations to the Owens Lab!

Congratulations to Dr. Gary Owens, former MSTP Director, on this amazing discovery!

Gene helps prevent heart attack, stroke — and may offer way to block effects of aging

May 17, 2016

Gene helps prevent heart attack, stroke — and may offer way to block effects of aging

An atherosclerotic lesion

 Findings in a nutshell:

  • Gene thought active only in embryos and permanently silenced in adults is actually critical in preventing heart attacks and strokes
  • Manipulating expression of this gene might help block age-related decline in the body’s ability to carry out repairs and heal wounds
  • Discovery creates potential new avenue for battling strokes and heart attacks
  • ‘We think this is just the tip of the iceberg’

U.Va. Acquires High-End Bioprinters for Tissue, Organ Fabrication

The University of Virginia has acquired two new state-of-the-art three-dimensional bioprinters and has begun training lab scientists and bioengineers to “print” tissues that could eventually be used to treat patients with illnesses and injuries ranging from burns to diabetes, and heart, liver and kidney failure.

The two bioprinters, manufactured by a leading 3-D bioprinting company, regenHU of Switzerland, are among only four such top-of-the-line machines now in use in the United States. The other two are at medical centers in Boston and Miami.

The printers enable bioengineers to “print” or “draw out” living cells, such as skin or bone or other cell types, onto a substrate, building tissue structure layer by layer, resulting in a custom-designed bit of living material that potentially could be implanted or grafted onto a patient to repair or replace damaged tissue.
The ultimate goal is to eventually fabricate full artificial organs and circumvent the current problem of donor organ shortages.
Shayn_Peirce-Cottler_05HR_DA“In the long run, we hope to develop alternatives to the use of human organs for transplantation,” said Dr. Kenneth Brayman, a transplant surgeon and researcher at the U.Va. School of Medicine who is focusing on the printing of bits of organs and tissues for treating diabetes. “The bioprinter is a tool that can help develop new horizons to address and treat human diseases. The potential for cell therapies is quite high.”
Presently there are numerous applications for 3-D bioprinting, everything from printing skin for burn patients; to printing precisely shaped pieces of collagen, cartilage or muscle for cleft palate repair; to fabricating certain tubular-shaped parts, such as a trachea or a short length of artery. U.Va.’s immediate focus is on printing bits of pancreas for treating diabetes, and bits of skin and muscle for reconstructive surgeries.
“This new capability will in the near term benefit patients being treated at the U.Va. Health System by influencing how doctors think about existing surgical procedures, and in the long term by providing entirely new treatment options for organ transplantation and surgical reconstruction of tissues,” said bioengineering Professor Shayn Peirce-Cottler, whose research program focuses on how blood vessels grow into new and regenerating tissues.
She acquired the two bioprinters – one for her lab in the Department of Biomedical Engineering, and the other for use in Brayman’s lab – with funding primarily from the Office of the Vice President for Research, and additional funding from the School of Engineering and Applied Science. The total cost was $300,000.
Currently, Peirce-Cottler said, the main hindrance to printing complex replacement tissues is the difficulty of providing a sufficient blood supply to the tissue.
“The major design challenge is in printing blood vessels, particularly very small capillaries, which are essential for providing oxygen and nutrients to cells,” Peirce-Cottler said. “The new printers provide a precise level of control in how we can design tissue samples using stem cells. We expect to be able to draw microscopic-sized capillaries into the tissue as we lay out cells.”
Peirce-Cottler noted that the new machines will synergize interdisciplinary research teams consisting of surgeons, engineers and biologists working to implement and test new strategies for designing, growing and regenerating tissue.
“U.Va. has substantial depth of expertise in all of the key areas that are necessary for successfully printing tissues and eventually organs,” she said. “We have collaborative surgeons, such as Dr. Brayman, with exceptional expertise transplanting tissues and organs. We have bioengineers with strong understanding of physiology and anatomy, and our team includes scientists who are successful at developing new therapies to promote tissue growth and regeneration. Plus we have a strong culture of cross- and multi-disciplinary collaboration in close proximity.”
Brayman added, “The presence of the bioprinters in the transplantation and bioengineering laboratories will enable our students and faculty to remain on the cutting edge of such research and enable us to compete for grants and the best and brightest students.”
While bioprinting is cutting-edge technology, it may be some years before the printing of complex organs is possible, Peirce-Cottler cautioned.
“We have to start simple, learn as we go, and then move on to more complicated tissues and organs,” she said. “I think that being able to print an entire multi-structural organ, like a liver, heart or kidney, is probably a long way off, but being able to print smaller, functional, clinically useful pieces of organs or tissues is an obtainable goal in the next few years.”

 

 

Nearly Indestructible Virus Yields Tool to Battle Diseases

Egelman with TitanMAY 26, 2015

By unlocking the secrets of a bizarre virus that survives in nearly boiling acid, scientists at the University of Virginia School of Medicine have found a blueprint for battling human disease using DNA clad in near-indestructible armor.

“What’s interesting and unusual is being able to see how proteins and DNA can be put together in a way that’s absolutely stable under the harshest conditions imaginable,” said Edward H. Egelman of the Department of Biochemistry and Molecular Genetics. “We’ve discovered what appears to be a basic mechanism of resistance – to heat, to desiccation, to ultraviolet radiation. And knowing that, then, we can go in many different directions, including developing ways to package DNA for gene therapy.”

Finding effective packaging for DNA delivery is important because the human body has many ways to degrade and remove foreign DNA; that’s how it combats harmful viruses. But that protective mechanism becomes a major obstacle for doctors seeking to use genes to battle disease. Creating an impenetrable packaging would overcome that problem, and this strange virus offers a promising template.

The virus, SIRV2, infects a microscopic organism known as Sulfolobus islandicus that lives in what Egelman described as “extremely unusual” conditions: acidic hot springs where temperatures top 175 degrees Fahrenheit. The research identified surprising similarities between the SIRV2 virus and the spores bacteria form to survive in inhospitable environments.

“Some of these spores are responsible for very, very horrific diseases that are hard to treat, like anthrax,” Egeleman said. “So we show in this paper that this virus actually functions in a similar way to some of the proteins present in bacterial spores.”

Spores are also formed by C. difficile, which now accounts for approximately 30,000 deaths per year in the U.S. and has been classified by the Centers for Disease Control and Prevention as having a threat level of “urgent.”

“Understanding how these bacterial spores work gives us potentially new abilities to destroy them,” Egelman said. “Having this basic scientific research leads in many, many directions, most of which are impossible to predict, in terms of what the implications are going to be.”

So how does the virus survive such inhospitable conditions? SIRV2, it turns out, forces its DNA into what is called A-form, a structural state identified by pioneering DNA researcher Rosalind Franklin more than a half-century ago.

“This is, I think, going to highlight once again the contributions she made, because many people have felt that this A-form of DNA is only found in the laboratory under very non-biological conditions, when DNA is dehydrated or dry,” Egelman said. “Instead, it appears to be a general mechanism in biology for protecting DNA.”

Egelman and his colleagues were able to crack the mystery only because of the remarkable power of U.Va.’s new Titan Krios electron microscope. Buried deep below Fontaine Research Park, the massive microscope is insulated within many tons of concrete to provide the stability needed to examine biological samples in previously impossible detail. The microscope is one of only a few of its kind in the world, and was funded, in part, by the National Institutes of Health. Researchers from far and wide, both at U.Va. and beyond, are tapping its power.

Egelman’s findings are among the first to result from U.Va.’s Titan, but others are expected to follow soon.

The discovery has been described in the prestigious scientific journal Science (subscriber access only) in an article whose authors are Frank DiMaio, Xiong Yu, Elena Rensen, Mart Krupovic, David Prangishvili and Egelman.

Josh Barney

U.Va. Health System

jdb9a@virginia.edu

434-243-1988

 

Sarah Kucenas Named Outstanding Faculty

Biology professor Sarah Kucenas, PhD received the state’s highest honor for professors, the Outstanding Faculty Award.

Kucenas recieved the award with another UVA professor, Stephen Cushman of the English Department. The awards, given by the State Council of Higher Education for Virginia and Dominion Resources, recognize superior accomplishments in teaching, research and public service.

Kucenas and Cushman are among 13 faculty members selected this year from a pool of 88 nominees from institutions statewide. They join 34 previous winners from U.Va. and one fromU.Va.’s College at Wise since the awards were first presented 29 years ago.

Virginia Gov. Terry McAuliffe will honor Cushman, Kucenas and their fellow awardees during a Feb. 19 ceremony at the Jefferson Hotel in Richmond. Each will receive $5,000 and a commemorative engraved award, underwritten by the Dominion Foundation, the philanthropic arm of Dominion Resources.

“With Dominion’s support, the annual recognition of Virginia’s outstanding faculty members is truly one of the agency’s most rewarding activities,” SCHEV Director Peter Blake said. “We are honored to highlight the accomplishments of these professors who lend their extraordinary talents to their students, their institutions and the commonwealth of Virginia.”

Awardees are nominated by their peers at Virginia’s public and private colleges and universities. A selection committee, made up of members of SCHEV and education, business and community leaders, chose the 13 winners.

“Professors Cushman and Kucenas are wonderful examples of faculty who commit to outstanding teaching, scholarship, research and service to our University, its students and the citizens of the commonwealth,” said U.Va. Executive Vice President and Provost John D. Simon. “The commonwealth’s highest honor is well deserved by both of these professors for their ongoing dedication.”

Stephen Cushman

Cushman, Robert C. Taylor Professor of English in the College and Graduate School of Arts & Sciences, specializes in American poetry. He publishes his own poetry and delves into historical research combining literature and the Civil War.

Two books of his were published in October: “Belligerent Muse: Five Northern Writers and How They Shaped Our Understanding of the Civil War,” from the University of North Carolina Press; and “The Red List,” from the Louisiana State University Press, his fifth book of poetry. He was the general editor of the “Princeton Encyclopedia of Poetry & Poetics,” published in 2012.

Since 2003, Cushman and U.Va. history professor Gary Gallagher have team-taught an upper-level undergraduate course, “Voices of the Civil War.” This year, both hold the Cavaliers’ Distinguished Teaching Professorship, a two-year chair that recognizes eminent scholars for excellence in teaching, administered by the Teaching Resource Center.

For 16 years, Cushman has taught one of the three survey courses required of English majors. He estimates that he and co-instructor Michael Levenson have taught 4,400 students in that class alone.

“The consensus of faculty and students year after year is overwhelmingly consistent,” writes Cynthia Wall, who chairs the English department. “Stephen Cushman’s teaching changes lives and lasts lifetimes. He is what we all want to be: intellectually rigorous, philosophically challenging, deft in directing discussion, and memorably effective teaching writing, close reading and argument. (Oh, and hilarious).”

Sarah Kucenas

Described by students and colleagues as a master communicator, mentor and role model for young women in the sciences, Assistant Professor of Biology Sarah Kucenas shares her expertise not only in the classroom, but also in forums in the Charlottesville community and through her research into the nervous system.

Balancing research, teaching and service, Kucenas uses innovative teaching methods and mentoring to incorporate undergraduate students into her research programs.

She challenges her students to think deeply and critically about their study material and to actively participate in their own learning. She also encourages her undergraduate students to actively participate in actual research in her lab, work that generally would be accomplished only at the graduate level. Her dedication to teaching has earned her a Department of Biology Distinguished Teaching Award and the U.Va. Alumni Board of Trustees Teaching Award, the highest teaching honor bestowed upon junior faculty at U.Va.

Kucenas is internationally known for her research to harness the regenerative capacity of the developing nervous system to help it repair itself during disease, research that could possibly lead to the development of target drugs that could help the nervous system self-repair. This has implications for the treatment of many childhood neurodegenerative diseases, including muscular dystrophy, pediatric multiple sclerosis and Charcot-Marie-Tooth disease.

During her five years at the University, she has earned nearly $2 million in research funding.

The Dominion Foundation has fully supported the Outstanding Faculty Awards program since 2005. Since the first awards ceremony in 1987, a total of 341 Virginia faculty members – including the 2015 recipients – have received this high honor.

“This is the 11th year Dominion has sponsored the Outstanding Faculty Awards,” said Hunter A. Applewhite, president of the Dominion Foundation. “When you read the nomination packets of these recipients, you are struck by their passion for their subjects and their devotion to sharing it with their students.”