News

IMV Ph.D. Graduate Student, Cassandra Houser (Paige Lawrence's Lab) received one of ten AAI Young Investigator Awards at the 22nd Annual Upstate New York Immunology Conference. The conference this year took place October 28th at Albany Medical Center. The award is based on the top poster abstracts submitted based on scientific rigor and significance to the field of immunology.

Congrats Cassandra!

Living microglia, genetically marked to glow green, in the cerebral cortex with magenta colored blood vessels from a mouse treated with URMC-099.

A new study published in the Journal of Neuroinflammation found that prophylactic treatment with URMC-099 -- a "broad spectrum" mixed-lineage kinase 3 inhibitor -- prevents neuroinflammation-associated cognitive impairment in a mouse model of orthopedic surgery-induced perioperative neurocognitive disorders (PND).

PND, a new term that encompasses postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorder, is the most common complication after routine surgical procedures, particularly in the elderly. Following surgery, such as hip replacement or fracture repair, up to 50 percent of patients experience cognitive disturbances like anxiety, irritability, hallucinations, or panic attacks, which can lead to more serious complications down the line. Currently, there are no FDA-approved therapies to treat it.

Developed in the laboratory of Harris A. "Handy" Gelbard, M.D., Ph.D., director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, URMC-099 inhibits damaging innate immune responses that lead to inflammation in the brain and accompanying cognitive problems. Using animal models of diseases like HIV-1-associated neurocognitive disorders, Alzheimer's disease and multiple sclerosis, Gelbard has shown that the compound blocks enzymes called kinases (such as mixed lineage kinase type 3, or MLK3) that respond to inflammatory stressors inside and outside cells.

Gelbard and Niccolò Terrando, Ph.D., director of the Neuroinflammation and Cognitive Outcomes laboratory in the Department of Anesthesiology at Duke University Medical Center, used an orthopedic surgery mouse model that recapitulates features of clinical procedures such as a fracture repair or hip replacement, which are often associated with PND in frail subjects. In a pilot experiment, they treated one group of these mice with URMC-099 before and after surgery, and another group prior to surgery only. Gelbard and Terrando's teams, including first author Patrick Miller-Rhodes, a senior pre-doctoral student in the Neuroscience Graduate Program working in the Gelbard lab at URMC, measured the following:

• How the surgery affected the central nervous system and the immune cells (microglia) that reside there was evaluated using stereology and microscopy.
• Surgery-induced memory impairment was assessed using the "What-Where-When" and Memory Load Object Discrimination tasks.
• The acute peripheral immune response to surgery was assessed by cytokine/chemokine profiling and flow cytometry.
• Long-term fracture healing was assessed in fracture callouses using micro-computerized tomography and histomorphometry analyses.
• For additional details see the "Materials and Methods" section of the study

The team found that the surgery disrupted the blood brain barrier and activated microglia (a first line immune responder present in the inflamed brain), which led to impaired object place and identity discrimination when the mice were subject to the "What-Where-When" and Memory Load Object Discrimination tasks. Both URMC-099 dosing methods prevented the surgery-induced microgliosis (increase in the number of activated microglia) and cognitive impairment without affecting fracture healing.

"A major concern regarding the use of anti-inflammatory drugs for PND is whether they will affect fracture healing. We found that our preventive, time-limited treatment with URMC-099 didn't influence bone healing or long-term bone repair," said Gelbard and Terrando, professor of Neurology, Neuroscience, Microbiology and Immunology, and Pediatrics at URMC and associate professor of Anesthesiology at Duke University Medical Center, respectively. "These findings of improvement in cognition and normal fracture healing provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND."

"Right now we have nothing to treat this condition," said Mark A. Oldham, M.D., assistant professor in the department of Psychiatry at URMC who treats patients with PND. "We work hard to provide good medical care, including helping people sleep at night and making sure they are walking, eating and drinking, but it isn't clear that these efforts have any meaningful long-term impact."

According to Oldham, recent studies that track patients following an episode of PND show that many of them don't resolve completely, and that they have a new cognitive baseline after delirium.

"It is increasingly an accepted fact that after delirium, people have suffered some kind of neurological insult, which leaves them cognitively or functionally worse off than before the incident," he noted.

Next steps for the research include identifying definitive mechanisms for pain modulation, immune cell trafficking and neuro-immune characterization in PND. Gelbard and Terrando are tackling some of these questions with funds from the National Institutes of Health (RO1 AG057525). The current study was also funded by multiple grants from the NIH (P01MH64570, RO1 MH104147, RO1 AG057525 and F31 MH113504). The University of Rochester has four issued U.S. patents and multiple issued patents in foreign countries covering URMC-099.

NIH grant will help identify new strategies to enhance immune response

Cutting-edge imaging technologies that allow scientists to watch the immune system work in real time are leading to a greater understanding of how we combat infection and disease. With a new $12 million grant, researchers will use this knowledge to explore strategies to better fight infections like the flu and beat back overactive immune responses in disorders like rheumatoid arthritis and lupus.

The five-year project, led by Deborah J. Fowell, Ph.D., Dean's Professor in the department of Microbiology and Immunology at the University of Rochester Medical Center, builds on a $9 million grant that her team received in 2014. Both program project grants were awarded by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

"When we take cells out of their natural environment and study them in a dish we're missing out on a lot of biology," said David J. Topham, Ph.D., a study project leader and professor of Microbiology and Immunology at URMC. "Imaging and tracking live cells is an emerging theme in immunology and one that I think is going to move forward meaningful discoveries in the field."

In addition to Fowell and Topham, project leaders include Minsoo Kim, Ph.D.,James F. Miller, Ph.D., and Patrick Oakes, Ph.D. Scientists from Cornell and Loyola University will collaborate with the team, as well.

New Wilmot Cancer Institute research shows that combining a type of radiation therapy with immunotherapy not only cures pancreatic cancer in mice, but appears to reprogram the immune system to create an "immune memory" in the same way that a vaccine keeps the flu away. The combination treatment also destroyed pancreatic cells that had spread to the liver, a common site for metastatic disease.

The result is that the combination treatment also destroyed pancreatic cells that had spread to the liver, a common site for metastatic disease. The journal Cell Reports published the study, with Scott Gerber, Ph.D., as corresponding author, and Bradley Mills, Ph.D., a post-doctoral fellow in the Gerber Lab, as first author. They led a large team of collaborators from the University of Rochester departments of Surgery, Microbiology and Immunology, Pathology and Laboratory Medicine, Radiation Oncology, and Environmental Medicine.

When immune cells get recruited to infections, tumors, or other sites of inflammation they exit the blood stream and begin searching for the damage. But how they effectively traverse the body's tissue and home in on their targets is unclear. A new study led by Deborah Fowell, Ph.D. suggests that T cells have distinct navigation systems that help them pinpoint their targets.

Fowell's research team, based in the David H. Smith Center for Vaccine Biology and Immunology in the Department of Microbiology and Immunology made the discovery by visualizing the immune system in real time using intravital multiphoton microscopy. The technology allows you to look directly into the skin and observe the dynamic behavior of immune cells 'live.' Their findings were published earlier this month in the journal Immunity.

"We thought that locating the infection foci was a passive event for immune cells; that they used the tissue as a scaffold to weave their way through this complex matrix to get to their target," said Fowell, Dean's professor in the Department of Microbiology and Immunology. "We discovered that they are pre-programmed to respond to certain cues within the tissue microenvironment that help them find their targets more efficiently."

The team hopes that discovering these specialized programs for migration in tissues will provide new therapeutic targets that enable manipulation of the immune response in a disease-specific or tissue-specific fashion, rather than globally suppressing the immune system. Possibilities include boosting protective immunity in diseases where the immune system is inefficient, such as chronic infections and tumors, and limiting immunity in diseases that are exacerbated by the immune system, like autoimmunity and heart disease.

Hen Prizant, Ph.D., a postdoctoral fellow in Fowell's lab and Alison Gaylo-Moynihan, M.D., Ph.D., a former student in the lab are co-first authors. Graduate students Ninoshka R.J. Fernandes, Hannah Bell, Dillon C. Schrock, Tara Capece, Brandon Walling, and Christopher Anderson contributed to the study. Faculty members David Topham, Minsoo Kim, Alan Smrcka and James Miller are also authors.

Fowell credits the new finding to the power of NIH Program Project Grants (P01), which allow faculty, trainees and students to explore uncharted scientific territory and branch out among different disciplines. For example, the team reached across Elmwood Avenue to have conversations with astrophysicists and engineers on River Campus about how objects move through and are found in space. The P01 that funded the research was awarded to Fowell (PI) and Kim, Topham and Miller in 2014.

After an extended hiatus, the Microbiology & Immunology department retreat will return on Monday, August 26, 2019 at the Memorial Art Gallery, located at 500 University Avenue.

Some agenda highlights include:

• We are hosting three "gurus", one for each branch of the department. They will be giving individual seminars, as well as participate together in an audience guided panel discussion.
  • Dr. John Harty, University of Iowa (Immunology)
  • Dr. Jacques Ravel, University of Maryland School of Medicine (Microbiology)
  • Dr. Luis Schang, Cornell University College of Veterinary Medicine (Virology)
• Lunch will include trivia hosted by Geeks Who Drink! One round will be questions pulled from poster abstracts -- hope you paid attention!
• The day will conclude with a happy hour to celebrate the achievements of the past year in the department.

If you have any questions, please see Jennifer Brennan in the Microbiology Administration Office.

Barbara H. Iglewski, professor and chair emerita in the Department of Microbiology and Immunology at the School of Medicine and Dentistry, has contributed landmark research on how bacteria cause infections. Her laboratory was the first to discover that bacteria use a communication system to coordinate attacks on human cells and initiate disease, and her work launched an entire field of study into how the system works in many types of bacteria. Several drugs that interrupt the bacterial communication process, thereby preventing infections, have been developed based on her work.

Barbara Iglewski is a trailblazer who paved the way for many other female scientists and leaders in Rochester and across the country.

Iglewski was the first female department chair at the School of Medicine and Dentistry and a trailblazer who paved the way for many other female scientists and leaders in Rochester and across the country. She pursued a career in science after accompanying her father, a country physician, on house calls. She received her Ph.D. in microbiology from Penn State University, and was recruited to the University of Rochester in 1986 to serve as chair of the Department of Microbiology and Immunology.

She holds seven patents, has published more than 180 papers and book chapters, and has received many awards and honors, including from the National Institutes of Health and the American Society for Microbiology. In 2015, she was inducted into the National Women's Hall of Fame, and has been recognized with the School of Medicine and Dentistry's Lifetime Mentoring Award (2009), the Susan B. Anthony Lifetime Achievement Award (2001), and the Arthur Kornberg Research Award (1999). She served as president of the American Society for Microbiology (ASM) from 1987 to 1988, and chaired its publications board from 1990 to 1999.

Please join our department in congratulating this year's winners of the URMC and MBI awards for Excellence in Teaching and Research.

• Maureen Banach - Co-recipient, Melville A. Hare Award for Excellence in Graduate Research
• Maxime Jean - Co-recipient, Melville A. Hare Award for Excellence in Graduate Research
• Zanah Francis - Melville A. Hare Award for Excellence in Graduate Teaching

2019 College Prize Recipients

• Katherine Woo: Ayman Amin-Salem Memorial Prize
• Fayth Kim: the Janet Howell Clark Prize
• Nicholas Lim: Irene Bush Steinbock Award
• Kavya Bana: Helen S. Jones Memorial Fund

Transitions and Trials

Stephen Dewhurst, Ph.D., Vice Dean for Research

Almost 10 years ago, Brad Berk had the idea that the Medical Center should position itself to take a lead in the new field of cell-based therapies by constructing a manufacturing facility that could produce those cells under the highly regulated conditions that are required by the FDA. Brad's vision was that, by doing this, we would enable UR to deliver first-in-human therapies to patients.

Fast forward, and the facility we built -- the Upstate Stem Cell cGMP Facility (USCGF) -- is working in coordination with Torque Therapeutics (Cambridge, MA) to produce modified T cells that are being infused into cancer patients as part of a clinical trial that started earlier this month.

As with most research partnerships, our relationship with Torque is fundamentally a relationship between people, and an expression of trust in the team led by USCGF Director Luisa Caetano-Davies. It's worth noting that only two years ago, Luisa was a postdoctoral fellow in Chris Proschel's lab. Her subsequent success and growth are the combined result of a lot of hard work, intelligence and -- in no small measure -- opportunities created by our URBEST program.

The Torque trial is a huge step for the USCGF because it represents the first time that a cell-based product produced by our facility has been administered to human subjects. But it's also an important step for our Medical Center, when viewed in the broader context of our evolving approach to clinical trials.

Pat Ames is heading up a new Office of Clinical Research, working with Martin Zand, Steven Wormsley and many others to lead the implementation of a clinical trial management system to improve our clinical trials infrastructure. This system will streamline and automate many cumbersome clinical research processes and reduce administrative burden on our research teams, helping us conduct more clinical trials and offer more treatments to our patients and community members.

At the same time, Paul Barr in the Wilmot Cancer Institute (WCI) was just awarded a major new grant to support WCI involvement in National Cancer Institute (NCI) cooperative group clinical trials. This award establishes URMC as one of 30 lead academic sites within the NCI consortium, a designation rarely given to an institution that (currently) does not have an NCI-designated cancer center.

Perhaps most exciting of all, Mark Noble and Nimish Mohile recently received a highly encouraging score for a proposal that would (if funded, as we hope it will be!) launch a first-in-human trial of a new cancer treatment that is the result of fundamental research conducted in the Noble laboratory. Based on a new tumor-specific vulnerability, and discovery of existing drugs with the unexpected property of attacking this vulnerability, the new therapy eliminates cancer stem cells in glioblastoma (one of the most deadly human cancers).

This is exactly the kind of bench-to-bedside science that Brad envisaged ten years ago. We've made lots of progress, and there's more to come. It's an exciting time to be involved in research at the Medical Center.

Influenza type B, though generally less widespread than type A, poses a formidable threat for vulnerable populations like the elderly and the young. In the 2012-2013 flu season, for example, influenza type B caused the majority of deaths due to flu among children, according to data from the Centers for Disease Control and Prevention. Findings published this week in mBio, ASM's open access journal, suggest that an efficient way to boost the efficacy of vaccines against influenza type B might be hiding in plain sight.

The researchers report that neuraminidase (NA), a protein found in small amounts in current vaccines, prompts the immune system to produce antibodies that may mount a broad protective response against influenza B viruses. Previous studies have connected NA antibodies to protection against the flu -- likely by preventing the spread of infection -- but this new study is among the first to show how that mechanism might be exploited for future, broad-acting flu vaccines.

"Targeting this type of vaccine response can help us develop a universal vaccine," said influenza virologist Luis Martinez-Sobrido, PhD, at the University of Rochester in New York. He co-led the study with immunologist James Kobie, PhD, also at Rochester.

Stephen Dewhurst, Ph.D., Vice Dean for Research

It's something we rarely talk about: how it feels when a grant application isn't funded. And yet, it's by far the most common outcome for any such submission -- an unavoidable consequence of paylines that are in the low teens or single digits.

The months between the submission of a grant and its review pass surprisingly quickly. And then time slows to a crawl. The self-doubt and self-criticism become more insistent. And hope flickers -- such a fragile thing, in the end.

Recently, after submitting a grant application, I found myself logging onto the NIH website every day after the review panel had met, to see if the scores had been posted. Eventually, they appeared.

This particular grant isn't going to be funded.

It's a horrible feeling. A private hurt that's immeasurably hard to share with colleagues, family and friends. That's because the narrative is one of failure.

But, I've chosen to write about it anyway -- because we've all been here. Because shame thrives in secrecy and loses its power when we talk about it (something I learned from Brené Brown).

What has helped is input from friends. One wrote: "Thank you for sharing this. I'm glad you did. As Directors etc., we don't share enough of the worries, the worthiness/unworthiness and the vulnerabilities that things like grants.... bring to the work and to our sense of ourselves as 'good' researchers, colleagues, leaders and people."

She went on to say: "I wish I had great advice. I have nothing. Except that you are a good person, a good mentor.... and whatever happens, you will still be those things. If you receive the grant, you know what your work will be; if you don't, you will have new and different work to do."

She's right.

It's also true that a life in science requires resilience -- the ability to pick oneself up after a fall and to learn and improve from failure. No one ever said that it would be easy.

In a few weeks, the summary statement will be released and I'll start thinking (with my colleagues) about ways to address the reviewers' concerns. Until then, I'll keep a space in my heart for these words of Samuel Beckett: "I can't go on. I'll go on."