Dr. Jose Herazo-Maya’s research may help identify new treatments to improve survival in patients with idiopathic pulmonary fibrosis and severe COVID-19

Caring for patients struggling to breathe drives Dr. Jose Herazo-Maya’s research to find effective treatments for pulmonary fibrosis — an incurable, debilitating and often fatal disease that causes progressive lung scarring.

“The primary goal of our research team is to identify genes that predict survival (a low vs. high risk of dying) in patients with lung fibrosis,” said Herazo-Maya, MD, an associate professor and associate chief of pulmonary, critical care and sleep medicine at the USF Health Morsani College of Medicine. “We believe that if you target these genes, you can develop new treatments to help improve survival in these patients.”

The only two drugs currently approved to treat patients with idiopathic pulmonary fibrosis (pirfenidone and nintedanib) may help slow disease progression, but they do not stop lung scarring or prolong survival, and adverse effects can occur in up to half of people with IPF. Lung transplantation can improve survival, but organs are limited and not every patient with pulmonary disease is eligible for the complex surgery.

CT scans of (Above) normal lungs and (Below) lungs with  idiopathotic pulmonary fibrosis, characterized by scars and cysts. Images courtesy of Dr. Jose Herazo-Maya, USF Health

Pulmonary fibrosis is a disease in which the tissue in and between the air sacs of the lungs (alveoli) becomes damaged and scarred. As the tissue (interstitium) thickens and stiffens, it affects the ability to breathe and get enough oxygen into the bloodstream. While toxic environmental exposures, smoking and certain other diseases have been associated with pulmonary fibrosis, in most cases the cause is unknown (idiopathic). Median survival for patients diagnosed with idiopathic pulmonary fibrosis (IPF) is three to five years.

“IPF is a devasting disease that needs better therapeutic options to improve quality of life and save lives,” Dr. Herazo-Maya said. “For me, taking care of these patients is a constant reminder that we need to do better.”

A return to academic medicine

Dr. Herazo-Maya joined USF Health in January 2021 from NCH Healthcare System in Naples, Fla., where he spent nearly four years directing a growing Interstitial Lung Disease Program. Before that, the physician-scientist was an assistant professor at Yale University School of Medicine. He is an expert in genomics, with a focus on studying how gene expression influences immunity and its association with disease progression and outcomes.

USF Health physician scientist Jose Herazo-Maya, MD, (far right) in his USF Health Heart Institute laboratory with his research team. Photographed (l to r) are Carole Perrot, PhD; Bochra Tourki, PhD; Alyssa Arsenault, LPN; and Brenda Juan-Guardela, MD. — Photo by Allison Long, USF Health Communications and Marketing

At Yale Dr. Herazo-Maya was part of team that discovered a gene expression signature in blood that reliably forecasts the likelihood of mortality and poor outcomes from IPF. The team subsequently led an international study that validated this risk profile based on 52 genes. He was among the inventors on the patent for the IPF gene risk profile, since acquired by a global company seeking to develop the scientific breakthrough into a simple blood test to be used for patient care.

Dr. Herazo-Maya returned to academic medicine after several years of private practice in Naples, in part he says because he was frustrated by the lack of research progress to identify pulmonary fibrosis treatment options. A surge in patients battling severe lung scarring from COVID-19 complications also prompted his decision to recommit to translating discoveries from the laboratory back to the patient bedside.

Soon after arriving at the USF Health Heart Institute last year, Dr. Herazo-Maya quickly began building a pulmonary fibrosis research program with the generous support of a $1 million gift made by philanthropist Timothy Ubben to the USF Foundation. (In December 2021, Mr. Ubben gave an additional $5 million to create the Ubben Family Center for Pulmonary Fibrosis that will accelerate research leading to new tests and treatments for patients.)

Dr. Herazo-Maya, a member of the pulmonary and critical care team at Tampa General Hospital, also treats patients at the TGH Center for Advanced Lung Disease — including those being evaluated for lung transplant. Along with fellow USF Health pulmonologists Dr. Kapilkumar Patel and Dr. Debabrata Bandyopadhyay at this leading TGH Center, Dr. Herazo-Maya is an investigator for clinical trials testing potential new drugs to treat lung fibrosis.

Bochra Tourki, PhD, looks at a computer slide of immune cells from the lung tissue of a COVID-19 patient with pulmonary fibrosis. – Photo by Allison Long

The impact of witnessing “air hunger”

From the start of his medical career, Dr. Herazo-Maya was interested in both critical care and science. While conducting a postdoctoral fellowship at the University of Pittsburgh School of Medicine’s Simmons Center for Interstitial Lung Disease, he was invited by his faculty mentor and center director Nafali Kaminski, MD, to accompany a group of the center’s patients, physicians, and scientists on a boat trip along the city’s rivers.

“I remember the patients using oxygen had a very hard time getting into the boat. They could not even take a few steps without becoming short of breath,” Dr. Herazo-Maya said. “Seeing how those patients struggled to breathe – their feeling of air hunger – had a big impact on me wanting to take care of them.”

While certain patients with IPF can live well for years, others develop worsening disease and die quickly. No prognostic tool yet exists to tell doctors which patients will experience rapid progression of pulmonary fibrosis, and which will progress slowly. But Dr. Herazo-Maya and colleagues are working on a molecular-level test to do just that.

A tool to predict the clinical course of IPF or any other type of lung fibrosis could help patients and clinicians make better informed decisions about care, Dr. Herazo-Maya said. “For instance, if a rapid test indicated that a patient’s genetic predisposition to mortality was high, they might need to get to the hospital to receive more aggressive medical care, and possibly be evaluated for lung transplant while they are still relatively healthy enough to withstand transplant surgery.”

Dr. Herazo-Maya (far left) consults with (l to r) staff scientist Carole Perot, PhD; postdoctoral scholar Bochra Tourki, PhD; and clinical research coordinator Alyssa Arsenault, LPN. – Photo by Allison Long

Genomic risk prediction can also increase opportunities for drug discovery, he said. “Each one of the genes we analyze is a potential drug target. We can study them in the lab to understand how they work and possibly come up with novel therapies.”

Pivoting genomic research to COVID-19

As the COVID-19 pandemic unfolded in 2020, pulmonologists and other critical care clinicians were inundated by patients in respiratory distress.

As he helped treat the influx of hospitalized patients, Dr. Herazo-Maya noticed that, like IPF, severe COVID-19 could also damage the lung interstitium leading to severe scarring. He thought about finding more precise ways to distinguish between symptomatic individuals likely to recover at home with appropriate monitoring and those likely to end up in the intensive care unit (ICU) and die. A prognostic tool capable of detecting which patients were apt to do worse before they became seriously ill could help health care providers better allocate limited resources like ICU beds and ventilators, tailor interventions, and potentially save lives.

“At the time investigators were scrambling to identify gene profiles predictive of COVID-19 outcomes,” Dr. Herazo-Maya said. “So, our basic question was ‘Can we repurpose a gene risk profile known to predict mortality in IPF to predict mortality in those infected with a new coronavirus that can cause lung fibrosis as well?’”

The preliminary answer appears to be yes.

Dr. Herazo-Maya’s computer monitor displays heat maps depicting clusters of COVID-19 subjects identified as having a low vs. high risk of mortality (Below), based on a gene expression signature in blood. The recent research showed that a previously validated technique for predicting idiopathic lung fibrosis outcomes could be repurposed for COVID-19. – Photo by Allison Long | Heat map image courtesy of Dr. Herazo-Maya, USF Health

Earlier this year, a multicenter retrospective study led by USF Health’s Dr. Herazo-Maya demonstrated that a 50-gene signature associated with a high risk of dying from IPF can also predict poor outcomes (ICU admissions, mechanical ventilation, and death) in patients with COVID-19. The findings were reported in EBioMedicine, a publication of THE LANCET.

More studies are needed, but researchers and clinicians may soon be able to apply the gene risk profile to help advance the care of both COVID-19 and IPF patients, Dr. Herazo-Maya said. His laboratory is currently developing a blood test, based on a more selective group of the 50 genes, that can be easily applied in clinical practice.

Two distinct diseases, same gene risk profile

The overlapping gene expression profiles for COVID-19 and IPF look remarkably similar, Dr. Herazo-Maya said. “That suggests there are immune pathways shared between these two diseases.”

Using single-cell gene analyses, Dr. Herazo-Maya has identified specific immune cells – monocytes, neutrophils, and dendritic cells — as the primary source of gene expression changes in the high-risk COVID-19 gene profile. Interestingly, he said, monocytes can give rise to macrophages involved in triggering scar formation.

Brenda Perrot, PhD, works on an experiment.

Dr. Herazo-Maya received his MD degree from the University of Cartagena School of Medicine in Colombia. He completed a research fellowship in interstitial lung disease and residency training in internal medicine at the University of Pittsburgh School of Medicine. Specializing in pulmonary and critical care, he conducted postdoctoral training in genomics, computational biology, bioinformatics and molecular biology at Yale and Pittsburgh universities.

The Robert Wood Johnson Foundation and the Pulmonary Fibrosis Foundation funded his research in the past, and his current work is supported by the USF Foundation-Ubben Family Fund.

Dr. Herazo-Maya has published numerous peer-reviewed papers, including in such high-impact journals as the Nature Medicine, the Journal of Clinical Investigation, Lancet Respiratory Medicine, Science Translational Medicine and the American Journal of Respiratory and Critical Care Medicine. He is the coauthor of several book chapters on topics ranging from biomarkers in assessing and managing IPF to applying personalized medicine (‘omics) to lung fibrosis.

Dr. Herazo-Maya and his wife Dr. Brenda Juan-Guardela (right), assistant professor of medicine at USF Health and medical director of Respiratory Care Services at TGH, have collaborated on pulmonary fibrosis research throughout their medical careers. – Photo by Allison Long

Some things you may not know about Dr. Herazo-Maya

If he did not become a physician and researcher, Dr. Herazo-Maya says he would have been a marine biologist. Growing up near the beach in Cartagena, he snorkeled and was “fascinated by all the sea creatures.”

Dr. Herazo-Maya is married to pulmonologist Brenda Juan-Guardela, MD, an assistant professor of medicine at USF Health Morsani College of Medicine and medical director of Respiratory Care Services at TGH. They met in medical school, trained in the same laboratory as postdoctoral scholars, and continue to collaborate on pulmonary fibrosis research. They live in Tampa with their two sons Christian, 6, and Lucas, 4.

In his spare time, Dr. Herazo-Maya enjoys playing soccer and baseball with his sons in their yard and watching their youth soccer league games.

From designing 3D printed test swabs, to researching antibody responses and engaging in leading clinical trials, USF Health scientists rapidly team up to help fight COVID-19

While the world waits for therapies to reduce death rates and a widely available vaccine to prevent COVID 19, team science at USF Health and other academic medical centers continues to take on an unprecedented sense of urgency.

Globally, scientists across disciplines are publicly sharing their ideas, expertise and data like never before – all singularly focused on finding solutions to a highly contagious and potentially life-threatening new virus known as severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2.

Since the pandemic began, the number of studies posted by researchers worldwide to open-access repositories like bioRxiv and medRxiv has skyrocketed. These preprints – papers written after a study concludes but made available before peer review – let scientists disseminate their findings more quickly and obtain instant feedback on their work. Researchers also continue to identify and share viral genome sequences, protein structures, and COVID-19 related epidemiological and clinical data through online databases.

Meanwhile, thousands of clinical trials have been launched as academic medical centers, hospitals and laboratories join forces with government and industry in the search for optimal diagnostics and therapies. At USF Health, more than 65 COVID-19 related laboratory, clinical and epidemiological projects are underway or in final stages of the approval process. These represent unique research efforts by the faculty of all four USF Health colleges, as well as joint efforts with pharmaceutical firms and biotechnical and software companies. Many of the patient-related studies are conducted by USF Health faculty physicians at Tampa General Hospital.  USF Health is also working with Tampa General to create a biorepository that collects, processes and stores health data and residual specimens from patients who test positive or negative for COVID-19 to use in future biomedical research.

“The need for rapid and accurate basic and clinical results has never been greater. The scientific community has risen to the challenge of a lifetime and continues to push forward,” said Stephen Liggett, MD, associate vice president for USF Health Research and vice dean for research in the Morsani College of Medicine. “Without a doubt we are still in the early stages of understanding this new coronavirus – in knowing who should be tested and how often, and which tests work best; in knowing how to treat patients and how effective vaccines will be in conferring immunity.”

//www.youtube.com/watch?v=8LWaITfItQA

View the interview with Stephen Liggett, MD, associate vice president for research at USF Health, who discusses how the COVID-19 pandemic has changed research here.

USF faculty and student researchers have been quick to mobilize their talent and resources, Dr. Liggett said. “They want to do whatever they can to find answers — both to help fight this pandemic and to prepare for future outbreaks.”

How are some key scientific areas contributing to the pandemic response?  Below are just a few examples provided by USF Health scientists:

Epidemiology:  Containing the spread of the virus

From the start, epidemiologists have been at the forefront of efforts to understand how fast and why SARS-CoV-2 is spreading. Also known as disease detectives or virus hunters, epidemiologists and the models using data they gather are instrumental in tracking and predicting the patterns of disease transmission in populations, said Thomas Unnasch, PhD, distinguished professor in the USF College of Public Health and codirector of the Center for Global Health Infectious Disease Research. Their work had been critical for both guiding policymakers’ plans to curb the pandemic and helping evaluate whether countermeasures to contain the virus are working.

“We’ve been hunkered down in the midst of a pandemic wildfire and testing only the symptomatic people most likely to be infected” — largely to prevent surges of sick patients from overwhelming the health care system, Dr. Unnasch said. “We’re still missing about 90 percent of the population with COVID-19 infections exhibiting mild or no symptoms.”

USF College of Public Health’s Thomas Unnasch, PhD, oversees the COVID-19 symptom surveillance network for Tampa Bay.

Dr. Unnasch oversees a symptom-based surveillance network launched in mid-April to help identify and map COVID-19 hotspots across the Tampa Bay region. USF College of Public Health researchers worked with the Hillsborough, Pinellas, Pasco and Polk County Health Departments to create the Tampa Bay symptom surveillance survey, adapting existing COVID-19 surveillance technology developed by the Puerto Rico Sciences Trust and deployed in Puerto Rico and, more recently, the Boston area through Harvard University.

The anonymous survey asks Tampa Bay residents questions about potential exposure and symptoms consistent with COVID-19. The information collected, which drills down to the zip code level, is provided to the local health departments and hospital groups.

Surveillance – a tool commonly used by public health agencies to identify and prevent the spread of HIV, tuberculosis, anthrax and other infectious diseases – can help fill in the gaps created by limitations inherent in a complex society, such as a lack of uniform testing, Dr. Unnasch said.

COVID-19 cases in Pinellas and Hillsborough County broken down by zip code, as tracked and entered by the Hillsborough County Health Department on April 16, 2020. Pasco and Polk counties have since been added to the symptom surveillance system.

“So far the only way to prevent the disease is to prevent transmission of the virus. That has meant everyone doing the right thing — staying at home, social distancing face masks, and hygiene,” Dr. Unnasch said.  “As we reopen our communities, surveillance can help us do that safely by detecting clusters of new cases early at a very targeted level, so we can stomp out the embers before they reignite COVID-19 outbreaks.”

Real-time mapping of suspected COVID-19 hotspots can be used to strategically direct Tampa Bay’s public health resources to specific areas where testing, contact tracing and isolation are most likely needed, he said.

“The more data we get and the more accurate the information, the more powerful the tool will be.”

Biostatisticians: Keeping the bias at bay

The data collected by epidemiologists or other health researchers can be fed into mathematical models that predict how fast COVID-19 infections may spread or the number of deaths expected in an overall population. At the community/clinical level, predictive models can help hospitals and medical staff triage patients and allocate limited health care resources (like ICU beds or ventilators) by estimating the risk of people being infected or having a poor disease outcome.

While they can be useful to prepare for worst-case scenarios, predictive models have differed widely in their forecasts – and sometimes they can cause more harm than benefit in guiding policy or clinical decisions, said Ambuj Kumar, MD, MPH, director of the Research Methodology and Biostatistics Core, USF Health Office of Research.

Dr. Kumar, a biostatistician and associate professor of internal medicine, points to a recently published systematic review analyzing studies of prediction models for the diagnosis and prognosis of patients with COVID-19. This review concluded that all 31 clinical models were poor quality, at high risk of bias, and their reported performance was likely overly optimistic.

Ambuj Kumar, MD, MPH, directs USF Health’s Research Methodology and Biostatistics Core.

Methodologist/biostatisticians like Dr. Kumar are trained to recognize the issues and complications arising from the analysis of human health data. They play a key role in any team designing and executing a model, providing the statistical methodology needed to draw meaningful conclusions or make predictions. These data scientists help reduce bias in selecting sample populations, observing or reporting findings, and measurement. They are attuned to factors that can interfere with an accurate estimate of cause-and-effect.

Requiring frequent updates, projections are only as good as the model’s underlying assumptions and the reliability and standardization of the data applied to the model, Dr. Kumar said.

For instance, the commonly cited Institute for Health Metrics and Evaluation model assumes social distancing and other strong voluntary measures to control viral spread will stay in place, but predicting how people will behave as the U.S. reopens in phases is tricky. And, the death data relied upon by many models may be confounded a lack of consistency in the way COVID-19 deaths are reported and counted by hospitals and health departments. (Public health experts have suggested that deaths are undercounted.)

Predictive modeling uses existing data and reasonable assumptions to forecast how an infectious disease spreads in the real world. As more data becomes available, it triggers adjustment of the model, resulting in different outcomes.

Many people understandably want to know now what to expect during this pandemic: How many more cases? How long will it last? When can I safely return to work, or school? Will there be a second wave?

But, many uncertainties about testing, immunity, susceptibility and treatments still influence the variables that make up the algorithms forecasting COVID-19 outcomes, Dr. Kumar said. As the reliability and accuracy of rapidly accumulating data improves, so should the models, he added.

“Predicting the future is particularly challenging when we’re dealing with a virus new to the entire world,” Dr. Kumar said.  “Whether you’re battling COVID-19 or another crisis, you can’t compromise on the systematic, standardized approach needed to create a useful model, or study. If you want accurate results, there’s no substitute for good, rigorous science.”

Virology:  Studying how SARS-CoV-2 works

To develop effective therapies and vaccines to combat COVID-19, scientists need to understand how the virus functions, including its interaction with human immune response. That’s the role of virologists like Michael Teng, PhD, associate professor of internal medicine in the USF Health Morsani College of Medicine.

Dr. Teng has spent many years working with the National Institutes of Health and other groups on research and development of a vaccine for respiratory syncytial virus, or RSV. While RSV was discovered over 60 years ago, researchers continue to work on a vaccine for this common respiratory virus that infects virtually every child by age 2.

Like many other scientists, USF Health virologist Michael Teng, PhD, quickly pivoted from his usual research activities to respond to the new global health threat.

Scientists and companies now testing a myriad of SARS-CoV-2 vaccines in the pipeline have benefited from the extensive RSV research, Dr. Teng said. “They’ve learned a lot from RSV about what works and what pitfalls to avoid in vaccine development.”

Like many other scientists, Dr. Teng quickly pivoted from his usual research activities to respond to the new global health threat. In mid-March his laboratory studied the durability and effectiveness of the 3D-printed nasal swabs successfully created for COVID-19 testing by a team at USF Health Radiology and its innovative 3D Clinical Applications Division, directed by  associate professor Summer Decker, PhD.  Faculty with expertise  in anatomy and infectious diseases as well as radiology contributed to the effort. The ambitious 3D design, modeling and printing project teamed USF Health with Formlabs, a 3D printer manufacturer, and Northwell Health, the largest hospital system in New York, the pandemic’s U.S. epicenter.

An integral part of coronavirus test kits that detect the RNA virus’s genetic code, swabs were in extremely short supply as the pandemic escalated. The slender, flexible device collects a sample from the nasal passages or throat, and that sample goes into a test tube containing transport media for preservation until the specimen is processed by a hospital or commercial laboratory. Using RSV as a proxy for a SARS-CoV-2, synthetic respiratory tract mucous (made by USF Health’s Sophie Darch, PhD), and a World Health Organization recipe for transport media, Dr. Teng demonstrated that the 3D-printed alternative swabs worked as well as conventional commercial swabs to safely collect enough of the sample, without leeching into transport media or interfering with the nucleic acid test’s ability to detect virus particles.

Top:  A USF Health Radiology-led team successfully designed, tested and produced a prototype 3D printed nasopharyngeal swab in record time. As of late May, more than 50,000 of the nasal swabs had been mass produced and were being used worldwide by health care providers to alleviate bottlenecks in COVID-19 testing. Bottom: Jonathan Ford, PhD, a biomedical engineer in USF Health Radiology, holds a cube of the 3D diagnostic nasal swabs.

.

The 3D printed swabs, fabricated with FDA-approved, nontoxic materials, also passed performance benchmarks when clinically validated in hospitalized patients undergoing COVID-19 screening at Tampa General Hospital and Northwell Health sites. (A larger-scale multisite clinical trial, led by USF Health Infectious Disease Division Director Kami Kim, MD, is further evaluating the performance of the investigational 3D swabs for diagnostic testing.) Meanwhile, several hundred hospitals and academic medical centers across the country, many state governments, and international agencies and health care facilities are already using the USF-patented swabs to alleviate bottlenecks in COVID-19 testing.

The team worked late nights, taking only about a week from swab prototype design and bench testing to the start of clinical validation. “That’s an incredibly fast turnaround time,” Dr. Teng said.

Dr. Teng is also a coinvestigator for a Morsani College of Medicine-College of Public Health project led by Dr. Kim, which is working to find and map epitopes, the parts of SARS-CoV-2 proteins recognized by the immune system. Antibodies are made by the immune system in response to a threat from a specific virus, bacteria and other harmful pathogen. Some epitopes are associated with protective antibody responses that neutralize (inactivate) a virus when that pathogen is recognized by the immune system again. Others may actually lead to a harmful immune response when a person is exposed to the same virus a second time. The USF Health team wants to identify specific epitopes triggering strong protective antibodies to help researchers design vaccines that mimic a beneficial immune response against COVID-19.

“The data we gather may also be useful in screening (convalescent) plasma for specific antibodies that may best be used to treat critically ill COVID-19 patients,” Dr. Teng said.

Thomas McDonald, MD, USF Health professor of cardiovascular sciences, is investigating whether genetic, physiological or medication-interaction factors may contribute to racial and ethnic disparities in COVID-19 infection rates and cardiovascular complications.

A coronavirus “pseudotype” created by Dr. Teng’s laboratory is being used by the team working on finding neutralizing antibodies and a second USF Health team investigating what factors may affect who suffers worse COVID outcomes.

The second team, led by Thomas McDonald, MD, professor of cardiovascular sciences at the USF Health Heart Institute, wants to know if socioeconomic differences alone account for racial and ethnic disparities in who gets sicker and dies from COVID-19, or if genetic, physiological, or even medication-interaction factors contribute to disproportionate infection rates and cardiovascular complications.

Human pluripotent stem cells grown in Dr. McDonald’s laboratory are prodded to become lung, immune, and heart cells in a petri dish. The stem cells come from blood samples donated by many patient volunteers of different ages, genders and races, as well as various pre-existing cardiovascular conditions. These tissue samples will be infected with the COVID-19 proxy virus engineered by Dr. Teng.

The substitute virus combines the well-studied vesicular stomatitis virus (VSV) with an outer shell containing the spike protein on the surface of SARS-CoV-2 that allows the coronavirus to enter human cells. This non-replicating virus is “a sheep in wolf’s clothing,” invading cells like the COVID-19 virus without harming scientists working with the pathogen, Dr. McDonald said. VSV also expresses the same enzyme, luciferase, that gives fireflies their glow. When hit with a chemical, this “firefly luciferase” lights up the virus so researchers can trace how much invades cells and which cell types are vulnerable.

“With a machine we can image the range of light, which is the level of infection coming out of the cells,” Dr. Teng said.

For the Dr. Kim-led study evaluating the ability of different serum antibodies to block the virus from entering human cells, less light would indicate that the antibodies protected against infection, he added.

Luciferase, the same enzyme that gives fireflies their glow, is helping USF Health researchers track how much proxy COVID-virus invades human cells and which cells are most vulnerable.

Structural biology: A key to drug discovery

Unraveling the structure of viral proteins and identifying the receptors they use to enter cells can help guide discovery and design of potential antiviral treatments.

Yu Chen, PhD, is a USF Health associate professor of molecular medicine with a background in structural biology and biochemistry. Dr. Chen applies his expertise in structure-based drug design using advanced techniques — including X-ray crystallography and molecular docking — to help develop inhibitors (drug compounds) that target bacterial enzymes causing resistance to certain commonly prescribed antibiotics such as penicillin.

Now he’s turned his attention toward looking for new or existing drugs to stop SARS-CoV-2.

Yu Chen, PhD, an associate professor of molecular medicine who has expertise in structure-based drug design, has turned toward looking for new or existing drugs to stop SARS-CoV-2.

One way to do this would be to block the virus’s main protease, known as M^pro, an enzyme that cuts out proteins from a long strand that the virus produces when it invades a cell. Without it, the virus cannot replicate. Dr. Chen works with colleagues at the University of Arizona College of Pharmacy (Jun Wang, PhD) and the USF Department of Chemistry (James Leahy, PhD) on this project.

“M^pro represents a promising target for drug development against COVID-19 because of the enzyme’s essential role in viral replication and the absence of a similar protease in humans,” Dr. Chen said. Since people do not have the enzyme, drugs targeting this protein are less likely to cause side effects, he explained.

This winter, an international team of scientists shared their description of the complex crystal structure of M^pro and in April published their discovery of its inhibitors, a half-dozen leading drug candidates identified by targeting the viral enzyme. Taking advantage of the breakthrough, Dr. Chen and other scientists worldwide hope to add more candidates to the drug discovery pipeline soon.

Together with the scientists from University of Arizona, Dr. Chen has found that several known protease inhibitors, including an FDA-approved hepatitis C (HCV) drug boceprevir and an investigational veterinary antiviral drug GC376, showed potent inhibition of the viral protein, and were more active than the previously identified inhibitors. Dr. Chen and his doctoral student, Michael Sacco, have recently determined the first structure of GC376 bound by M^pro, and characterized the molecular interactions between the compound and the viral enzyme.  Their paper describing these results will soon be published in the prestigious scientific journal Cell Research.

Generated by X-ray crystallograhy, this image depicts the overall structure of the COVID-19 virus’s main protease (Mpro), which plays a key role in viral replication. Dr. Chen and colleagues recently found two new protease inhibitors that offer promise in blocking the drug target. –Photo courtesy of Yu Chen.

Dr. Chen and colleagues are also looking for small molecules that can effectively stop the M^pro enzyme from working or last long enough in the body to kill the COVID-19 virus.

The researchers use the latest computer software to visualize and predict how different drug candidates (M^pro inhibitors) bind with the viral proteins. This 3D structural analysis of “binding hotspots” can help in designing and chemically modifying other types of protease inhibiting-drugs with improved activity against SARS-CoV-2, Dr. Chen said.

The most potent antiviral compounds would be tested in human respiratory cell cultures growing the virus. Only then can a drug candidate move to animal models, and, eventually, human trials.

Genomics: Linking genetic variations to outcomes

Why do some individuals get so ill from the COVID-19 virus, while others barely notice symptoms? Why do certain countries and populations have higher death rates than others? Age, underlying medical conditions, socioeconomic and environmental factors play a role – but genetic variation, both in the virus itself and the humans it invades, are likely part of the equation.

“This virus has swept across the world, and some differences in immune response, virulence and disease outcomes of people infected with SARS-CoV-2 could be due to various strains of the virus yet to be defined,” USF Health’s Dr. Liggett said.

Differences in immune response, virulence and disease outcomes of people infected with SARS-CoV-2 could be due to various strains of the virus not yet defined, Dr.  Liggett says.

Sequencing all genes that make up the COVID-19 virus — not just certain sections of the virus’s genome — will be key to uncovering genetic changes that could make a difference in patient susceptibility and outcomes, Dr. Liggett said. More than a decade ago, a team led by Dr. Liggett sequenced for the first time all known genomes of the human rhinovirus, providing a framework for antiviral treatments or vaccine development for this common respiratory virus implicated in asthma flare-ups.

“All parts of a virus’s genome work together for its existence, reproduction and infectivity,” he said. “So, to sequence only one part would be like looking at just the spark plugs, instead of the whole engine, when your car is not running well.”

The data gathered so far indicates that SARS-CoV-2 mutates slowly in the population. Most people have only 10 or so genetic variations in the 30,0000 nucleotide viral genome compared to the reference standard, Dr. Liggett said. “This may be a good sign that antibodies developed from an infection, a vaccine, or derived from an infusion, will provide long-lived immunity. This lower level of mutations also allows us to track a viral strain, potentially knowing how a community became infected.”

.

Noting where genetic variation does not occur is also important, since this may represent a “soft-spot” in the virus’s genome that cannot tolerate change because it is so vital, he added. “That might offer a clue about where to target a vaccine or therapy.”

As for human genetic variations that might influence whether certain individuals or subgroups of patients with COVID-19 fare better or worse, Dr. Liggett says the scientific community understands many human genes responsible for mounting an immune defense against this SARS-CoV-2 virus, and other respiratory viruses.

“With enough samples and epidemiology, we may be able to identify patients at genetic risk for serious, life-threatening outcomes,” he said. “However, it will be extremely challenging to find those needles in this big haystack.”

Clinical Trials: Testing treatments that attack on several fronts

As clinicians cared for more patients, one thing became increasingly clear – COVID-19 is more than a respiratory disease that injures the lungs.

It can strike many cell types and organs throughout the body including the brain, heart, blood vessels and kidneys; destroy taste and smell; cause life-threatening blood clots; and trigger a dangerous inflammatory cytokine storm. People with weakened immune systems are more vulnerable to severe illness – including the elderly and those with heart or lung diseases, diabetes, obesity or other underlying medical conditions. Black and Latino populations are disproportionately more likely to die from the virus. And while children are largely spared, a rare inflammatory pediatric syndrome with cardiac complications has been associated with COVID-19.

USF Health, working with Tampa General Hospital, had been at the forefront of a wide range of COVID-19 clinical trials in the Tampa Bay region.

Physicians and scientists are exploring many possible treatments to increase survival and improve prognoses for critically ill patients. Some target the virus itself or human cellular pathways that the virus exploits to replicate. Others aim to prevent collateral inflammatory damage in the human host. A disease affecting so many parts of the body will need drugs, or combinations of drugs, to attack on several fronts, said USF Health infectious disease physician-scientist Dr. Kim.

In the Tampa Bay region, USF Health, working with Tampa General Hospital, is at the forefront of a wide range of COVID-19 clinical trials. Creating drugs from scratch can take years, so several trials are investigating medications already prescribed for other infectious or inflammatory diseases to determine their effectiveness against SARS-CoV-2. For instance, Dr. Kim is local lead investigator for a multisite randomized controlled trial testing the safety and effectiveness of sarilumab in blocking acute lung damage in hospitalized COVID-19 patients. Sarilumab, approved for treating rheumatoid arthritis, is a monoclonal antibody targeting the proinflammatory cytokine receptor interleukin 6. Another trial will evaluate the ability of nitazoxanide, originally developed as an antiparasitic drug for gastrointestinal infections, to prevent respiratory virus replication in health care workers.

Dr. Kim is also working with Tampa General’s laboratory to analyze and validate the reliability of commercial tests that test patient blood samples for antibodies, proteins that provide evidence of past COVID-19 infection and recovery.

Kami Kim, MD, director of the Division of Infectious Disease and International Medicine at USF Health, leads a study evaluating the accuracy of antibody testing.

The accuracy of the antibody testing – different from the nasopharynx swab or saliva tests used to diagnose a current active infections – is important because it can give health officials a clearer picture of how widely COVID-19 has spread in the community and the extent of asymptomatic cases. Based on past experience with other coronaviruses like SARS and MERS, a positive SARS-CoV-2 antibody test would typically indicate some level of immunity. Researchers like Dr. Kim want to confirm that and hope to define the concentration of antibodies needed to confer immunity as well as how long that immunity lasts.

(In late May, the Centers for Disease Control and Prevention released new guidelines cautioning that some antibody tests have high false positive rates, and more definitive data is needed before they can be used to make decisions about returning to work, school or other public places.)

“We need to know if people who have the antibodies are actually protected against another infection,” Dr. Kim said. “It’s not yet clear… but, preliminary data indicates that a fairly large proportion of those people who recover from COVID-19 infection will have what are the protective (neutralizing) antibodies.”

SARS-CoV-2 shares genetic and some clinical similarities with the first SARS virus (SARS-CoV) — which caused a smaller scale global outbreak and has not re-emerged since the last reported case in 2004. But the new coronavirus is both more highly contagious and more apt to spread asymptomatically.

Based on past experience with other coronaviruses like SARS and MERS, a positive SARS-CoV-2 antibody test would typically indicate some level of immunity. Scientists are working to figure out how much immunity and how long it lasts.

“It’s the thing that has kept all of us in public health and infectious diseases up at night – a completely new pathogen that explodes before we had a real chance to get a handle on what was happening,” Dr. Kim said. “We’re learning more as we go, but teamwork is essential. No one will be able to solve all the pieces of this pandemic puzzle by themselves,” she added.

It will take time for scientists to fully understand the COVID-19 virus and how genetics, the environment, medications, lifestyle and public health measures impact the course of the disease.

“COVID-19 has essentially shut down the entire world,” added Dr. Kim, who as a clinical infectious diseases fellow at the University of California San Francisco in the 1980s witnessed firsthand the devastating consequences of the domestic HIV/AIDS epidemic. “A lesson we need to learn is the importance of maintaining preventive public health infrastructures — not only in our local communities, but globally, so that we can efficiently combat any future pandemics.”

Studies led by USF’s Dr. Stephen Liggett shed light on genetic variability of adrenergic receptors and how they might best be used to treat disease

Dr. Stephen Liggett, who leads the research enterprise for the Morasani College of Medicine and for USF Health, also oversees a genomics laboratory working on NIH-funded studies. Behind him is a radioligand binding machine used to determine the number of receptors in each cell.

While significant progress has been made managing asthma over the last two decades, about half of all asthmatics achieve optimal control of this chronic inflammatory disease using currently available medications.  Similarly, only about 50 percent of patients with congestive heart failure, which occurs when the heart is too weak to pump enough blood to meet the body’s needs, have an average life expectancy of more than five years.

More still needs to be  known at the molecular level about these common diseases to identify potential new targets for drug therapies, said Stephen B. Liggett, MD, associate vice president for research at USF Health, vice dean for research at the Morsani College of Medicine, and professor of internal medicine and molecular pharmacology and physiology.

What ties these two diseases together are the receptors on cardiac muscle and on smooth muscle of the airways. Dr. Liggett’s laboratory helps shed light on the genetic variability of adrenergic receptors and on how these receptors can best be used for treatment. The genetic studies have been particularly useful in developing the concept of pharmacogenetics, a tailoring of therapy based on an individual’s genetic makeup, for heart failure and asthma.

“Twenty years ago we had a handful of medicines for high blood pressure, and today we don’t use any of them. Now, we have a whole new group of more effective (antihypertensive) drugs with much fewer side effects,” he said.  “And, I’m sure that one day, we’ll have more tools in our toolbox to better treat heart failure and asthma – drugs that work better for subgroups of people as defined by their genetic makeup and environmental exposures.”

 Dr. Liggett comments on some of his laboratory’s contributions to the field over his career.

The research team led by Dr. Liggett, center, includes Ashley Goss, Hiwot Zewdie, Donghwa Kim, PhD, and Maria Castano. Not pictured: Alexa Woo, PhD.

Mining a “superfamily” of receptors for better drug targets

Dr. Liggett leads a USF team that studies the genetic, molecular biology, structure and function of G-coupled protein receptors, or GPCRs, the largest family of human proteins.  More than 800 GPCRs have been discovered within cell membranes in the human body, Dr. Liggett said, and one or more of these receptors plays a role in virtually everything the body does, including controlling thoughts in the brain, sight and smell, uterine contraction and relaxation, blood pressure, cardiac, lung and kidney function, to name just a few.

Consequently, malfunctions of GPCR signaling pathways are implicated in many chronic diseases including asthma and cardiovascular diseases.  Already this “superfamily” of receptors accounts for nearly half the targets of all prescribed drugs. But, a deeper understanding of the dynamics of the GPCR signaling network and how it maintains a healthy cell or responds to pathogens could lead to the design of drugs that more precisely target diseases with greater effectiveness and fewer side effects.

Dr. Liggett began his work with GPCRs in 1988 as a Howard Hughes Institute postdoctoral research fellow in the Duke University Medical Center laboratory of mentor Robert Lefkowitz, MD. Dr. Lefkowitz was awarded the 2012 Nobel Prize in Chemistry with Brian Kobilka, MD, for groundbreaking discoveries revealing the inner workings of GPCRs.

Building upon his interest and advanced training in pulmonary and critical care medicine, Dr. Liggett began early in his career to concentrate on one of the classes of GPCRs known as adrenergic receptors, which are stimulated by the hormone epinephrine and the neurotransmitter norepinephrine. They are involved in increasing the rate and force of contraction of the heart, as well as constriction and dilation of blood vessels throughout the body and of airways in the lung. For the last 28 years, he has been continuously funded by the National Institutes of Health (NIH) to study the molecular basis of beta-adrenergic receptors in asthma.

Biological scientist Ashley Goss

Dr. Liggett is the principal investigator of a four-year, $1.12-million R01 grant from the NIH’s National Heart, Blood and Lung Institute (NHBLI) that seeks to understand how beta-adrenergic signaling is regulated to influence the development and treatment of asthma. Over his career, he has also been awarded millions of dollars in NIH funding to explore the role of genetic variations of GPCRs in heart failure, including whether those variations may alter how effectively drugs work in individual patients.

Bitter taste receptors in a new place

Dr. Liggett is also currently a project principal investigator for a five-year, $2-million NHBLI P01 grant examining how airway smooth muscle bitter taste receptors might be applied as new treatments for asthma and chronic obstructive pulmonary disease.

Using a genomics-based method that Dr. Liggett pioneered, his team had previously identified bitter taste receptors, initially thought only to exist on the tongue, deep inside the lung at the airway smooth muscle and demonstrated they act to open the airway. “When activated, they appear far superior to the beta-agonists commonly prescribed to patients to open their airways during an asthma attack,” said Dr. Liggett, who published the discovery and the need for alternatives to current bronchodilators in Nature Medicine and other journals.

Overall, discoveries emerging from Dr. Liggett’s research have yielded more than 250 peer-reviewed papers, many highly cited and appearing in top journals such as Nature Medicine, Science, Proceedings of the National Academy of Sciences, and the New England Journal of Medicine. His work has been cited by other papers more than 26,000 times. He also holds 18 patents detailing potential new targets for drug therapy or genetic variations of known drug targets and how they might be used to predict response to medications and customize treatment.

 The serendipity of finding bitter taste receptors on smooth airway muscle in the lungs

Laboratory assistant Hiwot Zewdie

Among some of his laboratory’s major findings:

– While at the University of Maryland, Dr. Liggett’s team worked with colleagues at the University of Wisconsin-Madison to sequence for the first time the entire genomes (more than 100 different strains) of all known rhinoviruses, a frequent cause of respiratory infections including the common cold. The groundbreaking work, published on the cover of Science, provided a powerful framework for large-scale, genome-based epidemiological studies and the design of antiviral agents or vaccines to combat rhinoviruses. “I originally suggested sequencing 10 strains, and then my collaborator asked why not do them all,” he said. “This made the difference between a mediocre proof-of-concept paper and a full article in Science. I learned that it is important to think big if you want to make a real difference”

–  Discovered and characterized genetic variations that may predict which patients with congestive heart failure respond best to a life-saving beta-blocker drug.  These landmark studies occurred over several years and were published in Nature Medicine twice, and the Proceedings of the National Academy of Sciences three times. “This is a good example of the progression of an idea over time, where every year or so an unexpected turn of events occurred, and new insight was gained,” he said.

– While at the University of Cincinnati, Dr. Liggett, working with colleagues at Washington University and Thomas Jefferson University, found that a genetic variation of an enzyme, which inhibits beta-adrenergic receptor signaling, confers “genetic beta-blockade” in cardiac muscle and protects against early death in African Americans with heart failure.  The findings, published in Nature Medicine, provided insight into individual variations in disease outcomes. Another key study from Cincinnati revealed that a certain combination of genetic variants within a single gene conferred low vs. excellent responses to inhaled beta-agonists in treating asthma. These combinations, called haplotypes, had never been identified in GPCRs. The work was published in Proceedings of the National Academy of Sciences.

Dr. Liggett’s groundbreaking research sequencing all known human rhinoviruses, a frequent cause of respiratory infections, was featured on the April 3, 2009 cover of the journal Science.

Advancing outside his field of study

Dr. Liggett joined USF Health in 2012 from the University of Maryland School of Medicine in Baltimore, where he was associate dean for interdisciplinary research and professor of medicine and physiology. He received his MD degree at the University of Miami and completed both a residency in internal medicine and fellowship in pulmonary diseases and critical care medicine at Washington University School of Medicine and Barnes Hospital in St. Louis, MO.

Within two years, he advanced from a postdoctoral research fellowship in Dr. Lefkowitz’s laboratory at Duke to tenured associate professor and director of pulmonary and critical care medicine at the University of Cincinnati College of Medicine.  By the time he left Cincinnati for the University of Maryland in 2005, he held an endowed chair in medicine and directed the university’s Cardiopulmonary Research Center.

Though he had no significant wet-lab experience, Dr. Liggett was fascinated by the emerging science called “molecular biology” and was undeterred from branching into a field of study in which he had no formal training.

He secured a position as assistant professor at Duke following his fellowship there, and figured out how to sequence adrenergic receptor genes from a patient’s blood. While routine now, such genetic testing had not been done previously.  He unexpectedly kept finding multiple variations (called polymorphisms or mutations) in genes coding for the same receptors, so he sought out the advice of some classic geneticists.  At the time, Dr. Liggett said, their traditional thought was modeled after diseases like cystic fibrosis — if a person had the genetic mutation they developed the disease, if the mutation was absent they did not.

“There was no consideration for common genetic variants and how they might affect disease risk, progression, or response to treatment. It simply was not in their thought process,” Dr. Liggett said. He was told “it’s probably nothing and don’t quit your day job.” He did not take their advice.

 Some advice Dr. Liggett would give to emerging young scientists

Assistant professor Donghwa Kim, PhD

Instead, he returned to the laboratory to sequence and clone receptors from many different populations with asthma and heart failure, showing that the receptor genes did indeed differ from one individual to another, generally with several common “versions.” His team also created “humanized” mice expressing the human genes for asthma and heart failure so they could begin to understand the physiology of the receptors. They began to find that some genetic alterations increased receptor function, some decreased the drug’s affinity to bind (responsiveness) to a receptor, and still others altered how the receptor was regulated.  And, through NIH-supported clinical trials, the researchers correlated outcomes observed in patients undergoing drug therapies with the genetic variations uncovered in the laboratory.

“If there’s a lesson to be learned here by young investigators, I’d say it’s that you can collect information from experts in the field, but you need to use your gut to ultimately decide on whether to pursue a line of research or not,” Dr. Liggett said.

Personalized medicine challenge: Common diseases, multiple genetic variations

Realizing personalized medicine’s full potential will require a better understanding of how environmental variables – including diet, exercise, the gastrointestinal microbiome (gut bacteria) and toxin exposure – combine with genetic variations to affect disease and its treatment, he said. “Personalized medicine faces its greatest challenges in the common diseases like asthma, atherosclerotic heart disease and heart failure, because they involve multiple variations in multiple genes that interact with the environment to give you a disease – and also provide a set-up for unique ways to treat the disease.”

Biological scientist Maria Castano

Dr. Liggett was one of the first physicians recruited for what would become the USF Health Heart Institute.  He recalls that he still had the letter of offer in his pocket when he stood before the Hillsborough County Commission in 2012 to help USF Health leadership pitch the need for a cardiovascular institute to include a focus on genomics-based personalized medicine.  The county joined the state in funding the project, and Dr. Liggett was instrumental in the early planning stages of the Heart Institute before the arrival of its founding director Dr. Samuel Wickline.  The institute is now under construction in downtown Tampa as part of the new Morsani College of Medicine facility, a key anchor of Water Street Tampa. Already, 21 of the 31 institute’s biomedical scientists who will investigate the root causes of heart and vascular diseases with the aim of finding new ways to detect, treat and prevent them, have been recruited.

“There’s an excitement here and philosophy of excellence that’s rewarding to see,” Dr. Liggett said. “We have a strategic plan in place, including moving ahead to expand research in cardiovascular disease, infectious disease and the microbiome, and the neurosciences. Our departments are recruiting at a good pace, and the faculty we’re bringing in all have NIH funding and are highly collaborative.”

Dr. Liggett is an elected fellow of the American Association for the Advancement of Science – one of only five Morsani College of Medicine faculty members to receive that prestigious honor.  He is also an elected Fellow of the National Academy of Inventors and the American College of Chest Physicians. Last year, he was one of 30 scientists nationwide selected to join The Research Exemplar Project – recognition of his outstanding reputation as a leader whose high-impact, federally-funded research yields novel and reproducible results.

Over his career, he has served on several NIH study sections and on the editorial board of high-impact journals relevant to fundamental biochemistry as well as heart and lung diseases.  He is currently editor-in-chief of the Journal of Personalized Medicine.

 The potential of new treatments for asthma and heart failure

Dr. Liggett holds 18 patents detailing potential new targets for drug therapy or genetic variations of known drug targets, which might be used to predict response to medications and customize treatment.

Some things you may not know about Dr. Liggett:

• He has asthma, which helps motivate his research toward finding better treatments for this common lung disease affecting one in 12 people in the United States.
• Restores vintage cars, primarily DeLoreans. Although he recently finished bringing a funky lime green 1974 Volkswagen Thing back to life, and over the holidays restored a 1973 VW camper. 

• Lives with wife Julie on the beach in Treasure Island, where they enjoy surfing, paddle boarding, and photography.
• Has three children – Elliott, an engineer at NASA’s Jet Propulsion Laboratory at Cal Tech in Pasadena, CA; Grace, who recently completed her master’s degree in public health at USF; and Mara, an undergraduate student studying social work at Florida Atlantic University, and two step-children — Madison, an undergraduate at the University of Florida, and Tripp, a senior at St. Petersburg Catholic High School. He also has three grandchildren, ages 2 to 9.

Photos by Sandra C. Roa, and audio clips by Eric Younghans, University Communications and Marketing

USF to help meet critical demand, spurred by advances in genomics and precision medicine, for more trained professionals

Tampa, FL (Oct. 25, 2016) – The University of South Florida College of Public Health is the first in Florida to offer a graduate degree in genetic counseling. Last week, the college’s graduate program in genetic counseling earned a crucial accreditation from the Accreditation Council for Genetic Counseling. Accreditation as a new program by this national organization is essential for graduating students to be eligible to take the American Board of Genetic Counseling examination and become certified genetic counselors.

With that milestone met, the program leading to a master of science degree in public health and genetic counseling (MSPH) is now recruiting and expects to admit its first group of students in Fall 2017.

While more people with genetic predispositions for certain cancers or other conditions are seeking out testing, there is a critical shortage of certified genetic counselors to help guide patients and their families through the process.

Laura Barton, a genetic counselor at Moffitt Cancer Center and president of the Florida Association of Genetic Counselors, said the need for a genetic counseling training program has been long overdue. “It’s very exciting because now students won’t have to leave Florida to become a genetic counselor like I had to.”

Michael White, PhD, a professor in the College of Public Health who was instrumental in initiating this program pointed out, “We’re the third most populous state, but until now we didn’t have any genetic counseling training programs.”

Deborah Cragun, PhD, is director of the USF College of Public Health’s new genetic counseling graduate program.

The USF Genetic Counseling program is a 42 credit graduate degree (21 months) with estimated total tuition costs for Florida state residents of $19,000. The program is open to students with a bachelor’s degree; however, a few key undergraduate courses including molecular biology and genetics will be required to apply.

“We’re not restricting what their undergraduate major is, they just need to make sure they have certain prerequisites,” said Deborah Cragun, PhD, assistant professor in the Department of Global Health, and director for the new program.

COPH and the USF Health Morsani College of Medicine, Department of Pediatrics, teamed up with faculty across the university and throughout the Tampa Bay area to create the genetic counseling program. USF’s Division of Genetics & Metabolism, Moffitt Cancer Center, Orlando Health and other community partners will provide students with the hands-on counseling experience required for graduation.

Cragun said students of the program will be prepared to practice in multiple areas including cancer genetic counseling, prenatal counseling, pediatric counseling and newer specialties that are arising due to advances in genomics and precision medicine.

“Students go out and work with practicing genetic counselors so they can gain the experience they need,” Cragun said. “They will work with counselors who are certified themselves and who see patients in a variety of clinical settings. Currently we have partnered with all 10 clinical genetic counselors in Tampa and six clinical genetic counselors in Orlando. In addition, our students will gain experience shadowing and learning from several other counselors who work in industry or laboratory settings.”

“This program will help the state and the profession,” Cragun said. “It will be critical, because as we start doing more genetic tests, it’s really important that we have the expertise out there to help families accurately understand those results and make decisions that are right for them.”

According to the U.S. Bureau of Labor Statistics, employment of genetic counselors is projected to grow 29 percent from 2014 to 2024, which is much faster than the average for other occupations.

“Admissions across the country are actually highly competitive for genetic counseling training programs,” Cragun said. “To date, no other public or private academic genetic counseling program exists in Florida, and ours is one of only 35 accredited programs in the U.S.”

The COPH will host an open house for anyone interested in learning more about the field of genetic counseling and the new MSPH program. The open house will be 6 p.m., Wednesday, Nov. 9, in room 302 of the IDR Building on the main USF campus located at 3720 Spectrum Blvd, Tampa, FL 33612. Please contact Miki Pomeroy at mpomeroy1@health.usf.edu for more information and to obtain a parking permit for the event.

To learn more about the graduate program in genetic counseling, contact (813) 974-6505, preadmissions@health.usf.edu or visit http://health.usf.edu/publichealth/genetic-counseling.htm.

-USF College of Public Health-

Established in 1984 as the first college of public health in the State of Florida, the USF College of Public Health is a recognized leader in community health, online education, maternal and child health, social marketing, and global infectious disease research. The college offers multiple online and on-campus concentrations that lead to BSPH, MHA, MPH, MSPH, DrPH, and PhD degrees, as well several dual degrees, graduate certificates, and special programs. To learn more about the college and its 1800 students who commit to passionately solve problems and create conditions that allow every person the universal right to health and well-being, visit www.publichealth.usf.edu.

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Biomedical Sciences Graduate and Postdoctoral Programs, and the USF Physicians Group. The University of South Florida is a Top 50 research university in total research expenditures among both public and private institutions nationwide, according to the National Science Foundation. For more information, visit www.health.usf.edu

Media Contact:
Natalie D. Preston, USF College of Public Health
npreston@health.usf.edu, or (813) 974-7714

University of South Florida-led study helps refine personalized approach to breast cancer diagnosis and treatment

//www.youtube.com/watch?v=N83YjZnz0QE

Tampa, FL (March 6, 2014) – A method called molecular subtyping can help doctors better determine which of their breast cancer patients are at high risk of getting breast cancer again, a new study led by the University of South Florida reports.  This sophisticated genetic profiling of an individual’s specific tumor offers an additional resource to help identify patients who would most benefit from chemotherapy and those who would not.

The findings by researchers from USF and other institutions were presented in a scientific poster at the Miami Breast Cancer Conference, held March 6-9 in Miami Beach, Fla.

“The most important takeaway for our colleagues in breast cancer diagnosis and treatment is the potential value of molecular subtyping to personalize and improve each woman’s treatment,” said principal investigator Charles E. Cox, MD, McCann Foundation Endowed Professor of Breast Surgery, USF Health Morsani College of Medicine.

Dr. Charles Cox led the study looking at sophisticated genetic profiling tests that may help guide breast cancer treatment decisions. The findings were reported in a scientific poster presented at the Miami Breast Cancer Conference 2014.

Molecular subtyping is a way of classifying breast cancer tumors into one of four genetically-distinct categories, or subtypes: Luminal A, Luminal B, Basal (a subset of triple negative), and HER2-type.  Each subtype responds differently to different kinds of treatments, and some subtypes indicate a higher risk of disease recurrence.

“Our data showed that a substantial number of breast cancer patients — classified as low risk by one particular genomic test — turn out to be at high risk of recurrence once we determined their subtype,” Dr. Cox said. “These are mostly Luminal B patients, and their physicians might not fully understand their patient’s situation unless they do subtyping.”

The USF study examined why different genomic tests for breast cancer sometimes provide contradictory information about risk of recurrence. The key findings involved the 70-gene MammaPrint® test; the 21-gene Oncotype DX® test, which is an earlier commercially available test; and Mammostrat®, a gene profiling test performed on slides of the breast tumor by a pathologist. The tests have generally been assumed to provide equivalent information about recurrence risk, but that is proving not to be the case.

Researchers examined tumor samples from a total of 148 patients. The greatest discordance (lack of agreement) about risk of disease recurrence occurred in a group of 51 patients.  Of those 51, all were stratified by MammaPrint as high risk of recurrence, while Oncotype classified 18 of them (35 percent) as low risk.

BluePrint®, an 80-gene test to identify a tumor’s molecular subtype, was also used for those stratified by MammaPrint. This process revealed that the 51 patients were Luminal B, a molecular subtype with a high risk of recurrence.

Steve Shivers, PhD, a research scientist in the USF Health Department of Surgery, was a study co-author.

Patients with a high risk of recurrence are normally counseled to receive chemotherapy following surgery to prevent the cancer from returning.  In contrast, women whose subtype has a low risk of recurrence (Luminal A) will not benefit from the addition of chemotherapy. They may thus be able to safely avoid chemotherapy and its potentially damaging side effects.  At the same time, they can be prescribed treatments such as hormonal therapy known to benefit those with their subtype.

The additional information provided by genomic tests and molecular subtyping may help reduce overall treatment costs for breast cancer, by targeting chemotherapy only for those women who will benefit from it,  Dr. Cox said  “Personalized treatment guided by these tests may also extend the time that patients are free of their cancer.”

Registered nurse George Ann Vincent, a Tampa, Fla. resident and a patient of Dr. Cox, was diagnosed with early-stage breast cancer last year. The 70-gene test determined that her tumor had a high risk of recurrence, so she was prescribed chemotherapy.

“I’m certainly grateful that I’m getting the treatments that are right for me,” Vincent said. “Chemotherapy is no picnic, but it can save lives. The genomic tests I took made me confident I was being sent in absolutely the right direction.”

Dr. Cox clarified that discordance does not necessarily show that some genomic test results were wrong.

“These tests use different genes and were validated on different types of populations,” he said. “But if physicians use molecular subtyping as we did in this study, they will have valuable, additional information to guide the appropriate treatment for each patient.”

Using molecular subtyping in combination with traditional biomarkers, like tumor grade and hormone receptor status, for determining the biological nature of a woman’s cancer is a recommended guideline for breast cancer treatment in both the United States and Europe, Dr. Cox said.

Other poster co-authors included researchers from Florida Hospital Tampa; Morton Plant Hospital, Clearwater, Fla.; and Agendia NV, a molecular diagnostics firm.

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

Media contact:
Anne DeLotto Baier, USF Health Communications
abaier@health.usf.edu or (813) 974-3303

Combining advanced research with the best care,  the facility’s doctors and scientists will guide the way for new solutions to cardiovascular disease 

 //www.youtube.com/watch?v=ochVnl8Qy24

“>

//www.youtube.com/watch?v=ochVnl8Qy24

Tampa, FL (Dec. 17, 2013) — The University of South Florida today broke ground for a cutting-edge facility dedicated to changing the future of heart health by bringing together the latest research with the best cardiovascular care.

The groundbreaking ceremony represents an important milestone in making the vision for the USF Health Heart Institute a reality.

L to R: Mark Sharpe, chair, Hillsborough County Board of County Commissioners; USF President Judy Genshaft; Will Weatherford, speaker, Florida House of Representatives; Dr. Stephen Liggett, vice dean for research, USF Health Morsani College of Medicine; Dr. Harry van Loveren, interim dean, Morsani College of Medicine; and Dr. Arthur Labovitz, chair, USF Health Department of Cardiovascular Sciences.

The proposed $50-million, five-story, 100,000-square-foot facility will be built at the center of the university’s health campus — a dynamic hub of biomedical research that includes the USF Health Byrd Alzheimer’s Institute, Moffitt Cancer Center and the USF Health Morsani College of Medicine.

Within the multidisciplinary Institute, USF Health will bring together all the advanced technology and research needed to discover the most effective, creative solutions for heart disease, stroke, diabetes and other cardiovascular diseases.

Heart disease is the leading cause of death in the nation and, according to Florida Vital Statistics 2012, ranks a close second in Florida (narrowly following cancer).  It is also a leading cause of hospitalizations and lost productivity.

“This is landmark day for the University of South Florida and all those in Tampa Bay and the State of Florida who have friends or family affected by heart disease,” USF President Judy Genshaft said. “That is really is most of us, because heart disease is the number one killer in the nation. More than 40,000 in Florida alone die each year from heart disease and countless others are impacted.”

“USF is working tirelessly to make heart disease less of a threat to the health and well-being of our community. Today, we take a huge step forward in our efforts as we begin work on building our new USF Health Heart Institute,” she said. “We’re creating the scientific infrastructure that will make Florida a world leader in combating devastating diseases.”

USF President Judy Genshaft called it a landmark day for the University of South Florida and for all those in Tampa Bay region and the state who have friends or family affected by heart disease.

The project has secured $21.4 million in total funding, with anticipated funding of $30 million needed to complete construction. The State of Florida contributed $19.4 million over the last two years, joined by Hillsborough County, which approved $2 million in funding support last year. In addition, USF plans to invest up to $25 million in resources for genomics-based medicine research and recruitment of faculty.

The facility will include an auditorium, blood sample repository for genetic testing, four core laboratories and office space designed for interdisciplinary collaboration, as well as a clinical care center. The project is expected to attract high-wage jobs, industry partnerships, patents and other products that will advance economic development based on biotechnology.

Built with a community of partners

“From the day we began talking about how USF Health could do more to fight the causes and symptoms of heart disease, we have had an entire community of supporters working with us,” said Harry van Loveren, MD, interim director of the Morsani College of Medicine. “We will accomplish all of this because of their collective efforts.”

Governmental leaders both for the state of Florida and for Hillsborough County as well as community and hospital partners, including Tampa General Hospital and Florida Hospital Tampa and its Pepin Heart Institute, worked with the university to advance the USF Health Heart Institute.

Will Weatherford, speaker of the Florida House of Representatives, has championed the USF Health Heart Institute from the beginning.

In particular, President Genshaft recognized the leadership of Will Weatherford, speaker of the Florida House of Representatives, for championing the Heart Institute from the beginning.

“The legacy of his work on this project is something that will benefit generations to come,” she said.

Weatherford told the crowd gathered for the groundbreaking that the future site of the USF Health Heart Institute was the “heart” of where innovation was happening on the USF campus and across the Tampa Bay region.

“I can tell you that the Legislature, myself, and the Florida House are committed to seeing this project through — not just funding it, but making sure the resources and policy are embedded around it to make this a world-class institution in Tampa Bay and the State of Florida,” Weatherford said. “I can’t think of anything we will do in this next legislative session that’s going to make a bigger difference for people right here in this community than what we’re doing with this Heart Institute.”

The leadership and scholarly activity of many dedicated physicians and scientists at USF Health, including the USF Health Heart Institute’s acting directors Stephen Liggett, MD, vice dean for research at the Morsani College of Medicine, and Arthur Labovitz, MD, chair of the Department of Cardiovascular Sciences, helped lay the foundation for the institute and will navigate  its ongoing work.

Mark Sharpe, chair of the Hillsborough County Board of County Commissioners, said the county was eager to partner with USF on a project that will improve lives and spur economic development.

Mark Sharpe, chair of the Hillsborough County Board of County Commissioners, said the county was excited to partner with USF and invest in the forward-thinking, strategic project that will improve lives and spur economic development.

“We understand that health care is going to drive our state and our region,” Sharpe said. “With the tremendous team and the rock star research here, we’re going to do some great things.”

The future of heart research

The pipeline of new drugs for cardiovascular diseases is relatively dry.  That’s in part because the root causes of heart disease, including molecular and genetic aspects, are largely unknown or are more complex than anticipated, Dr. Liggett said.

The research performed at the Heart Institute will advance the fundamental understanding of cardiovascular diseases and will determine the best ways to apply the novel laboratory findings to benefit patients.

“The new knowledge will lead to new diagnostic tests to identify those at greatest risk for heart disease, so we can begin preventive measures early,” Dr. Liggett said.

The discoveries will also lead to new and improved treatments based on genetic signatures and other biomarkers of disease.  The findings may help guide selection and dosage of existing drugs to reduce side effects and optimize patient outcomes.

Dr. Harry van Loveren, interim dean of the USF Health Morsani College of Medicine, is interviewed by Mark Schreiner of WUSF University Beat.

The institute will promote what Dr. Liggett calls a “bench-to-bedside-to-bench” approach.

On the bench-to-bedside part of the equation, the institute’s researchers will continually strive to understand the underpinnings of the disease with a focus on direct application to prevention and patient care.  On the bedside-to-bench part, doctors may notice that a new drug undergoing clinical testing for one cardiovascular disease improves another.  This information can be fed back to the laboratory scientists to investigate how the unexpected positive outcome occurs, possibly leading to a new treatment.

“The sharing of basic and clinical research data in both directions can lead to better outcomes,” Dr. Liggett said.

One of the major areas of research emphasized by the institute will be genomics.

“Your DNA already knows if you’re going to have a heart attack and when. Your DNA already knows if one of our drugs will save your life or won’t,” Dr. van Loveren said.  “The heart research that will be done here will unlock the secrets of your personal DNA, see into your future and hopefully change it… Because of what we learn here, your children and my children will live happier and healthier lives.”

University, governmental and community leaders gathered for the groundbreaking  in the heart of the university’s health campus, a dynamic hub of biomedical research.

Raising the profile of region’s cardiovascular care

USF Health recently began its first genomic trial that links DNA analysis from blood samples to the American College of Cardiology’s clinical database of millions of patients with heart disease.

It’s just the start.

The Heart Institute will provide a home for the region’s only academic health center and its hospital partners to study every promising research avenue – from new molecular targets to looking at how differences in individual DNA may affect people’s cardiovascular health to investigating the potential of gene therapy or stem cells to repair a damaged heart.

The focus will be on translating basic science and research discoveries into well-designed clinical trials to improve patient care.

“The collaborative work we do will elevate the level of excellence for cardiovascular diagnostics and care in the Tampa Bay region,” Dr. Labovitz said.

“We will attract leaders in the field and offer patients opportunities to participate in a full range of clinical trials for cardiovascular diseases, including heart failure, coronary artery disease, arrhythmias and hypertension.”

– Lisa Greene contributed to this report.

Photos by Eric Younghans, USF Health Communications, and video by Joshua Jackson, USF Health Information Systems

Preliminary rendering of the USF Health Heart Institute

L to R: Dr. Stephen Liggett, vice dean of research, Morsani College of Medicine; Dr. Arthur Labovitz, chair of Department of Cardiovascular Sciences; Dr. Donna Petersen, interim senior vice president for USF Health and dean, USF College of Public Health; Will Weatherford, speaker of the Florida House of Reprsentatives; and USF President Judy Genshaft.

University, governmental and community leaders, as well as hospital partners, attended the groundbreaking ceremony.

Dr. Petersen, left, with Dr. Kevin Sneed, dean of the USF College of Pharmacy

USF Health leaders chat with, at right, Tom and Lauren Pepin.

The USF ambassadors were on hand to greet guests.

L to R: Mark Sharpe, chair of the Hillsborough County Board of County Commissioners; John Ramil, chair of the USF Board of Trustees; and Brian Lamb, USF BOT member.

USF President Judy Genshaft with Nancy Watkins, a member of the USF Board of Trustees.

The institute will change the future of heart health by bringing together the latest research with the best cardiovascular care.

An impressive team of community and hospital partners worked with USF to help make the vision of the USF Health Heart Institute a reality.

L to R: Steve Blair, associate vice president and chief development officer for USF Health, with Lauren and Tom Pepin

USF Health faculty members in medicine and public health scored major media hits this past week.

Stephen Liggett, MD, vice dean for research at the USF Health Morsani College of Medicine,  was among the academic  leaders in the emerging field of personalized medicine and genomics to comment in a New York Times piece about a new technologically-advanced machine  that interprets a person’s DNA blueprint for use in medicine, while keeping the highly personal data secure.     A multicenter team headed by Dr. Liggett recently identified alterations in DNA sequence, termed genetic variants, that predict which patients with heart failure can be saved from experiencing fatal arrhythmias.

Thomas Unnasch, PhD, professor and chair of global health at the USF College of Public Health, was prominently featured in a CNN Health story that depicts the misery suffered by Africans afflicted by onchocerciasis, commonly known as river blindness.  Dr. Unnasch is one of the world’s leading exerts on this rare parasitic disease spread by the bite of a black fly that breeds in fast-flowing rivers.   He chairs an expert advisory committee consulting with the Ugandan Ministry of Health on efforts to eliminate the blinding infection from Uganda by 2020.

Several clinical trials starting at USF Health’s new Heart Institute this year will offer gene and stem cell therapy approaches to healing damaged hearts

Over the past 18 months, David Skand has been hospitalized four times, twice in intensive care. In June, the 70-year-old Tampa Bay Downs racetrack veterinarian found himself in the hospital once again. This time was different, though. This time he was filled with hope.

Skand is the first of 10 USF Health patients enrolled in a clinical trial for a genetically-engineered drug designed to treat chronic heart failure. The drug, developed in Shanghai, China, signals a patient’s own cells to remodel the heart.

Senior research nurse Bonnie Kirby speaks with trial participant David Skand and USF Health Heart Institute Director Dr. Leslie Miller.

It is the first of several trials getting under way at USF Health’s new Heart Institute. The institute, which was recently awarded $8.9 million in state and county funding, is focused on regenerative medicine using the latest in gene and stem cell therapy, as well as genomics-based personalized medicine.

“This is a significant change in thinking and goals,” says USF Health Cardiovascular Sciences Chair Dr. Leslie Miller, a renowned cardiologist and leading international specialist in heart failure and transplantation who leads the institute. “We are not just helping improve heart function, we are driving the heart’s native repair mechanisms.”USF is one of 10 sites for the randomized, double-blind study—the first test of the drug in the United States. For some patients, the drug, called Neucardin, could mean the difference between a heart transplant and a simple drug infusion.

Of the 120 patients who will eventually be enrolled in the study, 80 will receive the active form of the drug, while 40 will receive a placebo.

Dr. Leslie Miller says it is important for patients, like David Skand, to hear from him, as well as the research coordinator, about the risks and benefits of a trial.

“It’s thrilling,” says Skand, who was diagnosed with chronic heart failure in 1993. “I think this is going to help a lot of people in this country.”

He’s not worried about the possibility of receiving the placebo. “I have a 66 percent chance of getting it,” he says with confidence. “But the point is, you are still getting evaluated by the top doctors and the top nurses and undergoing really tremendous diagnostic procedures every day.”

For eight hours a day over 10 days in late June, Skand received either the drug or placebo through a small subcutaneous cathether. Studies to date show minimal side effects from the drug, occasionally a little nausea. Doctors continue  to follow Skand closely since he left the hospital after the extended infusion, particularly in the first six months when the greatest change in heart function would likely occur.

“The best would be an improvement in my ejection fraction,” Skand says, referring to the amount of blood his heart pumps out with every beat. “That would make a big difference for me. I’d be less tired; I could do more things, like walking and climbing stairs. And it would help my mental outlook a great deal.”

A radiologist at the institute reads a CT scan of the heart.

The Neucardin trial is the first of five planned trials—three gene therapy trials and two stem cell trials—at the institute this year. The trials are focused on preventing and reversing disease processes. There’s also a major study in partnership with the American College of Cardiology (ACC) to identify genes that are markers of atherosclerosis and other forms of coronary artery disease.

The need for new diagnostic tools, such as the use of genomic markers to detect and predict disease, and new therapies, such as stem cell and gene therapy, is indisputable. In Florida alone, cardiovascular disease accounts for 40 percent of all hospitalization and deaths. Estimates put the state’s costs for cardiovascular care at $17 billion by 2020.

But the problem isn’t isolated to Florida. According to Miller, cardiovascular disease is the biggest health risk in the world.

“The data is unequivocal. One in four people in the U.S. have cardiovascular disease. By 2020, it will be one in three,” he says. “The new Heart Institute is a critical step toward saving lives by finding new diagnostic tools that will allow earlier detection and better prevention, as well as new and improved therapies to improve outcomes.”

Patients enrolled in the Neurocardin trial are closely monitored after leaving the hospital, particularly in the first six months.

The ACC selected the Heart Institute as its partner for the first-ever trial linking genomic screening with its clinical database of patients.

“The ACC has millions of patients enrolled in registries and all the data for every type of cardiovascular disease,” Miller says. That data could help researchers identify individuals at risk for disease, allowing doctors to intervene long before a heart attack.

It could even help identify, early-on, children who may be at risk for developing the same heart condition as their parents.

“We want to do some out-of-the-box thinking about interventional treatments,” Miller says. “We might be able to introduce a statin at an early age to retard the development of atherosclerosis.”

Genetic markers have already been used in other fields to predict the likelihood of disease and introduce interventional treatments.

Cancer researchers, for example, have found that a significant percentage of women with breast cancer carry the genetic marker BR2a. The correlation is so strong, Miller says, that an increasing number of women who carry the gene are choosing to undergo a double mastectomy to prevent or reduce their risk for the disease.

Along with understanding risk, genetic discoveries could help doctors identify which treatments are most effective for individual patients as well as provide insight on appropriate dosing.

The gene and stem cell therapy trials offered by the institute will focus on preventing and reversing cardiovascular disease processes.

It’s the future of cardiovascular care and it places USF at the center of some of the most advanced research in the world, which is attracting leading scientists.

In March, Dr. Jennifer Hall, a nationally prominent cardiovascular genomics researcher joined the institute in March.  Her work in translational genomics—using a patient’s own genetic code to guide medical care—will be key to the ACC study.

But, USF Health’s focus on personalized medicine isn’t limited to heart disease. In June, Dr. Stephen Liggett, a nationally prominent researcher in genomics-based personalized medicine,  joined USF Health as associate vice president of personalized medicine and director of the Center for Personalized Medicine and Genomics.  Liggett’s initial collaborations will include Miller’s work at the Heart Institute.

“This field is moving so rapidly,” says Miller, calling this the most exciting time of his career. “A tube of blood allows us to have your whole DNA analyzed—a huge array of data to put in usable form for doctors to take care of patients.”

Skand, a racetrack veterinarian, says the new drug could make a big difference, enabling him to do more things and improving his outlook on life.

It’s the kind of research that could revolutionize healthcare, according to Dr. Stephen K. Klasko, CEO of USF Health and dean of the Morsani College of Medicine.

“We believe that the technology developed here will herald a new day and that USF Health will be able to partner with the best industry and academic partners throughout the world to develop these new personalized and genetic approaches to health.”

Postscript:   Dr. Skand notes he has felt much better in the initial months following the drug infusion, but neither he nor the healthcare practitioners involved in the blinded clinical trial will know whether he received active drug for likely a year.

Story by Ann Carney/Reprinted from USF Magazine,  Fall 2012
Photos by Eric Younghans, USF Health Communications

Personalized medicine research at University of South Florida strikes early for heart genes 

Tampa, FL (Oct. 16, 2012) — A landmark paper identifying genetic signatures that predict which patients will respond to a life-saving drug for treating congestive heart failure has been published by a research team co-led by Stephen B. Liggett, MD, of the University of South Florida.

The study, drawing upon a randomized placebo-controlled trial for the beta blocker bucindolol, appears this month in the  international online journal PLoS ONE.  In addition to Dr. Liggett, whose laboratory discovered and characterized the two genetic variations, Christopher O’Connor, MD, of Duke University Medical Center, and Michael Bristow, MD, PhD, of ARCA biopharma and the University of Colorado Anschutz Medical Campus, were leading members of the research team.

Dr. Stephen Liggett, who joined USF just four months ago to lead the University’s Center for Personalized Medicine and Genomics, was a senior author of the landmark paper.

The analysis led to a “genetic scorecard” for patients with congestive heart failure, a serious condition in which the heart can’t pump enough blood to meet the body’s needs, said Dr. Liggett, the study’s co-principal investigator and the new vice dean for research and vice dean for personalized medicine and genomics at the USF Morsani College of Medicine.

“We have been studying the molecular basis of heart failure in the laboratory with a goal of finding genetic variations in a patient’s DNA that alter how drugs work,” Dr. Liggett said.  “We took this knowledge from the lab to patients and found that we can indeed, using a two-gene test, identify individuals with heart failure who will not respond to bucindolol and those who have an especially favorable treatment response. We also identified those who will have an intermediate level of response.” The research has implications for clinical practice, because the genetic test could theoretically be used to target the beta blocker to patients the drug is likely to help. Equally important, its use could be avoided in patients with no likelihood of benefit, who could then be spared potential drug side effects.  Prospective studies are needed to confirm that bucindolol would be a better treatment than other classes of beta blockers for a subset of patients with health failure.

Dr. Liggett collaborated with medical centers across the United States, including the NASDAq-listed biotech company ARCA biopharma, which he co-founded in Denver, CO.   This genetic sub-study involved 1,040 patients who participated in the Beta-Blocker Evaluation of Survival Trial (BEST).  The researchers analyzed mortality, hospital admissions for heart failure exacerbations and other clinical outcome indicators of drug performance.

“The results showed that the choice of the best drug for a given patient, made the first time without a trial-and-error period, can be accomplished using this two-gene test,” Dr. Liggett said.

The genetic test discovered by the Liggett team requires less than 1/100^th of a teaspoon of blood drawn from a patient, from which DNA is isolated.  DNA is highly stable when frozen, so a single blood draw will suffice for many decades, Dr. Liggett said. And since a patient’s DNA does not change over their lifetime, as new discoveries are made and other tests need to be run, it would not be necessary to give another blood sample, he added.

This is part of the strategy for the USF Center for Personalized Medicine and Genomics. The discovery of genetic variations in diseases can be targeted to predict three new types of information: who will get a disease, how the disease will progress, and the best drug to use for treatment.

“In the not too distant future, such tests will become routine, and patient outcomes, and the efficiency and cost of medical care will be impacted in positive ways.  We also will move toward an era where we embrace the fact that one drug does not fit all,” Dr. Liggett said.  “If we can identify by straightforward tests which drug is best for which patient, drugs that work with certain smaller populations can be brought to the market, filling a somewhat empty pipeline of new drugs.”

This approach is applicable to most diseases, Dr. Liggett said, but the USF Center has initially concentrated on heart disease, because it is a leading cause of deaths, hospitalizations and lost productivity in the Tampa Bay region and Florida.  Dr. Liggett is a recent recruit to the USF Health Morsani College of Medicine, coming from the University of Maryland School of Medicine.  His work at USF has been supported by several National Institutes of Health grants and $2 million in funding from Hillsborough County.

Heart failure is characterized by an inability of the heart muscle to pump blood, resulting in dysfunction of multiple organs caused by poor blood and oxygen flow throughout the body.  An estimated 6 million Americans are living with heart failure, and more than half a million new cases are diagnosed each year.  About 50 percent of patients diagnosed with heart failure die within five years.  The economic burden of heart failure in the United States is estimated at $40 billion a year.

Article citation:
Christopher M. O’Connor, Mona Fiuzat, Peter E. Carson, Inder S. Anand, Jonathan F. Plehn, Stephen S. Gottlieb, Marc A. Silver, JoAnn Lindenfeld, Alan B. Miller, Michel White, Ryan Walsh, Penny Nelson, Allen Medway, Gordon Davis, Alastair D. Robertson, J. David Port, James Carr, Guinevere A. Murphy, Laura C. Lazzeroni, William T. Abraham, Stephen B. Liggett and Michael Bristow, “Combinatorial Pharmacogenetic Interactions of Bucindolol and β₁, α_2C Adrenergic Receptor Polymorphisms,” PLoS ONE   7(10): e44324. doi:10.1371/journal.pone.0044324

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

Media contact:
Anne DeLotto Baier, USF Health Communications
(813) 974-3303 or abaier@health.usf.edu

Tampa, FL (June 13, 2012)  — Stephen B. Liggett, MD, a pioneer in the emerging field of personalized medicine, will help USF Health build an interdisciplinary center that will be a national leader in driving research needed to tap patients’ unique DNA profiles to tailor their medical care.

Dr. Liggett, who will direct the USF Center for Personalized Medicine and Genomics, joined the University of South Florida June 11.  He is vice dean for personalized medicine and genomics at the Morsani College of Medicine, USF Health associate vice president for personalized medicine, and professor in the Department of Internal Medicine. He will hold a joint appointment in the Department of Molecular Pharmacology and Physiology.

Dr. Stephen Liggett brings to USF Health a multi-million dollar NIH portfolio.

Dr. Liggett came to USF from the University of  Maryland School of Medicine in Baltimore, where he was associate dean for interdisciplinary research and professor of medicine and physiology. Supported by a multi-million dollar portfolio of NIH grants, he studies genetic variations in people and pathogens, with a focus on signaling genes relevant to heart and lung diseases.

“We are very fortunate to have recruited Dr. Liggett; he was highly sought after by other universities both in Florida and across the country,” said Stephen K. Klasko, MD, MBA, CEO of USF Health and dean of the Morsani College of Medicine. “Dr. Liggett’s leadership and expertise will be critical in helping USF Health, the Tampa Bay region and the state of Florida advance in genomics-based personalized medicine for heart and other diseases. This is the future of medicine – another terrific opportunity for us to be at the forefront of transforming how health care is provided to patients.”

If the promise of personalized medicine is realized, physicians could mine a person’s genetic code, or genome, for information to predict the individual’s disease risk, disease progression, or severity, and response to treatment.  They would take into account the patient’s unique genetic profile and physiology, including an individual’s ability to metabolize particular drugs, to select the best treatment and determine the right dosage.

Dr. Liggett describes genomics-based personalized medicine as a powerful, targeted approach that could achieve a level of optimal care surpassing current outcomes.

“Using a person’s genetic code to tailor their treatments eliminates the ‘trial-and-error’ approach, which is the way medicine is practiced now,” Dr. Liggett said. “We need to use the most sophisticated information we can to give patients receiving a diagnosis their best medication options right away, particularly for aggressive diseases where time is of the essence.”

At USF, Dr. Liggett will work with faculty members across multiple disciplines, incorporating personalized medicine in varying degrees into the research and practice of medicine.  The research will emphasize finding links between differences in genes sequences and responses to treatment, so that eventually genetic tests can be developed to help improve the safety and effectiveness of therapy and to lower costs.

Dr. Liggett’s initial collaborations will include Leslie Miller, MD, chair of cardiovascular sciences at the Morsani College of Medicine and leader of  the USF Health Heart Institute.  In April, the Heart Institute received a combined $8.9 million in state and county funding, which will allow USF Health to join with industry and academic partners to begin developing new genomics-based personalized approaches to health.

“There is a pressing need to bring to bear all our tools, including personalized medicine, to prevent and treat cardiovascular disease, the most common cause of death in the U.S., Florida and the Tampa Bay region,” Dr. Liggett said. “USF has already invested substantially in laying a foundation for personalized medicine in heart disease. So, to leverage this effort, one of the first group of diseases we target will be cardiovascular.”

Advances in the field of personalized medicine are expected to multiply over the next decade with strides in the clinical interpretation of genome sequencing and increases in the number of diseases that can be precisely diagnosed and then treated with a highly targeted therapy. Work by Dr. Liggett’s laboratory’s has led to greater understanding of how variations of genes and families of genes affect the disease processes of congestive heart failure and asthma and how a patient’s genetic makeup can be used to tailor drug treatment.

Among his accomplishments:

• At the University of Maryland, Dr. Liggett and colleagues identified a gene variation that appears to help determine which patients with heart failure will benefit from a beta-blocker drug commonly used to treat the chronic disease. That is important because it often takes several months to determine if a specific beta blocker is working for a patient.
• Dr. Liggett’s genomic investigations in heart failure have generated $6.1 million in National Institutes of Health grants, 10 new patents and resulted in the creation of two biotechnology companies.

•  Dr. Liggett’s University of Maryland team, working with colleagues at the University of Wisconsin-Madison, for the first time mapped out the entire genome of nearly 100 different strains of the common cold virus.  The work, published in the journal Science, may provide a powerful tool leading to the first effective treatments for the common cold.

•  Dr Liggettt’s team used a genomics-based drug discovery method that he pioneered to discover taste receptors in the lung and found a new target for treating asthma. This work, published in Nature Medicine, has stirred renewed interest internationally on development of new drugs for asthma and emphysema.

Dr. Liggett received an MD degree from the University of Miami School of Medicine.  He completed his residency in internal medicine and a fellowship in pulmonary and critical care medicine at Washington University School of Medicine and Barnes Hospital in St. Louis. Following a laboratory-based postdoctoral fellowship at the Howard Hughes Medical Institute at Duke University, he joined the faculty at Duke and then the University of Cincinnati College of Medicine.

At the University of Cincinnati, Dr. Liggett was the Taylor Endowed Professor of Medicine, Pharmacology and Molecular Genetics, and served as chief of the Pulmonary and Critical Care Division.  He moved to the University of Maryland in 2005.

Dr. Liggett has served on numerous NIH study sections and committees of the American Lung Association. He is a member of the Personalized Medicine Coalition’s Clinical Science Committee, working to advance the understanding and adoption of personalized medicine to benefit patients. He is an editorial board member for several high-impact journals and has authored more than 200 publications, including papers in peer-reviewed journals, book chapters and reviews.

-USF Health-

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a global research university ranked 50^th in the nation by the National Science Foundation for both federal and total research expenditures among all U.S. universities.

Photos by Eric Younghans, USF Health Communications

Media contact:
Anne DeLotto Baier, USF Health Communications, (813) 974-3303 or abaier@health.usf.edu