genomics

Lab Notes – Spring 2017

For MRSA, Resistance is Futile

UConn medicinal chemists have designed experimental antibiotics that kill Methicillin-resistant Staphylococcus aureus (MRSA), a common and often deadly bacteria that causes skin, lung, and heart infections. The new antibiotics disable the bacteria’s vitamin B9 enzyme. Without vitamin B9, the bacteria can’t make essential amino acids and they die. Not only do the new antibiotics kill regular MRSA, they also kill types of the bacteria with unusual antibiotic-resistance genes that had never been seen before in the U.S. And that’s no accident: the chemists designed the antibiotics to latch on to the enzyme so cleverly that if it changed enough to elude them, it would no longer be able to do its job with vitamin B9. This could make the new antibiotics resistant to, well, resistance. The research was published in the Dec. 22, 2016 issue of Cell Chemical Biology.

MRSA colonies are shown on a blood agar plate.


State’s Leading Institutions Launch International Effort to Advance Metabolic Research

overweight 3D model running with target on metabolic area

UConn, Yale University, and The Jackson Laboratory (JAX) have partnered with the Weizmann Institute of Science, a prestigious counterpart in Israel, to fill a research void in metabolic diseases that affect billions of people worldwide. The goal of the newly formed Metabolic Research Alliance is to unite the expertise of the institutions on research projects that swiftly move investigations into clinical application and commercialization. The Alliance will employ a novel approach to coordinating existing and new expertise in the areas of immunology, cell biology, microbiota, and the rapidly evolving field of genomics. While investigations will initially focus on obesity and diabetes, the research projects will eventually pursue solutions to additional metabolic diseases.


Innovative Imaging Could Save Sight

Connecticut Innovations has awarded $500,000 to a team of UConn researchers to speed the process to commercialization of the biomarker probe they’re developing to detect a precursor to blindness. The team — led by Royce Mohan, associate professor of neuroscience at UConn Health, and including assistant professor of neuroscience Paola Bargagna-Mohan and UConn School of Pharmacy medicinal chemistry professor Dennis Wright — is developing a fluorescent small molecule imaging reagent to help identify preclinical stages of ocular fibrosis, which is associated with an aggressive form of age-related macular degeneration (AMD) that causes rapid vision loss. AMD is the leading cause of blindness in the U.S. The method would both enable earlier intervention and allow physicians to monitor the progress and effectiveness of interventions before it’s too late.


DOACs Safer Than Warfarin, Study Shows

Patients who suffered blunt traumatic intracranial hemorrhage (ICH) associated with direct oral anticoagulants (DOACs) had significantly lower mortality rates and lower rates of operative intervention compared with a similar group taking warfarin, a study published in the November issue of Trauma and Acute Surgery by researchers from UConn, Saint Francis Hospital and Medical Center, and Trinity College shows. Although DOACs have been an increasingly popular alternative to warfarin for anticoagulation, physicians have worried their use might lead to an increase in patient mortality from uncontrollable bleeding, according to the study. The study, based on data on 162 patients in the St. Francis Trauma Quality Improvement Program database, aimed to help close a gap in research on DOAC safety.

bloodclot in vein

Tell-Tale Heart

‘Heart-In-A-Dish’ Sheds Light on Heart Disease Genetics

By Nicole Davis for The Jackson Laboratory for Genomic Medicine
Photography by Peter Morenus

Dr. Travis Hinson holds petri dishes containing beating heart tissue

Dr. J. Travis Hinson is seen holding petri dishes that contain heart cells. Hinson, a joint faculty appointment at UConn Health and The Jackson Laboratory for Genomic Medicine, has pioneered a system to study the genetics of heart failure by recreating beating heart tissue using patients’ stem cells. Photo: Peter Morenus


When a patient shows symptoms of cancer, a biopsy is taken. Scientists study the tissue, examining it under a microscope to determine exactly what’s going on.

But the same can’t be done for heart disease, the leading cause of death among Americans. Until now.

Dr. J. Travis Hinson, a physician-scientist who joined the faculties of UConn Health and The Jackson Laboratory for Genomic Medicine (JAX) in January, uses a novel system he pioneered to study heart tissue.

Hinson engineers heart-like structures with cells containing specific genetic mutations in order to study the genetics of cardiomyopathies, the diseases of the heart muscle that can lead to heart failure and, ultimately, death.

“We basically try to rebuild a little piece of a patient’s heart in a dish,” says Hinson, who developed the technique during his postdoctoral fellowship.
He combines cardiac muscle cells with support cells, such as fibroblasts, and other key factors, including extracellular matrix proteins. Although these tiny, three-dimensional structures do not pump blood, they do contract rhythmically, and their beating strength can be studied.

Making a Difference

Hinson is applauded for his ability to move seamlessly between research, clinical practice, and teaching — the three prongs of an academic medical center’s mission. He’s able to do so, perhaps, because his own career began at the intersection of multiple scientific specialties.

As a University of Pennsylvania undergraduate, Hinson interned at DuPont in New Jersey to explore interests in chemistry and engineering. But he soon realized his passion for science needed a real-word focus. “I wanted to do science that made a difference in people’s health,” he says.

The same summer, he volunteered in the emergency department of a local hospital. Impressed by a cardiologist’s calm and collected manner in a crisis, and gaining interest in the heart, Hinson changed his career trajectory from engineering to medical school.

Hinson and his colleagues can isolate skin or blood cells directly from cardiomyopathy patients and coax them to form heart muscle cells, making it possible to study the biological effects of patients’ own mutations.

Hinson joined the laboratory of Dr. Robert J. Levy, a pediatric cardiologist and researcher at The Children’s Hospital of Philadelphia, working to harness gene therapy techniques to make artificial heart valves and other cardiovascular devices more durable. Through this early foray into biomedical research, Hinson deepened his interest in biomedical science and gained an appreciation of the work of a physician-scientist.

In Dr. Christine Seidman’s lab at Harvard Medical School, Hinson chose to lead a project on Björnstad syndrome, a rare, inherited syndrome characterized by hearing loss and twisted, brittle hair. At the time, little was known about the molecular causes of the disorder, although the genetic culprits were thought to reside within a large swath of chromosome 2. Using genetic mapping techniques and DNA sequencing, Hinson homed in on the precise mutations.

In addition to casting light on disease biology, he glimpsed the power of genomic information. “I was fascinated by the potential for understanding new genes that cause human diseases, and how important that was to society,” Hinson says.

Matters of the Heart

Throughout his medical training, Hinson noticed there were some significant stumbling blocks to gathering a deep knowledge of heart disease, particularly cardiomyopathies.

Cardiac muscle has essentially two paths toward dysfunction and ultimate failure. It can either dilate — become abnormally large and distended — or it can thicken. Both routes severely impair how well the heart performs as a pump. These conditions, known as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), can stem from pre-existing disorders of the heart, such as a previous heart attack or long-standing hypertension, or from DNA mutations.

Fueled by advances in genomics over the last two decades, more than 40 genes have been identified that underlie cardiomyopathy. But unlike diseases such as cystic fibrosis or sickle cell anemia, where it is fairly common for affected individuals from different families to carry the exact same genetic typo, it is exceedingly rare for unrelated patients with cardiomyopathy to share the same mutation. With such a complex genetic architecture, figuring out how the different genes and gene mutations contribute to heart disease has been an enormous challenge.


Dr. Travis Hinson speaks with others in his lab

Above: Dr. J. Travis Hinson gives a tour of his laboratory. Photo: Peter Morenus


Because of this formidable hurdle, drug discovery for the cardiomyopathies has languished. “There really has not been a paradigm-shifting drug developed for heart failure in the last 20 years,” says Hinson. Moreover, the few treatments that do exist are primarily aimed at controlling patients’ symptoms, not slowing or halting their disease.

Hinson aims to improve this picture. With his “heart-in-a-dish” technique, he and his team are now unraveling the effects of genetic mutations on cardiac biology.

The system harnesses multiple recent advances in both stem cell and genome editing technologies. With these capabilities, Hinson and his colleagues can isolate skin or blood cells directly from cardiomyopathy patients and coax them to form heart muscle cells, making it possible to study the biological effects of patients’ own mutations. Moreover, he can correct those mutations, or create additional ones, to further probe how genetic differences influence heart biology.

Part of the allure of Hinson’s approach is that it can be readily applied to study other forms of heart disease. It can also be leveraged for drug discovery, providing a platform to screen and test compounds with therapeutic potential in a wide range of cardiovascular diseases.

In addition to his research lab based at JAX, Hinson continues to practice cardiology at UConn Health. He helps run a specialized clinic focused on genetic forms of heart disease, as well as arrhythmias, connective tissue disorders, and other conditions.

“We have an exciting opportunity to provide clinical services in cardiac genetics in the corridor between New York and Boston,” he says. That means state-of-the-art genetic testing, including gene panels and genome sequencing, as well as genetic counseling for both patients and family members to help inform disease diagnosis and guide treatment. Although there are only a handful of treatments now available, Hinson believes this clinic will be uniquely poised to take advantage of a new generation of personalized treatments that are precisely tailored to patients’ specific gene mutations.

“Travis really is a quintessential physician-scientist,” says Dr. Bruce Liang, dean of UConn School of Medicine and director of the Pat and Jim Calhoun Cardiology Center at UConn Health.

“He has a remarkable ability to link basic science with important clinical problems, and his work holds a great deal of promise for developing new treatments for patients with cardiomyopathy. I wish there were two or three Travis Hinsons.”


Hinson’s beating heart tissue. Provided by Dr. Travis Hinson

UConn to Establish Genetic Counseling Master’s Program

illustration of genetic material


UConn has awarded $300,174 to seed a new Professional Science Master’s (PSM) Program in Genetics, Genomics, and Counseling. Graduates of the program will work with doctors and patients to interpret the results of genetic testing, a rapidly growing area in health care that needs more trained personnel. Once accredited, the program will be the first in Connecticut and the only one in New England at a public institution.

“Our students are anxious. They want to do this,” says Judy Brown, director of the diagnostic genetic sciences program in UConn’s College of Agriculture, Health, and Natural Resources’ allied health sciences department. Brown is spearheading the push for the program along with Institute for Systems Genomics director Marc Lalande and UConn Health genetics counselor Ginger Nichols.

Once accredited, the program will be the first in Connecticut and the only one in New England at a public institution.

New genetics research and techniques have made it easy for the average person to get a read on their genome, or whole genetic code. Celebrities, including Angelina Jolie, who have openly discussed their genetic risk factors for cancer, and companies, such as 23andMe, that will provide a basic genetic report for a fee, have increased demand enormously. But there’s a lack of trained people who can accurately interpret and explain the results of genetic tests, limiting the potential benefits.

Ideally, a doctor who identifies “red flags” within a patient’s family history that indicate increased genetic risk for disease will call in a genetic counselor. The counselor can take a detailed family history, determine the appropriateness of genetic testing, discuss benefits and limitations of testing to help the patient make an informed decision, and advise the patient on who else in their family might be at risk. If testing occurs and results indicate high genetic risk, counselors can help discuss the options to mitigate that risk.

As a result, genetic counseling is the fourth-fastest-growing occupation in Connecticut. Many UConn allied health sciences majors would like to enter the profession, Brown says, but there are only 34 training programs in the U.S., and the acceptance rate is below 8 percent.

Institutions including Connecticut Children’s Medical Center and The Jackson Laboratory (JAX) have expressed support for the program. Kate Reed, director of the Clinical and Continuing Education Program at JAX, says JAX would combine its experience translating genetic discoveries into clinical applications with UConn’s experience in this area to give the PSM graduates a solid understanding of the research behind clinical treatments.

The exact roles of JAX, Connecticut Children’s, and the other institutions who support the new PSM have not yet been defined. The program’s curriculum first needs to be approved and accredited. The first students are expected to start the program in fall 2018.

Individualized

By Lauren Woods
Illustration by Yesenia Carrero

UConn Health’s Personalized Ovarian Cancer Vaccine Enters Clinical Trials

illustration of fingerprints overlayed on top of a woman's ovaries


Ovarian cancer relapses are deadly. UConn Health is testing its pioneering vaccine that could prevent them.

The experimental vaccine, named OncoImmunome, is administered as a simple injection in an outpatient setting. It works by boosting the patient’s immune response to enable it to destroy ovarian cancer cells, so that they do not resurface.

The genetic differences between the surface proteins on a patient’s healthy and cancerous cells constitute the fingerprint of that particular patient’s cancer, which is unlike the fingerprint of any other person’s cancer. Based on these variations, scientists create the personalized vaccine.

“This is the first vaccine of its kind developed for women diagnosed with advanced ovarian cancer,” says Dr. Pramod K. Srivastava, the vaccine’s developer, who is a leading cancer immunotherapy expert and director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health. “The personalized vaccine is specifically created using a patient’s own genomics information to prevent an often life-threatening recurrence of the disease and extend survival.”

There is no early-screening test for ovarian cancer. When a woman with the disease starts to actually experience non-specific abdominal symptoms such as bloating, the disease has often already advanced to stage III or stage IV cancer. Further, there is no effective long-term treatment for ovarian cancer. Even after a woman is successfully treated with traditional surgery and chemotherapy, the disease has a very high recurrence rate within just two years. Tragically, most women die within five years of their diagnosis.

But Srivastava believes that appropriate immunotherapy may stop an ovarian cancer diagnosis from becoming a death sentence.

“There is a huge need for a therapy to actually prevent recurrence in these women and I believe our approach to a vaccine may be just the tool to do it,” says Srivastava.

In October 2014, Srivastava published a study showing that his promising approach to cancer vaccines is effective in reducing tumor growth and in preventing cancer progression in mouse models. Based primarily on that work, the FDA approved testing of the experimental therapy in a human clinical trial.

The individualized vaccine is created using samples of a patient’s own DNA from both her unhealthy cancer cells and her healthy blood cells. Over a period of about two weeks, scientists sequence and cross-reference the entire DNA from both sources to pinpoint the most important genetic differences. These genetic differences constitute the ID card, or fingerprint, of that particular patient’s cancer, which is unlike the ID card or fingerprint of any other person’s cancer. Based on the cancer’s fingerprint, bioinformatic scientists, led by Ion Mandoiu of UConn’s School of Engineering, design the personalized vaccine that is meant to target the cancerous cells’ specific genetic mutations.

UConn Health’s new clinical trial will initially enroll 15 women with stage III/IV ovarian cancer and track them closely for two years, the window of time when recurrence most often occurs. Candidates for the clinical trial are women recently diagnosed with advanced ovarian cancer who will have traditional surgery and receive chemotherapy. If cancer-free three months after traditional treatment, the women will receive their personalized vaccine injections once a month for six months. Also, each month their blood will be drawn and evaluated for immune response.

“Our clinical trial will be testing the vaccine for safety and feasibility, but also will be testing whether the vaccine is making a real difference in patients’ blood; the timing of recurrence of cancers in these patients will also be monitored,” says Srivastava. “If, after receiving the vaccine, their cancer hasn’t recurred for a long time in a substantial proportion of women, we will know that the vaccine is promising.”


lab image of Ovarian Cancer cells

This UConn lab image shows how the new ovarian cancer vaccine works. Tiny immune cells known as lymphocytes (small purple dots) target and attack the cancerous ovarian cancer growths (outlined in blue) and prevent them from spreading to benign tissue (pink). Lab image courtesy of Dr. Pramod K. Srivastava


In October 2014, Srivastava published a study showing that his approach to cancer vaccines is effective in reducing tumor growth and in preventing cancer progression in mouse models. Based primarily on that work, the FDA approved testing of the experimental therapy in a human clinical trial.

Dr. Angela Kueck, assistant professor of gynecological oncology, and Dr. Jeffrey Wasser, assistant professor of medicine at the Carole and Ray Neag Comprehensive Cancer Center, are the principal and co-investigators of this study.

“We have received over a hundred messages from women in Connecticut and from around the world, in the hope of participating in our study,” says Srivastava.

He adds, “The most meaningful part of my life, at this time, is to serve. I hope that our results a few years from now will show that our unique ovarian cancer vaccine can prevent recurrence of the disease and even extend survival.”

If the clinical trials are successful against ovarian cancer, Srivastava plans to expand testing of his vaccine to bladder cancer and other solid-tumor cancers.

“This first-ever genomics-driven personalized vaccine has the potential to dramatically change how we treat cancer,” says Srivastava.