Former Scholars Use Award as a Springboard to Expand Their Research

Marcella Nunez-Smith, MD, MHS 2006 YCCI Scholar

Associate Professor of Medicine (General Medicine) and of Epidemiology (Chronic Diseases), YCCI Deputy Director of Health Equity Research and Workforce Development

Growing up in St. Thomas, U.S. Virgin Islands,an area with a shortage of health professionals,Marcella Nunez-Smith, MD, MHS, remembers countless stories of loved ones and membersof her community who struggled with theirhealth or died prematurely. That experienceled her to pursue a career in medicine andconduct research that focuses on vulnerablepopulations and their interactions with healthcare systems.

Ever since her arrival at Yale as a fellow inthe Robert Wood Johnson Foundation (RWJF)Clinical Scholars Program, Nunez-Smith has been on a mission to develop ways of addressing health and health care inequities wherever they are: in patient settings, in the health care workforce, and in medical education. As a 2006 YCCI Scholar, she gathered preliminary data for what is now known as PreDict(Patient-Reported Experiences of Discrimination in Care Tool). PreDict is a tool that assesses the patient care experience and measures hospital performance with the goal of improving the quality of care delivery. "The Scholar award was tremendously helpful because it allowed me to launch a line of inquiry that was new, and then provided me with the resources to complete the preliminary work that allowed us to be competitive for major NIH grants,” she said.

Nunez-Smith went on to develop the Eastern Caribbean Health Outcomes Research Network (ECHORN), a collaborative multimilliondollar research study funded by the National Institute on Minority Health and Health Disparities (NIMHD). ECHORN examines the risk factors and prevalence of cancer, diabetes, and heart disease in the eastern Caribbean, a region for which such data are lacking.

Both ECHORN and PreDict – which has spurred several relatedprojects undertaken by Nunez-Smith’s mentees – are now incorporated into the Equity Research and Innovation Center (ERIC), where she serves as director. ERIC builds on the local, national, and global experience of Nunez-Smith and 60 team members who are involved in research aimed at narrowing health and health care inequities, as well as disparities in the health care workforce and medical education.

As a former YCCI Scholar, Nunez-Smith appreciates the benefits of mentorship and serves as an academic advisor to Yale School of Medicine students. She also continues her involvement with the RWJF as a core faculty member of the Clinical Scholars Program and co-director of Community Research Initiatives. “I’m working towards synergy across all of these programs so they’re not siloed,” she said. “The idea is to think about core elements of knowledge for our faculty for population health and health equity, and engage stakeholders in our work.”

Elijah Paintsil, MBChB 2007 YCCI Scholar

Associate Professor of Pediatrics (Infectious Disease), of Epidemiology (Microbial Diseases), and of Pharmacology

In 1998, the HIV epidemic was in full force in Ghana, but Elijah Paintsil, MBChB, had no treatment to offer his patients. He came to the United States on a mission to acquire research expertise and find solutions to treat AIDS and other infectious diseases.

Already a practicing physician, Paintsil had to repeat his residency training before he came to Yale to pursue a fellowship in pediatric infectious diseases. His 2007 YCCI Scholar award helped support his research on the high rate of hepatitis C in intravenous drug users. He showed that the virus can live more than 60 days in used syringes. This finding led to collaboration with colleagues at the School of Public Health to investigate disinfectants and other means of reducing infection rates.

“The Scholar award provided me with the needed time, mentorship, and research support to successfully navigate through an academic physician-scientist career,” he said. It allowed him to compete for an NIH Career Development Award and seamlessly transition to an R01 award.

Paintsil makes ample use of such YCCI-supported resources as data analysis, study design, and magnetic resonance spectroscopy. During his term as a Scholar, YCCI’s focus on interdisciplinary research through the monthly Research-in-Progress seminars spurred him to consider conducting research overseas.

In New Haven, he had seen that pediatric HIV patients who were now adults were not complying with their medication regimen. He suspected that one reason for this negligence was that they weren’t being told their diagnosis. In Ghana, many thought that children with HIV would not live to adulthood; not surprisingly, only 21 percent of them knew their diagnosis. Paintsil designed an intervention using a culturally sensitive, adaptive approach for caregivers to disclose HIV information in an age-appropriate and personalized way. He is currently conducting a large multicenter trial in Ghana to determine whether this intervention will make a difference.

In his lab, Paintsil is investigating the side effects that almost half of those on antiretroviral therapy experience. His group has identified a mitochondrial protein in the blood that could serve as a biomarker of toxicity, negating the need for guesswork or a biopsy. The ability to conduct research in basic science and public health has been invaluable to Paintsil’s work. “It wouldn’t have been possible without the facilities YCCI has put in place,” he said.

James McPartland, PhD 2006 YCCI Scholar

Associate Professor in the Child Study Center and Assistant Professor of Psychology

As a clinical psychologist who directs the Yale Developmental Disabilities Clinic, James McPartland, PhD, spends a lot of time with patients with autism. He uses that experience as a neuroscientist to design experiments to understand how the brain works, and how development of children with autism differs from typical development.

McPartland’s research is focused on understanding the way people with autism process social information by using electroencephalography (EEG) to detect electrical activity in the brain. He published the first study to show that people with autism process faces with decreased efficiency, and he has continued this work to detect autistic development before behavioral symptoms emerge in infants at increased risk of autism spectrum disorder (ASD).

One of the challenges in conducting this type of research is to create ways to measure brain activity in real-life social situations. McPartland has worked with Yale cognitive scientist Adam Naples, PhD, to create realistic avatars that respond to eye contact to show that there is a specific brain marker for eye contact, a new finding. “This is important because autism is heterogeneous, but almost everyone has problems with eye contact,” he said. A video game in which participants are rewarded for making eye contact at the appropriate time illustrates his efforts to not just understand brain activity but also shape behavior.

The Scholar award offered essential support at a critical juncture in McPartland’s career. “By ensuring research time and resources to invest in a lab, it empowered me to develop a program of research and advanced my goal of bettering the lives of children and families affected by neurodevelopmental disabilities,” he said.

He recently received a large-scale longitudinal multisite research grant to lead the development of a battery of electrophysiological, eye tracking, and behavioral tools to measure social function and communication in people with autism. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a cooperative public-private research project based at Yale that includes Duke University, Boston Children’s Hospital, the University of Washington/Seattle Children’s Research Institute, and the University of California, Los Angeles. All the collaborating sites are members of the Clinical and Translational Science Award (CTSA) consortium. In addition to its behavioral measures and biomarker data, this community resource will include blood samples from subjects and their parents for use in future genetic studies. Data and resource sharing are key components of this project; all data generated will be made available to other researchers to view and analyze through the NIH-funded National Database for Autism Research and the NIMH Repository and Genomics Resource. “I would not be positioned to lead such an ambitious undertaking without the ongoing support of YCCI,” McPartland said.

Like many YCCI Scholars, McPartland has benefited from knowledgeable and devoted mentors. His Scholar award was the impetus for establishing collaboration with Linda Mayes, MD, and Michael Crowley, PhD, to build and maintain the Developmental Electrophysiology Laboratory, a highly productive core resource for the School of Medicine.

Yawei Zhang, MD, PhD, MPH 2008 YCCI Scholar

Associate Professor of Epidemiology (Environmental Health)

For Yawei Zhang, MD, PhD, MPH, a grant from YCCI has flourished into an ongoing collaboration. As a YCCI Scholar in 2008, Zhang sought to examine the fetal origins hypothesis, which connects perinatal nutritional deficiencies to cardiovascular disease, diabetes, and cancer in later life. She looked at how expectant mothers’ intake of one-carbon nutrients, such as folate, had an impact on the methylation status of DNA, which is vital to gene expression during fetal development.

Zhang used her preliminary data, which confirmed her hypothesis that folate intake has an effect on methylation, to develop a larger-scale birth cohort study of 10,500 mother-and-baby pairs in partnership with the Gansu Provincial

Maternity and Child Care Hospital in Lanzhou, China. The study was expanded to include research on the impact of air pollution, passive smoking, and many other environmental and lifestyle factors, as well as gene-environment interactions on newborns. The city of Lanzhou has some of the worst air pollution in China; and according to Zhang, approximately 30% of pregnant women are regularly exposed to secondhand smoke even though the negative effects of passive smoking on fetal development are known in China.

The Scholar award was tremendously helpful because it allowed me to launch a line of inquiry that was new, and then provided me with the resources to complete the preliminary work that allowed us to be competitive for major NIH grants

Marcella Nunez-Smith

The partnership led to a mutually beneficial relationship. While Gansu Hospital provides ongoing funding for the birth cohort study, Zhang has brought more than 30 physician-researchers from the hospital to her lab at Yale for research training.

Zhang’s work caught the attention of the Chinese government, which has lent further support to her study. Shanxi Province awarded her a grant to establish an additional birth cohort study in the city of Taiyuan. “Air pollution and passive smoking are hot topics in China right now,” she said. “There have been very few studies conducted in the Chinese population in these areas.”

Many other areas of China are also establishing birth cohort studies; Zhang is helping to foster this vital research by sharing her expertise not only with the scholars she trains at Yale, but also with researchers in China. Zhang is sharing her questionnaires with other researchers who are establishing a cohort study consortium, which, she hopes, will lead to additional studies on key health issues in China.

Kelly Cosgrove, PhD 2009 YCCI Scholar

Associate Professor of Psychiatry, of Diagnostic Radiology, and of Neurobiology

When it comes to smoking, men and women have differing behaviors, reasons for using tobacco, and responses to treatment. According to research conducted by Kelly Cosgrove, PhD, some of these differences may be explained by the effect smoking has on their brains.

Cosgrove uses positron emission tomography (PET) and single-photon emission computed tomography (SPECT) scans to gain insights into the brains of people after they’ve stopped using alcohol and tobacco. Her work has shown that smoking cigarettes activates a different dopamine-driven response in men compared to women.

“A lot of smoking cessation treatments are directed at nicotine’s action in the brain, but nicotine reinforcement is not what’s activated in women,” she said. “So we need to switch gears from replacing nicotine or targeting those pathways and focus more on the reasons women smoke.”

Trained as a clinical psychologist who worked with individuals suffering from drug addiction, Cosgrove was driven to conduct research in order to find more effective ways of helping her patients recover and avoid relapse. As a YCCI Scholar, she found that it takes up to 12 weeks after someone quits smoking for the number of nicotine receptors they’ve developed to decrease. This finding suggests that smokers may need long-term support to kick the habit. The award helped her start her research portfolio, which continues to grow and for which she utilizes such YCCI-supported resources as the Magnetic Resonance Research Center and Core lab.

Her recent work has shown that smoking interferes with the recovery of receptors for the inhibitory neurotransmitter gammaaminobutyric acid (GABA) during alcohol withdrawal. “A lot of times people don’t tease apart differences between alcohol-dependent smokers and nonsmokers,” she said. When she investigated these differences, she found that smoking seems to interfere with the neuroadaptations that happen during the first month of alcohol withdrawal. This difference may make it harder for smokers to stop drinking, and highlightsb the need for clinicians to consider the clinical implications of encouraging alcohol and tobacco cessation at the same time. “When I help people quit smoking, I ask them not to drink, because as soon as they drink, they’ll want to smoke,” she said. “Why wouldn’t we say the same thing for the reverse?”

Oscar Colegio, MD, PhD 2010 YCCI Scholar

Assistant Professor of Dermatology

While much is known about the genetic basis of cancer, less has been known about the role of the immune system in its progression until recently. Oscar Colegio, MD, PhD, aims to change that by studying tumor immunology to unravel how the immune response can lead to tumor growth.

His research is linked to his clinical work caring for solid-organ transplant recipients who are on an immunosuppressant regimen and therefore have a one-hundredfold increased risk of squamous cell carcinoma. His 2010 Scholar project focused on the role of macrophages, cells in the innate immune system that are found in all tumors. His hypothesis that communication between cancer cells and macrophages led to their activation and increased tumor growth proved to be correct.

Working in collaboration with his mentor, Ruslan Medzhitov, PhD, the David W. Wallace Professor of Immunobiology, Colegio went on to discover that lactic acid, a byproduct of cancer cell metabolism that has largely been overlooked, transforms macrophages into abettors of tumor growth. He has also found that certain key enzymes within macrophages are critical for supporting tumor progression, and is currently exploring whether their inhibition can lead to tumor regression.

Colegio’s collaborations with the Yale-New Haven Transplantation Center and Yale Cancer Center illustrate the benefits of crossing boundaries to train the next generation of investigators. Moving from mouse models to human cells, he is excited about the possible wider implications of his findings in developing cancer therapies that target macrophages or inhibit enzymes that play a role in tumor growth.

According to Colegio, the education and access to facilities afforded by the Scholar award have had a profound impact on his research. A sample grant he wrote during the grant writing course led to an award from the National Cancer Institute, which funds his current work. He has also received biostatistical support from the Yale Center for Analytical Sciences, and has found the Research-in-Progress seminars to be very helpful. “YCCI has provided very practical concrete support that is essential for investigators to have as they move their research forward,” he said. As his research progresses, he continues to turn to YCCI. “I keep going back to YCCI for all sorts of resources,” he said.

Abhijit Patel, MD, PhD 2010 YCCI Scholar

Assistant Professor of Therapeutic Radiology

“Detecting early-stage cancer via a simple blood test is one of the holy grails in oncology,” says Abhijit Patel, M.D., Ph.D. For many types of cancer, the probability of achieving a cure is much higher if the tumor is detected before it has had a chance to spread. Through the study of tumor-derived DNA fragments in blood, Patel hopes to move cancer care closer to attaining this goal.

As a 2010 YCCI scholar, and in ongoing work in his lab, Patel has been focused on developing technology to measure tiny amounts of DNA shed into the bloodstream from dying cancer cells. Scientists can zero in on these DNA fragments because they contain mutation signatures that are highly tumor-specific.

Using tumor DNA as a biomarker could expand a physician’s capacity to detect and treat cancer. “Tumor DNA is so cancer-specific, you are extremely unlikely to get false positive results in a healthy person— so that makes it very attractive as a marker for screening,” Patel said. The “liquid biopsy,” as this type of blood test is sometimes called, can also be used to determine the mutation profile of a patient’s tumor noninvasively in order to personalize therapy. Moreover, the test can be used to closely monitor changes in mutations over time so that therapy can be modified without having to resort to frequent invasive biopsies.

Currently, Patel is continuing his work to improve the sensitivity of existing technology to detect even smaller amounts of genetic material. He has continued his collaboration with YCCI through his use of its biospecimen software platform, which helps his team bank and track the thousands of blood samples he collects through collaborations with several other researchers and physicians from across Yale. He also has taken advantage of the next-generation DNA sequencing facility at Yale’s West Campus as well as the biostatistical support offered through the Yale Center for Analytical Sciences. As he progresses in his research career, he continues to take advantage of the support available from the YCCI-supported core facilities that are critical to his work.

Stephanie Eisenbarth, MD, PhD 2011 YCCI Scholar

Assistant Professor of Laboratory Medicine, of Immunobiology, and of Medicine (Immunology)

How the immune system goes awry to cause disease has long intrigued Stephanie Eisenbarth, MD, PhD. To solve this puzzle, she used her 2011 Scholar award to focus on the basic task of characterizing the immune response in healthy subjects.

While many questions in immunology have been answered using mouse models, Eisenbarth is applying these findings to humans. Studying the normal immune system has led her to study how dendritic cells – which act as messengers between the innate and adaptive immune systems – work. Her main area of interest is understanding and predicting why approximately 10 percent of the individuals vaccinated fail to respond. Dendritic cells act as a sort of field marshal for the immune system, regulating what it sees and therefore responds to. By focusing on how these cells function, Eisenbarth hopes to be able to devise methods to better target them and increase the vaccine response rate.

The Scholar award was one of the first major awards Eisenbarth received when she started her lab. “That kind of seed money is really critical,” she said. “It helps you get established.” Since then she has gone on to receive other funding, including a Hartwell Biomedical Research Award and a Clinical Scientist Development Award from the Doris Duke Charitable Foundation. She is poised to conduct more intricate research examining how peripheral blood monocytes move through an artificial tissue-like matrix in vitro. “It’s a very complex process that’s fundamental to initiating vaccine immunity,” she said.

Because immune cells don’t react well to being frozen, Eisenbarth has established what she terms a “living biorepository” that enables her to call upon healthy subjects to donate a blood sample up to eight times a year. YCCI has been instrumental in helping her recruit subjects. The program has grown exponentially and has been so successful that Eisenbarth is collaborating with YCCI to expand it and make it available to other investigators. She has contributed protocols and other research expertise, while YCCI has helped establish the database infrastructure via OnCore, Yale’s clinical research management system. YCCI is also marketing the biorepository through ads that are linked to its Help Us Discover campaign – an effort that will directly benefit Eisenbarth’s research, as well as that of other researchers.

Besides blood, Eisenbarth is collecting stool samples for the biorepository in order to investigate the role of gut microbes in regulating the immune response. The ability to obtain multiple samples from the same subject over time is crucial to her research and has benefited from her collaboration with YCCI. "Research is a team effort," she said. "Working with YCCI has facilitated our success."

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This article was submitted by Lisa Brophy on November 10, 2015.