Christopher Pittenger, MD, PhD 2009 YCCI Scholar
Associate Professor of Psychiatry; Director, Yale OCD Research Clinic
A “leap of faith” led Christopher Pittenger, MD, PhD, Associate Professor of Psychiatry, to the position of Director of the Yale OCD Research Clinic immediately after residency. While Pittenger always anticipated a career in the neurobiology lab, “during residency, I got more and more involved in clinical research—in particular, the Obsessive- Compulsive Disorders (OCD) Clinic, a long-established research program here at Yale,” he says. “At the end of my residency, the director of that clinic left for a job in industry. I came up with the terrifying, unexpected opportunity to run that clinical research program in parallel with running my own lab.”
The YCCI Scholar Award “came at a fairly pivotal time,” and helped him prepare for the daunting role of directing a clinical research lab early in his career. As director of the Yale OCD Research Clinic, Pittenger investigates a disease in which he was mainly interested on a basic science level prior to his connection with the clinic, and was now able to translate into clinical research with the potential to help patients.
As a YCCI Scholar, Pittenger focused on the imbalance of the neurotransmitter glutamate in people with OCD. He and a team conducted a magnetic resonance spectroscopy study in which they used a version of MRI to measure glutamate and gamma levels in the brain—a study which later led to an R01 grant. There was also a parallel treatment study which used an already FDA-approved glutamate modulator, Riluzole, to try to normalize the hypothesized glutamate imbalance. That study laid the groundwork for an industry-sponsored study on which Pittenger is the lead collaborator. “It’s something I am hopeful will really make a different to patients. The support for me to find my footing in clinical research was essential.”
Support from YCCI has continued to expand as Pittenger matures in his career. He later received a pilot award from YCCI that supported a program of research in his basic science lab to examine the neurologic underpinnings of Tourette syndrome; that work, he says, has become the foundation of several other grants and ten published papers. Two of Pittenger’s trainees, Benjamin Kelmendi, MD, and Patricia Gruner, PhD, are current YCCI Scholars funded for work they are conducting under his mentorship. Through this next generation, he says, “YCCI has continued to be supportive.”
Eda Cengiz, MD 2010 YCCI Scholar
Associate Professor of Pediatrics (Endocrinology)
For Associate Professor of Pediatrics (Endocrinology) Eda Cengiz, MD, the responsibility to help her own community accompanies the knowledge gained through being a clinical scientist. Cengiz is a pediatric endocrinologist focusing on type 1 diabetes in children, but she saw an unmet need among adult women with the disease.
“There is a common approach in diabetes care that is one size fits all,” Cengiz says. “But that is not accurate. What we know is that women actually have more acute and chronic complications of diabetes.”
Cengiz is currently investigating changes in insulin action during various phases of the menstrual cycle in women with type 1 diabetes. “Our preliminary results show that there is a 40 percent change in insulin action during different phases of the menstrual cycle,” she says. “It has a major impact on how we will treat diabetes in the future. Now there are so many new diabetes technology tools to customize treatment, we hope our findings will help develop treatments designed specifically for women that will reduce complications.”
Beyond her work improving care for women with type 1 diabetes, Cengiz’s work focuses on clinical research in pharmacokinetics and pharmacodynamics, and her lab is the only one in the world, she says, to conduct research on the action of insulin in pediatric patients. The foundation of that work was laid when she became a YCCI Scholar in 2010, then an assistant professor. With funding, she was able to test methods to accelerate insulin action, including next-generation ultrafast-acting insulins, and was able to show their effects on the efficacy of artificial pancreas systems on diabetes treatment.
To do potentially game-changing clinical research, “It takes a village, maybe a city,” she says. “You need a good infrastructure.” This infrastructure drew her to Yale, and then to YCCI. “There are only a few places where you can get structured, systematic clinical research training,” she says. As a YCCI Scholar, she not only received research and educational support, but also the guidance of three exceptional mentors: Robert Sherwin, MD, C.N.H. Long Professor Emeritus of Internal Medicine (Endocrinology) and founding director of the YCCI; Karl Insogna, MD, Ensign Professor of Medicine (Endocrinology); and William Tamborlane, MD, Professor of Pediatrics and Chief of Pediatric Endocrinology. From mentors like these, “You learn from them every minute,” Cengiz says, “and you don’t even realize how much you learn. It’s like osmosis.”
Lucia Jilaveanu, MD, PhD 2014 YCCI Scholar
Associate Professor of Medicine (Medical Oncology)
The lab of Lucia Jilaveanu, MD, PhD, Associate Professor of Medicine (Medical Oncology) seeks to uncover the mechanism underlying melanoma that metastasizes to the brain—a potentially deadly outcome that occurs in about half of melanoma patients, she says. Until now, “Research in this area has been limited, and there has been poor understanding of how brain metastasis really occurs,” Jilaveanu says. “Understanding the biology and how to target brain metastasis continues to be an evolving field that scientists like myself are trying to push for-ward for the benefit of our patients.”
As a YCCI Scholar, Jilaveanu sought to identify the distinct features of cancer cells that invade the central nervous system and drive the process of metastasis. With that funding, she was able to successfully demonstrate that the melanomas with a tendency to metastasize to the brain have a distinctive molecular structure, and also to uncover several possible mediators of melanomas that metastasize to the brain.
She was also able to expand her study to generate novel preclinical in vitro tests in animal model systems for the disease, which have been limited, she says. “These tools are valuable in the sense that I not only use them for the research I propose, but I continue to integrate them in my current studies for functional analyses and to dissect specific mechanisms in melanoma with brain metastasis,” Jilaveanu says.
This work laid the foundation for gathering preliminary data to apply for an R01 grant from the NIH, which Jilaveanu received in 2017. The ultimate goal of her research is to gather enough evidence to justify the development of new drugs that target molecules that she was able to associate with brain metastasis; and down the line, therapies that include already-existing inhibitors of pathways that these molecules regulate.
For Jilaveanu, the YCCI Scholar Award “was an invaluable asset for the start of my career,” she says. “As a junior investigator I came to realize that it is so difficult to obtain research funding. Seed funding is vital for any researcher who is in the process of building her own independent research. This is an especially vicious cycle, as it is hard to acquire preliminary data without having funding, and how do you get funding without preliminary data? It’s a chicken-and-egg paradox. The KL2 mechanism addresses this paradox that we face at the beginning of our careers.”
Forrest Crawford, PhD 2014 YCCI Scholar
Associate Professor of Biostatistics, and of Ecology and Evolutionary Biology; Director, Yale Developmental Disabilities Clinic
It was when Forrest Crawford, PhD, Associate Professor of Biostatistics, and of Ecology and Evolutionary Biology; and Director of the Yale Developmental Disabilities Clinic came to Yale that he realized that he could apply his doctoral degree in applied mathematics and statistics to solving some of the most challenging problems in public health. In New Haven, “I met some epidemiologists who were working on some very hard problems in public health,” he recalls. One of the most influential on the trajectory of his career was Robert Heimer, PhD, Professor of Epidemiology (Microbial Diseases) and Director of the Emerging Diseases Program at the School of Public Health.
“Dr. Heimer told me about the research methods that he and his colleagues used to study hidden and hard-to-reach populations at high risk of HIV infection in the US and internationally,” Crawford says. “He articulated several seemingly intractable inferential problems that could benefit from statistical and mathematical insight.” This initial meeting led to a long-term fruitful collaboration between the two researchers.
Crawford now seeks new methods for public health research in such infectious diseases as HIV, for such populations as injection drug users,men who have sex with men, sex workers, trafficking victims, and other people who are difficult to survey using traditional epidemiological methods—with the ultimate hope that these methods will contribute to better public health policy.
“I see my work as helping to provide a framework for making the best decisions possible, learning from the data that we have, and providing evidence that is understandable and persuasive to policy makers so they can make the best possible decisions.” Crawford recently collaborated with Gregg Gonsalves, PhD, Assistant Professor of Epidemiology (Microbial Diseases) on a study published in The Lancet HIV that showed that a 2015 HIV outbreak in Indiana could have been drastically reduced if the state government had acted more quickly on warnings.
Crawford received the YCCI Scholar Award in 2014. In 2016, he received the prestigious NIH Director’s New Innovator Award on the basis of his work as a YCCI Scholar. This NIH award supports exceptionally creative early-career investigators who propose innovative high-impact projects. The funding and the faith in his work that the funding implies “gave us the freedom to work on a variety of challenges that came up along the way in completing those projects,” Crawford says. “Many of those challenges had to do with estimating the effects of biomedical interventions, when outcomes are contagious. The support of these awards opened the doors to a wide variety of research questions that we have been able to pursue and try to solve.”
Tore Eid, MD, PhD 2009 YCCI Scholar
Associate Professor of Laboratory Medicine, of Neurosurgery, and of Molecular Physiology
Despite his call to the laboratory, Tore Eid, MD, PhD, Associate Professor of Laboratory Medicine, of Neurosurgery, and of Molecular Physiology, has always liked to work with patients. “I am a physician and I loved doing that,” Eid says. During his training, he covered health care needs, from childbirth to chronic illness to injury, in the remote north of Norway where he was only one of two doctors. After his medical training, he arrived at Yale, to conduct research into the mechanisms of epilepsy.
“I thought I would like to combine my clinical knowledge with research,” said Eid. At Yale, he completed a residency in clinical pathology, also known as a laboratory medicine. The field “melds well with research,” he says, as it examines fluids of the body to diagnose and understand disease. It was at this point in his career that he received the YCCI Scholar Award, and employed such techniques of laboratory medicine as mass spectrometry to understand the chemical changes in the brain that occur during epileptic seizures. He used samples of brain fluid collected during work with Dennis Spencer, MD, the Harvey and Kate Cushing Professor of Neurosurgery and Chief of Epilepsy Surgery. The samples were gathered from Yale patients who underwent electroencephalography, or EEG tests, after seizures to determine the location of the seizures in the brain.
Eid found that patients who experience seizures exhibit distinct chemical changes in the brain, some of which occur several hours before seizures begin. “We thought that these chemical changes may be very important for seizure triggering. That is important because there is a big need to develop medications for seizures; four out of 10 people cannot be helped with medications, and really the only option is surgery,” he says. “Our hope now is by understanding the chemistry we can understand why seizures occur, and be able to manipulate the chemistry changes in people as a treatment for seizures.” Using the results generated with his YCCI Award, Eid received an R21 grant to continue his line of investigation, and plans to apply for an R01 with the results.
In addition to his work in epilepsy research, Eid is a practicing pathologist and associate director of Yale New-Haven Hospital’s Clinical Chemistry Laboratory, which analyzes laboratory tests of all kinds ordered by clinicians. “What is great about being a clinician also is that I have available instrumentation that I can use in my research.” The lab is also a place where he can extend his research. With permission he can access the test samples that come through the lab, with the goal of building a biorepository of samples that can be used for biomarker studies, for any disease. Going forward, Eid says, “I would really like to focus on translational projects that are likely to have clinical relevance down the road.”
Shangqin Guo, PhD 2014 YCCI Scholar
Assistant Professor of Cell Biology
For Shangqin Guo, PhD, assistant professor of cell biology, cells are like children. “We can’t predict what a baby is going to be. Some will grow up and do great things; some are going to go bad,” she says. “We can never be certain what caused one child to behave one way and one another.” In her research, Guo is making films of the lives of cells to try to capture the moment that they, like an unruly child, “go bad,” which in a cell means to become malignant. Guo hopes that if she can pinpoint that moment and capture it on video, she may be able to determine the mechanism of malignancy, and eventually contribute to finding the means to stop it.
Guo was a YCCI Scholar in 2014. At the time of her award, she and a team had found success in visualizing some rare cell biology, namely the moment that a blood cell becomes an induced pluripotent stem cell. “That success gave us inspiration: perhaps we can use similar technology to visualize another rare biology that so far people haven’t been able to really get a handle on,” namely how a normal cell becomes malignant. “Textbooks say, luckily, most of the cells in our body are never going to become cancerous. What is the mechanism that really pushes those few cells to eventually become cancerous? What is the last straw? Our rationale is that if we can understand that, perhaps we can devise approaches to prevent cancer from occurring.”
Guo investigated how normal blood progenitor cells gave rise to leukemia-forming cells, as the tipping point for leukemia requires only one genetic abnormality; it is more easily pinpointed than other cancers that require several. By putting that cancer-causing genetic abnormality into mouse blood progenitor cells, Guo was able to essentially trick cells into expressing the abnormality, and was then able to examine them. “If we can put this same genetic abnormality into all of the blood-forming progenitors, will these progenitors become cancerous, or just some of them? If only some of them become cancer, is there anything different with those few cells?” The challenge was in finding out not whether the cells became cancerous, but why. Guo’s team suspected the reason lies in the speed of division in those cells.
We are seeing that it is the really rapidly dividing cells that are forming cancer,” Guo says, asking, “If we are able to slow down these rapid proliferation behaviors, are we going to be able to prevent the cancer formation?” Guo conducted animal tests on her hypothesis, and found that in a small sample set, the hypothesis proved correct: without intervention to slow down cell proliferation, all the mice died. This result was enough to elucidate proof of concept, Guo says. She is working on expanding the study, which if proven on a larger scale, could eventually lead to a preventive approach to cancer.
The YCCI Scholar Award “was one of my earliest funding sources,” Guo recalls. The pilot funding from YCCI led to larger awards, including the prestigious NIH Director’s New Innovator Award. At the beginning of her career, “The YCCI Award gave me encouragement and validation for my research, and led me to the NIH Award, which gives me the means to do it.”