Four researchers at the Vagelos College of Physicians and Surgeons have been named 2018 Schaefer Research Scholars: Alberto Ciccia, PhD, Harris Wang, PhD, Baojie Li, PhD, and Maria Concetta Miniaci, MD.
Each year, the Schaefer Research Scholars Program at P&S supports research scientists who have distinguished themselves in the study of human physiology. Scholars are nominated by a committee of distinguished research faculty and selected by the P&S dean. Each receives an award of $50,000 in discretionary funds and up to $220,000 in direct costs to fund research projects. The program is possible through an endowment from the Dr. Ludwig Schaefer Fund.
The 2018 Schaefer Scholars—two P&S faculty members and two visiting professors—and their projects are listed below.
Alberto Ciccia, PhD, assistant professor of genetics & development
“Analysis of clinically relevant gene variants using CRISPR-mediated base editing”
CRISPR-Cas9 technology has recently been widely employed as a means to edit the genetic information contained within cells. This system may enable scientists to easily and rapidly develop model systems for studying the effects of genetic changes and could ultimately lead to targeted therapies for diseases with a genetic basis. However, the use of CRISPR to induce targeted changes in cells remains inefficient, making it difficult to achieve these goals.
Recently, Ciccia developed a strategy to use CRISPR-Cas9 variants in combination with cytidine deaminase enzymes to disrupt human genes in a very targeted manner. Ciccia’s research suggests that this strategy could be used to model cancer-associated mutations that occur throughout the genome. Building on these advances, Ciccia’s proposed Schaefer project is aimed at further increasing the efficiency of CRISPR-Cas9 targeting to enable the generation of cell lines that harbor clinically relevant gene variants. This work will allow us to better understand how genetic changes enable cancer development and may facilitate the discovery of drugs that disrupt this process.
Since his recruitment in 2014, Ciccia has identified several new regulators of the DNA damage response. The intersection of biochemistry, molecular biology, and cancer genetics in his past and current studies gives him a unique perspective on the study of genetic variation and genome instability in cancer. Ciccia has received multiple awards, including scholarships from the Susan G. Komen Foundation, the Breast Cancer Alliance, and the Ovarian Cancer Research Fund Alliance.
Harris Wang, PhD, assistant professor of systems biology and of pathology & cell biology
“Systematic dissection of xenobiotic metabolism by the gut microbiome”
A systems and synthetic biologist, Wang develops new tools and platforms to determine how genomes in microbial populations form, maintain themselves, and change over time, across many environments. His goal is to use synthetic biology approaches to engineer ecologies of microbial populations, such as those found in the gut and elsewhere in the human body, in ways that could improve human health.
His Schaefer scholar project centers on a platform approach to systematically determine new mechanisms by which specific members of the human microbiome metabolize and alter drugs and pharmaceuticals. Wang and his group will evaluate the impact of the microbiome on drug efficacies using cellular and animal models, focusing on the gut microbiome—an important and underexplored area of research.
“There have been studies that suggest a key link between microbes and their role altering the efficacy of drug treatments,” says Wang, “but this area of research is unchartered territory, and there is more knowledge to be gained by pinpointing how a person’s microbiome could metabolize specific therapeutics by inactivation, degradation, or alteration of its chemical structures. The large-scale data generated from our project could improve drug prescriptions and clinical trials by reducing failures and classifying patients based on otherwise unknown, yet important, microbiome-drug interactions.”
Wang joined Columbia in 2013. In 2017, he received the Presidential Early Career Award for Scientists and Engineers (PECASE) from the White House. He is also a recipient of a Sloan Research Fellowship, a National Institutes of Health Early Independence Award, and the Pathogenesis of Infectious Disease Award (PATH) by the Burroughs Wellcome Fund.
Baojie Li, PhD, professor and deputy director, Bio-X Institutes, Shanghai Jiao Tong University, and visiting professor in biochemistry & molecular biophysics at P&S
“The identity and function of mesenchymal stem cell subgroups”
Mesenchymal stem cells (MSCs) are multipotent stromal cells with the ability to differentiate into a variety of cell types that can contribute to the development and maintenance of the skeleton, fat, and other tissues. MSCs are being explored for their potential to treat osteoarthritis, autoimmune diseases, and other disorders, but the clinical use of MSCs remains difficult, as these cells are not well-understood.
Li previously generated animal models that he used in his research to identify specific MSC subgroups and track their differentiation into other cell types. Very little is known about these subgroups of MSCs, the different roles they play in the body, and whether they each have an equivalent ability to repair damaged tissue. Li’s Schaefer project aims to advance his previous findings and determine how c-Abl and Aph2—genes essential for proper tissue development—can affect specific MSC subgroup development and functionality.
Li’s research complements studies of Columbia’s Stephen Goff, PhD, into c-Abl and Aph2 function. Li’s project, to be performed in collaboration with Goff, may ultimately give us a better understanding of how MSCs contribute to the development and maintenance of skeleton and adipose tissues and how MSCs may be used for tissue repair. This could allow for the refinement of MSC-based therapies in the future.
Maria Concetta Miniaci, MD, assistant professor of physiology, Università Federico II, Naples, Italy, and visiting professor in psychiatry at P&S
“Imaging noradrenergic synaptic function at cerebellar synapses during behavior”
Noradrenaline, a neurotransmitter that works throughout the brain, is involved in several important processes, including memory formation. Among these functions, noradrenaline has been found to modulate the activity of synapses between parallel fibers and Purkinje cells in the cerebellum. Depletion of noradrenaline from the cerebellum impairs the ability of animals to learn new motor skills, suggesting that noradrenaline activity at this synapse has an important role in augmenting memory formation.
Miniaci’s research suggests that noradrenaline regulates parallel fiber-Purkinje cell synaptic transmission bidirectionally. This regulation appears to refine signaling to the Purkinje cells, which is required for low-threshold stimuli to produce long-term potentiation, memory formation, and learning. However, confirming these findings has been difficult. Detailed study of noradrenaline release in the cerebellum has been limited by technical challenges, as the levels of noradrenaline that are released are often too low for accurate detection.
At Columbia, Miniaci will work as a Schaefer Scholar with David Sulzer, PhD, Dalibor Sames, PhD, and Eric Kandel, MD. The Columbia team has developed the means to measure noradrenaline synaptic release at single synaptic resolution in vivo. Miniaci will use this technology to conclusively determine whether emotionally arousing experiences cause noradrenergic release from projections to the cerebellum. Further understanding of this process may have relevance to the treatment of several neuropsychiatric disorders, as fear memory also appears to require long-term potentiation of the parallel fiber-Purkinje cell synapse and may be dependent on noradrenaline activity.