Dr. Greenberg [HHMI Fellow] is focusing on how sensory neurons that innervate internal organs develop and function under changing environmental conditions. Our ability to sense and respond to fluctuations in blood-oxygen levels or exposure to gastric irritation is controlled by sensory neurons from the vagus nerve or the dorsal root ganglia. These neurons detect changes in numerous organs including those critical to reproduction, and mediate responses. Understanding how sensory neurons respond to these microenvironments may provide new insights into how certain conditions contribute to tumor growth and identify targets for the development of cancer therapies.

A unifying hallmark of several types of cancer is the uncontrolled fragmentation of mitochondria, the microscopic compartments that generate energy for the cell. Although many key players have been implicated in this process, the manner in which these factors assemble to modify the mitochondrial architecture and induce the unrestricted fragmentation associated with cancer is unknown. Dr. Grotjahn [Nadia's Gift Foundation Innovator] uses cutting-edge instrumentation, powerful electron microscopes, and pioneering image processing techniques to visualize this process inside cancer cells. Her work has the potential to identify new targets to block mitochondrial fragmentation as a future therapeutic strategy to prevent cancerous cell proliferation and tumor growth.

Dr. Grunwald [Lallage Feazel Wall Fellow] focuses on the disconnect between genotype and phenotype. Despite our wealth of knowledge about the human genome, we are often unable to accurately predict which individuals will suffer from genetic diseases, including cancers. It has been proposed that cells have mechanisms capable of buffering genetic variation, such that the phenotypic outcome of these genetic variants is sometimes obscured. When buffering systems, or “capacitors,” are de-stabilized or overwhelmed by genetic or environmental factors, “cryptic” genetic variants are exposed. Understanding the mechanism by which organisms buffer accumulated cryptic variants may illuminate the evolution of complex traits while providing vital insight into the heritability of genetic disease.

Regulation of gene transcription is a major mechanism cells use to modify the levels of certain proteins in response to their environment. A specific class of genes called immediate-early genes (IEGs) responds rapidly to external stimuli to adjust downstream gene transcription programs before any new proteins are synthesized. Abnormal expression of IEGs has been implicated in multiple types of cancers, as well as in neurological syndromes like addiction. Despite extensive study, the regulation of IEGs remains poorly understood. Dr. Gu’s work focuses on revealing the molecular mechanisms of IEG expression in cells and establishing model systems to study the physiological and disease-related outcomes caused by misregulation of this process. Dr. Gu [National Mah Jongg League Fellow] received her PhD from MIT and her BSc from Peking University.

Dr. Gu [Fraternal Order of Eagles Fellow] is deciphering the combinatorial code of mammalian transcription regulation. The precise and robust regulation of gene expression is typically achieved through a combination of multiple transcription factors. However, we lack understanding of how a mammalian transcription system perceives, processes, and presents combinations of transcription factors. Dr. Gu will combine quantitative modeling and synthetic approaches to analyze the complex interactions among natural transcription regulatory proteins and apply the principles learned to engineer a programmable transcriptional platform with tunable logic. This work promises to deepen our understanding of mammalian transcription regulation and unlock new capabilities for emerging cell-based therapeutics.

Human cells have complex mechanisms to repair DNA damage, such as that caused by exposure to sunlight or chemical substances. If DNA is not properly repaired, however, it can lead to cancer. In fact, faulty DNA repair has been associated with the initiation and progression of all types of cancer and is often targeted in cancer treatment to stop uncontrolled cell growth. A better understanding of how cells naturally defend against DNA damage will allow for the development of better drugs to treat cancer. Dr. Hoitsma [HHMI Fellow] aims to investigate specialized proteins, known as chromatin remodelers, that make damaged DNA accessible for repair. This research will provide insight for the development of novel therapeutic strategies to target these critical pathways. Dr. Hoitsma received her PhD from University of Kansas Medical Center, Kansas City and her BS from South Dakota State University, Brookings.

DNA stores the information for making all the proteins in an organism. Transfer RNA (tRNA) plays a key role in building the proteins from this blueprint. tRNA molecules recognize specific sequences (three-letter codons) and deliver the corresponding amino acids needed to make a protein. Dr. Hsu recently found that certain starvation conditions can cause some tRNAs to be modulated in colorectal cancer cells. He will study the changes in tRNA levels that occur in response to cellular starvation states. He aims to shed light on how cancer cells adapt to starvation, which potentially can lead to new therapeutic approaches to target metabolic dependencies in cancer.

Immune checkpoint inhibitors, a type of cancer treatment that helps immune cells identify and kill tumor cells, have been a major breakthrough in the treatment of many cancer types. Unfortunately, not all patients respond to this immunotherapy. Dr. Hughes [Robert Black Fellow] is studying how gut microbes improve response to immune checkpoint inhibitors. The bacterium Akkermansia muciniphila lives in the gastrointestinal tract and has been shown to improve response to immune checkpoint inhibitors via poorly understood mechanisms. Dr. Hughes aims to discover how A. muciniphila improves response to cancer immunotherapies and to design microbe-based therapeutic strategies that will further enhance cancer immunotherapy responses. Dr Hughes received her PhD from UT Southwestern Medical Center and her BS from Baylor University.

Genetically engineered immune cell therapies have emerged as breakthroughs in the treatment of certain blood cancers. However, these advances have been limited to the minority of cancers that express a cell surface protein on all tumor cells; this protein is absent from essential normal tissues and can be recognized and targeted by therapeutic immune cells. Dr. Jan seeks to develop synthetic biology tools to engineer immune cells to recognize the heterogeneous tumor proteins present on many advanced cancers and then activate the body's tumor clearance mechanisms. His goal is to develop cell therapy candidates for direct translation to the care of people with advanced prostate cancer.

Dr. Jarjour is searching for novel methods to overcome resistance to immunotherapy. While immunotherapies have had a transformative impact for some patients suffering from specific cancers, some tumors are highly resistant to these treatments. These resistant tumors often lack the majority of immune cell types that could potentially attack the tumor. Dr. Jarjour is addressing this problem by developing antigen-independent methods to stimulate the innate proliferative capacity of tissue-resident CD8+ T cells, based on signaling molecules called cytokines. His generalizable approach could increase the efficacy of existing checkpoint blockade therapies on resistant tumors. His work has implications for many types of cancer, as well as vaccine development.