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.

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.

To prevent autoimmune attacks, T cells are screened in the thymus to ensure they do not react to self-derived antigens. Dr. Huisman studies the thymus and, specifically, a population of cells called “thymic mimetic cells” that mimic other tissues, such as muscle or gut, and assist T cells in developing tolerance to diverse cell types. Dr. Huisman’s research focuses on understanding how thymic mimetic cells develop. This work may lead to improved understanding of thymus-mediated tolerance to tumors, novel therapeutic opportunities for manipulating mimetic cells to induce anti-tumor responses, and increased understanding of thymic tumors. Dr. Huisman received her PhD from Massachusetts Institute of Technology, Cambridge and her BS from University of Michigan, Ann Arbor.

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.

Every cell contains specialized compartments called organelles that perform distinct functions, and cells employ counting mechanisms to finely tune organelle population. Centrioles are one type of organelle required for proper cell division and mammalian development. Cells normally contain two or four centrioles, depending on cell cycle state, and centriole gains or losses result in cancer. One exception to this rule are the cells that line our airways, brain ventricles, and reproductive tracts. These cells contain hundreds of centrioles-yet how these specialized cells break the rules of conventional cell cycle-regulated counting mechanisms remains a mystery. Dr. Jewett's [Merck Fellow] work utilizes primary cell culture and in vivo models to understand the molecular framework that allows increased numbers of centrioles in certain cell types. This work will advance our understanding of how defects in centriole growth cause human diseases such as cancer. Dr. Jewett received her PhD from the University of Colorado School of Medicine and her BS from the University of Denver. 

Dr. Johnson [HHMI Fellow] studies the role that a particular type of cell-cell communication, known as quorum sensing, plays in the development of spatially structured bacterial communities called biofilms. Biofilm formation promotes disease in many clinically relevant bacterial species, and infections caused by them pose severe risks for patients receiving chemotherapy. Dr. Johnson is currently investigating how quorum sensing within biofilms establishes patterns of gene expression, and in turn, how these patterns drive biofilm development and dictate biofilm architectural features. By defining mechanisms underlying biofilm formation and biofilm architecture, Dr. Johnson hopes to contribute to the generation of new approaches for disrupting quorum-sensing-controlled bacterial community interactions as a means of combating bacterial pathogens. Dr. Johnson received her PhD from MIT and her BS from Yale University.

Cells are compartmentalized into membrane-bound and membrane-less organelles, providing spatial structure to the cell’s concentration of proteins and nucleic acids. Dr. Kilgore’s research aims to understand the environment inside different organelles and apply this knowledge to the development of targeted cancer therapies, as better targeting within the cell will improve drug efficacy, increase potency, and decrease side effects. Using both live cells and reductionist models, he will investigate how molecules distribute themselves within the cell as a function of their chemical properties. Learning and applying the chemical grammar of this spatial partitioning will enable the design and preparation of molecular probes and drugs that synergize with the chemistry of the cell as a mechanism of treating all cancers. Dr. Kilgore received his PhD from Massachusetts Institute of Technology and his BS from the University of California, Berkeley.