To Investigate Range of Pressing Scientific Questions, Researchers Combine Efforts

The idiom “strength in numbers” often holds true for scientific pursuits. The response to the COVID-19 pandemic—particularly scientists’ ability to work together to develop highly effective vaccines against a previously unknown virus—has demonstrated just how powerful collaboration can be in the face of a global public health threat.

For more than 35 years, The Pew Charitable Trusts has supported early-career scientists working across the research spectrum to tackle some of the most critical issues in biomedical science. In 2017, Pew launched the Innovation Fund to support collaboration among alumni of its biomedical programs in the United States and Latin America. 

This year’s awardees—12 accomplished scientists with expertise in molecular biology, genetics, immunology, neuroscience, and more—have paired up to investigate critical issues linked to human health. 

Genetic mechanisms of fetal alcohol syndrome disorders

Paola A. Haeger Soto, Ph.D., from Chile’s Catholic University of the North and Adrian R. Krainer, Ph.D., from Cold Spring Harbor Laboratory in New York will examine the processes through which alcohol consumption during pregnancy can lead to neurodevelopmental disabilities such as fetal alcohol syndrome disorders (FASD). Children born with these syndromes exhibit symptoms ranging from cognitive disabilities to social and behavioral issues, but scientists are unclear as to how alcohol causes these impairments.

Gene expression, a process by which genes are made into messenger RNA (mRNA) and then proteins, is controlled at various levels in the body. Studies suggest that a step in the expression process known as alternative splicing, in which different combinations of genetic fragments are joined to generate a range of mRNAs, may be altered in babies born with FASD. In addition, research suggests that microexons—small genetic sequences in mRNA—are aberrantly incorporated into mRNA in autism spectrum disorder, a neurodevelopmental condition that has overlapping features with FASD.

The team will examine changes in neuronal function by studying the brain and profiling the population of mRNAs generated in a rat model of FASD. Researchers will then apply genetic tools to manipulate the level of microexons that are incorporated from select genes. Work from this project could identify potential biomarkers for FASD and provide insights into how exposure to ethanol in alcohols during pregnancy can reprogram the fetal brain.

How acute Chikungunya infections lead to chronic symptoms

Deborah J. Lenschow, M.D., Ph.D., from Washington University in St. Louis and Gabrielle Kardon, Ph.D., from the University of Utah will study how the Chikungunya virus, a mosquito-borne pathogen that causes fever, rash, and arthritis in humans, leads to chronic and persistent symptoms even after infection subsides. Scientists have found that viral RNA from Chikungunya can be detected in patients weeks after infection, despite the absence of a replicating virus; up to 60% of afflicted patients develop long-term muscle pain, joint pain, and fatigue. Muscles and connective tissues are known to harbor persistent viral RNA and therefore may be the source of chronic symptoms, but it’s not clear how muscle structure may be altered by the lingering viral genetic material and contribute to ongoing symptoms.

Combining expertise in viral immunology and muscle biology, the team will investigate how residual Chikungunya viral RNA changes cellular gene expression to cause structural muscle damage, as well as which specific cell types contribute to deterioration. This effort could provide critical insight into the mechanisms of chronic Chikungunya symptoms, as well as long-haul symptoms resulting from the novel coronavirus.

How gut bacteria influence age-related genes

Coleen T. Murphy, Ph.D., from Princeton University and Roberto Ricardo Grau, Ph.D., from the National University of Rosario, Argentina, will explore how beneficial bacteria in the gut influence longevity. Intestinal flora—which includes different microbial species in the gut, such as beneficial probiotic bacteria essential for maintaining individual health—can change over time because of diet or illness. Scientists now believe these good bacteria may even help prolong life and prevent age-related decline.

Murphy and Grau will explore how these bacteria may modify age-related genes using two model organisms: the roundworm Caenorhabditis elegans and probiotic bacterium Bacillus subtilis. Previous research by Grau discovered that this bacterium, when colonized in the gut of these roundworms, extended the organism’s lifespan. Now, the researchers will determine how B. subtilis activates host pathways to improve intestinal flora and support health and longevity. Their work could translate to novel means of delaying the effects of human aging. 

How the body communicates tissue repair signals

David R. Sherwood, Ph.D., and Kenneth D. Poss, Ph.D., both from Duke University, will investigate the coordinated signaling process that takes place within the body during tissue repair and regeneration. The lab run by Poss recently discovered that a wave of growth signal activity moves across tissues in zebrafish to support scale regeneration. But how this signal activity is initiated and whether basement membranes—sheetlike proteins essential for tissue architecture—can help support unidirectional movement of this activity is unclear.

The team will use gene-editing technology to visualize the movement of key signaling proteins and monitor zebrafish scale regeneration in real time. This work could provide important insights into how repair signals operate during tissue repair and inform new research in tissue development and regenerative medicine.

How bacteria enter and invade host cells

Juan E. Ugalde, Ph.D., and Carlos O. Arregui, Ph.D., both from the University of San Martín, Argentina, will explore the role of bacterial outer membrane vesicles (OMVs)—spherical buds of the bacterial membrane that are enriched with enzymes and toxins—in delivering and introducing virulent proteins to host cells, which helps initiate infection and cause disease. Brucella species and many other Gram-negative bacteria produce OMVs, and these researchers recently discovered that Brucella bacteria OMVs can provoke host cells to form membrane extensions. This in turn allows vesicles to fuse with the host cell to initiate host-cell invasion and can foster infection.

The team will incorporate approaches from biochemical, biophysical, and imaging methodologies to define the components within Brucella OMVs and determine the molecular mechanisms involved in inducing host cell extensions during bacteria and host cell contact. This work will provide critical insights into OMVs as an entry mechanism into host cells, which could inform new strategies for early infection intervention and disease prevention.

Stress response pathways that regulate cell aging

Elçin Ünal, Ph.D., and Gloria A. Brar, Ph.D., both from the University of California, Berkeley, will investigate the stress response pathways in regulating cellular longevity. Gametogenesis, a developmental event that creates reproductive cells, can reset the aging clock, producing cells that are devoid of age-damaged materials. But the specific materials eliminated during this process, as well as the mechanism by which this occurs, are unknown.

The Ünal lab has pioneered cellular imaging and molecular genetic tools to study aging in budding yeast. Meanwhile, the Brar lab has discovered that several stress response pathways—which help the body cope with internal disturbances, such as sudden shifts in temperature and oxygen availability or the accumulation of damaged proteins from infections and aging—are transiently activated during gametogenesis in yeast. The pair will work to further understand the activation of stress pathways during rejuvenation and how such pathways can control the resetting of age in a cell. This work is central to understanding how cellular quality control pathways influence cell age and could point to new mechanisms for reversing cellular damage.

Kara Coleman is the director of The Pew Charitable Trusts’ biomedical programs, including the biomedical scholars, Pew-Stewart Scholars for Cancer Research, and Latin American fellows programs, and Jennifer Villa is an officer supporting the programs.