Most significant accomplishment: Finding a novel mechanism that regulates the innate immune system, and using this to develop therapeutics for fibrosing diseases.

My long-term interest in how cells differentiate, form tissues containing different cell types, and how the different cell types sense each other led to a potential treatment for fibrosing diseases, where scar tissue forms in inappropriate places and interferes with organ function. These diseases, for which there is no effective therapy, kill more people than cancer. We found that the human serum protein SAP (also called PTX2, PTX-2, or pentraxin-2) prevents monocytes from differentiating into fibrocytes, which are fibroblast-like cells that participate in scar tissue formation. Realizing that SAP could be used to block scar tissue formation, I co-founded Promedior, a biotechnology company, to develop therapies for fibrotic diseases. Phase 2 clinical trials of SAP have had remarkable success in treating two lethal fibrosing diseases, idiopathic pulmonary fibrosis and myelofibrosis. Roche purchased Promedior and is now doing Phase 3 trials of SAP in pulmonary fibrosis patients. Our observations of SAP effects on neutrophils, monocytes, and macrophages, showing that SAP essentially calms the innate immune system, has not only reoriented basic research in this area, but may change how a broad range of deadly diseases are treated.

Our current work on fibrosis focuses on second-generation therapeutics, based on our identification of the key SAP receptors (SAP receptor agonists strongly inhibit fibrosis), and our identification of a novel mechanism where an extracellular enzyme called sialidase 3 potentiates fibrosis. In an exciting new direction, we found a new class of sialidase inhibitors that completely attenuate fibrosis in a mouse model, and we are working to take the sialidase inhibitors and the SAP receptor agonists into the clinic with the help of a new startup company I co-founded.

Other significant work: Fundamental discoveries in Dictyostelium signaling and development have led to new paradigms and potential therapeutics.

A key question in developmental biology is how a group of undifferentiated cells can break symmetry and become different cell types. I found that Dictyostelium cells use a musical chairs mechanism based on the phase of the cell cycle that a cell happens to be in at the time of starvation to determine initial cell type choice. This fundamental process of reading cell cycle phase to determine cell fate, a mechanism later shown to be used in mammals, changed the narrative in the field of differentiation. In addition, my interest in how cells sense and regulate the size of a group or tissue led to the discovery of a Dictyostelium signal that is used to sense and regulate the size of a group using a novel physical mechanism: when the group is too large, the concomitant high levels of the factor decrease cell-cell adhesion and increase cell mobility to cause the group to fragment. In a similar line of investigation, we became interested in the study of chalones, which inhibit the proliferation of cells to regulate tissue size. Starting in the 1930’s, a variety of experiments strongly indicated the existence of chalones secreted by specific cell types that inhibit proliferation of the associated cells when the chalone reaches a sufficiently high concentration in the blood. With the exception of myostatin, a chalone used by muscle cells, the other chalones and their signal transduction pathways have eluded identification, with purification attempts failing. We discovered two different chalones that inhibit Dictyostelium cell proliferation, and found that one is based on the unusual molecule polyphosphate. Since the identity of endogenous signals that specifically regulate the size of the liver, or some other tissue, could be useful in a therapeutic setting, we expect that our work on chalones in Dictyostelium will teach us, and others, how to successfully revisit the mammalian chalone problem. Lastly, while considerable effort has focused on chemoattractants, much less was known about chemorepellents. We discovered a Dictyostelium secreted factor that works as a chemorepellent, and identified a human orthologue that is a neutrophil chemorepellent. The human factor shows therapeutic efficacy by locally repelling neutrophils in mouse models of rheumatoid arthritis and the currently untreatable disease acute respiratory distress syndrome (ARDS). We identified the receptors for both the Dictyostelium and human repellents, and found that small molecule agonists of the human receptor repel neutrophils and show efficacy in the mouse ARDS model. We are currently working to elucidate the chemorepulsion mechanism, and, as with SAP, move this into the clinic.

Astronomy:

I designed and built detectors and data systems to allow very large telescopes to do new observational modes such as simultaneous very high-speed photometry and spectroscopy. This allowed new ways to map the movement and distribution of gas in accretion disks, and helped to show, for instance, that the rapidly spinning magnetic field of the white dwarf in the AE Aquarii binary acts like a paddlewheel to spray mass from the donor star out of the system. I stopped the astronomy work when I started working on fibrosis, but now that Roche bought Promedior, I have restarted this work.

Please go to the Gomer Lab Website for more information on current work.

1. Rijal, R, Gomer, RH. Proteomic Analysis of Dictyostelium discoideum by Mass Spectrometry. Methods Mol Biol. 2024;2814 :247-255. doi: 10.1007/978-1-0716-3894-1_17. PubMed PMID:38954210 PubMed Central PMC11414281.
2. Consalvo, KM, Rijal, R, Beruvides, SL, Mitchell, R, Beauchemin, K, Collins, D et al.. PTEN and the PTEN-like phosphatase CnrN have both distinct and overlapping roles in a Dictyostelium chemorepulsion pathway. J Cell Sci. 2024;137 (15):. doi: 10.1242/jcs.262054. PubMed PMID:38940195 PubMed Central PMC11317092.
3. Pilling, D, Consalvo, KM, Kirolos, SA, Gomer, RH. Differences between human male and female neutrophils in mRNA, translation efficiency, protein, and phosphoprotein profiles. Res Sq. 2024; :. doi: 10.21203/rs.3.rs-4284171/v1. PubMed PMID:38746380 PubMed Central PMC11092807.
4. Rijal, R, Gomer, RH. Gallein potentiates isoniazid's ability to suppress Mycobacterium tuberculosis growth. Front Microbiol. 2024;15 :1369763. doi: 10.3389/fmicb.2024.1369763. PubMed PMID:38690363 PubMed Central PMC11060752.
5. Consalvo, KM, Rijal, R, Beruvides, SL, Mitchell, R, Beauchemin, K, Collins, D et al.. PTEN and the PTEN-like phosphatase CnrN have both distinct and overlapping roles in a Dictyostelium chemorepulsion pathway. bioRxiv. 2024; :. doi: 10.1101/2024.02.23.581751. PubMed PMID:38464111 PubMed Central PMC10925239.
6. Rijal, R, Gomer, RH. Gallein and isoniazid act synergistically to attenuate Mycobacterium tuberculosis growth in human macrophages. bioRxiv. 2024; :. doi: 10.1101/2024.01.10.574965. PubMed PMID:38260681 PubMed Central PMC10802476.
7. Vukmirovic, M, Benam, KH, Rose, JJ, Turner, S, Magin, CM, Lagares, D et al.. Challenges and Opportunities for Commercializing Technologies in the Pulmonary Arena: An Official American Thoracic Society Report. Ann Am Thorac Soc. 2024;21 (1):1-11. doi: 10.1513/AnnalsATS.202310-872ST. PubMed PMID:37903340 PubMed Central PMC10867911.
8. Rahman, RJ, Rijal, R, Jing, S, Chen, T-A, Ismail, I, Gomer, RH et al.. Polyphosphate uses mTOR, pyrophosphate, and Rho GTPase components to potentiate bacterial survival in Dictyostelium. mBio. 2023;14 (5):e0193923. doi: 10.1128/mbio.01939-23. PubMed PMID:37754562 PubMed Central PMC10653871.
9. Kirolos, SA, Hatfield, CE, Rahman, RJ, Consalvo, KM, Dittenhauser, NK, Gomer, RH et al.. A phosphatidylinositol phosphate kinase inhibits Ras activation and regulates chemorepulsion in Dictyostelium discoideum. J Cell Sci. 2023;136 (14):. doi: 10.1242/jcs.260541. PubMed PMID:37259831 PubMed Central PMC10399982.
10. Rijal, R, Ismail, I, Jing, S, Gomer, RH. Starvation Induces Extracellular Accumulation of Polyphosphate in Dictyostelium discoideum to Inhibit Macropinocytosis, Phagocytosis, and Exocytosis. Int J Mol Sci. 2023;24 (6):. doi: 10.3390/ijms24065923. PubMed PMID:36982997 PubMed Central PMC10056890.