Shyni Varghese

The human brain has long served as a blueprint for computation, guiding evolution from early symbolic systems to modern deep learning models. Despite these advances, traditional computing systems remain fundamentally limited in mirroring the remarkable flexibility, parallel processing and energy efficiency of the human brain. To address these limitations, neuromorphic computing was developed, which mimics the architecture and signaling behavior of biological neurons. Building on this foundation, a new frontier is now emerging—organoid intelligence (OI). OI uses lab-grown brain cellular structures, such as living neural organoids with electrical activity, synapse formation and primitive learning, as a substrate for computation. Here we trace the evolution of brain-inspired computing from symbolic logic systems to artificial neural networks, neuromorphic processors and finally biohybrid computers that incorporate living neural structures. We explore the transformative potential of OI along with the substantial technical, biological and ethical challenges it presents.

The use of cellular systems to advance cancer therapeutics has expanded rapidly, spanning cell therapies to patient-specific tumor models. Platforms that recapitulate key features of the tumor microenvironment, including vascular and immune components, hold significant potential to improve the predictive power and translational relevance of preclinical models. Here, we report a vascularized tumor organoid platform that combines self-organizing microvascular networks with patient-derived tumor organoids and tumor-infiltrating lymphocytes. To minimize non-specific endothelial immunogenicity and enable broader compatibility across patient samples, we engineered the vasculature using β2-microglobulin-knockout endothelial cells. Leveraging this system, we established patient-specific, lymphocyte-incorporated tumor models that enabled quantitative assessment of T cell infiltration. In conjunction with immune checkpoint blockade, this platform distinguishes responder and non-responder patient samples, consistent with the clinical observations. Single-cell RNA-sequencing revealed tumor-intrinsic and immune-associated programs underlying this stratification, identifying tumor-driven hyperangiogenic signaling as a barrier to T cell extravasation. Pharmacological co-targeting of PD1 and VEGF restored T cell infiltration in non-responder organoids, shifting them from an immune-excluded to an immune-inflamed state. Together, this vascularized tumor organoid platform provides a predictive and mechanistic framework for modeling patient-specific immunotherapy responses and design of combination therapies.

Exosomes, an acellular regenerative biologic, have demonstrated success in resolving vaginal mesh exposures after pelvic reconstructive surgery; little data exists for their use for prevention of mesh-based complications. This study evaluated the early efficacy of purified exosome product (PEP) for preventing mesh exposures. Ten Yorkshire-crossed pigs underwent mesh sacrocolpopexy with two high-risk-for-exposure configurations: mesh fold ventrally, vaginotomy dorsally. PEP in hyaluronic acid (HA) or HA-only (control) was injected at baseline. Twelve weeks later, animals were euthanized and evaluated for mesh exposure and histologic changes. None of the PEP-treated tissues demonstrated mesh exposure (0/6); all control group animals experienced a mesh exposure (4/4 mesh fold configuration, 2/4 vaginotomy configuration). Control tissues exhibited higher fibrosis (vaginotomy fibrosis score: median(IQR); 3(3,3) control, 2(1,2) PEP; p = 0.03) and greater epithelial apoptosis (mesh fold TUNEL+area fraction: median 18.9 control vs 0.43 PEP; p = 0.02). Our study demonstrated that PEP treatment mitigated the risk of early mesh exposure.

Transposable elements (TEs), constituting half of the human genome, are essential for development and diseases. While the regulation of TE activity by cellular intrinsic mechanisms is well documented, their response to microenvironmental signals, particularly mechanical cues involving numerous biological processes, remains unknown. Here we show that various TE families, notably LTR7, undergo transcriptomic, epigenetic and three-dimensional genome changes in response to matrix mechanical cues in human embryonic stem cells. Interestingly, LTR7s act as ‘mechano-response enhancer elements’ (MREEs), controlling the gene expression and cell fate of human embryonic stem cells. Mechanistically, mechano-effectors YAP/TEAD1 control LTR7’s epigenetic activity by engaging with BRD4. Furthermore, YAP recruits CTCF, a key genome architecture protein, to facilitate long-range interactions between gene promoters and TEs as MREEs. In particular, a mechano-responsive LTR7 element is a distal enhancer for FAM189A2, thereby inhibiting definitive endoderm differentiation. These findings highlight the underappreciated role of TEs as MREEs that control human cell fate and gene expression.

Alveolospheres derived from AT2 cells in 3D hydrogels enabled the development of a vascularized alveoli-on-chip model, which was applied to study pulmonary responses to chemical exposure.

Bone fractures and related complications are a significant concern for older adults, particularly with the growing aging population. Therapeutic interventions that promote bone tissue regeneration are attractive for geriatric fracture repair. Extracellular adenosine plays a key role in bone homeostasis and regeneration. Herein, we examined the changes in extracellular adenosine with aging and the potential of local delivery of adenosine to promote fracture healing using aged mice. Extracellular adenosine level was found to be significantly lower in aged bone tissue compared to young mice. Concomitantly, the ecto-5′-nucleotidase CD73 expression was also lower in aged bone. Local delivery of adenosine using injectable, in situ curing microgel delivery units yielded a pro-regenerative environment and promoted fracture healing in aged mice. This study offers new insights into age-related physiological changes in adenosine levels and demonstrates the therapeutic potential of adenosine supplementation to circumvent the compromised healing of geriatric fractures.

Aging has been identified as a leading risk factor for many diseases, including neurodegenerative disorders. While cellular senescence has been linked to age-related neurodegenerative conditions, its involvement in peripheral stress-associated brain disorders is just beginning to be explored. In this study, we investigated the impact of senescent cells on peripheral stress-induced neuroinflammation using orthopedic surgery as a model. Our results demonstrate an increased accumulation of senescent cells and neuroinflammation in the aged mouse hippocampus following surgery. Intermittent treatment of the mice with the senolytic drugs dasatinib and quercetin (D/Q) showed a significant reduction in surgery-induced senescent cell burden. This reduction in senescent cell accumulation was correlated with reduced surgery-induced neuroinflammation, as evidenced by decreased glial cell activity. Consistent with these observations, we also observed reduced levels of proinflammatory senescence-associated secretory phenotype factors in circulation, following fracture surgery, in mice treated with D/Q. Overall, our findings underscore the pivotal role of cellular senescence in surgery-induced neuroinflammation and highlight the therapeutic potential of eliminating senescent cells as a potential strategy to manage peripheral stress-induced neuroinflammatory conditions.

Bone fractures pose a significant public health challenge, often necessitating surgical interventions to facilitate bone healing and functional recovery. Sensory nerve fibers innervate various compartments of the bone tissue, with the periosteum exhibiting the most extensive innervation that is susceptible to injury during trauma. Despite its importance, the effect of injured periosteum on fracture pain remains unknown. This study examines the impact of extensive periosteal injury on fracture pain by using a mouse model. Periosteal injury is induced by mechanical resection during unilateral transverse fracture and compared to transverse fractures with no periosteal injury. Our results demonstrate that extensive periosteal injury induces severe and long‐term pain, as assessed by von Frey and dynamic weight bearing measurements, for up to 12 weeks postfracture. Immunofluorescence staining revealed an increase in local neurofilament heavy polypeptide (NF200 +) nerve innervation and an elevated number of calcitonin gene‐related peptide (CGRP +) expressing neurons in the dorsal root ganglion (DRG). Additionally, flow cytometric analyses revealed increased presence of myeloid immune cells in the DRG. Furthermore, bone healing in fractures with extensive periosteal injury exhibited reduced callus size at all time points as assessed by Faxitron X‐ray imaging. This study describes a previously unknown effect of extensive periosteal injury in exacerbating fracture pain and establishes a potential model to study long‐term orthopedic fracture pain.

The field of cancer biology and therapeutics has soared in the past several decades with new therapeutic modalities and options for patients, such as chemoradiotherapy, immunotherapy, and combination therapy. This dramatic success in expanding patient options is primarily attributed to the development of various model systems to elucidate drivers of oncogenesis, tumor maturation and evolution, and response to therapeutics. While mouse models have been a workhorse of cancer research, technological progress in ex vivo patient‐derived tumor models has afforded more tunable and scrutable systems for patient‐predictive platforms and mechanistic study. This review explores the technological innovations in 3D solid tumor models and their applicability to various aspects of cancer biology and the identification of therapeutics. Features of the tumor and tumor microenvironment like spatial heterogeneity, multicellular populations, and genomic variations are addressed and elaborated through the establishment of new in vitro models. The integration of perfusable vasculature with 3D tumor models and the potentially wide‐ranging applications of these more complex platforms in precision medicine and cancer immunotherapy are further addressed. Finally, an outlook on the future of experimental cancer models for both biological investigation and bench‐to‐bedside pipeline development is provided.

The role of macrophages (MΦs) remains incompletely understood in kidney injury and repair. The plasticity of MΦs offers an opportunity to polarize them toward mediating injury resolution in both native and transplanted kidneys undergoing ischemia and/or rejection. Here, we show that infiltrating kidney MΦs augmented their own allograft inflammatory factor 1 (AIF-1) expression after injury. Aif1 genetic deletion led to MΦ polarization toward a reparative phenotype while halting the development of kidney fibrosis. The enhanced repair was mediated by higher levels of antiinflammatory and proregenerative markers, leading to a reduction in cell death and an increase in proliferation of kidney tubular epithelial cells after ischemia followed by reperfusion injury (I/RI). Adoptive transfer of Aif1 ^–/– MΦs into Aif1 ^+/+ mice conferred protection against I/RI. Conversely, depletion of MΦs reversed the tissue-reparative effects in Aif1 ^–/– mice. We further demonstrated increased expression of AIF-1 in human kidney biopsies from native kidneys with acute kidney injury or chronic kidney disease, as well as in biopsies from kidney allografts undergoing acute or chronic rejection. We conclude that AIF-1 is a MΦ marker of renal inflammation, and its targeting uncouples MΦ reparative functions from profibrotic functions. Thus, therapies inhibiting AIF-1 when ischemic injury is inevitable have the potential to reduce the global burden of kidney disease.