Institute for Translational Medicine and Pharmacology at Mount Sinai

Marine mammals, encompassing cetaceans (whales, including dolphins and porpoises), have evolved many specific adaptations to living underwater, such as approaches to managing a limited air supply while submerged. Our research has focused on the respiratory tract, as it is one of the most modified systems. For instance, studies look at varied mechanisms of laryngeal versus nasal sound generation and underwater transmission, air-recycling to turn over respiratory "dead space," and geometry of the larynx and blowholes/nasal region for respiratory protection from water and regulation of air releases. We are currently examining beaked whales to better understand their echolocation generation and transmission mechanisms, particularly their unusual "melon" (a fatty tissue that is thought to focus sound beams).

We have studied whale sensory systems, focusing on their eyes/orbit, skin, and brains. A new project is examining the tubercles on the heads of humpback whales for their potential role as sound sensors. The discovery of potential vomeronasal organ receptors challenges the notion that whales lack olfactory senses.

Additional areas of research explore adaptations to pressure changes. When animals dive into the sea, their lungs have an unusual ability to adapt. To investigate these protective features at the cellular level, we are examining the mechanics of lung compression and expansion across various depths of pressure. Deep diving also poses a risk for the formation of gas emboli in the bloodstream on ascent. We are studying whale vascular anatomy to determine whether these marine mammals employ a mechanism to trap bubbles and prevent decompression sickness ("the bends").

Past research has focused on musculoskeletal anatomy: flipper structure and evolution and the hyoid apparatus and attached musculature. This work has contributed to our understanding of the specific locomotor mechanisms used by marine mammals. We have also studied other aquatic or semi-aquatic species to understand the anatomy and function of their laryngeal and nasal regions, including manatees and hippos. We examined pinnipeds' (e.g., seals, sea lions, and walruses) craniofacial musculature and elephant trunk musculature to better understand feeding mechanisms. Ongoing work documents the anatomy and health status of very rare whales (such as Rice's whale population that lives in the Gulf waters adjacent to Florida, and the spade-toothed whale that lives in New Zealand).

To explore mechanisms that mitigate concussion, we are studying artiodactyls (e.g., muskoxen and bighorn sheep). Current work is examining the internal anatomy of the cranial vault to better understand whether its highly textured surface prevents brain "slippage" or enables multiple points of contact to diffuse the impact of the brain-bone collision experienced during a concussive encounter.

In addition, we are examining whale rib bone and sea turtle shell (carapace) anatomy for structural features that can reflect or transmit a pressure wave. The goal is to determine whether we can mimic these features to develop protection against the percussive shock wave of an explosion. The features could serve as models for new helmet designs or body armor for soldiers and construction workers exposed to blasting.

This study aims to define novel dosimetric predictors of female sexual dysfunction after radiotherapy and to identify quantitative imaging and microbiome-based biomarker indices associated with radiation damage to specific sexual organs. The study uses a refined classification of sexual dysfunction structured on functional anatomic organs (including dermatologic, vaginal, and erectile).

A study of 68 cadaveric livers from elderly donors identified steatosis in 35.5 percent, central vein fibrosis in 49.2 percent, perisinusoidal fibrosis in 63.2 percent, portal tract fibrosis in 47.7 percent, septa formation in 44.1 percent, bridging fibrosis in 30.8 percent, and cirrhosis in 4.4 percent of the samples. There was also one hepatocellular carcinoma and six metastatic tumors. Other studies have revealed that fibronectin and collagens I, III, IV, V, and VI constitute the matrices of fibrous central veins, perisinusoidal space, portal tracts, and septa. Elastin is rich in portal tracts and fibrous septa but absent from the perisinusoidal space. Hepatic stellate cells are ubiquitous in the liver parenchyma, while myofibroblasts localize in fibrotic foci. Factor VIII-related antigen expression signals sinusoidal to systemic vascular endothelium transformation, while collagen IV and laminin codistribution indicates formation of perisinusoidal membranes. Their coincidence reflects focalized capillarization of sinusoids in the aging liver. In response to fibrogenesis, hepatic progenitor cells residing in the canal of Hering in the periportal parenchyma undergo expansion and migration deep into the lobule. Concomitantly, intermediate hepatocyte-like cells increase in advanced fibrosis stages, which may be related to hepatic regeneration. Metabolic zonation of glutamine synthetase expands from the perivenous to non-perivenous parenchyma in fibrosis progression, but its expression is lost in cirrhosis. Meanwhile, cytochrome P-4502E1 expression is maintained in centrilobular and midlobular zones in fibrosis progression and expressed in cirrhosis. Hence, cadaveric livers provide a platform for further investigation of hepatic histopathologies associated with the aging liver.

Our prospective research includes the collection of additional liver samples from cadavers, particularly those exhibiting cirrhosis and hepatocellular carcinoma. We aim to evaluate the expression of NETs at progressive stages of liver fibrosis in cadaveric liver tissue using immunohistochemistry. NETs will be detected using antibodies against specific markers, including neutrophil elastase, anti-liver/kidney microsomal antibodies type 1, histones, and high mobility group box 1. The immunoperoxidase method with antigen retrieval will be employed on paraffin-embedded liver sections (Brinkmann et al., 2016). This project holds significant translational value due to the pathogenic potential of NETs. Their detection in patient liver tissue could serve as a prognostic and diagnostic marker for liver fibrotic disease, potentially improving clinical assessment and treatment strategies.

One of the least understood areas of human and mammalian biology regards the world of the inner ear. The mammalian inner ear is traditionally divided into two systems: the peripheral vestibular system (for balance) and the cochlea (for hearing). This bipartite model has shaped our understanding of inner ear evolution, function, and pathology. However, it groups the semicircular ducts (which detect angular velocity) and otolithic organs (which detect linear acceleration, vibration, and head tilt) into a single peripheral vestibular system, overlooking key differences in their structure and function.

Using advances in imaging technology, research led by Dr. Smith investigates whether the otolithic system is evolutionarily and structurally distinct from the semicircular ducts, with a focus on primates. Specifically, we assess variational modularity and phylogenetic signal in the inner ear across 14 primate species using landmark-based 3D geometric morphometrics within a phylogenetic framework.

Our results reveal previously unrecognized modularity in the primate peripheral vestibular system. The semicircular canals and otolithic organs show stronger integration within their own structures rather than with each other. Additionally, while the shape of the otolithic system does not follow a neutral model of evolution, its size evolves at a significantly different rate from that of the semicircular canals.

These findings challenge the traditional model of a single peripheral vestibular system. Instead, a bipartite framework—comprising distinct canalicular and otolithic systems—may better reflect the structural, functional, and evolutionary complexity of this "balance system" in primates, including ancestral humans. This revised model reshapes perspectives on vestibular system organization and has implications for studies on balance, sensory adaptation, and inner ear dysfunction. How and when this system evolved, and the effects it had on ancestral human head position and bipedality, will shed new light on understanding the trajectory of human evolution. (This research is funded by NSF Doctoral Dissertation Improvement Grants (DDRIG) to Dr. Laitman/Dr. Smith).

Much of the human aerodigestive tract is unique among mammals. In particular, aspects of the bony nose (both external and internal), communications with the paranasal sinuses and the middle ear (via the eustachian tube) have been shown by us (research led by Drs. Marquez and Pagano) to be highly derived (in many cases, uniquely so) in the line leading to living Homo sapiens. Using our studies on the comparative anatomy of extant species (via modalities ranging from imaging studies to dissection) in combination with extensive study of extant and fossil collections in the United States and abroad, our team has brought to the fore many of the unique features exhibited in the line leading to living humans and how our group differed from fossil groups, such as the Neanderthals. These studies have also shown the unique developmental features in humans, particularly differences in the orientation of the eustachian tube in infants that may underlie aspects of acute otitis media. This research has been funded via NIH and NSF DDRIGs.

One of the distinguishing features of humans is our ability for speech. How, when, and why the underlying anatomy required to produce the array of sounds used in human speech arose are questions that lie at the very core of what our species, Homo sapiens, is about. While many studies over decades have drawn inferences from features of the evolving mammalian brain, from remains such as natural endocasts, and others from remnants in the archeological record, few markers of the anatomy of the vocal apparatus have remained.

Human inner ear anatomy illustrating the traditional compartmentalization of the inner ear into the cochlear and peripheral vestibular systems.

Bipartite and tripartite conceptual models of inner ear organization.

Dr. Laitman, with colleagues Drs. Reidenberg, Marquez, Friedland, and Pagano among others, have pioneered the use of cranial and basicranial features of the skull based upon their extensive study of the comparative anatomy of the region in living mammals, and have ushered in new approaches to reconstructing the region in fossil ancestors. Findings from this ongoing research have enabled understanding of many of the unique features of the human hyo-laryngeal position, how our species differs from closely related groups such as Neanderthals, and when the ability for articulate speech may have arisen. Aspects of these studies have been funded by the National Science Foundation, Research Support from the Foundation for Research Into the Origins of Man, the Speech Origins Fund of American Museum of Natural History, and the Collège de France, among others.