The future of humans as model organisms

FitzGerald, Garret A.; Botstein, David; Califf, Robert M.; Collins, Rory; Peters, Keith; Bruggen, Nick van; Rader, Dan

doi:10.1126/science.aau7779

Cited by 34 publications

(24 citation statements)

References 13 publications

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“…One of the critical translational steps in identifying novel, causative genes in rare disorders is the discovery of genotype-phenotype associations to inform patient care and impact outcomes. A pragmatic focus on deeply-phenotyped individuals and "smart" experimental design cannot be overestimated 23 . With this in mind, we continued to study the molecular genetic architecture of PAH using the Bayesian approach BeviMed 18 .…”

Section: Discussionmentioning

confidence: 99%

Bayesian inference associates rareKDRvariants with specific phenotypes in pulmonary arterial hypertension

Swietlik

Greene

Zhu

et al. 2019

Preprint

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Total word count: 4422patients harbouring PTV in KDR. KCO stratification also highlighted an association between Isocitrate Dehydrogenase (NAD(+)) 3 Non-Catalytic Subunit Gamma (IDH3G) and moderately reduced KCO in patients with pulmonary hypertension (PP=0.920). The US PAH Biobank was used to independently validate these findings and identified four additional PAH cases with PTV in KDR and two in IDH3G. We confirmed associations between previously established genes and PAH. ConclusionsPTVs in KDR, the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2), are significantly associated with two specific phenotypes of PAH, reduced KCO and later age of onset, highlighting a role for VEGF signalling in the pathogenesis of human PAH. We also report IDH3G as a new PAH risk gene. Moreover, we demonstrate that the use of deep clinical phenotyping data advances the identification of novel causative rare variants.

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Section: Discussionmentioning

confidence: 99%

Bayesian inference associates rareKDRvariants with specific phenotypes in pulmonary arterial hypertension

Swietlik

Greene

Zhu

et al. 2019

Preprint

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“…Darnall 25 hypothesized a whole body approach to study pains, which are often associated with diseases. FitzGerald et al 26 proposed that humans are model organisms for future medicine for treating diseases.Though air pollution concentrations have gradually declined in the developed country, air pollution levels have continuously increased in the developing countries 27 . Population in the industrial cities are particularly at risks of air pollution 2,3,28 .…”

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confidence: 99%

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confidence: 99%

An association between air pollution and daily most frequently visits of eighteen outpatient diseases in an industrial city

Chau

Wang

2020

Sci Rep

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Toxic effects of air pollutants were individually identified in various organs of the body. However, the concurrent occurrences and the connection of diseases in multiple organs arise from air pollution has not been concurrently studied before. Here we hypothesize that there exist connected health effects arise from air pollution when diseases in various organs were considered together. We used medical data from hospital outpatient visits for various organs in the body with a disease-air pollution model that represents each of the diseases as a function of the environmental factors. Our results show that elevated air pollution risks (above 40%) concurrently occurred in diseases of spondylosis, cerebrovascular, pneumonia, accidents, chronic obstructive pulmonary disease (COPD), influenza, osteoarthritis (OA), asthma, peptic ulcer disease (PUD), cancer, heart, hypertensive, diabetes, kidney, and rheumatism. Air pollutants that were associated with elevated health risks are particular matters with diameters equal or less than 2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ), ozone (O 3 ), particular matters with diameters equal or less than 10 μm (PM 10 ), carbon monoxide (CO), and nitrogen oxide (NO). Concurrent occurrences of diseases in various organs indicate that the immune system tries to connectively defend the body from persistent and rising air pollution.matter present in frontal and temporal lobes and corpus callosum 5 . Combustion-derived iron-rich magnetite nanoparticles from airborne particulate matter pollution were found in the human brain 13 , showing that air pollution particles were directly transported and deposited in the human brain. Mice exposed to elevated levels of NO 2 (2.5-5.0 mg/m 3 ) were found to show the deterioration of spatial learning and memory, aggravated amyloid β 42 accumulation, promoted pathological abnormalities, and cognitive defects related to Alzheimer's disease 14 . Humans exposed to NO 2 and PM 2.5 were positively correlated with the incidence of dementia in London, England 15 . Toxins accompanying air pollutants into the body exert chronic activation of microglia, leading to direct neuronal damage and neuronal death in the central nervous system 16 Delicate communication exists between the brain and the immune system 17,18 , and evidence that connects health and emotions through neural activity in the brain 19 . These pathophysiological findings reveal that air pollutants affected the central nervous system, leading to the decline of brain function 20 and fatal diseases 18 .Pathophysiological evidence convincingly showed pathways of various diseases arose from air pollution 21 . Hence, more diseases associated with air pollution remained to be discovered in the population 22 . Kampa and Castanas 23 and Jay 24 showed that diseases associated with air pollution were found in various parts of human organs: cardiovascular and circulatory system, digestive and excretory system, endocrine system, integumentary and exocrine system, lymphatic and immune system, muscular and skeletal s...

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“…In view of the increasing availability of human genomic information and corresponding medical records, it does not appear unrealistic to foresee a future, where novel insight into CEACAM3 function might come directly from combined genomic-phenotypic studies in humans (100). Indeed, the occurrence of an unexpected high proportion of loss-of-function alleles in particular human populations (101) could help to reveal plausible connections between CEACAM3 deficiency and susceptibility for particular infectious diseases.…”

Section: Ceacam3 Evolution-a Red Queen Scenario At Workmentioning

confidence: 99%

CEACAM3—A Prim(at)e Invention for Opsonin-Independent Phagocytosis of Bacteria

et al. 2020

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Phagocytosis is one of the key innate defense mechanisms executed by specialized cells in multicellular animals. Recent evidence suggests that a particular phagocytic receptor expressed by human polymorphonuclear granulocytes, the carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3), is one of the fastest-evolving human proteins. In this focused review, we will try to resolve the conundrum why a conserved process such as phagocytosis is conducted by a rapidly changing receptor. Therefore, we will first summarize the biochemical and structural details of this immunoglobulin-related glycoprotein in the context of the human CEACAM family. The function of CEACAM3 for the efficient, opsonin-independent detection and phagocytosis of highly specialized, host-restricted bacteria will be further elaborated. Taking into account the decisive role of CEACAM3 in the interaction with pathogenic bacteria, we will discuss the evolutionary trajectory of the CEACAM3 gene within the primate lineage and highlight the consequences of CEACAM3 polymorphisms in human populations. From a synopsis of these studies, CEACAM3 emerges as an important component of human innate immunity and a prominent example of a dedicated receptor for professional phagocytosis.

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The future of humans as model organisms

Abstract: A “human phenomic science” approach could accelerate personalized medicine

Cited by 34 publications

References 13 publications

Bayesian inference associates rareKDRvariants with specific phenotypes in pulmonary arterial hypertension

Bayesian inference associates rareKDRvariants with specific phenotypes in pulmonary arterial hypertension

An association between air pollution and daily most frequently visits of eighteen outpatient diseases in an industrial city

CEACAM3—A Prim(at)e Invention for Opsonin-Independent Phagocytosis of Bacteria

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