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Editorial
Open Access | 
10.1172/JCI186113
The first century of JCI and beyond
Elizabeth M. McNally, Editor in Chief
Find articles by McNally, E. in: JCI | PubMed | Google Scholar
Published October 1, 2024 - More info
J Clin Invest. 2024;134(19):e186113. https://doi.org/10.1172/JCI186113.
© 2024, McNally et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
This issue marks the 100th anniversary of the Journal of Clinical Investigation (JCI). First published in October 1924, the JCI is the flagship journal of the American Society for Clinical Investigation (ASCI). The ASCI was formed in 1909, as a medical society of physician-scientists dedicated to better understanding mechanisms of human disease or what was defined as “The Science of Clinical Medicine” (1). Issues from the early years of the JCI described fundamental physiological mechanisms relying on observations made in humans or relevant animal species. Physiological discoveries were viewed as essential to gaining insight to active biomedical processes, and the emphasis on physiology in the early 1900s stood in contrast to the descriptions gleaned from autopsies, which were viewed as “last century” and even “the science of the dead.” As a society, the ASCI embraced a membership of investigators who were themselves active as physicians and scientists, emphasizing the role of experimentation and relying on new methods and modern techniques. Concomitant with this membership, the goal of the JCI was aimed as not only describing laboratory findings, but emphasizing papers on control and cure of disease.
One hundred years later, in 2024, the JCI retains this scope by publishing studies that uncover mechanisms of disease, identify potential therapeutic targets, or demonstrate the utility of disease targets in changing disease outcomes. When the JCI was established a century ago, the Journal’s founders felt there was not a home for this type of investigation and that publishing in the existing journals was too slow, limiting the dissemination of critical scientific information. On its 100th birthday, the JCI retains its core mission but through a modern lens, especially with respect to human investigation.
To recognize the many achievements of modern experimental medicine and emphasize the role that the JCI has played in these advancements, throughout this year we have been publishing a series of 100th anniversary Viewpoints, highlighting key discoveries from the past century. The Viewpoints cover topics mostly from the last 50 years, because it is these discoveries that have especially transformed human health and extended human lifespan. In selecting topics for these Viewpoints, the Editorial Board was drawn to many of the JCI’s most highly cited papers. These papers and others are notable for laying essential molecular foundations defining the science of clinical medicine and for the impact of the discoveries on human health.
The Viewpoint by Brown and Goldstein spotlights the JCI’s highest cited paper from 1955, which details the fractionation of lipoproteins in human serum and the application of this method to define LDL and HDL, opening up the field of human lipid biology (2). On this topic, I want to highlight a paper I find particularly intriguing that was not cited in their Viewpoint (mostly because we limit the references in these Viewpoints). In 1973, Dr. Goldstein described the inheritance patterns of serum lipid profiles in probands who survived myocardial infarction and their family members (3). As critical as the development of an assay is to the field, so is the ability to link clinical findings with laboratory tests. In this case, the authors evaluated over 2,500 participants, and from these data, they constructed pedigrees that demonstrated at least 5 distinct disorders, including familial hypercholesterolemia (FH), familial hypertriglyceridemia, and familial combined hyperlipidemia. The authors concluded that approximately 1 of every 160 individuals may carry one of these genes, underscoring the contribution to public health of these genetic findings. This paper brings together clinical medicine, laboratory science, and genetics, before the advent of modern human genetic methods. It was fibroblasts from patients with FH that enabled the subsequent identification of HMG-CoA reductase with the role of the LDL receptor and the eventual discovery of the inhibitors that would become statins. The more recent demonstration of PCSK9 inhibitors also derived from similar human genetic data, noting naturally occurring forms of PSCK9 loss-of-function mutations connected to intrinsically lower cholesterol (4).
Another Viewpoint outlines the discovery of the incretin pathway, especially glucagon-like peptide-1 (GLP-1) (5). The drugs that act on these pathways are currently transforming medicine, similar to the impact of statins on lipid management. The Viewpoint by Daniel Drucker recounts the critical papers in JCI over the 30 years that helped define the sites and modes of action of the GLPs for treating diabetes and control of gastric emptying and food intake (5). While initially approved to treat diabetes, GLP-1 receptor agonists impact appetite and gastric emptying as well has having effects on vascular health and inflammation. Perhaps even more interesting is their impact on obesity, which has gained the attention of the public, government, and industry for its potential reach to many aspects of health and lifestyle.
Papers in the JCI have had remarkable impact in nearly all branches of medicine, from neurodegeneration to novel cancer treatments to cardiovascular and renal health and infectious diseases. For example, in 1986, the elevation of natriuretic peptides in patients with heart failure was reported in the JCI (6), and today these tests are now routinely used to risk stratify and manage patients from the emergency room to the outpatient setting. More than 20 years ago, a JCI paper described the role of hypoxic mucous plaques in promoting Pseudomonas aeruginosa infection in cystic fibrosis (CF) (7), and it was observations like these that began to extend the lifespan of patients with CF. The JCI reported the importance of triple-negative breast cancer subtypes and specifically the role of targeted therapies (8), providing early rationale for precision therapies in cancer management and for this very high-risk group of patients with breast cancer. The JCI also published landmark papers on the importance of p53 in cancer and chemotherapy response, the combined effect of checkpoint blockade with radiotherapy, and improving CAR T cell–based treatment for lymphoma (9–11), with each of these contributions influencing clinical management and outcomes. In recent years, the JCI published an early report on the COVID-19 features associated with disease severity that helped guide patient management through the pandemic (12). The JCI also described the role of maternal fetal antibodies after vaccination with mRNA vaccines for SARS-CoV-2 (13).
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)