Marc Humbert : Pulmonary Arterial Hypertension, The Battle of a Committed Doctor
Inserm Grand Prize winner, lung specialist and researcher Marc Humbert has devoted his career to deciphering the mechanisms of pulmonary arterial hypertension. From disease characterization to the creation of registries, his research has transformed patient care, paving the way for innovative therapies such as sotatercept – a current source of hope.
One of the world’s leading specialists – if not the specialist – in pulmonary arterial hypertension (PAH), the Inserm Grand Prize pays tribute to Marc Humbert’s entire career. Characterization of the disease, creation of a national registry, development of innovative treatments... the unit director has made numerous contributions to fighting this disease. And despite a difficult field of study and medical practice, he remains enthusiastic.
Coming from a family of engineers, teachers and rural doctors, Humbert opted for the third path: he would become a doctor, but one committed to research, innovation, and teaching! Very early on, pulmonology became the obvious specialty to go for: « My internship in pulmonology at Antoine-Béclère Hospital (AP-HP) in Clamart made a great impression on me, through the quality of care and through the human and friendly ties between patients and medical staff. »
A decisive postdoctoral internship
After his specialized pulmonology studies and PhD in immunology, his mentors at the time – Pierre Duroux and Gérald Simonneau – advised him to do a postdoctoral internship abroad. He spent two years in London, where he studied the molecular and cellular basis of bronchial inflammation in asthmatics. “I did a lot of tissue analysis and reported new techniques: when I returned to France in 1995, I was ready to create my laboratory, he reports. I came back transformed by London and Imperial College, with which I continue to collaborate: I had been introduced to some of the major questions of medical research. » « We are enriched only by experience, » adds Humbert who is now a research director and hosts many students, specifying that « all countries are welcome ».
Humbert then wished to explore in depth the mechanisms of PAH. “The disease is caused by obstructive remodeling of the small pulmonary arteries and is characterized by a gradual increase in pulmonary arterial pressure that leads to right-sided heart failure, » summarizes the researcher. Its prevalence is 15 to 50 cases per million inhabitants, which corresponds to a few thousand patients in France. One of the problems with this disease is that its symptoms are not very specific at first, such as shortness of breath on exertion and fatigue. Yet it is life-threatening, and when diagnosed, results in death within three years! At least that was the case 30 years ago.
Back then, PAH was a so-called « orphan » disease: there was no known causative gene, or any specific treatments. « Only vasodilators and lung transplantation provided relief to patients. It was not until the 1990s that dedicated treatments were introduced, but they had to be administered by continuous intravenous infusion.”
Data bank and registries
Everything remained to be discovered, and that is what Humbert did. Over the years, he set up a database and a collection of lung tissue from patients with PAH or other forms of pulmonary hypertension. It contains lung tissue explants, lung biopsies, blood samples, and patient-related clinical and genetic data.
In the Department of Pulmonology and Respiratory Intensive Care that he leads at Bicêtre Hospital (AP-HP), he and his colleague Olivier Sitbon have also built one of the world’s largest pulmonary hypertension registries, with over 18 000 cases recorded. This allows for robust epidemiological studies and better patient follow-up. “Of course, we have adapted these databases as regulations evolve, » he explains. The department was thus designated a « reference center » for this disease starting from the first national rare diseases plan in 2004.
Humbert also relies on experimental cell and animal models (mice, rats, pigs) to develop cutting-edge translational research within the Pulmonary Hypertension: Physiopathology and Therapeutic Innovation unit. « With Inserm, Paris-Saclay University, the Paris public hospitals group (AP-HP), and Marie-Lannelongue Hospital in Plessis-Robinson, we are fortunate to work with specialists from many disciplines: biologists, engineers, doctors, surgeons, database and health AI specialists... Interdisciplinarity is very fruitful! »
These research activities are all motivated by the desire to ensure better clinical care for patients, some of whom have become friends. He also emphasizes the essential role of patient organizations: « We have grown together, they really support us in our research. »
On the trail of inflammation
Humbert was one of the first to discuss the role of inflammation in pulmonary hypertension: “At congresses where I was invited to talk about it, I was often placed last on the program…, » he recalls with amusement. What put him on the trail? The association of PAH with autoimmune diseases. Among his main discoveries, he and his team, now co-led by Christophe Guignabert, showed that dysfunction of the inner layer of the vessels is the starting point for vascular remodeling. Endothelial dysfunction that involves the recruitment of inflammatory cells and the release of cytokines and growth factors, molecules that bind to specific receptors and activate a cascade of reactions. This discovery is the basis for innovative treatments for PAH which have been tested in large international trials that he helped design, and published in international journals.
The lung specialist also shows that some PAH patients have mutations in the BMPR2 gene, which codes for a protein in the Transforming Growth Factor‑β family. This signaling pathway – a series of chemical reactions – usually regulates the proliferation and survival of cells in the lining of the lung vessels. When BMPR2 is mutated, this establishes a microenvironment that can promote pulmonary vascular remodeling.
This discovery has led to a completely new treatment that has just been proven in four successive clinical trials. Indeed, the Transforming Growth Factor‑β signaling pathway dysfunction is accompanied by the overexpression of activin, which contributes to cell proliferation. « So the idea was to inhibit activin, explains Humbert. We were contacted by a U.S. start-up, Acceleron Pharma.” The company produced artificial proteins able to block the binding of certain molecules to the activin type IIA receptors and thus limit its biological action. « So we set up a clinical research program together. »
An innovative treatment
And thus sotatercept was born. The results of a clinical trial published in March 2025 showed that adding sotatercept to the maximum tolerated standard of care for PAH reduced the risk of death, lung transplantation, and clinical worsening events requiring hospitalization and that it improved exercise capacity and functional class compared to standard of care alone. The results of the interim analysis of this therapeutic trial showed such a benefit that an independent committee requested its discontinuation so that patients in the control group – who received only the standard treatment – could benefit from the drug.
« My patients are very frail, so it was a relief to know that the treatment was generally well tolerated in the various clinical trials, even if we need to remain vigilant about long-term tolerability. What is more, it increases the level of hemoglobin – supplier of oxygen – which is also good news for PAH! » says Humbert.
Researcher, doctor and dean of the Paris-Saclay Faculty of Medicine among many other titles, Humbert says he loves to sleep. But is he able to reduce his sleep time when he gets enthusiastic, which seems to often be the case? A reason for this enthusiasm? Destination 2024. This university hospital research project, supported by the French National Research Agency as part of the Investments for the Future program, aims to promote the early diagnosis of a form of pulmonary hypertension caused by pulmonary embolism sequelae, assess its severity and propose a multidisciplinary care strategy, based on imaging, AI, biology, drug therapeutic innovation and interventional approaches using angioplasty – a medical technique used to unblock arteries. Other reasons for his enthusiasm, or rather his pride? His family – his wife and three children –, with whom he shares cultural and musical activities. When he learned that he won the Inserm Grand Prize, his first thoughts went to them. And immediately afterwards, to the extraordinary chain of solidarity of patients and their carers: thanks to them, there are now new solutions for managing a disease that remains serious but is no longer orphan. The route continues. A cure must be found for PAH.