Embracing Complexity:
A Conversation with Olivier Hermine

Dr. Hermine is Professor of Hematology at Paris V–René Descartes/Paris-Cité University in Paris, France, and a physician trained across an impressive array of fields including immunology, molecular biology, and rare disease medicine. He directs the Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders at the Hôpital Necker–Enfants Malades and the Imagine Institute, and currently leads a research project funded by the Fisher Center for Alzheimer’s Research Foundation. He is internationally recognized for his work in hematology and for his approach to the study of neurodegenerative disease, which has taught him to be suspicious of overly tidy explanations—especially when the brain is involved.

In this conversation, Dr. Hermine reconstructs the unconventional path that has led him to research neurodegeneration, his investigation of linkages between immune cells and Alzheimer’s, as well as the challenges and the opportunities of translating immune biology into new therapeutic ideas. Along the way, he reflects on how clinical practice continues to inform his scientific thinking—and why the complexity of human biology, albeit difficult to navigate, may be our best ally in the search for a cure.

You are both a scientist and a clinician. How did you combine these two vocations?

I did not always imagine myself as a scientist. My grandfather was a blacksmith, and for a long time I actually assumed I would follow him into that world of tangible work and craftmanship. He died when I was sixteen, and that’s when I began asking questions that have never left me since: What does it mean to die? And where does identity reside when the body fails?

Even then I was struck by the centrality of the brain. Personality, memory, judgment—everything that makes us who we are depends on the brain. And once brain function is lost, survival alone no longer feels like life in the full sense. That directed my curiosity toward understanding disease at its most fundamental level, and I decided to study medicine because it offered proximity to both people and biological mechanisms.

Medical education in France at the time relied heavily on memorization, with little emphasis on understanding why diseases behave as they do. So, I compensated by pursuing additional training in biochemistry, molecular biology, and immunology. It was demanding, but it taught me to see illness not as a static list of symptoms, but as a dynamic process—one that might be questioned, dissected, and with luck eventually redirected.

How has this idea of disease as a process informed your research agenda?

A defining chapter of my formation was when I came to the United States to work as a researcher at the University of Chicago. There, I encountered an intellectual environment that was far more tolerant of risk and originality, where ideas were judged less by their conformity to existing models than by whether they could be tested. That kind of freedom left a lasting impression on how I approach my own work to this day.

After three years I returned to France, I completed my PhD and my medical residency, and I eventually came to manage my own laboratory while starting a new department of hematology at the Necker Hospital. Because of the competition in treating common diseases, I did something that surprised many of my colleagues: I decided to focus on rare diseases. There were fewer people doing this, so I’d have more opportunities to build my expertise. But what truly attracted me was the fact that rare diseases often strip biology down to its essentials. Because they are extreme, they expose mechanisms that can be less visible in more common conditions.

Working with patients affected by rare disorders also taught me something else: rarity does not mean marginality. On the contrary, rare diseases reveal how certain dysregulated pathways can reshape an entire organism. So, I became convinced that by understanding these outliers, we can gain insight not only into more common diseases, but also into fundamental aspects of human biology—and, in some sense, into human nature itself.

Did your interest in Alzheimer’s evolve from your research on rare diseases?

Yes. In medicine there is a distinction between neurological disorders and immunological disorders, which doctors take for granted but that, over time, has begun to look a bit artificial to me. If rare diseases can illuminate common mechanisms, then perhaps neurodegenerative conditions like Alzheimer’s should not be approached as isolated failures of the brain, but as the outcome of long-term biological interactions.

My specific entry into Alzheimer’s research came through immunology and hematology—and particularly through mast cells, a type of immune cell present all over the body. While working on a mast cell disorder called mastocytosis, I repeatedly encountered people whose symptoms resembled those of Alzheimer’s patients—memory difficulties, impaired attention, executive dysfunction, and depression.

So I began examining mast cells more closely. And I realized that they possess a repertoire of chemical mediators—histamine, proteases, cytokines, lipid mediators—that are capable of directly influencing different types of brain cells, including neurons, glial cells, and the neurovascular unit. In other words, mast cells have a very important neuroimmune function compared to other immune cells located outside the brain.

So, that suggested that mast cells might play a role in Alzheimer’s disease, as well?

That realization fundamentally changed my view of neurodegenerative processes. Alzheimer’s research has long been dominated by a relatively narrow focus on the accumulation of amyloid-beta plaques and tau tangles in the brain, treating the disease as a late-life pathological development. What struck me now, by contrast, was the possibility that a person’s vulnerability to neurodegeneration may be established far earlier—during brain development itself. Mast cells play a key role in regulating the interaction of brain and immune system. And if that regulation is perturbed, the brain may age along a fundamentally different trajectory.

My group at the Imagine Institute, particularly with Mirjana Weimershaus, has been investigating this hypothesis using a combination of genetic and pharmacological approaches. First, we examined what happens when mast cells are absent or functionally impaired in mice that are genetically predisposed to develop Alzheimer’s. And we observed something truly striking: when mast cells are taken out of the equation, Alzheimer’s symptoms fail to appear. This suggests that mast cells don’t merely exacerbate the effects of Alzheimer’s, but may actively participate in the development of the disease itself.

We then asked a more difficult question: Besides playing a role in early developmental stages, do mast cells also influence later stages of the disease? To explore this, we used a pharmacological mast cell inhibitor called masitinib, administering it to aged mice that had already developed Alzheimer’s. And sure enough, we observed partial restoration of cognitive function and synaptic activity. These effects were modest, but they suggest that mast cells may be a potential target for therapy, even after the appearance of Alzheimer’s symptoms.

Do you think these findings may pave the way to new kinds of Alzheimer’s treatment?

Let me be clear: I do not claim that Alzheimer’s is a “mast cell disease.” It is not. It is a network disease—one that involves neurons, glial cells, immune cells, the vascular system, as well as a person’s entire developmental history. Nevertheless, mast cells appear to occupy a strategic position within this network, as they may also in other neurodegenerative and inflammatory disorders. And that allows us to rethink not only how Alzheimer’s progresses, but also how it begins and when and how we may be able to intervene.

I believe this work forces us researchers to confront the complexity of therapeutic intervention. Masitinib, for example, does not act exclusively on mast cells. It also affects microglia and other immune cell populations—raising important questions about how treatment actually works. Are the benefits we have observed due primarily to mast cell inhibition and the release of toxic mediators and cytokines, or also to microglial modulation, or reduction of inflammation, or reduction of Tau phosphorylation —or a combination of all these effects? Biology, I have learned, rarely offers a single answer in such cases.

Our research also intersects with debates about the drawbacks of existing therapies. Anti-amyloid drugs, for instance, are frequently associated with inflammatory and hemorrhage side effects, probably due to the activation of immune and vascular mechanisms, respectively. Mast cells reside at key interfaces between blood vessels and brain tissue. So, by modulating mast cell activation, it may be possible to mitigate some of these adverse effects. This raises the possibility that mast cell-targeted therapies could also improve the safety and tolerability of existing treatments that may pave the way for new combination therapies.

How do you envision these possibilities coming to fruition in a clinical setting?

When I think about the future of my work on Alzheimer’s, I do not imagine a single decisive breakthrough. I imagine a gradual shift in perspective, reframing the disease not as an isolated neurological failure, but as the long-term outcome of biological interactions shaped over a lifetime. To make real progress, in my opinion, we must embrace complexity: immune regulation, vascular health, development, brain resilience—all these factors intersect in ways that we are just beginning to understand.

In practical terms, this means several things. Scientifically, it means pursuing combination treatments rather than singular targets—therapies that are safe, complementary, and capable of intervening at different levels of the disease process. It also means investing in predictive tools that allow us to identify vulnerability before irreversible damage occurs. Ethically and clinically, it means proceeding with humility, treating patients at all stages of the disease with the utmost care, because therapy must never come at the cost of quality of life.

I am fully aware that the kind of early intervention suggested by my research raises difficult questions at many levels—regulatory, economic, and societal. It is far easier to treat a disease once it becomes visible, as I do regularly by treating hematological malignancies, compared to acting without apparent need. And yet, waiting has its own cost. In the brain, unlike other organs, damage accumulates silently, and it is rarely reversible. If we intervene only when symptoms are unmistakable, we may already be too late.

Would you say this shift in perspective is the most urgent goal of your work?

I have always practiced medicine alongside research, and this dual perspective continues to propel my work. Early in my career I worked in intensive care, often assisting patients with severe, life-threatening illnesses. Many of them did not survive. Those experiences taught me the importance of being able to speak honestly with patients, of recognizing their fears and hopes as the ultimate measure of my efforts, and so of understanding suffering not only in scientific terms, but in personal and emotional ones as well.

Ultimately, my motivation remains the same as when I first entered medicine—to understand disease well enough to change its course, and to do so in a way that respects both patients and the complexity of what they are going through. I do not expect easy answers. I do not expect quick victories. But I’m convinced that brave and persistent inquiry is our best chance to alter the future of Alzheimer’s disease. That is what brings me to work every day, and the reason I believe that progress may be slow, but very real, and worth pursuing to the very end. And most importantly, by doing scientific work may give hope to patients and more motivations to clinicians and caregivers.