Beyond the Paper: A Conversation with Dr. Paul Baudin

Interviewed by Dr. Paige N. McKeon, September 13, 2023

In their paper, Baudin and colleagues investigated autoimmune encephalitis, a condition in which the immune system attacks the brain and can induce epileptic seizures not treatable by conventional epileptic therapeutics. While these seizures have been associated with antibodies that target a protein (leucine-rich glioma inactivated 1 or LGI1) to ultimately alter potassium and glutamate receptor expression, a direct causal link between the two has not been demonstrated. The authors injected immunoglobulins of patients, containing autoantibodies for the protein, into the two main brain regions affected by the disease of rats. They found via multisite electrophysiology that neither acute nor chronic injections led to epileptic responses. Their negative data demonstrate that this method is not an effective way of targeting the protein, and thus critically inform the methodology to be used in future studies.

Paul Baudin, PhD.

Congratulations on completion of your doctorate degree back in 2021! What motivated you to pursue a PhD, and how has your PhD experience led to where you are now?

Thank you! I have always been attracted to the sciences and, after the baccalauréat, I hesitated a lot between going into medicine and other scientific studies. In the end, I decided to study medicine, and in my second year I heard about the medical-sciences double degree program. I was very happy to have this opportunity to combine the two approaches. So I entered the competitive examination for the Ecole de l'Inserm Liliane Bettencourt, an organization that promotes and finances double medical-scientific courses. I was accepted, which meant that after my third year of medicine, I was able to stop and do a Master 2 and then a PhD in neuroscience. After my PhD, I went back to medical school in my fourth year.

The experience I gained during my PhD gave me a solid grounding in methodology, science, as well as physiology and pathophysiology of the central nervous system. These are elements that are not much developed in medical studies, and which are complementary to having a complete background for medical research.

Could you tell us a little about Sorbonne Université, Paris Brain Institute – Institut du Cerveau and the work that this institute does?

The Paris Brain Institute is a neuroscience research center that brings together patients, doctors and researchers. The aim is to link advances in research with medicine, to enable, where possible, the rapid development of treatments for diseases of the nervous system, and to apply them to patients as quickly as possible. For further information, you can visit the Institute's website: https://institutducerveau-icm.org/en

What drew you to pursue this particular line of research? What are your future career goals?

I was very interested in neuroscience. The brain is the most complex organ in the human body, and we understand almost nothing about it, which makes it extremely stimulating to study. And from a medical point of view, the therapeutic possibilities are often limited, so development of fundamental research is essential.

For this reason, I wanted to find a research topic that combined both fundamental neuroscience and medicine. I was also interested in electrophysiology, which is the study of brain function through the various electrical activities that can be recorded. So, I met the team of Professors Stéphane Charpier and Vincent Navarro at the Paris Brain Institute, who work on epilepsy, which corresponds to electrical activity in the brain at its most extreme. My thesis focused on the study of epileptic seizures in autoimmune encephalitis. Autoimmune encephalitides are emerging entities in medicine, most of whose autoantibodies are of relatively recent discovery (new autoantibodies are discovered every year) and consequently for which research is still in its infancy.

When I finish medical school, I would like to be able to work as both a hospital neurologist and a laboratory researcher. In applied medical research, it is important to have some physicians who have a good understanding of the diseases and the issues involved. Seeing patients and diseases "for real" can give good ideas for research and elements to explore.

What advice do you have for young research investigators?

In my experience, learning to program has been the most useful thing I have learnt, as it has unlocked a lot of analyses. With the development of more and more powerful data acquisition tools, it is going to become almost indispensable to know programming in order to be able to carry out analyses. In fact, this is an increasingly common skill among young biology researchers. This is particularly true for electrophysiology, where methods for recording the brain's electrical activity can combine dozens or even hundreds of electrodes. However, it can be difficult because it is not necessarily part of our training.

Did the outcomes of the experiments in this paper surprise you? What challenges or surprises did you run into along the way and how did you overcome them?

Our article in eNeuro shows negative results. We did not show what we expected to find, i.e. the development of epileptic activity on contact with anti-LGI1 autoantibodies. Nevertheless, the pathogenicity of the antibodies had been shown in numerous studies, and we believe that our results are mainly due to methodological problems, which we [described] in the discussion of the article.

It was important for us to publish these results because this is a relatively classic method of studying the pathogenicity of autoantibodies, and one that applies to many autoimmune diseases. It is therefore highly likely that other teams have already attempted, or will attempt, similar experiments. With this article, it will push future research to find other methods of study.

Indeed, this is what we did when we subsequently studied the Kv1 potassium channel, which had been shown to be indirectly inhibited by anti-LGI1 autoantibodies. In an article published in Progress in Neurobiology in 2022, we showed that inhibition of this channel was sufficient to trigger epileptic seizures, and that these seizures had very similar characteristics to those of patients with the disease. We also showed the underlying electrophysiological phenomena which would explain the emergence of seizures in this context.

“The brain is the most complex organ in the human body, and we understand almost nothing about it, which makes it extremely stimulating to study. And from a medical point of view, the therapeutic possibilities are often limited, so development of fundamental research is essential.”

In your view, what is/are the most valuable contribution(s) of this paper to the field and where do you see the project going?

The major interest of this manuscript in eNeuro was to show that the methodology we used, pretty usual in the study of autoimmune diseases, does not work in the study of anti-LGI1 encephalitis. The aim is now to concentrate on developing alternative methods. In anti-LGI1 encephalitis the challenges are early diagnosis and difficult management, particularly of epileptic seizures, which do not respond to conventional anti-epileptic treatments and are responsible for long-term sequelae in patients. In my thesis work, we demonstrated the central role of Kv1 channels in triggering epileptic seizures. As a result, future studies could seek to develop anti-epileptic treatments that specifically target these potassium channels in this disease.

How was your experience with the eNeuro review process? How do you feel about the science review process in general and what do you think could be done to improve it?

The peer-review process went well and enabled us to add further clarifications to the article. It is important to have journals that publish negative results, which are part of scientific work, and which are largely under-represented in published studies. I am grateful to the eNeuro editors for helping to reduce publication bias. Peer review is important for checking the quality of articles. The problem associated with this system is the monopoly of private publishers on scientific articles and the enormous cost for laboratories both to publish and to access articles. This costs a lot of money for no reason, and limits scientific dissemination in fields where we could all benefit from sharing our knowledge. It is also one of eNeuro's great strengths to develop and promote open access research. 

Dr. Paul Baudin is currently at the Paris Brain Institute in lab of Charpier, Chavez and Navarro

Read the full article:

In Vivo Injection of Anti-LGI1 Antibodies into the Rodent M1 Cortex and Hippocampus Is Ineffective in Inducing Seizures
Paul Baudin, Delphine Roussel, Séverine Mahon, Stéphane Charpier, and Vincent Navarro