W. Oost with an idea

Multiple sclerosis under the microscope: nerve cells where no one expects them

During her PhD research into multiple sclerosis (MS), Wendy Oost came across something under the electron microscope that, according to the textbooks, should not actually exist. “That moment brought my research, and my view of MS, into sharp focus.”

Oost is a researcher at the Department of Biomedical Sciences and the MS Center North Netherlands. "For this research, I worked with brain tissue from brain donors with and without MS. These brain donors are registered with the Netherlands Brain Bank in Amsterdam. About eight hours after someone dies, the brain tissue is removed for scientific research. Sometimes I would receive a call in the middle of the night from a Brain Bank employee informing me that tissue was available for my research. To get it to the UMCG, I arranged for an express courier and cycled there myself to receive the tissue and immediately start the first investigations. That felt like an enormous responsibility, because this tissue is unique and requires the utmost care and attention.’

Signals

MS is a disease in which the protective layer around nerve cells, called myelin, becomes damaged. This layer can be compared to the insulation around an electrical wire. When damaged, signals in the brain and spinal cord are transmitted less effectively. People with MS notice this in various ways in their daily lives. For example, through persistent fatigue, difficulty walking or moving, problems with vision or concentration, or loss of strength. The symptoms and their severity vary from person to person and change over time, depending on where in the nervous system the damage occurs."

Why electron microscopy?

‘For my research, I used an electron microscope, a microscope that does not use light but a beam of tiny particles called electrons. Because the accelerated electrons have a much smaller wavelength than visible light, it is possible to zoom in extremely far, to a millionth of a millimeter. This is about a hundred times further than is possible with light microscopy.’

What are those nerve cells doing there?

‘Brain tissue can be roughly divided into gray and white matter. Gray matter can be seen as the ‘thinking layer’ of the brain, where information is processed. White matter is more like a network of highways connecting different areas of the brain.

‘When I zoomed in, I came across something striking.’

My original research question was simple: can I use electron microscopy to detect differences in the undamaged areas of the brain between people with MS and people without MS? And in the damaged areas, called lesions, I expected to find mainly the already known patterns. But in some of those MS lesions, I saw something that stuck with me: a large number of nerve cells and contact points between nerve cell extensions. Normally, you find these mainly in the gray matter, not in the white matter. That immediately raised the question: what are those nerve cells doing there?

Doubt, checks, and certainty

My colleagues rightly asked, “Did you accidentally remove gray matter?” I understood their doubts very well, because it was an illogical finding. But I was 100% certain that I had examined the right areas. And as I was able to better substantiate my findings and show that this image kept recurring, my colleagues also became convinced: this was not a coincidence or a measurement error, but a discovery.

'Didn't you accidentally remove gray matter?'

Eureka
In earlier studies—using different techniques—results that matched my findings were often seen as abnormal. They were then disregarded, simply because they did not fit within the existing framework. The fact that I saw them repeatedly felt like a real eureka moment.

From discovery to follow-up research

"A new research project will soon be launched to further investigate what exactly these unexpected nerve cells do in MS lesions. Simply put: do they help the brain repair damage, or do they actually cause additional problems? By investigating this step by step, we hope to better understand why recovery in MS is sometimes successful and sometimes not. This knowledge is important because it can ultimately contribute to better treatments for people with MS."