03/27/2023
This lab is challenging what we think we know about multiple sclerosis
In the pursuit of curing the incurable, neuroscientist Jessica Williams, PhD, knows that sometimes you must break the rules.
Dr. Williams and the members of her lab are challenging currently accepted knowledge of the connection between the immune system and multiple sclerosis (MS) – a disease where immune cells mistakenly attack the body’s own central nervous system.
Current treatments for early-stage MS suppress the immune system, preventing inflammation from causing any more damage. But the cells involved in the inflammatory response do more than signal to attack. During the later stages of MS, these cells play important roles in preventing further nerve damage.
Dr. Williams and her team have their sights set on discovering new treatments for this incurable disease by investigating the protective roles immune cells play in the disease’s later stages.
"Biology is never all-or-nothing – it’s dependent on time, on amount, on context,” Dr. Williams says. “The closer we get to narrowing those factors down, the better we’ll be able to inform patient treatments. We don’t want to stop something that might be beneficial.”
Take a look inside one of the labs at the Lerner Research Institute investigating multiple sclerosis to recognize Multiple Sclerosis Awareness Month. Learn more about our Neurosciences department here.
“Biology is never all-or-nothing — it’s dependent on time, on amount, on context.”
—Jessica Williams, PhD
MS is considered an autoimmune disease, where immune cells mistakenly attack the body’s own central nervous system. Immune cells induce inflammation that breaks down myelin, the protective sheath that surrounds nerves. The resulting nerve damage affects the control you have over your body and brain. There is no cure for MS – medications only slow it down.
Previous research demonstrated that cells in the immune system and the central nervous system may work together to protect the brain in MS. Now, the goal is figuring out how and why. Research from Dr. Williams’ lab showed that inflammation may even play a role in allowing new myelin to form.
“When I started in grad school, there were maybe 6 to 10 drugs available for patients,” Dr. Williams says. “Now there are almost 20 on the market, and it’s because people aren’t giving up. We’re all really pushing the field forward and developing new research techniques and working together to make huge progress.”
Studying the spinal cord
Lesions, or plaques, are areas of nerve damage or scarring. Most MS research has focused on brain lesions rather than the spinal cord, even though at least 70% of people with MS develop lesions there. But getting images of the spinal cord is difficult, Dr. Williams says.
“...people aren’t giving up. We’re all really pushing the field forward and developing new research techniques and working together to make huge progress.”
—Jessica Williams, PhD
The Mellen Center for Multiple Sclerosis maintains one of the largest MS patient tissue banks in the country. It provides a place for patients with MS to donate lesioned tissue after they die – similar to choosing to donate organs. The autopsy tissue bank includes samples from nearly 160 patients.
Many of Dr. Williams' colleagues work closely together to study aspects of neural inflammation, including Bruce Trapp, PhD, who designed the process for using tissue samples from deceased donors. When Dr. Williams was working on her PhD, her research often required her to read papers from Dr. Trapp, now her department chair.
“He’s a ‘science hero’ of mine, so it’s been wonderful to learn from him,” Dr. Williams says, “He’s very generous with his time – I've sat down at the microscope with him, and he’s read my grants and manuscripts. The resources he’s provided have just been phenomenal.”
Dr. Williams uses the samples to study spinal cord lesions in detail. Her group stains parts of the samples with different colors on microscope slides. Color-coding the cell types and anatomical landmarks makes it easier to compare healthy and MS-affected tissues under a microscope.
Examining understudied areas
The lab is also working on new ways to use these samples to study MS. They are collaborating with Kedar Mahajan, MD, PhD, a neurologist at the Mellen Center. They use an approach called “spatial transcriptomics” to closely examine how to closely examine how cells throughout the lesion carry out the instructions coded in DNA.
DNA provides the body with an instruction manual for how to act. If researchers can find the faulty instructions that cause an individual to develop MS, they can develop treatments that prevent those instructions from ever being read. These types of treatments can stop the problems before they even start, and may potentially even reverse existing problems.
The Williams Lab is also working with Dr. Mahajan to optimize MRI imaging when studying myelin damage in preclinical models.
Looking at these understudied areas can yield unexpected results. Smith published that an immune molecule called the immunoproteasome, which is known to worsen MS in the early stage, is beneficial during late-stage or chronic MS. His work suggests that commonly prescribed medications which suppress the immunoproteasome may not be appropriate when treating late-stage patients.
Victoria Anders, a technician in the lab, discovered that deleting a pro-inflammatory molecule called interferon-gamma does more than worsen nerve damage: it prevents the brain from developing properly. Existing neurons are not myelinated properly. Decoding the impact of the immune system on the intricate mechanisms of myelin formation could yield valuable information for studying myelin repair.
By pushing the boundaries of what we know about MS and the brain, research provides the knowledge behind the treatment programs that make Cleveland Clinic a national leader in MS care.
“Through working in this lab, I’ve learned not to forget the excitement – why you care about a particular disease and the experiments you’re running,” Anders says. “It’s consistently reminding yourself to go back to the ‘big picture’ of how this will help people down the line.”
