Have you ever wondered how epigenetic mechanisms influence multiple sclerosis (MS) progression and why some people experience rapid disease worsening while others have a milder course? Could there be hidden biological switches beyond genetics affecting MS? In this deep dive, I explore the fascinating world of epigenetics with Dr. Majid Pahlevan Kakhki, uncovering how factors like DNA methylation shape MS progression and treatment outcomes.
Join me as we discuss groundbreaking research on how lifestyle, environment, and molecular modifications influence MS. Could epigenetic therapies hold the key to slowing or even reversing disease progression? Read on to find out how this cutting-edge science is paving the way for more personalized and effective MS treatments.
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Introduction – Who is Dr. Majid Pahlevan Kakhki?
Sure! My name is Majid Pahlevan Kakhki, and I’m originally from Iran, specifically from the Khorasan province in the northeast of the country. My childhood was closely tied to agriculture, as I spent a lot of time working in the saffron fields alongside my parents. As I grew older, I wanted to support my education and gain independence, so I learned tailoring and became quite skilled at it. This allowed me to finance my studies while remaining self-sufficient. I pursued a Ph.D. in Molecular Genetics in Iran, and after completing my doctorate, I moved to Karolinska Institutet as a postdoctoral researcher. Since then, I have been working there, focusing on cutting-edge research in my field.
Personal motivation for your career choice?
That’s an interesting question. I’ve always been eager to learn and fascinated by new and innovative ideas. Looking back, I can see how this curiosity has shaped every step of my journey. I still remember my days as a tailor, working while constantly listening to the radio. One day, I came across a program discussing a fascinating study on brain research in animals. Just from listening, I felt an instant connection—I knew I wanted to become a researcher and explore the mysteries of the brain. Beyond that, my mother played a significant role in encouraging me to pursue education. She always wanted me to build a better future for myself, as she knew firsthand how tough life in agriculture could be. A defining moment came in high school when my teacher demonstrated a simple experiment—extracting DNA from an onion. That moment sparked my love for genetics, and from then on, I was determined to follow this path. I worked hard, pursued my studies with passion, and continued my journey in science until today.
Introduction to Epigenetics and MS
Could you explain what epigenetics is and how it differs from genetics in relation to multiple sclerosis?
Genetics refers to the DNA sequence we inherit from our parents—essentially, the „hardwired“ instructions that shape how our bodies develop and function. These genetic codes remain largely the same throughout our lives.
Epigenetics, on the other hand, is about how genes are regulated and expressed without altering the actual DNA sequence. It involves biochemical modifications, such as DNA methylation and histone modifications, which can turn genes on or off in response to environmental factors, lifestyle, and even disease processes.
In the context of multiple sclerosis (MS), traditional genetics has identified specific gene variants that increase a person’s susceptibility to the disease. However, genetics alone doesn’t fully explain why some people develop MS while others don’t, or why symptoms and disease progression vary so much between individuals.
This is where epigenetics plays a crucial role. Research suggests that environmental factors—such as infections, smoking, diet, and stress—can influence the epigenetic landscape of immune cells and brain cells, potentially triggering or exacerbating MS. By studying epigenetic changes, we can better understand disease mechanisms and identify new therapeutic targets to slow or even prevent MS progression.
What is DNA methylation and what role does it play in regulating genes that might influence the progression of MS?
DNA methylation is one of the key epigenetic mechanisms that regulate gene activity without altering the DNA sequence itself. It involves the addition of a methyl group (-CH₃) to specific sites on DNA, usually at cytosine bases in CpG sites. This modification can act as a switch, turning genes on or off depending on the context.
We believe, in multiple sclerosis (MS), DNA methylation plays a crucial role in influencing disease progression. MS is an autoimmune disease where the immune system mistakenly attacks the protective myelin sheath around nerve cells. Changes in DNA methylation can affect the activity of genes involved in immune responses, inflammation, and neural repair.
For example, abnormal methylation patterns in immune cells can lead to an overactive immune response, increasing inflammation and contributing to nerve damage. Similarly, changes in neural cells might impair their ability to repair myelin, affecting disease progression.
By studying DNA methylation in MS patients, researchers aim to uncover biomarkers for disease progression and potential therapeutic targets. The exciting part is that, unlike genetic mutations, epigenetic modifications like DNA methylation are potentially reversible, which opens up possibilities for new treatments aimed at modifying gene activity to slow or even halt MS progression.
One of the most fascinating aspects of DNA methylation is its dynamic nature, which makes it highly relevant in health and disease. It has three important features:
- Sensitivity – DNA methylation changes rapidly in response to environmental factors such as diet, stress, smoking, and infections. This allows cells to adapt to different conditions.
- Reversibility – Unlike genetic mutations, methylation patterns can be modified and even restored to normal, which makes it a potential target for therapeutic interventions.
- Stability – Once established, DNA methylation marks can remain detectable for long periods, making them useful as biomarkers for studying past exposures or predicting disease risk.
Genetic Factors and MS Progression
How do genetic variations at the 1q21.1 locus contribute to the risk and progression of primary progressive MS (PPMS)?
One of the main goals of genetic research in multiple sclerosis (MS) is to identify specific genetic differences between individuals with MS and those without the disease. By doing so, we can pinpoint genetic variations that may contribute to MS pathogenesis.
In our study, we took a slightly different approach by focusing on epigenetic factors, particularly DNA methylation, and comparing them between MS patients and healthy individuals. What we found was that in primary progressive MS (PPMS) patients, there were distinct differences in DNA methylation levels, suggesting an epigenetic influence on disease progression.
Through extensive analysis, we discovered a link between genetic and epigenetic mechanisms at the 1q21.1 locus on chromosome 1. Specifically, we found that certain genetic variations enriched in PPMS patients influence epigenetic factors, which in turn regulate gene expression. These changes ultimately affect neuronal function and may contribute to disease progression.
This finding highlights the complex interplay between genetics and epigenetics in MS, emphasizing the need for further research to explore how these mechanisms can be targeted for potential therapies.
How do specific genes like CHD1L and PRKAB2 influence the progression of MS?
Our genome contains over 20,000 genes, each playing different roles, but we still have a lot to learn about how they work together to regulate specific biological functions. In the case of multiple sclerosis (MS), certain genes have been identified as key players in disease progression.
Our research showed that CHD1L is involved in neuronal function. We demonstrated that CHD1L is regulated by DNA methylation, an epigenetic mechanism that can influence its activity. We found that altered methylation patterns at this gene can impact neuronal function, potentially contributing to MS progression.
To better understand its role, we tested CHD1L in neurons derived from stem cells in the lab and also in Zebrafish models, which provided further evidence of its involvement in neurodevelopment and repair mechanisms. Interestingly, the same genomic region where we identified CHD1L has also been linked to other brain-related disorders, including autism and schizophrenia, suggesting a broader neurological significance.
These findings highlight how genetic and epigenetic factors work together to influence MS progression, offering new potential targets for future therapies.
In what ways could these findings on DNA methylation and gene expression potentially lead to better understanding or treatment options for MS?
While we now have several effective treatment options for relapsing-remitting MS (RRMS), there are still very few options for treating progressive MS. One of the main reasons for this is our limited understanding of the mechanisms driving MS progression, particularly in the brain. The brain is a highly protected and complex organ, making it difficult to study in detail.
Our research focuses on uncovering hidden aspects of the genome, particularly through epigenetics, which adds another layer of information beyond genetics alone. By studying DNA methylation and gene expression, we can gain insights into how environmental and molecular factors contribute to MS susceptibility and progression.
By integrating genetic, epigenetic, and molecular data, we can move closer to identifying key regulatory pathways involved in MS. This knowledge could lead to:
- Biomarkers for Disease Progression – Identifying methylation patterns that predict disease severity and progression.
- Personalized Treatment Approaches – Developing therapies that target specific epigenetic changes, potentially reversing harmful modifications.
- New Drug Targets – Understanding how gene regulation affects neuronal survival and immune function, helping to develop more effective treatments for progressive MS.
By shedding light on these previously unexplored regulatory mechanisms, we hope to pave the way for new therapeutic strategies that could slow or even stop MS progression in the future.
Clinical Implications for MS Patients
Could these genetic and epigenetic markers lead to more personalized treatment plans for MS patients in the future? And how far or near is this practical use away?
Absolutely. Genetic and epigenetic markers have the potential to revolutionize MS treatment by enabling personalized medicine, where therapies are tailored to an individual’s unique genetic and molecular profile. Right now, most MS treatments follow a one-size-fits-all approach, but we know that not all patients respond the same way to the same treatments. By identifying specific genetic variations and epigenetic modifications, we could better predict:
- Who is at higher risk for developing MS
- How aggressively the disease might progress
- Which treatments are most likely to be effective for a given patient
For example, if a patient has specific DNA methylation patterns associated with more severe MS progression, doctors could adjust their treatment strategy earlier to slow down the disease. Similarly, understanding how epigenetic regulation affects immune and neuronal function could lead to new drug targets that modify gene activity to better control MS.
As for how close we are to clinical use, we are still in the early stages of translating these findings into practical treatments. While biomarker discovery is advancing rapidly, implementing personalized treatment plans based on these markers will require large-scale clinical trials and further validation. Realistically, we might see biomarker-based diagnostics and risk assessment tools within the next 5-10 years, but fully personalized treatment strategies could take longer—perhaps 10-20 years before they become routine in clinical practice.
However, the progress in AI-driven data analysis, genome sequencing, and epigenetic therapies is accelerating this process. With continued research and investment, we are moving toward a future where MS treatments are not just reactive, but proactive and tailored to each patient.
Epigenetic Therapies and Future Prospects
How might techniques like CRISPR or other epigenome-editing tools be used to correct harmful epigenetic changes in MS patients?
CRISPR and other gene and epigenome-editing tools are advancing rapidly, and we now understand them much better than before. While these technologies are not yet ready for routine clinical use in MS treatment, we believe that in the near future, they could become powerful therapeutic options.
Of course, safety is the top priority. Before these methods can be applied in humans, we need to ensure that they are precise, reliable, and free of unintended side effects. However, the potential is huge.
In our research team, we are actively working toward this goal. Our approach is to:
- Identify key genes and epigenetic marks involved in MS progression.
- Use gene and epigenome-editing tools to correct harmful modifications in the lab.
- Test the effects of these corrections in cultured cells and animal models to see if they restore normal function.
One exciting method we are developing is the creation of personalized disease models. By taking cells from an individual—either from blood or skin—we can reprogram them into neurons and create a “mini-brain” in a dish. This allows us to test how epigenome-editing techniques affect the patient’s specific genetic background before considering any clinical application.
While clinical use is still years away, the ability to precisely edit epigenetic changes could eventually lead to highly personalized therapies, offering new hope for MS patients, especially those with progressive forms of the disease.
Broader Impact of Epigenetic Research
Could the findings in this study help explain why conventional immunotherapies are often less effective in patients with progressive forms of MS?
Yes, absolutely. One well-known fact in MS research is that inflammation plays a dominant role in the early stages of the disease. When MS begins, there is a strong immune response in the blood, which has been extensively studied over the years. This is why most current MS treatments—which target the immune system—are effective in these early relapsing-remitting stages. Since inflammation is a common feature of many autoimmune diseases, we often benefit from research on other conditions as well.
However, progressive MS is different. In these forms, the primary issue is not ongoing inflammation in the blood but rather neurodegeneration—the gradual loss of neurons in the brain and spinal cord. This is a major challenge because:
The brain is highly protected, making it difficult to study and target directly.
Current immunotherapies work by suppressing inflammation in the blood, but they do not effectively address the mechanisms of neuronal loss in progressive MS.
In our recent study, we focused on the connection between the immune system and the brain. We identified epigenetic markers in the blood that correlate with changes in the brain, particularly affecting neuronal function. These findings suggest that while inflammation starts in the blood, it eventually influences neurodegeneration in the brain, which becomes the driving force in progressive MS.
This could explain why immunotherapies that are effective in the early inflammatory phase of MS fail to stop or slow disease progression. To develop better treatments for progressive MS, we need to move beyond immune-targeted therapies and focus more on understanding and protecting neurons.
What role do environmental factors (e.g., smoking, diet, stress) play in influencing epigenetic changes?
Environmental factors play a critical role in shaping our epigenetic landscape, including DNA methylation patterns, which can influence gene expression and disease progression. Unlike genetic mutations, which are fixed, epigenetic modifications are dynamic and reversible, meaning they can change over time in response to lifestyle and environmental exposures.
Several key environmental factors have been linked to epigenetic changes relevant to MS:
- Smoking
- Diet
- Stress
- Physical activity
Can lifestyle adjustments complement medical treatment?
Absolutely. While current MS treatments mainly target the immune system, incorporating lifestyle modifications could help improve long-term outcomes by influencing epigenetic regulation. For example:
Quitting smoking A well-balanced diet Stress management techniques may counteract harmful epigenetic changes that contribute to neurodegeneration.
These lifestyle adjustments won’t replace medical treatments, but they can work alongside them to provide a more holistic approach to managing MS. Since epigenetic modifications are reversible, targeting them through both therapy and lifestyle changes might open new possibilities for slowing disease progression and even restoring normal gene function.
Quickfire Q&A Session
Complete the sentence: "For me, multiple sclerosis is...."
„For me, multiple sclerosis is a condition that, while still challenging, is no longer as severe as it once was. With the rapid progress in research and new treatment strategies, I believe we will hear very good news in the near future.“
What development would you like to see in the field of multiple sclerosis in the next 5 years?
Any medication that can control MS progression.
Farewell
Finally, what message of hope or encouragement would you like to share with the listeners?
„Don’t give up. I know that some days can be tough, but please remember that researchers around the world, including myself, are working hard to find better treatments and solutions for you. I truly believe that one day, we will hear the news that MS is cured, and we’ll be able to focus our research on curing other diseases.“
How and where can interested people follow your research activities?
I have a LinkedIn profile (https://www.linkedin.com/in/majid-pahlevan-kakhki) and also the Karolinska Institute (https://ki.se/en/people/majid-pahlevan-kakhki) webpage where our research is reported.
Many thanks to Majid and his colleagues for all the valuable research they are doing and the insights provided into it today.
See you soon and try to make the best out of your life,
Nele
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