A diagnosis of Multiple Sclerosis (MS) is often made only when nerve damage is already irreversible. This disease can progress silently for decades. The question of its causes is often met with the answer: “The exact cause is unknown, but…” This is why any discovery that brings us closer to a concrete answer deserves special attention. Research from the University of South Australia promises significant progress in this very area.
Medscriptum had the unique opportunity to speak with Dr. David Stacey, a functional geneticist who is studying the risk of Multiple Sclerosis long before the disease is clinically evident. Using cutting-edge genetic methods, Dr. Stacey and his team are trying to uncover the early biological changes responsible for the disease’s development. This research allows us to better explain the complex relationship between our genes and environmental factors.
Salome Chkheidze: Your project uses a method called “recall by genotype,” which is a new approach in Multiple Sclerosis research. What distinguishes this method the most, and what advantages do you see in it?
David Stacey: Indeed, the Recall by Genotype (RbG) method uses natural genetic variants associated with a specific trait or disease to group participants based on their genetic risk. One of the main advantages of RbG is that it allows us to identify cause-and-effect relationships. We focus on participants who have not yet been diagnosed with the disease (in this case, Multiple Sclerosis) but differ in genetic risk. This allows us to determine what processes lead to the onset of the disease and to distinguish them from the mechanisms that are a consequence of the already developed disease.
RbG is also very efficient and accessible. Without prior knowledge of participants’ genotypes, a traditional study would require inviting a large number of participants to gather a sufficient sample size and statistical power. By using the RbG approach, we can observe a much smaller number of participants in the study, provided that we select them correctly and in a targeted manner.
Salome Chkheidze: MS Australia recently funded your research, which was the signal to start the project. Can you tell us what the main goal is and what questions you want this research to answer?
David Stacey: The funded project is a pilot study, so first and foremost, we hope that the results will soon help us plan a more large-scale study in the future. More broadly, we want it to help identify the early mechanisms associated with a high or low genetic risk for Multiple Sclerosis, which could lay the foundation for new treatments or early biological markers.
Salome Chkheidze: How do you plan to integrate genetic data and other environmental or viral factors in this research to better understand the predisposition to Multiple Sclerosis?
David Stacey: We will use the RbG approach to include two groups of participants in the study who differ in their genetic risk for Multiple Sclerosis. This is an approach aimed at maximizing the genetic and biological gradient. We will then compare these two groups based on parameters related to Multiple Sclerosis and the immune system. These indicators are: >1,000 proteins (~50% of which are known to be involved in immune processes) and the level of several different types of immune cells, including key B-cell subtypes. We will also compare the levels of Epstein-Barr virus (EBV) antibodies, which according to studies, is a necessary prerequisite for the development of Multiple Sclerosis.
Salome Chkheidze: The selection of participants based on their genetic profiles may be related to ethical issues. How will your team deal with these challenges, especially in terms of consent, data confidentiality, and sharing genetic risks?
David Stacey: This is an excellent question. Our two main concerns are: first, not to cause unnecessary anxiety or psychological discomfort in the participants, and second, how and in what way to return personal genetic information to the participants. We will address the first issue with clear and thoughtful communication. For example, terms like “genetic risk” are used in a “eumotive” way in scientific discourse (quite neutral when you understand what they mean) but can be confusing when we talk directly to potential study participants and the public, especially without explanatory information (for example, genetic testing is not used to diagnose Multiple Sclerosis or to clinically predict its onset). As for the second issue, within the framework of this pilot study, we will not provide participants with direct genetic information, but we will use an online survey. In this way, we will get the opinions of the participants on how and in what way it is best to share personal genetic information. One of the difficulties is related to whether providing this type of information has any practical benefits for the participants, which is highly dependent on the subject of the research—a specific disease or trait.
Salome Chkheidze: What kind of early treatment or personalized therapy could your research lay the foundation for if the project’s hypotheses are confirmed?
David Stacey: Our hypothesis is that there will be a difference in EBV antibody levels between the two groups. If this turns out to be correct, it will give us more evidence to confirm that using effective vaccines or antiviral drugs for EBV prevention or treatment may help in preventing Multiple Sclerosis. In addition, some of the planned work is more exploratory than hypothesis-driven. We will measure and compare the levels of >1,000 proteins between the two groups, which can help us identify early biological markers for Multiple Sclerosis. Early diagnosis of Multiple Sclerosis can accelerate the use of disease-modifying therapies, which may improve long-term outcomes for some people.
Salome Chkheidze: Your project is a global pioneer in “recall by genotype” research for Multiple Sclerosis. In your opinion, what impact will this approach have on future research of Multiple Sclerosis and other complex diseases?
David Stacey: This is exactly what we hope to find out in this pilot study, and MS Australia has given us a great opportunity to do so. Given that the RbG approach is well suited for identifying early precursors, we hope that this approach will help us find new treatments and early biological markers. Most importantly, we believe that RbG represents a research design with a different approach that complements existing studies (e.g., “case-control” studies) and provides another tool for verifying research results. This applies not only to the field of Multiple Sclerosis but to all other polygenic traits and diseases, and potentially to monogenic traits as well.
Salome Chkheidze: How will you define the success of this project—both from a scientific point of view and in terms of the benefits for patients?
David Stacey: The first indicator of success will be the successful engagement of participants and the completion of all visits. Given that this is a pilot study, our goal is to have a total of 24 participants (12 in each experimental group).
We will also include some “positive controls” in our measurements to ensure that proteins related to Multiple Sclerosis (e.g., NEFL, or neurofilament light polypeptide; and GFAP, or glial fibrillary acidic protein) are among the >1,000 proteins we measure. If we see differences in the levels of these proteins between the two groups (and in the expected direction), then we will conclude that we can discover biological mechanisms relevant to Multiple Sclerosis using the RbG design. However, at this stage, it is still unclear how reasonable it is to expect differences in the levels of these proteins, as they may only become apparent when the disease process has already begun. This is an interesting and useful hypothesis to test, which will help in the future use of RbG.
And finally, the main indicator of success will be whether we can obtain further funding for a more large-scale version of this pilot study.
Salome Chkheidze: How do you think collaboration with MS Australia and other stakeholders will affect the project’s results and their dissemination?
David Stacey: We will collaborate with MS Australia’s “Lived Experience Expert Panel” (LEEP) to jointly plan and define the directions of future research using the RbG approach. We are very eager to identify the specific needs of people with Multiple Sclerosis, their family members, and caregivers, so we can try to help them with this approach.
Salome Chkheidze: And finally, what was the inspiration for you and your team to start this project, and what impact do you think it will have on the lives of people with Multiple Sclerosis?
David Stacey: Our team was building a research base for “recall by genotype” in Australia, and we were looking for useful and interesting applications of this approach. Multiple Sclerosis researchers have had great success in understanding the mechanisms of the disease, especially recently, when the connection between the Epstein-Barr virus (EBV) and Multiple Sclerosis was highlighted with the help of the latest methods and technologies. Although scientists agree that the Epstein-Barr virus (EBV) may be a causative factor for Multiple Sclerosis, it is difficult to prove this unequivocally. To obtain such evidence, an effective vaccine or antiviral drug is needed, which could be tested in a randomized controlled trial. Also, there is currently no data that would allow other methods of cause and effect, such as Mendelian randomization. Therefore, we believe that RbG can make a unique contribution to the field of Multiple Sclerosis!
