Matthew Collin (Newcastle University, Newcastle upon Tyne, UK)
Year Awarded: 2023
Amount: 200,000 USD in partnership with the Leukemia & Lymphoma Society
Dr. Matthew Collin is a clinician-scientist at Newcastle University in Newcastle upon Tyne, UK. He was awarded a 2023 research grant to conduct the study Inferring the Origin of Erdheim–Chester Disease from Phylogenetic Mapping, which aims to trace the genetic mutations responsible for ECD and better understand how the disease develops at the cellular level.
Erdheim Chester Disease (ECD) is caused by mutations in the DNA of blood cells. Blood cells are formed in the bone marrow from stem cells that can live for many years producing many generations of new stem cells. The frequent questions that patients ask about ECD include: where did it come from? how long have I had it? couldn’t anything have been done sooner? why does my disease affect a particular site? Our research aims to shed new light on these important questions. The technique we will use is called ‘phylogenetic mapping’. This approach allows us to go back in time and ‘date-stamp’ the origin of mutations that cause ECD, to within a few years of a patient’s past life. The way that this works is by growing many clones of single stem cells in the laboratory and sequencing the whole genome of each clone. Each clone differs from the next by a few mutations in its DNA. Some of these mutations arose a very long time ago in the ancestors of the stem cell when the patient was younger. By sequencing about one hundred clones it is possible to reconstruct the life history of the stem cells within a person and so create a timeline of mutations as they appear over the years. Among these mutations will be the mutation that caused ECD in the patient. If we know the timeline of all of the mutations, we can ‘datestamp’ the ECD mutation. We can then estimate how long the ECD mutation lay dormant in the body, how quickly it grew to a size that could cause disease, and whether it was assisted by any other mutations on the way. These are fundamental issues. In other related diseases called myeloproliferative neoplasms, mutations arise in childhood and evolve into different types of disease depending on other events in the life of a patient, over decades. When we apply this analysis to ECD, we should be able to answer the questions about its origin. The potential benefits also include the possibility to detect ECD at an early stage before it has evolved to cause disease; to determine why there is a spectrum of affected organs in different patients; and, why some patients have higher risk disease that progresses more quickly. Finally, unraveling the ‘personal life history’ of ECD may help us in the future with personalized therapy for better outcomes.
Final Report
Erdheim Chester Disease (ECD) is caused by mutations in the DNA of blood cells. Blood cells are formed in the bone marrow from stem cells that can live for many years producing many generations of new stem cells. The frequent questions that patients ask about ECD include: where did it come from? how long have I had it? couldn’t anything have been done sooner? why does my disease affect a particular site? Our research aims to shed new light on these important questions. The technique we will use is called ‘phylogenetic mapping’. This approach allows us to go back in time and ‘date-stamp’ the origin of mutations that cause ECD, to within a few years of a patient’s past life. The way that this works is by growing many clones of single stem cells in the laboratory and sequencing the whole genome of each clone. Each clone differs from the next by a few mutations in its DNA. Some of these mutations arose a very long time ago in the ancestors of the stem cell, when the patient was younger. By sequencing about one hundred clones it is possible to reconstruct the life history of the stem cells within a person and so create a time line of mutations as they appear over the years. This is like drawing a family tree of how all of the cells are related to one another and is known as the ‘phylogeny’. Among these mutations will be the mutation that caused ECD in the patient. If we know the timeline of all of the mutations, we can ‘date-stamp’ the ECD mutation. We can then estimate how long the ECD mutation lay dormant in the body, how quickly it grew to a size that could cause disease and whether it was assisted by any other mutations on the way. These are fundamental issues. In other related diseases called myeloproliferative neoplasms, mutations arise in childhood and evolve into different types of disease depending on other events in the life of a patient, over decades. When we apply this analysis to ECD, we should be able to answer the questions about its origin. The potential benefits also include: a possibility to detect ECD at an early stage before it has evolved to cause disease; to determine why there is a spectrum of affected organs in different patients; and, why some patients have higher risk disease that progresses more quickly. Finally, unravelling the ‘personal life history’ of ECD may help us in the future to personalized therapy for better outcomes.