AFTD/Packard Center Scientific Meeting Highlights New Collaborations, New Approaches
ALS and FTD are complex diseases, with many steps in the disease pathways still unknown. But the two diseases share one major feature in common: In most cases of ALS, and most cases of FTD, vulnerable nerve cells accumulate abnormal clumps of a protein called TDP-43. Because of this common feature, researchers want to know much more about how this protein functions in healthy cells, and what role it plays in the onset and progression of both ALS and FTD.
This insight led the Association for FTD and the Robert Packard Center at Johns Hopkins, a major ALS research institution, to bring together over 30 scientists from across the United States and Canada for two days of intense discussion, to try to understand the “TDP-43 ecosystem.” Key points emerging from the meeting included the need to create new models to better understand TDP-43 in both health and disease, the importance of bringing together and sharing TDP-43 datasets and results from experiments, and the value of offering new opportunities for collaborations among ALS and FTD investigators, including both fundamental and clinical research.
“The primary goal of this meeting is to bring together people who are committed to finding the causes of and new treatments for FTD and ALS,” said Dr. Sami Barmada of the University of Michigan, who organized the meeting. “Our focus here is on a systems-level approach, in order to understand how all the parts we know about, and those we don’t yet know about, work together.”
TDP-43’s normal function is disrupted in disease
A key role played by TDP-43 in nerve cells is to regulate “splicing”. A cell uses proteins to carry out all its functions, and each protein is made using the “recipe” provided by a gene. For many genes, the recipe can be read in several different ways, producing slightly different versions of the protein. TDP-43 governs which version of the protein is made, by splicing together different parts of the recipe.
When TDP-43 clumps together, as it does in FTD and ALS, the normal regulation of splicing of all of its normal gene targets is disrupted. Several researchers at the meeting presented new findings about which targets were most affected, and what the consequences were for nerve cells. An important unanswered question is whether neurodegeneration (death of nerve cells) is due a widespread dysregulation of many different targets, or whether disruption of splicing of a few specific genes causes most of the problem. If the latter, it may be possible to design treatments that compensate for that specific disruption.
Modeling can help answer important questions
In understanding a complex system, it is helpful to create a simplified model that highlights a central feature of the system. For the TDP-43 ecosystem, models have included cellular and animal models that carry known disease-causing genes. Several researchers presented results from working with such models, and the group discussed ways to improve the models or combine them with other resources to generate new data from them.
Computer-aided modeling provides additional opportunities. This type of modeling is, for instance, how weather forecasts are created—huge amounts of data on current atmospheric conditions are combined with knowledge of physical rules and geographic constraints to create accurate predictions about the behavior of future weather systems. Similar approaches are possible in biological systems, including nervous systems. Researchers discussed what kinds of computer models could provide the most robust predictions based on the data currently available, and what types of data could be generated to improve the models. With such an approach, it may be possible to understand better the conditions that lead to TDP-43 clumping, and the various consequences of that event.
New resources can accelerate discovery
Collaboration is the engine that drives new discoveries across the scientific landscape, and a central goal of the meeting was to encourage and facilitate the kinds of conversations that lead researchers to create new collaborations and contribute to shared data resources.
Among the most pressing needs in ALS/FTD research is a centralized data repository for genomic (gene-based) and proteomic (protein-based) datasets, those already in existence and those yet to be created. And, researchers noted, to be of the most use to the widest audience, those data sets need to be “harmonized.” Two different clinical trials, for instance, might have used two different clinical scales to measure disease progression over time. Harmonizing that data would involve determining how change on one scale relates to change on the other, so that the subject groups could be analyzed together.
Data sharing and data harmonization are increasingly being recognized as key to new discoveries in rare diseases like ALS and FTD. Very large sets of clinical and genetic data can often lead to new genes or new understanding of known genes. Researchers at the meeting heard about important new data repositories set up to provide researchers around the world access to big data sets in neurodegenerative diseases, which will allow new ideas and new hypotheses to be tested by a larger group of scientists.
“We need this type of centralized resource for ALS/FTD related datasets and experiments,” Dr. Barmada said. “We need to encourage their use and we need to make them easy to use.”
Susan Dickinson, Chief Executive Officer of the Association for FTD, put it this way: “We welcome new researchers and new ideas to help solve this very old problem. This meeting is an important coming together of people who know this field well, and people whose expertise can bring something new and important to it.”