Answer ALS is using multi-omics (omics) analysis – novel methods of biological analytics and robotic imaging to comprehensively assess every aspect of motor neuron function in healthy people and ALS patients, from genome to epigenome, RNA, proteins and cellular metabolism.
Our omics process begins with an in-depth analysis of participant DNA (genomics). The genome is a blueprint and determines everything from the color of our hair to our disease predisposition.
Next we will look at participants’ epigenome. The epigenome helps to determine which genes are expressed within a cell. If you think of DNA as the roads on a map, then your epigenome would be the traffic lights and road signs—a set of instructions that tell your cell if and when to express various genes. While some aspects of the epigenome are inherited from parents, others can be influenced by lifestyle and environment. We want to understand if changes in how DNA is regulated could be linked to the ALS disease process.
We also will analyze other “omics” that will tell us more about how motor neurons from people with ALS are actually functioning. What genes are they expressing? What proteins are they making? And following cellular activity, what breakdown products do motor neurons produce?
Integrating results from this multi-omics approach will provide an unprecedented level of analysis that will help us to identify new mechanisms of disease initiation and progression, as well as revealing new targets for diagnosis, prophylaxis and treatment. In short, we hope to use these results to find an answer to an individual's type of ALS. Answer ALS is where Big Data meets Precision Medicine.
The human genome is made up of DNA (deoxyribonucleic acid), a very long and winding molecule that contains the instructions needed to build and maintain cells. Genomics is the study of the genome within an organism. Genomics involves the sequencing and analysis of DNA. In contrast to genetics, which refers to the study of individual genes and their roles in inheritance, genomics uses high throughput DNA-sequencing and bioinformatics to assemble, and analyze the function and structure of entire genomes.
Transcriptomics is the study of an organism’s transcriptome. For the instructions in DNA to be carried out by the cell, DNA must be “read” and transcribed into RNA (ribonucleic acid). These gene readouts are often referred to as RNA transcripts. The transcriptome is a collection of all the RNA transcripts present in a cell. The major type of RNA, called messenger RNA (mRNA), plays a vital role in making proteins. DNA can also be transcribed into other types of RNA that do not code for proteins. Such transcripts may serve to influence cell structure and to regulate genes. RNA-Seq is an assay being used in this study to sequence the transcriptome of motor neurons.
Epigenomics is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome. Epigenomics identifies functional regulatory sites involved in driving transcriptional changes associated with ALS. The field is analogous to genomics and proteomics, which are the study of the genome and proteome of a cell. ATAC-Seq is a relatively new transposase-based, deep sequencing based epigenomic assay used to assess chromatin accessibility and identify functional regulatory sites involved in driving transcriptional changes associated with cell responses to perturbations. For more on Epigenomics please visit the fact sheet from the National Institute for Health, National Human Genome Research Institute
Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions.The proteome is the entire set of proteins that are produced or modified by an organism or system. This varies with time and distinct requirements, or stresses, that a cell or organism undergoes. A data-independent acquisition (DIA) method will be used to compare protein abundance in control and ALS samples. We perform SWATH-MS (Sequential Window Acquisition of all THeoretical fragment ion spectra by Mass-Spectrometry), a data-independent acquisition (DIA) method.
Metabolomics is the scientific study of chemical processes involving metabolites. Specifically, metabolomics is the “systematic study of the unique chemical fingerprints that specific cellular processes leave behind”, the study of their small-molecule metabolite profiles. The metabolome represents the collection of all metabolites in a biological cell, tissue, organ or organism, which are the end products of cellular processes. Mass-spectrometry is used to establish the “chemical” fingerprint of motor neurons from ALS patients and health controls.
Automated robotic microscopy (RM) is used to identify and track live individual neurons in a high throughput and high content fashion over time. Automated image analysis is used to quantify intermediate changes in the physiology of a given cell and relate it to that cell’s fate. From these measurements, multivariate predictive dynamic models of cell fate are constructed that weigh co-variates based on the magnitude and nature of their predictive power. These models offer a signature of the cell’s biology and a blueprint for rational therapeutic interventions.