Understanding the patho-physiology of any disease is central to developing any cure against it. Current methods render this step a very laborious one. Systems approaches to disease enable a quicker, more efficient approach which can be extended to virtually every disease. Diseases are, in essence, just perturbations in the metabolite networks.
, Seattle carried out studies on neurodegeneration in mice brain after being infected by prions (infectious protein particles). They traced the mRNA expression in the brain across the 22-week period of disease progression. Differentially expressed genes (DEGs) were identified by subtracting the diseased brain transcriptomes from the control transcriptomes along 10 time points across the progression of the disease. These temporal dynamical studies revealed a few striking points:
- Along the course of the disease, 7400 RNA transcripts -encoded by nearly 1/3rd of the mouse genes- changed.
- 200 DEGs from four major biological networks appeared to participate in the disease progression with another 100 defined six smaller networks, not previously known to be involved in prion disease.
- The dynamics of transcript expression explained virtually every aspect of the pathophysiology of the disease. The same approach can be extended to reveal pathophysiology of any disease.
- The four major networks were sequentially disease-perturbed. The importance of this observation lies in new strategies for diagnosis and therapy that may focus on the most proximal perturbed-network for a particular patient.
- More than 100 brain-specific transcripts were identified -many of them coding proteins secreted into the blood- to constitute a specific blood fingerprint which could distinguish healthy brain from a disease one and the diseased ones according to the type of disease. Of these, just 15 proteins permitted early diagnosis of the disease, stratification of neurodegenerative diseases and to follow prion disease progression.
The idea is
“What we’ll be doing some 10 years in the future is we’ll have a little hand-held device that will prick your thumb, take a fraction of a droplet of blood and it will measure in your blood 2,500 proteins. Fifty of those proteins will be for each, from each of your 50 major organs. And by assessing their properties we’ll be able to say for each of those organs is it healthy or does it have disease. And if it has a disease we’ll be able to say what disease you have. And my picture is we’ll do this twice a year so you’ll have a longitudinal record across your life that follows your health as opposed to disease transitions in a most effective way”.
Jim Heath at Caltech has developed a microfluidic protein ELIZA chip that can make 50 measurements in 5 minutes from just 300 nL of blood. To detect 2500 proteins, we need to develop new, better types of protein capture agents for ELIZA assays.
Hood, L. E., Price, N. D., et al; A systems approach to prion disease, Molecular Systems Biology 5:252