Technical Challenges to the P4 Medicine


Dr. Leroy Hood, Institute of Systems Biology, envisions a future of medicine which would be oriented to wellness, rather than healthcare. He terms it the P4 – predictive, preventive, personalized and participatory. I have earlier written a post which highlighted the promises of this revolution in medicine.

P4 medicine needs radical changes in the healthcare sector, including the curriculum of medical schools, but I would like to elaborate here the technological challenges (outlined by Dr. Hood himself [1]) that are critical for it to surface.

Founder,Institute of Systems Biology
Founder,
Institute of Systems Biology

1. Family Genome Sequencing

Dideoxy terminator sequencing developed by Sanger dominated for 30 years and was the basis for the Human Genome Project. Since then, a lot many innovations have decreased the sequencing costs. It is estimated that the sequencing costs would fall 100,000 times between 2009 and 2013. Oxford Nanopore Technologies would soon launch MiniIon, a $900 disposable sequencer the size of a USB pen drive, which is expected to work well on smaller genomes or portions of the human genome. A larger version, GridIon is priced at $30,000. These are the first devices to use Nanopore sequencing wherein a DNA strand is read as it is pulled through a nanoscopic hole [2]. Using 20 GridIons together, a human genome could be sequenced in 15 minutes at around $1,500.

Individual genome sequencing would be a regular affair in the future healthcare scenario with the ever falling ease and price. Having the genome sequences of all family members would enable a physician to track a disease across space and time. Genome sequences would also tell the effectiveness of a drug on a particular individual, a field termed as pharmacogenetics. The best possible drug for an individual would be his “actionable gene variant” [1] for that particular disease. They would, in fact, facilitate development of drug targets for personalized medicine.

2. Proteomics

The human genome has around 20,000 protein coding genes. But, all the cells in our body combined contain millions of different proteins. This diversity results from a variety of post-translation modifications, phosphorylation, ubiquitination and other mechanisms. The proteome, coined by Marc Wilkins, is the entire complement of proteins, produced by an organism or system. It varies with time, requirements or stresses that a cell or organism undergoes.

Mass spectrometry has long been used for protein analysis, ranging from global expression profiling to identifying protein complexes and post-translational modifications. Recently, Selected Reaction Monitoring Mass Spectrometry (SRM-MS) has enabled targeted quantification of proteins wherein specific analytes are targeted in a data-directed mode [3].

Improvements in SRM-MS would facilitate discovery of biomarkers that can be fluorescent-tagged for disease prognosis. Jim Heath at Caltech has developed a microfluidic protein ELIZA chip [4] that can make 50 measurements in 5 minutes from 300 nL blood.

3. Metabolomics

Mass spectroscopy and gas/liquid chromatography have long been the choice for detection of critical metabolites. They are now being combined with pattern recognition array sensors to develop non-invasive diagnostic devices. Identification of selective patterns of volatile organic compounds in exhaled breath could be used as a biomarker of inflammatory diseases, including lung cancer.

An electronic-nose (e-nose) is an artificial sensor system that combines arrays for detection and algorithm for pattern recognition [5]. Development of more such innovations would lead to patient-friendly non-invasive diagnosis.

4. Single Cell Analysis

Micro-Arrays for Mass Spectrometry (MAMS) is an analytical platform for high-throughput analysis of single cells by MS. It involves unsupervised aliquoting of cell suspension into discrete recipient sites and the aliquoting effect is achieved due to the differences in wettability of the recipient sites and the surroundings [6].

Analysis of single cell gene expression would lead to better understanding of human disease parthogenesis and important diagnostic applications [7]. Better techniques to study cells at individual levels, including better imaging, would be crucial in solving the mysteries of gene regulation.

5. Imaging

Ever since Robert Hooke first observed cork cells, the biological world has been much indebted to the increasing resolution offered by microscopes – light, confocal, scanning acoustic, electron and scanned probe. The fact that most of the cell organelles have been named on their appearance, rather than their function (lysosomes are exception as their biochemical functions were discovered first and they themselves, later), is indicative of how crucial microscopy has been to the field.

Atomic force microscopy, currently the best with a resolution in a few nanometers, uses a metal-and-diamond probe which moves along the specimen surface to give a three-dimensional image of the specimen. An emerging technique, laser-sheet-based fluorescence microscopy field (LSFM) allows high resolution, non-destructive visualization of biomedical objects through optical sectioning with sheets of laser light [8].

6. Induced Pluripotent Stem Cells[9]

iPS cells were first developed by Dr. Shinya Yamanaka, Kyoto University, in 2006 for which he was awarded this year’s Nobel in Medicine. They provided an alternative to the highly debated embryonic stem cells. They have been used in regenerative medicine to find cures to Parkinson’s disease, spinal cord injury, platelet deficiency and macular degeneration. Patient or disease specific iPS cells have been utilised to devise drug candidates or model diseases.

Attempts at directly reprogramming from one somatic line to other have met with some success. The efficiency of converting mature cells into pluripotent remains lesser than 1%. Poorly understood stochastic events seem to be required for full programming to occur.

References

  1. Hood, L., Bailing, R. and Auffray, C, Revolutionizing medicine in the 21st century through systems approaches, Biotechnology Journal, 2012, 7:992-1001. doi: 10.1002/biot.201100306
  2. McGinn, S., Gut, G., DNA sequencing- spanning the generations, , New Biotechnology, 2012, doi: 10.1016/j.nbt.2012.11.012
  3. Elschenbroich, S., Kislinger, T..Targeted proteomics by selected reaction monitoring mass spectrometry: applications to systems biology and biomarker discovery, Mol. BioSyst., 2011, doi: 10.1039/C0MB00159G
  4. Wang, J., Ahmad, H., Shi, Q. et al., A self-powered, one-step chip for quantitative and multiplexed detection of proteins from pin-pricks of whole blood, Lab Chip, 2010, 10, 3157-3162
  5. Montuschi, P. et al., The electronic nose in respiratory medicine, Respiration, 2012
  6. Zenobi, R., Mӓdler, S. et al.,High-density micro-arrays for mass spectrometry, Lab Chip, 2010, 10, 3206-3209, doi: 10.1039/C0LC00211A
  7. Todd, R., Margolin, D., Challenges of single cell diagnostics:  analysis of gene expression, Cell, 2002
  8. Adriaens, D., Descamps, E. et al., The OPFOS Microscopy Family: High resolution optical sectioning of biomedical specimens, Anatomy Research Intl., 2012, Article ID 206238, doi: 10.1155/2012/206238
  9. Yamanaka, S., Induced Pluripotent Stem Cells: Past, Present, and Future, Cell Stem Cell Journal,  2012, doi: 10.1016/j.stem.2012.05.005
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9 thoughts on “Technical Challenges to the P4 Medicine

  1. […] would enable genome based prediction of complex disorders. Hers was the talk that I enjoyed the most due to my inclination towards systems medicine and here is a brief review of it. Predictive medicine aims to either individually predict disease occurrence or to individually predict further disease course in already diseased patients. The technical challenges to predictive medicine have been outlined in one of my earlier posts here. […]

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