Precision Medicine, Omics, and the Black Box

A better understanding of proteomics, genomics, and a variety of other biomarkers can help personalize patient care and shed new light on human physiology and pathology.

By John Halamka, M.D., president, Mayo Clinic Platform, and Paul Cerrato, senior research analyst and communications specialist, Mayo Clinic Platform

Some have called the human body a kind of "Black box". There is much we don’t understand about human physiology and pathology. Despite centuries of laboratory experimentation and clinical trials, it is not yet the standard of care to integrate multi-modal data - phenotype, genotype, imaging, digital pathology, and telemetry to provide personalized diagnosis and treatment.

Fortunately, tools are evolving that include a long list of omics like genomics, proteomics, metabolomics, and microbiomics. These tools are being coupled with medical imaging to develop a deeper, more personalized view of what lies within.

Here's an example. John Halamka has had glaucoma for 20 years (inherited from his father's family). He has lost 25% of the vision in his left eye despite maximal medical and surgical treatment. Why? Could it be another pathology overlaying the glaucoma? To answer this question, Mayo Clinic did orbital/brain MRIs (see the Figure), a ventricular flow study, and a brain elasticity study. These were compared to 2010 MRI images gathered as part of John's participation in the human genome project. What was found?

  • Abnormal T2 hyperintense signal in the left optic nerve
  • An abnormality of cerebrospinal fluid (CSF) flow dynamics is present of uncertain type
  • Chronically enlarged lateral and 3rd ventricles with increased size since 2010
  • Possible hyperdynamic CSF flow within the lateral and 3rd ventricles with normal flow within the aqueduct, possibly due to proximal aqueductal narrowing
  • Inferior displacement and thinning of the optic chiasm possibly related to chronic hyperdynamic CSF flow
  • MRE brain stiffness pattern that falls outside normal controls within a pattern seen in patients with abnormalities of CSF flow dynamics
  • Apparent asymmetric stiffness right vs. left of uncertain significance

These findings are chronic, have not caused any motor/sensory changes, and other than left eye visual loss over ten years have not had any consequences. In effect, these findings may represent normal variation for John. No one has ever created a gaussian distribution of the range of expected human 3rd ventricle size. Mayo Clinic Platform, leveraging its Discover product, will do that in 2022.

Although the clinical implications of John's imaging remain unknown, an analysis of his entire genome has found clinically useful insights. The genetic analysis found a liver enzyme variant called CYP2C9*2. The mutation makes him more sensitive to the anticoagulant effects of warfarin, which in turn can cause excessive bleeding if the dose is not reduced to take into account this sensitivity.

These two examples are only the tip of the precision medicine iceberg. There’s mounting evidence to suggest several biomarkers may soon be available to help clinicians recognize the onset of a stroke before it’s too late to administer tissue-plasminogen activator (tPA), the only FDA drug approved for ischemic stroke. In the field of proteomics, for instance, researchers have identified molecules that might help clinicians distinguish ischemic stroke, which causes a blood clot to form in the brain, from hemorrhagic stroke, which has the opposite effect, causing a brain bleed. Glial fibrillary acidic protein (GFAP) is rapidly released in the bloodstream during an intracerebral hemorrhage (ICH). Joan Montaner, with the Neurovascular Research Laboratory in Barcelona, and the colleagues explain that: “ A meta-analysis has shown that measurement of GFAP in the blood could discriminate between ICH and ischaemic stroke, as circulating levels of GFAP are higher in ICH. Another promising biomarker for distinguishing between stroke subtypes is retinol-binding protein 4 (RBP4). The combination of these two biomarkers improves discrimination.” If larger studies confirm these findings, these protein can serve as a blood test to give physicians a much-needed early warning system. That’s the case because tPA has to be administered within 60 minutes of the onset of the cerebrovascular accident.

The potential use of such biomarkers had generated so much interest among researchers and clinicians that it’s led to the development of an entire subspecialty: Omics Medicine. And the subspecialty is not limited to laboratory markers but also includes medical, family, and social history, prenatal genomic testing, and medical imaging.

While the human body remains a black box, new branches of molecular biology, laboratory medicine, and imaging are bringing clarity. That in turn is ushering in new ways to diagnose and manage a long list of degenerative, infectious and genetic disorders.

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