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Quantitation of proteins and RNA in tissue samples provides some useful information, but limited insights into the underlying biology. Immunohistochemistry (IHC) analysis of specific proteins sheds some light on cells within a biospecimen but understanding the underlying pathophysiology may require analysis of spatial localizations of multiple proteins (+/- RNA species) simultaneously within individual cells. Furthermore, co-expression of multiple biomolecules in tissue samples can provide critical insights into mechanisms of drug action or disease progression.

Meet Gerard Nuovo, MD, Medical Director at Gnome Sciences (Gnome).

Dr. Nuovo is a board-certified experimental and clinical pathologist who has spent 30+ years correlating histologic features with in situ detection of DNA, RNA, and proteins. His group invented several methodologies for enhanced in situ detection of mRNA, viral nucleic acids, and microRNAs, including RT in situ PCR and the ultramer extension method. He has extensive experience with in situ co-localization of RNA/DNA molecules and proteins. Nuovo has published over 400 manuscripts, written 7 textbooks, 38 invited chapters, and has been co-PI on over 20 grants. His group was the first to show that human papillomavirus induced a type-specific immunity and one of the first to show that HIV-1 causes a massive infection prior to the development of AIDS. His group has done extensive work on molecular events that underlie the pathophysiology of infectious diseases including many peer-reviewed papers on COVID-19.

How is Gnome different?

The name is new to the market, but our team has been performing molecular pathology and tissue-based services for the biopharma industry for decades. Gnome has been providing pharmacogenomics services and COVID-19 RT-PCR testing in our CLIA certified labs. First and foremost, Gnome is a scientific company. We excel at taking on complicated studies that require scientific oversight and expertise—the kind that the usual ‘stain and send’ pathology companies frequently pass on to us. We provide dedicated teams and have regular scientific meetings with our customer partners to discuss results and recommendations.

What are some important considerations for multiplex immunohistochemistry?

It is essential to design the studies around the scientific and clinical questions being addressed, including tissue and biomarker validation, selecting the right instruments, whether biomarker quantification is required, digital imaging, and other molecular analyses.

What is antibody optimization and why is it important for IHC studies?

For specificity, IHC tissue study success requires selection of the right proteins and epitopes, antibody type (mono/polyclonal), species, and label. Specimen preparation (fixation and antigen retrieval) should be optimized for detection of simultaneous protein biomarkers.

When are biomarker co-expression studies valuable?

Diseases typically show multiple cell types expressing different markers. Understanding the co-localization of these markers using Multiplex IHC is critical to the understanding of these diseases. For example, we recently published that the hyperphosphorylated tau protein that is at the epicenter of Alzheimer’s Disease co-localizes with several anti-apoptotic proteins that may not allow these dysfunctional neurons to enter the normal neuronal turn-over pathway.

Can you give an example of a recent Gnome biomarker expression project?

We performed molecular pathology on humans who died of heart disease after COVID-19 infection and on mice treated with SARS-CoV-2 Spike protein to identify how COVID-19 caused atrial fibrillation and other cardiac effects. We showed that it is Spike protein and not infectious virus that concentrates in cardiac interstitial macrophages. This endocytosis of circulating spike protein by cardiac myocytes induces a strong proinflammatory response that includes IL6 and TNFa.  This, in turn, causes perivascular edema and, critically, abnormal migration of key intercalated disc proteins such as connexin 43 and NAV1.5 that leads to arrythmias.

 

Visit gnomedx.com to learn more or to request a free IHC antibody optimization