From Bench to Bedside

In this episode Dr. Matheu challenges the hypothesis of “Immunity Debt” with real-world data and well established Immunology providing a counter hypothesis to the question of “why are we all getting so sick?” by explaining how Sars-CoV-2 causes immune system dysfunction and dysregulation. The episode finishes with questions about “White Lung Syndrome” the popularized term for the uptick in severe childhood pneumonia across the northern hemisphere this winter cold and flu season (2023-24). Companion reading can be found here: LIL’ Science Substack. 

References: 

1. Immune debt: Recrudescence of disease and confirmation of a contested concept. Cohen, R. et al. Infect Dis Now. March 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9756601/#
2. Pediatric Infectious Disease Group (GPIP) position paper on the immune debt of the COVID-19 pandemic in childhood, how can we fill the immunity gap? Cohen, R. et al. Infect Dis Now. August 2021https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114587/
3. Respiratory Syncytial Virus Infection: Immune Response, Immunopathogenesis, and Treatment. Domachowske, J.B. and Rosenberg, H.F Clin Microbiol Rev. April, 1999 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88919/
4. Immunity to RSV in Early-Life Lambert, L. et al. Frontiers in Immunology. September 2014 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179512/
5. Humoral and cellular immunity to RSV in infants, children and adults Green, C.A. et al. Vaccine October, 2018 https://pubmed.ncbi.nlm.nih.gov/30177258/
6. Respiratory Syncytial Virus Infection (RSV) CDC https://www.cdc.gov/rsv/about/symptoms.html
7. “Sweden's king says 'we have failed' over COVID-19, as deaths mount” ReutersDecember, 2020 https://www.reuters.com/article/health-coronavirus-sweden-king-idUSKBN28R1IG/
8. Sweden’s Gamble: The country’s pandemic policies came at a high price - and created painful rifts in its scientific community. Science Vogel, G. October 2020 https://www.science.org/content/article/it-s-been-so-so-surreal-critics-sweden-s-lax-pandemic-policies-face-fierce-backlash
9. Influenza in Sweden – Season 2022–2023 The Public Health Agency of SwedenSeptember 2023 https://www.folkhalsomyndigheten.se/publikationer-och-material/publikationsarkiv/i/influenza-in-sweden-season-2022-2023/?pub=126761
10. RSV in Sweden – Season 2022–2023, The Public Health Agency of Sweden https://www.folkhalsomyndigheten.se/globalassets/statistik-uppfoljning/smittsamma-sjukdomar/veckorapporter-rsv/rsv-sasongen-2022-2023.pdf
11. Intensified circulation of respiratory syncytial virus (RSV) and associated hospital burden in the EU/EEA European Centre For Disease Prevention And Control, December 2022 https://www.ecdc.europa.eu/sites/default/files/documents/RRA-20221128-473.pdf
12. Notes from the Field: COVID-19–Associated Mucormycosis — Arkansas, July–September 2021,  Dulski, T.M. CDC MMWR December, 2021 https://www.cdc.gov/mmwr/volumes/70/wr/mm7050a3.htm
13. T cell response to SARS-CoV-2 infection in humans: A systematic review, Madhumita, S. et al. PLoS One, January 2021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833159/
14. A comprehensive review about immune responses and exhaustion during coronavirus disease (COVID-19), Mohammed, R.N. et al. Cell Commun Signal, June 2022 https://pubmed.ncbi.nlm.nih.gov/35655192/
15. Severe COVID-19 patients have impaired plasmacytoid dendritic cell-mediated control of SARS-CoV-2, Venet, M. et al. Nat Commun February, 2023 https://www.nature.com/articles/s41467-023-36140-9
16. The detectable anti-interferon-γ autoantibodies in COVID-19 patients may be associated with disease severity Chen, P.K. et al. Virol J February, 2023 https://virologyj.biomedcentral.com/articles/10.1186/s12985-023-01989-1
17. B lymphocytes in COVID-19: a tale of harmony and discordance Mansourabadi, A.H. Arch Virol, April 2023 https://pubmed.ncbi.nlm.nih.gov/37119286/
18. Severe COVID-19 may lead to long-term innate immune system changes, National Institutes of Health August, 2023 https://covid19.nih.gov/news-and-stories/severe-covid-19-may-cause-long-term-immune-system-changes
19. Increased Risk of Herpes Zoster in Adults ≥50 Years Old Diagnosed With COVID-19 in the United States, Bhavsar, A, Open Forum Infect Dis, March 2022 https://pubmed.ncbi.nlm.nih.gov/35392454/
20. Incidence of Epstein-Barr virus reactivation is elevated in COVID-19 patients, Bernal, K.D.E. and Whitehurst, C.B. Virus Res. September, 2023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10292739/
21. Risk of autoimmune diseases in patients with COVID-19: A retrospective cohort study, Chang, R. et al. eClinicalMedicine February 2023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830133/
22. Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection, Wiech, M. et al. Front Immunol. June 2022 https://pubmed.ncbi.nlm.nih.gov/35757700/

Welcome to Episode 2 of From Bench to Bedside where we explore the history of disease and scientific advancements leading to treatments. In this episode host Dr. Melanie Matheu (PhD) provides an introduction to the history Diabetes Mellitus, the critical advances that led us to the treatments of today, and what is next.

Corrections: 

• GLUT4 is a glucose transporter (it was called a receptor).
• Tidepool’s app for monitoring glucose was cleared by the FDA earlier this year (2023).

Biotech Companies, Resources, and Start-ups of Interest

• JDRF (https://www.jdrf.org/)
• Bigfoot Biomedical (https://www.bigfootbiomedical.com/)
• Tidepool (https://www.tidepool.org/) 
• Vertex (Bought out Viacyte: working towards curative solutions)
• OpenInsulin.org 
• PDB: Protein Data Bank (https://www.rcsb.org/)

References: 

1. International Diabetes Federation https://diabetesatlas.org/
2. Quantifying the underestimation of projected global diabetes prevalence by the International Diabetes Federation (IDF) Diabetes Atlas Tonnies, T et al. BMJ Open Diabetes Research & Care,  2021 https://drc.bmj.com/content/9/1/e002122
3. Milestones in the history of diabetes mellitus: The main contributorsKaramanou, M et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707300/
4. Aretaeus of Cappadocia (2nd century AD) and the earliest neurological descriptions https://pubmed.ncbi.nlm.nih.gov/19291658/
5. A history of diabetes mellitus or how a disease of the kidneys evolved into a kidney disease Eknoyan, G., Nagy J. https://pubmed.ncbi.nlm.nih.gov/15822058/
6. Making, Cloning, and the Expression of Human Insulin Genes in Bacteria: The Path to Humulin Arthur D Riggs https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152450/
7. The History of a Wonderful Thing We Call Insulin https://diabetes.org/blog/history-wonderful-thing-we-call-insulin#
8. Regulation of glucose transport by insulin: traffic control of GLUT4. Leto, D & Saltiel, A. R. https://www.nature.com/articles/nrm3351
9. https://en.wikipedia.org/wiki/Proinsulin
10. 
    
11. Harmonization of immunoassays for biomarkers in diabetes mellitus, Hörber. S https://www.researchgate.net/publication/331307322_Harmonization_of_immunoassays_for_biomarkers_in_diabetes_mellitus
12. Evolution of Insulin Delivery Devices: From Syringes, Pens, and Pumps to DIY Artificial Pancreas, Kesavadev, J. et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261311/
13. JDRF:  NICE program https://jdrf.org.uk/knowledge-support/managing-type-1-diabetes/guide-to-type-1-diabetes-technology/insulin-pumps/can-i-get-an-insulin-pump-on-the-nhs/
14. Integration of Islet/Beta-Cell Transplants with Host Tissue Using Biomaterial Platform, Clough, D.W. et al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253249/

Host Dr. Melanie Matheu (PhD) and special guest Dr. Zachary Rubin (MD) a double board-certified pediatric Allergist and Immunologist discuss the history of vaccine development.

This massive topic is impossible to cover in one episode but for further reading on the giants in vaccine development feel free to read more about the scientists listed below. Scientific research is a team effort wherein discoveries and inventions are developed through collaboration between different laboratories and tens to hundreds of researchers each of them moving research incrementally forward. 

Edward Jenner: Smallpox Vaccine

Louis Pasteur: Rabies Vaccine

Max Theiler: Yellow Fever Vaccine (1951 Nobel Prize in Physiology or Medicine) 

Jonas Salk: Polio Vaccine

John Franklin Enders: Measles Vaccine (1954 Nobel Prize in Physiology or Medicine) 

Katalin Karikó and Drew Weissman: Advances in mRNA technology that allowed for the next generation of vaccine development (2023 Nobel Prize in Physiology or Medicine)