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Accounting for future populations in health research

BIOETHICS 2024年第5期38卷 401-409页

作者： Pierson, Leah Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard TH Chan Sch Publ Hlth Dept Global Hlth & Populat Boston MA USA

The research we fund today will improve the health of people who will live tomorrow. But future people will not all benefit equally: decisions we make about what research to prioritize will predictably affect when and how much different people benefit from research. Organizations that fund health research should thus fairly account for the health needs of future populations when setting priorities. To this end, some research funders aim to allocate research resources in accordance with disease burden, prioritizing illnesses that cause more morbidity and mortality. In this article, I defend research funders' practice of aligning research funding with disease burden but argue that funders should aim to align research funding with future-rather than present-disease burden. I suggest that research funders should allocate research funding in proportion to aggregated estimates of disease burden over the period when research could plausibly start to yield benefits until indefinitely into the future.

关键词： disease burden health policy longtermism priority setting resource allocation

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Protein-based nanoparticles for therapeutic nucleic acid delivery

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BIOMATERIALS 2024年 305卷 122464-122464页

作者： Eweje, Feyisayo Walsh, Michelle L. Ahmad, Kiran Ibrahim, Vanessa Alrefai, Assma Chen, Jiaxuan Chaikof, Elliot L. Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Surg Boston MA 02215 USA MIT Harvard & MIT Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Univ Wyss Inst Biol Inspired Engn Boston MA 02115 USA

To realize the full potential of emerging nucleic acid therapies, there is a need for effective delivery agents to transport cargo to cells of interest. Protein materials exhibit several unique properties, including biodegradability, biocompatibility, ease of functionalization via recombinant and chemical modifications, among other features, which establish a promising basis for therapeutic nucleic acid delivery systems. In this review, we highlight progress made in the use of non-viral protein-based nanoparticles for nucleic acid delivery in vitro and in vivo, while elaborating on key physicochemical properties that have enabled the use of these materials for nanoparticle formulation and drug delivery. To conclude, we comment on the prospects and unresolved challenges associated with the translation of protein-based nucleic acid delivery systems for therapeutic applications.

关键词： Drug delivery Gene therapy Recombinant proteins Nanoparticles Polypeptides

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Metabolic constraint of human telomere length by nucleotide salvage efficiency

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NATURE COMMUNICATIONS 2025年第1期16卷 1-14页

作者： Mannherz, William Crompton, Andrew Lampl, Noah Agarwal, Suneet Boston Childrens Hosp Oncol & Stem Cell Program Div Hematol Boston MA 02115 USA Dana Farber Canc Inst Pediat Oncol Boston MA 02215 USA Harvard Med Sch Harvard Stem Cell Inst Dept Pediat Harvard Initiat RNA Med Boston MA 02215 USA Harvard Med Sch Biol & Biomed Sci PhD Program Biol & Biomed Sci PhD Program Boston MA 02215 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02215 USA

Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.

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Postoperative Pathway Allows Elective Craniotomy Patients to Bypass Intensive Care Unit Safely: Commentary on Recent Article in Journal of Neurosurgery

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WORLD NEUROSURGERY 2023年 173卷 276-277页

作者： Hoffman, Samantha E. Gupta, Saksham Arnaout, Omar Brigham & Womens Hosp Dept Neurosurg Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA

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Combinatorial development of nebulized mRNA delivery formulations for the lungs

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NATURE NANOTECHNOLOGY 2024年第3期19卷 364-375页

作者： Jiang, Allen Y. Witten, Jacob Raji, Idris O. Eweje, Feyisayo Macisaac, Corina Meng, Sabrina Oladimeji, Favour A. Hu, Yizong Manan, Rajith S. Langer, Robert Anderson, Daniel G. MIT Dept Chem Engn Cambridge MA 02139 USA MIT David H Koch Inst Integrat Canc Res Cambridge MA 02139 USA MIT Dept Biol Engn Cambridge MA 02139 USA Boston Childrens Hosp Dept Anesthesiol Boston MA 02115 USA MIT Harvard & MIT Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA

Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air-liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles. Nebulized mRNA delivery has broad therapeutic potential but has proven challenging. Here, the authors report on a modified lipid nanoparticle with improved conditions to allow nebulization and demonstrate its application for delivering mRNA to the lungs.

关键词： Biomedical engineering Drug delivery Nanomedicine Nanoparticles

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A viable alternative for editor delivery

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BLOOD 2023年第9期142卷 755-756页

作者： Eweje, Feyisayo Bauer, Daniel E. MIT Cambridge MA 02142 USA Harvard MIT MD PhD Program Cambridge MA 02115 USA Boston Childrens Hosp Boston MA USA Harvard Med Sch Boston MA USA

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Biophysical principles predict fitness of SARS-CoV-2 variants

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024年第23期121卷 1页

作者： Wang, Dianzhuo Huot, Marian Mohanty, Vaibhav Shakhnovich, Eugene I. Sali, Andrej Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA Harvard Univ John A Paulson Sch Engn & Appl Sci Cambridge MA 02138 USA Inst Polytech Paris Ecole Polytech F-91128 Palaiseau France Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA MIT Cambridge MA 02139 USA

SARS-CoV-2 employs its spike protein's receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected to immune responses, while requiring efficient binding to host cell receptors for successful infection. However, our understanding of how RBD's biophysical properties contribute to SARS-CoV-2's epidemiological fitness remains largely incomplete. Through a comprehensive approach, comprising large-scale sequence analysis of SARS-CoV-2 variants and the identification of a fitness function based on binding thermodynamics, we unravel the relationship between the biophysical properties of RBD variants and their contribution to viral fitness. We developed a biophysical model that uses statistical mechanics to map the molecular phenotype space, characterized by dissociation constants of RBD to ACE2, LY-CoV016, LY-CoV555, REGN10987, and S309, onto an epistatic fitness landscape. We validate our findings through experimentally measured and machine learning (ML) estimated binding affinities, coupled with infectivity data derived from population -level sequencing. Our analysis reveals that this model effectively predicts the fitness of novel RBD variants and can account for the epistatic interactions among mutations, including explaining the later reversal of Q493R. Our study sheds light on the impact of specific mutations on viral fitness and delivers a tool for predicting the future epidemiological trajectory of previously unseen or emerging low -frequency variants. These insights offer not only greater understanding of viral evolution but also potentially aid in guiding public health decisions in the battle against COVID-19 and future pandemics.

关键词： viral evolution receptor binding domain fitness landscape SARS-CoV-2 antibody

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Identifying changes in viral fitness using population genetic structure

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024年第28期121卷 e2410274121-e2410274121页

作者： Petros, Brittany A. Broad Inst MIT & Harvard Genom Ctr Infect Dis Cambridge MA 02142 USA Harvard Med Sch Hlth Sci & Technol Cambridge MA 02139 USA MIT Cambridge MA 02139 USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA

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Optimisation and evaluation of viral genomic sequencing of SARS-CoV-2 rapid diagnostic tests: a laboratory and cohort-based study

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LANCET MICROBE 2024年第5期5卷 e468-e477页

作者： Paull, Jillian S. Petros, Brittany A. Brock-Fisher, Taylor M. Jalbert, Samantha A. Selser, Victoria M. Messer, Katelyn S. Dobbins, Sabrina T. DeRuff, Katherine C. Deng, Davy Springer, Michael Sabeti, Pardis C. Harvard Med Sch Dept Syst Biol Boston MA USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Div Hlth Sci & Technol Cambridge MA USA MIT Cambridge MA USA Harvard Med Sch Harvard MIT MD PhD Program Boston MA USA Howard Hughes Med Inst Chevy Chase MD USA Harvard Univ Dept Organism & Evolutionary Biol Cambridge MA 02138 USA Montachusett Publ Hlth Network Fitchburg MA USA Harvard Univ Wyss Inst Biol Inspired Engn Boston MA USA Harvard Univ Harvard TH Chan Sch Publ Hlth Dept Immunol & Infect Dis Boston MA USA

Background Sequencing of SARS-CoV-2 from rapid diagnostic tests (RDTs) can bolster viral genomic surveillance efforts;however, approaches to maximise and standardise pathogen genome recovery from RDTs remain underdeveloped. We aimed to systematically optimise the elution of genetic material from RDT components and to evaluate the eff i cacy of RDT sequencing for outbreak investigation. Methods In this laboratory and cohort -based study we seeded RDTs with inactivated SARS-CoV-2 to optimise the elution of genomic material from RDT lateral fl ow strips. We measured the effect of changes in buffer type, time in buffer, and rotation on PCR cycle threshold (Ct) value. We recruited individuals older than 18 years residing in the greater Boston area, MA, USA, from July 18 to Nov 5, 2022, via email advertising to students and staff at harvard University, MA, USA, and via broad social media advertising. All individuals recruited were within 5 days of a positive diagnostic test for SARS-CoV-2;no other relevant exclusion criteria were applied. Each individual completed two RDTs and one PCR swab. On Dec 29, 2022, we also collected RDTs from a convenience sample of individuals who were positive for SARS-CoV-2 and associated with an outbreak at a senior housing facility in MA, USA. We extracted all returned PCR swabs and RDT components (ie, swab, strip, or buffer);samples with a Ct of less than 40 were subject to amplicon sequencing. We compared the eff i cacy of elution and sequencing across RDT brands and components and used RDT-derived sequences to infer transmission links within the outbreak at the senior housing facility. We conducted metagenomic sequencing of negative RDTs from symptomatic individuals living in the senior housing facility. Findings Neither elution duration of greater than 10 min nor rotation during elution impacted viral titres. Elution in Buffer AVL (Ct=31 . 4) and Tris-EDTA Buffer (Ct=30 . 8) were equivalent (p=0 . 34);AVL outperformed elution in lysis bu

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Thymidine nucleotide metabolism controls human telomere length (vol 55, pg 568, 2023)

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NATURE GENETICS 2023年第7期55卷 1251-1251页

作者： Mannherz, William Agarwal, Suneet Boston Childrens Hosp Oncol & Stem Cell Program Div Hematol Boston MA 02115 USA Dana Farber Canc Inst Pediat Oncol Boston MA 02215 USA Harvard Med Sch Harvard Stem Cell Inst Harvard Initiat RNA Med Biol & Biomed Sci Program Boston MA 02115 USA Harvard Med Sch Harvard MIT MD PhD Program Dept Pediat Boston MA 02115 USA

Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR–Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR–Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.

关键词： Genetic engineering Haematological diseases High-throughput screening Stem-cell research

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