Customizing T Cell-Based Immunotherapies in a ‘SNAP’

Through expanding the targeting capabilities of chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors, University of Pittsburgh researchers have developed a “universal” receptor system that allows T cells to recognize any cell surface target. Given the potential previously seen in engineered antigen receptors, and CARs being the most clinically advanced of these technologies, the team of researchers began investigating a method to gain additional control over CAR function. By engineering T cells with receptors bearing a universal “SNAPtag”, CARs bind to the common tag molecule fused to the antigen-specific antibody, instead of directly binding antigen targets. This new approach allows for great expansion to antigen targeting and shows great promise in using CARs against additional immune-related diseases and other types of cancer.

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New Research Shows That Bacteria Get “Hangry,” Too

New research by Adam Rosenthal, PhD, assistant professor in the Department of Microbiology and Immunology at UNC, analyzed the cell states of isogenic bacterial populations via a developed probe-based bacterial sequencing (ProBac-seq) method. After confirming the sequencing method accurately identified known cell states and transcriptional heterogeneity of bacterial cells, Rosenthal et al. applied ProBac-seq to Clostridium perfringens and found that despite transcriptional heterogeneity, these identical cells behaved differently with varied functions within the bacterial population. Specifically, through single-cell analysis on C.perfringens and graph-based clustering, four distinct subpopulations were revealed, with all clusters preferentially expressed netB, a toxin responsible for necrotic enteritis disease. To investigate mechanisms affecting expression rates of the toxin, C.perfringen was treated with sodium acetate. Following treatment, the expression of netB was significantly less in comparison to the control cluster. These findings are just the beginning to understanding bacterial populations and mechanisms behind single-cell behavior and could lead to a new approach to antibiotic tolerance down the line.
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A swapped genetic code prevents viral infections and gene transfer

In a recent study published in Nature, researchers from Harvard Medical School report on a new E. coli strain resistant to viral infections but unable to release its modified genes, effectively reducing the risk of incorporating the modified genetic material into natural cells. How? Through swapping the genetic code of an E.coli strain via viral transfer RNAs (tRNAs). The team started with the synthetic bacterium Syn61?3, which has a reduced number of codons, previously generated in 2021 by UK researchers. After preliminary experimentation, it was found the original strain was susceptible to some bacteriophages and researchers decided to implement viral tRNAs as a mechanism to establish an artificial genetic code, hoping to make the Syn61?3 strain resistant to these bacteriophages. Through efficient codon reassignment and swapping of amino acids via viral tRNAs, the E. coli strain is resistant to viral infections as viral proteomes are mistranslated and is unable to release synthetic genetic information. This study provides a new concept for future applications beyond E. coli and greater commercial potential for synthetic organisms.

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James Adeosun is a student at Clare College of the University of Cambridge who spent the summer working in the lab at VIC.

This summer, I was fortunate enough to spend 11 weeks at the Vaccine and Immunotherapy Center (VIC) in Boston, immersing myself in immunology research. The VIC is directed by Professor Mark Poznansky, whose enthusiasm for science emanates around the lab. The placement was absolutely fantastic! From a research standpoint, the work seemed to be right on the cutting edge of immunology. The project I was working on centered around their self-assembling vaccine technology, mainly in the context of a therapeutic HPV vaccine. Specifically, I was testing whether using microneedle arrays was a viable method of vaccine administration, whilst also developing an in vitro assay for testing both this and other vaccines. We also theorized a new vaccine model based on some literature from a Chlamydia trachomatis vaccine trial at Hammersmith. Additionally, I got to go to the main MGH campus and see a few patients with Prof. Poznansky, which was very exciting as a medical student; the hospital was incredibly impressive. Beyond the science, the lab environment was very inspiring, with people from many different backgrounds working towards similar aims. Frequent lab events meant that I felt very welcomed from the start, and very involved by the end. For example, I was asked to arrange weekly seminars for the intern cohort, led by principal investigators of the various labs within the VIC. I was also afforded an in-depth insight into some of the technicalities of research, such as the grant writing process, as well as the possibility of having a mixed clinician / research role. The city of Boston itself had lots to offer in the downtime. Excellent public facilities and social venues provided a great cultural experience. Highlights included the famous Boston Freedom Trail, as well as eateries serving variations of the popular local hit, clam chowder. Furthermore, Boston is closely apposed to many important tourist destinations. This allowed me to travel to both Cape Cod and NYC on separate weekend trips, providing a more rounded cultural experience of the USA. In summary, the placement afforded me the opportunity of a lifetime, both academically and in terms of broader life experience, and for that I am incredibly grateful.

Celebrating the 20th Year of Annual Research Program at VIC for Clare College Students

Prof. Mark Poznansky is the Director of the Vaccine & Immunotherapy Center (VIC) at Massachusetts General Hospital and Harvard Medical School in Boston, which he founded to accelerate the discovery and development of new medical products for specific types of cancers, infectious and immune mediated diseases. One key part of VIC’s mission is the training of the next generation of innovators and scientists. Each summer Prof. Poznansky, who gained his PhD while at Clare College, provides stipendiary support for Natural Sciences or Medical students from Clare to spend 12 weeks at VIC under the supervision of a senior scientist. This annual program was initiated with the eminent Dr. Celia Duff at Clare and has been continued in a wonderful collaboration with Prof. Jason Carroll. While here at MGH, the Clare student receives extensive training in cutting edge experimental techniques and analysis of data and frequently gains coauthorship on publications ensuing from the original research conducted in the lab. Often times the selected Clare student has continued to be involved with the research remotely long after the completion of their studentship. Some Clare students requested to return for a second “tour of duty” at VIC the following summer. All the selected students from Clare College have been exceptional and many have gone on to successful careers in medicine and scientific research and report that the studentship changed their lives in pursuing a career in academia. We are now celebrating the 20th year of this very successful program that included former and current Clare students – from James Smith and Emma Anderton in 2002 and 2003 all the way to James Adeosun in 2022.

Ukrainian Fellows of the Harvard Scholars at Risk (SAR) Program Speak about Healthcare Challenges in Ukraine as War Continues

FEBRUARY 10TH, 2023, BOSTON, MA.

HOSTED BY: THE HARVARD SAR PROGRAM, HUG, AND GMKA, IN COLLABORATION WITH HARVARD MEDICAL SCHOOL AFFILIATED PHYSICIANS AND SCIENTISTS.

Ukrainian clinicians participating in the SAR program at MGH and BWH currently, discuss their work in healthcare in Ukraine, the needs of the country’s healthcare system and ongoing challenges.

Panel of Visiting Scholars:
Sofiya Hrechukh, MD Psychiatry; Lviv; BWH
Vadym Vus, MD Family Medicine; Rivne Oblast; MGH
Ali Dzhemiliev, MD General Surgery; Crimea/Kyiv; BWH
Veronika Patsko, MD Oncology; Kyiv; MGH

Moderators:
Mark C. Poznansky, MD, PhD
Director, Vaccine and Immunotherapy Center, MGH; HUG Co-Founder; Professor of Medicine, Harvard Medical School

Nelya Melnitchouk, MD, MsC
Colorectal Surgeon, BWH; Assistant Professor of Surgery, HMS;
President and Co-Founder, Global Medical Knowledge Alliance

gmka.org/
harvardscholarsatrisk.harvard.edu/
healukrainegroup.org/

Amid a ‘huge collective trauma,’ a Harvard program aims to train Ukrainian doctors

CAMBRIDGE — Dr. Dariia Simchuk flips through photos and videos on her phone of her hometown, Zhytomyr, about 85 miles west of Kyiv. They are vignettes of a country at war: buildings reduced to gray piles of rubble; windows of a hospital blown out by nearby explosions and patched up with plywood; an operating room with sandbags stacked in it for extra protection in case of an attack. “It is a huge, collective trauma for all Ukrainians,” she said of the ongoing conflict while seated in a cafe amid the Monday morning bustle of Harvard Square.
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FASEB Journal publication from VIC’s Dr. Susan Raju Paul

Susan Raju Paul MBBS, researcher at VIC, recently published results of an in-depth analysis of the tumor microenvironment (TME) using a small cohort of patients with non-small cell lung cancer (NSCLC), the most common histopathological variant of lung cancer. Results of the pilot study support the use of a patient’s unique TME and immune subpopulations as prognostic indicators for selection of appropriate treatment for improving patient health care outcomes. Future research lies in validating these findings with a larger cohort in effort to better characterize and understand expression of immune markers and subtypes of NSCLC and implications for treatment.
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