This episode of This Week in Virology (TWiV 1253) was recorded live at the Harvard Virology Retreat in Waterville Valley, NH, with host Vincent Racaniello. The episode features interviews with three Harvard virologists: Aaron Schmidt, Tatum Sass, and Ben Gewurz, discussing their diverse research interests and career paths.
Aaron Schmidt details his lab's work on protein engineering to understand and direct immune responses against viruses, particularly influenza, with a focus on designing next-generation vaccines targeting conserved hemagglutinin epitopes. Tatum Sass shares her research on developing CAR-T cells for HIV, aiming to improve the targeting of infected cells, and discusses the challenges of scientific communication. Ben Gewurz explores the complex pathogenesis of Epstein-Barr virus (EBV), its global prevalence, its role in various cancers (including Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer) and autoimmune diseases (like MS), and the ongoing quest for effective therapies and vaccines.
The discussion extends to broader concerns within the scientific community, including the impact of NIH and Harvard-specific funding cuts on morale, the importance of clear science communication, and the future of academic versus industrial research. The episode highlights the commitment of these scientists to advancing virology despite political and funding challenges.
Summarizing TWiV 1253: Harvard Virology is Not Retreating
0:00 Welcome to Harvard Virology Retreat: Vincent Racaniello hosts TWiV 1253 live from Waterville Valley, NH, for the Harvard Virology Retreat, marking his return after 14 years.
1:29 Guest Introductions: Vincent introduces his guests: Aaron Schmidt (Head of the Harvard Virology Program), Tatum Sass, and Ben Gewurz.
2:52 Tribute to David Baltimore: Vincent shares memories of David Baltimore, who recently passed away, highlighting his scientific brilliance and reissuing their TWiV 100 interview.
4:59 Purpose of the Retreat: Aaron Schmidt explains the Harvard Virology Retreat as an annual event to celebrate science, welcome new graduate students (G1s), and foster interaction and discussion about ongoing research.
7:15 Retreat Activities & Science Critique: Vincent recounts a trivia contest from the retreat, including clips from science fiction movies and TWiV-related questions. He also critiques a line from the movie "Contagion" regarding negative-strand virus recombination (it doesn't happen).
9:10 Pronunciation Debate: The panel engages in a humorous discussion on the pronunciation of scientific terms like "HEPES" (heeps vs. hepes), "Co-op" (coupe vs. co-op), and "apoptosis" (apoptosis vs. aptosis).
12:48 Aaron Schmidt: Grew up in Milwaukee, Wisconsin. Initially pursued theater, but convinced his parents to let him go into science. Attended Emmanuel College, then Harvard for his PhD, inspired by Todd Allen. Now runs an independent lab at Harvard and the Reagan Institute.
17:45 Tatum Sass: Born and raised in Seattle, Washington, moving to Dallas, Texas, for high school. Influenced by a sixth-grade biology teacher and a personal experience with a viral infection, she pursued biochemistry and genetics at Clemson, then came to Harvard.
19:43 Ben Gewurz: Grew up with parents who met in a lab, leading him to a "pre-programmed" path in science. Attended Stanford for undergraduate and then Harvard for an MD-PhD, studying viral immune evasion.
22:42 Aaron Schmidt's Lab Research: Aaron's lab focuses on protein engineering to direct immune responses, understand how pathogens evolve to escape immunity, and design next-generation viral vaccines, particularly for influenza.
23:51 Future of Vaccines & Political Climate: Aaron strongly advocates for vaccines despite current governmental skepticism, emphasizing their critical role in public health and pandemic preparedness.
25:59 Influenza Vaccine Design (Aaron Schmidt): Discussion on "Conserved sites on flu H1, H3, HA recognized by human antibodies" paper. Aaron explains how his lab identifies potent, broadly neutralizing human antibodies targeting conserved regions of influenza hemagglutinin (HA) to use as templates for vaccine design. He advocates for targeting the receptor binding site on the HA head over the stem for primary defense.
33:55 Resistance to Broadly Neutralizing Antibodies: While resistance to single broadly neutralizing antibodies can develop rapidly, an immunogen eliciting diverse antibodies targeting the conserved site from multiple angles would likely prevent broad resistance.
35:26 Future Flu Vaccines: Aaron envisions future flu vaccines that are structurally engineered to elicit specific, broadly protective antibody responses, administered in the same way, potentially as two distinct vaccines for Group 1 and Group 2 influenzas.
36:00 Critique of NIH Flu Vaccine Initiative: Aaron expresses skepticism about the NIH's "next-generation" flu vaccine initiative, which he views as a traditional inactivated virus approach.
36:28 Antigenic Drift and Recalled Immunity (Aaron Schmidt): Discussion of his paper "Antigenic drift expands influenza viral escape pathways through recalled humoral immunity." This concept, also known as "immune imprinting," describes how previous exposures (memory) influence subsequent immune responses, potentially expanding viral escape pathways, especially for closely related H1 strains.
41:09 Tatum Sass's Lab Research (HIV CAR-T cells): Tatum is working on developing CAR-T cells for HIV, specifically improving the targeting domain (CD4 component) to recognize and kill HIV-infected cells. She hopes to wrap up her wet lab work soon to begin writing her dissertation.
44:19 Scientific Perseverance & Love for Science: Tatum shares a story of overcoming a 70-base pair deletion in her gene block, highlighting the importance of perseverance. She loves the daily novelty and learning in science.
45:39 Dislike of Scientific Jargon: Tatum expresses frustration with the jargon-heavy nature of science, making communication difficult for non-scientists. She hopes to help fix this in the future.
47:01 Future Career & Academic vs. Industry: Tatum aims to go into industry, seeing herself more as a problem solver than a "big idea thinker." She believes industry relies heavily on academic labs for foundational ideas.
48:02 Worries about the Future of Science in the US: Tatum expresses concern about the current trend of science funding and opportunities in the US, considering job prospects outside the country.
48:57 Ben Gewurz's Lab Research (Epstein-Barr Virus): Ben's lab investigates Epstein-Barr virus (EBV), focusing on how it causes disease, evades the immune system, and its association with various cancers (nasopharyngeal carcinoma, Burkitt lymphoma, gastric cancer) and autoimmune conditions (MS).
50:41 EBV Infection & Mono: Over 95% of adults are infected with EBV. Most infections are asymptomatic, especially in early childhood. Mono (infectious mononucleosis) occurs when infection happens in teenage or adult years, with symptoms often caused by the immune response.
52:48 EBV Latency & Reactivation: EBV remains latent in B cells. Reactivation occurs when memory B cells are stimulated, pushing them towards plasma cell differentiation, prompting the virus to "wake up" and spread. Any infection, including COVID-19, can reactivate EBV.
54:49 EBV & Long COVID: EBV reactivation is seen in a significant fraction of long COVID patients, raising questions about association versus causation.
55:50 EBV & Autoimmunity: EBV exposure, especially later in life, is linked to autoimmune diseases like multiple sclerosis (MS), where antibodies to EBV proteins may cross-react with host antigens.
56:55 MS Connection to EBV: Studies, particularly a military recruit study, show EBV infection almost always precedes MS diagnosis.
57:04 EBV Transformation & Oncoproteins: EBV transformation involves both viral oncoproteins and the activation of host oncogenes, driving B cell growth. Integration of viral DNA is rare; it usually exists as an episome.
59:39 Geographically Restricted Tumors: EBV-associated cancers (like Burkitt lymphoma and nasopharyngeal carcinoma) have specific geographical distributions, likely due to environmental (e.g., malaria) and genetic cofactors, though poorly understood.
1:00:48 Therapies & Vaccines for EBV: Current therapies for EBV-associated cancers are largely generalized, but specific T-cell therapies are in development. A vaccine for EBV is being explored, potentially to prevent symptomatic mono and reduce risks of associated cancers and autoimmune diseases, even if it doesn't prevent infection.
1:03:15 Morale in Science Amid Cuts: The guests discuss the impact of NIH and Harvard funding cuts. While postdocs are particularly worried about job prospects, faculty are focused on supporting students and maintaining morale by celebrating science and its critical importance despite external pressures.
1:06:07 Aaron Schmidt: Would have been an actor, fulfilling his early passion for theater.
1:06:34 Tatum Sass: Jokingly a baker, but seriously considered architecture due to her interest in math and science.
1:07:07 Ben Gewurz: His "other hat" is infectious disease physician, as he pursued an MD-PhD.
1:07:34 Conclusion: Vincent thanks his guests and encourages listeners to support MicrobeTV to spread science. The episode ends with the traditional TWiV tagline.
Summary of References:
Harvard University, Division of Medical Sciences:
Highlights the Harvard virology community's role in the SARS-CoV-2 pandemic (vaccine candidates, diagnostics, pathogenesis research).
Emphasizes the community's long history of seminal contributions to basic virology, including viral structures, trafficking, cell growth control, and the design/testing of HIV, genital herpes, and influenza vaccines.
Expresses concern over "I'm Worried About the Future of Virology" due to federal grant terminations and scaled-back investments in scientific research, impacting morale among faculty and students.
Mentions specific virology student contributions to Nature and HMS News publications (Wanyu Li on Western Equine Encephalitis, Sadie Antine on Gabija protein complex).
"Conserved sites on the influenza H1 and H3 hemagglutinin recognized by human antibodies" by Daniel P. Maurer et al. (Science Advances, 2025):
Goal: Identify broad, subtype-neutralizing monoclonal antibodies (mAbs) targeting influenza hemagglutinin (HA) for prophylactic use and as templates for next-generation vaccines.
Methods: Isolated H1 and H3 reactive B cells from humans, sequenced variable genes, produced mAbs, and screened for neutralization. Used deep mutational scanning and cryo-EM to map epitopes and understand viral escape.
Key Findings:
Identified broad H1 mAbs binding the lateral patch epitope (H1N1 viruses from 1933-2021 and a swine H1N1).
Improved H1 mAb potency through directed evolution.
Escape mutations primarily occurred at position P122, with some N-linked glycosylation site additions in post-pandemic H1s.
Broad H3 mAbs targeted distinct epitopes on the HA head and stem, neutralizing H3N2 viruses spanning 50 years.
Despite in vitro escape, identified mutations are rarely seen in natural H1N1 isolates, suggesting these conserved sites are promising vaccine targets.
Implication: These mAbs reveal conserved sites that could be targeted by next-generation vaccines, informing strategies for eliciting broad immunity and predicting viral escape.
"Antigenic drift expands influenza viral escape pathways from recalled humoral immunity" by Daniel P Maurer et al. (Immunity, 2025):
Focus: Investigate how initial exposure ("immune imprinting" or "recalled immunity") to a rapidly evolving virus biases later B cell responses and how viruses escape these broad antibody responses.
Methods: Used deep mutational scanning of H1 influenza HAs.
Key Findings:
Antibody affinity maturation restricted escape routes for the eliciting strain, but escape occurred readily in antigenically drifted strains.
This "escape-prone" property in drifted strains is attributed to epistatic networks within HA.
Implication: Explains how influenza continues to evolve in the human population by escaping even broad antibody responses, emphasizing the challenge posed by immune imprinting.
"Epstein-Barr virus latent membrane protein 1 subverts IMPDH pathways to drive B-cell oncometabolism" by Eric M Burton et al. (PLoS Pathogens, 2025):
Focus: Understand how Epstein-Barr virus (EBV) oncoprotein Latent Membrane Protein 1 (LMP1) alters B-cell metabolism to drive cancer.
Methods: Performed metabolomic analyses on B cells with conditional LMP1 expression and studied IMPDH inhibition.
Key Findings:
LMP1 significantly induces de novo purine biosynthesis, making xanthosine-5-P (XMP) highly upregulated.
IMPDH inhibition (by mycophenolic acid, MPA) triggered death of LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCLs) and increased sensitivity in Burkitt lymphoma cells.
LMP1 drives B-cell GTP biosynthesis.
Key cytoplasmic tail domains of LMP1 are important for XMP production and MPA sensitivity.
Highlights crosstalk between purine biosynthesis and the EBV epigenome (MPA de-repressed EBV lytic antigens).
Implication: Suggests novel oncometabolism-based therapeutic approaches for LMP1-driven lymphomas.
Glossary of Medical and Scientific Terms:
ADCC (Antibody-Dependent Cell-mediated Cytotoxicity): An immune mechanism where an effector cell (like an NK cell) targets and lyses an antibody-coated target cell.
ADCP (Antibody-Dependent Cell-mediated Phagocytosis): An immune mechanism where phagocytic cells (like macrophages) engulf antibody-coated target cells.
Affinity Maturation: The process by which B cells produce antibodies with increased affinity for an antigen during repeated exposures, leading to a stronger immune response.
Antigenic Drift: Small, incremental changes in the genes of viruses (like influenza) that lead to changes in surface proteins (e.g., hemagglutinin), allowing the virus to evade the immune system.
Antigenic Sin (Original): Also known as immune imprinting, it describes the phenomenon where the immune system preferentially responds to the first strain of a pathogen it encountered, even when exposed to a new, antigenically different strain.
Apoptosis: Programmed cell death; a natural process of cell elimination that is regulated by specific genes.
Assay: A procedure for quantitatively or qualitatively assessing the presence or activity of a substance. In a broader sense, an experiment or test.
B Cell (B Lymphocyte): A type of white blood cell that produces antibodies and plays a central role in humoral immunity.
Broadly Neutralizing Antibodies (bnAbs): Antibodies that can neutralize a wide range of strains or subtypes of a virus, rather than just a single strain.
Burkitt Lymphoma: A fast-growing cancer of the lymphatic system, strongly associated with Epstein-Barr virus infection, particularly in areas with endemic malaria.
CAR-T Cells (Chimeric Antigen Receptor T-cells): T-cells that have been genetically engineered to express a Chimeric Antigen Receptor (CAR) on their surface, allowing them to recognize and target specific antigens on cancer cells or infected cells in an MHC-independent manner.
CCD (Charge-Coupled Device): An integrated circuit used in digital cameras to convert light into digital signals, enabling image capture.
CD4: A glycoprotein found on the surface of immune cells such (e.g., helper T cells) that serves as a co-receptor for the T-cell receptor and is a primary receptor for HIV.
Cryo-EM (Cryo-electron Microscopy): A technique used to determine the 3D structure of biological molecules and complexes at atomic resolution, often used for viruses and proteins.
Dichroic Mirrors: Optical filters that selectively reflect certain wavelengths of light while transmitting others.
Diploid: A cell or organism that contains two complete sets of chromosomes, one from each parent.
Dissertation: A long research paper, often part of a doctoral degree.
Epitope: The specific part of an antigen that an antibody or T-cell receptor recognizes and binds to.
Epitope Scaffolding: A vaccine design strategy where a specific epitope (the target for immune response) is placed onto a different, often immunologically inert, molecular scaffold to elicit a focused immune response.
Episome: A plasmid that can exist independently in the cytoplasm of a cell or be integrated into the host cell's chromosome. EBV typically exists as an episome in latently infected cells.
Epstein-Barr Virus (EBV): A common human herpesvirus that causes infectious mononucleosis and is associated with several cancers (e.g., Burkitt lymphoma, nasopharyngeal carcinoma) and autoimmune diseases (e.g., multiple sclerosis).
E-squared PROM (EEPROM): Electrically Erasable Programmable Read-Only Memory, a type of non-volatile memory that can be erased and reprogrammed electrically.
FPGA (Field-Programmable Gate Array): An integrated circuit designed to be configured by a customer or designer after manufacturing.
Glycans (Sugars): Carbohydrate chains that are often attached to proteins and lipids on cell surfaces, playing roles in cell recognition and immune evasion.
Hemagglutinin (HA): A glycoprotein found on the surface of the influenza virus, responsible for binding to host cell receptors and facilitating viral entry. It is a primary target for neutralizing antibodies.
HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): A buffering agent commonly used in biological and biochemical research to maintain pH.
Haploid: A cell or organism having a single set of unpaired chromosomes. Gametes (sperm and egg) are haploid.
HIV (Human Immunodeficiency Virus): A retrovirus that causes AIDS by infecting immune cells, primarily CD4+ T cells.
HLA (Human Leukocyte Antigen): A gene complex on chromosome 6 in humans that encodes proteins important for immune system function, particularly antigen presentation to T cells.
Holoendemic Malaria: A situation where malaria is continuously present at high levels in a population, with most individuals being infected from an early age.
Humoral Immunity: The component of the immune system that involves antibodies produced by B cells.
IMPDH (Inosine Monophosphate Dehydrogenase): An enzyme involved in the de novo synthesis of guanine nucleotides (purines), a pathway often exploited by rapidly dividing cancer cells.
Immunogen: A substance capable of eliciting an immune response.
Immunocompromised: Having an impaired immune system.
Inoculum: The material used for inoculation (e.g., a quantity of virus).
Kinase: An enzyme that catalyzes the transfer of phosphate groups from high-energy donor molecules (such as ATP) to specific substrates, a process called phosphorylation.
Latency: A state where a virus remains dormant within a host cell without actively replicating, but can reactivate later.
Latent Membrane Protein 1 (LMP1): An oncogenic protein expressed by Epstein-Barr virus during latency, known to promote cell growth and survival and subvert metabolic pathways in infected B cells.
Lateral Patch: A conserved epitope located on the side of the influenza HA head domain, often targeted by broadly neutralizing antibodies.
Lymphoblastoid Cell Lines (LCLs): Continuously growing B cell lines that have been transformed by Epstein-Barr virus (EBV) in vitro.
Metabolomics: The large-scale study of small molecules, commonly known as metabolites, within cells, biofluids, tissues or organisms.
Micro-lenses: Tiny lenses placed over individual pixels of a sensor (like a CCD) to increase light-gathering efficiency.
Monoclonal Antibodies (mAbs): Antibodies produced by a single clone of B cells, meaning they are all identical and bind to the same specific epitope.
Multiple Sclerosis (MS): A chronic, autoimmune disease that affects the brain and spinal cord, often linked to previous EBV infection.
Nasopharyngeal Carcinoma (NPC): A type of cancer that starts in the nasopharynx (the upper part of the throat behind the nose), strongly associated with Epstein-Barr virus infection, particularly prevalent in certain geographic regions.
Negative-Strand Virus: A type of RNA virus whose genetic material is a single-stranded RNA molecule that is complementary to the mRNA needed for protein synthesis. These viruses typically do not recombine.
Neutralizing Antibodies: Antibodies that block the ability of a virus to infect cells, often by binding to viral surface proteins essential for entry.
Oncogene: A gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.
Oncoprotein: A protein encoded by an oncogene that promotes cell growth and contributes to cancer development.
Opto-isolators: Electronic components that transfer electrical signals between two isolated circuits by using light, often for safety or noise reduction.
Organoid System: 3D in vitro cultures that mimic the structure and function of an organ, used for studying development and disease.
Pathogenesis: The manner of development of a disease, or the mechanism by which a disease is caused.
Peltier Cooler (Thermoelectric Cooler): A solid-state active heat pump that transfers heat from one side of a device to the other, used to cool electronic components like CCDs.
Phlatlight: A brand of high-brightness LEDs, often used in projectors and other demanding illumination applications.
Phosphor Conversion: A process where a phosphor material absorbs light of one wavelength (e.g., blue light from an LED) and re-emits it at a different, longer wavelength (e.g., green or white light).
Plasma Cell: A fully differentiated B cell that produces a single type of antibody.
Postdoc (Postdoctoral Researcher): An individual holding a doctorate degree who is conducting research under the supervision of a faculty member, typically as a stepping stone to an independent research career.
Protein Engineering: The process of developing useful or valuable proteins by modifying existing proteins or creating new ones, often through genetic manipulation.
Purine Biosynthesis (de novo): The metabolic pathway responsible for synthesizing purine nucleotides (adenine and guanine) from scratch, rather than recycling existing ones.
Receptor Binding Site (RBS): A specific region on a viral surface protein that binds to a receptor on the host cell, mediating viral entry.
Recombinant: Relating to DNA or cells that have been formed artificially by combining constituents from different organisms.
Recombinant Protein: A protein produced through genetic engineering, where a gene encoding the protein is inserted into an expression system (e.g., bacteria, yeast, or mammalian cells) for production.
Rhesus Monkey (Macaca mulatta): A species of Old World monkey commonly used in medical and scientific research.
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2, the virus that causes COVID-19.
Scaffolding: In molecular biology, a framework or structure used to present specific molecules (like epitopes) in a particular orientation.
Scyalic Acid (Sialic acid): A type of sugar molecule found on the surface of host cells that acts as a receptor for influenza viruses.
Seasonal Flu Vaccine: An influenza vaccine designed to protect against the strains of influenza virus predicted to be most common in the upcoming flu season.
Silica Gel: A desiccant (drying agent) commonly used to absorb moisture and prevent condensation, often found in sensitive electronics like cameras.
Somatic Mutations: Genetic mutations that occur in the somatic cells (non-reproductive cells) of an organism after fertilization.
Spectral Line: A specific, narrow range of wavelengths of light emitted or absorbed by a substance.
Stem Domain: A more conserved region of the influenza hemagglutinin (HA) protein, closer to the viral membrane, which is a target for broadly neutralizing antibodies.
Sterically Block: To prevent a molecule from interacting with another due to physical obstruction or hindrance.
Sterilizing Vaccine: A vaccine that completely prevents infection by a pathogen, not just disease symptoms.
Structural Biology: A branch of molecular biology, biochemistry, and biophysics concerned with the molecular structure of biological macromolecules (especially proteins and nucleic acids) and how they acquire the structures they have.
T Cell (T Lymphocyte): A type of white blood cell that plays a central role in cell-mediated immunity, directly attacking infected cells or helping other immune cells.
Thermal Block: A component designed to efficiently transfer and dissipate heat from an electronic device.
Thermistor: A type of resistor whose resistance is strongly dependent on temperature.
TTL (Transistor-Transistor Logic): A family of digital logic circuits commonly used in electronic devices, often referring to a simple digital signal for control (e.g., on/off).
Viral Escape: The process by which a virus evolves to evade detection and elimination by the host's immune system or antiviral drugs.
Viral Fitness: The ability of a virus to successfully replicate and transmit within a host population.
Virology: The scientific study of viruses and the diseases they cause.
Wavelengths (nm): A measure of the distance between successive crests of a wave, often used to describe different colors of light (e.g., 488nm is blue, 630nm is red).
XMP (Xanthosine-5-phosphate): An intermediate in the de novo purine biosynthesis pathway, often upregulated in certain cancers.
Zoonotic Spillover: The transmission of a pathogen from an animal host to a human host.