# Simons Society of Fellows Alumni Symposium

• Organized by
• Sonja Billerbeck, Ph.D.Columbia University
• Michal Breker, Ph.D.Rockefeller University
Date & Time

Simons Society of Fellows homepage

The first Simons Society of Fellows Alumni Symposium will feature a broad look at the application of biological research across fields, including neuroimmunology, plant biology, bacterial engineering, big data and genomics, and medical research.

• Agenda

#### WEDNESDAY, OCTOBER 10th

 6:30 PM Conference Dinner

#### THURSDAY, OCTOBER 11th

 8:30 AM Check-in & Breakfast 9:30 AM WELCOME — Sonja Billerbeck and Michal Breker 9:40 AM Michal Schwartz | Harnessing the Power of the Immune system to Combat Alzheimer’s Disease: From Basic Science to Clinical Implications 10:30 AM Samuel Sternberg | Harnessing CRISPR–Cas Immune Systems for Programmable Genome Engineering 11:00 AM Break & Posters 11:30 AM PROGRAM CONTEXT — Sonja Billerbeck and Michal Breker 11:40 AM Joe Pickrell | Toward the $10 genome: the coming era of ubiquitous genomics 12:10 PM Javier Fernandez-Martinez | Meeting the Gatekeeper of the Nucleus: Structural and Functional Anatomy of the Nuclear Pore Complex 12:40 PM Eva Billerbeck | Of Mice and Men and Rats: Finding a Model to Study Hepatitis C Virus Immunology 1:10 PM Lunch & Posters (group photos with Gerry, Yuri, Jim & Marilyn at 1:10) 2:10 PM PROGRAM CONTEXT — Sonja Billerbeck and Michal Breker 2:40 PM Tal Danino | Synthetic Biology: From Microbial Gene Circuits to New Therapies 3:10 PM June Medford | Design, Engineering and Production of Sustainable Systems 4:00 PM Break & Posters 4:30 PM Joachim Frank | Visualization of Biological Molecules in their Native, Hydrated States 5:30 PM Meeting Concludes • Abstracts Michal Schwartz Harnessing the Power of the Immune system to Combat Alzheimer’s Disease: From Basic Science to Clinical Implications Alzheimer’s disease and age-related dementia are becoming almost epidemic, with increased life expectancy and with changes in lifestyle. Currently there is no therapy that modifies these diseases. The continuous failure calls for better understanding of the disease and for a search for multi-dimensional therapy that will arrest common pathways that go awry and which contribute to disease escalation. Based on my team’s work over the last 20 years, driven by basic science and curiosity, we proposed fighting the disease by harnessing the immune system, which provides the body’s comprehensive maintenance, defense, and repair mechanisms. Yet, for decades, the brain was believed to be unable to tolerate any immune activity under any circumstances due to its unique structure, as a tissue behind barriers. My team was the first to break this dogma, by demonstrating that the brain not only tolerates but requires life-long support from the immune system for its maintenance and repair. Over the years, we identified a unique interface within the brain’s borders through which the immune cells can attain access to the brain. We showed that in mouse models of aging and in Alzheimer’s disease (AD), this interface dysfunctions, and as a result, the brain loses its support and repair mechanism; this dysfunction reflects imunolgical rather than only chronological aging. We further found in mouse models that unleashing/rejuvenating the immune system by blocking inhibitory immune checkpoints, regulatory pathways that normally maintain systemic immune homeostasis and tolerance, was effective in reversing cognitive loss, reducing brain inflammation, and mitigating disease pathology. This is the first approach that suggested targeting the immune system rather than the brain. Although a similar therapy is currently used in cancer, tailoring it for AD dictates different antibody, dosing and regimens. Samuel Sternberg Harnessing CRISPR–Cas Immune Systems for Programmable Genome Engineering Few discoveries transform a discipline overnight, but scientists today can manipulate cells in ways hardly imaginable before, thanks to a peculiar form of adaptive immunity mediated by clustered regularly interspaced short palindromic repeats (CRISPR). From elegant studies that deciphered how these immune systems function in bacteria, researchers quickly uncovered the technological potential of Cas9, an RNA-guided DNA cleaving enzyme, for genome engineering. Today, this core capability is being harnessed for a wide variety of ambitious applications, including human therapeutics, agricultural improvement, and the elimination of certain infectious diseases. In my talk, I will describe the molecular function of CRISPR systems and discuss our emerging understanding of how specific DNA targets are recognized and sliced apart by the Cas9 enzyme. I’ll end by outlining some of the latest biotechnology tools inspired by CRISPR research – from new ways of studying embryonic development, to novel methods of detecting pathogens – which collectively highlight the wide-reaching, innovative impacts of this fascinating biological pathway. Joe Pickrell Toward the$10 genome: the coming era of ubiquitous genomics

Abstract: The cost of sequencing a human genome has fallen from over $100M to less than$1000. During the next stage of these cost decreases, genome sequencing will fall from \$1000 to ‘too cheap to meter’. I will discuss our work on low-pass sequencing to accelerate the adoption of genomics, and current and future applications in population-scale genomic screening, disease diagnosis, and agriculture

Javier Fernandez-Martinez
Meeting the Gatekeeper of the Nucleus: Structural and Functional Anatomy of the Nuclear Pore Complex

The most prominent feature of the eukaryotic cell is the presence of the nucleus. This organelle is enclosed by a double membrane, the nuclear envelope, which protects the DNA but also disconnects it from the rest of the cell. Nature’s solution to this communication problem is a massive —by molecular standards—cylindrical configuration known as the nuclear pore complex (or NPC). The NPC forms a channel that traverses the nuclear envelope and through which imports and exports travel, connecting the bulk of the cell with the inside of the nucleus. The NPC thus serves as a checkpoint regulating what passes in and out of the nucleus; for example, genetic instructions transcribed into RNA are allowed to exit, while proteins needed inside the nucleus may enter. Other things, such as viruses bent on taking over the cell, are kept at bay. Underscoring the essential role of the NPC is the fact that defects in its function are directly related to serious human diseases, like cancer and neurological disorders. However, despite the central role of the NPC as gatekeeper of the nucleus, its large size and dynamic nature have impeded its full structural and functional characterization. To overcome these challenges, we have used an integrative approach that by satisfying diverse data types, including quantitative proteomics, cryo-electron tomography and chemical cross-links, have allowed us to determine a subnanometer precision structure for the entire 552-protein yeast NPC. The structure reveals the NPC’s functional elements in unprecedented detail. The NPC is built of sturdy diagonal columns to which are attached connector cables, imbuing the assembly with both strength and flexibility, and evoking the towers and cables of a suspension bridge like the Brooklyn Bridge. Taken together, this integrative structure allows us to rationalize the architecture, transport mechanism, and evolutionary origins of the NPC.

Eva Billerbeck
Of Mice and Men and Rats: Finding a Model to Study Hepatitis C Virus Immunology

The immunology of human hepatotropic virus infections is notoriously difficult to study. Access to human liver tissue is extremely limited, especially during acute infection. Further, hepatitis C virus (HCV) and other hepatitis viruses have a narrow host tropism to the human liver and the lack of suitable immune-competent animal models has hampered mechanistic studies of hepatic antiviral immunity. Interestingly, in recent years various hepatitis C virus (HCV)-related animal viruses were discovered in horses, bats or rodents, which opened the door for the development of HCV surrogate models. In 2014, an HCV-related rodent hepacivirus, named Norway rat hepacivirus (NrHV) was discovered in wild rats of New York City. We now showed that NrHV can establish a hepatotropic infection in common immune-competent laboratory mouse strains and that NrHV infection in mice shares several virological and immunological key features with HCV infection in humans. In conclusion, we have developed an immune-competent model for the study of antiviral hepatic immunity, a prerequisite for HCV vaccine development.

Tal Danino
Synthetic Biology: From Microbial Gene Circuits to New Therapies

Rapid advances in the field of synthetic biology have enabled the design and construction of genetic circuits capable of generating programmed behavior in microbes. Concurrently, the last decade of microbiome research has revealed an astounding prevalence of microbes in healthy and diseased tissue within the human body. These two emerging fields have prompted the exploration of microbes as a natural platform for the development of engineered therapies and diagnostics. In this research talk, I will describe our progress towards a new design framework for engineering microbial gene circuits that bridges computational modeling and in vitro characterization, to diagnostic and therapeutic applications for cancer in vivo. The talk will begin with a description of bacterial gene circuits that generate synchronized oscillations, and will then describe development of programmed bacteria as both diagnostic and therapeutic agents for cancer.

June Medford
Design, Engineering and Production of Sustainable Systems

Authors: June Medford, Kevin Morey, Tessema Kassaw, Alberto Donayre Torres, Diane McCarthy and Sara Oehmke.

Humans have long searched field and forest for food, materials and other products to meet their needs. Our technologically advanced societies today still require these items, but often acquire them through means that are not sustainable. Working with plant synthetic biology we have designed, engineered and produced new traits for human and environmental use. These traits allow us to use plants in new ways that reduce resource consumption or make use of otherwise unusable resources. First, we will describe our work on plants enabled with a computationally designed sensing ability providing an inexpensive means to sense pollutants and harmful substances. This sensing ability is enhanced with quantitative and predictable positive feedback circuits providing both memory and amplification of a sensing trait. Finally, we will describe our design and development of a synthetic desalination circuit that enables green plants to purify salt water and development of salt tolerant crops.

Joachim Frank
Visualization of Biological Molecules in their Native, Hydrated States

The approach of single-particle cryo-EM, the technique that has recently furnished beautiful structures of many molecules that cannot be crystallized, involves unusual mathematical and computational challenges in addition to those of instrumentation and sample preparation. The development of the various techniques is far from over, and ranges from automation in sample deposition and time-resolved techniques to mapping of states in a continuum.